Endocrine Physiology

Constance R. Martin, Ph.D.

Professor of Biological SCiences
HlJIl!8r Co llege
City University 01 New YorI<.

New York Oxford

Oxford University Press
'985
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To H.R.N.
 Preface
The centraltberne of this book i. the application of
molecular ertdocrinology principl .. to lhe under-
standing of whole animal in mammal"
Hormones performing oommon or related functions
arc grouped together in each of the subdiYisions.
Human is emphasi?.cd, and ",fc«,nccs
to the clinical literature been included. Since
most basic research is conducted on laboratory ani-
mals. species ,a.iations and the relevance of the find-
ings to human subjects arc oonsidel"<'d in some detail.
Nonmamm.lian vertebrate. and inverlcbrat•• ..,Ive
.orne of their biological problems in different way •.
They therefore can provide insights into differences
bctwe.:n "what is" and "what must be so." Despite
the advantages of limiting Ihe text to manageable
size. selected a'peels of CQ!l1parative endocrinology
are presented in the chapters on calcium metabo-
lism, Water balance, reproduction, and pituitary
gland functions_
The texl's formal was de'igned for versa@ly. The
section. in large type oover all of the major topics,
They should be easily oomprehended by students
who have oompleted elementary training in animal
physiology and biochemistry. and they are therefore
appropriale for use in graduale and advanced un·
dergradualc oourses. Some of Ihe sections in small
Iype demand more advanced knowledge of biochem·
istry. Othe rs are concerned wilh unresolved oonl...,.
versies. or wilh delails Ihat will interest only limited
numbers of ,<,aders. These scetion. can be omitted
wilh no loss of continuity in the lext.
Since thc index is liberally supplied with subhead-
ings and ero.,·references. the lexl Can also serve as
n convenient sourcc of information for investigalors.
for graduate and medical sludents requiring ,upple-
ments 10 shorter lexts, and for physicians seeking
badground malerials not generally available in clin-
ical books and journals,
Cerlain chapter's aSSume knowledge of material
presented in Ihe earli.. OfICS. However. Ihe index
provides ready aCCess 10 lerminology and details that
might be nceded if the texl is read in a differenl
order,
Most of Ihc references are la ken from the re<:ent
lilcrature. Each of the papers supplies additional ei-
tali"" •. and roview artide.s been .
I hope that authors whose works wOro omined will
recognize that it WaS not feasible to incorporate all
of thc imporlant findings,
Preparation of this book was made possible by the
scholarly approach and indulgence of Oxford Uni-
versity Press. The initial version of the manuscript
was begun in 1977, Because of rapid advances in the
field. earlier chapters were revised each lime a new
one was completed. Changes and additions were also
made when a new journal arrived hours after a sec-
lion had been rewrilleo, during copy editi ng and ex·
amination of Ihe galley proofs. and even after prep-
aralion of Ihe page proofs. Needless to say. Ihis has
taxed thc patience and endurance of many editors, [
am especially gralefullO Dr. William F. Cunis. who
good·naturedly bore the brunt of burden. I also wish
10 thank Mr. Jeffrey House. Mr, William Tilley. and
Ihe copy edilors. Ms Susan Meigs and Ms Brenda
Jones.
From the beginning. my husband, "enning Nor-
born. consislently provided inspiration and under.
standing. Without support. encouragement. and
scnse of humor. Ihe book oould nol have h«n
completed.
 Contents

PART I. INTRODUCTION TO THE

EHDOCAINE SYSTEMS OF VIRTEBRATES
Positive Feedback Controls
Direct Metabolic Control of Hormone
Secrelion: Parathyroid HQ'm<)I\e and
"
I. WHAT ARE HORMONES? WHAT
DQTHEY OO?
Caldlon;n
Endocrine Functions of lhe Pancreatic "
Changing Concepts of the Nature and
Functions of Hormones
The Functions of Vertebrale Hormones ,3
IslelS
Neuroondocrinc S)"llemS
Endocrine Functions of the
""
Endocrine System_Nervous System Gastrointestinal Tract 60
Interactions
Hormonal Interactions wilh Enzymes
1 Brain Hormones
The i\PUD Hypothesis
Hormone Se\:rt'tion Cycles
""62
and Coenzymes 1
Hormonal Intemclions wilh Nucleic The Pineal Gland 65
Acids 8 Circumventricular Organs
Growth factori ""
Interaclions wilh Minerals
Interaction. with Organic Nutrients "" Prostagla ndins and Related Regulators
"
Para hormones
Chalones "'"
The Thymu5 Gland
Rcfcr<:nC<'s "
68
Embryonic Inductors
"Growth Factors" '"'"
Pheromones
" 3. HORMONE BIOSYNTHES IS AND
ReFcr<:nccs

2. ORGANIZATION OF THE
" METABO LI SM
Biosynthesis of Amines and Related
12

Regulators 12
ENDOCRINE SYSTEM 32 Multiple Forms of Intermedi3tM.iud
What Is an Endocrine Gland? 32 Peptides 79
ldcntifica1ion of Hormone·secreting Largcr Pcptides 80
Structures ;J Pr()tein 83
Endocrine functions of the Biosynthesis ()f Polypeptide and Protein
Hypothalamus and Pituitary Gland
Ph)'$iological Importance of the " Hormones
Pr<:hormoncs and Prohormones
85
85
Adenohypophysis
Endocrine Glands Regulated by the Pars
Distalis Hormones
"
50
Hormones Deriycd from Pro-
opiomelanocortin
Glycoprotein Hormones
SO
88
Negative Feedback Control or Hormone Secretion of Amine •. Peptides. Proteins.
Secretion
Hypothalamic Cootrol Mechanisms "" and Glycoprotein.
The Biosynthesis ()f Thyroid Ilormones
90

"
vllt CONTENTS

Hormones Requiring Complex Post- Insulin Regulation of Cholesterol

Processing
Steroid Hormones and Calciferols "" Biosynthesi,
Insulin Regulation of Protein '"
Prostaglandins and Related Regulators
Hormone Interactions with Plasma "'OS Metabolism
Insulin Regulation of Carbohydrate '"
Proteins
Hormone DegrJdation and
Metabolism
Meehanisms!}f I""ulin Action '"
References
"0
"0 Insulin Innucnees On Carbohydrate '"
4. MECHANISMS OF HORMONE
Metablism of Neurons
Glucose Transport and Metabolism in '"
ACTION AND INTERACTION
'"
the Intestine and Kidney
Metabolic Functions of Glucagon '"
'83
Single vs. Multiple '·Primary'· Sites of
Hormone Acti!}n
'"
Somatostatins
".
Latent Periods
'"
Pancreatic Polypeptide
Other Islct Cell Peptides '"
"0
The Second Messenger Hypothesis
Cyclic Nucle<)tides ""
'"
NS ILAS and Other Factors Affecting

'"'"
Insulin Functions
Calcium Ions and Ca lmodulins
Mec-hanisms of Action of Steroid '" Biosynthesis and Metabolism of Insulin
Metabolism of Other Pancreatic
Hormones
Current Status of lhe ·'Steroids In. '" Hormones
'"
Pcptides Out"· Hypothesis
'"
Regulation of Islet Cell Secretion
Insulin Se<:retion '"
Mechani sms of Action of Iodinated Regulation of Glucagon Secretion '"
200
Thyroid Hormones
'" Paracrine Controls 200
Hormonal Interactions
Regulation of Hormone Receptor '" EXjlCrimental Islet Cell Hormone
Deficiencies 20'
Numbers and Functions
Some Problem. Enwuntered jn Ihe '" Diabetes Mellitus
References
202
206
Desi$n of Experiments
""
Ref.,"""es
'"
PART ". HORMONAL REGULATION OF
CAABOHYDRATI!, PROTIIiN AND LIPID
6. THE GlUCOCORTlCO IDS
Glucocorticoid Deficiency in Whole '"
METABOLISM
Animals
Glucocorticoid E,cess
InAuenccs of Glucocorticoids on the
'"
'"
5. THE ENDOCRINE PANCREAS
The Vital ImportallC<' of Maintaining '" Liver
Glucocorticoid. and Responses to
2"

Adequate Blood Glucose Nonspecific Stress 220

Anti· lnflammatory and Anti·lmmune
COIlcentrations '50 Effects of Glucocorticoid. m
Metabolic Functions of Insulin: An
Glucocorticoid Influences on Skeletal
Oveflliew
Skeletal Muscle Contributions to '" Muscle
Glucocorticoid InAuenccs on Bone.
228
Glucose Homeostasis
Insulin Regulation of Carbohydrate '" Cartilage, and Skin
Glucocorticoid Roles in Devolopment
22.
no
Metabolism in Liver
Adipose Tissue Contributions to Glucose '" Anatomical Organization of Adrenal
Glands and Related Structures 230
Homeostasis
Insulin and Glucose Regulation of '" Biosynthesis of Adrenocortical Steroids
Enzymatic n.rects of the Adrenal
212
Lipogenesis
Insulin Deficiency leads to the '" C!}rtex
Metabolism of Conicostercids
23'
2<2
Development of Ketosis and Acidosis
Insulin Regulation of Fatty Acid '" Synthetic Conioosteroids 2"
Biosynthesis
'" References
'"
7. ADRENOCORTICOTROPIN AND PART III. HORMONI!S RI!GULATING
CORTICOTROPIN RELEASING WATBR AND MONOVALBNT
HORMONES ", BUCTROL YTE MBTABOLISM
ACTH Regulation ",
Roles of Cakiurn Ions, Membrane
PhOlipho/ipiw, and Pn:Istaglandins in 9. ALDOSTERONE AND THE
Steroidogenesis
Regulation of Adrenocortical Cell
m RENIN·ANGIOTENSIN SYSTEM
Physiological Functions of Na · . K' , and
'"
Proliferation
Glueoconicoid Influerw;o:s on
'56 Related Ions
Functions of Aldosterone '"
D"
Steroidogenesis
Actions or ACTH .nd '" Biosynthesis and Metabolism or
Aldosterone J32
Related Molecules
Regulation or in tile '" Aidosterone Regulation of Sodium
Transport in the Kid ... y J32
m
f etus
RegulMion of ACTH Secretion '"
'"
Regulation of K' Excretion
Aldosterone Influcnccs on Other Cen
m
Pars Intermcdia Hormones
Regulation of CRH Secretion
Neglltivc Feedback Control of the
""
'61
Ty",
Aldosterone Receptor Numbers
Aldosterone Secretion
m
'39
'02
Circadian Rhythms
Syltem

'"
,,.
The Juxtaglomerular Apparatus
Re nins '"
""
Rdererw;o:s Renin Substrates
BiOlynthesis and Metabolism or tIM: '"
An,iotensins
Angioteru;in Regulation of Aldoslerone '"
8. CATECHOLAM INES.
SEROTON IN, AND RELHED Secretion
Other Physiological Regulators or
".
R EGULATO RS
Sitos of Biosynthesis and Storage
Extra_Adrenal Chroma"ln TII.sues
'"
2m
m
Aldosterone Se<:retion
Anaiotcnsin Influenccs on the '"
Cardiovascu lar System 3S2
Relationship of the Adrenal Gland to Direct Influences or Angioterl$ins on tile
the Central Nervous System
Hormonal vs. T!"lIrI$mitter functions '"'" Kidney
Tho: K.llikrei.... Kinin System
m
".
Adrenal Dcmcdullalion (Enucleation)
Immu n(IIi)'rnpa lhectomy '"
m Anaiotcnsin Inftuell«S on tile Nervous
S)"$tem and Adrenal Medulla m
Cllemic:al Sympathectomy m A·II Generation in Other Pam oftbe
Effoxl$ or E..ccssive Catecholamines 2n
Catecholamine Regulation of
"",y
'"
Carbohydrate Mctabolism
The "Fight Qr Flight"" Concept
YO. Inhibitory Effects
2n
'"
m
Rderenccs
'"
Adrenergic Reecpton m 10. VASOPRESSIN AND OTW: R
of Actioo or Epinephrine
• nd Norepinephrine ,.. REGULATORS OF WATI3R AND
ELECTRO L. YTE METABOLISM '69
Dopamine Receptors
Dopamine fu nctions
8 ios.ynt!tesis of Catccholamines
'"
'87
'80
DiaMIe5 IrI$ipidus
Effects of E..CC5Sivc AD ...
Chemical Nature of ADH and 0(
'69
n"
Alternate Pathways for Catecholamine
Biosyn thesis
'"
Related Ne urohypophysial Pcptides
ADII Receptor Antagonists '"
373
Catecholamine Metabolism
Additional Mechanisms for '" Physiological Mechanisms for
Concentrating Urine 373
Pharmacological Manipulation of tile
,<>3
Antidiuretic Actions of Vasopressin m
CA System
Serotonin 3<>,
ADI-I Regulation or Solute Transport
AD H Interactions with Adrenocoflial '"38'
Histamine
Referenocs ""
'"
Hormones
Vucular Actiorl$ 0( ADH
'"
•
Bi",ynth..i" Secretion. and Metabolism
of Vasopressin and Related Peplides
Regulation of A VP Secretion
InAuences of Vasopressin and of Related
Calcife rol Regulalion of Parathyroid
385 Hormone Secretion
388 Calcifeml Actions On the Kid ney
Calciferol Aetions on Skeletal Muscle

'"
Peptide, on Learning and Behavior 390 and Olher Tissues
Other AClions of Vasopressin 392
Prolactin Regulation of Water and
Electrolyte Excretion 393
References

12. PARATHYROID HORMONE.

'"
Other Hormones Affecting Sodium and CALCITON IN. AND OTHER
Water Excretion 393 REGULATORS Of CALCIUM AND
Comparative Physiology of Waler and
Electrolyte Metabolism
References
395
399
PHOSPHORUS METABOLISM
Parathyroid Hormone IXficicncy ,.,
'"
Chronic Hyperparathyroidism
Individual Differences in Response to
Changes in Blood Calcium
'"'M
PART IV . HORMONAL RI!GULATION OF
CALCIUM AND PHOSPHATI! METABOLISM
The Parathyroid Glands 'M

II. FU NCTIONS OF CALC IUM,

Parathyroid Hormones
Regulation of f'arathymid Hormone '"
PHOS PH ORUS, AN D THE
CALCIFEROlS 409
Secretion
Parathyroid Hormone Actions on the '"
Functions of Calcium
Specificilyof Responses 10 Changes in
409
Kidney
Parathyroid Actions on Bone
Mechanisms of Action of Paralhyroid
'"
"0
Calcium Ion Concentrations 410 Hormone
'"
Some Physiological Roles of Phosphorus
Some Calcium·Phosphate Interactions
Calcium -Binding Prot.ins
410
410
411
Other Actions of Parathyroid Hormone
Calcitonins
GO"t mi n1..1inal :CQ le;lon;n
'"
'"
Calmodulin' (CaMs)
Calcium Roles in Cell Motility
411
41 I
Interrelationships
Calcilonin Actions on Bone '"
'"
Calcium and Phosphate Influcnces on
Microtubulcs
Cell·to-Cell Communication
412
412
Calcitonin Actions on the Kidney
Additional Erre<:ts of Calcitonin in
Mammals
'"
Calcium Transpon Across Membranes: Calcitonin Functions in Birds
Mox:hanisms Calcitonin FunClions in Amphibians
Calcium Intaxe. DiSlribution. and Calcitonin Funclions in Fishes
Turnover
'" Adrenocortical Hormone Regulation of
Phosphale Distribution a nd Metabolism
Inorganic and Organic ConSlituents of '" Calcium Homeostasis
Influences of Gonadal Steroids
'85
, go
Boo,
'" O ther Factors Affecting Bone '88
Bone Cells
'" References
'"
Bone Extracellular Huid
Bone "Ground Substance" '"
'"
Calciferols
Conversion of DJ to ""
'"
PART V.
REPRODUCTION
AND
Metabolism of 25-OH.Vitamin DJ
Renal 25-OII·D, ltt'-Hydroxy lase
Calciferol Melabolism in Fetuses and
'"
'" 13. SEX DETERMI NATION AND
Neonates DIFFERENTIAnON OF THE
Clinical Usc of Exogcnoos Calciferols REPRODUCTIVE SYSTEM
Calciferol Regulation of Calcium and Ascxual 'is. Sexual Reproduction:
Phosphorus Absorption
Calciferol AClions on Bone and '" Fundamental Dirrercnce,
Reproduction of tne Somatic '"
Cartilage
'" Cells of lIigher Animals
'"
 Perpetuation of the Species 500 The GonadQtropins, Biochemistry.
and Di ... of Biosynthesis. and Secretion 588
Asexual Reproduction 500 Gonadotropin Releasing Hormones 50>
Gametes. Gonads. and Gender 500 Modanisms of LRH Action 596
Gender Identity and Gender Role 501 £xtra-hypothalamic LRH 596
Sexual Reproduction that Does Not
In_olve Gamete FClI'mation SO,
Prolactin
Hormonal Regulation of Imerstitial Cen '"
ZygO!cs. Embryos. Larvae. and Fetuses 50> Functions 598
Hermaphroditism 502 Hormonal Regulation of
Sex Chromosomes. Autosomes. Genes, Spermatogenesis. Spermiogenesis, and
and Alleles 502 Spermiation WO
Chromosome Separation During Mitosis 503 Hormonal Regulation of Accessory
Chromosome Separation During MeiOSis SO) Reproductive Glands 601
Fcni]ization and Sex Determination
Chromosomal Sex in Nonmammalian
506 Other Androgen Target Organs
Mechanisms of Androgen Actions ""
6<lS
Vertebrates 506 Age-Relatcd Changes in Tcsticular
Parthonogenesis
ACI'essory Reproducti _e Structures
506
S03
Functions
References
""
OI)
Secondary Sex Characteri'ties 5>0
Pseudohermaphroditism 5>0
Early Differentiation of Ihe Mammalian 15.· THE FEMALE REPRODUCTIVE
Reproductive Sy'tem: The SYSTEM 6>0

'"
Ambisexual or "Indifferent" Stage Common Characteristics of Male and
Differentiation of the Testis 5>J Female Systems 620
Differentiation of the Male Structure of the Adult Ovary 62'
Rcproducti_e S}'stem Duets 5>8 Ovarian Cycles: Morphological Aspects 625
Differentiation of the Male Steroid Hormone Biosynthesis in the
Ovary 635
Genitalia
Diffel'<'ntiation of the Ovary
Determination in
'"
5>0 Relationships Between Follicular F1uids
and Ptasma Gonadal Steroid, ..,
Vertebratcs 5" Plasma Gonadotropin Levels During thc
Sex Reversal m Menstrual Cydes 6"
Hormonal Regulatioo of Reproductive Hormonal Regulation of Ovarian Cycles
System Development in Ma le in Primates 6"
Mammals 526 Ilormonal Regulation of Ovuiation 6"
Control of Reproductive System Corpus Luteum Formation, Functions.
Development in Female Mammals 536 and Regression 65)
Disorders of Sex Differentiation 5" Regulation of Plasma Gonadotropin
Sex Di fferentiation of the Central Concentrations 6"
Nervous Systcm 55' Cyclical Change. in Accessory
Hormonal Regulation of Reproductive Reproductive Structures 6"
Reha_ior
Hormonal Control of Reprodu ctive
558 Mechanisms of E'trogen Act ions
Progesterone Receptors
".
".
'"
Rehavior in Primate, Gonadal Steroid Actions On Other
Refe...,nc ••
". Tissues
Pu hcrty Onsct in Females
6"
66'
14. THE MALE REPRODUCT IVE Menopause
'"
6J2
'"
SYSTEM References
Com]Xlnents of the Adult Testis
Production and Maturation of '" 16. CONCEPTION.
CONTRACEPTION. PREGNANCY.
SpcrmatOlOO
Seminal fluid. '"
5'0 AND LACTAT ION
'"
Steroid Biosynthesis and Metabolism
Androgen Release and Distribution
Androgen Degradation and Excretion
58>
589
588
Preparations for Fertili71!1ion
Fcrtili7..a.tion
Dc<'clopment to the Blastocyst Stage
'"
"6
683
 -,."
'"
t>tcparalions for Impla ntation
De<:idual Reactions
Formation of 11K: PIICC1111
...
690
IS. GROWTH HORMONES AND
SOMATOMEDINS 70S
6" TIle Comple1 Nature ofSamalk
Chorionic Gonadotropins 69. Growth
PI"cnlllLlclogcns
Additional Peptide_type Trophoblastic
". Biosynthesis and 5e<.:relion or Growth
Hormones
70S

786
HormO)/\Cs 70s HypOthalamic Regulation of Growth
Maternal and Fctoplaccntal Synthesis Horrnorn: S«relion 790
.nd Metabolism of Steroids
Duration of tbe Geslalim Period
Parturition
70s
708
708
Some Special Problems in tbe
Sludy of Growth HOfltlOM Physiology ,.,
TIIc Somatomedin H)·potbc:!;iJ 79'
Conlrlccption 71l Somalomcdin Actions 802
Maternal Adjuitmc:nu During the Growth lIol'TnOllc Actions Not l inked
PoIilpanum Period 123 with Sonutomedins 803
Lactation 123 Nutrition- Related Changes in Growth
HQrm<)llcs and Bl't'asl Cancer 73 ' Hormone Funtlk,"$ 80s
References m Ref.rences 80s

PART VI. HOAMONIS "'.....eTING aoDY

SIZI! AND COMPOSITION PART VII. THe HYPOTHALAMUS,
HYPOPHYSIS, AND THYMUS GLANDS

17. TlWROJD HORMONES, 19. HYPOTHALAM US AND

TH YROTROPIN. A ND
THYROTROPIN RE LEASING
HYPOPHYSIS
A"alUlIIY ''""
HORMONE
Thyroid Glands and Their Hormones '"'" Blood S upply
Comparative Morpholosy of tbe
."
Obvious Manifestations of
ll ypcrth)'roidism 7"
Hypophysis
Micl'05COpic Anatomy of the Pats
."
OlMout Manifestations 01 Thyroid
7"
Distllis ."
H .... hlOiK Deficiency
The Biosynthesis of Thyroid Hormones
Caloriaenic Act ions of Thyroid '"
El«lron Microsoopy althc PI., Distalis
Micl'<1SC'Qpi<: Anatomy of the Pa.,
Tubenlis
'"
830
Hormones 7" Microscopic Anatomy of the Neural
Thyroid Hormone Receptots
Thyrotropin Regulation of Thyroid
liormorte Secretion
'" 1.0'"
The Hypothalamus
Hypothalami<: Regulation of food
830
830

Thyrotropin Rel<:asing Honnonc

TRH Actions on Otber Cell Types
Neuroendocrine: Control of the TRH-
Intake and Body Weight
References '"
..3
TS H·Tbyroid SystCm 768 20. THE PI NEAL AND T H YMUS
I nnuenoes of Steroid Hormones 770
."
...
GLANOS
Hormone
Interactions 771 Structu re and Innervation of PillCal
Effects of Iodine Deficiency and Exce$$ 772 Glands
GoitrogeN 773 Regul3lots Synthesized in Pineal Glands 8S3
liuman Thyroid System Dysfunctions 776 Pinea l Gland Peptide. 860
Additional Reasons for lmpl iclti", the Pinal G land Regulation of Senonal
ImmullC System 778 Changes in Reproduction
Pineal Gland lnfl ... ncu on '"
Ref_nccs Pi&mcmation "7
Pineal Gland InnuenC<'$ on Other Thymus Gland Innuences on Other
Physiological functions 8n Endocrine functions 8"
functional Anatomy of the Thymus References 886
Gland m
Thymus Gland Involution 8",
Thymus-Gonad·Adrenal Intcraclions 883 INDEX SO,
_ __ PART 1_ _ _

Introduction to the Endocrine

Systems of Vertebrates
 1
What Are Hormones? What Do They Do?
Vertebrale hormone< are highly po1en1. special ized
organic molecules that as regulators and co-
orrlinaloi'1 of the biological functions ()f Ihe animal.
in which they art: synthesized . They exert lheir ae·
lion. 011 cells equipped with receplors thaI bind the
hormones with high affinity and specificity and cou-
ple thai binding 10 Ihe initiation of characteristic
respon .....
Dist inctions can be made between horlnOll<'S and
certain other regulators, such as inorgank iom.
zymes (acling on subslrate. ralher than rccc:plOn;).
walcr-soluble vitamins (derived from the die! or
from microorganismJ; ,",siding in the digestive tract),
macr(mUiriem. utilized in subslantial quantit ies a,
eilher energy sources Qr protoplasmic building
blocks). parahormone$ (ubiqui tous SUb$t3oce, 1"<»-
duccd by m<,)S\ cdl type.). and pheromol1..s that act
On other memb(m of the species. Hormoocs. how.
ever. interact with all of the preceding.
C HANGI NG CO NCEPTS OF THE NATURE
AND FUNCTI ONS OF HORMONES
Recently developed methods have brought ncw in·
sights into the chemical nalU res of hormone. and re-
ceptors; their sites of biosynthesis. activation a nd
degradation; and their mechanisms of interaction a t
the molecular level. We now appreciate Ihe wide dis-
tribution of target cells. the rapid changes in the hor-
mOne concentrations presented 10 them. and the fac-
IOns that modify the receptor numbens and functions .
Thcse advances have changed our undenstanding of
lhe endocrine system.
The "classical"' conceplS are nonclheless worth ex·
amining since they have been widely diS5<'minated
and are sti ll being taught. According to the tradi-
lional view. each hormone is a defined chrmirol m-
lilY that is synthesized exclusively within, and re-
, :
le .... d from. it. own 'pecial. morphologically
reoogni;,able cell type. The secretory units are Or·
ganized into distinct, drcumocribed structures
known as " Moeri"" glands whose aClivities are reg_
ulatoo by blood·borne demieal signals. The hor-
mone is discharged in to the circulatory system.
Ihroogh which it travels 10 a single Or limited num-
ber of lorget orgom for the purpose of exerting "spc·
cinc" .t imulatory or inhibi tory influcnces. The re-
sponses 13ke time to develop and are of Fonger
duraUon Ihan Ih<»e eliciled by neurolransminers.
Since each kind of endocrine gland seNC$ as the
unique SOU rCe of ilS hormone, surgical ablation lead.
to the emergence of a characteristic deficiency syn·
drome that can be alleviated by administering Ihe
missing produc\.
This neat. orderly arrangement distinguishes the
endocrine ( .... h<»e regulators are synthesized
in gland, and a re released into the blood.tream)
fro m the nervous system (which produces its mes-
sengcrs in neurons and releases them to synpascs or
neuromuscular junctions). h also impl ies thai hor-
moocs differ from locally aCling " autacoids" such a.
hi.tamine and prostaglandins.
T he picture presented in the precC<ling di scui>Sion
was almost universally accepted until quite recently.
When o'osc",ations that diverged from it first began
10 emerge, allemplS were made to pre,.",. t he
dogma by suggesting that regulalors failing to cOn·
form were unworthy of recognition as bona fide
members of the endocrine system. In time. however.
it became necessary 10 acknowlC<lge that the clai>Si·
cal views do not reflect biological reality.
The endocrine system is powerf . versatile . and
self-regulati ng. Hov.-ever. il is d ,dcdly 111)/ MOl;
and it has little respecl for time- nored traditions .
Its bounda ries merge impercep bly with those of
other r.gulatory a. ilS i fluences extend to
!
• WHAT ARE HORMONES? WHAT 00 THEY DO?
all facelS of biological function. Exceptions to all of
the traditional beliefs are cited in thi' dap!er, and
additional examples will be found throughout th.
text.
Chemical Nature ollhe Horm ones
Most hormones arc "families" of related molecule •.
TWQ or mo,.., insulins and several kinds of glucagon,
can be made by a si ngle species. Gastrins seem to be
universally present in multiple forms. Human pitu i-
taries con lain many genes Iha! direct the biosyn.
t hes;, of growth-promoting regulators. Testosterone
actsdircetly on some ceil types. bUI it requires trans-
formation to dihydrOle,\osterone, estradiol or other
steroid. before it affects different ta'gets.
Sites of Hormone Blosynthosi&
While it ;5 true that parathyroid glands serve as the
major sources of parathyroid hormones and Inal
pane""at;. bela cells make most of the insulins. most
(and probably all) hormones are synthesized at mul-
tiple sites. T umor cells unrelated to parathyroid
glands can make parathyroid hormone. insulin-like
molecules are synthesized in the brain. and biologi-
cally actiyc somatostatin originates (among other
places) m the brain. paocuatic !Sleu. thyroId gland ••
and gastroinleslinal tracl.
Relat ively rew of the regulators are made in Slrue-
tures rwognizablc as endocrine glands. MOSt of the
angiotensin I is formed extracellularly wilhin the
bloodstT<:am. while most of Ihe angiotensin II origi.
nates in the lungs. Some of lhe hormones Ihal reg-
ulate digestive sySlem functions aT<: synthesized in
e<:lls widely scattered in small clusters throughoul
the gUI. Neurons aT<: important sources of oxytocin.
yasopressin . and hypothalamic releasing hormones.
The kidney proyides uS wilh hormones thaI play
major roles in the control of erythropoiesis a nd of
blood pres5U"'. and the liver COnverts a va riety of
molecules into specialized produCIS.
We are now re<:ognizing Ihal many differenl kinds
of e<:lls make substances chemically similar to (or
identical wilh) the hormones lraditionally associaled
wilh specific endocrine glands . Related molecules
have been idenlified in worms. proIO'.oo. and plants
(59).
Mechanisms for Controlling Hormona
Secretion
It is Irue Ihat blood·borne signals ma ke substa ntial
contributiom to the regu1alion of horm<.>n<: sec retion.
For example. the va rious e<:lItypes of tbe endocrine
pancreas respond 10 changes in the glucose concen·
tration of Ihe systemic blood. wbereas parathyroid
gland and calcitoni n·seereting e<:lIs are affected by
the levels of calciu m ions. On Ihe other band. eyen
the "typical" endocrine glands arc richly innervated.
Interrelationships betwecn thc endocrine and ner-
vous systems permit the body to make adjuslments
tbat avert. rather than correct. imbalances: and they
proyide for inleraclions with environmental factors.
The pineal gland. the endocrine components of the
hypothalamus. and the adrenal medulla provide eX-
amples of hormone-secreting structures controlled
pri marily by neurons.
Hormone Tran8port
While many endocrine e<:lIs secrete into the systemic
blood yessels. those residing in the hypothalamus
and exerting their influences on the anterior portioos
or the pituitary gland pour most of their products
inlo a restricted part of the cireulatory system
kllOwn as the hypothalarrn:..hypophysia! porta!
system.
Hormones also gain acce$S to the target cells in
other wa)'s. for example, glucagon released by the
alpha ceils of a pancreatic islet can travel directly to
neighboring bela cells within lhe same islel (110). In
addi(lon. a hormone may aCt On the very cell that
produces il.
Tha Spaclflclties of the Target Organs
The largel organ concept is easily applied to e<:rtain
of the regulalors. For example , thyroid stimulating
hormone (TSH) actS mostly On the foilicular cells of
the thyroid gland, while adrenocoltiCOlropie hor·
mone (ACTH) stimulates Ihc lOna fasciculata of the
adrenal cortex.
On the other hand. insulin regulates hepatocytes.
adipocytes. skeletal muscle cell s. and some hypotha.
lamic neurons. while estrogens affect (among other
things) the oyaries. fallopian lUbes. ulerus. vagina,
mammary gla nds. bone. bone marrow. liver. Ihymus
gland. pituilary gland, and bra,n. It is difficult 10 find
a cell type Ihat docs IIOt contain receptors for glu·
cocorticoids (17). and eYen TSH and ACTH acl al
multiple si tes.
latent Period8 and Durations 01 Hormona
Actions
The bel ief tha! the responses 10 hormones take more
time 10 develop and last longer than those e lidted by
neurotransm;uers is oot supported by the facts. Tar-
get cells canOOt distinguish between norepinephrine
released from sympathetic nerve endings (and there·
fore regarded as I neurotransmil\er) and norepi·
nephrine into the by <.:<:lIs of
the adrenlll medulla. Some of the hormonal .Ction$
of glucagon on the liver are detectable "'ithin sec-
onds aftcr thil regulator reaches its rc«pton. and
there are efficient mc<:kanism$ for termination of tbe
I'CSpoi e ",hen this become appropriate. Atetyl.
choline and Olher "classical'· neurotransmillers eIen
Iong·range. trophic actions 00 tells eq uipped with to-
ccpton for lhose relullton (112).
Cum:ntly acceptable concepts of the endocrine
system arc like beautifuny blufT"Cd wrsions; of the
simple. 5harply drawn pittum made by ytStcn:by's
endocri llOloaists. Ideas hav-e changed II(l rapidly
within the past few years that there are roollfOYcrsics
coroccming ,,·hich of -'WI re,ulaton should be i....
dudcd in the official list of hormones. III this
teIt, all molecule$ meeting the criteria $0:1 fonh in
the opening paragraph a rc regarded IS components
of the cndocrine sy5lCm.
THE FUNCTIONS OF VERTEBRATE
HORMONES
Cell and Survival
Spedaliuttio!l$ permit each cell type to I'Crform
unique fu nctions Ihat roollribute to the versatility
and . ... vival of 'he or,ani.m '" • whole. Concom i·
tantly. they limit the abili ty of indi,iduai units 10
maintain autonomous existences. In ani·
the various cell types become highly dependent
on each other and on the rooltinuous presence of a
closely regulated internal environment.
"The endocrine system establishes the of <.:<:11-
t<H:e1l ."mmunication that foster cooperation. and it
thereby lCODUnu for many of the dilferellCe$ bc-
tween tell .ggregates and intcgrated indiyidua ls. It
monitors Ind maintains the compositions of the body
lIuids. Ind it favon spccialil;ltions by commandi",
cells of one type to suppan the Ictiyitict or l nother.
Through inftijellCe$ on glQ'to,h. differentiation, mat·
uration. proliferation, and metabolism. it ellCOUrages
each body component to il$ potenti.1 and \(I
assume iu appropriate ....
HOI"Jl"I/JIIoCS provide mcellani$nu whereby orpn-
isms as a whole gn make adjustmenu to c"-ngin!
internal ntedland external environments. They ac-
complish this in part by PlohiOling maturation of the
nervous system and by regulating the activities and
sensitivities of neurons. HortllOilCS ,1$0 roollribute in
.....,otial ways to perpetuation of the species. since
they are n«ded for differentiation and maturation of
the TcproduCliVi: organs. for the production of ga'
metes, and for the nurturing of COfIC<:ptu$CS and
neonates.
Nutrition, Matabollsm, and Body
Composition
Hormones affect the of foods and "uids .. i.
the inHuellCCS they exen on olfactory and gustatory
r«<pton;. on the apprcei3tion of and rcspon5CS 10
hunger and thiM. and on the locomotor IClivilie$ in-
wived in the acquisition and ingcstion of nUtncnts.
Tbcy promote digestion and absorption, . nd they en·
haoce the blood flow (() the gut duri", times when
no beayy demands are made upon the skclcu.1 mus-
cle$. They regulate the distribution of essential rna·
lerial$. and they encourage both the SlOfltge of nu·
IrienU following meal ingt!llion and the rce",itment
of rc5CI'"I'e during fasti", or when there is
n«d. They facilitate immediatc and Ione·ranle ad,
apt.uions lO changes in the qua lity, q\lllntity, and
liming of food intake. favorin& growth and repair
.. hen the supplies arc abunda nt . as ,,·ell as millimit,
illl such processes when suI'"I';val can be prolonged
by shunting very limited resources into pathways
that support vital functions.
Hormones regulate the com.t:f'lation of water and
electrolytes and the ClIcrel;on of metabolic wlStes.
They modulate the generation, distribution. and dis-
sipation of body heat and thereby contribute to lhe
maintenance of optimal internal temperatures. They
control the biosyn thesis and degradation bf struc·
IUral and regu latory molecules and play important
roles in the al\ainment of Ihe body oomposition char·
aeteri .. ic ()f species.
Activity and Rllt
Hormones provide mechanisms for initiating and
sustaining skeletal muscle aCli .. ity. for ."ping with
stress. and for reversion to the I"CSling Slale when Ihis
bc«Imes appropriate. Influences are uerted 00 the
eardiovucular and nervous systems. and also di.
reetly on the s keletal muscle$. The IIonnoncs e ....
oourate the suspension of digestion and oll'O,...' He ....
lial anabolism during tinICS of excnion and the
resumption of such functions and the institution of
repair during times or relaution. Theyoontribute in
major Wll)'S to the regulation of eirehoral. diurnal,
and seosonal rhythms. Animals deprived olthe reg·
ulators are iDQIpable of sustained elron, and they
readily succumb to conditions easily tolenued by i....
dividuals with healthy endocriroe systems.
Reproduction and Care 01 the YOIJn!l
Tbc crucial roles of hormones in regulating the
expression of phenotypic sex are perhaps best dcm-
onstrated by ob5el'"l'ations ol the effeeu of hormone
deprivatit)ll. Mammals with male-type $e.1
somes develop into steri le indi .. iduals with female·
, WHAT ARE HORMONES? WHAT DO THEY DO?
type external genitalia . while genelic females remain
sexually infantile. Birds wilh female-type sex chr<>
mooomes lake On masculine characteristics.
In addition to promoting the differentiation.
gm"'lh. and maturation of the &<lnads and a=sory
r<:pr(l(luclive organs required to accomplish ferli1i1.a-
lion, the hormones elic;! emergence: of Ihe secondary
sex characteristics thaI render the members of one
gender aurael;'" 10 those of the other. They alTec!
the timing of puberty onset as well as sexual interest
and performance. Influences on I'(:<:cplivily in fe-
males of subprimate spc<:ics and on Ihe secrelions of
endometrial and cervical glands of humans provide
prOleclion against the formation of defective zygotes
thaI could otherwise resuil from f •• (iliUllions ae-
oomplished by "overripe" gameles. Related fune·
lions in nonmammalian venebrates include regula-
tion of behavioral patterns that lead 10 the release of
spermatozoa and ()\Ia at the optimum times.
The hormones of eutherian mammal. prepare the
oviducts for nurturing zygOtes, for retaining young
conceptuses during the cleavage stages. and for re-
leasing blaslC)cysts into the uterus at the appropriate
time. They prepare the endometrium for implanta-
tion. and they are required for the maintenance of
pregnancy. Afterward. they assist in parturition and
then provide protection against the occurrence of
postpanum hcmorrha&c •.
hormonal inleractions contribute to the
maturation of the mammary glands, to initiation and
maintenance of lactation. to release of preformed
milk in resporISt to a suckling stimulus. and to re-
version of the glands to a reSling stale when lactation
is terminated. In some 'pecies. regulators associated
with provision of milk for a large litter bring about
delays in implantation if there is a subsequent fenil-
ization. In thi s way, the mother elfectively postpones
the burdens of a second pregnancy when the young
make strong demands on her mctabolic res.Tlles. In
giant kangaroos. lactational delays of implamation
provide protection against the birth of more young
than can be acoommoda"ted in the pouches. In ham·
Sters and other species, seasonal variations in the se-
cretion of hormones affecting reproduction assure
Ihat the )'oung wi!! be born during the month. mCSt
COIlduciv.: to SUTllival.
In birds. the regulators promote storage of nu-
trients within Ihe cgg yolks and the adjustments in
mineral metabolism needed to make egg sheUs. They
al so innuencc mating behavior and dev.:lopmem
of the crop sac. In some amphibians, hormones
elicit the "water driv.:" that precede, fertili?.a_
tion in aqueous environments. In many animal
types. influences on maternal behavior have been
described.
Prot ect ion agaloat Pradatora and Invader.
Through regulation of the dispersion and consper-
sion of the pigment granules of poikilotherm cbro-
matophores and of melanin synthesis by pigment
cells of homeotherms. the hormones contribute to
the acoompli'hment of camouAage. Influcnces on in-
Aammalory reaclions. on immune system fUnctiQ!\$,
and on temperature-regulating mechani,ms confer
resiilanee \0 invasions by microorganisms and to the
growth of SOme kinds of tumor celts. Effe<:ts cxerted
on the liver facilitate the of drugs and
oth.r poisons.
When the attack of a predator Seems imminent.
hormone-mediated "fight Or Aight" responses chan-
nel the blood supply to skeletal muscles and other
structures nceded 10 cope with the ,ituation. Wid-
ening of thc airways facilitatC$ more rapid
of respiratory gases. as release of erythrocytcs from
storage sites contributes to tbi s and provides
some protection if injury leads to blood loss. The
blood also cl(>l.s more rapidly at such timcs. and su-
perficial vessel, are constricted . There is temrorary
elevation of the pain threshold and increased aware-
ness of the environment. Piloerection can make some
animals appear large and ferocious. while "frcele"
responses render Others less allractive to would be
predators.
Self-Re gulation 01 th e Endocrine Sy.tem
Hormones play im!X>rtant roles in the formation.
translocation. and functions of Iheir own re«ptOrl
(S8) . In $Orne cases. protection is provided against
overstimuiation. while in otherl the processes can
comribute to more elfective stimulation. Chronic el-
evation of plasma insulin levels lead, 10 "down reg-
ulation" of insulin receptors, whereas the secretion
of small quantities of estrogens by developing ovar-
ian follicles leads to the acquisition of more estrogen
receptors.
Hormone, also alfett the biosynthesis and func-
tions of receptors for other hormones. An outstand-
ing example is estrogen-mediatcd formation of pro-
gesterone receptors in the uterus and mammary
glands. Estrogens also ine,""ase the numbers of pi·
tuitary gland receptors for hypothalamic hormones,
and this makes possible the moonting of gonadotro-
pin "surges" that promote ovulation. By contrast.
thyroid hormones decrease the numbers of pituitary
receptors for thyrotropin-releasing hormone. and the
process contributes to protection against excessive
stimulation of the thyroid gland.
Each of the hormones additionally influence. the
biosynthesis. use. and mctabolism of others.
as well as the sensitivities to different kinds of
regulators.
ENDOCRINE SYSTEM·NERVOUS SYSTEM
INTERACTIO NS
While "typical" neurons that synthesize neurotrans·
mitters and relcase them at synapse!; and myoneural
junction!; and "typical" endocrine glands that pour
their secretion, imo the bloodstream are recognized.
it is impossible to draw boundaries between the ncr·
vous and endocrine systems.
Hormone!; originating in endocrine glands help es-
tablish the pathways of neural communication by
promoting growth and maturation of neuronal de-
ments and by contributing to the regulation of mes-
sengu biosynthesis and release . They also serve as
neuromodulators thai aher the sensitivities to stim-
ulant!; and inhibitors. Neurons. in turn. affect hor·
mone secretion in several ways that include control·
ling the calibers of blood ,,<,ssels that supply the
glands.
Neuroendocrine cells a re properly classified as
components of both systems. They store.
and release oxytocin. vasopressin, and also a variety
of hormones involved in regulation of the adenohy.
pophysis (88). Many retain the morphological and
physiological characteristic, of the dements from
which they were duived. For example. they can de-
aClion ""Ienlial. and """""d 10 tran.mitter>
released by other neurons .
Certain e<:lls that originate in the neural crests
and r"dated strUClureS of the embryo enter into Ihe
formation of $Cnsory components of the centra! ner-
vous 'yslem and the sympathetic ganglia . Others mi-
gmte long distances. become associated with endo-
crine glands. and de,'dop the ability to secrele
hormones such as calcitonin.
Numerous examples can be ciled of substances
that function in some parts of the body as neufO-
transmillers or neuromodulators and in others as
hormones (20, 43. 44). Norepinephrine is perhaps
the most obvious since it is released by neurons
within the brain. by sympalbclic nerve endings, and
by the e<:lls of the adrenal medulla. Thyrotropin-re·
leasing hormone (TRH) was named for its ability to
promote lhe .«, mion of thyrotropin (thyroid-stim-
ulating hormone). II acts in this way when it is re-
leased imo the bypothalamo-hypophysial blood ves-
sels and travels to thc piluitary gland. TRH is also
made in the cxtnthypothalamic brain, and it is a pa-
lent nervous system stimulant. Luteinizing
hormone-releasing hormone ( LRH) is another hy-
pothalamic hormone Ihat regulates pituitary gland
functions. [t acts centrally as a modifier of reproduc·
live behavior in rats and other mammalian species
(24, 71). Glucocorticoids are probably best known
for Iheir influences on carbohydrate. lipid, and pro-
lein metabolism. They also affecl mood and taste
pere<:plion (46) . Arginine vasotocin is a major reg-
ulator of watcr balane<: in submammalian vert.,..
brates. yet it exerts influene<:. on hypothalamic neu-
rons of mammals when it is present in low
cone<:ntralions (86).
Those who are less than fascinated by complexily
may wonder if somatostalin (SS) was created pri-
marily 10 confu$C cndocrinologists. The peptide wu
named for its ability to inhibit the secretion of
growth hormone (somatotropin). This action occurs
under phy>;iological conditions when hypothalamic
neurons relea$C the hormone inlo the hypothalamo-
hypophysial portal blood vessels. In the gastrointes-
intal tract, neurons discharge SS at their sites of
communication with largel organ,. whereas epithe-
lial cells secrete Ih. hormone imo thc systemic cir-
culation. [n the pancreatic islets. the cells that pro-
due<: SS look like components of the endocrine
!;y>;tem; butlhe actions are exerted locally On neigh-
boring cells. withoul benefit of vascular transport.
Within Ihe extrahypothalamie brain. SS functions
as a neurotransmiller or neurom<.XIulator. II anlag-
onizes some actions of TRI-!, and il also affects lo-
comotor activity pallerns in laboratory animals. SS
is additionally made in thyroid gland cclls that se-
crele calcitonin, and it is believed to act there as an
intracellular regulator.
H...... "'-"'o, a(f",,( ... It, ... r It""-
rons in tWO different ways. During development.
they '-condition'" the brain for ,eceptivity \0 regula-
tors that will subsequcntly be presented. I n older an-
imals, they eXert '"aclivationa)"' influences. They do
nol initiate behavior, but Ihey can faCilitate its onSOI
when they act on receptive cells.
As already noted. the traditional concept thaI
neurotransmitters rapid. evan=ent actions.
whereas hormone.s mediate delayed. sustained regu-
lation_ is nm supported by the facts.
HORMONAL INTERACTIONS WITH ENZYMES
AND COENZYMES
En,.ymcs interact directly with substrales. They ae-
celerate reaction rales by lowering activational ener-
gies. Many require organic cofacleTS (coenl.ymes),
inorganic activators (e.g. calcium or magnesium
ions). Or bolh. to function.
Cocnzymes allaeh to the enzymes and they $Crve
as temporary carriers of intermediates such as hy·
drogen ions, CO" and acyl groups. They can couple
energy-yielding with energy-using reactions.
Examples can be ciled of melabolic reactions that
are regulaled primarily by the availabililY of sub-
strates Or by the rapidity with which the products are
removed. More commonly. reaction rates are deter-
• WH,o,T ARE HORMONES? WHAT 00 THEY 001
mined by the quantities of Ihal arc present
in activ.: form. In a t(lmpl¢x of the 1ype:
A - 8 - C - 0 - E. there is usually (lncltep thai
.
is catalyzed by an enzyme made in limited amounts.
For the reaction A -
. 8, It, is the rate
al which A is conVC"C<iIO 8, while It, is the rale for
romu.lion of A from 8.
When the reaction ;•• . . in vitro. the values of
k, and k. al Iny 81...:" temperature arc determined
by the p/lysi<;Of;hcrnical propcllies and OOnttnU:a·
lions of A anc! 8. The rct.live amounts of A and B
will change until equilibrium i. , uDiAl'd. AI Hult
point, k, _ klo al'ld the B:A ratio assumes. QOOS\anl
value.
En:rymcs Qln sIlortcn the limes required \0 auain
equilibrium. They cannot. haIo'eve •. alrect eilher the
of the ractions or Ihc: prodliCi fiLm (If
B:A hs a low ..,.,Iu<;, cntymc canOOl raisc
it in a system ptrmiucd \0 SO 10 equilibrium .)
Reactions in living cells seldom (i f ever) proceed
to equilibrium. If very small amou nts of A arc pre-
sented, or if B i$ rapidly rtrl'lOVtd. an enzyme can. in
fact. accelerate the conversion of A to B.
Many of the regulatory en7.ymcs arc present in
multiple (orms (i&Ozymes). All members of an iso-
._yme group act on the same subs trates. However.
they Can dIffer from each Other 1n kinetIC properties.
substrate affinities. and IU$Ceptibilities to re8ulation
by other eell oomponenu. The tendencies for actiV(:ly
oontracting skeletal muscle to convert large amou ntt
of pyruvate to laclate. and for liver 10 easily convert
laclate to pyruvale. are auributed in part to the prCl-
cnee of different lactate i&Ozymes in
the two limle types.
Hormones do IIOt do no! $CfYe as oofacu:n ror cy·
IQIOIic or nudear enlymes. The hormones Ire pre$o-
enl in exceedingly low COI'IQeJItrations. and they can
be effective .... hen they arc bound 10 receptors uso-
cialC<i wilh lhe plasma ( lOS). II is not
unu$ual 10 achieY(! maximal Jlimulation when only
5mall .... ,unugesoflhe receptors arc occupied(47).
Rapidly deY(!lopi", responscl to hormones are
linked to the act ivation r:I enzymes. As
discussed in CUP. 4, Ibis tan be accomplished in
seV(:ral .....ys. HOfIl"ll)lleS tan abo affect reaction
rales by ucnilll influences on lhe availabilily w Replica tion requires allachmenu of
Wbslrllies.nd modillcrs and 011 lhe remcMl l of the
Slowly develOping (adaptive) responses oommonly
involve regulation of biosynlbesis Of <kgra-
dation. Usually. such e ffeclJ are exerted on proteins
wilh short biological half-lives. Hormones tan al&O
affecl Ihe formation. composilion, or destruclion of
ribosomes. milochondria. I nd other organelles. T he
possibility that &orne hormones act on plasma mem-
branes 10 invokc rapid resPJnses and then enter the
cells 10 bring about delay<:d reaclions has been con-
sidered (60) .
HORMONE INTERACTIONS WITH NUC LEIC
ACIOS
Deoxyribonucleic acids ( DNAs) dctermille the
chemical compositions of all body oollSlitucnlS. T1Ic
ribonucleic acids (RNi\s) transcribed (TOOl lhem di-
rect lbe bicr;ynthesis of the proteins. includinl a ll of
the enzymes involved in production of lipids and
The chemical makeup of Ihe DNA is established
al lbe of fertilization. T he zygotc conlains all
the information for making every kind of moIccuk
characterislic of Ihe individual. When alb d ivide by
mitosis. oompktc copies are lransmillcd to the
progeny.
Cerlain genes (DNA base sequen<:es) code for the
biosyntltesis of molecules that are _ilal. and Ihese
are in all cell types. Others direcllhe pro-
duction of more spcciali7.ed substances, During the
ccurse of differentiation and maturation. the expres-
sion of cerlain of Ihe genes is seleclively inhibitcd
(9). As a result. the mature indivi dual acquircs some
0<>11 types .ha. are very differ.nt from Olnerl,
InflUences on DNA Biosynthe sis
The physiological functions of hormones do in· IlOl
volve alterations of the qwalilQliw nature of the
DN A. or of thc quantilies present pcr cell. Rother.
lhe regulators play major roles in determining ",hich
ponions of lhe geoornc are CXpll . ' ed. and 10 ",hal
eXlent.
eh"",ic .,...,.-.:Iosa1!C'l of '-"'ones <;O.ft ''',.'feU. In.
chances tU. mutalions will occur by e"",lOciq Ihc..,11-
Ioitintia ' 0 mutagen< lJId u.fections <w rcduci", .he _bil.
;ty to make DNA KPO-in. Some yin<$Q ir>l<rI foni,,,
DNA .ha. di$n&pu the ""'trol mc:e"'.........
Q",,'ilatiYe chanJCS in .he relali"" po"p"" ions 01_·
mal DNA «JmpontlllS(-",1IC amplificalions" "'V'C been
de«:ribtd fot dev<:1opi1lJ Impltibian oocytcs (") •• nd
duri"l Ihe <;OUr$!; olema,....., of dN I .tlisullK:C b)I
....... tUInot cells in cutlure (100)_
10 initialion sites of Jinglc-$.lrandcd
DNA lemplates. all """,nli.1 nucleoside-tri-phos-
pltates, al least 20 proteins (unwinding and nicking-
dosing enzymes. factors affecling poIYlTM:rase
binding. eIC.). polyamil'tCS. and spoxial RNA! that
function as iniliation or replicalion te rmi_
nators (A-2). DNA synthesis is 1101 directly linked
wilh initialion of bul hormones can shorten
cdl cycle S phases and I"<'gul.le organelles involved
in cdl division,
The pl"<'paralions lake time. When immature
uterus of a ral is exposed to eSlrogen. SOme 16 hours
elapse before ac<:eierated uptake of thymidine into
the nuclear DNA can be delecled. in Ihe
DNA contenl 31"<' not obvious until afler 24 hours
(55). The synthesis of proteins Ihat include RNA
and DNA pOlynterases is known 10 occur during the
lalenl period (4). The stimulation of DNA synlhesis
can persist for days. eVen if tbe hormone is with_
drawn several hours after it is pl"<'scnted,
can at.o indirectly aifeet DNA repli-
cation by exening inAuonces On the uptake of DNA.
RNA. and prolein precursors. Interactions with
chalones arc considered later in chapler.
Influences on Transcription
Hormones function in diverie ways 10 accekrate the
production of specific mCSSl'nger RNA (mRNA)
species (32. 49. 84, 118). They can aelivate preex-
isting RNA pOl)'merases. promole Ihe biosynthesis
of new cnzymes, increase the ra tes of uptake of
RNA precursors. Or provide encrgy sourees. They
also play roles in posuranscriptional processing and
degradation of Iranscripts. in the formation of pro-
tei ns that associate with the RNAS. and in thc intra-
cellular uanslocations of various kinds of macromol-
uuIG'. The dTGel3 may be inilialed vi" dircel inlG ....
actions with plasma and Iysowmal membranes (107) .
When hormone. hind '0 and ohango Ihe proportie. of
Ihcir receptors. Ihey faoililale a"""ialion. "ith Ihe ge-
nome and Ihereby affeci inloroction. "ilh DNA b.$C $C-
'1"0..,<' involved in ini'i'lion and regulalion of g<netra"..
$C,iplion (A_) . Tho nuolo"r m.tri. p"",idcsauachmenl
,ile, for aotivel), Iran,cribed gene. and normon. rtCOp-
10rs. and il ""nl.in, RNA poIym.rasc. (A_I, A-4), Re-
«,ptors may bind dir<clly 10 hi"on .. or "'.ddic·· nuciear
protein. Ihal undergo phosphor), lation •. ac.t)'lalio .., and
Olher reacti"". which modify tho interaelion. wilh DNA
(54). 5<;.eral growlh_promoting hormone, and lumori-
gen, may indirtc,ly aocelorale Iranscriplion via phoopilo-
'11,'ion of C),IOpla.mic prOlei ••.
The first detectable inHuence on mRNA produc-
tion is usually an accelerated rale of incorpOnl1ion of
precursors (e.g. uridine) into a high molecular
weight molccular species varioosly known as
"giant." "'heterogenous:' "DNA-like:' or "pre-mes-
senger" RNA (50). The product must undergo ex_
tensive processing before it can
funclion as a messe nger Ihat directs protein synlhe-
sis. In at least wmc cell types, the formation of nu-
cleolar (ribosomal) RNA is then augmented A SC\:-
ondary devation of the giant type follows. Prolonged
presenlalion of the hormone can eventually lead to
inc"",-,ed cell content of all RNA Iypes.
The quantitative consequences vary with both the
regulator and the target tissue. When estrogens in-
duce mRNAs directing ovalbumin synthesis by pre-
viously unslimulated cells of the chick oviduct. the
result is production of massive quantities of a protein
inilially pl"<'scnt in minute or u"detect.ble amounts.
Glucocorticoids selectively elevate liver cell concen-
trations of specific mRNA' and proteins thai are
made in small but physiologically impOrlant
amounts by unslimulated hepatocytes. Long-range
inAuences of growth hormone arc characterized by
generalized increases in cell conlent of many differ-
ent kinds of RNAs, with relalively small changes in
the propOrtions of Ihe various molecular species,
Proou<tion of cylopla,m ic RNAs invol,.. , <omple>
pr"" ..... Ih.1 arc only partially understood, 11 hu been
propo«:d that cell. c<>ntain three classes of the mRNA'
",h.,.. form.ti"". and conversion, 10 oytoplasmic .ffe<:·
IOrs are regula led in differenl ways (2).
The mRNAo directing the ')'nlh"i' or ovalbumin be-
long 10 Ihe "',uperproval,n)" group. A 'Ir<>ngly ,Iimu-
laled colloon ""ntain"p 10 150.000 c<>pie.lh.t account
for 50% of the 101.1 nuclear mRNA (whertu hormon ..
dep'ived cell' conlain minute or undete<:tablo quanli-
tiles). The mRNAs in,oIv<d in Iho produclion of h.mo-
globin provide '<!(llher .,Umpl•. NOl all diff,rtnti. lod
c.Il, make molo<:ulo. of this kind. Hormones .. om to .f-
foot Ibe production by .. rving a. "'inilialion Iriggers."
All coil. c<>nl.in mRNA, of the olh er two type" "'mod_
eralely pre •• lonl" ones wilh 15 10 300 c<>pi., per ccll, and
'-complex-<:IU' mKNAS" with! 10 I) copi ... Tho rate.
of tranSCriplion m.y be .imil" for all memberSof Ibc lwo
groups. bUI Ih. numbers of mRNA molecule< Ih., ul1i_
malely be<:omo associaled wilh Ihe ribosomes dopend on
tho mechani. m, for OQnlroiling processing. intranuolear
degr.dation, and lran'port . It hu bee. prop<><ed thai re-
petitiyo RNA sequence. within Ihe "UcleU' (1ranscribed
from repelilive DNA SC<lu,..,es Ihal Ort int.rspersed
amons Ihe muctural gene.) participale dire01ly in lhe
regulalion.
Certain influences can be expressed only during
specific phases of the 0<'11 cycle. In some cases, one
hormone promotes Ihe progression of Ihc cell, into
the phase in which another can act. A hormone that
promotes cell proliferation can increase the numbers
of targets for a second regulator.
Developmental Changes
As cells diifel"<'ntialc and mature, they undergo
change. in the properties of the chromatin. In some
cases. tbis leads to permanent blocking of specific
DNA sequences required for respOnsiveness to a hor-
mone, while in olhers it leads to increased transcrip-
liOll of genes coding for receptors Or for enzymes in-
volved in the respOnse •.
Some fetal cells that are insensitive to insulin ma-
ture inlO ones highly dependent on the hormone for
" WHAT AflE HORMONES? WH ...T 00 THEY 001
regulation of their glucose uptake. The changes are
associated with acquisition of insulin ree<:ptQrs and
therefore. presumably, with "unmasking" of Ihc
DNA r<:quired for transcription of the associated
molecule:;.
While certa in cell types can be "lurned on" a1 any
time, others are receptive only during reSlricted de-
velopmental slages. T,Hodothyroninc is onc of the
hormones that aC\Son both kinds ofla rgc\s. Humans
born without thyroid glands and denied replacement
therapy have infantile rcproductive organs and suf-
fer stunted growth and menIal retar<:lation. If treat-
ment is begun after many years, the skdctal and reo
productive systems malure. bUI the brain remains
pcrmanemly defective:.
Innuanc es o n Protei n Synth eel. Not Directly
R.lated t o the mRNA,
Hormones affect the formation and functions Qf mi-
tocoondria, daboration of the cndQplasmic reticu -
lum. and the a=mbly of polysomes. Ril>osomes
taken from insulin- Or growth-honTIonMeprivc:d an-
imals make proteins II1QTe .lowly than organelles
taken from healthy controls. Hormones can also ac-
celerate the uptake of certain of the amino acid ••
inAuenees on postlranslalional processing (94),
a nd alter sequestration and degradation of cyto-
plasmic proteins. Some additionally augment food
and water intake, modiFy renal excretion, and c0n-
tribute to the regulation of the composition of body
fluids.
INTERACTIONS WITH MINERALS
lnorganie ions a rC essential regulators Ihat arc tran ...
ported through the biological fluids and acrOSS
plasma and organelle membranes. Somccombine re-
versibly with ions of opposite charge to form poorly
dissociated and mhers become incorpo-
rated into organic molecules that include enzymes.
Minerals can affect the biosynthesis. proc:<=ssing,
release, and degradation of organic regulators, the
binding of hormones to receptors, and all of tile
events that follow hormone· receptor interaction •.
They play roles in the regulation of enzyme activi-
ties, in the assembly and functions of organelles. in
the generatiOll and use of energy, in membrane de-
polari1.3tions and repolarizations, in the biosynthesis
of nonhormonal macromolecules, in cell-to-cell COm-
munication, in the exchanges of materials betwcen
cells and their environments, and in the functions of
contractile proteins. Hormones regulate the levels of
Ihe inorganic molecules in the cell' and extracellular
fluids by exerting innuences on food intake, on intes-
tinal absorption and both renal and biliary
on between cells and the surrounding
fluids, and 011 the sequestration within and release
from intracellular binding sites.
No·, K· , and cr are prescnt in high con<:<:ntra·
tions. Their roles in the regulation of water and acid-
base of cardiovascular funetioM. and of the
secretions of several horll1Qnes are discussed in Part
II I. along with the mechanisms whereby aldosterone
and other hormones control their metabolism.
Ca h may well be the most important mediator of
hormone aclioJlS. It i. directly involved in the gen-
eration, use, and degradation of second messengers,
and it can serve as a second or third messenger in its
own right (see Chapters 4 and 11.). Small changes
in Ihe blood concenlrations ha.e profound innu.nees
on the heart and blood vessels. on neuromuscular ex-
citability, and on functions of the brain_Calcium di-
rectly and indirectly regulates Ihe activities of a wide
variety of key enzymes, the assembly of microtu-
buIes, the generation and use of ATP energy, the
biosynthesis of macromolecules, the release of hor-
II1Qnes and neurotralUmitters, and the properties of
the contractile (see Part IV).
In addition to performing roles of their own, phos-
phore ions interact in many ways with calcium ions.
They determine the fraction of total calcium present
in ionic Form, combine with Ca" to accomplish se-
questration within the mitochondria, ",gulate tho
deposition of calcium into bone under normal con-
ditions, and contrihute to metastatic calcification.
Phosphoryla tion-<lephosphory lat ion mec ha nisms
rapidly affcct the activities of a variety of kcy met-
abolic enzymes (42) and contribute to the control of
membrane tran'port. Phosphorus is a component of
phosphoprotein!, phospholipids, and numerous gly-
cosaminoglycans, and it i. a major determinant of
their elcctrical charges. It is also an essen tial con-
stilUentof ATP, A DP, AMP, GTP, and related lin-
ear nucleotides. of cyclic AMP (cAMP), cGMP,
and Olher "'gulalors, of coentymes that include
NAD, NADP, FAD, pyridQxal phosphate, and thia-
mine pyrophosphate, and of RNAs and
The list of hormones contributing to the control of
calcium and phosphate concentrations in cells and
biological Auids includes parathyroid hormone, cal-
ciferol., calcitonin, norepinephrine, estrogens. an-
drogens, glucocorticoids, triiodothyronine, and
growth hormone.
Mogne$ium is an essential cofactor for many of
the phosphate-transferring enzymes, includins ones
involved in ATP generation within the mitochondria.
ATPases that provide the cells with energy in usea·
ble form, and the adenylale and guanylate cyelases.
It is needed for protein synthesis, since it facilitates
 activation of amino acids and attachment of RNA
to ribosomes (45); and it is a component of bone
mineral.
Magnesium ions antagonize thc effccts of Cal< on
ske letal musele. neurons. and secretory C<'lIs. They
exert generalized inAnence. on many endocrine
glands, and more specific ones 011 the parathyroids
(102). They modify thc calcium-mohilizing effects
of parathyroid hormone, the bone·mineralization
functions of the calciferols, and the se<:retion as wen
u the calorigenic actions of thyroid hormones. Cal.
cifcrols promote intestinal absorption of dietary
magnesium; thyroid hormones affect the plasma
magnesium levels; and there i$ indirect evidence for
parathyroid hormone and calciferol regulation of the
urinary of the metal (92).
MangaMSt is a trac¢ elemem whose specialiud
roles in lipid metabolism extend 10 the biosynthesis
of fauy acids and Cholesterol (45) , It is required for
normal development of the skeleton; and deficiencies
during fetal life affe<:tthe bones of the middle ear as
well as those of the limbs and skull. Manganese4e--
prived fetuses also suffer abnormalities of the central
nervOuS system and defective of glywsa-
minoglycans (48). Postnatally, tho element is needed
for maturation and maintcnanc¢ of the "'productive
system and for lactation (85), While Cal > can sub-
stitute for Mnl> as an activator of certain enzymes,
the roles of Mnl< in oontrolling succinic dehydro-
genase. arginase. peptidascs. and prolidase are
essential,
ZillC i, a component of numerous enzymes, in·
. eluding carbonic anhydrases. alkaline
digestive of the pancreatic juice, lactic, al·
coho!. malic and glutamic dehydrogenases, and both
RNA and DNA polymerascs, It is also an inhibitor
of ribonuclease (85) and a stabilizer of other en·
zymes (90),
Not surprisingly. therefore, zinc plays important
roles in cell growth, differentiation, and prolifera·
tion, in the estahlishment and maintenance of fertil·
ity and lactation, and in wound healing, The severe
malformations seen in the ovcrwholming majority of
infants born to zinc-<leprived mothers, which include
defects of thc skeleton, nerVOus system. and lungs.
have been linked most closely with impairment of
thymidine kinase activity (48),
loss of appetite is an manifestation of post.
natal zinc ddlciency thai has widespread conse-
quences. It has been associated with deterioration of
the taste buds and olfactory epithelium, but abnor·
malitic::5 of the gastrointestinal tract and decrcas<:d
secretion of hormones affecting food intake make
their oontributions, The resuiting anorexia compli·
cates the problems of interpreting the more specific
roles of the zinc, Delayed innuences affect many
other body components. including the hair follicles.
The lymphocyte count in the peripheral blood is low-
ered and erythropoiesis is impaired. bUl the hema·
tocrit may be elevated, Growth retardation and some
other features of the zinc-<leficiency state have been
allributed in part to defects imposed upon the ade·
nohypophysis (98).
Zinc interacts with prolactin, vitamin E. pT05ta·
glandins. and other regulators to maintain vascular
functions (68), and in other ways with vitamins A.
C, and Bll . Prolactin affects zinc uptake rates by
SOme cdltypes (96, 104) while glucocorticoids and
glucagon are more important at other sites. The very
high concentrations in thceye may be related to zinc
participation in vitamin A metabolism. It is sus--
pected that the accumulations in human testes and
in rat lateral prostate glands are linked with innu-
ences on blood now to those organs and with 3S yet
undcfined roles in spermatogenesis. sperm viability.
and fertilization.
Zinc also ooncentrates in thc pancreatic islets. Its
ability to oomplex with insulin is not known to be of
physiological importance, but inAuenC<'$ of the cle-
ment on glucagon secretion and on glucose tolerance
have been deseribed.
Steroid hormones and oral oontraceptive. stimu-
late hepatic production of plasma proteins that func·
tion in the transport of zinc. and they thereby affect
the blood levels of Ihe metal. Ferrilin is best known
for its roles in the binding of iron. but it also seems
to be involved in the physiotogicat uptake and distri·
bution of Metallothionein, on the other hand,
i$ made in large amounts when the concentrations of
zinc and some other metals ri,e excessively. Its pri_
mary function may be protection against toxicity
(90).
Chromium is present in trace amounts. It supports
insulin-stimulated glucose uptake and utili7.ation
and amino acid uptake. Links between chromium
deficiency and maturitY-<Jnset type diabetes mellitus
have been proposed (85). Chromium interacts with
vanadium (83), and it is implicated in the regulation
of blood cholesttrollevels.
Iron and (opper are best known for their roles in
oxygen transport and utilization. Iron i. a compo-
nent of hemoglobin and myoglobin. or heme-
oontaining enzymes that include catalases. mito-
chondrial cytochromes, endoplasmic reticulum
cytochrome P-450s, nonheme iron-sulfur ferrodoxins
(needed, among other things. for the biosynthesis of
the steroid hormones), and of some of the flavopro-
lein,. Copper i$ a component Or oofactor for mito-
chondrial cytochrome oxidases, for dopamine ti-<Jxi·
dase (required ror the biosynthesis of norepinephrine
and epinephrine). of tyrosinase (involved in the bio-
synthesis of melanin pigments). and of lysyl <>.<idase
(which participates in the Formation of collagen and
cialltin).
"
Traces of copper are ne<:ded for Ihe normal ab-
sorption and transport of iron and for the usc: of the
metal in hemoglobin formation. Ceruloplasmin is a
plasma pr(llein that transpons copper. It possesses
acti.ily and it regulates Ihe metabolism
Qf both of Ihe melals.
['on is requ ired fOT the conversion of carolene \0
vitamin A. for the synthesis of purines, collagen. and
anli'oodies. for the clearance of blood lipids, and for
Ihe hepatic detoxification of drugs (45).
Erythropoietin Ihe major I\orm<>nal regulator of
rod blood cell prod uction and therefore (indirectly)
of Ihe U$C of iron for hemogj()bin synthesis. Other
hormones that aCI in various ways to alfect erythro-
poiesis include growth hormone. glucooortiooids, sex
5t.mids, and triiodothyronine. Vilamin E indirectly
contributes to iron conservation, since it stabilizes
red blood cell membranes (85).
The uplake of dielary iron, Ihe lransfers to and
from sites, and the conservalion oflhe metal
are all closely regulalcd. This i. essential sina: iron
is bolh nea:ssary for the support of vilal funclions
and loxic when present in excessive concentralions.
hydrochloric rel.a",. mueh of th. food
iron in Ihe ferrous form which i, dir«tly aboorbed. As·
corbic aeid. cy.t.ine. and olh.r components of intestinal
lumen fluid. miuce f."ie 10.... and O<OOfble acid .• mi..,
adds, and sugars additionally facilitat. ab>o<ption by
oombining with fe".
Apof. rrltln i. a widely dimibuled 460.000 dah"" pro-
tein with 24 i'(I!'I-binding , ites per moleeule. It combine.
wilh ferric hyd'OlIidc-fcrric pho>phate compk,e. to yield
f"mln. the storage form of Ih. metal. Intestinal apofer.
rili. tak •• up (and thereby COI\$CrYes) di.tary iron that i.
no! directly .bsorbed. while hepatic apoferrilin r.tains
iron that i, rel •••• d from detorior.ting erythr«ytes. R.,..
ticulo.ndothelial cells contribute to lhe regul.tion of
plasma iron le.tls. and they. 100. contoin apoferritin. (),;_
idation·reducti"" pot.ntials determine Ih. rale, al which
Ihe fe" i. con.erted 10 fe" and ... Ieas.d from the pra-
tein. The t .... n.f.r ra,O$ accelerlt. when p\J..m. f."
declines.
Apot,allSf. "ln i. a 6, glycoprotein wilh • moIecula,
weilh, of 76.000 thaI circulates in the blood. It ea n lake
up iron from ferritin. When its two f e' · binding .i,••• ",
it is known as The lauer p,ovides
iron to ""II. by ;nte",eling with plMrna m.mbrane ......,.
eiated apoferritin. Ceru loplumin catalyze. th. oxidation
or f." to f.". It thereby maw iron available for"p"
take by both apoferrilin and apotra ..f.rrin.
Th. mechani.m. serve ...eral purposes. Sin(e iTOn i.
avidly con .. rved by inte. tin,1 and h.palic apoferritin>.
only minute amounts of th. m.... l mu" be supplied by
the diel. (Mensl,ualion .lightly increaus Ih. rC(jui ...·
m.nts, pregnaney makC$ greater demand •. and hemor_
rhages can hay •• ubotanlial inftue""",.) Und.r nom,,1
conditions, Ih. sam. apoferritin molecule, ... ur. the
mainl.nance of adequate lev.b of trall$ferrin, whil.
pla,ma m.mbrane-associated apofe,rilin. regulate celiu-
lar uplake of iron and reticuloendolh.lial.ystem pTOteill$
,emo ••• x'.... Uular accumulation •. E.ce»i"" intake of
iron can lead to the deposilion or ferritin au,e",le. (he_
mosid.rill$) in the cell._ Apoferritin .ynthC$i. inere>.se$ al
. uch times. and it alford, limit.d protecti"".
/odjM is both an essential oonstitucnt of thyroid
hormones and a regulalor of Ihe Ihyroid gland (see
Chap. 17). Iodine metabolism is. in lurn. oontrolled
by thyroid-stimulating hormone. Defeelive melabo-
lism of Iodotyrosines released from Ihe thyroid can
impair the biosynlhesi, of (sec Chap.
S).
Selenium and sulfur are discussed in the section
on lipid-soluble vitamins.
INTERACTIONS WITH ORGANIC NUTRIENTS
The concepl that organic differ from hor-
mones in that the former mUSI be provided by Ihe
diet, wherea, the Jailer are synthesized in the body,
is simplistic. &sential amino acids go inlo Ihe for-
mation of the peptide_protein Iype hormOtlC$. essen-
tia! fany acids se",e a, the precursors of Ihe pros-
tagl<tndins Dnd r"luted r.gulotors, and dietary
cholesterol i. a substrate for the prodnclion of .te-
roid hormones . Calciferols ar. needed in the diet
only under ""rlain conditions.
It is somelimes useful to distinguish between rna-
CrotlutritniS (e.g. glucose and amino acids). which
provide fuel or enter into the formalion of prolo-
plasmic constitnent', and Ihe miCn)tlUl,jtnlS, or vi·
tamin, thaI perform regulatory functions.
Mae ronutrlents
Glucost is an essential fuel for neurons. and also for
erythrocytes (which lack mitochondria). metab-
olism ATP energy for muscle contraction
and NADPt1 for anabolic processes. It is a major
precursor of muscle and liver glycogen, of ribose,
galactose, glucuronic acid , and related
substances. and of fa ... choleslerol, and other lipid •.
Glucose is also a component of glycoproteins, gly-
col ipids, and glyCOtlaminoglycans .
Glucose stimu lales Ihe biosynlhesis and secretion
of insulin and the formalion of panc reatic bela eell
glucose receptors. It inhibil$ the secrelion of gluca-
gon. contributes 10 the control of somatostatin. pa..
creatic polypeptide, and growth hormone release.
and plays roles in the regulation of food intake. The
extracellular concentrations may determine the
qualitative effects of somatostatin On the pancreatic
islets (l08).
Glucose uptake by skeletal muscle. adipose tissue.
and some other body components is regulat«l by in-
sulin . glucoconicoids. and growtb hormone. These.
together with thyroid hormones, glucagon . a nd cat-
echolamine!, determi ne the balances betw«n Car-
bohy<lrate storage and re<:ruitmcnt.
AmiIW acids are the building blocks for body pro-
teins and for many of the hormones. There are no
storage forms comparable to glycogen or fat; but
body proteins Can be broke n down to supply amino
acids during times of food depriVation . Some amino
acids are used as glucose precursors, and all can
SCT\'e as energy sources.
Arginine and cortain other amino acids affect the
secretion of insulin, glucagon, and growth hormone.
Glycine a nd are among the ones that
function di rectly as neuromodulaton.. Tyrosine is a
precursor of catecbolamincs, thyroxine and mela-
nins; trytopban is used to make serotonin and mola_
tonin; and histidi ne is easily convened to histamine.
The urea formed during amino acid catabolism can
function as a regulator.
Growth hormone, somatomedins. insulin. gluca-
gon, and glucocorticoids are among the many hor_
moncs that modulate amino acid metabolism.
Tria.;y/glyCf'roI. (fats) are the major storage
fonns of fuel. Those found in adipose tissue differ
from the kinds ta ken with food . but they arc dcrived
from them. Fats play essential roles in the regulation
of body temperature, since they are botb insulators
and sources of body heat; and they form "cushions"
for delicate tissues of the eye, adrenal gland. and
other structures. Fatty acids are essential compo-
nents of phospholipids and other protoplasmic con-
stiWenlS. The ones with two or more double bonds
("'essential'" fatty acids) can be made into prosta-
glandins and leukotrienes.
Dietary lipids affect the secretion of gastrointes-
tina l hormones. The also promote the How of bile
and thereby inHuence cholesterol melabolism, the
absorption of fat-soluble vitamins, and the "entero-
hepatic ci«:ula tion" of hormones such as thyroxine.
Fa\ly acids derived from them affect the properties
of cell membranes and antagonize some of the infiu-
ences of insulin on glucose uptake. In at least a few
sP""ies, they play physiological roles in the regula-
tion of gl uC3goo release.
Phospholipids and cholwerol arc essential com-
ponents of membranes. Small variations in the com-
position affect transport and other funclions. Phos-
plloHpids play roles in the mediation of hormone
actions. Lecithin (a phospholipid) is a major SOurce
of the choline needed to make acetylcbol ine, wbile
cholesterol is the p=ursor of steroid hormones and
the related calciferols.
Water-Soluble Vitamins
Humans require milligram quantities of most of the
members of the '"vitamin B complu" in their daily
diets. A noteable is the cobalt-containing
vitamin B" (cyal1OCobalamin) which ;s needed in
microgram amoonts tha t are often adequately sup-
plied by bact:.ia of the colon. After conversion to
it participates in nucleic
acid metabolism and thereby supports neuronal
functions and hematopoiesis. DcficienciCli usually
arise because the gastric glands do not produce
cnough of an "intrinsic factor"' that promotes intes-
tinal absorption of the vitamin.
Thiam in i$ a p=ursot of tbiamin_p)"rophosphat<, • co-
faclOr for the decarboxylation of ,,·k.toacids ineludinll
pyruvat •. Niacin (nicotinamid.) is u..d to make the
NAD and NAD P involved in ,,",idation'reduction rc,e-
tions requiffil fo, .teroid hormo ... biosynthesis, while ri-
boflavin i. a cOOlponent of FAD and of FMN.
Pyrido.ine form. pyrido..1 phosphat. and relat.d
coenzymes that contribut. to Imino llrouP transf.rs and
arc needed to convert dopamine 10 nor.pinephrine. Pan-
tothenic add i. tLIed for the form.tion of coenzyme A. I
key sub'tanc. involved in lipid m.tabolism. Folic .tid i.
• vitamin aWlCiOled with htmatOpOi",i •. It Rives rise to
t.trahydrofolie acid. a mediator fo, the transf.r of ,ingl.
ca,bon group'. It i. invol,ed in nucl.ic acid metaboli. m.
and it is a cofac,or for tyfO$ine hydroxyl ..e (a
i'ing fOf the biosynthesis of catecholamine. ). Bio-
tin giv •• rise to biocytin. and it i. involved in CO, t .... nsf.'
reaction. inctuding 0"<:$ in glu<>lncogcne,i, p. thw.ys.
The vit.min ha. recently betn .ho"n to enhane. lluany·
lite eyela.. activity (l (3).
Ascorbic acid is an essential vitamin for humans,
monkeys, and other specie!, but it can be synthesized
by many of the vertebrates (ineiuding laboratory
It SCT\'es as a cofactor for sevcral important
eHymes classified as "mixed,function oxidases."· Its
role in Ihe biosynthesis and maintenance of collagen
(a nd therefore its ability to promote wound healing
and to maintain the integrity of capillary mem-
branes) is directly related to its interactions with
prol ine hydroxylase. Vitamin C is also ne«led for
normal metabolism of tyrosine, and especially for
the activity of dopamine .8-oxidase (which catalyzes
the conversion of dopam ine to norepinephrine). High
concentrations are found in the adrenal cortex, and
one method for the bioassay of ACTH depends on
the ability of that hormone 10 rapidly lower ascorbic
acid cone<:ntr3tions. Inhibitory infiuences On the ac-
tivities of bydroxylases involved in steroid lIormone
biosynthesis have been described (57). The aliCOfbic

acid of adrenal is
high.
Ascorbic acid the intestinal absorption
ofiron and calcium. in part by augmcnting gut acid·
ity. [t is a major watcr-$Oluble physiological antiox-
idant, and it interacts with vitamin E (a major lipid·
$Oluble antioxidant).
The purported beneficial effects of pharmacologi·
cal dosages that include increased resistance to in-
fections are JM)t supportod by controlled studies. It
has been speculated that inhibitnry on
glucocorticoid synthesis can be involved in $Orne
= cidental pOisoning has occurred in inra nt. whose mothc"
Fat-Solubla Vitamins
VITAMIN A
Twn major forms of vitamin A are recognized. Both
are alcohols (retinols):
""
" only around 20,000), the complex is not filtered by
PlanlS synlhesi7.c a variety of carolenoid pigments
that can serve as vilamin precursors. At least 10 dif-
ferent ones are present in edible fruits and vegeta_
bles. When acted upon by digestive tract enzymcs.
each molecule yields eilher one or Iwo relinals (re-
tinaldehyde, vitamin A-aldehydc, Fig. )-1). The al·
dehydes are reversibly convened by animal enzymes
to relinols.
Small quantitieS of Ihe pigme nl$ ar. ab$orbed wilhOOI
hydrolysis. They can accumulate in Ihe ad,enal gland.
and adipose twue, of plan!..:.ti", animal •. In bird •. they
.e",. as SOlI"''' of pigmenl$ for rtathe" .
Higher animals do nQl seem capable of synthesiz-
ing molecules of this kind . They store them avidly,
however, and several metabolites can be reCOllered
from liver and from other lipid·rich lissues,
A bsorptinn dep"ndent nn salIS. Enzymes
within the intestine (and elsewhere) catalyze the reo
versible reductinn of retinals to retinols (Fig:. 1-2).
The alcohols Illen form eslers with long·dain fally
WHAT ARE HO!lMONES? WHAT DO THEY 001
acids. and especially wilh palmilate. The esteTS are
hydrolyw.J shonly before Ihey are absorbed by in·
testinal mucosal cell$. The retinols arc Ihen reester·
ified. incorporated into chylomicrnns, and delivered
10 Ihe Iymphalic vessels. Afler transfer to the bl<X>d·
stream, the chylomicrons are taken up by the liver
and vilamin derived from Ihem is slored in
lipoproteins.
Hepatic 'Ionge permit. maintenance of ,ilamin A
function. dur;ng tim .. when the dietary supply i. inod.,..
quate. Ho"'e .. r. it also Iccoonts for the de,elopment of
t<)xicity wben targe amounts are repealedly ingested. Ac-
were unaware of lhe high potencies of vitam;n prepara-
lion •. and in arclic explOfers who Ite lhe vilamin·rich li.·
e" of pOI., be.rs. Toxicily i•• Iso. problem for pa lienls
givcn pharmacological amounls for tbe lreatmenl of ",mc
form. of cancer, Un like the wat.r·",t"bte regulatOl"$. the
lipid-soluble vitamins arc nol e.creted in appreciable
.mounts by the kidne)'.
MobiliUllion from the liver requi res the transfer
of the retinoltn a specific a, globulin called retinol·
binding protein (RBP). which is made in the liver,
Human RBP has 187 amino acid moielies, three di-
sulfide bonds, and one binding site for retinoid. (93).
other mammals are similar tn mucture.
RB P i plasma prea lbumin (trail$-
thyretin), and retinol stabilizes the complex. Unlike
the RBP alone (which has a mole.:ular weight of
the renal glomeruli . and therefnre its formation con·
tributes to the conservation of the vitamin . However,
the kidney is Ihe major site for RBP degradation .
Prcalbumins bind thyroxine, and in ralS and SQrne
other species they arC majnr prnt.in. for the trans-
port nf the thyroid hormone. However, thyroxine
binding is not essential for formation or .tabili •.ation
of Ihe complex.
RBP the transfer of relinoids to the tar-
get The first step is combination with RBP re-
ceplors at the Following this, the reti-
noid the cell, while the RBP remains within
the surrounding medium . The contain specific
proteins for the binding of the retinoid . A cellular
retinol·binding prolcin (CRBP) known to differ
chemically and in other ways from a cellular retinoie
acid-binding protein (CRABP) (38). The intracel-
lular proteins have been implicated in Ihe transfcr of
the retinoids to the loci of action.
Hepalic enlymcs al$O eata ly.", formation of
reliny] a major excretory product that
leaves via the bile.
 A·CorOlene

r Carotene

A. Carotenes yi!lOing one molecule 01 Yilamin "

/l·C.r",ene

Retinol is irrewrsib!y oxidized to retinoic acid in glycosides and also glycosyl·relinyl-pbosphales,

largel organs Ihal respond 10 Ihal melabolile. (These
include inlestine, liver. kidney, bone, respiralory n1O·
cooa, and skin.) The relinoic acid induces enzymes
Ihat calalyze ilS r3pid degr3dation. The acid has
been called a "partial vitamin."' since il mimics Ihe
actions of vitamin A on bone and on some of the ep-
ilhelial muelures but does not corrCCl lhe effects of
defieienq on the eye or reproduelive syslems of
males and femaks.
Different melabolites are formed al various .ites.
and lhere is good reason 10 believe lhal many serve
as the '"aetive" forms of Ihe regulalors. Retinyl phos-
phales are produced in Ihe inlestine and liver. He-
addilionally make se,'eral kinds of retinyl
Celt. of Ihe Ihyroid gland make similar molecules.
and lhyroid hormone deficiencies increase the di-
etary requi rements for vilamin A. Current research
is direcled al idenlifying the molecular species in-
volved in each kind of action and lhe degradation
that are excreted via Ihe bile (28).
The roles of vitamin A in vision have been well
defined. and lhey are discussed ialer in this section.
Actions al olher sites vary from tissue to tissue.
h hs been proposed lhal retinoids bind 10 intra·
cellular receptors and function in lhe same way as
sleroid hormones for induction of interferon and
depr=ion of ornithine Other inAu·
enees on Ihe immune sySlem se<:m to depend on lao
" WH .o.T ARE HOflMONES? Wl-IAT DO THEY 001
<
<
A- C _ O
R- C - ()I-j
Aetir>al
R-COOH
Rotinok _ __
, acO:j (RA) - Plealbumin - _ ••
A.tiny! glyC<>$Ode.
biliution of ly5mQrnal membranes with oonsc:quent
release of hydrolytic (8).
Vitamin A derivatives 3r" essential for promoting
IH)rrnal growth and differentiation of the epithelial
ceUs of skin. rnuOOU5 membranes. reproductive or·
gans. and some sensory structures; and they in-
nucnces on mucus secretion, kenHinization, and
other processes. They deler the development of hy.
perplasia, dysplasia, and metaplasia and have there-
fore been tested for use in patients with some forms
of canccr (8). They play roles in dirC<:1ing growth
and remodeling of bone (82). and they protect
against overgrowth at sites of innervation. Deficien-
cies impair skeletal development, hut they a1"<' also
associated with periosteal proliferation in some "'-
gions, with excessive OIlteoblastic activity, and with
neurological disturbances related to bone impinge-
P
A- O- C-C" H.,
R elinyl p3l""tatc
large' cel
,elil'lOl.cRBP
RA·RBP·
cell
complex RA_CRA6P
DfK;artJolCf/a,;oo pro(Juc"
;,
0,,,,,,
o,
ment On the nerves (30). Such effects are accompa-
nied by changes in the RNA and DNA content of
the tissues, and they probably involve interactions
with other regulators. InAuen<:cs on the binding of
epidermal growth factor to fibroblasts have b«n de-
scribed (Sl).
Other effects have been linked wilh roles in regu-
lation of Ihe biOllynlhcsis of glyoosaminoglycans. gly-
coprotcins, and maimoplipid •. Retinyl phOllphate
serves as a &ubstrate for mannosyltransferasc (51),
and il can the1"<'by exert inAuences on membrane
components as well.
It has also been suggested that retinoids exert "vi-
tamin-like" actions by "",rving as coenzymes for re-
actions that promote the incorporation of sulfa te and
glucose into glycosaminoglycans.
Laboratory mammals maintained on Vitamin A -
deficient diets stop growing, acquire numerOuS epi·
the]ial cell and connective tissue disorders. and be·
come blind and sterile. Retinoic aeid can prevent or
alleviate rn()St of the elfects. including Ihe keratini·
zali(l1l of the conjunctiva and fail·
ure to estab]i.h and mainlain estrous cycles. How·
ever. reliMI or a precursor is needed for
spermatogenesis, for the ability to sustai n preg·
nancy, and for the formation of vi,ual pigments.
The synthesis of rhodopsin (··visual purp]c·') in
the rod cells invo]vcs the combination of a specific
isomer of {.I·retinal (retinene) with the protein opsin.
The vila min derivalive that directly ente .. inlo the re-
action 'eem, 10 be ll..,is·retinyl.phosph.tidylelhanot·
ami"" (61) (Fig. 1-3). Upon exposure \0 ]ighl. the.1>o-
dopsin undergoes a .. ries of re.clio", culminating in Ihe
isomerization of th. retinal. This bdng, .OOt1\ rele .... 01
the prolein and the initiation of an action poten l;a] in Ihe
associated neuron.
The "o",·retina] resul!inj: from the isomerization i,
then belie..d to combine with. phospholipid 10 form
m,,,,.retinyl-phoophatidylethanolamine. The laLler i,
<",,",,"ned to the II·d, fo.m 10 starl Ihe n• • 1 visual cycle.
(In th. coo<s of mammalian eye,. retinals C()mbine with
differen' proteins and parlieipate in C()lor perception. 3-
Dehyd1'Ol'etinai h.. be"" idenlifiod a, a <omponcnt of the
porphyropoins of r..h ... )
VITAMIN E
The ·'speculation·to-faCI ratio" found in the litera·
ture on vitamin E is exceedingly high. and many is-
Sues related to the functions of the vitamin and its
influences On the endocrine systcm remain unre-
solved. The ingestion of high· potency preparations
has been advocated for Ihe treatment of cardiovas-
cular problems, muscular dystrophies, diabetes mel,
]ilus. infertility, menopausal distress, cystic mastitis,
skin lesions, and malignancies of various kinds, and
for the prevention of 'ponlaneous abortion. In most
cases suggestions that the vitamin can exert benefi·
cial effects are based primarily on observations made
in other species that have not been verified in pri-
11<:;':·Ret"yHdifle
phoSp/1atic1ylclhanolamine + Opsin )
PlIOSpI1atidy1et""noIa_
-Ret"ylkline
phospMli<!yIelMnoIIJmine
Fig. 1-3. Foonation. use. ond re.ynlhfl$i. of rho<:Iopsin.
mates; hard evidence for therapeutic crrcctiveness is
indeed sparse.
Some studies arc difficult to interpret because of
the marked species variations in deficiency 'yn-
dromes and vitamin requirements. and the wide
ranges of potencies of substances included in the vi·
lamin E calegory_ Other problems arise from only
recenlly apprecia ted interrelalionships with "poly.
unsaturated" (i.e. essenlial) fauy acids, su]fur-{;()n·
taining amino acid" selenium, vitamins A and C.
prostaglandins, inositol. metallic ions and other fae-
(101). and the influences exerted on the hepatic
metabolism of other agents (15).
Severa] tocopherols and tocotrienols are produced
in plants and are 510red in the seed,_ a-Tocopherol
(Fig. 1-4) is more potent than other naturally occur-
ring molecu]es, and it may be the active form. It i,
concentrated in mcmbrane phospholipids, and at·
tempts have been madc 10 relate its functions to in·
fIuences c;<crtcd on the plasma, mitochondrial. ]yso-
somal, and endoplasmic reticulum membranes (81).
In chicks, vitamin E deficiency syndromes include
encephalomalacia (a degenerative disorder of the
centra] nervous system) and exudative diat hesis
(characteri,.ed by the accumulation of fluids under
the skin). Rats surrer liver degeneration. The male;
also display deterioration of the germinal epithelium
and cessation of spermatogenesis. Fema]es can Ovu·
late and conceive. but Ihcy resorb the fetuses when
thc deficiency Is severe. When gIven sma ll but In·
adequalc vitamin supplements. Ihey bear severely
malformed pups.
Muscular dy'lrophy is a term applied 10 a group
of diverse conditions characterized by degenerative
changes in and weakness of the voluntary muscles.
It can be invoked by vitamin E deficiency (alone. or
when aggravat.d by other dietary manipulations) in
guinea pigs, rabbits. duckli ng!, lambs, turkeys, and
young rats . Cardiae muscle lesions in young pigs
have been attributed to related mechanisms (101).
Vitamin E deficiency has nol been shown 10 cause
muscular dystrophy in humans, and nnempts 10
lreat the elinical disorder with large d(lSes of tocoph.
Rr-.QclOp$On
Irans·Retinal
 WHiO.l ARE HORMONES? WHAT 00 H!E¥ DO?
"
,)-
'" I l:CH, i
,
'T,", '",

r
I I(CH, ;''",
"- Fig. 1-4. :so- .... MII,y ooo",'ing
'", T ° '", torm. ot v itam in E.

'",

"0 V
(""CH, '",
CH , V '0' V
'",
,,· TO<01 ''''not

erols have not been There has been sim-
ilar failure 10 relate vitam in E to reproductive S)'S-
tern disorder. in humans.
Human adult. depr;""d of the vilamin have been
known 10 develop macrocytic anemias and rcd blood
celt fragility, while hemolytic anemia has been ob-
served in premature infams .
Vitamin E is the most potent known physiological
lipid-soluble antioxidant. The bclid that it preserves
essenlial fatly adds and some OIhcr biologically im.
portant molecules, and in .hal way stabilizes mem-
brane phospholipids, is supported by severallinc. of
evidence (41). Diet. cxcC<'dingly rich in unsaturated
faIt I' acids ;nc",asc the need for vitamin E (117).
and some of the defociency clTeet. can be elicited in
previously sympwm·free animals On minimal vita-
min intake if fish liver oils are added to thc food. The
requiremenls for nUlrients Ihal arc casil)" oxidi,_cd .
for eJCample . vitamin A . arc incrca.ed in vitamin E
deficiency stalCS .
Since il is the major WQ/eMOlublc antioxidanl. as-
oorbic acid sometimes can subslitule [or vitamin E.
liowever. il does nol gain access 10 sileS requiring
lipid solubility_ Moreover. when ascorbic acid func·
lions as a reducing agcnt, it becomes converted to
dehydroascorbatc. which is an oxidant. Gl utathione
(glulamykystcinyiglycinc) interacts wilh ascorbic
acid and its oxidalion product. Vila min E reduces
the need for dielary q-steine. while cysteine lowers
the vilamin E requirement .

-
Glu'a'_ {GS·SG)

Glutathoone 12 GSHI ,e<t""e<t fo<m

.
Glutathione peroxidase catalyzes Ihc removal of other cn'_ymes afTecl rdaled reuctions involving the
hydrogen pofOxide (another potent oxidant). and sulfur-<:nntaining amino acids.

Glut.th:ooc pe'o,,,,.. w
2 GSH . H,o, - - - - - - - -- - GS-SG · 2 H,O

Selenium deficiency is associated wilh synlptoms
resembling those described for vila mine F. deli.
c icncy. and one of the agcnts can partially substitute
for Ihe olher_ It is li kely that such observalions arc
related to the role of selenium as an aCliva tor of gin·
tathione peroxidase (97). It has been suggested Ihat
the antioxidant properties of Ihe vilamin decrease
the formalion of toxic peroxides from essenlial fatty
acids, whereas seknium promotes removal or per·
oxides thaI do form. Conditions in which selenium
has been reported to confe r protection include eryth-
rocyte fragility, live r ne<;rosis. diathesis.
SOme forms of muscular dystrophy. and the deposi-
tion of brown pigments ("ceroid") in fatty tissues.
in which the actions of vitamin E have
nol b«n linked with antioxidant properties (and in
which selenium is ineffective) include testicular de-
generation and fetal resorption.
VITAMIN K
Many different substances with varying biological
activities are included in this group. All are chemi-
cally related to 2-methyl· I .4-naphthoquinone:
o and ones that are synthesized within the body.
I lhe administration of vitamin D. On the other hand,
o uitous
The vitamins are synthesized by microorganisms
of the la rge intestine. Deficiencies usually result
from Ihe use of cither antibiotics thai kill the bac·
teria or agenls that inlerfere with bile production
and lipid absorption. The amagoniSlic influences of
high levell of vitamin A are believed to be exerted
on the sma ll intestine (106). whereas dicoumarol (a
component of spoiled clover) is an amimelaboll,e.
A vilamin K.depcndent carboxylase calaly1.es Ihe
conversion of glutamic acid to ')'-carboxyglUlamic
acid' (Gla). The latter is an essential componenl of
prolhrombins and of several Other calcium-binding
proleins. In vilamin K deficiencystat.s. inability to
make normal prothrombins and other clotting fac-
tors leads 10 severe impairment of blood coagulation.
,
00<>< ,ooe
,
H,N - C-H
HCOi
,
H:N -C-H
"'",ooe
,
"'",
/"'\
Glut.m;c acid
A circulating vitamin K.dependenl. 10.000 dalton
"protein S" containing approximately 10 Gla resi-
dues has been implicaled in complement activation
(22). Bone Gla prolein (SGP. ostooca!cin). which
contains 49 amino acids and three Gla Ihat
bind dire.:tly to hydroxyapatite. is the most abun.
dant noncollagenous protein of lhe skeleton. ( In calf
bone. one I1l<lIe.:ule is made for each trOpOCOll agen.)
It also present in bl()<)(j. and it is believed to play
imponant roles in calcium homWSWis (91). BGP
a polent inhibitor of calcification. and it ",ems to be
released from tht h)'droxyapatite during demin-
eralization (89). In women. the levels rise progres-
sively with advancing age (25).
Vilamin K may act at other sites \0 promote the
synthesis of specific proteins. It functions as an el=
Iron transport carrier in baCICria. but a comparable
role has nol been demonstrated in higher animals
(106).
VITAMIN 0
Vitamin D completely obliterates the distinctions be·
tw«:n regulators that must be provided by the diet
When mammals are deprived of sunlight. they de-
velop deficiency syndromes thai can be corrected by
the .itamin can be totally synthesized from the ubiq-
c.g. aeetyl-coA and the cholesterol
deri.-ed from it. As discussed in Chap. 3. intestinal
enzymes convert ehQlesterolto 1.dehydrocholesterol.
which is also known as provitamin O. The product
of lhe reaction travels to the s kin. Ultraviolet radia-
tion then promotes the formation of vitamin D)
(choleca Icife ro 1).
Once formed (or ingested), chOlecalciferol is sent
to the liver. and then 10 the kidney for further pro-
cessing. II is C<)nverted to metabolites that include
1.25.dihydroxy-vitamin D. The latter functions in
every way as a "true" hormone. It exerts its most
obvious actions on the intestine. where it is nceded
10 promote the absorption of calcium and phospho-
supplied by the food. The hormone also acts at
several other sites 10 regulale minerali7.alion
and calcium and phosphorus home(lS\asis. It inlcT-
acts in many ways with parathyroid hormone. cal·
citonin. and other regulators (26).
In some of the fishes. there a rC indications that not
even sunlight is required for the biosynthesis of vi·
tamin O.
PARAHORM O NES
Carbon dioxide is a ubiquitous, blood·borne regula-
lOr that is synthesized by and released fronl all kinds
of cells. It differs from conventional hormones in the
al1l<lumS formed. the generali7.ed sitts for biosyn-
thesis. and its ability to serve as a substrate for en-
zymes (espec ially carbonic anhydrase). It is widely
accepted as the most obvious example of a
parahormone.
There are concerning lhe inclusion
of other substances such as urea. histamine, and
prostaglandins in the category. The term autacoid
has b«n applied to the last two. since they 1"'rform

"autocrinc" functions (i .e. thcy alTect the cell types
that make them). However. the same molecules act
elsewhere as "truc" hormoncs, neurotransmitters. or
neuromodulators. Histamine is discussed in Chap. 8
and prostaglandins in Chap. 3.
A problem with the parahormone concept i. that
0/1 edl types seem to be capable of synthesi .. ing hor-
II"IQne5 (59). Moreove r, the "typical" horm<>nes can
aCt locally to regulate their Own ra tes of biosynthesis.
Such ohservalions weaken Ihe stipulation that hor-
mones must be "specialized" molecu les.
CHALONES
Endocri!lOlogislS once believed Ihal blood-borne reg-
ulalors could be classified imo substances Ihal slim-
Ulal! and ones Ihat inhibil cell activities. The former
were called hormones, while Ihc term cha/OfU> was
applied to th. inhibitors.
The concept is not espe.:ially useful. sirlCe many
metabolic processes a re leversible and requirc regu-
lation in both directions. Thus. insulin can be said to
"stimulate" the production of liver glycogen. How-
ever. it can be elTective only when it simulta neously
inhibits glycogenolysis. Similarly, glucagon "stimu-
lates" glycogenolysis as il inhibilS glycogenesis.
When insulin "inhibils" glycogen breakdown, it does
so by increasing the aelivily of a phosphatase.
The lerm chalone is I>OW used 10 designate groups
of tinu,","speeific (bUi oot species-specific) peptides
Ihat regulate cell proliferation 06, 35). Separale
factors alTecting the mitoses of epidermal cells. fi-
broblasts. melanocytes. lymphocytes. granulocytes.
erythrocytic elements, hepatocytes. and kidney cells
have been identified_
Chalones are synthesi'.ed in Ihe tissue types in
which they aCI. They accumulate within the cells,
the immediate extracellular e nvironmenl, and the
blood plasma in quantities that are propOrtional to
the tissue masses. Thei r actions are re,.. rsible and
noneylotoxie.
The regulators have been directly implicated in
the maintenance of optimum sizes of the liver, kid-
ney, and other organs. permitting full regeneration
when the edl populations are reduced following in-
jury or surgical ablation while protecting against
overgrowth. They to be imponant for Ihe
maintenance of appropriate skin thicl;nesses Over
"arious pans of the body surface and of optimum
numbers of erythrocytes and leukocytes in the sys-
temic blood. They play {mpona"t roles in wound
healing a nd are believ<:d to provide protection
against tumor growth.
According to some authors. thcy are nOl "true"
WHAT ARE KORMONES? WHAT DO THEY 007
hormones. since they act on the cdllypcs that make
them. As already noted. the distinction may not be
useful. Chalones interact with regulators that are
universally regarded as components of the endocriM
syStem_ Thus, epinephrine and glucocorticoids are
.ilher for the functions of epidermal chal-
ones Or serve as powerful potentiators of their ac-
tions. Hormones Ihal suppre.. cell proliferation may
do so in pari by enhancing chalone innnences. while
hormones that inc lease cel! populations may accom-
plish their missions by antagonizing chalone effecls.
There is a limit to the magnitude of cell proliferalion
that can be achieved by the chronic administration
of hormones that promote such processes, and chal-
ones have been implicated in the regulation.
EMBRYONIC INDUCTORS
Chemical messengers exchanged by neighboring
cells of devdoping embryos were at one time ex-
cluded from the hormone classification. since many
act before the cireulatory system is established.
Howe"er. celtain regulators (e.g_ MOlie rian duct in_
hibitor and testosterone) exen some of their actions
following release into the bloodstream, while some
adult hormones act on neighboring cells wilhout en-
tering the circulation.
A minor hi.toeompatibilily 'nligen pre"" nt on Ihe
surfaces of somatic cells of mal. but not female
mammals (Ihe H-Y antigen) directs testicu lar dif-
ferentiation (see Chapter 13). Since it combines with
specific receptors and functions in many ways as a
horll"lQne. il can be said to provide one of the major
linb between the immune and the endocrine
systems.
" GROWTH FACTORS"
Somatomedins. epidermal groMb factor, and nerve
growth factor are examples of species-specific regu_
lators that act within the body and on cells in culture
to promotc growth and affect cell differentiation and
prOJliferation. Their hiosynthesis is regulated hy mol-
ecules that have long been recognized as "typical"
h<}TlI"IQnes. Since Ihey are produced hy one cell type
10 aCt on another, are elTecti"e in low concentrations.
and bind 10 spe.:ific high-affinity receptors, they are
now included all"lQng the hormones.
The peptides interact witb re<:ently identified
"tumor-derived growtb faet()fl;" that can be re-
covered from the urine of subjects bearing Ihe tu-
mors and from the media in whi,h such cells are
grown. Other peptides classified as growth factors
are released from approprialely slimulated leuko-
cytes. It is suspected thai impaired regulation of
growth prOOuction and releasc to
the development of cancers.
PHEROMONES
Pheromones ha'" been defined as regulators r.leased
by one member of the speci.. that aifectthe func-
tions of other members of the same Since
they can coordinate the of pairs or groups
of individuals and thereby contribute to the estab-
lishment of rocial order. defense against predators.
reproouetivc efficiency. and rearing of the young.
they have been '"rocial hormones:'
Th. term eclohormom: encompaSS<'s all regulators
releascd including those that act on other
kinds of animals. The allomonts are bencficialto thc
animal that maKes thcm. but they can have noxious
on the recipients. Kairomones are advanta_
geous to the recipients. but not necessarily to thc do-
nors (6).
There is universal agreement that insects and
many other invertebrates make "true" pheromones.
Examples are cited. so that m.ss.ngers made by ver-
tebrates can be compared with them. Many investi-
gators extcnd the pheromone concept to "lower"
mammals. especially to nocturnal ones whose life-
styles place limitations On by visual
and auditory means (13) . ElIensiv<: studies
been in mice and in olher rOOents, and
some of these are atso described. There are contro--
concerning whether chemicals released by
primates thaI afTect Ihe behavior and
functions of other individuals of the species should
be regarded as pheromones.
Substance. that have be<:n said to be ectooor-
mones are appropriatc subjects for inclusion in en-
docrinology (3,62, 109). since (a) prOOuction
and release are controlled by hormones. (b) many of
the actions are exened On the endocrine systcms of
the recipients. (c) hormones afTe<;t sensitivities
and responses to external chemical stimuli . and (d)
a molecular species Can serve as a hormone. a
pheromone, a pheromone precursor. a that
stabilizes or enhances the effectiveness of a phero-
mone. an allomone. or a kairomone (109. 115). For
example. the progest.rone made in a rabbit's ovaries
supports ulerine functions within the animal but it
also have deleterious eff""" on an
while the androgen. made in the lestes of some
mammals give rise to sex attractants that afTectlh.
females of the same spe<;ies. Pheromone-like signals
by simple organisms may be the evolu-
tionary forerunners of the hormones of higher ani_
mals(115).
While some authors speak of separate disciplines
of exocrinology and endocrinology. others suggest
thai pheromones and hormones are components of a
continuoos of substances used for chemical
(3).
Insect Pheromones
insects have been called "tightly controlled behav_
ioral machines." (74) d.pendent On ph.romones for
the coordination of highly sureoryfWd aetivily pat-
terns that eontribute to socicty maintenance and
long-<;listance communication. Many observations
consistent with the n<ltion have been made. Several
small. lipid·soluble moleculcs of amazingly high po-
are known to be released from specialized
glands and to function by interacting with ol-
factory or gustatory receptors of oth.r individuals.
In many cases. the responses are predictable and
invariable.
On the other hand, cerlain reactions to those se-
cretions are casily modified by the simultaneous pre-
s.mation of olher kinds of stimuli (chemical. visual.
auditory. Or tactile). and a fe'" arc by past
Some authors believe that insects
'"learn:' while others deny this. The animals can ad-
ditionally display responses to other forms of
stimulation. for example. ones provided by food
sources.
Not all of the chemicals released from Ihe exo-
crine glands are totally synthesized within the ani_
mals. It has becn suggested thai there ts a con-
tinuous spect rum rangong from messengers
manufactured from simple precursors. through ones
thai are melabolites of ingested 10 mer
sengeTS that are first ingested and then released in
the original form (103).
It is very difficult to define the chemical natures
of the media to"'. Many of the molecules are present
in minute amountS as minor components of complex
mixtures. Purification procedures bring about
modifications. The observation that a substance ex_
tra"ed from an exocrine gland elici ts predictable re-
sponses does IKIt prove that Ihe is a phys-
iological mediator. or that it acts under natural
conditions.
tn IIoneybee cotonies. a .ingte qlletn la)1 .11 of the
egg •. Some 2O.()()()-6().OOO worker. (nonrepl"Oduclive fe-
male.) engage in ne" cofUtruction. care of the queen and
of tbe hi.·c. f"'aging. and the manufacture of a "toyat
jclly" on wbich the yon08 arc nnrtured. Seve ... t bundred
dtone> (male.) are .1.., ...."dat.d with tbe colony. They
carry 001 mOling function> at oppropriate time •. but do
IKII ..em to .""tribute to the hou.ckeepi08 chore. (36).
The queen moinloin. her Slatu. by secreting phe,..,.
mo .... inciudi", a "queen ,ubolan.e.··
enoic acid (9-<uod..,enoie a.id. fig. 1_5) that.be makes
in her mandibular gtand. and spread, over her body sur-
" WHAT ARE HORMONES? WHAT 00 THEY DO?

"
"o . ""
H C - C-ICH,I. - C . C- COOI-1 "" "
Ii C - C - ICH,j,-C - C - COOH
H b
"
Ii

acid 9-Hydr0"l'-2."..,_ 0<0:1

Ii Ii, H
H,c, c C C 011
...... CV' 'c""'" . . . C::Y 'c""""
I H, I H,
CH, eH,
B. Gera ......

.
H·COOH
Form;c Fig . 1-5. Scm. In..." p.>.romontlS .

Undec.",

C. Some lUI' pI1 ••",mon...,

HHHHI1H Ii
H,c - C - C-C - C- C- C-IOI>)o -C-OH

"" "
D. Bomby'"'' (melh ... . ltfactanl)

face. The pheromone i. distributed throughout tho .<>Iooy
in .. ' .....1 ways. W<>rk ... 01011< to tho queen ing<'t it
(along wilh Ollie, mO$$<ngcl'$). They I.,., regu'lIi,ate il.
bUI can """spread il wilh ,h.i, body ,.,f.ces, Addition-
ally. ",me pheromone may reach distant work... vi. air
currents. Olro.\O,y ««pto", seem to be required for the
re$pon$C._
The queen .ubslance bloch lhe ability of lhe worKers
Ie cons.,uc' addilional "royal ""II," fo< t he rearing of
",,'" q"«ns, and it 01.., p>r!ially inhibit. developmen' of
,h.ir ova'; ... A related '"M,anCe, 9.bydrruydeecnoic
acid, complet .. ,he o"",ian inhibi'ion. It con bo made by
boe. ingesting 'he qu<tn sub.t.nce. The effecl. or the
,besi •• 'he 9-<lxn-2-<1.ce...,ic add. which t h.n funaion,
fi,st . . . . .x a'''aClanl. and loter (during lhe nU!'Ii.1
nigh,) as an aphrod isiac that "imul.t.. the drooe. ,
B... also ...,rele "alarm ,ub$tancu" tha, ale" otbo"
to danger. and 'hey exude a "hive odor"' ,hat aUraets =t
mates . When they find. new soo,ce of food. ,h.y e",ago
in a "waggle d.",." lhat imp.m .i,ual informat ion on
the location and qu.nlily. However. lh.y aho rei....
aniol frQm th.i, abdominal gland. as th.y fan their wi", •.
Th. geraniol is a ",rail pher<>mone," It i. secreted by
o,her boes ,hat ,eceive th. ini,;.1 "imuli . and ,hi, contino
ue. until the food supply bocome, exhau"ed.
Ant. and Other " ... wling insects are more d.pendent

cenlration •. It h.. boon .U"..

me ... nge .. on boh.vic, may dopend on lh. con·
led th., the bo .. farth.st
removed rrom ,h. qu<t. ar. Stimulated to foroge. while
onel tha, are clos., groom and feed lhe que.n.
If,h. qu •• n I.av •• '0'" up. ne,.. colony, Or if . he die •.
lh. loss Of h.r phOTomo ... perm itS the emergenot or
,uCCCSS(Kl,
"" new .i'llin queen. Inai. ,exual maluri,y 'hey.yn.
lhan bo., on ,rail ph.r<>mo_. They, '00, el.oo,.t. sev.
eral specio'''pecific m.... "g.". ;",Iud;ng ala,m .ub-
and they use them in conjuocti.,.. with tlclile and
auditory,ign.I"
The r.p,oducti.ely malure vi,gin ant queen ha, w;n&$
,h., are u.ed during the nuptial fti,ht. Mt., matin,g. the
queen .. ttle, down. break$ off her wirlp, .nd use. the ,e-
main. to nurture lh. fim or her offspring. A. the latte,
develop inlo workers, Ih. queen relea ... a pheromone
Ihal inhibits Iheir s<> ..1 deydopmenl and wing forma·
lion, When Ih. colony enlarge •. SOme workers escape Ih.
inhibilion. malur. inlo qu ...... rId I.aye Ihe colony to
male and 10 "'Iablish n..... mpir ••.
Ant pheromones inciude formic acid. whieh repel. i...
Yaders. and undecane Ind dlronellal. which serve a.
alarm pheromone. Ih., .an promole the moonli", of
aUreuion againsl Ili.n he<: Fig. 1·5). (Xad Onts
,150 .,ude. substance Ihat OIimulate. Ii_ing ones to carry
tbem off for burial. (A living Inl covered with the .. me
chemical i. similarly carried off (40).)
While chemical .ill"ls can direct an animal 10 ito own
colony, il h.. been pointed ou, Ihatlhi, does not n...,...
... rily demonmate lhe IbililY 10 distingui.h belv.-""n its
own and foreiln odor> (103). It i. likely Ihat Ihe
•lance made by iii ne" mate, provides an appropriale
stimulus, ... he"o. olh.r chemic. l. may simply fail to do
Speci.... pcdftc sex allractanlS pr<Wide rertil. male
flyi"3 inse." ,,·ilh information on Ihe ... hereaboulS <>f di$-
lanlly Iocaled female •. Sinee lhe male. are sensiliv. to
differences in oon«ntralion,. Ihey Ire guided to ,h.
source of the pheromone, Se. attrlctanlS of a Ie ... yolalile
nalur. are ulilized by crawlina i.... IS ,ucb a, cock·
...,..che •. In desert locust •. I ,ub"ance released by adult
male. accelerat •• the maturation <>f Ihe )'<lung <>f bolh
...... and it Iher.by ",rves to ,ynchmnize reproductiv.
funetion. (40).
Information derived from studio, of chemical commn ·
nicalion in in ..cts has been put 10 pra.lical use by hu·
mans. Fertile males <>f unde.irable .pecie. are lUTed inlO
"of» ""itoo "ith 'l'<c;"'''I''''';r" ><A
f,om female. or .ynthe,;""d by biochemi"" Th. males
can then be sterili,,ed by radiation and released to seek
OIlI f.nile fern. I.,.. Since nIOSl rem;tl. insec," mat. just
<>n<:e. Ihe' pTocedure cln rapidly reduce population num·
bers wilhout .lfcclinll olher animol, or pollutina the en·
vironment. The aUractants .an also be u,ed 10 p'OYidc
information On Ihe "Umberl of •• within lhe viein·
ily. or to promote au,egalion of de.irable insects 10 a
locale .
Alarm 'UMtance. h",'e been incorporaled in'o ,kin I.,.
lio.. ,...:I •• ndle, 10 repel in$«l$. It i•• 1"" posSible 10
disorient m>1c-seeking mal .. by .pra}'ina th.i, habitats
with perfume. and OIher ,ubstances thaI interfere ..-ilh
pheromone perctp'ion.
Pheromone Type s
Insecl pheromones have been divid.d into lWO catc·
gories on the basis of the eff.cls On Ihc recipients.
Rele(;str pheromones aCI promplly to bring aboul
changes in behavior. in sensitivities to other stimuli.
or bolh. 11 is presumed Ihat Ihe signal picked up by
Ihe receptor i, relayed direelly to th. central nervous
system , The sex attractants and alarm sUMlan<:es
preYiously cited provide examples. The pFimu phcr·
omones iniliate more slowly deyeloping cvenlS,
While they may aCI first on nervous system compo.
nents. the sec<>ndary conscquen<:<:s usually inyolve
change. in endocrine fun<:ti<>M. The queen bee mes-
sengers that inhibit the maluration of Ihe ovaries of
the workers are of this kind.
AuemplS have been made 10 apply similar term;.
nology 10 signa ls released by vertebrales , Some au·
thors consider il appropriate to designate chemical
made by one animal Ihal affccl the be·
havior of anolher a. reltaser pheromones, Chemical
communication is involved in the establishment of
social rank. in Ihc elicitation of aggression and sub-
mission. and in sexual arousal in mammals: and sig·
nals released by some fishes have been called alarm
subSlances (87). It is recogni,.cd. however, that the
aClivilies of venebrales (and especially of those with
highly devel<>ped brains) are complcx and variable •
Ihat they are modified by learning, and that chemi.
cal signals are in conjunction with informa·
lion obtained in different ways. There ar. those who
prefer Ihc term signaling pheromone. since it implies
Ihat Ihe recipient receives a message but does not
r.quire the animal 1<> Ilten engage in a totally pre-
dictable. rigidly defin.d response (11). Others con·
sider Ih. term bthavioral pheromone to be more ap-
propriate (I \4). Vertebrate secretions thal aCI via
neuroendocrine mechanisms to regulale the func·
liOllS (and somctimes also the structures) of repro-
ductive organs have been caUed '·primer"
phcromones.
Do Vertebrates He ye " True " Pherom o nes ?
Vertebrates possess numerous specialized exocrine
structures whose primary functions appear to be the
release of chemica! signals 10 the environment.
There are. for chin . inguinal. larsal. pre-
putial. vaginal. and anal glands that make aromatic
subSlances. Vcrtebrates are a lso C<luipped with
highly sensilive receplors. There is lillie dOUbt Ihat
One member of a species exudes chemicals Ihat in·
voke responses in aoolher, or thai Ihc communica·
lion can be accomplish.d when lite materials are
present but Ihe animal is not. 11 i. also possible to
present numerous in which effecls on the
endocrine systems of the recipients are predklable
and "producible. Studies On fishes. amphibians and
repliles (10. III). and on many different kinds
of mammal. (including mice. rats, guinea pigs.
hamsters. V{)\es. rabbits. cats, dogs. pigs, goalS,
sheep. deer. horses. caule. monkeys and humans
139.111]) have dearly established Ihc innuences
of cnyironmental stimuli on reproductive system
funclions.
It has been argued. however. that the manner in
which Ihe stimuli ar. utilized by vertebrates. and the
responses 10 Ihe chemicals. are quile different from
th. ones deseribed for insects; and thai the term
not appropriate (5).
 " WHAT JJl£ i1OANONES? WHAT 00 ntEv DO?
Chemical Signaling in Mice
Since mice ll'i: nocturnal. and they spend much of
their livC$ confined 10 small enclosures, they have
been favorite subjects for the study of chemical oom-
muniealion. Some of tbe be$t·kllOlOll respon$C$ arc
cited.
SUPPRESSION OF OVAR IAN CYCLES
Although animals living under nalural conditions
display sea_I varia tions in rcprodU<:live fU lIClions.
singly C38(:d adu lt female mice un<krgo sponla·
IlCOUS. regularly recurring ovarian (est roos) cycles in
the laboratory. ThdC arc lS5<Xiated wilh a period of
$Cxual re«ptivity (cs1rus) duri ng Ihe pcri()\l ulalOl)'
plwe. The durations of the cycles vary with the
"rain. and al$o alOOll! individuab of the Nmc sttain
(12), The cycleun: Ionge.. nd more i=gular when
odors emanating from the urine oI'mature mala arc
e, eluded (11) ,
The cycles arc prolonged if the females are hou$Cd
in pairs.. Additional cffe<:u arc tftn if they arc kept
in larger 1fOUp$. a nd mice of some m:ainll tend to
cn1",.. Slate of during which lhey
fail 10 ov ... late (11 4). Similar inhibition or ovari.n
cyclicity can be achic.ved if si ngly animals Ir.
•• posed to \>oddin, thal hn. boon .oiled by other
adull fcmala Of SpB)-cd with urine (5 2).
The suppl'"ssion or tbe ovarian fUnc1ion is known
as the tJJ«I. It has beell all ributed 10 i...
fluences or I uri .... ry pheromone on the endocri ...
S)'$tcm. The euct nature of the underlying endo-
Cline mechanism is difficult to define for several rca-
5OOS. Intact animals uDderao oontinuoos.ly changing
hormone levels. a nd are malked
individual differences ill tbt- <:OIICCntnolions. Female
mice that been ovariectomized and maimaincd
on small dosages of estrogens respond to grouping
by lowering tbeir serum concentrations of luteiniting
hormone The pituitary hormone can incrcasoc:
QlI"Og<'" secretion and ;t is essenlial for ovulation.
They also sIlow incrcll!lC:!l in the levels or prObClill
(PRl). It is likely that the or intact fe-
males 10 the urinary phemmO(H: involve similar
changes in LH and PRl ilCC rellon (12). The elTects
urine lIe abol ished if olfactory bulbs are
destroyed. The si,nal tMt is must be a
complicated OIIC. sintt each mouse adapls to
odor of her own urine as she retains semitivity to lhe
subslances made by h.r cage males.
It h .... been suggested Ihat the lee-Boot effe<:t is.
laboralory Irtifact. since all·female ,roups totally
removed from odon left behind by males are un-
likely to occur ill nature.. The notiollthat the leo-
Boot effect contributes to the control of pofl<Ilation
density is 00\ (lsy to aceept. sinee it can be demo...
strated only in the absence of males (93).
A related obsoervalion is that the urinc of adull vir.
gin females can illhib;t the matunotion of the "'pro-
ductiv.: s)'$tems of youn,cr memben or the: group
(1 9). While ccmparisons alii be made with the inHu·
e!ICes exerted by queen bee substances on the ovaries
of workers, there are very Qbviou$ differences. The
mouse in hibition is tranlient and incomplete. It i$
slowly overridden when the stimulus is oontinuously
pruent, and it is nopidly overcome if the )"011"8 fe-
male moves ' ,"8Y rrom the croup or ir a male is i....
trod ... eed. Moreover, the experi.ncing the
inhibition does not contribute to the reproductive ef·
ficiency 0( the mature female. except in sense
tMt she docs not immediately compete fot. newly
illtroduced maJe.
THE ·' WH ITTEN EFFECT"
When an adult male moose of the same stra in (or
his urine) is introdllCCd into I room in which femal ..
hav.: been displayin, tbe lcc-Boot inhibition, the
ova rian .y<:I.. are lOOn MorC(W(: r, all ma-
ture females .ntcr into $ynchroni'.cd ovari.n cycles.
11 is believed that the si,nal p!"l)Yided by the male
promptly augmenu the release: of LRII . That hy·
pothalamic re,ulatOf soon promotes the secretion of
lU from the pituitary alanlb. It is known tbat ovar-
iectomiw.! remales put OOt more LH when they are
exposed to the urillC or adult mal .. (12).
Production of the urinary fac tor is androgcn-dc.
pe ndent. The stimulant is present in urines 0( in-
tact adult males and of Indrog .... inj«ted cw.not..
of both SCXC$. It cannot be detected ill spcci .... ns
taken from UlltTCated castrated males.
[I was initially believed thaI the urinary phero-
mone was a steroid metabolite derived from testos.
lerone (the major testicular hormone). More recenl
wort. sus.scsu that it is a peptideusociated with
urinary proteins.. Sites implicaled ill iu production
illClude the liver and kidno:y. There a re .bo indica·
tions that $Ccretions of the pr.putial ,lands (which
may be lipids) ma ke some CQntributions to the stim_
ulation (69).
MALE INFLUEI'fCI:S ON REPAODUCTIVE
SYSTEM MATURATION IN FEMALES
(VANDENBERGH EFFECT)
The urino: of adult, intact males accelenotes matu-
ration of the reprodllCtive s)'Slems of )'QUnt females.
The elTccu are reminis«nt of the observations de-
scribed for locusts. However. the difference. are at
least as important as the similarities. First. chemical
stimuli do oot the sole controlling innuenee.
Whcn young females arc to adult males.
they achieve higher blood level. of LH , maintain
them for longer time periods. and secrete more es-
trogen than females re<:eiving ju,t the urinary sig.
nals (14) . Tactile stimulation by the IfIlIles ,eemS to
be an important factor (19). Second, female mice re-
spond to inhibitory signals from other females atthc
same time. The male innuence is most effectivc when
the number of females in the group is sma ll. Third.
dominant males make mOre androgen and more of
the pheromones than do subordiMte males (65).
Thereforc, Ihere can be preferential transmission of
the genetic contributions of the strongest animals.
fourth. crowding leads 10 inhibition of androgen
(and therefore of pheromone) secretion. especially in
subordinate males (7J). Fifth. nutritional deficien.
cies also depress pheromone formation. Thc last two
factors may protect against the production of more
young than can easily be reared .
Some of the difficulties involved in delineating the
endocrine responses to urinary signals can be appre-
ciatcd from attempts to mimic them with selective
hormone administration. Injections of LH alone do
nOt accelerate puberty oruet, but they can increase
estrogen prodUction. Estradiol injections arc effec-
tive in young females deprived of thc urinary stimuli.
but they al.., lower the blood COI1centro.,icn. of LH.
Carefully timed injection $Chedules and more fre·
quent determinations of hormone levels may provide
new insights.
INFLUENCES OF FEMALE URINE ON MALES
T he urine of adult. cycli ng females stimulates sex ual
arousal in adult males. It is believed to augment LH
release and to thereby promote testosterone secre-
tion. The female urine elicits only Iransitory aug-
mentation of LH release in immature males. and the
amounts are inadequate for acceleration of pUberty
onset. However, the physical presence of adult fe-
males can promote rapid sexual maturation (70).
MALE INFLUENCES ON IMPlANTATION
(BRUCE EFFECT)
When the stud male is permilled to remain with the
female he inseminates for two or more days. the in-
cidence of pregnancy is increased. lloW<'ver. if he is
removed and a different male (or his urine) is intro-
duced within the first four days a fter conception. the
pregnancy is oflen promptly terminated. and the fe-
male soon resumes her ovarian cycles. Inhibition of
implantation occurs with even greatcr frcquency if
the male is of a different strain. The signal presented
in the male urine seems 10 interfere with the female's
ability to release adequate amounts of prolactin. A
recently inseminated female can be protected by the
administration of exogenous prolactin . Females in
advanced stages of pregnancy and ones that are lac-
tating make relatively large amounts of prolactin.
and they arc resistant to the pheromone. They also
release something that interferes with the ability of
the male to elicit the Bruce effect.
It has been proposed that pregnancy Icrmination
in this way plays roles in maintaining the quality of
the DNA pools. sinC<: it facilitates transmission of
the characteristics of the dominant males. It has
been pointed out. however. that the territorial be-
haviors of mie.:: make it unlikely that an alien male
will come in coniact with a pregnant female . The
effect may therefore be an undesirable but in-
frequent phenomenon that occur.; because Ihe uri-
nary pheromone that promotes female maturation
also causes abortion. The ability of a prcgnant fe-
male to recognize the stud malc may thcrdore be
part of a device, mediated via noradrencrgic path_
ways and the vomeronasal organs described later.
that permits the female to continue her pregnancy.
Some Compari s ons with Rats
The widespread use of mice to study mammalian
pheromone. carrie< the danger tht gene",lizalion<
will be applied to other rodents. It is therefore useful
to consider observations made on other species.
Only a few on rat. arc cited here.
Adult female rats tend to have quite regular ()\Iar-
ian cycles when housed in the abs..nee of males.
They are not known to exhibit either the Lee-Boot
or Whitten efreclS. and there is lillie evidence for
consistcnt implantation failure in Ihe presence of for-
eign males. Although affecting behavior
have been described. ralS may be far morc depen_
dent than mie.:: on visual cues and audilory signals
(espedally the emission of sounds too higb pitched
to be perceived by humans) (2. 66).
The ovarian cycles can be disrupted by maintain_
ing the females in continuous light. The animals
then enter into a state of "persistent estrus." in
which they are sexually receptive but fail to ovulate.
Ll1 release and ovulalion can be accomplished by
mechanical stimulation of the vagina or uterine ccr-
vix. This can be acbieved in the laboratory with the
use of a glass rod. as well as by introducing a sex-
ually active but sterile male. Females in persistent
estrus may alsoovulale whcn exposed to the urine of
an adult male. However. while female micc can re-
spond to the od= of male urine that are presented
via air currents Or when they are ,epa rated from
soiled bedding by wire mesh. rats require direct COn-

tact with the pheromonal substances. This has becn
attributed to the use of different kinds of receptors
by the tWO animal types (53) (see next section).
A substance produced by lactating rats that at·
traclS young pups is present in the feces of the
mother. and it has been called a pheromone by SOme
observers. Production of the signal depends on pro.
lactin (a hormone essential for lactation). The cf·
fe<:ts seem to be exerted on the liver and to involve
influences on the composition of the bile. However,
the actual synthesis of the attractant has been local·
ized to the cecum. This form of communicatioo
seems to be important during the first t 6 days in the
lives of the neonales, after which visual cues assume
dominance (7S).
Ma mmali an Re eepto ra lo r P he ro mo nes
Volatile substances that are effective when presented
at a distance probably act mostly on the "pri mary
olfactory syslem." which receptors of the
nasal mucooa , the main olfactory bulbs. the first cra·
nial nerve, and the central nervous system com]lO'
nentS with which these are associated (80). Pa th-
ways of this system ntediate oonscious awareness of
odors.
11 is recognilcd, however. that environmental
chemical. UM sensed by other structures. and thO!
olfaction additionally involves Ihe vomeronasal (Ja·
cobson's) organ and its oonnections with the acces-
sory olfactory bulbs (116). Ihe septal organ of Mas-
era. portions of the trigeminal nerve. and terminal
endings of the nervuS terminalis (53). A role for gus-
tatory receptors has also been considered (I). Addi.
tional putative receptor sites include Ihe cornea and
internally located cells affecled by the bloodweam_
Most subhuman vertebrates rosS"" vomeronasal
organs. The !tructures are prucnt in human fetuses.
but there are unresolved questions concerning
whether Ihey function poslnatally (52). Usually,
they lake the form OflUbular sacs Ihat open via min_
ute pore< inlo the nasal cavity. the oral cavit),. Or
both. They make associations with the accessory rn-
factory bulbs and with limbic and hypothalamic re-
gions of the brain (99). These organs are not be-
lieved 10 contribute 10 conscious pereeplion of odors.
They are generally not affected by the minute con-
centrations of airborne sub:stances that travel long
distances and act On the primary olfactory system.
but stimuli can reach them when animals sniff and
sometimes also when they ingest materials. Primary
olfactory receptors may play roles in directing ani.
mals 10 resions in which Ihe stimulants can be found
(52) .
The sniffing, nuzzling, and licking behaviors of
IiORMONES?WHAT DO THEY OO?
mammals, and Observations that SOme to
urinary components can be elicited upon close con-
taci but not when the signals are some distance from
Ihe re<:ipient. suggC$1 that the vomeronasal organs
play important roles. Some obsc",,1'$ believe that the
"Hehman:' a grimace observed in deer and some
other mammals when they sniff the secretions left by
conspeeifies. contributes to transport of the chemi-
cals 10 the sensilive sites_ It has also been demon_
strated lhat lesions affe<:ting vomeronasal (but not
primary olfactory) structures aoolish the effects of
male urine On ovulation in rats with persislent estrus
(52). It has been proposed that the two Iypes of 01·
factory organs "provide parallel. separate rOOteS of
chemosensory influence into the hypothalamus'·
(116).
It is exceedingly difficult to sort out the specific
functions of the lWO systems (80). Destruction of the
primary olfactory pathways is usually associated
with damage to Ihe accessory pathways. Procedures
utili,-<:d to inflict the damage. and others involving.
for example. the use of nasal plugs. can cause seVere
discomfort and constitule a form of nonspecific
stress.
Problem s InVOlve d In Interpretatio n of th e
Re s po nses to Env iro nme ntal Chemicals
The aforementioned responses of rodents can be fit_
ted 1005c1y inlO the pheromone concept. The effects
elicited are reproducible, and there are no indica-
tion.. that they involve learni ng Or judgmenlS. How-
ever, even in rodents. experience affecls the reaclions
to chemicals that influence behavior. Thu s, "naive"
male adult rats respond differently to urine from
adult females than do males who have had previous
sexual oontaets.
Many large mammals leave territorial markings
that have been referred to as pheromoncs_ When an
animal perceives the signal left by a conspecific. its
reactions may be of a very different nature. The re-
cipient is likely 10 lake note of the imensily of the
stim ulw and ilS loca tion. Both kinds of informalion
can provide insights into the size of the dooor. The
decision to avoid a staked-()\lt lerritory may be more
similar to the one of a human confronting a NO
TRESPASSING sign than 10 that of an ant that
perceives an "alarm pheromone."
Monkey " Phero mo nes"
In contrast with ·'Iower·· mammal. that have estrOus
cycles in which receptivity is limited to the pcriovu·
lawry phase. monkeys have menstrual cycles and
can receplivityat all times. However. a male
given acceM to seV<'ral adult females will seek out
and copulate with the ones in the fenile (periovula-
tory) phases. When caged with a single female. he
undergoes cyclical changes in reproduclive behavior
Ihat are synchroniZ<'d with her ovarian cycles. He;s
likely to ignore invitations she extends during her
nonfertile periods (77) .
Adult male monkeys will press bars many times
to elevale panilions that separate Ihem from intaCI
adult fcmales. Thcy show little or no intcrest in ovar-
iectomiled females, eVen when the animals have had
estrogen applied to the sexual skin. Th ey I"<'act to
castrales pl"<'tl"<'ated intravaginally with estrogens.
and to animals that have had vaginal washings from
estrogen-inje<:led animals applied to tile sexual skin
(77).
Males lose interest when their nolles are plugged .
bul the responses to inlact and to suitably Irealed
ovaricclomiled females are promptly reslored when
Ihe plugs are I"<'moV<'d (76).
It has therefore been proposed that estrogens pro-
mote the formation of a vaginal pheromone. ropulin.
that acts on the olfactory receptors of males to stirn·
ulate sexual interest and performance (77). (A dif.
ferent volatile substance has been identified for dogs
[39J.)
However, other studies were performed in which
formalin was applied to the olfaclory epithelium for
the purpose of destroying Ihe sensory epithelium
while avening the discomfon and breathing impaIr-
ment associated with the nasal plUgs. Allhough 1=
of the sense of smell was confirmed by the inability
of the animals 10 discriminate between different non·
pheromonal odors. the monkeys continued to display
cyclical changes in behavior when caged with nor·
mal females (3J).
Several different interpretations are consistent
with the observatioru;. First, eopulin is a pheromone
that aCts on vomeronasal receptors which are pre·
served when the primary olfactory system is dam·
aged by formalin. However, the diSCllmfort associ·
ated with the nasal plugs ""eTls nonspecific effects
on Ihe behavior of the monkeys. Second. copulin a
pheromone Ihat acts on olfactory receptors, and it
contributes 10 the regulation of behavior under phys-
iological conditions. However. when the primary 01-
faclory system is damaged by formalin. bUltbe an·
imals arc otherwise comfortable. it is possible 10
maintain reproductive interest and performane<: by
using other Third. copulln is not a pheromone.
It is an odorous substance that imparts information
concerning the condition of a pOtential sexual part-
ner. and it may additionally have effeclson monkeys
comparable to those of perfumes on humans. Sup-
port rIJr the third concepl derives from al leasl two
&/Jurces. Females undergo changes in the coloration
of the se:cual, thigh, and facial skin (21). which peak
before ovulation. The males show mnimum interest
at the time when fading begins. The color changes
may be di«:ctly allraclive to the males. and they
may additionally provide indicalions of olher
changes (e.g. in the vagina). It is also known that a
male continuously housed with the same female
eventually shows waning interest. but Ihat I1e can
readily be aroused by a different partner.
Humeri " PherOmOI"l81"
Attempts haV<' been made to apply pheromonal in-
terpretations to the pleasures of kissing (and of nose
rubbing in some cultures), to some of the unex-
plained aUractions betwcen individuals. to the high
incidence of conception that follows rape during u<u-
ally infertile phases of the menstrual C)·clc. and 10
the high incidence of conception in previously child·
less women who adopt infants (114).
Observations have been cited that are reminiscen t
of ones described for rodents. Adolescents attending
Summer camps and living in Ihe same quarters often
have synchronized ovarian cycles. Close friends in
all-female collcges can develop elongated, synchro-
nous cycles, and they experience shonening when
they establish recurrent contaclS with males (72).
Some, but not all, women repon regularly recur-
ring changes in b·ds of sexual interest thai coincide
with specific phases of nalural ovarian cycles. and
changes in the paneTns when they take oral contra-
ceptives. Volatile fatty adds similar to the monkey
copulins have been recovered from human vaginal
secretions. They reach higbest concentrations close
to the time of ovulation. The release pallerns arc dis-
rupted by the oral contraceptives (75). Cyclical
changes in olfactory perception Ihat are synchro-
nized with the menstrual cycles have also ocen de-
scribed (34).
On the other hand, nonpheromonal explanations
for all of Ihe phenomena are easy to flOd. Psycholog-
ical faclors that are not well understood underlie at-
Iractions between individuals. Attempls to rule out
lhe effe<:1S of physical activity patterns on cycle syn-
chronizations may not have been 10lally successful.
Stress and the associated release of adrenocortical
and other hormones probably account for rape·,....
lated conceptions, while changes in life·styles prob-
ably contribute 10 the conceptions that follow
adoption .
The concept Ihat copulins function as human
pheromones is questionable on several grounds. Th e
behavioral responses of humans show marked indi-
vidual variations, and they are quite differenl in the
same individual at one time compared with another.
No consistent behavioral links with menstrual cycles
have been established.
If pheromones could. in facl. funclion as at-
" WHAT ARE HORMONES? WHAT DO THEY OO?
tractants, it becomes difficult 10 undemand the al·
most universal use in developed countries of soaps,
deodorants, and perfumes Ihat remove or ove rcome
their effe<:ts. The existence of functioning vomcro.
nasal receptor.; has not been demonstrated for adull
humans. and i\ is well reoogni"ed thai the phenom.
enon of "olfactory adaptalion" soon blums Tespons..
to volatile slimuli.
REFERENCES
I. Amoot<, J. A. Computer COffel ation of Mol""ul••
Shape wilh Qdoo" A Model for StruclU",·Activity
Relation.hips. pp. 294-.-5 of Wo\£,enhoimc. G. E.
W.. and Knight. J.• ed •. To.It and Smdl in V",,..
(eiba founda tion) j. &. A. Churchill. lon-
don, 1970.
2. Barfield. R. J .• and Geyer. L. A. Sau.1 Behov"'"
Uhrasonic I'<>stejaeulalory Song of the M.le Rat.
&;mu 176: I 1972.
3. Barrington. E. J. W. An InrroJuCli()Jl to
alUf Comparallw £/ldo"illQ/oty. 2d ed. Oxford
Unive"i'y Pre ... New York. 19n.
4. B.. I;'u. E.·F .• W ir •. C. R.. Milgrom. E... nd Ray·
naud-lammet. C. Ribonucleic Acid Synthesis and
Qew,.diol MtiGn in thc U'e"'$. pp. 5 of Di·
cdaln.y. e<l .. ref.rence 3 I .
5. Beauchamp. G. K .. Dot)". R. L" Moulton. D, G..
R.' A. The Ph",,,,,,,,,," C""""P' i"
Mammalian Chcmkal Communication: A Cri-
tique. pp. 144-60 of Doty, e<l" rtfertnc¢ 33.
,.
Bi.ch. M. Chap. 1, pp. 1_1 of BirCh, cd" r.f<rtnce
1, Birch. M" ed, ... EI.evier. Ne"" York.
1914.
8. Bollag. W" and Mauer. A. From Vitamin A 10 R.·
,inoid. in Experimental and CI;nical Onoology:
Achiov.mena. Failure. and Outlook. pp. 9_23 of
DeLuca and Shapim. ed ... reference 29.
9. Bonner. J . Tnt Mc/t,u/ar BiOIOf>' of Dtvtlopmrm.
Oxf<>r<l Uni"""ity Prns. Ne ... York. 1%5.
10. Borow,ky. R. Social Inhibition 01 Ma,uration in
Natu.al of XiphophOl'u, vQrioW'
(Pi,,,.,.: Poeciliid •• ). &ittw 101: 933 - 5. 1978.
11. Bronson. F, H. Pheromon.1 InfiuenC« On Rep""
ducti"" Activiti.,. in Roo.m •. Chap. 18, pp. 344- 5
of Birch. ed" reference 1.
11. Bron$On. F. II, Serom fSH. LH and Prolactin in
Adult Ovarioctomiz.e<l Mice Bearill$ Sila"ic Im-
plan" 0/ £<tr.diol: ResponSC$ 10 Social C ue., BioJ.
Rtprod. l5: 147-52. 1916.
13. Bron$On. F. H, Urine Marking in Mice: Can.esand
Eff.cts. Chap. 6. pp. 119-41 of Doty. cd ., .. fe",nco
"
14. Bron.... F. H" and Maruniak. J. A, Differential Ef·
feets of Male S,imuli on Folhcle-.$'imul.ting Hor·
mon., lutein iling Hormone and Prolactin Secre-
tion in Prepubertal Female Mice. Endocrirw/. 98.-
1101 _8.1976 ,
15. Brown. R. 0" Mau""i •. E.. and Toe.hini·V.len·
ti ni, G, P. On the Role of Gene Amplification, pp,
307-16 of Dinlalusy, ed .. refe",nce ) I.
16. Bullough. W. S. The Ch.lo""s: A Review, pp. 5-15
of Forscher and Houck. cd ..... ference 35.
17 . Cake, M . H., and Litwack. G . The Glu<:<><:Orticoid
R.ceptor. Biochtm. A'I/o"," oj 1l''''nI>M' 3: 311-
90.1915,
18. Carpenter. M. P. Vitamin E and Mi.rO$Om.1 Drug
Hydro,ylatiGn'. pp, 81-92 of Nair and Ka)'d<n.
cds .. "'ference 81.
19. Colby, D. R" and Vandenber&. l . G. Rcgulat<>ry Ef-
fecls of Urinary Pheromone. on Puberty in the
Mou ... BloJ, II: 268_70. 1974.
21). COOper, J. R.. Bloom. F. E" .nd Rot h. R, 11, TM
BiocMmical Basis of Nturopnarmocc/oty. 3d e<l.
Oxf<>r<l Uni.c"i,y Pr .... New Yo.k. 191&.
21 . Czaj., J, A" 1'.;",1 •• S. G.. and Goy. R. W. C)'elical
Change. in the Se,u,l Skin of Fem.le Rhesus: Re·
lation.hips to Mating Behavior and Succ<: •• fui A"
tifici.lln><:minatior\. Ftd. Pto<:. 34: 1680-4, 1975,
21. Oahlb&ck. B" and Stcnflo. l, High Molo<:ular
Weight Com pi.. in Hum.n Plasma Between Vita-
min K.Dependent Protein Sand Complemon, Com·
ponenl C 4(>.B;ndin& PrOlein , Pro<:. N{JII. A""d. Sd.
USA 78: 2512- 16. 1981.
23. Da .. id"'n. E. H" and Bri".n. R. l . Regulation of
Gene f.>;pr<$lion: Pos,;ble Rol. of Repetit;,'e Se-
quences , S<ltltu 204: 1051- 9. 1919.
24. D •• id""". J, M, H (H"UOolQ and Ropu•.JUCli.·c lI<;--
hu;ar. Chap, 3, pp, 63-134 of levine S .. ed, /l",.
""""" and Bthavior-. Academic Pres,. New York.
1912
25, Delmas. P. D.. Sto"n<r. D" Wah.cI, H. W" Mann.
K. G... nd RiW. n. L. Serum Bone GLA PrOlein
Incre'$<:> wi.h Aging in Normal Women : Im plica·
tions for Age-Relate<l Bon. Loss , Ab'lr. 41h A"",
MtI'r;ltg Am". SOC. BOM & Mln"al lUck. $-4.
1982.
16. DeLuca. H. F. The Control of Calcium and PhQs.
pho.u. Met.bQli.m by 'he Vitamin D Endocrine
System, AM. N. Y. A""d. Sci, ]55: 1-11. 1980.
11. DeLuca. H, f ., cd. TM Fal-So/ublt Vil"",i,.,.
Handbook of Lipid Re,earch 2, Plenum. New York,
1978.
28. DeLuca. H. F" Zile. M" and Sietsema. W. K. The
Metabolilm of Retinoic Acid to 5.6-Epoxyre';noic
Acid, •. and Other Polar
Metaboli,es. Ann. N. Y. A((Jd. Sci. 359: 25-)6,
1981.
29. Deluca. L. M.. a nd Sh'piro. S. S" ed •. Modularion
of Ctllular InUra"i"", by Viramin A and [)ui",,·
Ii"'.
New York. 1981.
N.Y. Acad, Sci. MO""iraph 359.
30, DeLuca. L. M. Vitamin A, Chap.!. pp. 1-67 of
DeLuca. e<l .. reference 11.
31. DiCIlalu'Y' E .. cd. Gt'" TM,.,,,ipUon /n
riw Tissut. Karolin. h Inlt;\ut.t . Stockholm. 1912.
32. Di. on. G. H. The Ba.ic Protein. of Trout Testi.
Chromatin: of 'heir Syntho.i •• Post,S),n.
 thotie M<><iifieatmand Binding to DNA. pp, 130-
52 or Die,falu<y. ed .• referenc. 31.
ll. Doty. R. L. .•d. Mammalian OIjaC-,iM.
Ii", PrtxtSJtJ Gnd Ikhav;lJ', Acadomic Pre". New
York,1976.
34. Doty. R, L. Em/otri'"
up"" f/uman NaJal ChtmOJW,plioll: A Rtv;t .."
Chap. 15. pp. 295_321 of Doty. ed .. referene<: 33.
35. Forschcl. B. K. •• nd Houck. J. C .. cds. Chalon"."
Conup,. and Cunen' N",orchn Nati"".1 Cancer
Institute MOllOsrapb 38. DHEW Publicati.",
(N!II) 73...(25. Bethwla. 1973.
36. Gary. N . E, Ph.,omone. tbal AIf"'t thc Beh.-ior
and Physiology <>f Iloney Be.., Chap. II. pp. 200-
21 of Birch •• d .. rde"'nce 7.
37. Goldfoot. D. A.. Essock.vilalc. S, S .• A•• . C. S ..
Tllornton . J. E.• and I.•• hot. A. I. AJ\O:!mia in Male
Rbesu, Monkeys Do« NOt Aher Copulatory Aeliv·
ily with C)'cling F.male" &;tlV:t 199: 1095-6.
1978.
38. Goodman. DeW. RetirIQid.Binding PrOlei". in
PI.sma .nd in Cells. Ann. N. Y. Arod. Sci. 69-
78. 1981.
39. Goodwin. M.. Gooding. K. M.. and Regni.,. F, So,
Pheromone in Ihe Dog. &;'na 2M: 559_61. 1919.
40. Gordon. M. S. Animal Ph,.s;o/0lfY: Principl.s and
Adap'(J/iOlU. 2d ed. Macmillan. New York. 1972.
41. Grecn. J. Vil3min E and tbe Biological Antto,idant
Theory. Ann. N.Y. AC"ad. &i. 2OJ: 29_44. 1972.
42. Grecngard. P. Phosphorylated Protein. and Pby,·
iological Elfeet""'. &;t/lU 199: 146-52. 1978.
43. G"illemin. R. Ptplidos in tbe Brain: Tho New En·
docrinology of the Neuron. 201: 390-402.
1978.
44. Guillemin. R, The Expanding Signif,c'ne<: of Il y.
pat h.lamic Peptides. or. Is Endocrinology a Branch
of N.uroendocrinology? N«. Prog, f/arm. fUch .
H: 1_20. 1977.
45. Guthrie. Il. A. Iniroduc,lJ'Y NUlri,iow. 4th ed.
Mosby. St. Loui •. 1979.
46. Henkin. R. I. Th. Role of Adren.1 Conioostoroid<
in Sensory ProcC$ses . Chap. 1'1'. 209-30 of
Bla"'hko. H .. S.yers. G .• and Smilb.lI. 0 .. ,aI .• d,.
Handbook oj Physiology. sec. 7. '01. 6. Amerioan
Phy.ialogioal Sociely. Wa.hington. D.C. 197 5.
47, Hollenberg. M, D .• and Cutree . .... P. Sludie, on
the Interaction. of Hormone, ,,·ilh Plasm. Mem·
brane Reoept""'. Biothtm. At,iOn< 0/ H",_> 3:
42-85.1975.
48. Hurley. l. S. Teratog.nic Aspec" of Manganese,
Zinc. and COpper Nutrition. Phy.liol. R.". 61 : 24'f-.
1981.
49. I.n •• n. E. V.. and DeSombr •• E. R. Estrogen.R.·
ceptor Interac1ion. SeiMa IS}: 126_34. \973.
50. len .. n. E. Y.• and DeSombro. E. R. Eslrogen. and
Progesti .., Acllon oj /formaNS 2: 215_
1972.
51. 1011on. A. M. Action of Retinoid. an<! Phorbol
Ie" on c.n Growth and Binding of Epidermal
Growlh Factor. AM, N.Y. Acod, Sci. 359.. 200-17.
1981.
52. lohn .. M. A. Thc Rol. of th. Vom.ron ... l Syslem
in Mammalian Reprod"cti" Ph)'siology, pp. 341-
64 of MUller"&hwarze. D.•• nd Silvtr$tein. R. M.
ed •. Signals. Plenum. N... York. 1980.
53 . lohns. M, A.. Fedc,. U. H.. Komisa,uk. 8. R..• nd
May.r. A. Urine-induced Refie, Ovulation in An·
ovulatory Rat< .\ by be. Vomeronasal Elfect , No·
'Ul"t 271: 446-8. 1978.
54, Johnson. E, M.• and Allfrey. V. G. Pos15ynlhetk
Modifica1ion, <>f Histone P,imary StruC1Ure: Phos·
phorylation .nd Acetylatton a, Rcl ated to Chr<>-
matin Conform.tion and Function. Bioch,no. Ac-
rio,,", 0/ 5.- 1- 51. 1978,
H. Kat",nell.nbosen. B. S .. and Gor.ki. J, Estrogen
Action,.", Synlh.... of MacrOrnQlecuies in Targ.t
Cell •. Bioth,m. Acr;OIU 0/ J/OflnD,",S J: I 81-243,
1915.
S6. Kew:rne, E. B.. and De la Ri'a. C. Pheromones in
Mice: R",iptocall nlcroction Bet"'«n the Nose and
Brai n. Na/uff 196: 148-1 50. 1982,
51. Kit.bohi, A. E. CorticQ<teroidogenc,i. in Isolated
Adrenal Cell Prep.ution. of Vitamin E·Dencicnt
R.... Ann. N. Y. A""d. S(';. 203: 123- 6. 1972.
58, Kolata, G, B. Ilormone Receptors: How A", They
Regulated' Sde"" 196: 747_8. 1911.
59. Kol.u. G. B. New Theory of llorrnQne, PropO<ed.
SC"imu }IJ: 1383-4. 19&2.
60. Kolat •. G. B. PoIypep1ide Hormones: Wb at Ate
They Doinll in Cell,? Se;'III."' 201: 895 - 7. 1978.
61. lehning.r. A. l. PrillCipl•• oj Bioch,.";.,,,..
Worih. New Yor .... 1982,
62. l eshno,. A. I. An Imroliu('/i()t! 10 8tha"i()rQ/ E,..
docrillOlov. Oxford Universil)' Pre". Ncw York.
1978.
63. l.'ander. O. A.• and Chen,. l. .•d,. Mlcronulri""
Vi,amlllS. Mi,rua" and lIazardous
EI,m. nu. N.Y. Mad, Sci. Monograpb 355. 1980.
64. lombardi. I . R.. and Vand.nbergb. J, G. Ph.ro.
mcnally Induced Soxual Maturation in Pemales:
Regu lation by the Social Environment of tho Male.
196: 1977.
65. lombardi. J, R.. Vandcnberah. J, G.. and W hitsell.
I . M. Androg.n Control of the S..ual Matura1ion
Pheromone in Ilouse Mouse Urinc. Bioi.
/J: 179-86. 1916.
6(;, Lore. R.• and Flan.dly. K. Rat Soci.tic •. Sci.nUji.
Am,"" 236(5): 11)6..16. 1977.
67. Machlin. l. J .• and Gabriel. E. Interaction. of Vi·
lam;n E wi1h Vitamin C. B" and Zinc. AM. N. Y.
Acad. S('i. 15$: 98- 108. 1980.
68. Manku. M. S.. Horrobin. D. F.. Karmozyn. M.. and
Cunnane. S. C. Prolactin .nd Zinc Elfects on Rat
Va,c"lar Rcacti,ily: P.,..ibl. Relationsbip to Di·
homo--y.Lil'lolenio Acid and to Prostaglandin Sy'"
the'is. EndocriNJ!. UN: 114-9. 1919.
69. Marchl ..... ka.Koj. A. Pregnancy Block Elicit.d by
Urinal)' Protein. or Male Mie<:. Bioi, 17.-
129-32.1978.
70. Maruni.k. J, A.• Coquelin. A.• and Bronson. F. Il,
The Release of LH in M.I. Mio< in RespOn.. to
Femalo Urinal)' Odors: Cboractcrislic. of th. Re-
'pOnse. in Youna Male., 1#01. Rtprod, IS: 2S1_5.
1978.
" WHAT ARE HORMONES? WH AT DO THEY DO?
71. Marx. J. L. learning and Bchulor. J. ElfcclSof Pi·
tuitary Hormone • . SrltlfCt /1)().. 367_71): II. HypO-
thal.mit Pel'lides, 1975.
12. McClintock. M. j. Menmual Synchrony and
SUPP'''';'"''Na,,,,.. 219: 244_5,1971.
73. McKin .. y, T. D., and Puley. J. N. Effect. of S<>-
dal and So<;ial Disr"ption in Adull Mal.
Hous< Mice. Gm & Cornpa', t'ndoc,;Mi. }Q: S79_
83.197).
74. Menul, R.• and Erb<r. J. Learning and Memory in
Sdt.,ijic Ame' . 239 (1): 102-10, 1918.
7S. Michael. R. P.• &null, R. W .• and Worner. P.
Human V_ainal Sec""",,,.: Vola'ile F. uy Acid
Content. 186: 1217-19, 1974.
76. Mich •• l, R. P.. and K.... n•• E. B. Primalt Sex
Pheromones or Vagin.] Ori,i., 215: 84-5.
t 970.
17. Michael. R. P.. Ke •• rne. E. B.. and 800 ...11, R. W,
Pheromones: 1""lalion of Male Sex Au .... l,""
from a Female Primat •. Sci, <ICt 171: 964-6. 1971-
7S. Moh •. H.• and Leidahl. L. C. Bilc. Prolaclin. and
the Maternal Pheromone. 196: 81_3. 1977.
79. J. J.• and C¢hn, D. The Effecls of Cal·
dum and on Ihe Secretion of Paralbor·
mone and Parathyroid Secretory Protein by Iso-
lated Porcine Parathyroid Cell,. End"",jltl)/. 103:
2081-90.1978.
SO. Murphy. M. R. Olfaclory Imp.irmenl. Olfaclory
Bulb Removal. and Mammalian Reproduclion .
Chap. S. pp. 9S-1 17 <>f Ooty •• d ...... fo'<'nc. ll.
SI. N.ir. P. P.• and Kayden. H. J.• ed,. V/,arnln E and
/I! Rei, in Mt!oi>oIiJm. Ann. N.Y. Amd.
Sci.. '01 . :!O3. 1972.
g2 . Na, i•. J. M., and Ha"i,. S, S. Vilamin A Influe""e
00 Calcium Me!aOOli.m and Calcificalion, Ann,
N, Y. Acad. Sri. 3jj: 45-5-6, 1980.
g3 . Nielsen. F. H., Hunt. C. D..• nd Uthu •. E, O. In_
teraction> Belween Essenlial Trace and UI"."acc
Elemenll. Ann. N. Y. Amd. Sci. 3jj: 152-62, 1980.
84. O·MoU.y, B. W., and M.an •. A, R. The Mode of
Action of the Female Sox Steroid •. Chop. 6. pp.
181- 210 of Rickenbe,,, II. V., cd . BiQ(:A' mi"'yof
Hor_J. vol. 8. Un ive,sity Park Pr . ... Ballimore.
1974.
85. O'ten. J. M.• and Neuhaul, 0, W. Humon Bir>-
ch,,,,i' ''y, 9th ed. Mosby, SI. lou i•. 1915.
86. Pavel. S .. Cri.w .... anu. A.. Gold't.in. R .. and C.lb.
10.1, lnhibilion of Release of COr(i<mropin Rel<a$ing
Hormone in Cau by Ememely Small AmounlS of
VaSOlocin Inj.cICd inlo the Third Ventriclc of the
Broin. E.idenee for the lnvol .. ment <>f 5·Hydf<)'y·
tryptamine-Containing Neuf<)n" EndoC'in«, /01 :
672-8. 1977
87. Pfeiffer. W. Phef<)mon .. in Fi.h and Amph ibia.
Cbap. 14, pp. 169-96 of Birch, ed .. ref<rerlC< 1,
88. "",ter. J. c.. ed . HypOlholomic HormOMs and Pi·
lui"',y R. gulmion. PI.num. New York. 1917,
89. Poser. J. W.• Sunberg. R. J .• Franci •. S. L. and
Benedicl. J. J. The Bone y.CarOO,yglutamale-Con·
taining Protein U an Inhibitor of
Seed.d CrySlal Gro,,"'th, Aim,. l Ib Ann. MHlin:
Am." SQ(:. Bont-Min".1 .. 5-26. 1982.
90. Pri". D.. aod JQllhi. J. v. Ferrilin: A Zinc Deloxi·
cant and Zinc Ion Donor. Proc. NaIL. Sci,
91-
USA 79: 3116-19. 1982.
Pric •. P. A., and NilhimolO. S. K- R. dioimmu·
""".. ay for the Vilamin K·Depend.nl ProI.in of
Bone and its Disc,,..ry in Pla.ma . Pr()('o Na,l. Acad.
Sci. USA 77: 2234_8. 1980,
92. Quamm •. G. A.. ond Dirkl. J. H. Mag"",ium
Transporl in the Nephron. Am. ,. J. PhyJleI, 239:
F393-401. 1980.
93. Ra.k. l.. Anundi, H .• 8(lhme. J.. E,ikSlQn. U"
Roone. H .. Seae. K" and Pelerson, P. A. Struclu,al
and Fun<lionol Studi.. of Vitamin A·Binding Pre-
loill$. Ann. N. Y, Acad. Sri. J1'9: 19_90, 1981-
94 . Revel. M.. and Groner. Y. Post·transc,iplional and
Tr.n,lalional Controls of Gene E. pression in Eu·
karyole. , Ann. Rn'. BiQ(:htm . • 7: 1079_1126. 1978.
95, ROlle", J. v ., Jr.. and B"'uchamp. G. K . Some Ec·
oIogicallmplicalion. of Primcr Chemical Stimuli in
Rodents. Chap. 9. PI'- 181_95 of Doty. ed .. ferer·
<nco 33.
%, Rosoff, 8.. and Marl in. C. R, Effect of Gonadolre-
phi". I nd of Testosteron. on O'lla. Weights and
Zinc-65 Uptake in lh< M.le R.L Grn & Campa',
£ndoc,jrro!. 10: 7S- 84. 1%8 .
97. Rotruck. J, T .. Pope. A, L. Ganlher. H. 1':.. S .... n·
son, A, 8.. Hafeman. D. v .. and Hoekl\f., W. v .
S.I.nium: Bioch. mic.l Rol .. Componen' of
Glutathione Peroxidase , &1_11« 179: 588-90. 1973.
98. Sand$1ead. H. H., Prou d, A. S .. Fa.id. Z .• Sohu·
Ier!. A" Miale. A.. Jr .. Ba"i\ly. 5 .. and Darby. W.
J. Endocrine Manifestalion, of Human Zinc Def,_
ciency. Chap. 16. pp. 304-25 <>f Proud, A. S.. cd .
Z;II< Mtrolx>lism. Thoma" Springfield, III .. 1%6.
99. Sc.li • . F.. and Winan,. S, S , Ne ... Perspeclive, on
the MorpltoloiY of the OlfaclOry Systcm; Olfaolory
.nd Vom<rooa,al Palhways in Mammal •. Chap. 2.
pp. 8-28 of Doty, cd .. ,eferenee 3l.
100. Sehiml:e. R. T .. Kaufman. R, J .• All. F, W .. "nd
Kellems, R. F. vene Amplification .nd Drug Rc.i,·
la""" in Cultuwi Murin. Cell •. Sci",,, ]f)2: 1051 -
55. 1978,
101 . Soot!, M. L. Vitamin E, Chap. 3. pp. 133-210 of
Deluc •. ed .• reference 27.
102. Shill. 10.1, E, Magnesium. Calcium, and Pa ... lhyroid
lnl .... cliO/l$. Ann. N.Y. Acad. Sci. 3U' 165-80,
1980.
103. SOOre),. H. H. Animal Communlm,iOft by
_<$. Academic Pr . ... N.... York. 1976.
104, Smilh. J. C .. Jr .. Th. Vitamin A·Zinc Conneclion:
A Review. Ann, N. Y. ACdd. Sri. JU· 62-74. 1980,
105. Suthe,la od. E. W. Sludies on the Mecbani,m of
Hormone AClion. Sci",,.. 177: 401-8 . 1972.
1()6. Suttie. J. w. Vitamin K. Chap. 4. pp. 211_11 of
DeLuoa, <d .. rere«n<:e 27.
101. S,ego. C. 10.1, Parallels in Ihe Mod« of ACI;on of
Peptide and Steroid Hormone" Mcmbrane Effects
.od Cellula, EOlly. Chap. 19. pp. 431_72 of
 McKer ... K. W .. ed. Srrucrurt of 114. Whitten. W. K.. and Champlin. A. K. Th. Role of
Gorltld(JI1'(Jpi",. New York. 1915, Olf.ction in Mammali.n Reproduction. Chap. S.
lOS. Tai. T.·Y .• and POX. S. Direct Stimulation by PI', 109-23 of Grtep. R. 0. , ><iI. ed. Handbook of
Growth Hormone of Glucagon and In$ulin Release SeC. 7. vol, 2, Am.ri •• n Physiology S0-
from Isolated Pucrea •. EndoaillOl. 99: 669_17. ciety, Was hington. D.C .. 1973.
1976, I 15. Wilson, E. 0 ., Eisn." T .. Briggs. W. R.. Dickerson.
109. Turner. C. D.. Bagn.... J. T EndIXri- R. E.• Metzenberg, R. L.. O·Brien. R. D.• SUlman.
lIOIog)'. 6th ed. Sauode ..... Phil.delphia. 1976. M.. and Boggs. W. E. On 2d «I. Sinauer.
110. Unger. R, H.. Dobbs, R. E., .nd Orci. l. I.. ulin. Sund.rland, Ma .... 1978,
Glucagon and Somat""1I1in Secretion in the Reg. 116. Wina ... S. S.• and Scalia. F. Amygdaloid Nucleus:
ulatioo of Metaboli.m, Ann. nyJia/, 40: 307- New Afferent Input fr<Hll the Vomeron ... 1 Organ,
43.1978. 170: 330--2.1970.
III , Van Tienboven. A. Rt",oductiw 117, Wiltin,. L. A. The Role of Polyun .. turated Fatty
Saunde ..... Philadolphia. 1968. Acid. in Det.rmining Vitamin E Requirement.
112. Varon. S, S, Trophic Mechani.m. in the Peripheral Ann. N.Y. Acad, Sci. }(H' 192-8. 1912.
Nervous SY$lem. Ann, I: 327-61. lIS. Yamamoto, K. R .. and Alberts. 8 , M, Steroid Re·
1978. «pto .... , Element' for Modulation of Euhry<>tic
113, Ve,ley. D. l. Biotin Enhances Guanylate Cyel"", T,.nscription: A"". 45: 721 - 46.
Acti. ity. Sd,nu 216: 1329-30. 1982. 1916.

A- I. Barrack. E. R.. and Coffe)'. D. S. 8i<>logi •• 1 Prop-
erti« of th. Nud.ar Matn" Steroid Hormone
Bioding. /l.N". Prog. HOI'''', IUch. J8: 133- 89. 1982.
A·1. Belja ...i. M, R'guiali(m of DNA
and Tronuriplion, S. Karger, N .... York. 1983.
A-3. Chamben. P.. Dierieh. A .. G•• b. M,·p., Ja kowl, • .
S .. Jon8"'" J .. K'U'l . A.. LoPennee. J.·p.. Oudet.
P.. a nd Rc.delhuber. T. P,omoto, mome nt. of
Genco Coding for Proteins and Modulation of
Transcription by Estrogen, and P"".. to,one.
Prog. Ho,,,,. R"h. 40: 1-39, 1984.
A4. Ciejek, E. M.. T.. i. M·J. and O·M.lIey. B. W. Ac-
ti.ely Tran.c,il>«! Gene. are A<$OCi.,.d with the
Nuele .. Mat rix. 306: 1984.

Organization of the Endocrine System
WHAT IS AN ENDOCRINE GLAND?
The term mdocrine gland is applied \0 all members
of a group of anatomically discrete. but functionally
related organs Ihal synthes;,-<, hormones and release
Ihern into Ihe bloodstream. An acceptable lisl could
inclUde Ihe pituitary> thyroid, parathyroid, and 3dI"<"
nal glands. the lestes and ovaries, the pancreatic is-
leiS. and perhaps also the thymus and pineal glands.
Howevu, more . hormones are produced ouuide
such emitie. than within them . Many different cell
types engage in synthesis of Ihe regulators. and SOme
hormones are made eX lracdlularly. Ii has become
virtually impossible \0 formulale a definition of an
endocrine gland thaI accommodates aU the sites of
biosynthesis.
If Ihe traditional criteria for membership in Ihe
endocrine system were to be applied toda}', it i.likely
that no vertebrate structure would meet the qualifi-
catiens. The pararhyroid glands woul d fare bener
than 111051. They are morphologically re<:ognizable
entities that secrete a well-defined honnone into the
systemic cireulat ion. The obvious target orga ns are
bone and kidney. and the hormone acts upon them
to regulate calcium and phosphorus metabolism.
Ablation of the glandi lead, to the emergence of a
characteristic deficienc)" syndrome that can be aIle·
viated by injection of suitably prepared parathyroid
gland extracts.
Impeccable credential,? Perhaps. One w<lndcrs,
however. whether the admissions commillee would
be willing to overlook some of the following points:
(a) the molecular heterogeneity of parathyroid hor-
mone (PTH); (b) the secretion of equimolecular
amounts of a parathyroid secre lory protein ( PSP)
Ihat may function as an additional hormOllC' (72); (cl
the release by certain tumOr celis of substances
chemically a nd biologically related to PTH ; (d) the
2
evidence for neural regulation of secretion; (e) the
difficulties invol.'ed in defining ·'the target organ'·
since PTH roportedly acts On more than one kind of
bone cell, both proximal and distal tubular compo-
nentS of the kidney . renal cells conlributing to the
metabolic activation of vitamin D. mammary glands
of mammals and vertebral lime sacs of frogs, thy.
mocytes. some bone marrow components, the
smooth muscle of arterioles, and corneal cells; and
(I) obse rvations Ihat PTH contribu tes to the regu·
latlon of funct ions primarily controlled by other hor-
mones. The lisl indudes appetite a nd food intake.
acid-base balance, the renal of sodium.
water, and other substances. neuromuscular excita-
bilityand brain neurOn activities. and the secretion
of several other hormones.
The endocrine components of Ihe pancreu pr0-
duce major regulators of carbohyd!'3te, protein. and
lipid metabolism; and destruction of the islets has
fatal consequences if no replacement therapy is pro-
vided. Vet the islets weuld face certain rejection by
an admission. committee that adheres to traditiona l
criteria. Each islet of a typical mammal contains
same cells that secrete insulin. others Ihat relea$C
glucagon. and dilTerent ones that make somatostatin
(55) (107). In addition. many islets have cell, that
produce pancreatic polypeptide (PP) (24, 41) and
some may also relea$C gastrin (8.123 ). Insulin , glu·
cagon and SS exert loculiu d comrols Over functions
of neighboring cells (witheut benefit of transport
through the bloodstream) (1 07. 109). Moreover, SS
is made in Ihe hypothalamus. the thyroid gland. the
gastrointestinal tract . and elsewhere. Glucagon-like
molecules are sec reted into the bloodstream by cells
of the gastrointestinal tracI and they arc also found
in the brain. while peptides wilh insu lin,like activity
are present in the blood of pancreatectomized ani-
mals. In common with most (and probably all) hor-
 mone-sox:reting ccll$, the islet$ are oontrollcd in pan
by Ihcir innervalions.
The hypolhalamus is a component of the brain. It
oontains respe<:lable neurons Ihat commu·
nicale wilh other neuron$, dcvelopaclion polentials.
and rclease (82). Yet it i. One of
Ihe richesl sources of bloo<H,orne regulato",. lIS rep-
ertory includes vasopressin (VP. which travels 10 Ihe
kidney but also actS on the pituitary). oxytocin (besl
known (or its .rreets on the uleruS and mammary
glands). and sc"eral hormones thaI Iravel throogh a
restricted portion of the circulatory syslem to main-
tain the functions of the adenohypophysis. Mosl of
Ihe hypothalamic secretions act at onc site as her·
ll'IOIles and at others as neuromodulators Or neuro.
transmitters (27). For example. dopamine regulates
both neuronal functions and Ihe secretion of some
pituitary hormone. (124). Many molecular species
arc oommon to the hypolhalamus and the gut (38,
18.93).
Structures thaI have nol ocen lraditionally asso-
•
, •
Fig. A. o! "'Y'oO;I gtaod. (1)
LoOOIeS. (2) ""Pto, (3) l<>llicles. X23 . B. s.gmMlI 01 rol
thyroid gl.od . .ttct,on mier_op'" ( I) L.,II'" loll"' .... (2)
"""'" l<>lti(:le'. (3) <;<>n<>tCt<vo 11 _ _ , " . (4)
".",Ie.
pafal<>llicula, calli. (5) .rteriole , (6) (1)
Iympholic capill...... (6) blood Cllpilla"*_C. <>l ,.t
IhYfoO;l l<>ltiCle. """"ron mIcrOgraph. ( I) CollOid in con"" 01
dated with the endocrine sYStem but are now known
w contribute 10 hormone production include the
skin. liver and lungs. the .. Iivary glands of some spe-
cies (9,12.34). the extrahypothalamie brain (21).
thc retina (10). and cv<:n the mammary glands (I 7).
The importance of adipose ti ssue as a source of es-
trogens has rcccntly lxcn re<;Ognized (sec Chapter
15). The abili ty o( tumor cells to make a wide vari.
cly of regulawl"S contributes to a growing oclier that
all have the potential for synthesizing and
releasing hormones.
IDENTIFICATION OF HORMONE·SECRETING
STRUCTURES
Morphologicol studies of whol. organs provide few
guidelines for Ihe identification of endocrine glands .
The ceU. that engage in the biosynthesis and release
of thyroxine (T.) and tri.iod01hyronine (TJ) are or-
ganized (Fig. 2.1). while {hose produc-
ing parathyroid hormone form cell cord5 (Fig. 2· 2).
.'
•
•
..,
"
1001i<:1e. (2) .....,...; 10 foIli<:uIa, epit ..... 1"",10. (3)
pe<il<>llieul.r ""pill.ries. (.) pooit<>lli(;ul. , _ s <>l
coltagenOUS (5) nuclei 01 IbrODIa.t •. X 1600.
(RI>odin, ,e!. 67) D. .. ota;r>e<! C celli ...
11>00 thYI'<)M:! ot a rn ... ,.f.
C CtH •• ,. identified by
.rrOwS. X33. (\>tong end Go",,,,, rei . 79)

Fig. 2· 2. Top: H..... n pa,all'lyroicl gland. ( I) Fat call •.
(2) cIIiet call •. (3) OX1Ph11cell •. blood ""pi""....
X200. Righi : mia__ ph survey 01 cords of calls
in paralhy'o-kI gtll.l. (I) Fal celt •• (2) chief celis.
(3) oxyphil celli. (_I blood ""pin.'... . cor.-"",!ive
II..... $81>1 •. (R_in. "f. 87)
Calcilonin i$ secreted by organized. innervated
struclu res in many of the vertebrates; bu t most of
the calcitonin in mammals originates in scattered
cells that lie between the thyroid follides Or are sit·
ualed alons lheir peripheries (FiS. 2·1). A peplide
chemically rolaled 10 calcilonin may be prescnl
in pituilary cells thai are quite differenl in
appearance.
The endocrine lissue of Ihe pancreas is organized
into islets ne$lltd amons Ihe acina r components.lhal
manufacture digestive enzymes (FiS. 2·3) , However.
PP is made by acinar regions as well (24).
Three differenl arrangements of sleroid hormone-
se<:reling cells can be found in Ihe adrenal cortices
of most mammals: whorb or glomeruli situaled be-
neath the capsule. cords or fascicles in the middle
region, and a nelwork or reticulum closest to lhc me-
dulla (Fig. 24A and B). The cellsofth. adrenal me-
dulla that secrete norepinephrine and epinephrine
relain some of Ihe characleristics of Ihe neuronal
elements from which they were derived (Fig. 2-5),
but they lack axons a nd dendrites.
Although the biochemical pathways for the syn·
thesis of adrenocortical and sonadal steroids are
sim ilar. Ihe cell arrangements of the organs are quile
different , Androgen-secreting cells of Ibe lestis lie in
dumps near tbe peripheries of Ihe seminiferous lU,
buies (Fig. Hi). Most of the progesterone lhal en·
lers Ihe bloodstream of females is made in well-de·
fined C<lrpora IUlea cf Ihe ovary (Fig. 2·7).
Granulosa cells of ovarian follicles lake up andro-
sens supplied by neighboring cells and conven those
steroids 10 estrogens.
ORGAN IZATION Of' THE ENDOCRINE SYSTSM
•
Oxytocin and vasopressin originate in hypotha·
lamic neurons thaI have large perikarya grouped
into easily rerosnizable nuclei and very long axons
thai travel in bundles to lhe neural lobe of the pitu·
itary gland. Different hypothalamic hormones are
made in small ncurons. "Gastrointestinal" hormones
oome from celb Ihat are isolated Or collected into
small grouJl5. Some of the "gut endocrine lissue"
shares embryclosical oriSins with cenlral nervous
system components (78).
Cells thaI makc prolein. peptide. and amine·type
hormones store their products in
dosed granules. However. granules are also found in
nonendocrine cells. Moreover. steroid-sccreting cells
lack such orsanelles. They accumulale lipids in
droplets bul do not build up substantial hormone
reseT ......
It ;s often pcMible to identify hormone«cr",i"g
cells by adminiSlering specific anlilxxlies directed
against the regulators and ootinS Ihe attachment
siles (126). It is important to recognize. however.
that (3) Ihe anlilxxlies sometimes fail 10 gain access
to Ihe binding si tes; (b) the antibodies can auach to
other molecules thaI ha ve :;orne simi lar chemical
groups; and (e) hormones made by one cell Iype can
be laken up by anolher. Microoisseclion procedures
 , , T- •
." .
-,...-,.,... .
,
.
. ..

..
.

,
'-
Fig. 2_3. EleC1ron ""''''9I.• pn oj edge of 1M! 01 (8) nucl_ 01 ( 9) nuclot 01 C coi l• .
l or>gertoanS. '., pane'.... (Pion. oj MICI"" jM;cale<l by. 01 "'" Iy,,"" II baSe<l on .Mly'" 01 Ih" fiOld
in io.., .) (1) lu"""" 01_ capin.ri4rs. (2) _ II 01 . , N\ll>er" "",gnificolion •. X .500. inN(." " '" oj l ll'lQ8'hons.
""",II>oli. , (3) nucleus oj peric)'ll. (.) noclei 01 homl n poner .... (I) Cord. 01 coi l. in _ , (2) c<>llapSe<l
(5) b<o>dIN 01 collagenous fiDrils. (6) r"tU<:IfIi 01 _ capill.,ie • • (3) .ciol oj peniotl 01p,I"""'.',
Ilphl (glo.>cogon) (1) nuclei 01 betl (;"suI"') e<oHo. (.) pt . ... 01HCliotI. X 1110. ( _ n. ,.1. 87)

haye CQntribUled to the ability 10 identify regions of ENDOCRINE FUNCTIONS OF THE

the brain thai contain regulators Or the enzymes reo
quired for their biosynthesi s (II).
Not all hormones are made in cells. Angiolensin I
is formed in Ihe bloodstream when renin (an en·
zyme) is released from lhe kidney to on a plasma
protein (renin substrate) made by Ihe her. The sub-
strale has been called a hormoncgen. A different en-
zyme in Ihe lungs converts angiotensin I to angioten-
sin II.
HYPOTHALAMUS AND PITUITARY GLAND
Fun ctional Anato my of tha Hypolhelamu8
The hypothalamus is a bilalerally symmwkal
organ that forms the Aoor and lower walls of the
third ventricle of Ihe brain . The portion of
the Yenlricle Hoor (Iuher dlltreum) leads into the
funnel-shaped Jlalk. (infundibulum ) from which the
pitu itary gland is suspended (Fig. 2-8),
 FlII.2""" "To,", $cooMing" " ""
............ """ 01 "",,,'iofl _ . " ...
,_.'M.... (Zl')ot" ....,_x.
:r<lftOI (lG) _."...,..

XS30. Bo"o ... , S"_01 .......

, .. iaoIario .. _
......... _ 01 .....
.........."'*'
by _ . - ""'" 1Orm.
IIMIeuIat pIe'UI (AP) , (lI_
S K.,<Ion . '-'. S: CION _10001
_ . _ , 01_ 01.",...,. _'Y.
sI\o";nv di... _ 01 ,r.. cot! •• Inlo thr. .
.,.,.",..,tr;c .onet. )( 100. (Lor>g, ,.t.

,
I

•
"

F ig. 2·5. Ro' , '''_, medullo •• ""tfOn microg,aph. ( I )
... ",1 .... M ... _.... CAli. (oJ
cell. (3) cor_ oj cOlI tlfIlOngi"ll to ,""" ,"'iCulari$. (4)
eapdlary lumen. (5)
_ h e l i . l ",,''''. (7) intercollu!ar spaco. (e) .......
..,dings. X.!5-00. (Rhoc!in. ",I. 61)
axons. The two kind. of molecules are later relcased
into neural lobe capillari.s that lead inlO the sys-
temic blood vessel •. The neurophysin. are believed to
originale from precursor molecules Ihat also give rise
to lhe hormones. No physio1osical functions have as
yet ocen established fOf the neurophysins.
The impre .. i"" wu at one lime gained that att of the
VP i$ 'ynlht$i,ed in diserele. dearly demarcal.d su-
praoptic nuciei. ,nd th.t all of Ih. hormone act, primar_
ily on the kidney to promote water con.er •• tion. Simi_
larly. il was thought that all of the oxytocin j, synthesized
in the p..... v.ntricul.r nudei. and that it acts extlu.ively
On the uteru, and mammary gland •.
It i, now recognized Ihat VP i, additionally made in
difl"use el."... of neuron, Iocaled bel" •• n the promi_
nent. bilateral . uprooplie nuctei (SON) and at.., in otbcr
part' of the brain (1 4). The hormone arreelS learni ng and
memo.y (t 6). and it probably acts cent .... tty a. wett a.
peripherally 10 inftuerote Wlller bol.nce (21). VP derived
ilS name from observation.th., high concent .... tion •• tim·
ulate the . mooth mu.cle of the blood v.... I•• and ;1 is
tikdy that phy.iotogicat level, perform $0"", rdated
funelion •. The non, of $Orne SON neuron> terminate in
Ibe vieinit)" of Ihe pars intermedi. of the pituitary gland.
of sped.. thal pOs'." such >lructur.,. Othe.. release VP
into blood """.1, of the "",dian eminence. and they con·
tr ibute to regutation of ACTH se<:rttion.
While Ih. parav.ntric").. nuclei (PVN) .upply much
of the oxytocin that ente .. the peripheral blood. $Orne of
,h .. peptide i. mad. in 'he SON. Oxytocin i. believed to
$C . . e .. a prohormone. ,;nee it <an be <le,,'cd to .m.tter
0' ""'..."...."....,...
peptidesthat atreellhe ..cretion of pars inter"",dia hor·
(6) monc1. l! , tOO, i. made in thc Ul .... hypoth.t.mic brain. in
which it ,eemS '0 f"rotti"" a. a neuromodutalor. The
PVN are also sources of .eg"lators that afTect pituitary
gland secret'On of fottict ... timutating hormone (FSH)
and of thyroid·stimutaling hormone (TSH).

In the region above Ihe infundibulum. Ihe large

cell bodies of specialized neurons an: grouped into
while clusters of smaller peri_
karya enter into the formalion of parviullular (par-
vocel1ular) nudei. (83)
THE MAGNOCELLULAR NUCLEI
The supraoptic nuclei (SO of Fig. 2·9) are localed
above the opLic chiasma (OC. the crossing of the
optic ncrves). The parowmlricular nuclei (rV of Fig.
2-9) are dClSC to the third vent ride. Bundles of long
axon. (the hypothalamrrh}"flOphysial tracts)
connect the nuclei with the neural lobe of the pilu·
ilary gland .
I n mammals. the hormones syn thesized within the
nuclei include vasopressin (a nlidiuretic hormone)
and oxytocin . Those regulators are packaged. ' klng
with specific proleins (neurophysins [14.91. 97,
115]) into large granules that travd down the long
THE PARVICELLULAR NUCLEI
These are less well defined. and they contain mOre
heterogeneous cell populations. Hormones synthe-
sized in the perikarya arc sent down relatively .hort,
fone that project to the eXlernal "lOne of the
median eminence and terminate close to the blood
vessels of a specialized compartment of Ihe circula-
lory system known as the hypothalamohypophysial
flONal system (HHPS). The hormones (which are
sometimes called "release faclOrs") travel through
the blood vessels to the pars distalis of the pituitary
gland. They play important roles in the maimenance
of the st ruclures as well as the secretory functions of
Ihe pituitary gland. The group ineludes thyrotropin-
rdeasing hormone (TRH). corticotropin·releasing
hormone (C RH) , luteinizing hormone-releasing hor-
mone (L RH), and growth hormone·releasing hor-
mOne (G RH ). The arcuate and ventromedia l nudei
(AR and VM of Fig. 2·9) are major sources. I\. sim-
 ORGANIZATION OF THE ENDOCRINE SYSTEM
"
,

,,,,.
«11

malo_
goniurn
cdt
Sot/oil

'"'

P'imarll
.,..m(J'·
ocgu in
mil.,.;.

S..,oIi Cell'j
<>I
,'''m

Fig. 2-e. S<!c1iOn Of humIIn tesli. (ob1a;".,.a ., operation),

Tile Ira n_led WW •• $how v.'""'. Sla \lOS Qf
•. X 170. (AM_ .... A . Max/mow.) (81oom

plified version of the interrelationships between the
hypothalamus and the pituitary gland is shown in
Fig.2·}0.
THE MEDIAN EMINENCE
to the outermost zone. which <:<lntains the ve!.sels of
the hypothalamohypophysial portal system . The
cells (taneytes) have been implicated in the transfer
of materials between the cerebrospinal Auid and the
capillaries (43).
2. The ()f' fibrous zoN' <:<lmains the

The bulging upper end Qf the infundibulum is known
as the median eminence (MEl. It surrQunds an ex-
tension of the third ventride (the infundibular .e-
c<:ss) that is filled with cerebrospinal fluid. Three
subdivisions are
l. zone or intll'r surrounds
the cavity. Specialized e<:Us of this region se nd pro-
cesses inlo the infundibular r = and others
axOnS that make up the hypolhalamohypophysial
nerve tl'lleu. The term i'lj"ndibU!Q' Siern refers 10
the exclusively neural portion of the infundibulum.
It includes the middle layer orthe median eminence
and the lower extensions of the nerve tracts.
3. The external/oyer ()f' palisade zane <:<lnlain! Ihe
hypothalal1l()ohypopophysial portal and fine
fibers thaI form the wbero-injlmdibular nnw !raelS.

Cop,.,.
0' ,.f."",
•••pu.
BI.od ......,
,
Fig. 2·1 . CfO •• S/lClion of .,..-ipMt.1I.y,", of h"",.n
oor"". Mourn or Plegnof"lC"l. st • .,., """ ,.,leul., ' ''"'"
rho 9ielsehowSf<y meIh<>d. X23S. t ...1t...... .... Ma x"""",. )
(Bloom a F. v.<ee1t. ,et. 7)
The laner conlain axOnS of parvicellular neuronS.
They receive projections from the anterior pcriven·
tricular. relfochiasmalie. and posterior parts of the
hypothalamus. from the thalamus. and from the
amygdala, in addition to branches of the hypothal·
am<rhypophysial nerve Iracts and ascending fIbers
from the midbrain (86).
This zone is therefore rich in h)'po(ha/amic hor-
mOMS. (from both parvkellular and magnoce!lular
nuclei). in (some of which originates in
the hypothalamus). and in (norepi.
neprhine as well as dopamine) arriving from the as·
cending fibers. In addition, tile region contains high
oonccntration. of pituitary hormo""s. which appar·
ently ascend via the portal vessels (4).
Additional details a re presented in Part Vl1.
The Pltultery Gland
The two major subdivisions differ from each other in
structure, functions. and embryological origins. The
adeMnypophysis. Or gland ular portion (pars glan.
,
"
dularis), is distinct from the hypothalamus but
makes functional conne<:tions with i\ via the portal
blood vessels. It contains cells that symh.siu and se·
crete hormones. The neurohypophysis. is an exten·
sion of the hypothalamus . It does not produce hor·
mones. but it MoreS regulators formed in the
magnoce\\ular nuclei. and it releases those JlCptides
into (he systemic circulation. In addit;oo to axon
endings and capillaries, it oontains pituieytes that
may be a sJlCcial kind of neuroglia (Fig. 2-11) .
Pituitary gland morphology varies widely with the
species (42). He descriptions that follow contain
generalizations that apply mostly to mammals.
THE ADENOHYPOPHYSIS
This portion of the pitui(ary gland ,j(ve\ops from
Rathke's pouch. a structure ini(ially associated wit h
the roof of the embryonic mouth (see Chap. 19).
Until recently. most investigators believed that (he
pouch was form ed "elusively by buccal ectoderm.
A few. however. championed the concept that the se-
 OR(JANIZ/ITION OF THE ENOOCRINE SYSTEM

. Me<lian
.. eminence
In/uMibuium
cinereum
_ _ _ _ InluMlb\Jlar
\\,\,

F'oslerior
Fig. 2 -6. Top : Rough cj;aQlamm.tic
a n<!
p;luitary QI&n<!. Bonom :
• • nd
MUrohypop!1yl il .

'"
, FIoo< 01 " , od . On1"C I.
hube, c,,,,,,ouml
... tube,ah •
• m",.nce

erctory cells derive (rom neural oomponents that mi·

grate to the at a very early The concept is
,
now strongly supported (see lalor discussion of
APUD cells) , The adenohypophysis bu Ihree sub-
divisions (Table 2·1). Par. ,0,
I. Tilt paF$ dis/alis by fa/ Ihe largesl comp<>-
nent. The lerm comes from Ihe location, since Ihis
part of Ihe pituitary is fa/(hest from (most dista l to)
Ihe brain. The cells that synthesize and release hor·
Fig. 2·g. Diagrammatic repre ... ta(!on oj hypolhlllOmie
mones associa ted with the "ante rior pilu itary" or Ali, a n'trior h)'lX>!hIIlami<: : AR. ,'"",,'e; DM.
"anterior lobe" reside in (his region, and each cell dOrIOm6CIial; OC, optic CIlia."..: PH, pc>olarior
type is named for its secretory product (see Fig. 2· I>ypotlralamie: PO. preoptic; pv. SCH,
12 and Table 2-2). ...",.. ChiII ..... lic; SO, suproroplic; VM, vonlr"","",i.. l.
 ""
'""
""
G'"
"
."
'"
HyWhalarno-
"""
.essels
Fig . 2· to.
on ,1>1 gl_tld, (3M 101>10 2-310< t<.OlM ...... 01
hOrmono •• )
The cells were initially studied by light micros-
COPY and classified as either "<:<Ilar·loving" chromo-
phils containing granules thai lake up dyC!5, or
"color-fearing" chromophobes that lack such organ_
elles. On the basis of differences in morphology and
staining Characteristics. several kinds of chromophils
were then defined, and a Gl"<'ek lelle' was assigned
to each.
Information on the associated hormones was ob-
tained by observing lhe morphological changes thai
acoornpanied naturally occurring evenls such as
pregnancy, lactation. the phases of Ihe ovarian cy-
cles, and Ihe seaonsal varialions in reproductive
organ Functions. Additional data were derived from
animals subje<:led 10 thyroide<:tomy. adrenalectomy.
and other manipulations of the endocrine
Since certain cell tYP"$ are clustered within defined
regions of the pituitary. the glands of large mam·
mals could also be sectioned, extracted, and used for
hormone bioassays. A different nomenclature was
then introdue<:d. For example. the {J e<:lIs most ob-
viously affe<:led by thyr()idect()my and thyroid hor-
OXYTOCIN
""
""
VASOPRESSIN
Hypoltlal.m<>-
hypophy"aI
"""'" ,rae"
.... sion 01 hylK"""'-"""
meme administration were called thyrotrophs (since
horm()ne was then called thyro-
trophin). whereas the {J cell$ believed to se<:rete gon-
adotroph ins were called gonad()lrophs.
More re<:ent studies with the electron mic!"OSCOp"
have markedly advanced our insights into the rela·
betw..,n nl()rphology and function. and
they have made it possible to identify additional e<:11
typ"s. Although thc findings support many of the
cone<:pts developed by the light microscopists. it is
oow recognizcd thai the formerly highly respocted
"one cell type-one hormonc" hypothesis is no
longer tenable. Two or three different regulators can
coexist within a e<:1I. and even within the same se·
cretory granule.
The suffix ""troph"" implies nourishment. It is !lOw
regarded as inappropriate, and it has been replaced
by ""lropo" which indicates "'attraction to". Thus. in
the current literature, TSH is called thyrotropin.
and the cells of origin are known as thyrolropes.
The cell types of the pars distalis are described
briefly below and in greater delail in ChapteT 19.
,

., .. .,
1
.. -,; 1
r I 1 \,
,

FIg:. Z_l1. Deloil Ol the 1>0. ... ot ..,. f.' """,o/lypophyoll. ot ( .) nuclei of , _ ••,., (5) """'.
..... by intr....cu4ar peliusion, mier<>vrAp/I. ( 1) P«>OO ...... (6 ) Herring 1>OdiO • • X 1900. (_in. "'t. 6T)
Cop;llarIM ( ..... ooid.l. (2) (3) ...,..;

TOIIle 2· 1 Sut>dii.')(II OItI>e Hypophysio ond ThW ReIoIionstOps 10 tI>e..."._ 0tId _ _

NuitaIY GI.>da

M.d,," <min<n« Po" of hypolh.lomu.

No. roh),l"'ph),.i< H)'I"',no l. OIOhyJ>O¢),>I.1 r." oI" inrundibolum
no"", Ir.clS
:-: •• ,.1 lobe
""',<rio< pi,.ilO'),
= Po,. inte,med i.
P." ,ube ",l i.

Pu, di".li.
 Fig . 2· 12.$&<:1;0" 01 '"t , n'orio< pituitlry gland. Arrows
poInl10 granulolo(llngcl., eell. w;lh .".,...,"ic
X600. (ForquNI, et al., 'el. 23)

C<l1 Typo: A$>O<,,,<d Uormont>(.) M"" Otw.,.. Fo",,';""

Thyr<>l1Op< ThyMd·"'mul ... ", 1Iormon< (TSH.
I hyr<>l ropi n, I hyroll<>!'hi n)
CorticotlOp< (oorti«>lroph. AdrcnooorliCOlropic horm<>n<
oorticotipOllOp< ) (ACTH.oor,;COIrop;o.
OOt,icotrophin,: .Iso lipolropins
.nd
Som>l"'rop;o!>or"","" (STH .
hormon,)
l-,"e,,,,1Op< (laCIQlrop-h, P,oI.c,in ( PRL. l.e'OI"",ie
mommOl,,,,,h) ho, mOn<. 1.01or rop; n.
mammo1,,,,,in)
FOil"," lo11opO (foll","101 roph) foll;cle->I;m ul.. i", hormortO (FSH.
foll;'ropin)
L.,,,,,,ro,>C (Moo""ph. Lutein;,inl!>or"""", (LH,
in'<r>li'''''roph) in,m,i,i.1 ,<II·,, ;mu I"i n,
1>o<m<>n<.ICSIt.I.'ropin)
ChromopOOb<
Follicular «II Id<n, ifi<d by doe,,,,,, m",_y: ""
1Iortl'>MO: "" «I.. ion,hi?
to follieu l"'""""
Sem'"," of 'hyroid
I'''''th of ,hy,oid ,I,nd
Sec'<lion of .drcnooonk.1
ho<mone/.; , ,""th
of.d", .. 1 oort .. , ... lQ
pain and "'e>:>
G""'th of ;mmot"'" . n;"",!>
G,_h of "".. i.n fol l;el.... n"n«d
""fO!On ,«,.,;0" in f<molo>;
matu,ation of Se"ot; coli •. VO"'th
of ",minif""",. ,ubule> in m, le.
Promotes ""u l.. ion, formalion of
"'"I"" I.,,,um. "'OI",ion 01
" '",,"0 ond p''''..,....... io
fem.le; Il"OWlh.nd «<t<><tcronc:
"" "'tion by ;n'm!;1 ;.1 «II. of
,..,i.i. "", I.
May be ;mm""n: p«oul$O<of ,he
.bo,. or , "",,,nulate<l «II 'hot
h.. di",h..,.d hor"""", Of b
""",,,,,""i ng
_bay"", dir<ot I1''''''I.d in
,«ro 'i""
 • •• •
"'., ,
,1:'<,.

-,
•
,• •
• •
••
3 '\ .
,
3 • .'.....,
."/ "-

- .'

..
Fig. 2_14. tete: (AC) YIOwing RighT : Somo.If""" (ST) OhOwir>g """"""". "'<911 MCr.tOfy
NC,. tory gra"""" a lig..-l "'- pot_.",a membra ... granulU. X 7000. ( _ ..... a Marlin. ",I. 3)
" cy!opI"smic ,,",00&,' i• ..,.., IHttwMl> twO Othe, c.llo. X
4S00.

CHROMOPH ILS physial hormones (36) . They also affect pain thresh-
olds. and they may be of pleasurable
Thyr()(ropes TS H in very small granules sensations (99). The term ·' lipotropin" implies a fat-
that are along 1:<'11 (Fig. 2- mobilizing funelion. but these peptides are believed
13). promotes growth of thyroid 10 serve primarily as precursors of other regulators.
gland follicles and secretion of T. and T J. SomalOlTOfMS are usually the most abu ndant of
COrliCOITOfMS are exceedingly difficullto identify the pars dislali, cdl •. are noted for their nu-
the light microscope. since they have highly merous and prominent secretory (Figs. 2-
irregular contours, long processes Iha t par- 13. 2-14, and 2-15). Their major product is !H)W
tially encircle ne ighboring cells. and conlain very called growth hormone (GH). but in the past il has
small granules (Figs. 2-13 and 2_14). They synthe- been as somatotropin (somatQtropic hor-
size large proleins (pro-opi<)..me]anOCQrtins) that arc mone. 5TH). The most obvious inn.cnces are ex·
subsequently cleaved to yield ACTH. erted on Ihe long bones of juvcniles. but GH also acts
and other biologically potent peptides. As its name di",c\ly on liver, skelelal muscle. adipo&C tissue. and
implies, ACTH stimulates the cell, of the adrenal other structures. It promotes Ihc ,ynthesis of soma-
but thc Same (or a chemically similar) pep- tomedin" that arc widely bclicvc<:l 10 me-
tide is found in Ihe brain. Endorphins diate many of the effects On skeleton .
morphine-like molccules) are released inlo lhe pe- LaCIOlropeJ are among largeSI of pituilary
ripheral blood along with ACTH during limes of cells. and their granules show the greatest variations
Slress. They. too, are made at OIher sittS. Endorphins in sizes and shapes (Fig. 2-13). They are numerous
are impliealc<:l as regulators of secretion of in the piluitaries of laetaling mammals. and the pro-
growth hormone, prolactin, and other adc!H)hyPCl"" lactin (PRL) they pmue. is best known for its

•
F!g. 2-13. Section oj ,ot &d«IotIypoptlysil, tIee1,.,... $Omoto""",,>. of martlrl'lOlr<>p8. (6) nUClei of
ml<>"oQo"oph. ( 1) NtIC""'. oj """ITat)' _ _ ;al cell. (2) lhyrot,"PM. (7) n""IOoi 01 o<I<ooooo<tiootropN. (8) nudfli
co.p;HOry rn..n. (3) int.. cOllular _co. (4) """IOoi of 01 chromophob/t pr"""_ collI. X5300. (Rhrxlln. ref. 87)
 ORGANIZATION OF THE SYSTEM

Fill. 2- 1 5 . ll'IrM oomalolrO!>H (ST) af'>d pa rt o! 1"-

cyloplaom o! • lhy,Wope (TT) Irom cell "'openoion.
'"""on mIcroOr'ph, X 10,000. (Farqohar. el .r., r. f. 23)

fe<:(s on (he mammary glands. lysosomcs rapidly
deplete the hormone contenl soon afler the infanls
stop sudling (23).
PR l performs many other functio!!S, including in·
duction of hormone receptors in the gonads, In rats
and some other mammals. PR l i, ne.ded 10 main-
lain the corpora IUlea of pregnancy. It has therefor.
been called luteotropin, The term '-lutootropc" has
been applied 10 laetotropes_ bUI it can be misleading
(since no comparable PRL function has been dem-
f ig. L.fI: Pa,ts oj cytoplasm . nd 01 a
\IONI<I<>l,ope (GT), On FSH--=notiog cell.
o<!iaooot to • ""pinory ium,"", X 1200. Right: Gona<l<>t'_
on'lrate<! for Roloo in the facilitation of
maternal behavior in rodents. and in thc regulation
of fetal salt and water balance in many of the mam-
mals have been proposed (48).
PRL stimulates the crop sacs of birds. and it in·
vokes the "watcr-<lrive" that precedes mating in am-
phibians. A related hormone (paralactin) permits
some curyhalinc to adjust to low_saline
environmcnts.
produce fSH . which stimulates
growth and maturation of the ovarian follicles. and
luteinizing hormone (LH). whiCh is needed for Ovu-
lation and the formation of corpora latea, In males.
fSlI aCIS on Ihc scrtoH cdb of the testi s. Since LH
promotes Icstosterone biosynthesi s when it acts on
Ihe interstitial cells. it is sometimes called interstilial
cell stimulating hormone ( ICSH).
According to SOme observers. one kind of gona-
dotropc (the folliculotropc) makes fSH. while a dif-
fcrent kind (the interstitiolropc) produces the LH .
Two cell types "'ilh different tnorpoological features
have been deserihed (Fig. 2-16). However. it has also
been suggested thai a single type of gonadotropc can
undergo both structural and functional changes and
produce either of the hormones. Some of the cells
bind either anti-fSH Or anti-Ui. but othors take up
both of the antibodies, The oomrovorsy is discussed
further in Part V.
(GT) . prUIJmol>ly oj LH type, wifl'lrorge oi ....n •• Ollhe
endopI"""'" , lOt""",,",. X to.2OO. ( _ .... & Martin, ,-'.
"
CHROMOPHOBES
Electron microsoopy studies support thc belief that
cells identified in this way under the Hsht microscope
comprise three subS roup'.
Trllt rhro",ophobes shar<: many with
but they totally lack granules. Some
may be chromophil precursors (stem cells) that have
not as yct acquired secrelOry granules. O thers are
thought 10 he chromophils Ihal have been depleted
of their hormone content or are undergoing
degeneration.
may be hormonc-se-
crcting cells whose granul.s do oot up under
thc light microsoope bocause they are too fine. 100
reI" in number. or unable to bind the Siains (lOS).
Follicular n ils surround small. fluid_filled spa=
(Fig. 2-17). Since Ihey lack secretory granules but
contain numerous their function may he
destruction of chromophils that are present in
sive numbers Or are undergoing degeneration .
The adenohypophysis inHuences target organs in
ways that cannot be attributed to the hormones cited
above. Some evidence has boen presented for the se-
cretion of a regulator that actson the adrenal corlex
to promote androgen production (76). and for the
release of a different stimulant that affects the
parathryoid gland (57). The cell types that
.. ORGANIZATION OF THE EHDOCI< INE

Fill. 2- 17. Ct..le< 01 f<>1Iicul." c.I. ( Fe), The c opill.ry som, '01r"PO' (ST) with;" a follicular cell.
pole of 0<>1 OJ1"" "rgo
C40n" eon1. in •• vacuole Only • thin ,.., of lOllicula, cel l C1'''''''''''' (Cy) ,",rounds
(PV ) w ith gr• ...,... <Ie<i.ed ltom • """, &lc>ry cell. t .... Prepo'.,"" .. to<' FiQ. 2' 15 . X 1I1.T00.
X 10 .200. In • • I: A ".cuoIo (pv) containing . ( Farquhar. 101 '1 .. ,ot. 23)
 produce the prop:::.scd regulators have not
identified,
2. The pars tubera/is extends upward from the
pars distalis toward the tuber cineream. and it usu·
forms a collar around Ihc median eminence
(Fig. 2·8B) . The portal blood V<'ssels pass through
this region. and it is n(lW koown that pituitary and
hypothalamic hormones trav'! within them in both
directions (4). According to at lust SOme ohservers,
the pars tuberalis also contains ceUs that seercte
hormones.
3, The pars imermedia forms at the points of con·
tact thc dcveloping pars distalis and the
neurohypophysis. but in the mature gland this por-
tion is usually separated from the neurohypophysis
by a cavity (the hypophysial or residual cleft) . Thcre
is evidence for an inductivc inlluence of hypotha-
lamic anlage on the differenliation of Ihc glandular
cells. (No pars intermedia is found al any slage of
development in birds, or in whales, porpoises. and
other mammals in which the pars distalis fails to
make early contact with the !loor of Ihe brain.)
In many of thc mammals. the pars intermedia de-
velops into a large inlmnediate loIN, This parI of the
pituitary gland is especially prominenl in camels.lla·
mas. and other animals noted for Iheir resistancc tu
dehydration in arid environments,
A pars inter media forms in human and other pri·
mate fetuses. It may play roles in the regulation of
water and electrolyte balance (32), and in develop-
ment of the adrenal cortex. The structure later be·
comeS and it is represented in thc
mature gland by pars intermedia type cells that
are seattered within the pars distatis and
neurohypoph)'sis.
In mammals that have inlcrmediate lobes. the se-
crelory cells are mcianotTOpeS. They make melano-
cyto-stimulaling hormones (MSHs. mclanotropins.
intermedi!l$) thaI act on chromatocyles 10 promOle
the production of melanins. The hormones thcreby
affect skin. hair. and fur coloration.
ACTH Can be cleaved to yield .... MSII and a pep-
tide known as eLi P (cOrtiCOtTOpin·likc intermediate
peptide). Different regions of the protein precursor
of ACTH contain the amino acid sequences for /3.
MS H and for other peptidcs Ihat affect pigmenta·
lion (63). The hormones thaI regulale this function
in humans have nol been identified. It is known.
however. thaI Addison's disease and mher conditions
associaled with excessive production of ACTH can
cause skin hyperpigmentation. Human fetuses make
MSHs and CUP. and roles in the regulation of the
fetal adrenal gland have been ,uggested (13). MSHs
are made in the brains of human aduhs, and they are
believed \0 function as neuromodulators (16, I 03).
The pars inter media may also release endorphins.
Calcitonin is said to be preSCnt in all partS of the
putuiwy gland (15). but secretion inlO Ihe blood-
stream has not been demonstrated. The VP found in
the pars intermedia may get there via the hypothal·
alOO-hypophsial OCf\le tracts. (Delivery by the portal
blood vessels is doublful . since this region is poorl)'
vascularized.)
Poikilothermic vertebrates have chromatophores
with moveable pigment granUles. and in many of
thesc. MSH promotes granule dispersion . In certain
of the fishes. amphibians. and repliles. the pars in-
termedia fuses with the neurohypophysis to form a
ltf'ur();ntermedia1e lobe.
THE NEUROHYPOPHYSIS
This division of the piluitary gland develops from thc
noor of the cmbryonic brain. It is made up of Ihree
components. two of which are also parts of the
hypothalamus,
The neural lobe (infundibular proccss) is some-
times referred to as the posterior pituilary or posle·
rior lobe. It is the bulbous enlargement of the distal
end of thc infundibulum that contain, the awn end-
ings and pituicytes, The prominent collections of se-
crelory granules that arriV<' from the hypothalamic
neurons have callcd He"in! bodin The infun-
dibular stem and median emineMt Were described
above.
"AnterIor" end " Posterior" Pituitary Glands
When the ventral surface of the pituitary gland of
an experimental animal such as the rat is exposed.
and an attempt is made to separate the adenohy_
pophysis from the neurohypophysis. the break occurs
at the wcakest point (i ,e. in the vicinity of the hy-
pophysial cleft belween the pars i"lermedia a nd the
neural The portion of Ihe gland closC.!t to the
invC.!tigalor (and most casily removed) is the "an·
lerior pituilary'· . It COnsiSlS of Ihe pars distalis plus
some of the pars tuberalis. The ··posterior pituitary'"
which is comprised of the pars inter media, the
neural lobe, and the remainder of th. pars tuberalis.
Can then exciscd.
Although ··anterior" and "posterior" pituitary are
cited in elementary textixx:lks. the term. are not es-
pecially useful since the former includes only part of
tlte adenohypophysis. while Ihe latter is made up of
tissues Ihat differ in structure. function. and embry-
ologic origin.
PHYSIOLOGICAL IMPORTANCE OF THE
ADENOHYPOPHYSIS
liypophysectomi,.d animals denied replacemen\
therapy can sUf\live under car.fuUy controlled labo-
ratory conditions. However. their ability 10 adjust to

changing internal needs a nd external environ menl:l
is severely impaired and they rapid ly succumb to ad-
versities that ar<: easily t(lleratcd by cootrois with
healthy endocrine systems, They cannot cope with
marked changes in environmental temperatures (or
with smaller changes that are rapid ly imposed).
They do not withstand even brief periods of food or
water deprivation, the loss of small amounl:l of
blood, or exposure to noxion They cannot
perform that require muscle st"" ngt h
and endurance, and they are incapable of reproduc-
tion and lactation. Young animals fail to grow a nd
matu"". Despite some re.:ent suggestions that hype>-
physectomy extends the life span of animals raised
under idcal conditions. most investigators find that
survival time is shortened.
ENDOCRINE GLANDS REGULATEO BY PARS
D1STALlS HORMONES
ThyrOId Glands
Thyroid gland follicular cells Sttrctc T" along with
small quantities ofT j. Most of the target organs con-
vert T, to T j • which is probably thc active form. The
hormone is essential for the development of the ner_
vous system and for maturation of the skeletal and
reproductive system •. It ""lIulnte' metnbolic rate,
exerts important influences on protein . carbohy-
drate. and li pid metabolism. and affects the fu nc-
tions of the heart, kidney. and liver.
Humans deprived of thyroid hormones early in
li fe r<:main infantile and suffer permanent brain im-
pairment. Thyroid--deficient adults arc sluggish . in_
fert ile, and unable to adjust to changes in environ-
mental tempc ralUres.
The thyroid cells undergo atrophy. and Ihey pro-
duce inadequate quantities of hormones when they
are not st imulated by TSH.
Parafollicular cells of the thyroid glands of mam-
make calcitonin. The need for r<:gulation of the
secretory functions by pituitary hormones has not
been demonstrated .
Adrenal Cortex
The cells of the adrenal COrtex most obviQusly af·
fe<:ted by ACTH are those of the zOna faseiculata
t hat se.:rete glucorort icoids. Cortisol is the major
glucocorticoid for humans, mon keys, guinea pigs.
and some othe r mammals. Rats and mice a re among
the species Ihat make corlicosteronc (which lacks an
OH group present in cortisol). Many othcr mam-
mal. (including dogs) se.:rete mixture, of tWO
steroids.
ORGANIVo TION OF THE £ NIXlCRIN£ SYSTEM
Glucocorticoids arc esse ntial for life. They accel-
erate the conversion of amino acids to glucose a nd
the""by maintain blood sugar level, during times of
fasting. They contribute 10 digestive systcm and Car-
diovascular funclions by maintaining the lonc of
smooth musele, and they act in several ways to suP'"
port the abilities to engage in demanding museular
work and to cope with Slr<:SS. Glucocorticoids addi-
tionally contribute 10 the regulation of wa ler bal-
ance, and they exen inAucnccs On higher brain ccn-
ters and on the thymus gla nd,
ACTH is nceded to maintain the rona fasciculata
of the adrena l cortex and the se<:relion of adequate
quantities of the glucocorticoid •.
Aldosterone is a "eroid hormone produccd by dif·
feret cell. of the adr<:nal cortex. It regulates water
and electrolyte metabolism and is therefore known
as a mineralOC<lTlicoid. The aldosterone-secreting
cells are affected by ACTH and by a pept ide of pi_
tuitary origin that augments the availability of the
cholesterol precuroor necded to make Ihe steroids.
However. hypoph)'seetomil.cd animals retain much
of their abili ty to control ele<:trolyte metabolism.
The renin-angiotcnsin sySlem (diseussed later) is the
primary regula lor of Ihe ,ona glomcrulosa region in
which the aldosterone is made.
The adrenal also ma kes some progesteronc,
androgens. and ACTIi can augment the
production of those steroids, but its abilily to do so
is of limited importance for animals with functioni ng
gonads. (Roles for adrenocortical ste roids in facili-
tation of puberty onset have becn described ,)
Hormones of the Testes and Ovarlas
The gonads seCrete steroids that are most obviously
nceded for reproduction. However. all of Ihe hor-
mones addi lionally affect other InAuences
on behavior are more obvious in rodents than in
primalCS.
Tes(os(e'Wlt and related androgens secreted by
the testis promote the biosyn lhesis of p1'<)\cins, and
Ihey contribute to the prepubertal "growth spurt"
seen in males. They inc""a.e appetite, hasten bone
mawration, enbanee red hlood cell production.
strengthen skeletal muscles, and affect water and
electrolyte metabolism.
Ovarian tSlrogens exerl influences on every known
body cell type. They participate in Ihe control of
bone ma tu ration and calcium metabolism. affect the
sec«:tion of scveral pituilary gland hormones. pro-
mote Ihe of scverallivcr proteins (including
some that bind hormones). and contribute to the reg-
ulation of li pid metabolism and fat dislribut ion.
They aff«:t the texture of the skin art<! act directly
on brain ""urons.
Although ovarian progtslageru aff«:ts mostly re-
productive structu.-.:s, they exen SOme inA nenees On
body temperature art<! the secretion of other
hormones.
NEGATIVE FEEDBACK CONTROL OF
HORMONE SECRETION
Hormones funct ion properly only wben present in
optimum concentrations. The target glands play im·
portant loles in the regulation of the secretory activ-
ities of the pituilary gland .
The TRH-TSH-Thyroid System
In addition 10 promoting secretion of Ihyroid hor_
mones. TSH aCIS on the thyroid glands to stimulate
RNA and protein synthesis. and it sustains the abil·
ity of the cells to r.pond 10 tbe pituitary .-.:gu lator
(26).
TSH tlavels from the adenohypophysis to the thy·
raid glands via Ihe systemic bloodstream. Thyroid
hormones released into the blood "essels travel back
to tbe pituitary gland to exert " negative feedback
control"' over TSH secretion. The interrelationships
arc shown in Fig. 2-18. Since T. is the most abun·
dant of the ci.-.:ulating thyroid hormones. only T. is
TI,yrvlrup<:. I"""''''''' a Ihal 00,,·
vertS T, to T). and it is believed that the T, aCls di·
rectly On the pituitary cells.
,, ,
The regulatory meChanisms provide for the main_
tenance of fairly constant leve ls of TSH and of T, in
Ihe blood plasma. When 100 much TSH is secreted.
the levels of T. rise transiently. The high levds of T.
then suppress TSH secretion. This leads 10 a decline
in T, output. As the T, levels fall, the inhibition is
lifted and mOre TSH is secreted.
The processes have been compared with thel"ltl<)-
Slatic regulation of room temperature. When the
temperature rises above a predetermined set point.
the thermostat arranges for tbe furnace to be shut
olf. When the room cools to below that set point. the
furnace again provides heat. The analogy is imper-
fect but useful.
The eff""t. of thyroid hormone. on the pituitary gland
afO more complcx th.n th. ,u&lIe't •. They tak.
time 10 develop. the produclion of specific pro-
teins .• nd .a n be blocked by inhibitors of p(Qtein . ynth'"
.i, (67). Thcr< is some evidence that T. affeet' th. quo/-
iloli", natufO <>fTSIl (I 25) and tnat chronically elevated
blood T. a«em piluitary gla nd store. of TSH (7S).
It was onee fashionable to administer tbyroid hor-
mones to individuals wno wished to reduce body
weight, in the belief that the "'burning up" of body
fat could tben be hastened. It is now recogni7.cd that
small doses of the hormone inhibit TSII ",cretian.
Therefore. nothing more is acoomplished than suo.
stitution of exogenous for endogenous thyroid hor.
mone. (Lighling a fireplace has comparable elf«:ts
on the thermostat and furnaee.) The metabolic rale
can be elevated by very large docs ofT.. but the un-
desirable consequences include over5timulation of
Inc heart.
The negative feedback controls just described are
useful for maintaining fairly constant levels of T. in
the circulatin8 blood. They cannot. however. provide
adjustments to changing needs. Ihbernalion. sea-
sonal breeding. and exposure to vcry cold environ_
mentS are conditions that often involve changes in

,,, thc rates of thryoid hormone production.

The hypothalamus ",crctes T RIl, which is essen-
tial for maintaining the funetiolt$ of the thyrotropes.
When the amotlnt of TRH fOlea",d into the portal
!:
,,
i, blood vessels increases. the thyrotropcs rospond by
putting out more TSH. This in turn leads to the se-
,, cretion of more T •. Thus. the entire system can func-

,, FOIlicul3( eel. ¢j
tion at a higher level. TR H control of Ihc thy","
tropes is somewhat complex. however (81. 84). It is
, ,,
thyfOid glar>:i discussed in Chap. 17.
If the blood levels of T, rise t xctsslvtly. negatiye
feedback control m«:hanisms arc sct in molion_ The
,, T. seems to exen its inhibitory inAucnces primarily
" ,• yia .-.:duction of the sensitivities of the thyrotropes to
TRH stimulation . Tbis eff.ct is associated with di-
Ftg. 2-18. TSH Slim<ll&18S tflfl S<K:r..iOtI of T•. T. inhibi.. minished numbers of TRH receptors per thyrotrope
the S<K:r .. iOtI oj TSH. (55).
 ORGANIZATION OF THE ENDOCIltNE SYSTEM

TSH can travel from the pituitary gland 10 the hy·

pothalamus (4). and reiati,-ely high concentrations
of thc hormonc arC detectable in the median emi· uti. 01 h1POThaia"""

,, ,
nenCe. The belicrthat TSH inhibits T RH =retion
is su pported by observations that exogellOus pilU'
ilary hormone injected into the hypothalamus has
,,
,,
such an effec!.
The inAucoces of T. on the hypothalamus a rC ,, ,
,,
complex , Small amounts arc essential for maintain· ,
, ,,, Cortico'fOPI'S ol r

,,
ing the functions of TR H«croIing neurons, and the {
intrahypothalamie administration of small d=s
, ,,
augments TR H seen':tion in thyroid..deficienl ani-
mals (84). Larger inuahypothalamic dosages have
,, ,, ,, ,
been reported 10 decrease TSH secretion. However. ,, , ,
,
, ,
thc possibility that Ihe T. traveled to the pituitary
gland to act thcre was 1101 ruled OUI in such studies.
Large increases in both hypothalamic TRH and pi-
,, ,
tuitary TSH have becn found in animals subjected ,, '' Zona lascieu!al' of
ad'""at COrte'

, , ,' ' ' ,,

to thyroidectomy. On thc other hand. the syslemir
injection of T. usua lly reduces TSH levels without
affecting the TRH (67).
, ..."
... - GLUCOCORTlCO!D$/
,
When a thermostat is u,ed to control room tem-
perature. wmeone muSt determine tnc appropriate Ftg. 2·20. The CRH·... CTH.g/uco<:ortieoi<l.ystem,
sett ing. (It will be different if the room is used for a
lecture than if it serves as a gymnasium.) Similarly,
information must be supplied to Ihc hypothalamic Thyroid and hormones affect those neurons ,
cdb that make TRH. It comes from neurons in Additional fine COntrols arc exertcd locally. T.
vllln I""'" vf ,lie l>n1in On , h. 'hyroid cell •. TSH On the ,hyrotropes .
nections with internal and and TRH 00 the hypothalamic neuronS, Figure 2-19
5ummarizes TRH-TSH· T. interrelationships.
Norcpineph,;ne i$ released; n resPQn'" 10 e'po$ure 10
CQ[d ...ironmenlallemper.IU ..... In at lea.t rome 'pe.
de •• il aculely iI;m. lales TRH releale, Dopamine (rc·
TRH..oeG!eting
cell. 01 hypothaI3""'. lealed from diff<r<,n, no.ron$) inhibit< TRH rdease .nd
blun'$ some response, 10 cold. T. contributes 10 the reg·
ulatioo <>f cal.eholamine 'u"""er in the !>.. in.
A f",m of cont rol not shown in Fig. 2-19 involves the
, conversioo of T. 10 T,. Under condilion. in which a low·
,
, ,, ,, erinB of melabolic ra'e can ""nlri!>ute '0 sur.i •• 1 (e.g.
during sub$lantial ,mountS of T, con·
,, ""'Icd 10 .. rc ..... T," (rT,). I metabolite thot I.ck, lhe
stimula ,ory effect. of T, (62).
,, , hlrahypothalamic . ilO$ f"r TRH sy nthO$il ar. dis-
,, ,, , , ,, cur.scd in Ch.p, 17. They do nol seem 10 be invol.ed in
,, lh. ""n"{ll of 'hyroid hormone seerelion. Subst.n,;.1
,, , u
T$H:::::' '" ,
,
.mount. arc m.dc in Ihe'..I.. hypolhalamic brain (98.
110). in which they can .ffeet behavior and body lem_
,
,, ,, ,,, peralu re (71). In r11)g<. most of 'he TRH in the $ystemic
blood ",igin.te. in Ihe skin (44),
, ,, The CR H-ACTH -Glucocorllcold System
,, Similar feedback arc inVQlved in
of the CRH-ACT H-glucoconicoid system (Fig. 2-
_ -,_ ' $limul.,ion ";.;;", 20). ACTH maintains the structures and secretory
- - _ IMibiIio<>
functions of the cells of the zona fasciculata . and ;t
F!g. 2·ti. ot lhe TRH· TSH·T. $n'om. promotes secretion of glucocorticoids , The activit;""
 _.
"""I --- - LRH.-...ing
00Ib 01 htP<MI I I.......
the unall volume of blood in that system. only small
quantities of tbe regulators are needed. Pituitary
«"lis ta ke up the hormones. and they make enzymes

, ,, , , ,, that degrade them. Unokr normal oonditions. only

,, , - , ,,,
minule amounts gain access 10 the systemic circu-
Lation. The <;ooccntrations in peripheral blood rmy
be 1(1(1 low to be deteclable by available metllods.
,, ,, ,
, ,, If the pit uitary stal k through which the portal ves-
sels pjlss is severed . and 3 barrier is then imposed
, G_'OPOI <)I

,,
between the pituitary gland and the hypothalamus
,
,, ,, ,,, (10 prevent reestablishment of til<: circulation ). Ihe
,, adcnohypophysi.al «"lis arc deprived of the regula·
,, ,, ,,, LH::; ". . U)f$. The wrticotrupes, th)·roIropes.. aoo ganado-

,, ,, ,, trope$ (. 1Id also the somatOlropes) atrophy and be

the abilily to release substantial quantities of their
,, , , hormones. Comparable cell ular defeets are Sttn if

, ,, , I"*,,,ual celli the pituitary gland is ",moved from ilS usual location
and is transplanted to a peripheral site wilhin the
, ,,' ,, ,, sa me animal.

-- - TESTOSTERONE __ -,
, ""
FI9. 2. 2 1. Tho lRIH.H·\eI_ ...... . , .......
of the «>t'licotropes a re augmented by hypOthalamic
and they are by giuooconiCQid$.
The CRH-s«reling neUr(l1IS are in functional com-
municalion with other ne urons. Fine controls analo.-
gous 10 the ones described for Lhe T. system also per-
lain. A diffcrcoc<: bc\we.:n the tWO s)'Slems is seen in
the marked inhibition Ihal glUCQO()IlicQids exen O\Ier
CRH secrelion. Gh' COOOf1icoidJ a lso inhibit prolif.
C'flIlion of adrenocortica l cells (94),
ACTH has been idcnlificd in tile pars imcrmcdia
of $OmC species. Wbile il may be re lused in rcsponse
\0 cerl. in forms of stress. il don not contribute 10
pilrs distalis COlltrol Over giuooeonicoid secretion.
The LRH·lH·r •• toaleron, Sytt'm
Superficially, II least, the panerns for C<NUro! of the
secretion of testosterone by tellicula. <:ens rescmbk
the ones described for the aluc:oronicoids (Fig. 2·
21).
l RH a lso promotes the n: lease 01 FS H . A differ·
ent hormone (inhibin) is to be se<:!"Cted by
Sertoli of the testis a nd cells of the
ovary a nd 10 pjlrticipjlte in negative f«dbac k control
over this gonadotropin.
HYPOTHALAM IC CONTROL MECHANISMS
Regulation of Ihe Adenohypophylls
The hypothalamic hormonc$ that act on the aden&-
hypophysis arc released into tbe bypoc balamobyP'>"
physi.1 blood vessels. Since there is lillie dilution by
Effecls 01 Ih. first procedure ca n be reversed by
removal of Ihe barrier. and .ffects of the sc:<:()nd by
",Iumi n, the pituitary glaoo to il$ OI"i&i03I location.
Adcnohypophysial functions are a lso restored if the
pitu ita ry is implanted into a region of the hypochal-
Im us known as the hypopbyslotropic a rea (HTA ,
IIA). It was formerly believed l!utt llCurons within
the HTA directly provided relnsin, hormones to tile
Irans pl ant. There is !lOW good reason to conclude
that upwMd llQworb lood from Ihe median emi nence
for much of the hormone delivery (27).
Adenohypophy$ial cells underlo simila r changes
if hypot halami<: lesions that destroy tile 10 .....
crete the re ..... ing hormones are made in animals
with intact pituitary g lands. Inje<:tions of a ntibodies
directed against lhe hormones can . Iso disnopl the
(unctions. Electrieal stimulation oIapproprialc hy_
pothalamic sites in inlacl animals leads to aug·
menled rates of hormone sec retion .
Pituita ry celb can be maintained in Culture. When
deprived of hypolhalamic re&ulators. their ability to
release ACTH. TS H . FSH. and GH declines.
It ean be restored selectively by direct in vitro pre-
senlalion 01 tile appropriate hypochalamie hormone.
Faadback Loops
Three types of feedback loops are reoognized:
I. l.oItg: These invol>'e ionl..:iiSlal"H:e travel via the
periphera l circulation. [nnuenees of TS H. ACTH ,
and LH 00 the thyroid glands, adrenal glands. and
8Onads, respectively, and those of T •• glucocorti·
coids. and testQ!Otcrone on the adenohypophysis pr0-
vide obvious eu.mplcs.
2. Siron: hormones lravel
n:latively short distances throu,h tho; hypolhalamo-
hypophysial portal system. Adenohypophysial hor-
mortCI affeet th. hypothalamic DCUr"On$ via upward
migrat ion through the !.arne vaseular system.
,.
3. Vitro-short: Locali,ed inAucncc$ that hormones
excn on thoi, Own synthesizing cells do not require
vascular lranspon.
Re gulation of Growth Hormone Sec re tion
GH aelSon a wide variClyof c.llty""s, and;1 affects
Ihe secretion of many other hormones. There is 00
"specific" target gland with which ;1 interacts to es-
tablish Ihc kinds of negative feedback control just
described. Some of Ihc actions on the skeletal system
have been attributed to induction of mediators (so-
SM,), and there is evidence for soma-
tomedin participation in the modulation ... f GH
secrelion.
The primary regulators arc hypothalamic growth
hormone releasing hormone (GRH. SRH). which
stimulates thc somalotropes of Ihc adcnohypophysi$.
and somatostatin (55, somatotropin relnsc inhibit-
ing faclor. SRIF. growth hormone inhibiting hor-
mone, GIH). Bolh peplidcs nave been identificd
wilhin Inc ventromedial and arcuate (inrundibular)
nuclei. SS synthesized outside the hypothalamus
(III) does not seem to contribute substantially to
the rcgulation (102).
The ventromedial nuclei make functional connec_
tions with other parts of the brain that include Ihe
hippocampus and amygdala. Eketrical slimulation
of those I"<'gions alters GH release pallcms. Dopa·
mine. norepinephrine, serotonin. P-<:ndorphin and
otner neurotransmitters contributc to the controls
(53.64) , GH acts centrally to promote SS release.
and SS exerts inhibitory innuences over thc GRH-
secreting neurons. In addition. the iCCl"<'tion of GH
is aff«:led by thyroid hormoncs, by TRH (65). by
steroid hormones, by circulating levcls of glucose
and certain amino acids, and by many other faclon;.
Regulati o n o f Prolac tin S acre tlon
By contrast wilh the adenohypophysial wntrols al.
ready cited, the secretion of proiaclin (PRl) is
mostly inhibited by Ihe hypothalamus (I, 96, 113).
" substance found in hypolhaiamic extracts, kllOwn
as prolactin inhibiling factor (PI F). is believed to
exert tonic inhibitory control OVCr the lactOlropes.
When vaSl'ular connections betwcen thc hypothala·
mus and the pituitary gland are interrupted. the lac-
totropes enlarge and secrete more hormone than
they would under normal conditions. When pituitary
glands are maintained in culture. the amount of
PRL released into Ihe medium is reduced following
the addition of hypothalamic ewacls.
As discussed in Part V. strong evidence has been
presenled for the concept that PIF is, in fact. dopa·
mine. On Ihe olher hand, PIF activity has been
ORG"N IZ"TiON OF THE ENDOCRINE SYSTEM
found in hypothalamic exlraCts from which dopa-
mine has been excluded (I).
Concentrations of PR L in Ihe peripheral blood
rise during phases of the ovarian cycles in which the
eslrogen levels arC highest. The steroid aelS centrally
and peripherally to neurotransmitter turn_
over and lower the sensitivities of laclotropes to do-
pamine inhibition (54) ,
A separale prolactin faClor (PR F) may ac·
count for the prompt "'lease of PRL during lacta-
tion. TRH C3n promote PRL secretion under some
condilions (25). but il is 1101 believed to serve as the
PRF. Endorphins and other brain peplides affect
PRL as well as GH sc¢relion.
The regulatory factors exert complex influences
On the lactotropes that include elTecls on the molec·
ular form of the hormone. a nd possibly also on lhe
mechanisms for sequestration within the cells.
The major hypothalamic hormones implicated in
regulation of Ihe adenohypophysial cells a", listed in
Table 2-3.
POSITIVE FEEDBACK CONTROLS
While negative feedback control systems predomi-
nale, thel"<' are special conditions under which it is
desirable for a hormone to eilher stimulate its o,,'n
production or enhance its own effectiveness,
fSH and LH aCI togelheron Ihe ovary 10 promote
estrogen production. In developing follicles, FSH
acts in conjunction with estrogens to augment the
numbers of FSH and LH receptors. Shortly before
ovulation, estrogens stimulates lH release.
DIRECT METABOLIC CONTROL OF
HORMONE SEC RETION: PARATHYROID
HORMONE AND C ALCITONIN
The feedback systems provide for fine·tuning of the
endocrine system. However. the mechanisms are
timc-consuming. They involve the sc¢retioo of two Or
more hormones Ihat must I"<'ach the target organs in
adequate concentrations. Once the regulating hor-
mones appear in the peripheral blood. lime is re·
quired for their destruclion or inactivation.
Some hormone functions cannot be regulated in
this way.
Parath yroi d Hormo n e ( PTH, Perathormo ne)
Calcium ion concentrations in the bloodsl",am must
be continuOllsly maintained within very narrow lim-
its. Small reductions below the optimum levels in_
crease neuromuscular excitability , Somewhat largcr
ones can lead to death because of spasm oflhe mus-
cle. of the larynx Or diaphragm. Sudden rapid elo-
1 01M 2·3 HypoIhOlamic I""manoa Ac\enoI'IypopIryoiol F,-""tions
R.ma,k>

Th)',oltopio-,<I •• "", OOtrnone (TRH. M. in"i"" "fI"'.'" f."",ions of

. nd of .."OIi,O«I "",""r.; .1..
,hy,o<ropi. ,01, .." fo<,or. TRF. ,hyroid· ,hytOt rope" "h.""c, TS II • yo, 11<0,
hypoth.l>m",
"d "" ,h.
Sl,","I"'nl iI<><<nOtI< ",lea.. f.clOt. TSH· """,.";",,
'0
Cor'ico'ropin ,eI .... lacto, (CRF. Mai.tai"" conico"Op<$. enh ..",,, 41..,,,,,,,,, .oid ide"'ified. Many
<Or1,C01ropio-,d" "'1 00t"""",. C RHl ACT Il ""',.";",, othe, qc." "haoce ACTII
"",,,ion
Soou",.,..in (SS. ""'"""otropi. ,eI..", So,,,.1 rOfm. incllllli"I'
inhihi,i.1 f«,or. SRlf. g_,h 110<_ '" ,II(> . y .,Ioco' "
"' ..... ,.nib'''o, foetor. OR lf. S''''''" I'Iln"",•." .....h. i.,,,,i ...
hot"""", inhibi'i", f«, ... OIF) "". hn""h.lamic br.;n, ma.y
othe, oel"'"
O_,h hot_rcl<"'nl iI<><"",o< (ORH. M".",,,, wo,,,,,,,,,,,,,.,nh,,,,,.. " .. m''''' •• io;! pePl"'" 'dcnt ifiod.
,,,,,,,,h hot""",. "I..", fwo<. ORr G il ",mOl;"" En<k>rphin,. «he, hypoth, l,mic
somalOt"'!'in ,01•• " r,etor. <:Omi>J"." p_e Gil .... "t;""
P"",cti. inhi biti Ill! f «,.. (PI F) $"",,",, not .."OI"hc<i. Son><
in"",'i",,,,, bc l;e,,, ,h., dopamill<
is ,ke PW ... ' UlC'" ,hat
dopamine is. >ocotHiory "'l "11Io.
Proia"" . " .. _ r.o' .. (PRF. prolactin. P,,,,,,,,,.. '<c"""," of prol.ctin Impor".' in may be ;mporlan'
"I, .,in, ""mott.) I.c",,,," i. TRII
"h''''''' PRL .. <, .. "" ... " , not
io;!.n,icol PRF
I."" i." .illl! i>o>"",oe " 1..,,., horm.... Main"i,.. ,....dou.".. .•• h. nc .. O' .... ptide of .."h!i,hc<l S(tu<'.",
(LRH. LH RH. L."ini,inl hormone ""e';"" of LII ,n<! FSH
,,1 .... lootor. LRF) . ..",.<I¢Iropi ...
tcl"".gllormott •. GnR Il
foiliclw,im.l .. inJ ""mono ",I.",. fo" .. Enhanc .. >c<""ion of FSH No r."'''' poIoi' i" Iy io;!,", ified, ""'"
(FSIl·Rf. FRI1 ""''''''''otS
>cpa,."!Ior,",,",
';"'b, .. i"en« of
FSH'"
no< Ul

Promole ...,,«ion 0/ molo"""y'" l'e."pePl,d< o1e.y<d /r"", O,ytOC" ,

S(,","I.,illl! 1Ior"""", (MSIl) in
".;mals ,h ..
;o",m«Ii.
Inh ib" «I .... 0/ MSH, ••• ,,,,.1.
'hat h... , I'll" in'ermedi,
Not oni"" .... lIy ••«plod ... lrt1<
Two cI ..""d from O,y'ocin
ro»<l> , .,k .Cli.;,y. Hor_
""• • not f.I I)' ..... bli.hed .

vations of the calcium ion concentration can bring
about systolic am:SI of Ihe hcart.
PTH in several ways 10 elevate Ihc calcium
ion concentration. The ""lis of the parathyroid gland
are directly sensitive to reductions in the COnCentra·
tion of Ihe ion. They respond by pUlling oot mOre
hormone . When 'he Ca" rises ex=sivcly. Ihis in·
hibits furi her PTH release (Fig. 2·22). Direct effecls
of magnesium ions on PTH have also been
proposed (72).
Calcitonin (C T, Thyroca lcitoni n, TCT )
It has been argued that of PTH secretion
by high Cal> cannot very rapidly restore normal Ie.·
cis of that ion. because previously sccrelcd PTH is
slill present. Calcilonin is released in 10 hy·
percalem;a, and it acts on bone and OIher target' to
lower th. blood Cal> (Fig. 2·B). However. it
doubtful thai CT contributes in this way to calcium
homeoslasis under normal conditions. Mammals
ra rely sudden . dangerous elevalion of the
plasma Cal<. Moreover. Ihey easily maintain eu,al·
""mia when they lose their CT-$ccreting ,ell'_ More
subtle functions for CT have been proposed. and
Ihese are discussed in Part IV . Neurons {68. 69).
g3slrointeslinal hormones. and other factors (30) are
known to affect Ihe se<:re! ion rales. SS is a re<:og·
niZed inhibitor (40, 60). and il is preSenl in thyroid
glands.
. OAGANIlA lION OF THE ENOOCRlNl: SYSTEM

FaII.,ea> · ......-.""" 0\0 the aCli...: hormooc. There arC indications thai
1.2S-HCC is involved in the negative fttdbllck <,:JOn.
lrol of PTH Sttre';';" (18).

..
Paol 'tIytoi(I
ENDOCRI NE FUNCTI ONS O F THE
; PANCREATIC ISLETS
;
; Blood glucose C(llK'cntnuions must be continuously
; maintained at adeq\l.l.te k""ls because neurons and

,,,
; crythroc:Yll::S arc directly dependenl on the supply 10
,,
,,
, inability 10 perform demanding menIal work. Larger
Aiw in Ca'·
Illteractloni with Calciferol.
Vita min 0 nndergoc:s metabolic conversions in the
Knd kidney, and II thereby becomes
formed into D. a polen! ste-
roid·type horroone also kl>OWn as
cholCQIkiferol (1.25-IKC).
The steroid acts slowly on the intestine 10 promote
lhe absorption of dieta ry Qicium and pbospbonJ.,
and il acts on bone a nd elsewhere to build up stores
of Lho$.c: minerals. PTH elevates blood Ca" by rc-
c!'1.1iling the SIOrcS. PTH also oon lribu.cs 10 control
of the rate-limiti ng step in the c(l!1vcrsion of vitamin
CAlCITONIN
rNlinuoin their functions. The hi,her CCntefS 0( the
brain arc ulremeiy sensitive \0 dcf>" -s;"n or lhe cir-
culalin"luoose ooncc:nlral wns. Small changes elicit
$ymplOOls of resll=nc:u.nd a nxiely, along .... ith an
ones can lead in short order to convul$ions followed
by coma.
Exeeui"" elevation of the plasma glucose COIlcen'
lratlon invokes d ilferenl problems. The sugar soon
appears in the uri ne, 'Iona wilh large qllanlitie$ of
.... Ier. The senous consequcnces include C(;llular de-
hydl1ltion and conll1lClIon or lhe circulating bk.M.>d
volume.
GlucalOfl aetS rapidly on live' edls 10 promote
alyeoaen breakdown arid the consequent discharge
of ,jucose into the bloodstream . It is rdeal'Cd when
the blood 81u= bo;gin 10 fall during the in·
,"'1\5. lervals between meats. arid the sec retlQn IS mhlt>ncd
by hi,h concenlr3tKms of ,Iucose.
Insulin aelS on ske lttal muso:le arid adipoiSC lissue
10 ", olllote rapid uptake or ,Iucose from lite bk.M.>d-
stream. Ind on muscle a nd liver to loccier3le lhe
convcrsioo\ of gluoose 10 gly<:ogen. It is KCrttcd in
response 10 elevation of pluml ,Iu<;osc concenll1l'
lions. I nd it ean r3pidly the levels.
The dual control system is similar 10 Ihe one
shown for PTH arid calcilOnin (see Fig. 2·24).
It is important 10 reoosni,.c:. however. thaI pan·
erC<l lic islet hormones perform many OIhe, fune-
\iorIt. They contribute 10 the regula lion of lipid, pra-
tein and nueleic acid mctabolism. balance.
and rood inUtke.. The: ttlls lhal sec;f"Ctc them require
mult iple control mechanisms.
HiOI' _ gIuQOIII

/ , "
lNSWN GLUCAGON

= -_
--::!": il'lC«l_ '"
DKrN.. '"
\.oW _
//
glYCQ II
,.,.2-U. Po" ..... .-,,_Iot
' ....... 01 pIo_c. •• . '1,. 2·U . Dual con"'" 01 _ 111'< ... """"'Ut""".
 Each pancreatic islet is a complex, in nervated
organ that comains se,-eral kinds of se.:rctory cells
(Table 2-4). Gap junctions. desmosomes. tight junc-
tions. and the interstitial fluid that surrounds the
cells are all componenlS of a highly ordered com-
munication system (107-109) . Glucagon
by alpha cells acts on neighboring beta cells to pro-
mote insulin release . Insulin act" within the islel 10
inhibit Ihe
term
of (scc Fig. 2·25). The
is applied to locali1.oo controls of this
ki nd that do nOI involve hormone transport througb
blood vessels.
When pancreatic SS is present in low COnCentra·
tions. it aCls on thc alpha cells to inhibit glucagon
releas:. It is suspcctoo that some patients wilh dia·
betes mellitus (a condit ion associated "'ith rcialive Or
absolute insulin deflcicncy) develop very high blood
glucose levels because Ihey fail 10 se.:rcte adequate
quantitics of SS. Potent long·aCling synthctic SS an·
alogs that selectively affcct Ibe alpha cells have
proven to be beneficial in SOme individuals (31).
Vcry high concentrations of SS also inhibit insulin
release. This effect may be pharmacological. but dif·
Itormonc Remork>
1."lin lie". 8 Centr.lly toe. ,ed in man)"
or ,I>< ", . mm.I •.
",_.'i,,! for abou,
60% of ,lie i,l<1 cell
_<eo'
lI.lpo,.1I·2 U •• ally .tWl"I<l
of ;"1<1. of ma mma l•.
00"",, 01iol for .b<>.,
.--
30% of i,l« «II """ent:
al.., .)·.,M.i,o<I oo"i<le
Dolt •. A·I lhUo1 llr atWO<! peripllery
of i.le" of m.mm.l ..
• e"",,0';'8 10, ._,
10$ of i,lel cell OOn'eOI:
' yn'1I«ited in
h)'po! ,,",I.m U'.
l»"o;.'",'i",,1mu""",.
.nd d""M..
Pane, .. ,ie F or X NOlI""od i. an i,I.."
poiypepli<l< mos' . y",1I«i,o<I outside
i.Ie". in <_rill< li ... <
of .1..,
.y.,k,""'d i.
,."roinl<>'i..1 mu«>U
Ga"';. G. '" varian' Id,n,ifi.d in 1".1 1"""....
of D 'Yl" . nd 'u"""" some
"""'fOVOr>y ove,
_.i",", P'=""< in
. duH mammal i,I.",
moo' i..)·.'hai,o<I in
,h, ,,,,,<Oj n<e,,in.1
m.e"",
PANCAEATIC
POLYPEPTIDE :::=======--:
• GASTRIN
"
"
SOMATOSTATIN
, , , , ,
,, ,
,
,
GLUCAGON
/
- --- - -- - - INSULIN
Fig. 2·25 . ESlatlliOl>ll<l aM propoO/:<l p.!l,aorine conl,OIs it>
p.!lncteali<: is .. to. (Ioteracl it>1 bel_ ...... ., ond gfucagon,
or>d somatoOlal ;n iMibition of gl\.O;ogon _'etion. have
beer> <Iernor> .... ,0<1 wi,h p11Y'iOIOgi<:.!Il "",",""',olion. of "'"
flOrnIone • . )
ferent SS analogs Ihal preferentially de.:rcasc insu·
lin release are useful research tools.
Animals that cat infrequently depend heavily
upon insulin·medialed of metabolic
Their islets contain more PP than glucagon. PP re-
lease is Slimulaled by meals thaI are rich in protc{n
bUI poOr in carbohydralc. by falling blood glucose
levds, and by gastrin; and it Can be inhibiled wilh
SS. While innuenees On the seer:tion of SOme gas--
lroint:stinal burmon:s have been described, Ihc
funel;.n< "f PP hAVC nn! hun 11 ...
lease may be controlled mostly by thc islct cdl in·
nervation. since alropine (an acetylcholine re.:cptor
anlagonist) blocks the secretion (41).
Nour<)1en,;n (NT) is • small pep'ide found in broi.
. nd inleslill< thaI .lfect. the o.<:rction of SS. glucagon.
.nd pp ... it i, prescnt in 1_ oono<",,,,tion>. T he glu.
coso concentralion. in the fluid ••• ,rounding the i.lot. de-
termine ",hether NT u imular•• ,.. inhibit. (19). It i"u,"
pec!<d Ihal NT contributes 10 control •. bUI
the peptide has not as yet been iden,ified within the ;'Iets.
Paraerine controls have also been described for
Ihe central nerVOUS syslem. Substane.:s thaI aCI pe-
ripherally as "true" hormones have been observ:d to
invoke the production of "pinpoint depolarization!"
(microvolt potentials) in dendritcs and axons. (fhese
diffcr from thc minivolt cbanges lbat lead 10 propa·
galoo action polentials [38).) One consequence may
be the release from Ihe neurons of enzymes that
cleave brain peprides 10 smaller molecules with spe-
cialized funclions.
NEUROENDOCRINE SYSTEMS
The simplest possible neuroendocrine s)'stem COm·
prises a single speeiahed neuron (neurosecretory
cell) that can dire.:tly respond to slimulali<ln by
releasing a hormone {Fig. 2·26Aj. Most ncuroen·
" ORGAN IZATION OF THE ENOOCRINE SYSTEM

$'"",,1". .0 . . 0 ..0
Nourose<:<e'OtY
Cell v.ith Graoules

00
00
, 00
, Inl""
mediate
N$",Oon
Nevro·
transmiMr

Fill. 2 _26. N"'-"<>Mdocr ..... ...".01iOt1. A: Nouro$8Crtl'or.,.

" ..U Qi,oe!ty to stimulus and it. hOrmOoO.
6, N.... 'oseere!Ot'l un;1 ;,,.oMng • rKeptOO' ."" ;",6<_1<1
oeu,on .

docrine fUTlCtions involve more complex arrange-
mentS. Receptors that are especially sensitive to one
form of stimulation convey mCSoiagcs to neurosccr<:-
lory cells. either directly or via intermediate neurons
(Fig. 2-268).
Systems of this kind confer versatility on the or·
ganism for "".eral ",,,,,,,no:
L Almos\ ;ru;tantaneous secre lion of the hormone
can Ix achieved.
2. Receptors Ca n Ix located at body surfaces and
olher sites removed from Ih. bloodstream. There-
fore, "anticipatory" respon>es that avert. ralher than
oorrcct. changes in blood ooncenlralions arC possible.
3. Several kinds of re<:eptors can affect the seere·
tion of the same hormone.
4. A single kind of stirn ulus can elicit the secretion
of two or moT<: hormones that work together for a
common I'IIrpo:sc.
The Secretion of Vasopressin
The magllOCllllular neuronS of the hypOlhalamu,
provide good examples of neurosecretory cells. The
ones that synthesize and release VP make functional
connoctions with several kinds of recepto" (89. 90.
104). The hormone is released into neural lobe cap-
illaries. It travel s to the kidney and promotes water
conservation. Sine<: it thereby reduces urine volume.
it is also known as antidiuretic hormone (ADH).
Water deprivation, heavy sw..ating. and excessive
water loss from the respiratory tract can all deplete
plasma water and invoke henlQConccmration. Or·
moreceplo--s then signal the need for more VP. Ac·
cording to some observers. "sodium sensors" affect·
ing VP release are also stimulated.
Hemorrhage leads directly to the loss of both salts
and water. Usually. waler is then r<:cruited from the
extracellular spaces. The blood is diluted. but the
plasma volumc may oot be totally r<:store\l, Under
sach condit;oons, baror«rplorS within the vaseular
system stimulate VP release. The same =PIOI1I can
be activated when water deprivation . weating
lowers th. circulating blood volume.
Sweating and vasodilation can rid th. body of ex-
cess heal. The processes are facilitated byaugmen-
tation of the blood volume , ThermOfUtprors then
play important roles in stimu lation of VP secret ion.
Painful and stimuli also increase VP se-
cretion , The responses ar<: mediated via the central
nervous sys tem. and some evidently depend upon ac·
tivation of pIlln It has been suggestcd that
VP release;s an appropriate response to some forms
of stress beca use water =1"II3tion could be useful
in the event of injury with hemorrhage.
However, the ability of VP to inercas<: ACTH secre-
tion rna)' be more important under these condition"
Caffeine, tobacco .• nd some other agents prob.bly
promote VP secretion by acting on chemoreceplors.
The responses may be pur<:ly pharmacologic. and
ther<:fore not necessarily beneficial. On the other
hand. ethyl alcohol inhibits VP secretion. and one
notion is that more rapid 10&5 of water into the arine
aoxelerates excretion of the alcohol and its
metabolites.
All of the roceptors cited Can rccrnit different reg·
ulators that contribute to the physiological adjmt-
mentS. The barorcceptors promOlc the r<:lea"" of
norepinephrine, and thaI catecholamine counteracts
the hypotensive effects of plasma volume depletion
by stimulating thc heart a nd the smooth muscle of
the arterioles_ haroreeeptor.; addilionally pnr
mote the releaS<' of renin by the kidney. Renin that
systemic circulation cleaves a plasma pnr
lein. and Ihis leads to the production of angiOlensin_
The angiotensin aCIS in S<'veral way. to rai,e blood
pressure and incl"<'aS<' blood volume. For • • ample, it
is a highly poteN vaSOC<)nstriclor, and it stimulates
Ihe cells of the adrenal cortex Ihal S<'erete aid(JSle-
rolU'_ (AngiOlensin al"" act. on neurons to invoke
thirst. However. the molecules ser.,.ing this function
are probably made within the brain In, 29).) AI-
dosterone·s influences on Ihe kidney indirectly pro-
mote waler retention. Potassium ions are physiolog·
ical depressants of Ihe myocardium . and aldosterone
lowers the plasma K ' concentrations. The described
mechanisms for coping with water deprivation arc
summarized in Fig. 2·27. Addilional conlrol. arc
discussed in Part HI.
The Adrenal MedUlla
The innermost portions of mammalian adrenal
glands are actually extensions of the central ne'"ous
system. The cells that secrete norepinephrine and
epinephrinc originate from Ihe Io3me emhryonic pnr
genitOl'5 thaI give riS<' to Ihe sympalhelie ganglia.
They relain some neuronal characlerislies. including
S<'nsilivity to acetylcholine and inabilit)· to prolifcr-
ate. However. the cells do not possess axon. or
dendrites.
Ae<:tylcholine·secreting neuTOn' pass, Wilhoul
synapsing. from the intermediolaleral columns of Ihe
spinal cord, via Ihe splanchnic nerves. to the adrenal
_ _ _ _. Reduced pla.ma H,o
low t>IOOd
,
low tlIood p'essurc
•_
', ; NOREPINEPHR INE
" j
\ '
, ' v a$OConstr<:tion
.... Ca",,"c stimulation ____
I
_ - - - - - - ALOOSTERONE
1( . Excretion •-
- _. Stimulation '" """ e"",
• _ __ IMitlition '" decrease
Ftg. 2·27.
aolju£tment. to wall< depti".t;oo.
medulla. They are comparable 10 the preganglion ic
ne:urons that serve Ihe sympathetic ganglia, and aco-
tylcholine is the stimul us for Ihe I"<'lease of th. ad-
I"<'nomedullary hormones.
The horrnOl1es are besl known for their participa-
lion in the "fight or flight'· responses and for c0op-
eration with glucocorticoids in adaptations to stress.
They stimulate Ihe heart. increase respiration, shunt
blood from the vi.cera and skin to the skeletal mus-
cles. and exert other actions that contribu te to the
abilily to engage in sustained physical effort. Epi·
nephrine promotes glycogenolysis in skeletal muscle.
enhances museie contraction. and elevales blood glu-
cose concentrations. Norepinephrine: contributes
substantially to the mainlenance or bl<Xld preMure
and to the adjustments 10 cold tem_
peratures. Animal. deprived of the catecholamine
hormones can SUT'live in protected environments, but
they have limited ability to cope ,,·jth stress. How·
ever. Ihe roles in emergency situations should not be
overemphasi7.ed. since the hormones also regulate
blood pressure and other physiological proces,"s
under nonstress conditions.
Some Additional Examples of
Neuroendocrine Control
Although pancreatic islel cells are regulated to a
great by chan.ll,es in Ihe blood coneentralions
of gl ucose and Olher nutrients. and by the hormones
described above. they are innervaled as well. Small
amounts of insulin are secreted when food i. ingested
a nd even when the inta ke of food i. merely conlcm-
Wa'er <leprivation
I _ - - - - - - ....
< ",
I ___
Impai'ecI - -
"".110.. .... "
'
\
/ C )' )
VASOPRESS IN -____ "
•• //
consf>r"\<at<>n - _
----
RENIN . - -
t _ _ _ _ l hirslanil
ANG totENStN d''''1<ing
j
N. · .nil Watet Re'cntion _ _
NouroendoCrioe m6Ch.nism. C<>ntoburing 10

"
plated. Such anticipatory control provides enough
insulin 10 a,'crt excessive blood glu= elevation
during meal ingestion , The effects depend on the
vagus nerve (which also controls anticipatory release
of gaslr<)in\cs\inai hormones). Neurons of lhe ven-
tromedial nuclei of the hypothalamus (a region in·
volved in regulation of food intake) chronic in·
hibitory control over insulin secretion (5 ).
Ne uronal regulation of calcitonin secrelion has al.
ready been mentioned . Thyroid hormone secretion is
stimulated by sympathetic nerves and il is inhibited
by cholinergic ones (68). All of the releasing hor-
moneS of the hypothalamus arc made by neurosecre-
lory cells. It was noted earlier that their fUI)<;I;ons
arC regul aled by ncurons located elsewhere (as well
as by hormones that arrive via Ihe blood stream).
Milk release a nd ovulat ion a rc neuroendocrine
reflexes.
The outpouring of gillcoconicoids in to
stress is mediated by neurons that communicate with
cells . The endocrine rh)'thms de-
scribed later are dependem OIl neuron funCiions. The
activities of the gastrointestinal organs arc also reg-
ulated largely via neuroendocrine mechansims.
ENDOCRINE FUNCTIONS OF THE
OASTROINTES.T INAL TRACT
The mucO&a of the gastrointeStinal tract contains at
leaSt I kinds of hormonc-sccrcting cells
(6). and it has been called ··the largest endocrine
organ in tile body·· (45). Some of the regulators are
identical with ones found io pancreatic islets. and
most a rc addilionally found in Ihe central nervous
system . Each of Ihe regulators performs multiple
fUClions and interacts wilh other components of the
endocrine system (120).
Gastrin
Allhough best known for its stimulalion of hydro-
chloric acid prOOllcl ion by parielal ,,<,lis of the Slom-
ach, gastrin affects intestinal motility. exer .. long-
range lrophie inH uences on Ihe gastrointest;nal
mucosa . and <XImributcs 10 the cakitonin ,,"cretion
associa ted with food ingestion , The G cells thaI
make the hc>rmone arc under neural oontrol. butlhey
are also inhibited in a feedback manner by high con·
,,<,ntrat ions of stomach acid.
Cholecyalokinln-Pancreo zymi n (CCK-PZ)
This rcgulator received its fancy name when it was
recognized that the choleq-slokinin that stimulales
gall bladder wall smooth muscle and relaxes the gall
ORGANIZA r lONOF THE ENDOCRINE SYSTEM
bladder sphincter is identical with the pancreozymin
thai promotes the syn thesis of pancreatic juice
en/.ymes.
CC K-PZ stimulates pepsin secrelion in the Slom·
ach. increases the water and bicarbonale content of
both pancreatic juice and bile, augments the release
of both lowlin and glucagon . a nd potentiates Ihe ac-
tions of <ccrelin. Since it sha res common amino acid
seque nce. with gastrin. it mim ics some of the actions
of that hormone but competitively inhibils olhers. It
is a growth factor for Ihe exocrine pancreas, but it
depresses HC] production.
Most of the I cell. in which the hormone is made
are in the jejunum. but a few a re scattered through·
OUI the ileum. The arrioal of partially digested rood
seems to provide the major stimulus for secretion .
The ··gastrin·· preoiously reported to be pre,ent in
Ihe brain is now believed to be CC K-PZ or a chem-
ically related peptide (88. 100), Problems of iden ti-
fication arise because the two hormones share some
immunological properties, produced
CC K. PZ is implicated as a ··satiely factor"· that lim·
i.. food intake. Caerulein is a very similar peptide
made in frog . ki n poison glands thaI exerts CC K.
PZ·li ke a ctions in mammals.
SecreUn
This hormone originales in Ihe S cells of the duo-
denum and jejunum , There are good reasons to be-
lieve thaI the acid products of gastric digeslion pro-
vide Ihe secretory stimulus. This is difficult 10
demonstrate. because only minute quamities are
needed when Olher gastrointestinal hormoncs are
present (35).
Secretin promoles Ihe release of walcr and sodium
bicarbonate into Ihe pancreatic jllice and bile. and it
antagoni1.es several actions of gastrin. It ;s chemi-
cally and physiologically related to vasoaClive imes·
tinal peptide.
VS$Osclive Inlesl lna l Pepllde (VIP)
This regulator was named for its vasodilator effects
on in testinal blood vessels. It is made in H cells of
the esophagus. duodenum . colon. and rectum , and ;t
is present in concentration! 40 times greater than
those of secretin.
In oommon wilh secretion and gilleagon (which it
resembles chemically), vl P promOleS insulin rekase.
It mimies glucagon inHnences on gJ)'oogenol)'l;is in
the liver and secrelin effccts on the pan·
creaS and gastric glands. 11 also relaxes the
muscle of the gut and increases Ihe formalion of in·
tcstinal nnids.
 VIP is widely distributed throughout Ihe brain.
whet<: it has implicated in numerous functions.
11 is also present in spinal ganglia. in adrenal glands.
in the genitourinary traCt. in the trachea. and in the
salivary, sweat. lacrimal. and Harderian glands of at
least SOme species (93).
Somatostatin (SS)
5S may well be Ihe most widely distributed of all
hormones. Within the digestive system. it inhibits
the sccr<:tion of gastrin, gastri<; HC!. pepsin, secre-
tin. GU (see neXt section). mOlilin. pancreatic en·
7ymC">. saliva. and a""tylcholine. It reduces the fI1O-
tility of the stomach, small intestine. and gall
bladder, and it retards the absorption of sugars. It
has been proposed that S5 provides protection
against the development of postprandial hypergly-
cemia by retarding the entry of nutricnts into the
bloodstream.
Enteroglucagon
Enteroglucagon is a peptide (or group of reb ted
ones) made in the EG cells lhat arc sC"l\cred
throughout much of the gastrointe,'tinal tract. It af-
feclS gastric and intestinal motility and the intestinal
absorption of sugars. and it may in this way contril:>-
ute 10 the rCJ\ulation of carbohydrate metabolism
during times of meal absorption. Production is in·
creased following pancreatectomy (I 09).
The term glucagon-like immunoreaclivilY (GLI)
is applied 10 several peptides Ihat share immunolog·
ical properties with pancrealic glucagon but differ in
biological activities and to some e,lent in amino acid
composilion.
GastriC Inhibitory Peptide (GIP)
As its name suggest. G IP is a potent inhibitor of gas·
tric acid and pepsin r<:lease. and of gastroi ntestinal
motilily (but it enhances Ihe secrelion of intestinal
juice). !t seems to be the regulator responsible for
the greater release of insulin seen aftcr oral admin-
istralion of glucose than arter inlravenous injection
of an equivalenl quantity of susar.
Early physiologists observed tht the ingestion of
fau; lead. to inhibition of several gastrointestinal
tract functions. They named thc as,;ociated compo-
nenl of their eXiracU; "enterogastrone." GIl" may be
Ihe peptide that exerlS this kind of action.
Neurotensln (NT)
NT is a tridecapeplide that has been identified in tbe
inlestine of humans and other mammals. !t has been
reported 10 promote contraction of tile fundus of the
stomach and of Ihe ileum. but to promote reluation
of the duodenum . It can dir<:etly stimu late gastrin
secretion. whercas it antagoniles the influences of
that hormone on the production of HC!. High con-
centrations stimulate bolh alpha and beta cells of the
endocrine pancreas (119).
The peptide is beller known for ils central aclions .
!t has bttn implicated in mediation of pain percep-
tion. and il can lower body lemperature. !t is also a
known stimulant for several of the pituitary gland
hormones (113). While much of the brain NT is
probably made locally. some secms to originate in
the pituitary gland (20).
Other Gastrointestinal Hormones
Additional peptides identified in the imestine (and
also in Ihe brain) include subslance P (SP), enkeph·
alins. and a chemically uncharacterized molecule
thai exerts CRH·like activily. Putative hormones in-
clude motilin. chymodenin. and bulbogastrone.
Histamine inAuenees on gastric functions are dis_
cussed in Oap. S.
BRAIN HORMONES
The brain oontains an imprcssive array of peptide
hormones that arc similar to or idenlical wilh oneS
made elsewhere. Hormones oommon to the brain
and gastrointestinal lract indude SS. CCK·PZ. SP,
G [P, V Ip. endorphins, and bombesin. Peptides com·
mon to Ihe hypothalamus and e'trahypothalamic
brain include TR H. LRH. SS. VP. oxytocin, and an·
giotensins. Small peptides made up of amino acid so--
quences contained within ACTH and other pituitary
regulato", are also found. and in SOme CaSe, enlymes
capable of cleaving 'pecific bonds of the larger mol-
ecules can be identified . Cerlain of the regulalo", a re
derived from the pituilary gland. while olhe'" may
be synthesized in the pineal gland and other struc-
lUres. However, the con""ntrations of several are un·
affected by either hypophysectomy or pinealcetomy.
The brain can function as neurotransrnit_
le",or neuromadulators (33. J? ) that act clC>se to the
sites of synthesis. A few may travel through the ce-
rebrospinal tluid to find Iheir targets.
Mosl of the research on brain peptides been
concerned with influences on behavior and thresh·
olds to other stimuli. or with regulatory roles in the
release of hypothalamic hormones.
THE APUD HYPOTHESIS
This hypothesis was formulated 10 explain the wide·
spread OCCurrence of similar molecules in the brain.
brain-3ssociated 'truClures such as Ihe retina. Ihe
digestive traet. the adrenal medulla and elsewhere,
" ORGANIZATION OF THE ENDOCRINE SYSTEM
and for "ectopic" bormone production by tumor cells
(3&, 78).
It has long been known that the adrcnomC<luliary
the caici\(min,secreling ceUs of mammalian
thyroids and nonmamrnatian uhimobranchial bod·
ies. and Ih. MSH'responsive pigment cells arC de-
rived from the embryonic neural c,ests thaI also give
rise \0 Ihe sympathet ic gall$lia.
On Ibe basis of convincing evidence from embry-
ological and hislocy(Qchcmical studies, it has more
recently been proposed Ihal all cdl, synthesizing
and secreting bQrmones of the prolein. pcplide. and
amine type, originate from neural componcnl.orlh"
embryo. Seven of the endocrine cdl types seem 10
oome from the neural crests. "'hile 29 others arc de-
rived from specialized neuroectoderm components of
the neural lube. neural ridges, and neural placodes.
(Th. plawdes also give rise to optic. olfactory. and
auditory ,tructu res a nd cranial nerves).
APUD refers to common properties of these celis
and is an acronym for amine precursor uptake and!
or decarboxylation. The celis contain amines (e.g.
norepinephrine and scrotonin) along with decarbox·
ylase enzymes that catalyze conversion of amino
acids to amines. Thcy also display similar staining
properties.
W hile the concept is useful, there is good reason
to believe that ali cell, originating from a COmmOn
lygote possess thc potential for producing every kind
of molecule found in the individual. The ability to
produce a given regulator can therefore be indepen·
dently developW by more than one ceil type.
HORMONE SECRETION CYCLES
Regularly recurring rhythms have been demon-
strated fOT all level, of biological activity from indi·
vidual enzymes to ..... hole organisms. Cytoplasmic
clocks have ocen described (39). while othcr forms
of difC(:tioo havc been altributcd to nuclei. Endo-
crine secretory rhythms coordinate physiological
processes in complex animal,. and they. in turn. de·
pend on other body systems for their establishment
and maintenance .
Durations of the Cyclas
Thc endocrine cycles that have ocen most intensively
investigated arc approximately 24 hours long and
arc therefore called cirrodian (circa. appro,imaldy,
die •. day) (2). They arc usually synchroni1.oo with
change, in environmental lighling. However. social
cue,. temperatu re changes. and recurring evenlS re·
laled to feeding·fasting and slcc p-waking palltrn.
can contribute. Wh en a rtificial conditions such as
continuous darkness are imposed, 50me of the
rhythms are abolished. while others become '"free·
running."' Then. some individuals of a previously
synchronized group acquire cydes with periodicities
of less than 24 hours. while oth ers havc ones that
span 25 or more hours. Continuous light has been
known to abolish cycles that can be maintained in
darkness.
Ulrradian cycles are mort commonly lin ked with
specific metabolic pathways or changes in mem-
brane activities. Some found in neurons occupy frao-
tions of a second. cardiac cydes are COmpleled in less
than I minute. and certa in of the secretory pan.rllS
for endocrine glands follow periodicit ies of I or more
hours. (In many cases. the short '"bursts"' of glan·
dular activity are superimposed on ci rcadian cycles.)
Infrodian rhythms occupy morc than one day.
These includc ova rian cycles that reCur ev<:ry four to
five days in 50me of the rodents a nd al interval, of
closcr to 28 days for many of Ihe primates. Seasonal
variations in reproductive functions. migratory aCliv-
ities, body weights, and melal.>olic rale, of some spe-
cics provide examples. a, do the alternating period,
of hibernalion Or lorpor and wakefulness.
E)(ogenou8 Endogenous Rhythms
Exogenou, (or "'passivc'") rhythms arc driven byex-
ternal cUeS that can include changes in humidity.
barometric pressure. and food availability as well as
environmcntallighling. Animals of the Same species
tend to have cycles Ihat are ""in phase"" with thosc of
others housed in Ihe same room . witn maximum
crest. zenith) and minimum (trough. nadir)
values occurring almost simultaneously. Th e timing
is easily shifted by manipulating the environmenl.
Cycles of this kind can persist for a time if tne driv.
ing stimuli arc withdrawn. However, the oscillations
are soon dampened and the panerns are eventually
lOSt. Usually. thc rhythms are reinslaled when the
env ironmental cues a re provided again.
Endogenous (" 'aclive ") rhythms depend upon the
functioos of inlN",,1 oscilla tors or '"biological
cloc ks."' The timing can usually be "entrained" to
environmental fact01'5 just as an alarm
clock can be set for the desired hour. The internal
clocks of groups of animals of the samc specie,
housed under identical conditions are then synchro-
nized. Within limits. thc durations of the cycle, Can
be modified. HowevcT. if the imposed for
environmental cues have intervals that differ mark-
edly from those of Ihe internal signals. the intrinsic
regulatory factors assume dominance. Within a spe·
cics. individuals differ in their adaptability to the
zeitgebers.
Phy , Jolog lcllllmportance o f the Endocr in e
Cycle,
Se'en: di ... uplion oI lhe cycles can bave serious con-
sequences. Deliberate. repealed interference hu
b«n reported 10 sborten the life spans of mice (2).
Minor forms of manipulalion can be tolerated . but
systems do flO1 then perform at OfKimum levels.
In humaM, muchoftlte d$:omfOl"t ("jet laS") u-
perien<;cd Ifter Ioog-distanc.:. air-
plane trips is Duribnted to delays in adjustment of
Ihe endocrine rhythms 10 Ihc new tillt<' schedules.
Pcrsoll!l unable 10 "'(lrk on nisht shifls
scem to have difficuhics in copins with lIdrenooorH·
<:al rh)"lhms that an: imposed by environmental euCl.
S o me Pro ble m a En countered In the Siudy 0 1
Endocrine Rhythm.
MOil hormones are released in "bursts" of "lIrY'na
ma",ituck IMt recur at im=Sular intervals Ihrouah-
(lUt the day. The frequencies and amplitudes of Ihe
discharges often peak at certain limes of the day und
5110 ..' minimum values at difJ"erenl hours. TIH.: pat·
terns <:an be fuliy defined only when then: is conlin-
uous monilorina, U'lU.l.lly, thc)' diifer from one day
to the next. II is often impossible 10 obtain sufi"ocicnt
numbers of blood samples 10 delermine Ihe pauern
for an individual. This is especially true when smatl
whh limited bkx>J .,.oIurne. ,,'" .tudled.
Sinoce the members of a group are seldom in pcrfcct
phase. lhe poolina of samples can )'icld misleading
data.
The men: associa tion of a b;oIogical rh)1hm wilh
a recu rri", environmenta l change docs not establish
a relationship. Animals showing an ab-
rupt rise in the conccnlrati01l of a horrnoroe h:tlf an
IIour after Ihe liahu arc turned on in the room o:ach
mominS may be rcspondina to noises al sllCh times,
Of 10 the movcmcnlsor their C<lacs.
Persisten<:e of a rbythm foliowing removal of a
usua l Cue docs nOt pro,.., that the cyde is endoge-
nously controlled, Animals dependin& upon one kind
of signal unckr ord inary conditions can "leam" 10
11K a dIfferent one. MOfCO'ICr, internally "'!ulated
can provide Ihc dri\'a for passi'" onu.
The can be e"cecdinaly complex a nd
involve multiple neurons, transmitters, and hor-
mones. Attempts 10 \lUt the comp::.nents may
provide stimuli that are BJ1 used uOOcr pb)-»oIogical
conditions.
Neural Pa lhwey. lor Tren .ml"lo n 01 Ph o ll c
S l lmulilo Ihe End ocrine Sya tem
Relinoltypochaiamic tracts Ihat link I'CCI:ptOfl in the
eyes a'llh Ihe h)·pothalamus have been i!ll:nlified for
rats. mice, chimpanzees, and orher sp«ia (70, 11).
Evidently, tbey do no! convey informalion related to
visual perception or eye rclkltcs. Animal.
that fail 10 display behavioral responscs to visual
and have IOSI Iheir pupillary renexes foliow.
ing destruction of the major optic tracu can retain
lisht-<lependcnt rhythms. "Th<lsc rhylhms I", abol-
ished.however, if the animals are blinded by damage
to the relina, $evering of the optic nervu, or re_1
of the e)'C$. Technical difficulties involved in selec-
live destruction of juS! the retinohypothalamic tracts
have not been overcome. [t ,s suspected tha t accom-
plishment of tbal feat would provide uS with animals
that...: bul fail to maintain lighl-dependent cycles.
("The n«d fOf an inlaCt lfllet does not imply tMt
other optic palhways cannot inHuence the rhythms
under physiologica l condilions.)
THE SUPRACHIASMATIC NlIClEI (SCN)
Biblel'lll structures that undcrso circadian "lIna·
lions in metabolic activities and are aifected by tight
on the relina have been identifoed in a wide
varielY of vertcbrntes. The SCN may be internal os-
cillau:W1tllal PM' O/t b;oIoaical rhylhms or serve as
pacemakers (47, 92). They receive inpul$ from lhe
traCIS. a nd they make functional
COIlnoclions with pam 01 the h)'poIhalamu$ engaged
in the secretion of hormones. (They arC not. however
the only <)$Cil1alors present.)
[)estfllction of Ihe SCN in rn\.!. is fol lowed by loss
of all known ei!'Cadian rhythms. LocomotOf aetivi·
ties. fccdina sleep-wake
of pineal aland enzymes. recurrent changes in blood
conc.: ntralions of glucocort icoids and growth hor.
mones. and light-dependent componenls of O"ll rian
cycles are ali afJ"ccted. Electrical ",imulalion of the
SCN <:a u$C$ phase shiflS, and injections of !lCuro-
Irnnsmitten in lhe vicini ly affcci pineal gland
rhythms (92).
In primates, ovulation is cont rolled in different
ways, ",hile r..,ding, slccping, and locomotor aClivity
patlerns are affected mostly by $OCtal cucs. However,
patients with lesions in Ihis pan of the brnin, and
tltose wilh IUmon exenin, pressure on the re,ions.
lose their circadian ,h>COCO<'licoid rhythms. Re-
moval of the tumors often restores normal patlerns.
Cireadian can also be when le-
sions block the lransmission of signals from tlH.: SCN
to other par\.!. of the hypothalamus. If the eiferent
pathways a nd the nudei are preserved. bUI the input
from the retina is destroyed, exogenous.lighl-dcpcn·
dent rhylhms are lost. \lowever, endogenous cycles
persist They become "'re<:,running"' and can have
periodicities of slightly more or slightly less than 24
hours. Groups of animals tre.ated in Ihis Wly are no
Ionser n<:C"f? rily in p/IUC wilh each other.

The Importance of Glucoc ortic oid Rhythms
Glucoconicoids play essential roles in maintaining
blood glucose concentrations during limes of fasting.
They accomplish Ihis largely by fadlitating the use
of ami1l(l acids for gluconcogenesis. Activity of Ihis
kind must be dosely regulated. If it i< inadequate,
the blood glucose falls to dangerous level,. If it is
excessive. too much 1xxI)' protein (which supplies the
amino acids) is destroyed.
The hormones a rc mOSt needed around the time of
awakening. since glycogen reserves arc depleted dur-
ing slcep and glucose is required to fuellhe skelelal
muscles that ,,'ill be used 10 find In hu-
manS a nd others that arc acti ve during daylight
hours. Ihe blood glucocorticoid levels arc highest in
the early morn ing. and the)' dedine to VCr)' low levels
in the late afternoon or carl)' eveni ng. In nocturnal
animals such as rats . the larger meat. are taken at
night, and the gluCOC<lnicoid levds pcak shortly be-
fore the onset of darkness.
Individ uals who feel wide awa ke in the carly
morning but fatigued in the late afternoon have their
glucocorticoid pea ks at carlier hours than "cvening
people" who takc longer to get started but arc more
alert later in the day . When the choice i, available_
adjustment of work and relaxation schedules to Ihe
natural body rhythm. 'can !'e<ult in Breater comfort
and efficiency.
Patients with C ushing'S syndrome (excessi ve Se-
cretion of glucoconicoids) often have normal blood
concentrations of the hormone when sample< are
taken in the morning. They may not. ho"·eoer. show
the afte rnoon and evening decline. Knowledge of the
cycles is useful for determining the hour:< al which
blood samples should be ta ken for diagnostic
purposes.
Pathways Involved In Mediation 01 the
Glucocorticoid Rhythm s
A proposed palt,way lead ing from Ihe light-sensitive
cells of Ihe retina to the adrenal glands shO"'n in
Fig. 2-28. Some dctail$ are missing beeause we havc
ill3dequate information On the locations of the
CRH-sccrcting neurons. and because the roles of
many of the ncurotransmitlcrs involved (46) are
only partially understood. Moreover. nonphotie eues
are used to synchroni7.e thc rhythms. and the SCN
receive inputs from neurons that mediate different
fUfIClions.
T he scheme is an oversimplifIcation. and a prob-
lem with it is that ACTII rhythms do not show peak.
that immediately precede the rises in blood gl uco-
corticoid leve ls. ACTH <ceretion is affected by fac_
ORG"NIZATIOtl Of' THE ENOOCRtNE SYSTEM
light
I
R.liIl3
I
Optic ReNe
I
RetiO<lhyP<tIMlamic
I
Suprachia.ma'ic """Icus 01 hypOlhOtomuS
i ) the, ",,",on'
.... u'''''$
I
cor1k"I'.,.,.,.
I
Zono lasOcvt.ta 01 adrenal corte'
2_2S. P,<>po'Od plIlhway 1<>< . yn<:hrOni, alioo 01
gIuCOOOI1icoid rhyt""" with ot>Ongel "' ..,oiront'r\wn181
1I\I1l\;"g.
tors other than C R H. and thcsc include 'asopressin
(",'hieh is prescnt "'ithin the SCN). Cydical changes
in the sensitivities of adrenocortical cells to a sped-
r,ed dose of ACT!! have been reponed for rats. The
adrenal are dire<:tly innervated . and the impor-
tance of lhis r,nding for control of the rhythms re-
mains to be Adrenocortical cell, main-
lained in culture show cyclical changes in
steroidogenesis. e'-Cn when the ACTH in Ihe me-
dium is kept at constant levcls.
Since they engage in negat i'e feedback control.
glucocorlicoids affect the secretions of both CR!!
and ACTH. The sensitivilies to glucocorticoids also
show cyclical 'arialions. Practical usc can be madc
of lhe observation that Ihe suppression of ACTH se-
crelion is greater in the evening than in the morning
f<>< human subject .. There are clinieal conditions in
",'hieh the di rect actions of exogenous glucocorticoid!
are bener,cial but ACT!! suppression is nol. Morn-
ing admin istration is then indicated. In other pa-
tiems. inhibition of ACTH is desired . and evening
treatmenl is more clfeetive.
Some Consequences of Experimental
Msnlpuletlon
Rats maintained under natural lighling and gIven
con tinuous aCCeSS to food become most active in the
carll' even ing and eat the bulk of their food then .
Their glucocorticoid, f""ding. and locomotor acti,ity
palleTnS arc synchronized . (52.118).
If lhc animals are blinded or maintained in con-
tinuous darkness they continue to have normal blood
glucose levels during their times or fasting. T he glu-
cocortiooid levels peak shortly before they ingest
their largest mcals. and the locomowr activity is
maximal at such times, Thc«:fore. the steroid. fcoo·
ing. and looomotor activities a«: in phase with each
other. but the timing of the cydes is no longer linked
with the hours when others see daylight. II is possi.
ble to shift the timing at will. if food is offeroo only
during certain hours of the day.
Intact rat.s can be trained to cat soon arter the
lights arc turned on in Ihe laboratory if food is of·
fered only at that lime. Then. the glucocorticoids rise
'hortly before the meals. For rats. this means Ihat
the 'teroid hormone rhythms arc oot of phase with
the environmental lighting changcs, They a«: also
Out of phase "'ith somc other biological rhythms,
Effects of $Iress
St«:&1 increases the need for glucocorticoid,. When
it is imposed during times of the day associated with
low glucocorticoid levels. the CRH·ACTH-adrenal
system Can be stimulated. The magnilude of the rc·
sponse. howcver. is smaller than if the stress is im·
posed during peak hours.
When hypothalamic lesions dc-'tmy Ihc sourees of
ACTH and VP. animals subjoctoo 10 sevcre. chronic
stress (e .g. prolongoo surgical manipu lation and
trauma) utilixe peripherally producoo regulalors 10
increase their ACTH secretion (61).
Growlh Hormone Rhythms
Only SOme of the actions of GH are anabolic. The
effects on somatic growth arc most obvious shortly
after the onset of sleep in well'!IOurished juveniles.
At such times. the opposing catabolic elfocts of glu·
cocorticoids arc minimal.
While is released in short "bursts" through-
out the 24-hour period. secretion rales are great"'t
soon after the onset of the nighttime sleep in humans
(and daytime sleep in rats).
Children suffering growth retaMation because of
inadequate endoge!lOus GH can rcspond only to
growth hormone preparations from primates. It is
therefore difficult (and expensive) to obtain ade-
quate amounts of the «=gulator for therapeutic pur.
poses. When moderate amounts arc injected, they
have quantitatively greater effects if the hormone is
given al bedtime than if it is gi"en in the morning.
THE PINEAL GLAND
The pineal gland develops from the neuroectoderm
of the roof of the third ventricle of the brain. In
mammals. it usually takes the form of a small. com·
pact I:nob allaehed to the rest of the brain by a fine
stall:. The cavity of the ventricle for a van·
able distance into the stall:. Pineal gland regulators
are socreted into blood capillaries. but small
amounts may be released to the cerebrospinal fluid
(see Chapter 20).
Although the organ is a part of the brain. most of
the innervation is indirect. Axons from the SeN pro-
ject to the retrochiasmatic nuclei of the
mus. The neural pathway then passe, through the
medial forcbrain bundles of the hypothalamus,
through the midbrain reticular formation. to the
upper intermediolateral cell columns, The laller pro-
vide preganglionic inputs to the lYn'ical
gonglin of the sympathetic s}'stem (located in the
neck region). Postganglionic f,bers then pass to the
pineal gland (50).
The amino acid tryptophan is taken up from the
bloodst«:am by pineal gland cells (pinealocytes) and
is converted to serotonin. An cnx}·me. N.... cetyltrans-
ferase. catalyzes the formation of N.... cetylserolonin.
T he en,yme undergoes circadian variations in activo
ity. Since light perceived by the retina acts on the
neural cireuit to reduce the activity. mOre N·acet}'l·
serotonin is made at night. while mOre serotonin ae·
cumulates during daylight !lours.
The N.... cetylserotonin is the precursor of the pi·
neal gland hormone. me/alonin. and of the chemi·
cally related indole derivati"es that include 5-hy·
droxytryptophol and 5,mcthox)'tryptophol. The
availability of N....cctylser(llonin can be a major de·
terminant for the rate of melatonin synthe£is. but the
activity of a!lOther enzyme. hydroxyindole·().meth,
yltransferase, is involved in the regulation. At least
SOme of lhc mammals make mOre mdatonin during
the winter months (when the da}'s arc short) than
during the summer.
The synchronization of the pineal en7.yme
rhythms with changes in environmental lighting reo
quires all of the pathway just deseribed_ It is dis·
rupted if mammals arc blinded. kept in continuous
darkness. or subjected to destruction of any of thc
following: «:tinohypothalamie tracts (which. a,
!IOted. have not as yet been destroyed selectively).
SCN. pathways leading from the SeN 10 other parts
of the hypothalamus. the medial forebrain bundles.
the superior cervical ganglia. or the connoctions the
ganglia make with both the central nervous system
and the pineal gland. However. the N.... cctyltrans·
ferase rhylhm is cndogenously controlloo. It be-
comes "free'running" when inputs from environ·
mental lighting arc lost (85. 122),
The pineal glands have been directly implicated in
the regulation of several functions associated with
changes in envimnmental lighting. including most
obviously the seasonal hr.eding panerns of many
'poeies. They also regulate looomotor patterns in
birds (in which the functions of the inncrvation
differ).
..
Melatonin \0 mediate some of the effecls on
the reproductive systems and 10 perform several
olher functions_ Its influen= are oomplcx (see ParI
VII). However, in addition 10 this horrn(>ne. the tryp-
toplophots, and sermonin. Ihe pineal gland C<lnlains
ma ny other biologically active com!X'nenls. some of
which arC symhesized Ilte re. The list includes hista-
mine. T RH. and several peplides. There;< only lim-
ite<:! information on the functions of those
substances.
11 has be<:n spe<:ulaled thaI lhe arginine vasotocin
(A VT) reported \0 be present in Ihe gland is of phys-
iological importance. AVT is a major regulator of
water metabolism and sm<)Olh muscle CQntraction in
nonrnarnmalian venebratcs (lltal do 001 ma ke vaso-
pressin). Amazingly sman quantities of A YT can in-
fluene<: lite secretion of hypothalamic hormones in
mammals if the peptide is injoxted into the «rcbral
ventricles. For example. g (fewer than 60 mol.
ecules) can diminish the «,lease of CRH, while
g can inhibit the releas.eof LRH (77). The of-
fects are attributed to actions on serotoninergic neu -
rons, a nd it has been suggesled Ihat a single mole-
euleof A VT can change the functions of one neuron.
Melalonin promoleS Ihe conspersion of pigment
gra nules of poikilolherms, and its actions a rc op-
posed by the mclal1OC)'tHtimulating ),ormones. In-
teracl ions involving melalonin. MSH. and i\ VT
have been proposed. Melatonin and the MSHs are
also involved in conlrol of Ihe fur color of mammal$
Ihat change their coots during the winter.
CIRCUMVENTRICULAR ORGANS
The pineal gland and the median eminence of the
hypothalamus are included among Ihc "Iructures
wilhin the central nervous system Ihat contain neu-
roglial elements lining the ventricles of Ihe brain and
also making contact with the blood capillaries, They
have been implicated in pfOl'ision of funclionallinks
between the blood circulation and the cercbrospinal
fluid , The group includes the subfornical orga/lS,
said to contain the angiotensin-sensitive "Ihirst re-
cePlors:' the organ vas(ulruu", of Ihe lamina Ie,.
"'i/fa/is (OVL n. which has a high LRH content_
the subcommisural organ (SeO), the area poslrema,
the mammillary organ, and also the neurohypophy.
sis (101.1161
GROWTH FACTORS
Sevcral peptidcs exerting powerful in nucnces on
growth , differentialion, and proliferation of specific
OAGANtZA.TION OF THE ENDOCRtNE
cell types have recently been added to Ihe list of bor-
mones. They play important roles in development,
regeneralion, and wound hcal ing. Excessive amounts
probably contribule 10 tumor growth.
Each of regulalors is produced at multiple
sitcs, Both the synthesis and actions arc affected
by other hormones , The peptides have been found in
blood. urine, lymph, and olher nuids, Some have
been recovered from "conditioned media" in which
cells have grown and proliferated (34) , Howcve r, the
peptides are diflieul t 10 study because (a) they arc
released in very small quantilics, (b) their biological
properties overlap with those of other regulators, (c)
m05t exist in mu lti ple forms, and (d) no storage sites
have been identified for most of Ihem .
SommomedillS arc synthesized in the liver, and
probably oIsewhere. in to growth hormone
(1 12). They are be lieved to mediate some of the ef-
fects of GH on bone and cartilage. The failure of
GH to promote growlh in malnourished children ii
attributed to effects of the food deprivation on he-
patic synthesis of Ihe peptide.•.
The lerm lfOtl.fuppreuible itl.fu/in--lik( a(livily
(NS ILA) designales substances in blood plasma
that exert insulin-like actions On adipose and other
tissues but differ from the panc reatic hormone in
that Iheir effects not blocked by antibodies di-
rected against insulin. Some NS ILAs arC similar 10
Or identical with some of the somatomed ins,
Epidermal gl'owlh factor (£GF) stimulates
growth and proliferation of many types of epi thelial
cells. including ones found in the skin, mammary
gland, kidney, ovarian granul05a, lung, oral cavity,
esophagus, stomach , and cornea. It also acts on glial
cells. but has no inHue nce on tissucsderived from the
embryonic mesoderm (e.g. smooth muscle and adre-
nal cortex) . When administered (O neonalal rats and
mice, it promoles eruption of the incisoTll
and opening of the eyelids (12).
Human EG F SetITlli to be identical with urogas-
trone (3 peptide found in human urinc that inh ibits
gastrin and gastric Hel secretion). Since it promotes
growth of the gastrointestinal mucosa, it offers
promise as an agent for the treatment of stomach
ulce rs. High concentrations of EGF arc found in Ihe
salivary glands of male rodents. Production is in-
c«'ased by test05terone.
Nerve growrh fac/or (NG F) can also be: extracled
from rodent salivary gland,. but il is chemically and
biologically diuinct from EGF (58). h occurs in
even higher concentrations in some snake vcnom
glands. NGF is for the survival, matura-
lion, and functions of the neuroblasts of the embry-
onic neural Crests. It induces Iyrosine hydrox)'lase (a
rate-limiting eM.yme for the biosynthesis of dopa-
mine and othe r catecholam ine.), and it exe rts im_
portant influences on the accumulation of ncuroma-
ments and on growth ofaxons. The dfects on
.ynthesis persist after differentiation
has been completcd , Antisera d irectcd against NG F
block development of the systems of im-
animals_ and they bring about deterioration
of those: of adults. Roles in the physiology of sensory
neurons have also been suggestcd. Thyroid hormoncs
inc«'ase NGF concentrations in the brain (114) and
some of their influences on neuron struclure a nd
function may depend on this.
Fibroblast g,awtn factor (FGF) is pre..,"t in pi_
tuitary gland extracts. It supports proliferation of
adrcoocortical cells , As noted_ this action is opposed
by ACTH . which promotes growth and spc.:iali1-<l-
tion. FGF additionally acts on mammalian fibro-
blasts and other embf)'onic mesoderm derivative.
that includc chondrocyte! and smooth muscle <:<:11 •.
Such innuences are not alfe,led by ACTH . T hese
and <JIher growth-promoting peptidcs arc discussc<.l
in Chapler 18.
PROSTAGLANDINS AND RELATED
REGULATORS
PrOl'ltaglandins (PG s), thromboxa nes (TXs), pros-
tac)'Olin. (PG I.). and I.ukotrien., (L To) are .ynthe_
si>-ed from (polyunsatu rated) fatty acid
p«,cursors supplied by the diet (56, 95). They arc
formed in every known coli typo, with the possible
exeoption of the erythrocytes, and they ha,-e been
implicated in every physiologica l function. For ex-
ample, they affect platelet aggregation, ,,'ater bal-
ance, blood p«'ssure, body temperature regUlation,
bone demineralization, lipolysis, ovulation, pnrtori-
tion, and appetite, as "'ell as the secretion of gastric
HCI and of many hormones . They mediate innam_
matory reactions and pain sensations, Disturbances
of their metabolism have been lin ked with a wide va-
riety of pathological conditions (12 1, I 27).
Precursors for their biosynthesis arc sequestered
as components of membrane phospholipids, and of
trigl}"<:erides and cholesterol esters, while
catalyzing their formation have been identified with
the endoplasmic reliculum. The quantity of frc<:
(unesterified) fatty acid p«'cursor is the major de-
terminant of the amount within the celL
Many hormones, and a variety of nonhormonal stim_
uli (e.g. mechanical p«'ssure and trauma) aecelerate
release of the fatly acids. Once formed , some of the
regulators act locally wilbin the cell, while others arc
mtDsportod through body fluids 10 their targets. The
actions are generally of short duralion bc<:ause of the
prevalence of enzymes tha t rapidly degrade the
«'gulalors.
The PGs are a group of chemi.ally related spe-
cialized fa tly acids that differ from each other in the
numbers of double bonds and in the 1000tions of
ygcn groups. In SOme cases, two differont PG. e xen
similar actions on a target cell , while in otbers, the
effects a re unrelated or an tagonistic. (For example,
vascular smoolh muscle that rela xes in «,sponse to
PGs of the E type may rontract when exposed to
PO Fs.) Species diffe«,nces in sensitivities to the reg-
ulators are marked.
The biosynthesis is depressed by glucocorticoids
and by a number of commonly used pharmacological
agents, induding aspirin. Functions of Ihese ..,gula.
tors a.., discussed throughout the text.
THE THYMUS GLAND
This gland is best known for il< roles in the devel-
opment of cellular immunity. It provides a special-
iled cnvironment that supports the proliferation and
maturat ion of T lymphocytes (thymocytes), and it
releases thymosin! and other peptide hormones into
Ihe bloodstream.
The most obvious lnftucnces on tho immune sys-
tem arc exerted early in life. In ratS and mice, the
"critical period" terminates several days after birth
(four weeks postconeeplion ). If the thymus gland is
removed du ring that time, the ability 10 rce<>gni><
and deal with foreign e<=lIs and to cope with most
viral infcctions is permanently impaired. If the gland
is retained until the sccond postnatal week. there arc
more subtle effects on the immone system that can
be exaggerated by exposing the animals to X-irra-
diation or by administering antilymphocytic sera. A
similar critical period during prenatal life is proba-
bly in volved in maturation of the immune systcms of
humans and other large animals. Some of the defects
resulting from (or congenital abscne<=
of the gland) can be alleviated by the administration
of thymic hormones, whereas others arc more effec-
tively corrected with compatible Ihymus gland
transplants.
The thymus gland continues to increase in abso-
IUle si>-e until early adulthood. A process of "age in-
volotion," which i, more obvious for SOme spc.:ies
than for others, is thought to begin before the
imum gland weight is attained. The incidcnccsof ao-
toimmune disorders and of e<=rtain other diseases
with advancing age. Some observers link this with
declining thymus gland functions (59). On the other
hand , small amounts of tissue, especially the epithe-
lial components, persist throughout life.
The thymus gland evide ntly plays important roles
in maturation of the ovaries, and il affects other en-
..
docr'n. funclions. Glucocorticoids. androge",. and
estrogens reduce the Si7.e of the gland. whereas GH
increases il.
REFERENCES
I. Arimu ..... A.. a nd Sd,. lIy. A. V. Prolactin Releo«
Inhibit ing and Slim"lating Fac,,,,, in th.
thal.mg,. Chap. J 2. Pl'. 231_52 of Porler. cd .. ref·
erence 80.
2. Aocholf. J. Circadian Rhythms: Ge .. ral Features
and Endocrinological A,p<01S. pp_ 1-61 Of Krieger.
cd .. ror.rence 51.
3. Beh,ens, U.. and Marlin. C. Ult",,,,uc!u,al
ehanB'S in lhe POr$ Dj".Ii, of Ihe M aturing Male
Rat. J. Morpho!. 136: 53-78. 1972.
4. Bergland. R. 1'01., and POBe, R. B. Can th. Pituitary
Secrete Directly to the Brain? (Aff"mati •• Ana·
tomical Evidence) , Endocri""l. 101: 1325-38.
1978.
S. Berthoud. H.R .. and Jeanrenaud. a. ACule Hype',
in •• linemi. and il' Reversal by VagOlomy afler Le-
• ion. of the Vcntromedi.1 Hypothaiamul in AnC$-
thcti""d Rats. End<XFiltOl. 1M: 146-51. 1979.
6. Bloom. S. R. Ga .. roint."inal Hormone<. Chap. 3.
pp. 71-103 of Cran •. R. II ...d. Gaslroint. sUIUII
Physiology II. I nt.rn.tional R.,iew of Phy<iology.
vol . 12, Vni.eriity Po,l Press. Bahimoro. 1977.
7. Bloom. W ... nd Fn'c<l1. I). W . A r."hntlk nj m .<_
tolot}". 10th cd. &uooors. Philad.lphia. 1915,
8. Br •• l.n, J. T .• Greid." J. E.. McGuigan, N. E..
snd Minlz. D. H. G.min in th. P.rinMal Rat Pan.
Cr." and Ga.triC Antrum: lmmu""fluor=.nc.
Loc.li .. lioo of Pancrealic Gaotrin C.II, and Ga,·
Irin Sterelion in Monolaycr Cell Cul'u .... £ndo-
"rino/, 684-91. 1976,
9, Braddt ..... R . A. NOT" Growtb Factor. Ann. Rev.
Biorhem.47: 191-216. 1978-
10. Breoh •• N.. Kart.n. H. J.. and La..,rad. C. En·
keph.lin Com.ining Amacrine C.II, in th. Avian
Re lin •. Immunohistoch.mical Locali1,ation. Prot:.
Nail. Acad. Sci. USA 76: 3010- 14. 1979.
IL Brownllein. M . J .• P.lkovil'. M .. S.a,<Xlra. J , M ..
and Ki, .r. J. S. Distribution of Hypothalamic Hor·
0'10 ... and NouroHan,minors Within lh. Dion·
c<ph.lon. Ch.p. 1. pp. 1-23 0( Martini ,00 Gan·
ong, ,eference 66.
12. Corpent.r. G .. and Coh.n. S. Epidermal Growth
F.otOri. Bilxh.m. A<,iOKl 0/ Ho"tlO'It, j: 204-47.
1978.
13. D."ghad.y. W. H. Anterior Pilu ita.y, Chap. 2. pp.
27_71 of ["gbar. S , 11. Y"'rin EMorrill()/ogy
1977. PI.num. New York, 1978.
14. Defendi. R .. and Zimm.rman. E. A. Th. Magn<>-
eollul.. N.uros.co ... tory of Ihe Mamm.lian
Hypothala mus. pp, 137-52 of Reichlin.t .1 .. od ...
... forence 83 .
IS. Ddtc<. L. J .• Burton. D.• Cath.nvood. B. 0 .. Bono.
H. G.. P.nh.mo .... J. G.. Guill.min. R.. Walkins.
ORG .... NlZIITtON OF THE ENDOCRINE SYSTEM
W. B... nd Moo,e. R. Y. Demonstration by 1m·
munop<roxida .. IHSlochemimy of Calcitonin in
the Anlorio, Lobeof the Rat Pituita.y. j, t·,..
dorriMi. 47: 457-60. 1978.
16. DeWied, D. Pituilary Neuropeptid., and Behavior.
pp. 297-3 14 of et .1 .. cd ... rofo ... ""o 27.
17. D; amond. J. M, Mammary Gland •• an Endocrino
Orian: Implic. tion< for Masteclomy, 295:
191 _2. 198 2,
18. Di.tel. M .. Dorn. G .. Montz. R .• Ind E.
In nuenee of Vium;n 0,. 1.25·Dihydro, yvilamin
0 ,. and 24.25·Dihydroxy.itamin 0,00 Paralhyroid
Hormone Sec ... lion. Aden",in" 3' .S·.Monoph",-
phate RoIea ... and Uhramuelu,e of Paralhyroid
Glands in O,gan Cuhure. EndorriMi. 1M: 237_4S,
1979.
19. [)ol.i$- Kitabgi. J .. Kilabgi. P.. B.. ' .... P .. and
F... yehet. P. Eff.el of Neuroten.in on Insulin. Glu-
cagon and Sorm,tostatin Ro l. ... f,om lsoialed Pa.·
cr.alic 1,I.t•. Endocrjnol. IQj: 2%_60. 1979,
20. Do, .... D. M .. De Kloet. E. R.. E .. and
DeWi.d. D. Piluitary.Brain Tr.nsport of Neuro-
.. n,in: Funelional Sign;f'cancc of Retrograde
nan,porl. End()l:rill()/. 1{)4.- 1663-6. 1979.
21. Eld •. R .. and HOkfeh, T. Distribution of Hypolha·
lamic HO,mOn<1 "nd Othor P.ptides in lhe Brain.
Chap. I. pp. 1- 33 of Ganong and Martini .• d...... f-
erence 28.
22. Ep<t.in. A. N. Neuroendocrinology of Thirst and
S,lt 4 . rr. In 1_34 of Gan<>n& and
Martini. ed •.. reference 28.
23. Forquhar. M, G.. Skuilolsky, E. H __ ,nd Hopkins.
C R. Structu .. ,nd Function of Ih. Ant.rior PilU'
ilOry .nd Di.persed Pilui\3ry Cells. In Vitro Stud·
ies. pp. 83-135 of Tixi.r· Vidal and Farquhar, .d$. .
referonee 105.
24. Floyd. J. C. Jr .• FOljan<. S. S .. P.k. S .. and Chance.
R, E. A N.wly ReCO!inized P.ne""t;. Polypeptide;
PI .. ma Lt¥<1. in Health and Di ..., •. 11.«. Prog.
/lorm. ii: 519-56, 1977.
U. Frant<, A. G. Studies on th. Role of Thyrolropin
Rel.asing Hormone in Man . Chap. 14. pp. 279- 98
of Porter . • d..... fo ... lI<e 80,
26. Friedman. Y.• Lang. M .. L...... urs, S ... nd Burke.
G. Demonmalion of a Tonie Regu latory Thy'Otro-
pin Eff«t on Thyroid Funelion. EndorriMi. 104:
467-75.1979,
27. F., •. K.. Hokfelt. T .. and Luft . R...d•. Central
of 1M £ndOt;riM S>,'"'''' Plenum. N.w
York,1979.
28. Ga""ng. W. 1'.. and Martini, L, ed"
N.u_ndot;rIMioty, '01. 5. Raven Pre$l. New
York. 1978.
29. Ganl.n. D.• Phillips, M. I.. Mann. F. E.• and Gan.
ten, U. The Brain [", ... nin.Angiot.nsin Sy".m:
Bioch.mi$lry Loc.li1.alion .nd Possible R<>Ie in
Drinking .nd Blood Pr ... ur. R'iulation. Chap. ).
pp. 61-99 of G.""ni and M.rtini. ed ... ref.rence
"
)0. G.rel. J,,"d .. and Ik$nard. P. Milk Factors Con·
 trolling Plasm. Caloitonin Le ..1 in the Now.
born Rat £mJocr;IIOI.I04: 1617-2). 1979.
)1. J. E. Use of Somalostatin in the Study of
Carbohydrate Homoosl ..i> in Man: Biologic. Poth·
<)logic .nd Therapeutic Consideralion •. Chap. 15.
pp. 299-318 of Portcr. cd .. rdo"'ncc 80,
n. Glickman. J. A .• Carson. G. D.• and Challi •. J. R,
G. Diff¢r¢nlial Effce," of S),nthctic Adrcooc<>rtico.
Iropin 1-24 ond a -Mdaooc)'lo..$timulalinl\ Hor-
mone on Adrenal Function in Human and Sh«p
Fetu .... £mJ<>r'iMJ. 104: 34-9. 1979.
33. G""ki. R. A, Neural Cell. as s.:cretory Uni ts.
Chap. 16. pp. ) 19-)8 of POrler. cd .. rdorcncc 80.
34. GO$podarowicz. D" and M<>ran. J, S , Growth Fac-
tors in Mammal;.n Cell Cullure. Ann. R(V.
Bi«htm, 45: 53 1_58. 1976,
)5. Grossman. M. I. Effcots of
testinal Ho'mo .... Fro. PrIX. J6: 1930-2. 19 77.
)6. Guillemin. R. Biochemic. l and Ph)'>iologicll Cor·
",late. of I!)'pothalamic Peplide •. ne Ne'" Endo-
orioology of Iho Neuron. FP. I of Reioh lin et
01" .d •.• reference 8).
37. Guillemin. R. The Endocrinol"llY of the N.",on
and Ihe Neural Origin of Endocrine Cells. Ch.p, I.
pp. 1-12 of Po.ler. ed" .. f... n,"" 80.
38. Guillemin. R. nc Expanding Signifie.nce of Hy.
pothalamk Peplide •. or. I, Endocrinology" Br.neh
of NeuroendocrinolOgy? Ru,. PM: . I/o'm. Rtch.
33: 1-20. 1977.
39. Hara. K., Tydoman, P.. and M, A Cy.
topla.mic Clock w;th lhe Same P.riod a, th. Di.;·
sion C ycle in Xtnopu. Eggs. Pr-ex. /Vorl. Acad. Sci,
USA 77:462-6. 1980.
40. Hargis. G. K.• William •. G. A.. Ro),nolds. W, A.•
CnOrlOw. B. S .. Kureja. S. c.. Bo•.-.er. E. N.. and
H.nderson. W. J . Effect of Som.tos1a1in On Para-
thyroid Hormone and Clle itonin Seerelion. enda-
"illOl. 102: 745-50.1978.
41. Hedo,J . A.. Villanue.a. M. L. and Marco. J. Stim·
or
ulotion P.ncrUl;c Pol)'peptide Gluoagon s.:.
e .. tion by 2-Deoxy.D-Glucose in Man, E.idon,""
for Choli n"rgic Modiation . J. Clin. EmJo",inol.
Mtlab. 47: 366-7\, 1978,
42. Holmel. R. L-. and 8>.11, J. N. Th, Piruirary Gland.
A Comporal;w Ae«>unI. Cam bridge Uni'e"il),
Pr .... New York. 1974.
43, Jackson. l. M. D. Extrahypothal.mic and Ph)'lo.
genetic Distribution of Hypolhalamic Peptides. pp.
217-)1 of Reichlin cl aI., cd ... rdorcncc 83,
44. Jackson. L M. D... nd Reiohlin. S. Thyrotropin R.,.
loa.ing Hormone in tho Blood of lho Frog. lI"na pi-
pie",: [IS Notu", and POS.ible Dcri ... ion from R.,.
iion.1 Localions in lho Skin. ENlIX,jMJ. 104:
1814-21. 1979.
45. Joh nson. L R. Gutroinle,,;n.1 Hormones and
Their Function,. Ann. II .., PhY'/o/' 39: 135-58.
1977.
46. 1""••. M. T .• llillhou, •. E .• and Burdon. J . Se<:r.,.
tioo of CorhCOtropin.Rcle •• ing Hormone in "';(ro.
Chap. 7. pp. 195-226 of Martini and Ganong ... f·
• rence 66.
4 7. JO$Cph. S. A" .nd Knigge. K. M. The Endocri ....
Hypothalamus; Rocenl Analomical Studi... pp.
15- 47 of Reichlin et 01 .. eds .. reference 83,
48. Jooimoyich. J. B" K .. and Boccclla. L
Amn;Olic Prolactin Control o".r Amniotic and
Fetal Extracellular Fluid Walcr and Ele<:troiyte •.
£mJorrinoi 100: 564-70. 1977.
49 , Ke ... l, R. G .. and Ka.don. R, H. TiJ<utJ and ()r.
&an.<: A T,XI_A II". 0/ Sconn;ng £/rrINJI1 Mic,os-
copy, Fre.man. San Franei"",. 1979,
50. Klein. D. C. The Pine.1 Gland: A Model for Ne.·
roendocri .. Regulation. pp. 303_27 of Reichlin el
al.. ed ... ",fo",nee g3.
51. Krieger. D. T .• ed. EmJorrlM RhYlhmJ. R..on
P"''', New Yor •. 1979.
52. Krieger. D. T. Rhylhm. in CRF. ACTH and Cor·
ticoot.roids. pp. 123_42 of K.ieger, <:<I .• refe.ence
"
53. Krulid. L C.ntral N.urotran,mincri and Ihe
cretion of Prolactin. GH. LH and TSH . Ann, /I,".
s.:.
PhYsiol. I: 603 - 15. 1979.
54. L.brie. F.. Borgeal. P .. Drouin. J .. BeauH.u. M"
Lasace. 1... F.rland. L.. and Raymond. V. Mecha_
nism of Action of H)'pothalamic H""mones in Ihc
Ade""hypoph),>is. A on, /I... Phy.jO/, 41: 555_69.
1919.
Lab.i•. F.• D.ouin. J .. Lagace. L. Fcrland. L. Bau·
lieu. M.• Raymond. V .. and Ma"i<:oue. J. Inlcr.",
t;o," Belween H ypol halamic and Pe,ipheral Hor-
mone, atlhe Anterior Pituitary Level. pp.
of Fu,. el .l.. cds .• "'ference 27.
56. Land •• E. M. The Biooynlho.is and Melaboli.m of
Prcotaglandins. A nn, R,". Phy.jO/. 41: 633-51.
1979.
51. Latman, N. S. Stimulation of Ihe Par .. hy ,oid by a
Pituitary Propa.atioo . P'IX. J6: 296 (.<>Str,).
1977.
58 . L..i·Montalc;ni . R.. and Cali'$(II>O. P. The: Nerv.
Growth Factor. S,itolijic- Am". 240: (6) 68_77.
1979.
59. Le",i •. V. M.. Twomey. J. J .. B.alm.ar. P.. Gold-
. lcin. G... nd Good. R. A. Age. Thymio In.olut ion.
and Circulating Thymic Hormone Acti.ity. J. C!in.
t:ndordlIOI. MtMb. 47.- 1979.
60. Linen.n. W. M .• Cooper. C. W .• Bolman. R.. III .
ond W.lI •. S. A.. Jr , Inhibition of In ""'" Secrelion
of Calcitonin in tho Pig by SomatOStatin. ENllXrj·
Il0l.104: 1602-7. 1979.
6OA. La",. J. A. The Adr.nal Gland. chap, ]1. p. l lQJ
of Wei .. and Greep, <:<I •••• eference 117.
61. J. R" and Brod"h. A, Ti"uo CRF:
an ElIra.hypolhalamic C<>rtieotrophin ReleaSing
Factor (CRF) in the Pe.ipheral Blood of Strossed
Rats, NtU'otMIX, /nol. 12: 225 _35 .1 97].
62. Maci.l. R. M. B.,Ouwa. Y.. Chopra. r. J .
Subcellular Loc.liution <>f Thyroxine and R.ye,...
Triiodothyronine Out.. Ring Monadciodin",ins
Acti.itie., ENlOCTi MJ. 104: 365-71. 1979.
63. Marks, N. Biotran.fonn. tion and Degrad.lion <>f
Corticotropin •. Lipotropin, and Hypolhal.mic P.p-
tid ... Chap. 12. pp. 329_77 <>f Ganong and Marlini,
cds .. refe.ence 28 .
64. Martin, J, B. Brain R'gul alion of Growth 110rmone

Secretion, Cll;lp, 5. pp. 129_94 of Martini a nd Gan-
ong .• d,,, ref.rence 66.
M. Martin . T. F. J.. and Tashjian. A. J .. Jr, c.n Cui·
ture Studi", of Thyrottopin.R.I •• si1\3 Hormon.
Action, BilXkm•. Aclio,,", of Ho<monts f: 270-31 2.
1977.
66. Martini. l.. and Ganong. W. F .. ed,. Fronli"J in
NtufWndlXrinology. '01. 4. Ra.en Pr .... N.",
York. 1976.
67. McKenzi •• J. M.• Adiga. P. R .. and Solomon. S. H.
Hypothal.mic Control <If Thyrotropin. pp. H5_50
of Martini. l.. Motta. M .• and FraSChini. F.. ed •.
Tht lIypOlhalamu •. Acad.mic Pr .... N.", York.
1970.
68. Melander. A.. and Su"dl.r. F. Pr=n« and Innu·
.n« of Choli nergic Nerves in the Mouse Thyroid,
t:ndlX,inol. /05: 7-9. 1979.
69. Mell. S. A.• Ddt"'. I.. 1.. Baylink . D. J.. and ROO-
ettron. P. Neuroendocrine Modulation of Calci·
t<lnin .nd Parat hyroid lIormoo. in Man. J. CIi•.
I::ndlXr;,.ol. Mttah. 47: 1978.
70. M<>ore. R. Y. C.n"al Neural Cootrol of Ci=dian
Rhythms. Chap. 7. pp. of G.nong and
Martini. eds .. reference 28.
71. M<>ore. R. Y. The Anatomy of Central Noural
Moch.nisms RegUlating Endocrine Rh),thnl$. pp.
63-87 Krieger •• d" ",f.rcnee SI.
72. M<>rri=)'. J. J .• and Cohn. D. The Effects of Col·
cium and Magn .. ium on th. S.cr.tioo of Parathor-
mono and Parathyroid Secretory Protein by 1<0-
I.ted Porcin. Parathyr<>id C.lIs, EMlXdnol. 10J:
2081-90. 1978.
73 . Moss. R. L. Actio", of Hypothalamic-Hypophy>-
iotropic Hormones on the Brain. Ann. PhyJioi.
1979.
74. Nichol"",. W, E.. Barlon. R. N.. Pu.ll. D.. Orth.
D. N ... nd liddle. G. W. Evid.nce for R.notropic
Acti.it)' in O.in. Pituitaries. Ifndrxrinol. 105: 16-
20.1979 .
75. Obregon. M. J .• P,$(:ual, A.. Morreale de J'.w;>b-.,.
G. and E.5<obar [)(;I Ray. F. Pituitary and Plasma
Thyrotropin. Thytoxino and Triiodothyronine: .rltr
Hyperthyroidism, IfndocFinoi. I(N' 1467_73.
76. Parker. L. N .• and Odell. W. D. Evidenc. for 13,·
;".nee of Cortical Androgen-Stimu latin! Hor·
mon •. J. Physioi. 236.- E616_E620. 1979,
77. Pav.I.S .• luco. N.. Ca lb. M .. " nd R. In·
hibition of ReI.as. of lut.ini,.!ng H<>rmon. in th.
M. I. Rat by ['t",mely Small Amounll of Argi.
nine Vasotocin: Furth.r E.idenee for In.ol.'.m.nt
of 5·llydrO.<)'lryptamin • ..cQnt.ining N.urons in
th. Me<:hanism of AClion of Ar!inin. Vasotocin .
t:ndoainol. I{#: 51 7_23. 1979.
78. P...... A. G. E. Peptides in Bra in and Inte"ine.
Nmuu 262: 93_4. 1976.
79, P.I\3, T...c .. and Gar..,r. S. C. Il)'porcalcitooi..,.
mia Associat.d ",ith Return of Se,um Calcium
Concentration Toward Normal in Chronic.lly
Parath),roidectomiled Rats. I:."ndocrinol. /04:
1624_30.1979.
Ql'lGANtZA.TlOtI OF THE ENDOcRtNE
80. Porter. J, c.. •d. Hypolhalomi(' P'pI/d, Honnon"
ond PilUilary Rqul{JIion. Plenum. New York.
1977.
81. Porter. J. C .• E1kay. R. L. Oliver. C .. Ben.Jona·
than. N.. Warberg. 1.. Parker, C, R.. Jr .. and Bar·
n.a, A. R.I .... of Hypothalamic Hormones under
in Vivo and in Vitro Condition$. Chap. 9, pp. ISI-
201 of Port.r. ed .. ",f.",nee 80.
82. ReiChlin. S. Introduction. pp. 1_12 of Reichlin 01
al ... ds .. rcf.. cnce 83.
83. Reichlin. S .• Bald.... rini. R. J.. and Martin. J. B..
.ds .• Tht HypOlhalamus. Raven Press. Ne,. York.
1978.
84. Reichlin. S .• and Mitnick. M. lliosynthesis 0( H)"
pothalamic Itypophysiotropk Facto ... Chap. l. pp.
61-88 of Ganong. W. F.• and Martini. L , eds,
in N.UfWMIX,inoloty 197 J. Oxford Uni·
vefiity Pr .... Ne'" York. 1973,
85. Re iter. R. J . The Pi_I. vol . 1 of Horr<>bin. D. I'..
ed .. Annual Research Re.i ..... , Ed.n Pr .... Mon-
troal. 1978.
86. Ronaud. L P .• Blume. H, W.• and Pillm.n. Q. J.
Neuropharmacology of th. Hypothalamic Tuber<>-
infundibul.r System. Chap. S. pp. Il5-62 of Ga.·
01\3 and Mattini .• ds" ref.renc. 28.
87. Rhodin, J. A. G. His,o/OtJ-·. 1\ T.xl and Alia,. Ox·
f<.>rd Uni, .... it)" Pr.ss. N...' York. 1974,
88. R<>bberbrecht. P .• Oe$chodt·lanel:m an. M .. and
V.nderha.gh.n. J, J. DemoMtration of Biological
Activity of Brain Gastrin·like Peptide Material in
th. lIuman: lis Relatioo,hip with the COOH·t.,·
minol Octapeptid. of Cholecystokinin. Pro<:. Nail.
Acad. Sri. USA 75: 524-8. 1978.
89. Robertson. G, l. The Regulati,," of V• ..,p.... in
Function in Health.nd Di ...... R.c. Pro&, /lo'In,
Ruh, 3J: l33-74. 1977.
90. Robertson. G. l.. Ath.,. 5.. and Sh.llon. R. l. 0..
motic COOlrOI of Yasop .... in Funct ion, Chap. 6. pp.
125_48 of Andreoli. T. W.• Grantham. J, Land
Rector. F. C .. Jr .. cds. in Body Fluid
Osmolalily. American PhYSiological Soc iety. Be·
thesda.1977.
91. Robinson. A. G, An Aid to Under.
standing the Structu,," .nd Function of tbe Ne.r<>-
hypophysis. Chap, 2. pp. 3S- 59 of Gano1\3 and
Martini. rofe",nce 28 .
92. Ru ..k, 8.. and GtoOII. G, Suprachiasmatic Stimu-
lation Ph • .., Shifts Rodent Circadian Rhythm •.
Sci,,,,,,, ]15: 1407-9. 1982.
93. Said. S. L. ed. Vas"""iv. Raven
Pr .... New York. 1982,
94. S.ito. E.. MuKai. M., Mur.ki. T .. Ichikawa. Y.•
and Homm •. M. Inhibitory EIf.ct of C<>rticosteronc
on Cell Proliferation and Ster<>id<>gone,i. in the
Mou .. Ad,enal Tumor Cell Line y.1. Endrx,i"ol.
1{#:487_92.1979.
95. Samu.lsson. B.. Goldyn •. E.. GrarI>tnlm. E.. Ham·
bert. M" Hammarstrilm. 5" and Malm"e •. C.
p"",,.gl.ndin, and Thromboxancs. Ann, H••.
BilXh.ro. f7: 997-1029. 1978.
 96. Schally. A. V.. Arimur'. A .. Coy. D. H .. K'Slin. A.
J .. Me)·e". C, A .. Redding. T W.. Chih.ro. K..
Hu.ng. W. V.. O.ng. R, C C .. Pedro,.... E .. arid
Vilche",MafliM'. J. HypOlh.lamiC Hormone.
Regutaling Piluil.ry (and olll<r) Functions: Their
Phy.iology arid Biochemi",y •• weil as Recenl
Studies with thei, Synthetic An.IOis. pp. 9-29 of
Fu,. el .1., ed ... reference 27.
97. Seif. S. M .. and Robinson, A. G. Locali,.ation .rId
Rele •• e of Ne.mphysins, Ann, Ht>. PhysioJ. 40.-
345-76.1978.
98. Smilh. J. R .. La H.nn. T. R .. Che.nut. R, M.. Cor-
ino. M. A., arid HOt'ita, A, Thyrotropin_Releasing
Hormone : Stimulation of Colonic Aeli.ily Follow-
ing Intr.oorebro.entrieulat Admini .tration. Sci_
ellM 196: 660-2.1976.
99. Stein, L.. arid Bell ... i. I, D. Brain Endorphins:
Possible Mediators of Plea.ure.bk Sme •. Chap.
34, pp. ]75 - 89 of Usdin, E.. Bunney, W.. Jr .. and
Kline. N. S. eds. i::miol."hi", in Mtnlaillealth
Odor<l Unive"ily P",ss. Ne'" York. 1919.
100. Slraus, E., and Y.low. R. S, SpceicsSpceificityof
Cholecystokinin in Gut and Brain of Se..,ral Mam_
mali.n Specie' , Pro<:. Nat/, Acad, Sci. USA 7j:
486-9.1918.
101. Stumpf, W. E.• and Sar. M, Stcroid Hormone Tar_
gel Cell< in Ihe Pcri.. ntrieul .. Brain: Relation.hip
10 Peptide Ilo,"lOne Prooucing Cdl •. Proc. 36:
1913_1.1917.
102. Tannenba um. G. S.. ROr<tad. 0" and Bra,eau. P,
Effec" of Prolonged Food Deprivation on Uhradian
Growlh Hormone Rhythm .nd Immunorea"i'e
Som.tost.tin Ti".< le.el . in the Rat tondo"'illol.
104: 1733-8. 1919,
103, Thad)" A. J , The MSH Peptide.,. A.odemi. P", ...
New York. 1980,
104. Thorn. N. A .. Russel. J . T .. Torp-Pederscn. C ... nd
T rtiman. M, Aelivation of Rele.se and Mech.nism
of Rd.a .. of NeurohypOphyseal Hormone •. Pl'. 49_
60 of Fuxe el .1.. ed . .. refe",noo 27.
10:1. Ti,ier-Vidal. A.. and Farquhar, M. G.. cd" The
Pi,,,lIary, Academic Pr .... N.", York,
1915.
106. Uhl. G. R .. Child.". S. R .. and Sn)'der , S. H.
Opi<>id Peptide. arid the Opia l. Receptor. Ch.p. I I,
Pl'. 289-328 of G.""", and Martin i. ed •. , refer.,..>,
".
101. Unge<, R. H-. and Ore i. L PhY$iology and Path(>.
physioloiY of Glueaaoo, Phy.• iol, Ht>, 56: 118-826.
1916,
108. Unger. R, H .. Dobbs, R. E .. and Orci. L In,ulin.
Gluc.gon and SomatOStatin Secrelion in the Reg.
ulalion of Melabolism. Ann. Rev. Ph,'siol. 40: 301-
43.1978.
109. Unll"" R. Ii .. Ras kin. P" Srikanl, C. B.. and Orci.
L Gluc.gon and the A Cell •. Hee, Prot. HtNm,
Rsch 33: 477_511. 1916
110. Vale, W.. Ri.ier, C, arid Brown, M. Regulator)'
Peptides of Iho HypolhalamU$. AM. Rt>. Phy.,ioJ.
)9:473-521.1971.
Ill. V.le, W.. Rioier, C .. Brown. M.. arid Ri .ier. J.
Pharmacology of Thyrotropin Rclc'$ing FoetOT
(TRF). Luteini.i", Hormone Releasinll Factor
(lRF) and Somatostatin. Chap. 1. Pl'. 123_56 of
Porter. ed .. reference gO,
112. '(U Wyk. J. J .. Knd Underwood, L E, The Soma-
tomedins Ind T heir AClioo$, af
Hom"",,. 5.- 101-48. 1918.
Ill. Vijayan. E .. and McCann. S . M. In '(iY{) and In
Vitro Effects of Substanoo P and Neurolensin 00
Gonadotropin and Prolaelin R.le.se, f.'miocrinol.
105:64-8.1919.
114. Walker. P.. Weichse!. M. E.. It .. Fisher. D. A..
Gup. S, M.. and Fisher. D. A. Thyro, i.. Inc"'a ....
Net •• Growth Faeror in Adull Mouse Brain. Sri-
tI1u]()4: 421 -9, 1979.
11 5. Wahet, R.. ed. Ne urophy.ins: Carriers of I'<:plide
Hormon",. AM. N. Y. Arod. Sci" ..01. 248,
116. Weindl. A. Neuroendocrine A,pec," of Circum.en·
trioul,r Qrgotru. Chap. 1. pp. 1_12 of G.nong, W.
F.. and Marlini. L. eds, Fromi". in NeUTfvmiocTi-
nolag}' 197), Odord UniversilY P..,... New York,
1973.
117, We .... L. and Greep. R. O. lIi'toJOKY, 41h ed.
McGraw-Hill, New 1971 .
118, Wilkinson, C W.. Shin.ako. J .. and D.llman. ;<.\ .
F. Daily Rhylhm . in Adrenal Re.pon.iven"" lie
Delermined Primarily by the Time of Feeding in
Ihe Rat, f:rrJoc,illol. /Of: 350- 9. 1919.
119, WiliiamJ. R. H. GastrOinlestin.1 Hormones. Chap.
14. pp. 68S_714 of WilliamJ. R. H .. ed. Textbook
a/l;.'"docri""lor.v. 6th ed . Saunders, Philaddphia.
198 !.
12/). Windoxk_ R.. Brown. E. M.. Gardner. D. G., and
Aurbach. G. D. Effecl of Gam<>inteslin.1 Hor-
mone. on lsolal.d Bovine Parathyroid Cells. 1:.',..
doc,;no/, 10): 2020-6.1918,
121. Wolfe. L S .. and Coceani. F. The Role of Prosta-
glandins in the Cenlral No!>ou, System. An", Hev.
PhysloJ. 41: 669- 84. 1919.
122. WUnman. R. J.. A"lrod. J., and Kelly, D. Th. Pi_
MIJ/, Academic Press. New York. 1968.
123. Y.m.moto. T.. Schu<d7.iarra. V.. • rId Unger, R. H,
Pancreatic and D Cell F.n¢Iion in Hypeph_
yO-CClomi,.cd nog.. i::ndoc,llIoI. I(U: I 559- 62, 1919,
124. Yen , S, S. C. Studies of the Role of Dopamine in
the Control of Proiaclin and Gonadotropin Secre·
tiorl in Human •. pp. 3S7-416 Qf F..e el aL. ed, ..
tefe",noo 27.
12:1. Yora, T .. Mm ..a ki. S., Kondo. V., and Ui, 1'1 ,
Ch. nge. in the Contents of Multiple Components
of Rat Piluitary Thyrotropin in Altered T hyroid
States. £miocT,IIoI, 104: 1682-S. 1919,
126. Zimmerman, E. A. Loc.liution of Hypothalamic
Hormone. by Immunocytochemical Technique •.
Chap. 2. pp. 25-62 of Marlini and Ganong. refer-
ence 66.
121. Zor. U.. and Lamprechl, S. A. Mechanism of Pros-
toglandin AotiOO in Endocrine Gland<. Biochtm.
Arlio/lS of Hormon .. 4: 85-133. 1917.
_ _ ___ 3
Hormone Biosynthesis and Metabolism
On the basis of chemical makeup and the associated
pallcrns for biosynthesis. storage. release. and me-
tabolism, it is convenient to divide the hormones into
the following groups:
l. Ami1U's and related regulators. each syn the·
Si1.cd from a single amino acid
2. Small pep/ides comprising just a few amino
acids that al"<' joined in peptide linkage
3. and prOleiru containing larger
numbers of amino acid, and peptide bonds
4. Gl)'(Oproteins containing carbohydrate moieties
as e"emial oompOnCnlS
S. lodinarNf thyroid hortmJltf's. with lyl'()Syl moi-
eties held together in ether linkage
6. Steroid hormones and calerJero/s. sy nthesized
from cholesterol
7. Prru/aglandins and rdated molecules derived
from essential fally acids
There h.ve been suggestion. thaI glyc=miooglycao,
(GAG.) .nd other sugar derivali.e. pcrf<>rm cndocrine
funclions. The chem;cal mueture. of the pr<)p<l><d regu·
lators. their mochani,m. of .ction. and the f.Olors that
controllheir rei ••,. have not as yet \>Con determined_
BIOSYNTHESIS OF AMINES AND RELATED
REGULATORS
small. waltr·soluble molecules are d«arbox-
ylmed derivativcs of amino acids provided by food.
The enzymes Ihat catalyze the reactions are free in
the cywsol. associated with the endoplasmic reticu·
lum. or enclosed within organelles. When more than
onc step is involved in the pathway. theT<' is a rate-
limiting enzyme_
The cells that make these regulators have mem·
branrxnclosed granules that serve some or aU of the
following functions: (a) storage of the hormone; (b)
protection of Ihe molox:ules againSI degradation by
cytoplasmic enzymes and leakage aCross the plasma
membranes; (c) participalion in the mechanisms for
secretions; (d) reuPlake of molecules previously re-
leased (which permits rapid termination of thc hor·
mOne actions. and also prcservalion of the hormone<
for recycling); and (0) provision of a suitable cnvi·
ronment and appropriatc enzymes for transforma·
lion of one molecular species into another.
Histamin e
Histamine is made directly from the amino acid his-
(Fig. 3-1 ). 11 ;" syn the,i.od in substantia!
amounts by the mast cells of most species (!9). and
those account for the high histamine contenl of
organs such as the liver. Histamine is also made by
neurons (9!) and by basophilic leukocytes_ It is pres-
ent in parts of the hyp:Xhalamus and piluitary gland.
This rcgulator se ...... as both a neurolransmiller
and a hormone_ II promoles Hel secretion by gastric
glands. contributes to Ihe regulalion of the adernr
hypophJlSis. and is in_olved in ovulation. 11 incre35Cs
capillary permeabili\)" affects Ih •• mooth muscle of
some blood Ve"5els, is a mediator of inflammatory
and allergic reactions. and is involved in thc sensa·
ti0T\5 of pain and itching.
There markcd species variations in
In highly resistant animals, such as ralS. serotonin
lakes OvCr some mast functions Ihat are
by hislamine in others (19). In guinea pigs. minute
quamiti .. can invoke falal bronchoconwiClion.
Gamma-AmlnoButyr lc ACid ( GABA )
GABA is made directly from glutamic acid. It is
present in the hypolhatamu$ and in Ihe
thalamic brain, in which it Serves as a neurotrans-
mintr and It is an important reg·
ulator of several kinds of endocrine cells and it is
believed by some to function as a hormone.
 Serotonin
The prcliminary oonvcrsion of tryplophan 10 S-hy-
droxylryplophan is Ihe rale-limiting step for the bio-
symhesis of serotonin (5-h)'droxytryptamine. 5- HT)
in the pineal gland . some brain ne urons. the mast
cells of many species. the enterochromaflin cells. and
also the parafollieular cells of the thyroid glands
(22). The amine is taken up by. stor<:d in. and re-
leased from blood platelets as well as mast cell s of
most vertebrates.
Serolonin functions dire<:lly as a regulalor. and it
also It"C! as thc pre<:ursor for hormones of the pi_
neal gland. including melatonin (N-acct}'I-5-hy-
droxytryptaminc). 5_hydroxyuyplophol. and 5-
met hox ylryplO phol.
Cetecholemines
Tyrosine is directly takcn up from thc blood,u'cam
by c3te<:hoiaminc-sccreting cells. bUI cn7.y mcs thai
catalyze the formalion of Iyrosine from phenyla la -
nine are widely distributed_ (Therefore. phenyla la-
nine can serve as an alternate precursor.)
The Tate-limiting step for Ih. biosynthesi, of do-
pamine (DA) is thc conversion of \yro«ine \0 DO PA
(dihydroxyphenylalanine. Fig. 3-2) , A dccarboxyla·

,/ , ,
, ,-
, Histidine decOlbo)()'la... , ,,C-'
He C-C-C-H HC C--C-C--H
I I H I - 00, I I H

',-
N....
,
NH COOH
,
HIST,o,MIN E

,,, Glutama'. d"""rbOx),!"'" , "

HOOC-C-C-C-COOH H-C-C-C- COOH
I' , - CO. •
I "
,-'
,-'
" "
Glut>.mic acOj
"''' ,
8 , <::,
,
- 00,
'" , ,I
C-C-H

ov-"-,, ,,
S-OH -Tf)'Plopha n
'"
o S EROTONIN

, i-Ii
"COCH,
,. ,....H;jjr.::cP
,
j_"
',00 8 "',r- HI"'HHO H H
, ,I
C-C-H
· CH, Ii
C-C-H
H
C--c-OH
H H

MElATONIN j
5·0H·TRYPTOPHOl

, ,
, ,
C-C-oH

,/"---,,
5-METKOXVTRYPTOPHDL
Fill. 3-1 . hi.ta""".
Bio. ynt!les<. of G,o,e,o" aoo a<;id """",bOxylasa. (3) .... acelylt'.n.l ....... (.1
melatonin , ( 1) T'yptophan hydroxyla ... ( 2) 'CO' ..... I.. .. a ... _
" HORMON E 61O$VNTHE$I$ -'ND META6O\JSM

"1/"
•
I"
"C - C-H
" ,
"0
D;/)yd,.,J<YpIHlnylalani"" (OOPA)

"
,1/"
II\'H I
HO-(I \}-C - C- H
_ H

DOPAMINE

,0 -
Ji-o• .,ase

/" P t>enylelhanola m;ne'

y" --,,, H i'CH, N·CH .-T,onsle.-a.e
(PNMT)
HO-( r C - C- H •
o, "
"
EPINEPHR INE NOREPINEPHRINE

tion 'lep then provides the DA. which is laken up by
secrelory granules (10).
Dopaminergic neurons directly release DA (Fig.
3·3). The amine serves important !lCul'I)lransmiltcr
functions. Among Olher things, it participates in Ihc
conlrol of skeletal muscle contraction. affects behav-
ior. and dilates ce,tain of thc peripheral blood vcs-
<;<:1 •. It is a major regulator of prolactin release and
;1 inAuences the secretion of olher adcoohypophysial
horm<)lle$.
The $Ccretory granules of noradrcnergic neurOIlS
and adrenomedullary cells contain an enzyme thai
oxidizes dopamine to norepinephrine (NE). Suo.
stantial amoun ts of NE accumulate in sympatheti·
cally innervated organs such as the heart .
Certain neurons and some cells of the adrenal me-
dulla contain a ditTerent cnl.yme that catalYlcs
methylation of norepinephrine to yield epinephrine.
Since the enzyme is in the cytoplasm. norepineph.
rine must lea"c the granule to be actoo upon.
Amino ACids
Amino acids that function directly as ncurotrans-
miltcrs and neuromodulators include glycine. glu-
tamic acid. and taurine. No true hormone functions
have been establishoo.
Acetylcholine
Acetylcholine is mentioned he", because ;t exertS
long·range trophic aClions that arc hormone-li l e
 BIOSYNTHESIS OF SMALL PEPTIDES
Thyrotropin-Releasing Hormone (TRH)
Although dipeptide, that affect behavior havc been
de!iCribed for the brain (15), TRH (a tripeptide) is
the smallest hormone of Ihis group with funy eSlab-
lished fu nCiions. As it. name indieale._ it promotes
th. sceretion of thyrotropin (Ihyroid-;<;timulating
hormone, TSH). II affects the release of prolaclin

--
and of other pituitary honnones. TRH is made in
Saaebon
g'an<Jie

.'-
Saaetion

conlaining
/!-o"".e
.- ""'"aining
<Iopamine
/I-oxidase
neurons outside of. as well as within the hypotha la-
mus, and it has been .hown to inOuence behavior and
other brain functions . It also present in the pineal
gland. in the gastrointestinal tract . and at many
other sites.
II ha, been proposed Inat TRH synthesis is aC-
( ) ( ) complished by cytoplasm ic en'.ymes; and a TRI-!_
symhetase bas beo n described. In support of
NOI'EPINEPHRINE NOREP INEPHRINE lhe cancepl, it has bee n demollStrated that labeled
S. Norad'"",,'gic glutamate is incorporated into TRH in cell-free
oeuron 0""
ad<er>ome<Iulla"1
j
EP INEPHRINE tems cantaining hypothalamic componen ts, a nd that
the process is unaffected by agents that block ribo-
C. Adr.ne'gie somal assembly of peptide chains (63) ,
Od",norneOuI""1
However. it has also been shown tha t the rate of
TRI-! production is more rapid than woul d be com-
pa tible with the gl utamate incarporation mecha-
Fig . 3·3 . - . 01 .... '.,oty go-ar\IJle. in nism . and that impair the symhesis
, 'orage, and of calecholamln • •. (50). This suggests thai a mechanism, involv-
ing cleavage of the tripeptide from a la rger precur-
sor. supplements (or is more important than) the cy-
(80) and it is p!"<'sent in nonneuronal tissues (10), toplasmic enzyme system.
Ahhough choline Can be obtained di!"<'ctly from food,
it is also synthesized along pathways that resemble
Melanocyte-InhibitIng Faetor ( MIF-I)
the Ones described for amine hormones. The amioo
acid serine is first dccarboxylatcd. S-adcnosylmc- Ce rtainly. cleavage of large pcptides is the major
thionine and acetyl..:oon7.ymc A are then used as mechanism for the formation of the small peptidcs ,
methyl and acetyl donors. re&jlC\:tivcly (52). The Melanocyte-inhibiti ng factor-J is a tripeptide impli-
same molecules are needed for the conversion of se- cated as a regulator of melanocyte-stimulating hor-
rotonin to melatonin (Fig. 3-4). mone (MSH) release (66). It i'l iden tical "'ith Inc

H H ....... H
--;;::-'- HQ - C- C-N
- co, H H "H

H H ,/"CH,
HO - C - C - N - CH,
H H "CH ,
Fig_ 3-4 . Bio' ynth§l. ot
ACETYLCHOLINE -,yIot>otioe,
 I-!OFIMONE BIOSYNTHESIS AND r.tETAIIO\.ISM
" til H, ma kc ""ninc vasoprcuin (A VP), ..·hich is also
0-,\ 0 0 H If k _·n IS antidiu",lic hoiiiM1C (AD H) because of
I K H H II ...C-C 0
o-c I II its potent innllCnees on lhe kidney. Domeslic pigs
......... . / ' "C-C-C-NHr and al least one specic:sof mice make the biologically
N ?H' H H ",llled l)I$ine vasopressin (lVP), while hippopota-
PytogM.myI " He"
,,0,
NIf ProIino_
muses and some of Ihcir relatives form both pep-
lides. The names are dcrived f!"(Om Ihe etTe<:ts of high
Iiil lidy1 concentralions on Ihe smooth muscle of the blood
vessels. Physiological amounts probably contribute
A. THYROTROPIN RELEASI'tG HORt.IONE (TflH) to lhe control of blood pre$!;u", aoo blood
distribution.
" H Va$OJll"cssin (VP) can nament the secretion of
1 / ,0H H f { H
&luoocol1icoids by actin& on neurons. conicou0pc5.
0 H II0
H C_C_N--C-C-H_C_C_ NH, and Idrenocort ical cells. It affects leaming and
H I H
H CH, Rel ated peplide! implicated in regulation of blood
I
0- pressure and watcr metabolism in nonmammalian
n
vn
-
PfC/y1 CH. eH, GIycN_ verte brates include arginine vasotocin (A
( whic h is also reported to be prucnt in mammalian
brain and pineal gland). mCSOloci n, and i5010Cin (I).
9. M£LMIOC'I I E INIiIBlTlNG FACT()R.I (MIF·I) A P=UIWI" protein is cleaved 10 yield vasoprcosin
plus In a»OCiated peptide variously b,o,",n as vaso-
Fig . 5,
prasin-ncurophysin. nicotinwtimulated neurophy-
sin. and pressoph)l$in. A ditTerent precursor gives
rise 10 oxytocin plus oxyltK:in-neuroph)l$;n (eslrogen·
side chain of o:<ytocin. and enzymes catalyzing 111P- slimulated neurophysin) (f"lg. Hi). While Ihere has
lure of the Cys· Pro peptide bond arc pr<:Knt in pi- been much spe.: ulalion coMcern;ng possible functions
\ILita ry extracts. (hg. 3· S). of the neu!"(Ophysin& the suggestion that
molecules of Ihis kind found in largct organs serve
as receptors), no definilive roles have been es\.ab-
O)l.ytocln, Vllopr...lnl, l od Re ,ated
Hued. An intrigui ng sUggc:$tiO!l Ihal a yel Larger
Peptlde. protein KfVCS as a coo"ll_ p=ursor of VP. Wl)·tG-
'J'hc5c I>ormclMs ring s1l'uewres held IQgClher cin and both neurophysins (604) is not e;uily recon-
by disulfide bridges. and sbon sido-<;hairu;. An CQn- ciled wilh some very re«nl studies discussed in
.. in tyrosine. proline. asparaaim:, glycinamide, a nd C hap. 10.
LWO cY$icines. Each of the peptides can be c leaved to yield
O xytocin was initially identified as a hormone smaller molecules that atTect brain functions. The
made in magl>OCellula r nuck:; or the hypothalamu5. rina su ucture of (Iocinoic acid) is also
stored in ,lie neural Lobe of the pituitary gland, and known 1$ MIF· [!, since il may contribute \0 regu-
released"into the peripheral blood 10 ael on myoepi. lation of MSH secretion. while a pcntapeplide coo-
thel ial cells of the mammary gland and on uterine sistina of or 11K: amino acids of lhe rina lias been
musele. n..: bonnone present in the cxlra hypot ha· called MRF (melaflOC)·IMlimulating
lami<; Inin, in which il can II'f'cc:t behavior. It hu leasing ractor) (Fig. 3-7) (66. 72).
also been found in the oval'ks (20, g2). In
nonmammalian venebrates. il on smooth mu ..
Spiel.. SpeclflcltL..
cle (including components of the oviducts of bird.).
Within the mammalian hypolhalamus. most of Some of the &malieSI peptides a ppea r 10 be idcntica l
the oxytocin is synthesized in neurons of Ihe para- in aU speci es. These incl ude TRH and LRli (71).
nudei. bUI some is made by Ihe supmop- Olhers a", ditTerent, but usually the molecules made
lie cells. by one animal type are bioIoaically active in others.
VlSOpreuins we", fi<$t shown 10 be synlhe5ized in All 01 the larger pcptides show species variations.
the supraoplic nllclei. but they I"' also made in and there are corresponding varia tions in the prop-
neurons Jnd in olher p,aru of lhe hy_ cnies of the hormone receplon.
potha llmus IS well as the Cltrahypotha1.tmic brain. Species specificilY for one regulator cannot be pre-
Production may be limited 10 mammals. MOiI'I dicted from knowledge of another. Thus. whereas
 p",Iein P",curso< P rOl"" PrewlOO'

/\
Vasopre • ..., VASOPRESSIN
/\
N .... opnysin
OXYTOC IN
NO .. c>phyS" /

S"",IIo<, BIologically
Acli"" Peplide. TOC INOIC
ACID
(MIF·II) MIF·I

Fig. l-tI. Hypotl>eticl.l oe".""" lot

D'ner bioeyntl>e.I. 01 ' 0 __ .',;0,o.y_ .
It.RF PCplode. .nd 100o",d small peptKIM,

'" TYI,
·1 1e Cys
I I
Gin Cys .P,o· Leu ·Gty·NH ,
''00/
OXYTOCIN ARGININE VASOPRESSIN

LYS INE VASOPAESSIN

I
Cys· T)"". IIe·Gln.A$n.OH ARGIN INE VASOTOC IN
MAF1

"'T)"" .....
lie Cy'
I I
Gin ........ ",Cys.Pro.no.Gty. NH,
'00

" T'I" .....

lie Cyo
I I
$c, "),.,( Cy$. P ro.I",.Gty.NH,
Fig. 3·7. N.....""ypopl>y.i.1 po&ptidlrs
ond ,"18tllod !'l>OlectJlM. •Pr.ssI". III ••
pl>enylatlni.... I t OIdicol"<l poSiti"",
ISQTOC IN IOCins III' . looIeuc;ne.
 "
pip produce. different from Ihal of hu_
mans, Ihe two sptties synthesi« idcnlkal anglo/t ....
li",; bUI C<)WJ and human.s lhe oamc va·
sop«:ssin. whil<: their angiolen.sins arc slightly
different.
Some Other Hypothalamic PeplJde.
Luteinizing hormone-releasi ng hormone (L RH )
contairu; 10 Imi no add moieties. It promotes Ihe
lease of both rollicl<>-s(imulaling harmonc and h.-
leinizing hormone by pituitary ,lands. is a s.imulant
of reproductive behavior, and ucrts other
on the brain , Large doses of LRH can inhibit p
n.adal funcl lons, probably because they inlerael wilh
=ptors for . different . bu1 chemically related pep.
tide. The IlJe of \ong-ac1ina synthetic analo&s for
conlra«pli()JI has been proposed. but prdiminary
ItslS indicate thai Ihey 100 effectively depre.os Ihe go.
nads to be of pract ical U!-C.
Somatostatin (SS) is the most ubiquitous of all
peptide-type rcaulalOf'S. Amoog other things, il in-
hibits the Sttrction of growth hormone by pituitary
cells. of glucagon by the palKfCaS. and gaMnn by
stomach glands. The first re<:ognizcd form. which
ball 14 amino acid and is therefore now
S5-14. i. shown in Fi., l.a. S5..28 and OIher
members of the aroup. alona with Ibe putative JlfC'"
a N: diKUssc=d in Chap. 18.
Pcplides Ihal ACTll and GH have r(o
cenlly been identif,ed (see Chap$. 7100 18. fUJ!«-
lively). Dopamine is a major inhibitor of PRL
tion. but prolactin.rdeuing factor (PRf') Bnd
addilional prolacti ..... nh ibitins hormones ( PI Fs) are
still being sou,ht.
Neurotensin Ind Substance P IN: found in the hy-
pochaLamus (IMI also in the ,ut and al OIher JitC!l).
Pyro-G .. ·HOo. Trr .(l,ty·l ....... 'V' P,g..GI¥.N Ii,
lUTEINIZING !1Q!!MONE IIElE"'S'NG HQII!,!QNE IllIHl
N.·Gty·Cys.l \'I ........ Pho-""-- T'P"l.,.. Ttr·Phe· TIV' .s.r.Cys
, I
SQM",TQST ... TIN·14
GIu-Uu- Trr.Q.,.AsM. ,s.f'fo."'V"""lI.p...,.T1'1' ·/Ie·leu
NEUROTENSIN
A.r9· P,o-l\'l·Pro-GIn·Oln·"""·f>he.Gty·letl·"""
SUBSTANCE P
fl9 .3.... Some I>OJI'Wt lila,
_ _ • to "" I I R _ _ 01 piluitary
Thcy s«m 10 fUlKtlon mostly as !>Curocra,"milters
Or neuromodulators. Their precursors arc a lso being
!iOU8bl.
A llhou8h ansiotensins a re synthesized II many siles.
those formed when re nin is released from the kidney
arc Ihe t>cst known.
T he livc:r ..... a slycopMcin
and delivers il to the bloodstrea.m. "The prefemxl
name for the prOIein is now rmin sutmrou. Older
ones indude angiotensinogen, hypenensinogen. and
The term refcrs to enzymes made in the kid·
ocy and 1\ other sites that deave a dceapcptide. an-
aiOleouin I. from til<: slycoprotein. While Ihat pcp-
tide has _ bKIIogical .etions. much of it is aeted
upon by an enzyme in Ihe lungs (convc:n,na en-
zyme). A dipeplide is Ihen rerncwed. and a ngiotensin
II (A-II) ;1 formed, The anliotensins I and II found
in humaou and many OIher IIUImma ls are sbown in
Fig. 3·9. Aminopcptid ascs an deave lhe A· II 10 a
heptapeptide. A· III .
Among OIher Ihings. anaioxensins are major reg-
ulators of aldosterone secretion. They are hiahly p0-
tent vasoconstrictors, and they slimulale the sym·
pathetic system. IJra in anSiOiensin is believcd to be
involved in Ihirst perception and in cenlral "'Iula-
lion of .... ter balaroce and eardiovascular f"nctions.
Bradykinin is a vasodilalor produced at several
sites. The an8i01eouin converting en1.yrt\(: also aets
on this substrate. However. in thi' case it cleaves a
biokog ica lly potent molecule and Ihereby brings
aboot illtJNi<'Qlicn. (T herefore. conver! ins enzyme
aclS in more than one way 10 raise blood pl"essure.)
Inhibitors Ire Il0''0' used to lreat hypencnsion.
MULTIPLE FORMS OF INTERMEDIATE-SIZED
PEPTlDES
ll>c gtlSlrilJ5 are SpeCiCHpccific hormones present in
multiple forms within tlte $O rne individual (4. 81).
The need for $0 many d ifferen t types is IlOI under_
stood , si nce molecule. Ihal are of sim ilar .ize do IIOt
S«m 10 dilfer in biololieal activities.
Type II pstrins have a sulfaled tyfO!;yl moielY.
" 'hereas type I gastrins are devoid of su lfur. " Lillie"
gaslrins (with or without lhe S) have 17 amino acid
components. They arc rapidly released in substantial
quanlilies in response to the siahl. smell , and tasle
of food. and when food enters the stomach. Among
other functions. the)' p'OihOie lhe Sttretlon of hydro-
chloric acid.
 ,
... NG IOTENSIN Asp-Atg. II al· T yr ·11e·Hi$·Pr.,.Phe H;$' Lou

J ConvMiog en"Y"'"

,
ANGIOTENSIN Asp. Arg. II aI· Tyt ·110 ·Ift$· Pm· F'tIe

j "'mioopeplidase

A.NGIOTENSIN "''9.11 aI· Tyt ·11o·H;s.Pro·Phe

Fig. 3·g . Biosyntl"l<llil ol aogio""'lios.
'"
"Big" gastrins arC found in higher concentralions
in Ihe secretory cells. but only small amounts are re-
leased at mealtimes . G-34s resist enlymalie degra·
dation and are oonsislently presenl in the plasma.
They are only 20% as polenl as G- 17s for stimula-
tion of Hel. Since they are cleaved by panerealic
trypsin. thcy may be precursors of the sma llcr mol-
ecules. It has been proposed Ihat Ihey exert Iong-
range, growth·promoting innuences on Ihe gastroin·
leSiinal mucosa and On Ihe exocrine pancreas (81 I.
"Mini" gastrins laCk !he firsl Ihree amino aci ds of
the G-17s. Their biological aClivi!ies are ., im ilar 10
those of Ihe G-l7s. and they may be either lrue hor-
mones or degradation products thai rotain biological
aClivity (Fig. 3-10).
All of Ihe mammalian liule gawins ... similar in
amino acid makeup and biological poIency. Thc.se pro-

• • " • • '0" ...... .... "

T,p.l .. ,.m ,.m,.r.. .,.r..". AI •. Tyr .GIy. T .... .,,·"""

HUMAN MINIGASTR IN·II 1G·14)

,, , , , , , •,
" ...."a· T"yr. GIy·
Pyro-Glu. Gty. Pro· T'P"leu·G ... ·GI<J·G ... -Giu ·Giu· " " "
" T"'p"Met·Asp.Pf\e
I
'0,"

HUMAN UnlE GASTRIN II (G.17l

BIG GASTR INS

Fig. 3 ·10. SI,uctur. . of t..man rrint. liWe. on(! big

gastrino. "'''0_ in<Iicoll oillO of .. vage by j,yp.....

"
duced by bog. differ from lho human 100100"1.. in the
substitution of a melhionine moiety for lh. i<uO;". com·
ponenl at pO$ition S. thO&< of the dog na". Ihc .... me me-
thionin. ,.Mli,",ion pius an .Ianin. group in pT."" of
glutamate at position 8, while the ones found in 'hocp and
CO"" ba'e. valine in Ihc fir,h position and an .Ian;"" in
,h. 'enlh,
Most Q( lhc biological activity resides in Ihe car-
boxy terminal tetrapeptide amide of lhc larger mol-
W ilile all of the hormoll<'s are formed from larger
precursor proteins, the ·'big·big" gamins found in
thc blood arc believed 10 be molecules of thc sir.cs
sllown above thai arc complexed wilh oonhormonal
proteins.
LARGER PEPTIDES
Pancreatic Glucagon
Pancreatic glucagon. frOO1 mammals .$ divcrsc as
the human. camel, and rat all have the same ar-
rangement of 29 amioo acids. T his somewha t un-
usual (but oot un ique) finding is probably relaled to
the observation Ihal the entire moke"le is needed for
biological activity.
Guinea pig •• ynthesi2< an atypical l!lueagon. (They
also make iMulins. grOWlh hormones. and Ih)"roglobul ins
Ihat differ from those of most other man1mal .. ) The glu·
cago,," of birds and amphibi'n$ di]fer from the mam·
malian type •. Thi. may be related to speci.1 the
hormone $trve. in those vertebrate •.
In mammals the most important effccts are ex-
erted on the liver. They incl ude stimulation Ilf gly-
cogenolysis and of other metabolic processes that
contribute 10 thc maintenance of blood glucose
concentrations.
ImmUl10reactlve Gluca gon (IRG) and
Glucagon-Like Immunoreactivity (GLI )
Molecules sharing immunological properties with
pancreatic glucagon arc collectively koown as I RGs
HORMONE ANO METABOLISM
ecules. and this component alone exh ibits somewhat
more Ihan 10% the (lOlency of G·1 7s for stimulation
of hydrochloric acid secretion. A highly active syn-
Ihelic analog. pemaga.<Ir;tl. is widely used in reo
search studies and for clinical diagnoses. II is an N·
terl-bUlyl ester of Ihc !clTapcptide amide that has an
N..:arboxy-P-alanyl group attached to tile trypto-
pllan moiety.
(16.77). "T rue" with 29 amino acids has
a molecular weight of 3485. and IRGs of this size
are known as glucagon 3.sClO. They have been found
in Ihe fundus of the dog and in extracts of
Ihe small intestines and oolons of pigs. G lucagon
2000, which lacks biological activity. is be·
lieved 10 be a degradation product. Glucagon 9000
has been called Its ])0-
tency is si milar 10 lhat of gl ucagon )SOO. Biologi·
cally active IRGs with weights of 29.000 and 70.000
from human and rodent salivary glands may be ag-
gregates. since they dissociate to yield "fragment$,"
one of which is similar to the 3500 form.
The pancreases of several species contain IRGs
with molecular weights that range from 12.000 to
65.000. These. and a glucagon 4900 present in small
amounlS. have not i)e<,n shown 10 poSSess biological
activilY·
Four lRGs have been identified in blood plasma.
including 2000. 3.sClO_ and 9000 types. The fourth,
referred 10 as "big plasma glucagon:' BPG. Or
"macro- IRG," seems to be true glucagon associated
with a circulaling protein.
The name was given to the major G U
component of the intestines of several mammals. be·
cause it was initially believed to contain 100 amino
acids. When purified by gel filtration. it has an ap-
parent molecular weight of 12.000. T he peptide has
recently been sequenced, and it is oow known to have
60 amino acid moieties and a molecu lar weight of
8128. It contains the entire sequence for pancreatic
glucagon, and it way well be thc proglucagon that is
cleaved to yield the active hormone (22/\).
h bl& 3- 1 ... rnioo ... "'" 01 GIuCOQO<I 3500, creatic enzyme prrxluclion_ The best·known form .
SfJeretirt, YIP, a<><I GIP with 33 amioo acids. contain, the terminal penta·
peptide sequence found in gamins (Fig. J.! I). It is
G lo", '>1\ &<0,«;.
'"
GIP
'" not surprisi ng. Ihcrefme, that CC K-PZ can act in
, II i. 0 0
,,0 J(l GI,
some ways as a ga,trin receptor agonist and in OIhc,",
as a C(Impetitive antagonist. How",'cr. unlike Ihe ,il·
2 s",
'"
0 0

l (an ( I\'r A.p ) Glo "»

J2 GI)' uation described for gastrin. the runc,ions of CCK.
• GI)'
j Th ,
0

0
",
V.1
0

0
L)'J
). L)'J
PZ are lost if the sulfate group is removed.
CCK-PZ has been implicalcd in the rcgulalion of
"'" 3S Se,
0 0 0
food in ta ke. since oxogenous adminiSlration leads 10
7 Th,
'" )6 Asp
0 0
ea rl y termination of meals wi,hom excrling obvious
Se, 0
M, 0
JJ T)"
9 Mp
10 Tp ,,,
Glu r,,"
T)',
0

0
)g
39 !!"
t Is etfcct$. /\ smaller molecule sharing immune>-
logical and biological properties has been identified
HI, 40 I\,n in the brain. and il may inH"ene<: behavior. /\ higher
"
0 0

M, molccular weight CC K-PZ variant. with 39 amino

12 I.)"
11 Tp Leo '"' "
.\101
"4l4) Gin
'"
Tn, acids. has been found in the gut.
.. Leu
15,I,p
16 s",
M
0

0
'"
I.),>
GIn
0

L)'.
Caerulein. ewacle<.l from frog skin. is a decapop-
lide that chemically resembles Ihc terminal jXlrlion
,II. of CC K.PZ. and it mimics aClions of thai hormone
17
"'S 0
M"
M, '"
0 when injectcd into mammals ,
,q AI, I.,," GI. The Slruclural similarities of the "gut" peptides
20 (; In
M,
0
'"
L)'.
I.)"
0
are consistent with sUggeSlions thai all mRNAs for
"IIJJ !'he "'g
l.0" Tl"
0
Ihis group were dcrived from common "ancestral"
genes,
V,I ( I.," I.,"
,,, I 0

14 (an 0
M,
II Ttp G I)'
"'"
0

0
Catclton!ns
J6 1.<" 0

II Met Calcilonin, are by the parafollicula r "" Ils of

A," '"'__ :o'm ,
",
I."
", mammalian thyroid glands. and in the ultimobran-
29 Th'

, • "",;.., . <id """,it- '" -«'<oi'

'".'" "or'"
or," '·W ,I,,,
chlal gla nds of vertebrale" They havc also
been found al (IIh"r sites. including the intermediate
lobes of mammalian pituitaries,
While all of Ihc molecules st udied thus far have
J2 amino acid moieties. a disulfide bridge lin king the
Secretin at positions 1 and 1. and a terminal proli·

This hormone has 21 amioo acids, 14 of which arc

idcntical with ,hose of glucagon JSQO (Table 3·1), II ly.·AI •. P,"'Se-r.Gry-... ,g. YoI.Se'-Met-IIe· .....
sharos some biological proporlios with glucagon, in-
cluding ,hc ability of high C(Inccntra,ions '0 stimn· Se,-IIe-.o.rg.His.St"P,o-",Sp-ltIJ.Ser-GIn-leu)
la,e insulin secretion (4). However. it is bellor
known for ils roles in augmenti ng ,he V<llumes and "'-AsP.""9.MP. T yt, -Met-<GIy' T,p.Mct.A.p.Pi;)
bicarbonatc C(Intents of panc reatic a nd bile. Se·
crelin also shows chemical simila rities to vasoactive
intestinal poptide(VIP). CHOlECYSTOISININ·PANCREOZYMIN·:)3
Gastric inhibilory poptide (G IPl is anothcr mcm·
ber of Ihis group. and il a highly potenl slimulant
for Fifteen of the first 29 amino acid
5·(>• .,. P,,,,GIn' ASp.. TY, -<lily-T'p.M't -Asp-pile>
are the same as those of glucagon J500. ,
Cholecystoklnln·Pancreozymln (CC K-PZ ) C... ER UlEIN
first pari of name of this peplidc rdc"" to FIg . 3 _1 1. "'mino lOCi<! C<>mp(ai'''''' 01 CCK·PZ·3(1 l lId
slimulatory inAucnce, on
gall bladdor bile; CYSI.
$mooth muscle ()f Ihe
kinin. actio
c.".,,,,,",,,Pon,ap*pti<le "_ nee wilh ;.
citcltod. Mt .... isl<. SI>Ow add it;onal Imino acid. common to
vator). while the seC(lnd deootes stimulation of pan· CCK·PZ ond ClonM<n_
 IiORMOtlE BIOSVNffiESIS .... NO METABOLISM
" Ser· Trp-Ser ·Met ·G1u- His·PIle .Arg .T'!>"G1)i
(£) @
CyS_GIy_A.n.leu_Ser. ltv -Cys· Me1·l..,·G Iy. Thr· T)'t-Thr·8 In
, , )
(@ ® Ala -TN -Gin-Pro- Pile· Thr· Hi.·Pt>e·l y•. A",.Phe-A$j>
®@ ®@@ l
pt,e·Glu·Leu·Pro-Phe ·...... )
lie· GIy· GIy-AIo-P'<>-NH,
3-13. Amino aCid 10< hurnIon ACTH .
erE-) ® @ ( 1) (M". ...CTH hu (2)"''P. "'CTH 1>&0 Lou. (3)
"".....nd too,i,.. "'CHI ha. . Gin.
Fig. 3·12. An>ino aoid for humin calc;tonIn.
Ami"" acid moi.t;n oj salmon ""\<:it",,;,, lhal . r.
ohown In to. cOr ... o.

mans and other species making mostly conisol pr<r

namide, (here are marked varialions in the
amino acid sequences (60) (Fig. 3·12). More than
ORe ki nd il made in some of (he fishes.
Adrenocortlcotroplns ( ACTHs) and
Melenocyte-Stl mulatlng Hormones ( MSHs)
The "liltle" ACTH. of all studied thus
far have 39 amino acids and identical scqucno:<:s for
po:;itiQns 1_24 and 34-39. Porcine and bovine lill1e
ACTHs diff.r at One position. and ovine ACTH at
\WQ (Fig. ).1). The hormone' from one animnl type
stimulate adrenocortical cells of another. and all of
the molecules (hus far isolated arc active in humans.
Since th. molecular weights are a11 close to 4500.
"lillie"· ACTH is also known as 4.SK ACTH. '·I rt-
tumediate·· (13 K) ACTHs (with apparent molecu·
lar weights close to 13.(lOO) contain the same amino
acids and. additiona11y. carbohydrate. Rats, mice.
rabbits. and others make more of such molecules
than of the oonglycosylated type. It has been pointcd
oot that these animal. also mostly oonicostc-
ronc as their primary gluCClOOrticoid. whereas hu·
duce the 4.5 K ACTH as Ihe predominant form (54).
However, suggestions of a cau......:ffect relationship
have not been supported by observations of the re-
sponses to administration of Ihe Iwo kinds of ACTH
(21 ).
"...Melaoocytc stimulating hormone (a- MSH) is
an acclylated derivative of Ih. first 13 ami,..., acids
of ACTH . It is made in substantial amounts in the
pituitary glands of mammals that have brgc inte r·
mediate lobes. and also in the glands of human fc-
IUseS. In addition to its actions on pigment cdls. this
peptide exerts innuences on water balance. repro-
duction, and other biological functions (76) ...·MSH
is also made in the brains of all adult mammal ••
where it serves as a neurotransmitter or
neuromodulator.
Species-specific 18-amino acid ,8· MSHs that
share a 7-amino acid sequence with the a·type hor·
mone (sec Fig. 3·14) are found in bovine pituitary
gland extracts. The belief thai humans makc a pep--
tide of this kind is no longer held . but ..,...MSH s (y.
melanQtropins) wilh $Omc similar chemical and bi.
ologieal charactcristics have been identified. All of
the ACTHs and MS Hs arc derivatives of pro-opi·

Fnl 13 .""no
acids of /lCnt: Ser· T.... ·S"' ",1 ·Glu ·His·Phe·Arg· T yr·G ys·Pr,,"Voi

JJJ
CH,cO· Ser· T..... Ser et ·GIu· Kis·P he· ... rg. T .... ·G
J II
yo·Pto·Val

Asp.$er.Gty· Pro· T..... l y. el·G/u·fI; .. Phe·Arg. Tyr.G r·Pro·Pro·lys·AW

Tyr.Val Me l

Fig. 3·14. Compo,ri"",.ol MSH. wiln lflii 13 amino

ae"" 01 "'CTK. Tho _nee".-.quire<llor .,imlJ lation 01
pigment cells ar • ..-.closed.
 . ...--...
•
,
FIg. 3-15. St'UC1U'''' of ;nsulins ar>d ,erato<l ••. A.
1><0""" "
RoI.t;o.,,,,'Ps
inoulin. EaCh
pr";noulin ond ,he A on<;! B chains of
rOflf'lOMlS 0"" amino .oicI ro"""-. T""
Diad< ",,010. belong to ,he C Chain 0< oonMCting
"'- e;rcle • • how the A "".In; arod e .,,"-in i,
,,,,,, • ...,tOd by 01<'101 eire .... Ci<e!ft. X
Qmelan(lCQrtin. a large precursor protein that is dis-
cussed later in tbis chapler.
Insulin8
The insulins are sl"'cic<-S[lC<:if,c peplides
A chaim linked by disulfide bridges to R chaiM(33).
They arC cleavage product. of larger prO;n.,ulins
that additionally have a ronn«ling (Fig. 3·
151\). T"'0 dipeplide, oontaining arginine and lysine
arc discarded when the molecules arc process.d. but
some prolinsulin and oonllCcti ng peptide arc ,olea,.d
into the blood along with the hormone. The amino
acid Fot human insulin ar<: shown in Fig.
3-158, along with the posit ions for wh ic h speci""
variations have demonstra led.
The A ehain; of caul. have an al.nyl moiety
at po$ition 8 and a valyl al posilion 10. "..hile lhooc of
sheep. goals and eleph.nls diWer from hum.n in,ulin. al
po$ihons 8. 9 and 10. The 8 chain, are idenlical in hu·
man. and elephanls. Tho:« of co".. ... h«p. goats.
and dot' arc identi""l 10 e.ch mhor bUI .11 have . ler_
min.1 al.nine. Gui""a pill insulins diW.. from the hum.n
molecule, in 18 placo, . and these "n im.l, rc."""d poorly
10 hormon .. I.ken from moot ot her mammal •. MOSt of
the fi,he. have an extra amino .cid in the " _1 0> po$ition
(i .e. preceding what COfrc'pondlto Ihe fnl t moiety of the
mammalian forms of the hormone).
R." and mi.e produce idenlical pepli de' .• 00 both
make at le"1 tWO different kinds (i"-'ulin 1 and insu lin
II) . Multiple for ms ha.e al'" been found in fishe •.
'I'1it of <luting 100000tioo 01 &elive h<>rm(>ne. B.
_ acid sequence 01 hun,.n .... uI .... .... t<tri ... . iMicoI.
poli1l0n, lor which ..,..;u diW",,,,,,,,, • •
indiC/It" !lrst om; rtO aCid ot ... -<:hain;
r. kf><)wn . .... ,
B-t indat •• first
amino acid 01 B-e/Iain.
PROTEIN HORMO NES
Authors disagree on where to draw the line between
large pcplides and small prolei ns. Some refer 10 in·
sulin as a peptide. while others call il a prole in. The
same can be said for the parathyroid hormones.
Tbe {IOTOlltyroid hOTmoneS (rTH) are species·
specific molecules. T he most prevalenl forms idenli-
f,ed contain 84 amino acid componenlS. 1\ higher
molecular weight pro-hormone and smaller frag·
menlS are also prescnt in the blood plasma (Fig. 3·
16). The parathyroid hormones are secreted by am-
phibi.ns. birds. and reptiles as well as mammals. hut
Ihey have not been found in fishes.
rTHs a rc major regulalors of calcium and phos-
phorus melabolism. and of bone growlh and remod·
eling. They also contribule to Ihe mainlena nce of
acid-base balance.
Growth hOTm()lles (GH s. somatotropin,) exhibit
tne mOSt obvious species specificities. Thc hormones
made by callie and sheep stim ulate growlh in ralS
and mice. but th cy are inclTeclive in humans. The
most oommon monomeric form in humans. oom·
monl)' referred toas hCH, has 191 amino acid moi_
elies (42) (Fig. 3·17). Different molocular species
are present in normal human pitu itary gla nds and
blood plasma . The proteins share some common
amino add seq uences and biological properties with
prolac!ins. hCH is e.en more closely related 10 a pla-
cental hormone. :;ornalomamrnotropin (human pla-
cenlallaetogcn, h PL).
 BIOSYNTI1 ESIS AND MET A60l1SM
"

' ....
(-31 to _7) H,.N.MeI.""" )

cs:. .oJa.L)'S.ASP' MeI.VaI'Lys. VaI.Me"lie.v a l.Mel)

--
'co
( - 6 10 -1)
.... r9'AI" lOU' P..... CY' -U.-Ala-Leu

L ys-s"r -V..·L ys-L YS-A'9)

(Ala -VaI-s..r-Glu-lle-G ln-P""-Met_H;s·"""·Leu

.
""
(1-&1) .'
( GJUov a'.Atg.GIU.Met.s..r.Ser. Leu. HiS. LYS.Gly
)
Trp.lOlJ·Ar9"Ly$.Ly ••

Se<.l)'$.GIn-Hi"SOf.GI<J.VoI.LOU.VaI.A$n.ASP)
(!.eJ.(;,ly.OIO.Ala .... sp.L,s-Al ...... P.Val •.o.sp-V31
HOOC·GIn,P'o-l ys-..... ·LYS.!I<I.lOU)
Fig . 3 · 111. Am;no aQd _ o o s tor
t>oYiOfl pre-propor. thyroid I>o<0'I0n&.
....'''';sIe. ShOw poSilionS on P TH 1-3.
lor wt>;ch spooc", ••,fllion. a ,. k oown.

• " ..

- ''' -

",

•
, --",
,.- . . .

Flo;! . 3 · 17 . Tile amino ocOd seq-.ce 01 hGH. All amino

ad<l1; . r. '*ogl • .., in , .... t form. (LI. re! o42 )
BIOSYNTHESIS OF POL YPEPTJDE AND
PROTEIN HORMONES
Amioo acids supplie<! by the bloodstream are taken
up. combined with the appropriate transfer RNAs.
and sent to the ribQsomes for a"",mbly into peptide
dains.
The messenger RNAs (mRNAs) that direct the
synthesis arc made in the nuclei . They code for per-
tide chains considerably longer than the hormone
molecules. The hormone plus the additional amino
acid sequences eonstitUlo the pre-prMo'mone Or
p,ehormone,
A "signal hypothesis" for the me<:hanisms of bio-
synthesis of proteins destined to be from
tbe cell has ocen formulated. and it is well supported
by experimental data (45) . It applies to albumins.
coliagens. pancreatic enzymes. immunoglobulins.
and other oonhormonal secretory products. as well
a, to proteins incorporated into thc plasma
membranes ,
[)etaile<! studies of the biosynthesi s of parathyroid
hormone (25. 26) are consistent with the following
scheme. which depends on ",Ieetive protcol%is ,
I, An amioo tcrminal "signal sC<jucnce" contain·
ing hydrophobic amino acids is assembled on frec rio
bQsomes. The chains proje<:t into the cytoplasmic
matrix,
2, When the chain is long enough to span the large
<uhunit of the ribosome (20-30 moiet ies)' thc sianal
sequence promotes association of the ribosomc.pc!>,
lide chain complex with the membrane of the endo-
plasmic reticulum.
J. A methionyl peptidase catalY'.es removal of the
initiator componcnt. and Ihe nu<eent chin i. dis·
charge<! into the cisternal space.
4. Amino acid chain assembly continues within
the spae<:. Shortly before all of the amino acids have
been added. or imme<!iately afterward. an en1.yme
("clipase") associated with the endopb smic rcticu·
lum catalyzes cleavage of the glysyl·lY1yl bond be·
tween the signal and the "pro" sequences. This 1'(:.
suhs in shortening of Ihe initial gene product of II S
amino acids to a prohorrnone containing 90.
S. The signal sequence is probably mpidly dc·
graded. since it cannot be found in parathyroid gland
cells. (h has been recovered from e<:1l·frce s%lemS
used for translation of mRNAs extracted from
glands. Those syslems lack degrading enzymes.)
6. The prohormone is translocated to the Golgi reo
gion, in which a different, trypsin-like "prohormone.
converting enzyme" within the vesicles catalyzes re-
moval of the prosequenc. to yield the active hormone
conlaining 84 amioo ac ids.
The Iransl""ation is time..,.""uming, When labeled
• mill(l acid. are incorporated inlO thc peptide. Ihe label
cannot be detected in lh. Goigi reg",n until oftcr 2(} min.
The proccs$ts evidently require A TP erl<rBY but not ne,.
protei", (.inco they can be disruptcd by agento that im·
pIIir ATP formation but not by protein synthesis inhibi·
10.. (71).
Somc inve'tigators envi.ion a "pe,;".1tic" type of pI'<>
pulsion lhrough a <:Qntinu,,"S tubul .. network
"".n,it"'nal dements" of the endopla.mic reticu1um
..-ith GolSi ,'.oiete •. Evidence in favor of direet partici.
patiOn of GolSi <:Qrnponents inc lud •• ob$crvatiOl1o that
amin •• and "'nophor<s blocking remov.1 of th. N·ter·
min.l amino acid "q ue"ce also cau" chang'" in th.
Goigi memb .. nes (26). Othe .. h" 'e ,uu.sted that the
.e.id•• enclosing lhe molecule, actua lly by!>"ss the
Golgi, MicrOlul>ulu sum to be involved. , ince <X>ichicinc
.nd vinblastine impair thc proceueo,
Not all of the prohormone is cleaved.
7. Finally. thc hormone. along "'ith some prohor-
mone, is enclosed in secrctory granules. It is stored
for subsequent release into thc bloodstream. The
granules seem 10 CIl'iginate from the vesicles. Their
"maturation" includes a process by which the hor·
mone is concentrated,
PTH can be found in the granules
30 min after the pre-prohormonc is formed . When
the PTH requirement. are low, much of lhe hor.
mone is degraded within the cell.
Following discharge into the bloodstream ,
undergoes furthcr cleavage. Some of the fragments
(ones oontaining the f,rst 34 amino acids) are biolog-
icallyactivo.
PREHORMONES AND PROHORMONES
While all polypeptide hormones seem to be derived
from p",horntones. some may OOt have the pro S(;.
qucnccs (Fig , 3-18). None retain the prcscquences
PRE·PROHOAMONE RiMsome
(PRE HORMONE)
)
EnOopIasmc
,eticYkJm
.Ii PROHOAMONE
I
i
o
o
•.
1' - PCp4ide 1"''''''lu'e
"",,' ctO<}'
ACTtVE HORMONE
Fig . 3-18. BioS)'fIthosiS of prot..., aod peptKll> hOrmon..
1,,,... hig/le< moItoJIar .. preo..roorl.

(which are discarde<:l after the peptide has been di·
re<:tcd to the endoplasmic reticulum).
Proposed and Demonstrated Functions 01
Pro hormones
I. At least some of the prosequenccs arc needed
to stabih>e the thre&dimensional configuration of
the peptide chain. By maintaining proper align·
menlS. they assure that the intramolecular bonds
subsequently formed will be in the right places. This
function may be especially important for hormones
such as insulin that have disulfide bridges,
2. Ribosomes synthesize only large peptides.
Many of the polypeptide hormones are too shart to
be directly .ynthesi7.cd and rdease<!.
3, The prohormones seem to havc properties that
suit them for intracellular transport and paebging
into vesicles. (In COntraSt. the finishe<:l hormones arc
spcciali7-C<1 for interactions with re«ptors.)
4. Since CQIlversion of a prohormone to a hormonc
is accomplished rapidly. the larger molecules Can
serve as readily recruitablc reserveS.
5. Shortening of the proharmorn: requi«,s a special
en1.yme. Regulation of ilS activily can provide cells
wilh a control sile for hormone production Or
,kgradati,""
6. Prohormones are gern:rally mal"<' resinan! to en-
zymatic degradation and excretion than thc smaller
molecules, and they have longer half-lives when Ihey
enter the bloodstream. They could Iherefore serv<:, in
SOme cases. as trophic agents Ihat exert long.range
effe<:u. As noted earlier. the "big"' gastrins (which
can be cleave<:110 yield the smaller ones) exert such
influences on the pancl"<'as and gastrointestinal tract.
7. Several of the prohormones have biological
properties resembling tnose of Ihe hormones. but Ihe
potencies are low. Prohormones could therdore be
«'leased during times when the need for Ihat of
regulator il; limited.
II hm; also been speculated that molecules used
earlier during Ihe Course of evolution in the form
arc now being processed in specific ..-a}'.
to subsuve new funclions.
The concept is compatible with suggestions thaI
"as one ascends the cvolulionary scalc·'. "'new uses
are made far old hormones". Thus, for example, thy·
roid hormones affect reproouclive system malura-
tion in fishes and metamorphosis in amphibians. bUI
they take on the funclion of accelerating metabolic
raleS in mammals. Similarly. prolactin-like proteins
regulate water and eleclrolyte balance in fishes.
while their best known actioo in mammals is
wilh milk production.
HORMONE BiOSYNTHESIS ... NO MET "'6OltSM
HORMONES DERIVED FROM PRO-
OPIOMELANOCORTIN
Pro-opiomdanocortins (POMCs. pro-cortieotropin·
lipotropins) are large glycoproteins made in pitu-
itary glands and brain Ihat serve as prohormoncs for
ACTH s. me\anOlropins. endorphins (38, 39, 47 )
(Fig. 3·19). and also for newly discovered peptides
that synergize wilh pituitary gland regulalors of ste-
roid hormone production (55). They were at one
time referred to as ··big·big ACTHs··.
The primary u-anslalion product of the mRNA is
a protein with a molecular weight of around 2lI.®
(28K ACTH) (Fig. 3·20). It has been recovered
from cell·f«,c systems in which the synthesis is di.
rected by RNA extracted from piluilary glands.
Within the glands. the prolein undcrgoes rapid gly·
cosylation to form prodUCIS namcd for Iheir appar·
ent molecular weights 29K, 12K. and J4K ACTH.
(All have approximately 240 amino acids. but they
differ in carbohydrate content. The exact weights
arc difficult to determine. because gcl separation
methods arc affecled by molecular sh ap<: and this
often leads to overestimations.) The 31 K form ini.
tially describe<! seems to be a mixture of glycosy·
late<:l forms. Nongly=ylated ACTH precursors Can
be recovered from cell s troated wilh tunicarnycin.
Pul"" ... ha"" .t udi..,. """d to determine
the arrangements of the hormone-yielding segmcnts
wilhin the pl"<'cursor proteins. Adcnohypophysial
corticotropes oontain en1.ymeS that catalyze thc for.
malion of mostly ACTHs and ,lkndorphin (and Ihe
IWO regulators are known to be «,leased from the
:lamc granules) (27. 46), Pars intermedia mclano-
lropeS cleave ACTH and thereby make .,·MSH and
CLIP . may be arlifaetually derived from
the lipotropi n sequence during
The .tructural gene coding for human POMC
been ,hown to be similar 10 Ihe oorrcsponding genes
of other mammalS . Regulatory sites for glucocor-
ticoid con trol have also been identified (9). The
peptides Inat promote melanin synlhesi. in humans
may be -y-melanotropios. Lipotropin· rich exlracts
of pituitary glands oonlain substa nces wilh such
aeti. ity,
Pars distalis and pars intermcdia process the en-
dorphins in different ways (90), The della, gamma,
and alpha forms seem to arise from cleavage of tne
beta Iype at specific points.
Endorphins are present in both brain and pitu·
itary. The enkephalins predominale in most partS of
the brain (although there is considerable p.endor-
phin in the hypothalamus). Although the amino acid
sequence for mel.enkephalin is conlained in the en·
dorphin molecule (Fig. 3·21), it is certain Ihat mOSI
 e" 16K
", A I _3& ", jHI?QTROPIN S<:l9rnen1
/11- 9 '
,W
!

I'
E]

,,·END
61_76
I
I'
6 1_65

Fig . 3-1g , ,. 1.,0<1 pept;(\w, (II ",,'min. , P'lPli<Ie: NTP, amlno-l.,."";n,1 pePI;OO; W M,
I>os oot _ "..,'0'''''.'0<1
' hat tI·oodOq>/>in i. prO<:4'_ peplido UOOC1in1l c"",e .. "'YI "tor. .." ".M.
... _no '" '''''' FB aM Met.", made;" (hi. way.) Pro.,
CP. e<>n..c1;ng OP, "",'o<»:.y. oondorphin. FB. ACTH 1._ _ , oft"", ing _.ioI,
.... MSH; CLIP. OOO'licotrop;Mb ..I _ I e I'@!lIKle:END .

I N·Peplido !l-LIPOTROP IN

,
I I I
r
ACTH CP tl- LIPQTROPIN
,
0<, ? Cart>o/'Ty<l<ale

, ,
CP ! tH IPQTROPIN ••
".
'00 '00

Fill. 3 _20. F<>fflUltionOI"" il!ie" ACTH

--",
* nongIyc<»yl.,od) . tId
"lntermedia t. " ACTf'! (13K ,
0<, gly<:osy\el00d), CPo OOM/JC1ing P'lPlido.
..
or all of it derives from precursors (32).
Oynorphin is a highly peltent heptadecapcplidc
includes the leu-enkephalin sequence (23) and is
known 10 be present in the magoocellular neurons of
Ihe hypo(halamus (83), Re«ntly. a proenkephalin
CQn taining Ihe sequences for both the met and leu
pentapeptides and for related octa- and hcp\apep-
Tyr-Gly.(Jly.Phe-Leu-Arg-Arg· IIc-Arg· Pro-Ly ... Lcu_Lys·Trp-Asp-Asn.G ln
Dynorphin (Icu-en l cphali n sequence is undcrlined)
GLYCOPROTEIN HORMONES
While $Omc of the ACTHs contain carbohydrate
components, only thc amino acids are required f()l"
biological activity. Synt hetic ACTH 1-39 is fully as
potent for stimulation of the adrena l cortex as
ACrH extracted from pituitary glands. Indced.
cven ACTH 1-24 elicits all biolosieal
actions.
In contrast, scvcml hormones ha''C carbohydrate
components that arc tutntial for their functions.
These include follicl .... timulat ing hormone (FS H.
follitropin). lu teinizi ng hormone (LH. lutropin. in-
terstitia! cell-stimulating hormone. JCS H ). the do-
,ionic gonadotropins of the trophoblast and placenta
(e./!. human chorionic /!onadotropin . hCG). and the
pregnant marc's serum gonadotropin (PMSG) of
ho=.
All a re species specific. but thc hormones made by
one anima! type are effective in anothcr_ " Micro-
, sequences.
H-GkI·Leu· Tnr ,,·Gln·A1.·
. .Io.·...il.·Ala.$er.GkI.AIa.GIn.Ala.Glu.p'O.GIY)
C""9-Ala-Glu·Leu·G,,·TY" Gly-Leu· II"eAta)
\ - l ys.l ys·GkI·..... ·..... ·G" -""a-Giu
/"
...:-Ser-G ty·p,... Tyr·lys· Met.Gtn'HII)
___ C"J>" l YI' p,,,.p ,o-Ser-G Iy. TrJ>"A rg.Phw
, "
Or.Gty·GIy-P"he· MSD-ltv- .$e,·GItJ·l ys·Ser \
C
1a -... ",-lys-Pl>e-l OlJ-Ttv-· II a'-Le u-P,o-Tn, -0'"
"
tle·!Ie·l ys·Asn· Ala ·H$-L YS-Lys·GIy·Gln. 01'
Ftg. 3·21 . Amiooaei<l tor
( _ Y . ,et. 6) is _n;n
l>OI<I type. MOt_OI>NoIin sequence (6'-65) jl eirCl..:!.
HORMONE BIOSYNTHESIS AND METABOlISM
tides has been found. along with a prodynorphilf that
Can give rise \0 dynorphin 1-17 a nd several Olher bi-
ologically polent peptides (64A, 1\·2).
The small peptide,; identified in brain thaI afTect
bchaviar and contain ami"" add sequences found in
",·MSH and ACTH (e ,g. ACTH 4- 7) arc probably
fragments of precursors other than Acnl.
heterogeneities" within a 'JlC"ies al"<' attributed to
variations in the carbohydrate constitue nts_ These
can influence potencies but do oot scem to affect the
qualitative nature of the biological actions.
Subunit Strueture
Each molecule two dissimi lar slyC05ylated
peptide chains (subunits) held togethcr in noncova-
Icnt linkage. Within a given species. all alpha suJ:>.-
units are almost identical in amino acid sequences.
a nd homologous regions have boen demonstrated for
a lpha components derived from different mammals.
The human alpha subunits ha,'C 89-92 amino acids.
Those I"<'leased as oomponents of whole hormones
ha1l\l molecular weight' of around 14.000.
The beta subunits al"<' dijferen/ for each of the bor-
mone types. and thcy determine the nature of the
biological mponscs. TS H, FSH, and UI betas have
peptide ehaill$ similar in si,e 10 the alphas. but heG
and PS MG contain additional C·termina! peptide
When precautions are ta ken to avoid denat ura-
tion. the subunits can be rever.;ibly dissociated and
recombined. Moroovcr. the alpha from one hormone
type can associate with the beta from another. Thc
process<=s bring about re\'Crsible changes in molecu·
lar configurations tha t incl ude. for example, masking
and reexposure of tyrosyl residues. The conforma·
tion of the molec ule as a wbole (3) and of th. alpha
subunit . a re determined by the nature of the beta
component (75).
Neithc r the alpha nor the beta portion displays bi-
ological activity whcn presented alone in conce ntra-
tions resembling those found in blood plasma_ Evi-
dently. the whole molecule is required for effective
pl'Csentation of appropriate groups to the hormone
receptor. The components must be associated before
they in teract with the ta rget cells. Injection of one
subunit. followed by the other. is ineffective (43).
Reoonstituted glyooprotcins consisting of alphas
deri1l\ld from any of the hormones plus betas from
another display biological properties of the I'Cgulator
from .... hich bela was Thijs. for example.
FSH alpiQI + TSH beta has TSH.like actiyilY.
whefeu FSI-I beta + TSH a lph' is fS H-like. Spe·
cies in affinities for lhe r«eplOfS aR: also
10 the beta QJmponcnt (H).
is not. """"'ve•. • ". .... for tbe
limi6-copcc:,any if lhe ",In ""rmilille leslinB of mol.·
cul.s derived from one animollypc on tar.el p... pa.olion.
."",IIe. and 1'1000 no I"¢Strielion. on 11K: cMccnl .l·
u.. d. llIe compoSi'ion< 01 hybtid molecule< made
from compone"I< okriv.d from div.,"" ,poei... or llIe . ,.
pc,i",.. lal tondition<.
Th ••• /lave beeo ... pons lhal very ooncetIlralioos
01 bela IIIbunito.. and 01 frll-JmnlJ ok.iml from lhem..
an .. imwlale sl.""dose .... is "'hen alone (H)
.nd IMI I'" oddi,;"" olla.*" u«ISfI$ of betlS 10 "'IooIe
&,ycoprol.inl ;mpa;.. bindin, of Ihc wbole 100. ".,,'" mol·
ecules'o Iheir ... ceplors. Ho .... vet. whil. some f.eo .Iph.
is fOllnd in no.m.1 blood pll.ma (89). (.ee be,a 8e"" .. lIy
;s not.
The ... arc ma.k.d .pcd., dilf.rcl"l<:es in Ih. receplo ..
for 'he .Iycoprolein hormMes. Some .nimals (•.•.
_ kes) ...... 'd '0 mIke ""Iy one killd or IOnadolr<>pin
(n). Morcov<:'. ilhas bc<n propoMd ,hal all or Ih. II,..
OQ9.otcin _ .......'" .voIved from _
parenl molecular lypc(4)).. _ p l ..... il-I.'" wilh lhe
prac_ of I>oonoIocooas .mi..o acid 1«Iu<"r>e<:s in beta
..il< 01 diffe •• n, hormones (l4). It is lherdore..,. .., •.
prisinl .hal .he ....... ,.,.". .,... •• law'IIJ bioIockll P"'P"
c"iet. For example. TSIi can ef·
feclS. Mammalian FSH bela is .1"" said 1<> be .. pO.en,
aI whole glyeop.",.in for lI;mulalion of 'po.million in
li,a«1l.
Considerable progress has been rnade in defining
tM polypeptide sequcnces a nd Clrbolt)dratc c0m-
ponents of fS H (35). Lit (36). and hCG (34). and
in understanding lpecies varialiool (61). An inlcr·
csting ob5crvation is Ihe simila. location of tM di·
sulfide bonds (57).
Cllbohydrete Componentll
Subslantial variations in IlTI(lUnts and kinds.
foond .... Mn IX)mparison$ made bel ...·een alpha
and be" Subunits of the htli" ........ differenl
forms of I honnonc ";Ihin I sinal. species. and lhe
....\0&0II5 hormooes from anirnal t)·pes
(67). T he circulating forms ,150 differ from ones
found in pituitary glands ()7). Tumors often releaIC
glycoproteins with larger amounts of carbohydrates
than Ihc regulalOrs by oorma l pilu itary
glands (74).
Some illlilhi inlO the imporllnce of ,he carbohyd .... 'e
compoMnl$ has been obutined from II""'" u.itiri"l (I)
,Iyalprold'" .. bjectcd in ';Iro \0 ,Ilq' ...... lIIeb as DCur·
ilJIIinidaK (wbicb removes sialic acid).nd .. bOlOSid ....
prior '0 in vivo adonio .... n..ion; (b) prcpa ... tiom ""';oW
from cell-free .ynlhelizinl O)'$IOil'l$ l\\al do ..,. OOOIlli.
lbe mombtancs required for .ly«llyl.,;.,.,; (e) prcpa""
110", m.d. by cells eIpoMd 10 (an anlibiO!k
,"'1 bIocklllle synlhc>is of
phoryl-<101ichol ancllberefore the for .... 'ion of ,he man-
nooe-ricb oIilOl"-""harido: lha' compriKs the "con:" ar·
bohydrlle 1i..1 added \0 I'" pt"ptide chai",); (d)
moIeouln .<:eonsliluled wilh he ..ily Ilyoo.syl • •ed alph.
"nill Ihal aft fOlln(! in lhe "'ftc(:"' form and differ from
Ih. alpha compon.nlS of ,h. eornpl(.ed alyc<>p.oteins;
and (e) hormone. rel.aoed from lumor cell •.
The carbohydmles to facilitate ptp-
rid, thol" fold;"t p.ior 10 csllblishment of IhI: di-
sulfide bonds. and to pfOICCI tM Imi..o acid chains
from '".nJCtiiuior They alTeet the abil-
ity of Ih. subunits to lUSOda't with ea,h other. and
lhey prolan, the of the hormones within
circulalory s)"Slem . Limiled deglYCXlSylation may
im:rease homw"t'Hctp'OI" whe.eas cxten-
sive loss impairs the interaction.
TSt! is a a:\ycop.ote in .... ith a molecular weighl of
around 2\1.500. (Values ranlli", belween 26.000 and
36.000 have been dependina on tIM: ana·
l)'1ic methods cmplo)'ed a nd lhe $pUies from which
lhe hormotlCS .. derived (s-6].) The carboh)-drllIC
contenl is appnnirnalely I for most species.
but dilTer.nces among IhI: animal Iypc:s have been
cnoounlercd. Some variations in carbohydrate <:(In-
tenl associaled wilh endocrim: stalus may also Ottu.
.... ithin individuals. The oli,lO$.aecha.idcs comain ru·
cose. mannosc.lIlucosamim:.lIalaeIOSaminc. and gao
Laclose (at leasl in SOme species). Human TSH i$
reL1tively rich in sialic acid.
A molecular .... eight of 17.000 has been .eponed
for human FSH (62). butlhe hormone ca n undergo
dimeritations; and "'-eighu "'nain, from 29.000 10
33.000 have been ciled by variOlll inVC$ligalOfS (68).
The sialic Icid content may be especially imporunl
for Ihis gl)'<lOproicin. since .... uraminidase (.... hich
destroys il) very markedly reduces the potency. It
has also been reported that the ca rbohydrate content
and the Ilormone vary .... ilh endocrine
SlalU'. A "'lYoo-FSH" produ<;ed by adult remaic
"'IS (Ind by castrated an;nI'" of eilher sex treated
.... ilh eslrogens) differsrrom the Mandro-FSU" made
by adull males and testOSleA)O"lC-lreated cutnlles .
Unltcaled gonadectomized animals seCKte an inter·
medialo-Iypc: M ....utcr_fSU .. (5).
I...H eontains lillie or..o ,ialie acid. and ils activily
is unalTected by ncu.aminidose. Molecular weights
vary from 26.000 for humall$ to 44.500 for horses
and rau. Carbohydrate contents or diffeKnt prepa·
ralions from a single species can be dilSimiLar.
AllhOIlah many of iu actions m.cmble those of
LH . heG contains 30% by .mahl of ca .boh)'d",IC
in eaeh of iu subunits. and.some 2-&eetamido-dcoxy·
&\ uc:oso: and 2-l1octamido--dcoxygaiaclOSC are amonK
It... oomponcnu(2). PMSG. which differs somewhat

in biological propcnies, has the highest kllOWn Car-
bohydrate content of the hormone group, estimated
at 40%-45% by weight.
Biosynthesis
While mort known of the mechanisms for biosyn'
ofTSH than for the other glycoproteins (79).
there are good indications that thc proccsses are
ila rforall(13).
Evidently. pre-alpha and pre-beta chains are as-
sembled on separate ribowmes. each under the di·
rection of its own mRNA. Hybridi7.3tion studies in·
dicate that the genes coding for the RNAs are {In
different chromowmes. The possi bilit y thaI gene duo
plication ac.:oums for the generally greater quan.
tities of the alpha subunits has been wnsidered (79).
Suggesti<.>ns that separate controls are exened Over
synthesis of the pcptides (S7) arc supported by the
identification of gcnes ooding for hCG, LH. FS I.,
and TSH betas. and a single gene for the alpha com·
ponents (A·t).
Mannose·rich "core" oligosacdaridcs 3re at·
tached to asparagine residues of lxlth subunits of
hCG while the chains are still attached 10 the ribo-
somes. but probably after cleavage of the "signal"
sequence. Further processing involves the "trim-
ming" Of the oligosaccharides. with release of SOme
glucose and mannOSC. This is followed by sequential
additions of glucosamine. galactose. fuoose. and
sialic acid. Much of the processing is accomplished
in the Goigi region _ Glyoosylation for the other hor.
mones of the group similar
SECRETION OF AMINES, PEPTIDES,
PROTEINS, AND Gl YCOPROTEINS
All horrnQ""s of this kind are packaged in to granules
for storage and subsequent release by
Limited quan tities do, however. "leak"' (\\It acro<s
the plasma membranes. Antines (which arc partially
or tOlally synt hesized by cytoplasmic enzymes). a nd
Shorl pcptideslhat are cleaved from longer ones. Can
do SO without ever entcring granules. S ince proteins
and large peptides are packaged soon after the
amino acid chains are assembled. re-
lease probably involves mostly molecules that have
escaped from their sequestration sites.
acwmplished in several slepS:
I. srcrewry granules m"'·e loward Ihe pltl.rma
membra"". Microtubules and mierof,laments are be-
licv<:d to play essentia l roles in the translocations.
and agents that disrupt their funetions also interfere
with hormone sccre\i{ln_
According to one concept, the arc
"trolley traeks" that guide Ihe granules 10 Inc cell
H<)flMONE BIOSY NTHEStS liND METllBOI.tSM
peripheries, while ntierofilamcnts prontote associa·
lions between the granules and the microtubules.
Electron microscopy has nOI fully supported the
idea. Microtubules are neither consistently abundant
nor invariably orientcd in the directions. A
different hypothesis that conlractions of mi·
crofilaments a lter the cytoskeleton formed by the
microtubule, and thereby alTecl granule movements.
Explanations olTered for the obscrvati<.>n that
Slrong stimulation promotes preferential release of
recently synthesi?.cd hormone include more periph.
eral locations of newly formed granules and greater
sensi tivities of the immalure ones 10 the Mimuh.
2. MembraMs of rhe granules fusr wirh the
plasma membranes. This may be accomplished in
tWO stages: fusion of tlle outer mcmbrane of the
granule with the inner pan of Ihe plasma membrane.
followed by fusion of the inner membrane of the
granule with the OUter pan of the plasma membmne
(7).
Obst,.ation. made on components of cell·free s)'Stem. in-
dicate (hat ;nteraet;"", ,'. «Il-$pedfie (but no' """CO-
sa,ily 'pee ie, .peeific). For example. membrane, from
i,let «11. of One animal t)'pe w;1l fu.e with ;<I<t cell gran-
ule. from another. but the ilranule. frOOl an cndocrine
cell $Ccre,ing one ilormQne will I'IOt fu<c with membran ..
r",,,,, ",11 prOOuei"f.' di!ferent h»rmo",,_
3. The cOntmts oflhr granules discharged inta
Ihe rXlractllular spact in the vicinity ora blood cap-
illary. The substances released can include all of thc
granule wnlents thai are IIOt bound, for
ATP. ions. enzymes. and nonhormonal proteins.
4. The .."ntnanU af Ihe granule menl-
bralif' Qre internalized. (If this did not occur. the
plasma mcmbrane would enlarge excessively "nd
lose its normal composition.) S<lme granule rem-
nants are destroyed by Iysosomes. but others seem to
be recydcd_
Calcium ions play important roles (65). S<lme cell
Iypes cannot discharge hormones when they are
ba thed in calcium-deficiem media. bUI others mobi-
lize sufficient mineral from imernal sequestration
sites to adequately raise thc cytosol Ca". lone-
phores that carry Cal> into the cell stimulate the se-
cretion of most hormone •.
-Calcium ions are implicated in regulali<.>n of the
functi<.>ns of microfilamems and microtubulcs. It has
also been suggested that they facilitate fusi<.>n of the
plasma and granule membranes by lowering repul·
sive ncgative charges. (However, other divalent ions
such as Mg " canoot replace Ca".)
A more re«nt concept i, that .rynHin. a calcium·
binding protein identified in "",relory cells. acts a
receptor for Cal> that in itiates It pro-
 moles a Ca"-sp«ifie associalion belw"",n granular
and plasma membranes (59).
ATP $CCms to be consislently invo\...::d in hormone
release, but it. roles have not been fully defined.
O ther high...,nergy phosphates (e.g. GTP) cannot
substitule. bul in some cell type .. AMP-PN P, an an-
alog Ihat is nOI dephosphorylated . enhances thc ef-
fects of physiological stimuli.
An eXlernally oriented Mgl> /ATPase has been
identified for chromaffin granule •. It may function
as a proton pump that sends calions into Ihe granule.
Eleclroneulrality of Ihe interior is Ihcn maintained
by entry of anions (especially chloride) Ihal pas-
sively follow a concentration gradient As a result.
thc osmotic pressure rises. an:! water uptake may be
a major faclor for accomplishment of granule lysis
(59). Locally relei\l;ed fally acids (especially araen.
idonic) have been implicated as agems Ihm wcaken
portions of the gmnulc membrane and thereby fa-
cihtate discharge. They may also contribute 10 mem-
brane fusion (II ).
Many secrclagogue/; promote gener.llion of cyclic
J',Y-adeoosinc monophosphale (cAMP), and the
nucleotide conlribules to hormone secretion in a va-
riety of celllypcs. It may ils actions on mito-
chondria and other organelles and thereby facililate
release of Ca" 10 Ihe cytOSOl, contribute 10 the func-
tions of microlubules, and aClivale protein kina",s
that calalyze phosphorylations of regulHtory mole-
cules which inClude memt>rnne component<.
Hormones hI 8100d Plasma
In addition to Iheir major secretory prodUCIS, endo-
crine cell. can release prohormones and also peptide..
Iht are formed during hormone processing and
degradation .
Proteolytic enzymes in blood plasma calalY7.c the
formation of smaller peptide!_ The '·mini'·l1ormones
are usually biologically active fragments. ·'Big··
hormones can be dimers or polymers of Ihe "lillIe"
hormones, or liltle forms associaled wilh other
protein •.
Tumor cells are more likely than normal ones 10
relea", incomplete ly proce=d peptide •. They also
somelimes $Ccrete molecules thai differ chemically
from Ihe hormones bUI contain components Ihal in-
leraCI with hormone reeeplors.
THE 810SYNTHESIS OF THYROID
HORMONES
The thyroid gland i. unique in many resp«ts. It
makes hormones thai contain a sp«ial clement. i0-
dine, and ones Ihat haoe the amino acids held 10-
gcther in finer (not peptide) linkage. The prelimi-
nary formation of a large storage glycoprolein
(thyroglobulin) conlalmng the hormone in demi-
cally bound form provides a meChanism for main-
taining adequate reserves during times when Ihe diet
is poor in iodine. Since thyroxine (T.) and triiode-
thyronine (T,) are small molC{:ules, their retention
as oomponents of the Ihyroglobulin also provides
prolection against leakage into the bloodslream.
8iosynlhesls of Thyroglobu lin
Peptide c"ains are assembled on multiple ribosomes,
subjected to po5l1ranslational processing (including
the addition of carbohydrate oomponents). and oom-
bincd to form a large glycoprolein precursor, pre-
rnyrogloh"lin_ The lallCr is synt hesized in Ihe follic-
ular cells of the thyroid gland and imo the
lumen (where il is converted 10 thyroglobulin)_
The follic ular cells also engage in active up/ob of
iodide from t1lc blood plasma. The iodide is concm-
troud. /rmupotted 10 the luminal border. oxidized.
and incorporaled into lyros)1 components of Ihe
glycoprotein.
While still allached 10 the thyroglobulin. iodi-
nated tyrosyl moieties are '·coupled'·. A monoiodo-
tyrosyl component combines with a di-iodolyrosyl 10
form a T) pr..::ursor, while lwo di.iodotyrosyl s join
to yield a T. precursor.
Endncytosll. end the Secretion of ThyroId
Hormones
Thyroid cells lake up the thyroglobulin from the
lumen by a phagocytic process known as mdocyro-
They incorporate Ihe glycoprolein inlo ·'conoid
droplcts" or vesicles, and the latter oombine with Iy-
S<lS<lmcs to form phogolywsomes. Within Ihose or-
ganelles. proteolytic enlymes catalyze cleavage of
specific peptide bonds 10 yield free T ) and T•. The
thyroid hormones diffuse out of Ihe thyroid cens and
enter the bloodstream.
HORMONES REOUIRING COMPLEX POST·
TRANSLATIONAL PROCESSING
The biosynlhesis of nerve growlh factor (N GF) be-
gin. with the formation of two pro-NGF peptidcs
Ihat oombine 10 form a dimer. Each unit of the
dimer Ihcn combines wilh an enzyme molecule
(gam ma subunit) that cataly1.es conversion of the
pro-NGF peptide! to NG F peptides. Howeoer. the
dimeric form is retained. and Ihe gamma subunilS
mainlain their attachmenlS. Two "alpha subunits"
of dillerent composiliOll join \0 make a complex thaI
",rves as thc swrage form of the hormone Th. NGF
peplides must be liberated from the alpha and
gamma subunits before Ihey can combine wilh the
recepwrs(see Figs . 3-21 and 3-22).
 ••

..- ,LA",'"
"". . ."
.AS.A"";"" 0, Glye ... . ,,-
""0......

'.
'"
0"
' ",AR'IC >.COl
CYST,,,,,,,
... """,
OtU' M"C AC",
-",
."
"
",
'''.'' """"
IS<XEUC"':
lEU<: ...
lV,,""
• " ' H<lf<lNe
"'IEN""'-""""
"<
,.
..
".'"
, ..",cc',,"'"
",YPTOf'N>,N
TY"",,,,
VAllH[

Fig. 3·22. Ptimary at<UCI",e of NGF 10 ohown po.it' .... ct\I'ge<I ( ""- ). ".gotw.IY Charge<!
-'licolly . . . ne<;l<Iace of omino 0<;i<I unli •. Tfle cII ... (WIIH. ) , incorporo.ling u . ,,,,,,,,'ie ring ( . ,
).
it bri<lg6<l at thr .. points by ooval6n! bOn<Il t>etw,"", In. i<ICOrpOfating SUlfur 01""" (_ J, IOd _ rg.o<l
sulfur glOUpS of cYSI&ine "" ito. ". i. Iro. of all p<'Oltin •• , .. (wMo), Abo .. I coitic.1 cone.ot<ot;on. two
of am'" aekj . in Itlo choin g;",,' ,i" to a unique Chain. <>f NGI' . •• en •• ing • moI9cuIar 01 'J.2W
,h_..:l imMSiOOaI Sl'I.'Cture. wtNctI I. the result o! ...... k
int.. aetion. omong II,. amlno . cld un;", TI>o p<@Ci " lo1d"v
pIItt"'n 01 NGF fill. no! y.' _del .. _ , TM " .riow
wfI_ 8 • ...,;.t. l0 'Orm . Oi...,..
It iO...,t yot k"" .....
'he monomo' Of the " ' _ i. , he !<>rm of
1""1 i. &e,i .. , (Levi-Mont.ron &
to.
NGF

co_;el of .mit><> a cld .r. lndico.l«I by o/Iod;"g: CeHosano. 01 )

Fig. 3·23. Monufact .... 01 NGf

r<lqUl!'fl • .......w ot · ' prQCeoslng··
".po, TflfI iniliol tom. ot the i•
• poro>cu,..,.. ct\Ii/I coiled poroNGF, _
101m•• d_. The p'oNGF cho i". . ..
Cle • • 0><:1 by an oozy"'" known o. the
gamma lubunill0 V4ld th. NGF_.
The twO go"..,.. """""its _ in
•• soci. lf>d with the dimer oHer n i.
oen ..... to><:l, I nd two , <XIltional p'otolnJ,
t1>o ' Iph, SUbunits, bind to the compl&x.
Th. associllion ot the alpl'lO . nd
gamma . _ . w;!h the NGF <limO,
PRECuRSOR "PP'lre"tIY protect. Item further
{i>'"NOF OtM€A) d9gra dation by "'her ""zy""", . (l ..... •
M"",alei,,;'\ ... no. rOI, .I)
 " "
c ,
" "
,
, "
8
. Fig. 3·24. Cho ...,emlOIfUCtu,.
STEROID HORMONE S AND CAlCIFEROLS
Cholestero! is the precurwr for the steroid hormones
of thc adrenal oort ••. ovary. and testis. and for vi·
tamin D a nd its derivatives. The numbers assigned
to each of its 27 carbons. and Ihe lelters Ihat desig·
nate the ring structures are shown in Fig. 3-24.
Steroid hormone..eercling cells have plasma
mcmbr:lne receplors thai facilitate eholestero! up-
take from the blOCld. The supply is usually greater
than the demand. and some hormone prccurwr is
stored in lipid droplets. The reserves arc mostly in
the form of cholest •• yl .SleN wnkh must be hydro-
lyzed before they can be used. f><,ptide hormones se-
creted by Ihe pituilary gla nd regulate thc formation
of the receptors and thc activities of Ihe .",lcraSCS.
When the uptake rate does nat keep pace with the
requirements. the harmone-scc«:ting cells can syn·
thesize cnolesterol from acelyl A.
Produclion of all of the ste roid hormones begins
with oxidation of carbons 20 and 22. and Inc subse·
quent cleavage of Ihe cholesterol side-<:hain. Tne
products are pregnenolone and isocaproyl aldehyde
(fig. 3·25). The cholesterol oxidation and deavage
reaction. are coupled. and they are rate-limiting for
hormone •. ACTH acceleralC$ them in
the rona faseiculata of Ine adrenal comx, while UI
does this in the gonads. The aldehyde undergoes
spontaneous oxidation to isocaproie acid. afte r which
it is discarded.
The fate of the p«:gnenolone depends on bolh the
e<:\l type and the species. Corpora lutea of Ihe ovary
oonven much of Ihe steroid to progfsre,one (Fig. 3·
25). They di«:etly sec rete substantial quamities of
s.I>ow"'sl OUmDeo""'sI'y.tem k>f "",bon
atoms. "'now Ind.,.,••• 11. lor side·
chi;'" . . .... >hOw carbon
.'om, involved In to. o.idot;o.n. thaI
"'''''_ ClOava\l*.
the product. but they also produce scvera l melabo-
li tes. The reactions require twO cn'ymcs thul work
together to remOVe a hydrogen at position 3 and to
shiftlhe double bond from position 5.{i to 4·5.
Progesterone is also a major intermediate far the
syn thesi s af several steroids in both the zona fas-
ciculata and the lestes of ralS. mie<:. and other oor-
tioosleronc-sccrc ters. The adrenal glands and
lestes of humans and guinea pigs (which are oorli_
sol·secretors) make only limited amounts of pro-
gesterone. Muc h of Ihe p«:gnenolone is hydroxylated
at the 17 posilion. The 17 ,,-Oll-pregnenoione thus
formed is then COIlverled 10 17 «-Oll-proges/emne
(Fig. 3·26).
Adrenocortical mineralocortiooids and glucocor·
ticoids have an alcoholic group at position 21. Con-
.. ersion of progesterone to II-deoxya)Tlicoste,olli'
(DOC) and of 17 ,,-OH·progestcronc to II-drox}'"
cortisol are calalyzed by 21·hydroxylasc en7.ymcs
(fig. 3·26). DOC can perform mineralocortiooid
functions. but usually only small quantities arc reo
leased to the blOCldstream. Much of the DOC under.
goes a scCOlld hydroxylation al the II posilion to
yield COTliros/rronr. Zona glomerulosa cells funher
metabolize the product to Ihe major mineralooorli·
wid. a/dos/eralli' (structure G af Fig. 3-26).
In ra ts and mice. zona fasciculata cells large
amounlli of oortioosterone. and Ihis steroid is directly
sec reted a. the glucocortiooid characleristic of such
species. In humans. gluoooo"icoid, are made mo:stly
from I 7 a-OH ·pregncnolone. wilh ll-<lcaxyoortisol
scrving as an intermediate. The final Slepof the mel·
abolie pathway yields cortisol (which is also
as hydrocortisone).
.. ,
HOflIdONE BlOSYNTHESIS "ND MET "BOLISM

" ,"
HHHH ..... CH. 2t CH.
, • O=C-C-C-C I
•
, • H H "cH. 00 =0
/ aldehyde

"+ •
'" "0

A. C/>QIeSlero!

21 CH,

I
,",
I I

--
" "
, -<',
y
• <0 '"
C, PROGESTERONE O. 17 ","OH·PREGNENOlONE

1"11· 3_'5. " .."",,""'" '" r><OQM""ono.

and

Naturally occurring androgens have only 19 car-
bons. The precursors must be hy<lroxylaled al Ih. 17
posilion before the twentieth and twenty-first Car-
bons can be discarded. TrsloslerGMe is made in large
quantities by the testes. and in smaHcr ones by ova-
ries and adrenal glands. Corticoslerone-sttrc:tors usc
Ihe pathway shown on Ihe lefl side of Fig. J-27. and
t:.'·3.I7-<JnJroslenediQnt is an intermediale with an_
drogenic pOlency thai is also secreted. Cortisol-so-
crelOrs Can make small quantities of androgen in this
way. but the maj<lr pathway (see right side of Fig.
3-27) proceeds via 17 a-OH-pregnenolone and
hydroepiolUiroslerone (DHA. DHEA). The latter is
a "weak"' androgen (a hormone thai tlCerts teSIO$-
aClions but is of low polency). Some
DH A is directly secreted.
Estrogens differ from androgens in tw<l ways: The
A ring is unsaturated (aromatic) and there is no
19th carbon. Estradiol-I 7 fJ (structure N of Fig. 3-
28) is the most potent of the mole<;ules. It is inter-
convertible with estrone (0 of Fig. 3-28 ).
Since both Ihe pregnenolone synthelase (choles-
terol side..::hain cleavage .nlyme. scq
and th. II
are located wilhin the milochondria.
whereas Ihe 21-hydroxylase and several other en-
zymes are associalcd with the endoplasmic reticu -
lum. precursors and intermedia tes must be shuttled
baek and forth across the organelle membranes. The
reactions do not always procee<i in the order de-
scribed. It is possible. for e. ample. 10 go from pro-
gesterone to II ",.oH-progesterone. and from Ihere
to conicosterone.
Some Notes on Nomenclature
Sieroid hormones can be regarded as derivatives of
a bypotbetical substane<: formed by the fusion of a
5.a1rbon ring (cyelopentane) to a fully
(pcrhydro) phenanlhrc:ne. Cyclopcntanopcrhydro-
pbenanthrene (structure D. fig. )-29) is also known
as SUrQne (or gonane). All of Ihe naturally occurring
hormones have a methyl group anac hed 10 Ihe thir-
te<:nth earbon. The carbon of that mcthyl group has
the number 18 (Fig. 3-29E). and the resulting struc-
ture is known as eJlrQtIt (sine<: the estrogens have 18
carbons).
Androgens. progesterone. glucocorticoids. and
mineralocorticoids have a second methyl grt>llp at-
 PRooeSTEAONE \7 ,,·OH·PREGNENOlONE

\ ,
21 C H,()H
/ , ,",

" 0 "0
--
"
'+
o" '" 0 "
E. l1·DEOXVCORTICOSTERONE IDOC) H. 17 ".QH.PROGESTERONE

,
'""" ,
'"""
j "0 j "0
-
"' "

o
y
" o " "
F. CORTICOSTERONE I. \ 1·0EOXYCORTISQl

,c=o
'""" '"""
,
j "0
--
"'
o
y
"
G, ALDOSTERQNE J. CORTiSOl

tached (0 Ihc tenth carbon (sce Fig. 3·29F). The di-
methylated structure is called Qnr/rosrallt (sirlC<' Ihc
androgens have! 9 carbons).
Progesterone , glucocortiCQids and mineralocorti·
coids additionally have a t""O-Carbon "side chain" at·
tached at position 17, The new carbons have the
numbers 20 and 21, and the completed muctur" is
pregnonr (Fig. 3·29G).
Since steroids have &everal asymme1ric carbons
(e_g. at positions 5. 8, 10. 13. 14, and 17 ofprcgnen-
olone), a system is needed for defining lhe spalial
configurations when substitutions or additions a re
made. Ahhaugh lhc mo\e.:ules do not cxiSllhis way
in nature, it is convenient to regard them as having
ring structurCS that lie ftatlcnod (a. they arc drawn
OIl paper) . Substitutions that can be regarded as pro-
jecting downward from the paper arC said \0 be in
the trollS or alpha (a) position. and tlleir attach-
menlS a1"<' rep1"<'sented by brOKcn lines. Those Ihut
project upward are d . or bela (P), and solid lincs a1"<'
used.
Tho suffix 01 can be used to dc.signate an alcoholic
group (as in cholesterol). Dio/ and tr;oI arc used
when there are t,,·o or three such groups. respec-
lively. (For example. see $\ruCIU1"<'S N and P of Fig.
3-28). Usually. the positions a1"<' also specified. e.8 .
 HORMONE 810SYNTHESIS AND META80liSM

PROGESTERONE 17 wOO.PREGNENOlONE

I
17 ,,·QH·PROGESTERONE
I 0 I o
J,.
"
, + •

o
y
,/ o
y
'"
K. 6'-3.1 1-ANDROSTENEDIONE M. DEHVOROEP IAI-IOROSTERON€ (DHA)

I o"
A

o
y
'"
L. TESTOSTERONE

Fig. 3-27. of •.

as in androstane-J«(7<Hliol. An ahcrnalc system
names the position and with ·OH (see
Fig. 3-29H). Ketone groups arc signified by OM (as
in estrone). or as either oxo or O\y. Thus. the substi·
tutions on the androstane molecule found in testos-
terone (Fig. 3-28L) can be represented as either 3-
or as 3-one·1 7Q-<)I.
When the rings are fully I-aturaled. !his is indi·
catc:<l by aM (as in androsla nediol. ' t",cture P of
Fig.,3-28). The su[Ji\es tM. ditnt. and IrieM are
used For one. Iwo. and thre<: double bonds. respec-
lively. Aecoroing 10 Ihi, system. androstenedione
that has a double bond joining carbons 4 and 5 and
ketone groups at position, 3 and 17 can be called an·
drost-4-<:ne-3.11-<1ione. The symbol 11, followed by a
superscript. is also used to designate unsaturated
bonds. The steroid just cited can be called Il.·-an·
drostene-3.11-<1ione.
This nomenclature makes it possible to fully de-
fine the chemical structures. HoweYer. lhe names
generated can be long and cumbersome. Cortisol, for
example. would be given the following designa-
lion: 11·-pregnene· 3.20-.:.ne. lid, 17«.2Q-trioi. Trivial
names such as oortisol. progesterone. and leStoster-
One haYe Iherefore ocen introduced for many of the
steroids. Substitutions can easily be shown when
these are used. For example, I I-<leoxycortisol d iffers
from ronisoi in lhal it lacks an alooholic group al-
tachc:<l to the carbon at the II position.
Steroid Hormones as Pro hormones
Some of the steroids released from endocrine
glands interact dire<:tly lhe rcceplol'li of their
target organs. Olhcrs are first acted upon by intra·
cellular enzymes thaI catalyote oonvcrsions to other
steroids.
x..Reductases in prostate gland., seminal vesi-
cles, and other male accessory reproductive organs
convert teStOSterOne 10 5<Hlihydrotestosterone
(OHn. which is. by many criteria, far more potent
than teslosterone. The OHT then combines with the
hormone re<:cplOrs 10 its characteristic actions.
Certain of the neurons have aromatase enzymes that
oonYerl lestosterone to estradiol. and many effects of
teSlosterone on the brain can be mimicked with es-
tradiol (but nol with OHT, which docs not undergo
aromatization). Adipose tissue also makes estrogens
 o"
"
"

L. TESTOSTERONE

o"
,/ \ o" o
1
"
o
,, ,,• 0'

"
M. S,. -DIHYOROTESTOSTEOONE N. ESTAACIOL· 111l O . d'·ANDROSTENE·DIONE

j o"
1 II 0

......,. ., "'-,/'"

"
f> 3... A NDOOSTANE -OIOL
Q. ESTRONE

from androgens. Thus. testosterone functions as a
hormone at some silcs. bul as a prohormone at oth-
ers (86).
Celclle rols
1-D<:hydrocholCitcrol. which is also koown as prov;-
tamin D" is an intermediate in th. pathway from
acctyl coc:nzymc A to cholesterol. It is prescnt in
food , in hepatocytes and other ctlls thai synthesize
cholesterol. a nd in the skin. Dietary cholesterol can
be used \0 make the provitamin. since the small in-
testine conlains a choleslcrol_7-<lehydrogenase (Fig.
3-30). When epidermi. that hs ta ken up thc steroid
is exposed 10 ultraviolet radiation of suilable wave-
lengths. provitamin 0 , is converted 10 pre-vitamin
0 ,. The product of the undergoes a spon-
taneous. rearrangement that
yields vilamin D) (cholecalciferol. D,) (29). The un-
fortunate IcrmirIQlogy results from the failure of
early investigators 10 rocogni,.c the of the
pre-vitamin. The laner is shown in IWO forms in Fig.
3-30. to demonstrate its rdationships 10 both choles-
lerol and D,.
D, can also be (Jbtained from the die\. fish (Jils are
especially rich D, is in capsules for
usc: as a dielary supplement, bUI vitamin D, (D" er·
gocalciferol) is widely used since it is cheap. Ergos-
 HORMONE; BIO$YNTHI:SIS AND MnAeoLISM

o
,.. C,doj>e<>ta"" ". - MM

c """ "• ..
A B • • • •,
•• • •
.
" "

E. Eolta"" F. Dime1hy1cy<;loptnlarwlPtrhydrop/>ellafllhl_
(AO<Iro$tane)

,
01, 2'
CH, 2C
1
,
T ,
, o
1
,
..
H. 3a-Oti , 51l-CH,-slerane
o '"
I. l'-t7.8-QH·Androstene·3-one
Fig . 3-29. Cyche hyd'ocarboo1
str..clUl6S 1Q .retoO:l
flormone • .

lerol, which ;$ made by plants. is chemically ",Imod
10 cholesterol (Fig. 3-31). It is irradiated in vitro 10
oblain 0 1_ Humans and many olher mammals ca n
usually substitute Dl for D,. Chickens arc among the
animal types that canoot (14).
VITAM IN D METABOLISM
Some vitamin is stored in lipid· rich (is,ues. espe-
cially when the supply is abundant. Usua lly, most is
sent to the liver, where ;1 is acted HPJ" by a 25-hy·
droxylase enzyme. 25·Hydroxyvilamin DJ (2S-OH·
Dj • 25-h}'droxydlOlecalciferol, 2S-HCC) can aCCu-
mulate in blood plasma when it is formed in large
amounts. This ii fortunate. iince neither dietary DJ
oor sunlight i. continuously available to most ani-
mals. Pharmacological concentrations of 25·HCC
a rC biologically aClive. but il is !lOt kllQwn if this me·
tabolite functions as a hormone under ph}'$ioIogieal
conditions.
 , ,
;
,,
, " •
, A• " "-, •
"" "
7·d'" 'r<l'ogcoo.c ,
"
, . I',
, ." .. inc
"-
A. CHOLESTEROl

, " /•
"
, "
I
""
, f, •"-
•, "I" , •
,• .h

C- L Pre·vitamin 0,
,
" ,
• • '
' 9CH,
""
Co2. Pre.vit.min D>

""
•
'I
f'
• •
, ,)J ,0 ..

D. VITA MIN 0" CHOlECAlCIFEROL

The kidney oontains a la-hydroxylase that cata· PROSTAGLANDINS AND RELATED

Iyzes oonvcn;ion of 25·HCC to a vcry powerful hor·
mone, 1.15-dlhydroxyvitamin D, (U5-HCCj,
which promotes absorption of dietary calcium and
phosphorus and exe rts other important infiuences on
mineral homeostasis.
A dilfcrent renal enzyme oonverts 25-H CC \0
24.2X1ihydroxyvi(amin D,. Its activity rises when
the Ca" levds are high. $orne additional metabo-
lites are shown in Fig. 3-32.
The cholecalciferol derivatives resemble steroid
hormones in their mechanisms of action and in their
metabolism. They are called s<:co&lcroids, a term
thai indicatcs opening of {he Bring.
REGULATORS
All mcmbers of this group arc synthesized from
"polyunsaturated" rany acids that must be supplied
by the diet. From a quanlilati,·c standpoin t. arachi·
donic acid (AA) is lhe major precursor. The struc·
ture of this 2().carbon fany acid ",ith double bonds
at positions 5. g. II . and 14. is shown in linear a nd
folded forms (Fig. 3-33). MealS and peanuts contain
small amoun ts. but lhe liver forms most of;t from
linoleic acid (Fig. 3-3 4). AA is the precursor of the
prostaglandins (PGs) with two double bonds. and of
scV<'ral other biologically polent thai
 HORMONE BlOSYNTliESfS AND MH ASOUSM

" "
"
"" - I

...,CH,

"
Ergooterol
",

2S-OH-D>

Fill. 3 · 31. Co,,. ...."" 01 ergootorolto .;,_" D, an(!

metabolit ••.

SOme authors classify as prostaglandins: proslacyclin
(PG I,), thromboxanes (TXA, and TXB,), and leu-
kotricnts (LTs).
Dihorno-gammalinoleic acid (DGLAI and ,j.·5. 8,
11. 14. acid a", the precursors of
PGs with one and three double bonds. respectively.
Although linoleic acid can be used 10 make those
fatty acids, the composition of the diet affects the
relative amounts of the various types of PGs synthe-
s ized. Evening primro5e oil is a rich source of
DGLA. and i( hu b«n prescribed for certain clini-
cal conditions (30).
Chemistry and No menclature of the
Prostag landins
AI! prostaglandins are 20-carbon fatty acids with a
five-membered ring. a double bond linking carb<ms
13-14. and an alcoholic group 3uached to carbon
15. T hey are named on the basis of their chcmical
relationship to the hypothetical prostall<)ic acid thai
is s hown in fig. 3·35. In aClXlrdancc with this n0-
menclature. PGE, is Il.1 Xlihydroxy-9-ketoprost_
l3·tranH:noic acid (73A). The Iwen; R, and R,
designate thc fany acid side chains.
PGs differ from each other in the numbers and
locations or additional double bonds and alcohol or
ketone groups. The rapj[o/ /elltrs define the ring
structures . Thus. all proostaglandins of the c group
(PGEs) have a ketone at position 9 and an alcohol
at position II. All PGFs have alcohol groups at pos-
tiom 9 and I I, while all PGAs. PGSs. and PGCs
have unsaturated rin8'.
The numbers designate the double bonds. Thus.
the PGE, has a double bond between carbons 13 and
14; PGE l has an additional one at position 5-6; and
PGE l has yet a third site of unsaturation at position
11-18.
Substitutions for either of the hydrogens at posi-
tion 9 can lead to the formalion of slereoi""rne",.
Groups projecting downward from the plane are des·
ignated a$ {to and they are represented by a broken
line. PGf,. (fig. 3-35) is the most abundant of the
PGFs, but PGf ,. and PGf,. al"" occur natu rally.
Groups projecting upward from the plane arc des-
ignated as {J and arc represented by a wlid line.
While PGs of such kinds arc formed during $Orne
 " •
"
" I
.

6 . 2S-oH·D,

"o

'".
C. I.2S-0'HYOFlOXY·(J,

"o

)
I .... CH,

"0
F. 25. 26·DihyOroxy·O,

extraction ;1 has not been demollSlr3tcd

Ihat they arc made by cells.
The relationships bet"'een chemical structures
and biological aCli.ities are complex. Two different
members of Ihc group can excrl similar influences in
one tissue and opposing ones in anolher. T hus. both
PGE , and POE, promQ!e vasodilation in some vas-
blood ves.els in other regions and on plaleiel aggrc-
gatiQJI. High concentrations of a PG can inhibit pr()-
ce= stimulated by lower ones. Morro"" . thcre are
marked .pecies variations in sensitivities. These arc
easily demonstrated when the same PG is presented
\0 corresponding organs in differenl kinds or ani.
'" HORMONE BIO$YNlME$IS AND META6OI.ISM

& S'"
H H H H Ii Ii H Ii Ii H H H Ii Ii H H fl Ii H
H C -C - c- c c- C - C = C - C -C " C - C - c - c -C - C - C - COOH
HHliHH H H HHHH HH

,.
" " " "

H H H H H H H H H H H H H Ii H H H H H
H C - C -c - c - C-C= c- C - C= C - C - C = C - c - c =c - c - C - C - COOH
HHKHH H H HHHHHH

S, ""ac_ 20;4 8. 11. 14

C . .IS. 8. 11. 14. 17 EicoI>ap"nle..,;c

Fig. 3 ·33. Fa lly acid preew.Ofl 01 pro. 1011Iar><lin • .

mals. Within a single cell type:, the pre"ailing con-
ditions can affecilhe responses (17 ),
Biosynthesis end Metabolism
The major rate-limi ting factor for PG synthesis is
Ihe availability of the ratty acid precursor. Cells usu-
aUy contain substantial quantities of enzymes in ae-
*e form. but they sequester the fatly acids in mem-
brane phospoolipid s and in cholestc.y] esters.
Iriacyiglycerols. and lipopr()\ein$. Al most siles, lhe
2-posilion wilhin phospholipids i$ lhe primary
soo rce. il is espc.;ially rich in arachidonalC
(61). Howe"er. triacylglycerols arc imponanl
sources of AA in lhe kidney. whereas lipoproleins
are abundant in the blood plasma.
Phospholipases. cholC$terol esterases. lriglyceride
lipase •• and li poprotein Jipases lhat calaIY'.e hydrol-
ysis of lhe lipi ds can be activaled by numerous '·non.
spc.;ific·· faclors. T hese include mechanical pressu rc.
lemperalurc c!lange<. and mi ld trauma.
One proposed function of PG. is prolection of cclls
againSl ovcrslimulation Or injury.
 ( linol9ic_) THE CYCLOOXYGE NASE PATH WAY

i\ cydooxygenasc enzyme system Ihal binds n heme

cofactor and additionally requires nonheme iron cal-
l.inoIo<'Ii<: ac .. alyzes the formation of PGG, from aradidonic acid
18:3 12. (69). The rate-limiting slep i< thc removal oflhe hy·
( y-lino1eiC add) drogen atl3cbed 10 carbon number 13 (13A). The
18:3 J6. 9. 12 subsequent events are summarized in Fig. 3·36.
Analogous reactions are involved in the biosynthesis
of PG ,s from DOLA and PG lS from eioosapentenoic
acid.
PGG, is a highly unstable endop.roxide that is
rapidly oonverted to PG H,. The eyclooxygenasc also
catalyzes the second reaction. and the enl.yme is
therefore also known as the prostaglandin $}"nthewse
system (69). (PGO, will, however. go to PG H,. even
( Atachdonic aci<I )
without the en7.yme 15Ij.) The cyclooxygenasc ad-
ditionally ill o""n destruction and thereby
20:4 ..IS. 8. n . 14 limits PGO production after a time (731\).

I '"
( 5. 8. 11 . 14. 17·E"ocosapentenoic acid )
20:5 ..15. 8. 11.1 4. 17
Fill. 3·34. eiooyn,,,,,s" o! pro.,aglonclill p<ecl.<OOfS !tOm
linoleic aCi<!.
Tbcre are also specific oomrols. For example.
TSH activates phospholipase A, in thyroid gland
cells: ACTH exerts similar effects On the
cortex: LH acts on the ovary: and estrogens exert
oomparable innuenccs on many cell types. Angioten·
sin. bradykinin. and serotonin affect the enz,'mes at
some target site,;. A oomplex system inl'Olving
thrombin. Ca " , pbClSphohpase C. and a phospholi-
pase A, that specifically affects phosphalidic acid
has been described for plalelets (4{1). Zinc i, said 10
preferentially release DGLA (30) .
Glucooortiooids inhibit PG production in many
cells typC5. and tbeir anti·phospholipase effects con-
tribute to the anti·inHnmmalOry properties of large
doses (8). as well as to estrogen antagoni sms.
Although ;1 has a very short biological halF-life.
PGH , exert. powerful inHuenees on platelet. and on
vascular and respiratory system smoolh muscle (69).
Before it was identified. some of its activities were
allribulcd to the PGs derived from it.
The fate of the PGH, dep.nds on the cell type. In
mOSt parts of the body. a PGE isomerase catalyzes
the formation of PGE,. or else Ihe PGH, goes to
PG F,.. (The existence of a PO F. reductasc has been
po5lUlatoo but not demonSlrated.) In platelet •• a Slu·
talhione·S-transferase catalyzC$ the synthesis of
PGD,. The PGA,. PGB" and PGC, shown in Fig.
J_36 are found in extracts. but in vivo formalion
has not been cstablisboo. The molecules are biologi·
cally active when administered. PGA, is of pharma-
oologieal interelll because it is a vasOOilalor that
lowers blood pressure (18). Unlike PGEs. which
are acted upon by reductases. oxidasell. decarbox·
ylases, and other enzymell. and are follow-
ins a single passage through the lungs (througb
which every drop of hlood paSSeIl en route from the
right ventricle to the left atrium), PGAs arc quile
stable.
The major degradation products of PGE, and
PGF). reoovered from urine are shown below:

o
" "o

7••·OH· 5. 11 -<1""'101" " a· :;. •. 7,,·dihydroxy· 11·ke:olwa·

flOfpt o>'aoe- l .16·do;c aciO flOfpt o>",,,,,·I .l lklioO; acid
(I'om PGE, ) l(rom PG F,..)
'" HORMONE BIOSYNTHESIS AND METABOLISM

, , ",
• , .' •• • coo·

" . " "

" " " "
" " "
"
A. Prost.rOc adO' F. PGF fl Seties
o o
" \\ _A

,,
.. '5
,,.
Q '
p "
o
.
S, PROSTAGLAND IN E, (PGE,) G. PO '" Ser""

• • • • • COO·

••
0 "'"
",, ,
" C. PGE,
" H. PGe Series

0
" •• • ,

"'"
-
,.r ,,
, " "
0

"
0
.
D. POE! I. PGC SerieS

"C!,.
• COO ·

,
0
",, ,
" , PGF ...
" J. PGD $",,,,

Fig . 3-35. StfuCluru Of prOO1anoic toiO. POE. PGE,.

!'Gr:" PGF... &00 rings 01 0"* pr""' oglandins .
 C-.t",,,.
•••

Free ....

PGG,

• En(Iope'o,idaS(l
PGE PGH, P'''''!acycr;" S)n1I11etase
PGt,

I I
"',
:l'
'/
PG6,
§
PGD,
HHT + MOA I
Fig. 3·36. Sour"" 01 a,t<hidoMt. 8nd _18bo1it". 01 the
pathw.y.

THROMBOXANES
In blood platoiets (thromlxlcytcs). much of the
PGH, converted 10 thromboxane (TX) At, since a
thromboxane synthetase is presen!. This highly un-
stable metabolite is a potent stimulant of platelet ag-
gregation. It plays roles in anaphylaxis. and it is be-
lieved to account for at least somc of the activity of
rabbit aorta.conlracling substance (ReS). TXA, is
rapidly con,'crted 10 TXR,. which has a somewhat
longer biological half_life. Its innnen""" on platelet
and On thc wntraction of vaseular
smOOth muscle oontribute to physiological protection
against the loss of blood that would othcrwise result
from the regularly recurring minute break s in Ihc
vessel walls of normal animals. (Excessive produc-
tion is believed to invoke pathological changes in Ihe
vessels.) TXs have also been suspected to exert neg·
ative fC"dback control over AA but OOt DGlA re.-
lease, and to thereby favor production of relatively
more PG, s than PG l • (30). TXs arc additionally
formed in brain. spleen. kidney. leukocytes. and
granuloma tissue.
PROSTACYCLINS
A prostaeydin synthetase cataly7.es formation of
prostacyelins (PG Is) from PG Hs in Ihe endothoiia of
aorta and coronary vessels. Prostacyclins are potem
vasodilators and inhibitors of platelet aggregation.
They can diminish thrombus formation and arc be-
lieved to provide protection against excessive levels
of thromooxanes (48) by exerting opp"'ing inftu-
en= Over the accumulation of cAMP (24). How-
ever. PGE h which is also made. is a more potent va-
sodilator for some vascular beds. It opposes
angiotensin 11 (88). and its actions are more sus-
tained (18).
In the vesscls. PGI , is rapidly metabolized 10 6-
keto-PGF ,. (Fig. 3-37). The prolonged inhibition of
platelet aggregation following administration of
PGI, is attributed to oonvers;on of the 6-kcto-
PGF ,. to 6-keto-PG E, . The laller is biologically p<>-
lenl. and a 9·hydroxydehyrogenase that can catalY7.c
the reaction has been identified in liver and kidney
(88). Different metabolites are made in the kidney
and in other parts of the body in which PGI, is gen-

Fig . 3-37. ""0"ac1clin I"
.... tabolit ...
(kidney, lungs. siomach, uterus. seminal ves-
iclo:s, and granuloma tissue).
HYDROXYHEPTADECENOIC ACID
Some of Ihe PGH1 is split into hydroxyheptadccen·
oic acid (HHT) and malonyl dialdehydc (MDA).
This may he a degradation pathway. but MDA is
chemically reactive. Among other things, it can
cross-link proteins (73AJ.
The Llpoxygenose Pathway
in lung. liver. and platdets catalyze
Ihe formalion of hydroperoxycicosatclracnoic acids
(HPETEs) and hydroxycioosaletracooic acids
,,
6·Kc'o-PGF,"
throml;>o • • ""S. ond oll>e< PGH,
(HET Es) from arachidonate. 5-HPETE is the pre-
cursor of leukotrienc A. (LTA.). The laner. in turn.
can be hydrolyzed \0 Icuko"i.n. B. (5, I 2·DiH ETE,
LTB,). In Ihe prescnce of glutathione reductase and
glutathione. A. is made into C. (LTC.).
Loss of the glutamate componem yields LTD,. and
further deletion of glycine kads 10 formation of
LTE. (49) (Fig. 3-38).
The IcukOlricnes were named for their form"tion
by leu kocytes and their content of three conjugated
double bars. They are extremely potent agenu that
exert diverse innuences (A·)). They interact with
their precursors. with PCs. and with histamine (58).
Ftg. 3_38. Ar&<:llidonllle l'f'Iftlat>olile. OllipoxygeM""
•
pall>waYI.
"'----f'c,
"" 12-HPHE

-"
" ,,
,
12·HETE
0
5 -HETE

,=,

7=,
1

"0 LTII.
, Gt<J'''hoooe

, ""
HC-CON-C-COOH

"
"
o
1
""
HN - COC- C - COOH
H NH,

" "S-r H, H "

HC-CON-C - COOIt
, "
LTD,
"""

''-,'s-o;
,
H

,
HC-COOH

"",
lTE.

H ETE is for leukocytes (73), and LTil,
promotes the release of lysozyme and other
from neutrophils as it attraCtS ooth these and cosin-
ophilic (49). HPETE has been implicated as a
regulator of prostacyciin biosynthesis (73). while
LTC, and LTD, may increase Ihromboxanc produc-
tion (49) . The "slow-reactive substancc of anaphy-
laxis" (SRS-A) may consist of mixtures of leuko.
trienes. The SRS·A acting on rabbit aorta has been
identified with LTC, (731\). but the can
be rapidly converted to LTD,; and the latter flOW
reported to be the SRS cltl1aincd from basophilic leu·
kemia cdls (26A).
The LTs are se.cral orders of magnitude more
powerful constrictors of bronchiolar muscle than
either histamine or the PGs. and (in contrast to the
others) they act on the smaI1est of the airways. LTC,
is also an extremely potent stimulant of the smooth
muscle of arterioles. and it is suspeetcd of contrib-
uting to angina. LTB, additionally promotes adhe·
sion of leukocytes to the endothelium of postcapil_
lary venules.ln physiological amounts. these "':"'''
probably make very important vascular
tions to to noxious stimuli (I 2).
may be a regulator of i'G1, synthesis (73). and LTs
of thromboxanc synthesis (49).
acid can be metabolized in othcr
ways to yield iwmers of some of the LTs described
above. In addition, different fatty acid precursors
give rise to related substances that include leuk<l-
trienes A), A1, C ), D). E,. and F, (26A).
Inhibitors
The glucocorticoid suppression of synthesis of PGs
and related regulators is allributed to induction of
lipomOOulin. a phospholipase A , inhibilor thaI has
been isolated from neutrophilic leukocytes ClCposcd
to tbe steroi,d. Some rheumatic diseases have been
linked with production of an antibody directed
against the enzyme (28). Since the steroids reduce
availability of Ihe precursor, they lessen formation of
products of both Ihe cyc!ooxygenase and lipoxygen-
ase pathways. Pharmacological dosages Can also an_
tagonize Ihe actions of previously released
molecules.
5,8.II,I4-Eirosatetraynoic acid (ETYA, Fig. 3-
39) eompete. with the naturally occurring fally
acids. and it thereby blocQ both the
and lipoxygenase pathways. Aspirin. indomethacin
(indocin). mefenamic Aufenamic acid. and ibu-
profen (Mouin) are among the many agents thaI
have been used for their analgesic. antipyretic, and
anti-inflammatory actions. All are cyc!ooxygenase
inhibitors. and aspirin causes irreversible inactiva-
HORMONE BIOSYNTHEStS AND METABOLISM
tion. Their effccts depend to a considerable ex(cnt on
reduction of PG synthesis. but they also inhibit con·
version of HPETE to HETE (73). Their interference
with TX synthcsis can also be useful. but there is
simultaneous inhibition of prostacyc!in formation.
These agents do nOt diminish (and may cven indi-
rectly enhance) production of the regulators sy nthe-
si7.ed via the lipoxygenase pathways.
There is considerable clinical interest in acquisi·
tion of agents that specifically block thromboxane
synthesis. ImidalOlcs Can do this to some extcnt. and
they are therefore useful investigative 1001$ for ani.
mal studies. A prostaglandin analog that strongly in·
hibits thromboxane synthetase has been synthesized
(Fig. 3·39). and other analogs that diffcr from each
other in their effecls on TX receptors have been de-
scribed (24) .
HORM ONE INTERACTIONS WITH PLASMA
PROTEINS
Plasma bind hormones with varying amni·
lies and sPl"'ificities (S4). Albumins are prcsent in
highest concentrations (3.3-5.5 g/IOO ml of blO<X!
for normal humans). and they have very large num·
bers of binding sites for thyroxine and steroid hor·
mones. Approximately I 5% of cortisol and 10% of
tbyroxine travel with this protein through the
bloodstream.
Corticosteroid-binding globulin (CBG) auaches
mostly to glucocorticoids bnt it also binds $Orne
progesterone. Although its concentrations are only
J / I000 those of CBG binds 75% of cortisol
in humans (44). Approximately 1000f that steroid
circulates in "free" form. A sex steroid·binding gloo.
ulin (SSBG. testosteron«:strogen-binding globulin.
TeBG) associates with most of the androgens and es-
trogens. although it is present in very small amounts.
Usually only 0.03% of thyroxine circulates in free
form (35). Plasma Ihyronine binding globulin
rrBG) concentrations of only 2 m&llOO ml arC suf-
ficient to bind 75% of that hormone. Thyroxine-
binding prealbumin (TBP A) associates with another
10%-15%. Calciferol-binding proteins are also
present.
Most of the peptide-protein type hormones asso-
ciate with albumins and to a lesser extent with glo!).
ulins. but no specific bindins proteins are known. So-
matomedins are among the exceptions 10 this
general rule.
Se.eral have been altributcd to (hc pro.
tein binding:
I. For hormones that are fIOt very soluble in blood
plasma in free forms (stcroids and thyroxine). the
proteins may facilitate transport.
 r< }o
I I
,,<.o
I
OOC - Ct1,
"II
5. 8.>1,1 4-Eeosaletlaynoteacic!
(ETVA)
Fig. 3·39. Som8
.. aehiGonic acid
2. The PfQIeins protect smaller molecules
from loss via the and they can mask the Siles
for attachment 10 degrading enzymes, They may
also slow uptake by the liver.
3. The hormone tbat is bound to protein is tran·
siently inactivated. II is therefo", p<:>SSiblc to
large amountS of rearlily recruitahle reserves in the
bloodstream while maintaining the ooncemratiorlS of
free regulators at levels oons;S!cnt with good endo-
crine function. Hormones that do not bind apprecia-
bly. for example. aldos terone and T,. drculate in
concentrations much lower than those of glucocor-
ticoids and To. and they a'" m01"<' rapidly deared
from the bloodstream .
4. Since Ihe plasma proteins (and especially ontS
with high capacities and low affinities) usually have
most of th.ir binding siles unoccupied. a "buffer"
function is sct>"w . The sudden releasc of excess hor·
monc into the bloodstream is followed by occupation
of some of the f",e sites. The",foxc, the levels of flU
<
"
1 \)-"_ 1
"
"
-
Meclcte""""",,
9. 1 H"'prost- ' 3'enoatc
(TM)tl'\D,,,.ne . yolhel . ...
inhi;lilOr)
"""
hormone do not risc rapidly. Similarl y, depletion of
the hormone leads to release of molecules previously
bound loosely to the low·affinity proteins (since the
binding is concentration dependent).
S. The affinities of hormones for Ihe plasma pro-
leins 3re lower than their affinities for larget cell re-
ceptors. The proleins are believcd to play roles in
regulating Ihe rates of hormone presentation to Ihe
receptors.
6. Since nutritional and endocrine factors affect
the bi(lSynthesis of the proteins in the liver, an ad.
ditional sile for control is provided.
Estrogens increase the production of steroid and
thyronine bi nding globulins. This makes it possible
for pregnant women to have high levels of IOlal hor-
mone withoul disruption of their endocrine func·
lions. Some of the regulatOl"$ thaI circulate in Ihe
maternal plasma are easily lramferred 10 Ihe fetus.
The proleins probably also confer physiological pro-
lection against the rapid transfu of biologically ao--

tive molecules from the fetoplacental unit to the
mother.
Similar elevations of plasma binding proteins are
seen in women taking oral contraceptives. Corn·
monly used pharmaceuticals. including aspirin and
barbiturates, affect plasma protein symhesis and
binding properties.
HORMONE DEGRADATION AND EXCRETION
The liver plays major roles in steroid hormone me-
tabolism. Reductase$ accomplish mo&t of the con·
versions of biologically aClive molecules to ones that
possess few Or 00 such propc:rties. Other enzymes
acting on the steroids include oxidases and Iyases
that bring about side chain cleavages. A few of Ihe
reactions lead 10 increa.•ts in biological activities Or
transformation of one kind of regulator to another.
(For example, progestagens and glucocorticoids can
b<. made into androgens.) The steroids arc also con-
jugated. mostly with glueuronate or sulfate. Intro-
duelion of pola r groups increase. water solubility.
Tlte metabolites. along with small quamities of
unaltered hormoncs. are into the bile. Most
are then eliminated wilh the feces. However. some
are reabsorbed from the intestine. I nteslinal bacteria
aher the steroids that appoar in Ihe fccc.<. and some
of the metabolites thus formed may b<. absorbed into
the bloodstream.
The high activities of hepalie enl.ymes explain the
ineffectiveness of oral administration of the natu-
rally occurring sleroid hormones. When Ihese are in·
gested, they travel directly via Ihe hepatic portal
blood vessels to the her. Parenleral injection per_
mits Ihe steroids to cireulate for a time in the blood·
strea m and to gain access 10 the target organs. Syn·
thetic analogs Ihat resisl desradalion in the liver are
widdy us«l for Iherapeutic purpoocs.
Thyroid hormones are also metabolized in Ihe
liver and excreted into the bile. lioW<'ver, the reac·
lions include conversion of SOme of the T. to the
more polent T,. as well as deiodination to yield rT)
and other inactive metabolites. There is exlcnsi ve
··enterohepatie circulation·' of thyroid hormones.
Proleolytic enzymes in the liver inaclivate 'mu lin.
glucagon, and many other protein hormones. The
products are released mostly to the bloodstream.
Hepatocellular disease. biliary obstruction. and
the use of IheraPOUlic agents thai compete with hor-
mones for li'·er enlymes can all h.,-c profound innu·
enCeS on endocrine balanC<'.
Small, water-soluble molecules arc filtered by the
renal glomeruli. However. some of Ihe biologically
active substances arc reabsorbed by the lubules.
Renal enzymes catalyze degradation of many of the
HORMONE BIOSYNTHESIS AND METASOUSM
poptides, including some Ihat are made within the
kidney. Others (e .g. cholccaleiferoll<>-hydroxylase)
contribute to hormone activation.
Peplide hormones arc also broken down by circu-
lating enzymes: and enzymes relea sed by neurOOS af·
feCI regulalors released within Ihe cenlral neTVOUS
systcm. Targel organs "internalize" proteins as well
as smaller molecuks, and lysosome, within Ihe C<'lIs
contribute substamially to hormone destruction.
REFERENCES
1. i\eher. R. ChemiStry of 'he Neurohypoph)">ial
Hormones: An Example of Molecul .r Evolu,ion.
Ch.p. 6. pp. I 19_30 of KtIObil. E .• and Sawyer. W .
H .. eds. HandbotJk of PhY$iology. sec . 7. vol. 4.
Part 1. America" Physiological Society. Washing-
tOn. DC. 1974.
2. Bahl. O. P. The Chemistry and Biology of Human
Chorionic Gonadolropin.o<I ils Subunils. Chap. 2.
pp. 11-24 of Ore"p. R. 0 .. a nd K<>blinsky, M. A..
eds. In and Fmi/i,y C""..
,,01. MIT Pross. Cambridge. Ma" .. 1977.
3. Bewley. T ...... Ciroular Dichroi.m of Pituitary Hor·
mones. R«. Prot. I/orm. Rsch. Jj: 1$$-210.1979.
4. Bloom. S. R. OaS'rQintc"in.1 Hor,""",,". Chap. 3,
pp. 71-103 of Crane. R. K.. Gaslroinl,slinal
Physiology II. Unive"il)· Par. Press. Bal,i,""re.
1977.
5. 8ogdanove. E. M., Campbell.G. T .. and Pecl-.h.m.
w. D. fSH Pleomorphi.m in Ihe R.t_Regulation
by Gooad_1 Sieroid •. EItd<x,. Rsrh. Commun.
1:87_99.1974.
6. Bunney. W. E .. Jr. or
p.• ix Usdon ct
aI., .. 'ororene. 18.
7. Butcher. F. R. Rogulalion of Exocy,osi•. Biorhem.
Aeri"", 0/ H(JI"m(Nr<J j : B-99. 1978.
8. Ch"ndabr"", . K. A .. Lapelina. E. G .. Schmitg...
C. J.. Sicgel. M . I.. and Coatrecasas. P. AClion of
Corticos,eroid. in Regulation of Pros'agland in Bi ....
synthesis in Culiured Fibroblast... PrtX. Nail.
ACIlJ. Sci. USA 7J: 2 I 4_17. 19 78.
9. Codet. M .• Chang. A. C. Y.. and Coh.n. S. N .
Ch.racteri>.ation 01" the Struclu,al Ge"" and Pu_
UI,i.e Y·R<:gulotory Sequen"". for Human Pro-
opiomelanocortin. NQlu,..197: 335-9.1 98 2.
10. Coope,. J. R., Bloom. F. E .. and ROlh. R. fl .
Basis of N.uropharmac%gy. 3d od.
Oxford Universi ly Pr .... New York. \978.
I I. C. Oi.eussion; Calcium ACli"" and Hor·
mono ReI.a", in Exocytosis. R« . Prot. H",m.
J7: 325--6.1981.
12. D.hl';n. SA: .. BjOrk. J., H.dqvist, P.. A,lo". K.·
E.. H.mma"'r<:Im. S .• Lindgren. J .·A .. and Sam·
uelsson. B. LeukOlrion.. Prom<>te Pl.sma Le.kaso
and Loukocyt. Adhesion in Po.-tcapill.ry Venule"
In Vivo Effects wilh Releva",e 10 thc Acute In·
n.mmatory Re$pOlUC. Pf'(X. Na,l. A<:aJ. Sd. USA
78: 3881-91. 1981.
 I J. Daugh.day. W. H. Anteri", Pitu itary. Chap. 2. pp.
21-76 of Ingb.r, S. H., ed . Con""'f'OrorJ Endr>-
<ri/OO/oV' l. Plenum. New York. 1979.
14. DeLuca. H. F., cd. Tilt Far-So/"b/l' Vira",i""
Plenum. New Y"'k. 1978.
15. I)eWied, D. Pituitary and Beha.-
ior. pp. 297-314 <)I" Fux<. K,. H6Heh. T .• and Luft.
R.. ed •. oj Emil><:ri'W SJ"
Plenum. New York. 1979,
16. Dobbs. R, E,. and Unger. R. H, Glucall"" and»
matosratin. Chap. 8. pp. J07_H of Freinktl. N .•
ed. ConrempOrary Merabolijm , vol. I. Plenum.
Ne'" York. 1979,
17. Feigen , L P. Aotio", of Pr""aglandins in Periph.
eral Vascul .. Bed •. Fd 1'_. 40: 1987-90. 1981.
IS. Feigen . L P.. and Hyman. A. L Va.cular Influ·
ence. of P''''lagl.ndins. Pro<. 40: 1985-6.
198 I.
19. Fern ... M. Ma$t·CLII Willi,m, &
Wilkins. Baltimore. 1968.
20. Flint. A. P. F .. and Sheldrid. E. L Ova,ian St<:re-
tion of O,ytocin i. Stimulated by Prostaglandin.
NaIU,", 197: 587_8.1982.
21. GaO$Qn. J. C. Sleroid<>&enie Ae'ivity of Hig" Mo-
lecular Weight Form. of Cortie{>(ropin. Bil><:h'm-
iSlry 18: 4215_24. 1979.
22, Gershon. M . D.• Kana",k. D,. and Nune •. E, A.
Calcium·lnduccd Release <)I" \.Hydro.ytr)"ptomine
from Thyroid Lobes in Vir", "nd Ac""mpon),ing
Ultrastructural Changes in P.rafollicular Cell •.
101: 1128-43. 1978
22A. M. A .. llttenhal. L 0.. M. \' ..
ChristolidOS. N. D .• Moody. I\. J. and Bloom. S . R.
Molee.lor Forms <)I" Glucagon-like Immu""",ac-
,i.i'), in Porcine [ntestine "nd Panerea •. t"ndrx,j·
noI. 112:917-23. 1983.
2). Gold.tcin . A.. Fi"'hli. W.. Lo"'ncy. L. I.. Hunka·
piler. M .• and Hood . L Porcine Pituitary D),,,,,,,
phin: C""'plete Amino Acid Sequence of thc B.,.
logically Ac,i,'e Heptapep'ide, Proc. Narl. Acad.
Sd. USA 78: 7219-33. 1981.
24. Gorman. R. R .• Shcbuski. R. j ,. Aikcn. J, W .• and
Bund)" G. L Anal)"i. of thc Biol<>&icaIActi.ityof
Azop''''tanoids in Hum.n Plate leis, P'I><:. 10:
1997_2000.1981.
25. Hobener. J, F.. Kemper. B. W.. Rich. A,. and
Po"s. J. T. BiosyntheSi' of P.rathyroid Hormone.
Rl" . Prot. I/om,. RJrh. 11: 249-99.1977 .
26, Habener. J. F.• and Kronenbe •• H. M. Parathyroid
Hormone Bios)'nlhe.is: Struct"", and Funetion of
Bios),n,hetic Precu1'S(I'" Fd Pruc, 17: H61-6.
1978.
26A. H.mm .... 'r<lm. S. leul:O!rienes. Ann. R",.
U' 355-77. 1983.
27. Herbert. E,. Roberts. I. l.. Phillips. M.. R.,... P,
1\., Budarf. M .• Allen. R. G .. PolicastrO. P. F.. Pa·
qucue. T. L.. and Hinman. M. Biosynthe.i. and
PrC>CeS£i!l3 of. Common P",c"""'r '0 Adrenowr·
licotropin and IllPH in Piluitar), Cells.
Chap. 14. pp. of Uiden ct al.. eds,. ",fcr·
en"" 78-
28. Hirata. F .. Del Cormine. R,. Nelson. CA .• A.. I·
rOO. J .• Schiffman. E .• Worabi, A.. De 810•• A, L..
Nirenberg. M .• Mangonielio. V" V.ughan. M .•
Kumagai. S .. Green. I.. De<:ker. I . l.. and Stein·
berg, A. D. Pr.sence of AUto:ilntibody for PhO$pilo-
lipase Inhibitory Pr{>(ein. lipomodulin. in Patien ..
wi," RheumatiC Diseases. P'I><:. Natl. A<:O<i, Sci.
USA 78: 319()-4. 1981.
29. Holick. M. F .. and Clar •. M. B. Thc Pho.oi>joge.
nes;. "nd Melabol ism of Vi'amin D, Fed. I'"x, 17:
2567_74. \978.
30. Horrobin. D. Cellular Ba.i. of Prolac,in Ac,ion:
In.ol,'ement of CycliC Nucleotide .. PoIy.mine ..
Pros'aglandin.. Steroid.. H<>rmone •.
Na/K ATPase, and Calciu",•. Relevance to Brea"
Cancer and the Men.lrual Cycle. MedicDI II}""
poIh,m 5: 599-620.1979.
JI. H,ueh. A. I. W .• and Erick"",. G, f . htrltpitui.
tar)' M,lo" of Gonado\ropin·Rek •• ing Hormone:
Direct Inhibition of O.. rian S,eroidogenesis. Sri-
l()4: 854-5. \979.
n. Hu.ns. W._Y .. 0."3. R, C. C. Kastin. A. J ..
Coy. D. H" and A. V. ho\a,ion and Struc.
'u", <)I" Pro-Me'hion ine-Enk.phalin: Po'en,i,1 En·
lephalin Preeu1'S(lr from ""rcine Hypothalamus,
Prl><:, Narl. Acad. Sci, USA 76: 6177-80. 1979.
33. Humbel. R. E.. Ilosshard. H. R .. and Zahn. H,
ChemiStry of I",ulin. Chap. 6, pp. 111-32 of
I/andbwk oj I'h}".ioIOV·. o<oc. 7. '01, I Amoric.n
Ph)'siological Societ)'. Washing'on. D.C. \972.
H . Hu$Slt, R. O. Siosyn'hcsis of Hum,n ClIorionic
Gonadotropin. EndI><:Y. R",. I : 268- 94. 1980.
tn81»., S H .• "rl w"""", K A n" ny,Oirl
Gland. Chap, 4. pp. 95- 231 of Williams. R. It.. cd.
T,xrbwk oj Endorrin%gy. 5,h ed. SaundcrS.
Phil.delphia.1974.
36. Ke.tmann. H. T .. Dawson. B.• Bishop. W. fl .. and
Ryan. R. J. SUUetU", of luteinizing Hormone
Alpha Subunit. t:mirxr. RJeh. Commun. 5: 57_70,
1978.
n. Koorides. I. A .. Hoffman. B. I ..• nd Landon. M. B.
Difference in GI)'c",y\ation BellO, een Secre'ed and
Pituitar)' Free .... Subunit of tbe Glycoprotein Hor-
mOnes. J. Clin. Emil><:yjrwl. 51: 1372-7.
t980.
38. Krieger. D. T .. and Gano!l3. W. F .. ed •. ACTH
and Related Pep'ides: Structure. R.gulation and
Action, Ann. N.Y, Acad. Sri .. vol. 297.1977.
39. Krieger. D. T .• and Liotta . A. S, Pi'uita ry flor·
"",nos in Brain: Whe",. H",,' and Why? Sdtllu
105.366_72, 1979,
40. Lape';n •. E. G,. Bill.h. M, M.• and C.,treea,...
P. The Phosphatidylinosi.oI Cycle 000 the Rcsu-
la'ion of Arachidonic Acid Production.
192: 367- 8. 198\.
4\. levi.Mont.lcini. R,. and Callss.no. P. The Ncr ....
Grow\h Factor. Sclmrific Amu. 140(6): 68_77.
1979.
42, Li. C fl. Curren' Co""epts in the Chemical Biol-
ogyof Pi,uilary Hormones. Bioi. M,d.
11:498. \968.
43. Licht. P.• P.pkoff. fl. . Farmer. S .. Muller. C. fl..
Tsui. H. W .• and Cro ..·s, D. Evolu'ion of Gon.d<>-

lropin SI .... elun: and fullCl ioft. H«. PFOK. H",,,..
Ib<-Jr. 1): Ind Oifcu ....... pp. 243_8.
1977.
Liddle. G . W .• and Melmon. K. L. The: Adre .... 1o.
Chip. 5.!'P. 223_322 01 Williamf. R. H .•• d. Two
Ix:>ok of t.·""<xri1t()/"V'. 5lh ed. Sounder.. Philadel·
phia. 1974.
• 5. UnSOPpo.. V. R.• Ind Blobel.O . Early E.cnl. in the
BioIoynlhesi. of S.erelllrJl and Membrane P""ei ..:
The Si,....1 H}·POlhesis. R«. hof. II",,,,. Rsd•. J6:
4$1_1S.1980.
46. M .i.... R. E.. I nd Eipp"" O. A. Co-<>rdi .... ,. Syn-
Ihc.sd a nd ReI .... 01 COO1ioo1ropiund E"""'pllill.
ChIp. 11. !'P. 14.1--51 <I II .. ed ... refe,'
71.
cr>ec:
47. Mark$. N. Oiol..alllformalion and o..radalion of
Corlitol",!,i!ll. li pocropi!ll Ind lIypolllalamie
F'eplidcs. C hap. 12. pp. 329_17 of 0. no n8. W. f ..
Ind MI.tin. L..•d •. FrtHlti",in
ot)". vol. S. R.... Pr",,'. New York. 1977.
48. Mlr>. J. L. Blood CIottin.: Rok of lhe PTOS-
lq:llndins. Sl"IMN 196: 1072_S. 1911-
49. M arx. J. L. Tbc: in Alief&)" Ind in-
flammation. Scinw 11': Il80-J. 1982.
SO. Me KeI.,.. J. F. Biooynlhcailof 1I)·poch.!ami<; I'tp-
ticles. Chap. S. pp. 77_98 oIl'I:wI.r. J. c..
ed. H,..
Prptidr H",_.
PI.num. New YQ.k. 1977.
U/Qljc",.
d"" P;,uiuu,. Rq-
5t. M oncadl. 5 .• Flower. R. S•• and Va ... J. R. PI1)$-
1., londin>. PrO<locycl;n ..d Thrombouno A, .
ChIp. 28. pp. 668-81 of Gilmln. A. G .. Goodman
tz"./ GII"",,,,,-" Basis
TIvr/JfNllli<s. 6th cd .• Mlcmill .... Ncw Vorl<.
1980.
S2. Monl ...... ry. R.. [)rye,. R . I... Conway. T. W .•
Ind Spector. A. A. Bio<:MmlWy. !>Iooby. SI. louis.
1974.
U Moyle. W. R. Biochcmi,try« GOIIIdotrophin Rc-
C hip. 4. pp. 12l _2O-I of finn. C. A .• cd .
Oxford Rt1I;t:W. of H,produrtlot BloIoV". • C>i. 2.
O d Q.d Uni.eni,y Pre ... New Vork. 1980.
S4. Orlh. D. N .• and Nichol_. W. E. Dilfe ... nt Mo-
lecular forms« ACT Il . Alii!. N. r . ANMI. Sci. 291:
27-45. 1977.
H. R. c..
Bto..-nie. A. C .•• nd Lina.. N . Pro-
... Oeri.cd Pcp/id...:
Action OIl A4renal SI.rvidOCe .... is.
Sdt"", 108.' 1044-6, 1980.
56. Pi...... J. G. Cbem illry « Thyroid-5limulati",
Il ormonc. C hap. 24 of K!\ObiI. E.• Inc! Sa wy<:<, W.
ft.. ed •. Handlx:>ok of PAYlloiOty. Ie<. 7. PI' 79-
101 .<>1. 4. Po .. 2 America n PhY'io!osica l Sociely,
WllhinllOfl. D.C .• 19U.
S7. Pi.rce. J. G .• lnd PI""". T. f . Olycoprot.in lIot.
motlOl: Ind function. AJIIf. Rn-.
50: -«;5-95. 1981 .
I'tlmo. S. 0 .. Sic,.I, M. I.. K.,.,y-SoboIka. A .• Ind
Lichle""cin. M . U..,.YI.n .... PnxI • .". Modulat.
HistamilOt R.1ease 1ft Ilaoopltils.
191: 'S5_1. 1.. 81.
HORMONE BIOSVNTHESIS AND METABOI.ISM
59. Pollard. H. B.. Pazolcs. C. S•• Ind Cre.n... C . E.
Mcch"';"" of C . lei.m A<lion aM Rclcuc of V. .
icle- Bound Hormones Exocyloois. R«.
""'t. /I",,". RscA. Jl: 199-HS. and 01 ............
J2S-l2. t981.
60. PolIJ. J. T .• Ind Au'b&eh. G. D. Cbemimy of
CalcitOOins. Chap. 18. pp. 421-64 of ,,",bach. O.
D .• 0<1. Hdndbook of PAJ·Jiolot)". .01. 7. &c. 1.
Sockly. W .. hi""Ofl.
D.C .. 1976.
61. Ra m""lI. P. W .• Leovey. E. M . K .• and Si,.,etos.
A . L RCluiation «Ibe AflcMdonic C .... de. BioI.
16: 70-37, 1971.
62. Reichen. L E. HumaD FSIl; Pu.ilicalion. Pmp-
.nies. and some SI .... e'ure-function Rcla' ionsloipo.
9. pp. 107-19 of Sa..... B. B.• Beli",. C.
G .• a nd Gondy. H . M .. cdl. G"""dol/·opiru. Wiley.
Intel"$Cien<:c. New VQrk. 1972.
61. ReiChlin. 5 .. and Mil nic\:'. M . Biooynthesi. Qf lIy.
pIllh. tamic Hypophyliotropic foclon. Cha p. 3. pp.
61-lS «Ganofll. w. f .• lnd Marlini. L.. cd •.
FTOIrlit's of A'Nrot"oO", lttoIoV ·. 191J. OdOf<l
Uni""';,>, Prc>:s. New Vorl<. 1973.
6'. R_niot. J. C. NOflh. W. G .• • M Moon:. G. J.
Plot.ti.. Pm:u.-:s« ValQPf"OSSin. Ind
Nco",!,hysins in 'he RII lIypoch-alamul. E""IKri·
1t(J/. If)II: 1067-72. 1931.
641\. Rossie,. J. Opioid Peplidd Ha.e I'""nd T h.ir
Rootl. 198: 221-22. 1982.
6'. R. p. dn</ lA, S H ""W}' P,_ ...
Plenum, Ncw York.
of 64. SaWra". M . lIypocllalam" COfIlroi of lhe &cretion
of Mel:lJlOCyle-Slimula tins 111",,"0... (MSH) Ind
Adre_icotropin (ACTH). Chap. II. pp. 225-
«
)5 Porter. J. C .• ed. lIypo(lul/tzmir I'rptftk H",...
...."'" """ PiluillU)' Rqooid.iott. Pknpm. Ne ..
V"'k. 1911-
61. Soi,.m, M . R .• I nd Popko/!". H . Chemislry of Pi,
luillry Gonadotropin •. C hap. 26. pp. 111_11 of
KIlObit. E., and Sa wyer. W. II .•• d,. Handbook of
Phy.iol"V'. >Ce. 7 .• C>i . 4. Pari 2. Ame.ican Phys--
ioI"Ii.11 Soci.ty. WUhin.ton. D.C .• 1974.
68. Soiram. M. R .. Papl;o/!". 1\ .. and U. C . II. The
Chemistry « o.inc Inlem ilial Cell Slim"lalin,
H... C1u.p. 12. pp. IU_ SI «Sue ..... B. B..
Bel; .... C. G .. Ind Glndy. H. M .• ed .. CoIlOdOl,.,.
piIV. Wiley-lnlCl"ICic_ Ne .. Vorl<. 19 72.
69. Samu."""'. B.• Goldy .... M .• E.•
Hlmbe.,. M .• Hlm"..<1lnlm. S .. Iftd MIlm".n.
C . Proslall,ndilll and AM. Rn-.
Bjorhrlll. IT: '197_1029. 1978.
70. Slnde. H .• Kemmle •. W .• Rube n"cin . A. H .. and
Stei .... D. 1'. Studi.. on Insu lin Biosynthesi. Ind
Secrelion in 1$Oj.,ed blelS a nd I Bela
Cell T umor. Chap. 4. pp. 77_II} Qf f .ill. i. B, ed,
......,....... Academic Preas. New Yorl<. 1912.
11. Seh-ally. A. V_. Coy. D. H .• lnd Meyers. C . A. Hy-
pOlh-alamic Retul1tllrJl Hor"KM.... AIIIL RN.
Biorlttm. 17: 89_ 118. 197• .
n. Sellolly. A. V.• Ind Ka llin. A. J. Hypothllamic
 Releas;", and I nbibiting Hormon ... Gtn. ,{ Com- 83 . Watson. S, J .. Akil. H.. Fischli. W.. Goldstoin. A..
par. EruJocrilll)/ Suppl. J: 76-85. 1<)12- Zimmerman. E., Nil •• " , G .. and Greidanu .. T. B.
73 . Siegel. M. 1.. McConnell. R. T .. Porter. N. A. • • nd van W, Dynorphin .nd Vasopressin: Common Lo-
Cuatreca ..... P. "'.chidon.te Met.bolism ,i. Li· cali.ation in Magnoodlular Neurons. 116:
I 2.L. HydropOro.<)" 5.8.10.14.1""". 85-7,1982 .
• tetraenoic Add Pcro.idase So",iti.e 10 Anti·ln· 84 . W.. tph.l. U. Binding or Hormone, to Sorum Pro-
llammatOI)' Drugo, Proc, Norl, A<dd. &i. USA 77: tein •. Chap, 6, pp_209-65 of Litwack, G .. ed. Bio-
308-12. 1980 chemical AUio", oj J/ormollts. vol. I. Ac.d.mic
7JA, Smith. E. 1... lIill. R. 1.., Lehman. I. R.. lenowi1'. Pre ... Ne,," York. 1970.
R, 1., Handl ... P.. and While, A. P"',,cipl,s oj Bio- 85. Whitley, R, J.. KeHtman, H. T., and Ryan. R. J.
ch,rni'lry: MarnmaUan 71h cd, Isolation and Ch.racterization of the Subunit> of
McGraw·Hili. New Yo.k, 1983. Porcino Hormonc. £ndo<r.
74. Snyder. P. J .. Johnson, J.. and Mu"yka. R. Abnor· R.cA Carnrnun, 8: 61 - 81, 1981.
mal S«retion of Glycoprotein ""Subunit and Fol· 86. Wil$On, J. D, Metabolism of T o'ticular Androgen,.
licle·Stimula1ing Hormono (FSH) in Chap. 25. pp, 491-508 of Handbook oj Ph,',iO/ogy,
Men with Pituitary Adenomas and FSH Hypo ..... vol. 5, ""'. 7. Ameriean Physiologieal Soci.ty,
• "'tion . J. Clin. Endocdlll)/. Me'ab. 51: 579_84. W.shinKlon, D.C., 1975 .
1981). 87. Wocber. K. A.. and Bra"orm an. 1.. E. The Thyroid.
75. S1rickland, T. W .. and Pum. D, a-Subunit Con- Chap. 3, pp. 77_117 of Ingb .., S_ H .. cd_ Conum-
f<>rm.tion in Glycop)"(>loin HO)/mone. and Re.,",,- pora,y Endo"'/n%gy /, Plenum. N.v.- York. 1979.
binan" a, A" " sed by Sp<:cirtc Anti«ra_ Endo<d_ 88_ Wong. P_ Y __ K.. Le., W. H., Quilley, C P_, and
111)/,111:95-100.1<)82. McGiff. J. Metabolism of Pros1.eyelin: Form.1ion
76. Th(>dy. A. J . MSII Nplid". Ac.demic Pre ... of an Active M.t.bolite in the li'.r. Fd. PW(. 4(),
Ncw York, 198(1, 2001-4.198\
77 . Unger, R, H. Glucagon 000 Som.tost.tin. Chap. 89, Workew)'cb. J .. and Chena. K. W. [)e'olopment of
l. pp. 101 --42 of Thr r . ar in Mtla/)o/ism 1977. Glycoprotein Hormones and their ,,- and
Plenum, !'ew York, 1<)78. "nit. in Ekwinc Fotal Pituitary Glands. II. Quanti.
78 . Uoden, E .. Bunney. W_ E. k and Klinc, N_ S .. ed s_ !ation of r",c <>- and It-Subunits by Radioimmu_
t'ndorphi'" in Mm'al N".arch. Oxford """"')'5 and Com,I'1ion or Free ,,-Subunit with
Univef1ity Press, New York. 1979. Thyrotfopin. Hormone. and
79 , Vamvakol"'uios. N. c.. and Koorides. I. A. Iden· Luteini,ing Hormone, Endo(,"fi""'. 104: 1075-82.
of s"p'"'' ",RNA< t":Mine f."." 'nrl fI 1070
Subunit> of Th}'fOtropin, P1'tX. Na.l_ Sci. 90. Zakarian. S... nd Smyth, D, H. !'i-Endorphin i.
USA 76: 3809_18. 1979. Proe .... d Dilferently in Speciroc Region. of R.t
80, Varon, S. S. Trophic Mochani.m. in the Peripheral Pituitary and Bra;n_ 296: 250-3, 1982.
Nervous System. Ann. •. "",u'oui. I: 327-61. 91. Zimmerman. E. A. Loc.lization of Hypothalamic
1978, Hormones by lmmunocy"x:hcmical Technique._
81. Walsh. J, II . Gastrin Itoterollenoity: Biological Chap. 2. pp. 25-62 of in "".urotndocri-
Signifieance. I'M. Proc. J6; 1948_51. 1977. fIO/OU. Vol. 4. Ra.cn P..... New York. 1976,
82. Wathes. D. C .. and Swann. R. W, Is O.<ytooin an
O .. rian Hormone' 1<)82 .

A-I_ Fiddc$. J_ c..

and Talmadge. K. S1fucturc. Expres-
sion .• nd Evolution of Gencs f<>r 'he Human GI)".
coprntein Hormones. Rt<:. Prog. lIorm, R.cA, 40:
43_74.1984
A·2. Matsuo. H, Ne<Xndorphi'" .1Id Dynorphin •.
AMtT. #S. 126, p. 40 7th Int. Congr. Endocrinoi-
oSJ. Quebec City, Canada. 1984_
A·3. Piper, P. J, Forma1ion and Action. of
nyJ_Rn-. M: 744_61. 1984_
____4
Mechanisms of Hormone Action and Interaction
inv<:sligators attempt to define the mecha-
n;.ms of action of a hormone. they must deal with
the diverse and complex roles of that regulator, the
idiosyncrasies of the larget preparation the
limitations of the «,scarch looIs, and the dogma as-
sembled by predecessors,
Hormones can sCI within 'l"conds Or minutes 10
alfecllransporl of molecules and ions across plasma
and organelle membranes, activities of preexisting
enzymes, production and usc: of ATP. polymcr;7.a·
(ion of microtubnles. contraction cf microfilamcnlS,
assembly of peptide chains On preexisting ribosomes.
and pOSt-transiational modifications of macromole-
cules. They act over longer time-periods 10 promote
the biosynthesis of nucleic acids. proteins. and Olher
macromole.:ulcs. and the assembly or destruction ()f
organelles. Slowly developing influenccs can affect
0011 growlb. dilfcrentiation and proli feration. In in·
tact organisms. bormonC!l regulate Ille functions of
thc cireulalory, l"eipiralory, digestive. ex·
cretory. reproductive, and immune systems; and they
mediate responses to environmental stimuli . In ad·
dition. each regulator alfeclS tbc biosynthesis. rC-
leaie. metabolism. and use of many OthCTS.
A hormone can act simultanwusly or sequentially
at many sites. Thus. for e xample. insulin accelerates
glucose uptake. glucose oxidation. glycogen synthe·
sis. amino acid uptake. and protein synthesis. when
it is presented to skeletal musele. Since each cell type
bearing receptors for Ihe hormone bas its unique
repertory of response the effeelS 0b-
served for one target preparation a«' not necessarily
elicited in another. When insulin acts on hepat<>-
cytes. it accelerates glycogen and protein synthesi,.
but it does not directly «'gulate glucose uptake. In
adipose tissue. insulin accelerates glucose uptake
and oxidation. but much mOre of Ihe sugar is used
there to synthesize fats. Examples can be cited in
which a hormone exerts reproducible influences on a
target in one species but fails to have such elfcelS on
the related organs of other animal typel; .
The condition of the cell at the lime of hormone
presentation modiflCs «,sponscs to thc regulator. G H
markedly accelerates somatomcdin production when
it is presented to hepatocytes of p«,viously wen·
nourished juveniles. hut it has lillie inAue"ce on the
synthesis of those peptides during times of food de!,"
rivation (see Chapter 18). G H is also «,portod to act
mostly on th. be:ta cells of islots to pro-
mOle insulin release when the glucose concentrations
of Ihc su rrounding Auids a«' high. but to stimulate
mostly glucagon-scereting alpha cells when the glu·
cose levels are low (135) . Tlte hormone can initiate
changes in :lCnsitivity. When ;1 is presented to skel·
clal muscle taken from hypophyscctomi7.Cd animals.
GH acutely accelerates glucose uptake. After;t has
acted for 20-30 minutes. it inhibits gluC<ll<C uptake
by the sam. cells. (Only the inhibitory inAucnces are
"",n when the hormone is tested on mUSl'le taken
from suhjects with intact pituitary glamh.) Each
hormone additionally affects the formation. func-
lions. and degradation of its Own rc«ptor5.
Th. hormone concentration and its manner of pre·
sontation introduce addilional variables. Acute in
vitro responses of a single celltypc to high and low
levels of thc same regulalor can be: opposite in direc-
tion or qualitatively dilferent. In some cases. a re·
sponse is dieted only when the upper physiological
ranges are approached. For example. dilute p«'pa·
rations ofTSH have lillie influence on the fat me·
tabolism of adipocytes, but more concentrated ones
accelerate lipolysis. Pharmacological dosages can
activate receptors that arc not affected under phys'
iological conditions. Brief exposure. sustained pres-
ence, and pulsatile presentation of the same hormone
can each inVOke special efTects. Intact animals are
 often affected in diffcrent ways by 0011. parenteral.
and Glher forms of admini$trat ion.
A liingle kind of response o;an be elicited by more
than one mechanism. Thus. the fat dcgradatioo that
rapidly follo..-s norepinephrine bindilll to plasma
membra'lC rccc:ptors or adipoeyla <.::In be discin-
guished from the slowly developing lipolysis accom-
plished by glucocorticoids Ihat enter Ihe cytoplasm.
Thyroid hormones and GH act in yct difTcr<:nt ways
to affect fat metabolism in the same cell typcs,
available research tool has i15 limitations.
when investigators use several approaches 10 a
probk:m, lhey generally find it 10 incor-
porale assumptions inlo the they
formulaIC. Each lime rKW technologial adval"l«S
make il po$IIible to actually meaSure a parameter
wl\os(: dimemion'l were previously estimated. III<: hy·
potheses must be
An avalanche of new informmion has had (and
conlinues 10 have) far.reaching inHucnccs on the
coocepts of mc:chanisms of ac tion al the molecular
leveL Since .." now can detect and purify wbstanccs
prcscnl in very \ow concentralions. "nc""" horrooncs
are being discovered on an a lmOin regular basis. as
"old" ones and their receptors arc idenlifled in pre-
viously unsuspttted plae= Each of the ",galalon "
now known to share ito reign oycr metabolic palh-
wa ys with many subordinates. The mech,onisms for
cooperalion with inorganic ions nod other nonhor·
monal agcnls are being elucidaled. and there is
growing awareness of Ihe impon an« or communi·
Cluion with other ttlts and with the microcn";ron-
ITloI:nls. Moreover. Ihe relalionship$ betwc:<:n sp«ift
hormollli stim ulation and more gencflli7.e<! ttll pt"r·
11I.b3lion (134) an: Tttci";na appropn.te o;onsider·
alion. In o;as(s, species varialions have demo
OA'llrated that a physiological objective can be
accomplished in more than one way.
SINGLE VS . MULTIPLE " PRIMARY " SITES
OF HORMONE ACTION
Many I llempu hayc been made to ckfine a primal)'
site 0( actioo upon "'hich all subscqttent .vents de-
pend (Fig. 4-IA). It has been Pl'Opos..-d. for
that the inAuences of insulin 011 glYCOlen. protein.
ar>d lipid synthesis all ruul\ from ae«lerated uptake
of glucose. The concept is ael\hctieally a ppealing.
but il is 001 supported by experimenlal findings. AL -
though glucose uplake contributes substa nlilUy 10
the alllboiie actions. insulin can increase Imino acid
uplake and th. efficiency or peptide chain formation
eycn "lien ttlls an: bathed in
media. It is li kely lhat 01/ hormones act al multiple
siles "'hen they associate with thei. receptors (Fig.
4-18).
It cannot even be assumed that a single type or
response depends on j ust one prim/lry mechanism.
Thus. cpinephrine Qtn enhance in adipo5C
tissue (31. 144) and a lfe<:t &I)'COIenoiysis in li\'Cr
(63) in more lhan one way.
C• • ead • •
Certain ph)"liol08ical adjuslment! demand rapid.
massive changC'l in metabolism. For example, when
blood glucose concentrations fall to levels that can·
nol support brain funetiom. substa ntial
quantities of liver glycogen must be immediately
broIo:cn down to replenish tile supply. Ii"""'''''r. if the
associated ""re oonlinuously Jlfescnl in ac·
live forms. Ihc llepal<X)'les could lIl'\'Cr build up lhe
&I)'COIen reserves.
Clueagon is released in response to Ihc fall in
blood glucos.c. Wben only limiled numbers of the
hOfmonc molecules imeract with their recep tors. a
caseade that permits Ihe libcratiOlt 0( a million mol·
ecules of glucose "'ilhin I minulc is initiated. For·
mation or the rettptor is "coupled" 10 ac-
tiVilion or a plasma membn.nMlssocialed
that Cll talyzes the gcncralioo 01 an inlracellula.
messenger." Since each clI1.)·me molecule
the production of m:lny moLe<:ules 01 the
messengcr. the hormone effe<:1 is ampl ified . Th.
messengcr then activates a second cnzyme who5c
is )'CI a third en'.yme. This provides for
[unher am pl'fica\1on . The third enzylTlC then cata·
Iyzcs glyoogcnoI)'$is and thereby the productiO<l of
&IIbsu.nlill.l amoun" of gluoosc pllosphate. (A f01lrth
cnzyme. which iJ not pan of the Cllsc.adc. accom-
plishes ckphosploor)ialion 01 tho gll/C05C pho!;phate.)
A simple eavack i, shown in Fig. .... Ie. It pr0b-
ably doe$ not in naturc. liince all hormones
seem to act at multiple sites. Whcn glucagon accel-
erates glycogenolysi,. il ,i nluhancou,ly decn:a..,.
Ihc activities of enzyme, that promote glycogen "IOr-
age. Only s lightly l'igher physiological conCcntra·
,i0<l5 additiona lly stimul",c gluconeogenesis. When
ACftl activales cnz)'mes that accelerate gluOOCOl'
tiroi<\ production. it acts in other "'11)"1 to increase
blood IIow 10 thc adrellli &land and facilitate choles-
ICrol uptake. 11K somewhal more type or
c1lKade is lhown in Fig. 4- 1D .
Casc.de pher-.om .... ar. by no .... an. unique to the en-
doc.i'lC s)'Slcm. They . ", inV(>lvcd in blood coagulation
_rid In Ihe f01"mation or comp lement. II .,011 a. in nu_
other processes.
Dom ino .,•. Sustained Ac t ion.
Some hormone dftc\S are elicited when the n:gula·
tor is pt"esc:nted for justa few moments, and thcy can
persist even if thc cells are Ihen washed . This holds
\rue for regulators Ihal an: known to eKen their im-
". MECHANISMS OF HORMONE ACTION AND INTERACTION

/'
_ _ ,
B. Mullil'"C primary ... es
A. Single ",mary ..19

D. Comple. cascade

..
A __ 8 _ C ___ 0 _ _ £

E. '"[)omioo"' eH..ct ,-- _ ,

,----··.'0
, - ----- •.., Fill. 4 ·1.M""" ........ wl>e'oby one
F. Suslan.<! ""lion ""'<leI hormone CIOn eliCit ....." '."""""".

mediale inHuenc.s on <xU membranes without cnlcr- LATENT PERIODS

ing the cytoplasm. The first oontact of lhe hormone
with its ro:eplor may slart a self-perpetuating chain
reaction (Fig. 4-1 E).
Other funclions "'<.juil"<' the hormone to be CQnlin-
nowly prcS(:nt for ,.,,<,ral hours, Estrogen stimula-
lion of ulerine growlh provides an example (62,
\ 28). One poolibilily i, that the "domino effect" pr<>-
gresses slowly . Another is thaI long-lerm OC(;upalion
of the estrogen receptor invokes changes that cannol
be aOOlmplished acutely (see Fig. 4·1 Fl.
The latent period is lhe "lag" (time interval elaps-
ing) be(we<;:n the moment of horlTlOne-receptor com·
formation and the first dctectable change in cell
function. It can be subdivided into an absolute com·
ponent (when no effect is obscr.ed) and a relative
phaS<'. duri ng which the builds 10 a plateau
(= Fig. 174).
Something is obviously happening during the ab-
sol ute latent period. When cells are to the
 hormone for just a short time. subsequent washing
of the preparation usually docs I'IOt impair the pro-
gression of slowly developing events. Moreover. nei-
ther continuous presentation of the regulator nor el-
evation of the concentration can shonen the time
lag.
The duration of the latent period depends on the
parameter seloxted for measurement. When thyroid
hormones are administered. two weeks may be rc-
quired to achieve marked elevation of the metabolic
rate. However. some innuences of the same hormone
on RNA metabolism can be demonstrated within
hours. and dfects on mitochondria have been de-
tected within minutes (127),
The lengths of the lalCnt periods can pro_idc in-
formation on Ihe moxhanisms of action. especially
when agents that inhibit specific metabolic processes
are available.
Responses observed after ul/ra-shOT/ latent pe-
riods (measurable in second. or fractions thereof) in-
variably involve hormo",,1 influences on pre/'x;sl;ng
cell components. These include enzyme activation
and changes in membrane properties. In some cases.
the sites can be pinpoinled with the use of highly
specific en'yme inhibitors. or by comparing the
physicochemical pr<Jperties of membranes of cells
exposed to the hormone with those of cells taken
from animals previously made deficient . If the hor_
mone's effects can be mimicked with high extracel.
lular K' , this suggests (but docs nOl pro,'e) that the
h<'rmone promotes depolarization.
Vuy snorllatent period. (lasting Ito SI'"eral min·
u,es) are for enz)'me cascades. intracellular
translocation. dependent upon assembly or depoly-
mcriz'lIion! of mierotubules, and event. that follow
closely ul"ln changes in cytosolic concentrations of
substances derived from organelles or surrounding
fluids. Enzyrne inhibitors are also useful here. but
several other tools can be used. Colch icine and vin·
eristine are among the drugs used to disrupt micro-
tubular funclions. Changes in cytosolic Ca" me-
diale many hormone actions. If the hormone
promotes Ca" uptake from the surrounding fluids.
its elfects may be mimicked with A 23 187. an iono-
phore thaI carries calcium into the cell , They may
be blocked by bathing the cell. in calcium-<lencient
media. However, it is important to remember that
calcium-<lcpleted media (and chelating agents used
to remove the ions from the fluids) can norupecifi-
cally impair cell membrane functions. whereas arti-
ficial elevation of cytosol Ca" can stimulale cells in
ways not accomplished by the hormone. Aequorin is
somctimes used to estimate intracellular calc ium
concentrations. since it emilS photons when it binds
Ca. (It muSI. however. be injected into cells,) Other
agents that alfect calcium uptake directly Or indi-
rectly are cited in Chapter II. These include Ca" /
ATPase inhibitors and vcrapamil. as well as telro-
dotoxin and valinomycin (which affect 1"a ' and K'
transport, respectively). Some information on up-
take can also be obtained from studies of the effects
of hormones on the rates of accumulation of radio-
active ions added to the media.
Actions that depend upon ATP generation are
also sometimes seen after very Sholl tatent periods.
Oxygen and substrate deprivation. and agents thaI
"uncouplc" oxidative phosphorylation all impair
ATP synthesis, whereas ATPase inhibilors interfere
with the use of energy obta ined from ATP.
Assembly of peptide chains on preexisting libo-
somes can be accomplished within shorl latent pe-
riods of one-half to I houl if the cells already C<lntain
the appropriate mRNAs, Puromycin is an antibiotic
chemically simil ar 10 aminoaeyl-tRNA. It stops
chain elongation by forming a puromycin-peptidyl
complex that is discharged from the ribosome. (It is
effoxlive in both eUkaryotcs and prokaryotes.) Cy-
cloheximide (cyclohexamide, ac!idionc) binds to the
large subunit of eubryotic ribosomes (but not to mi-
tochondrial ribosomes that resemble the ones found
in prokaryotes). 11 bloch protein synthesis by inter-
fering with the formation of peptide bonds. Chlor-
amphenicol. by contrast. associates with mitochon-
drial and prokaryote ribosomes bUI not with the
cytoplasmic organelles of eukaryotes.
If the actions of the hormone depend on induction
of specific proteins that wcre pre_,ously present in
inadequatc amounts, the inhibitors cited can be ex-
pc<:ted!O abolish the tlfecls. On the other hand, Ihe
antibiotics have influences on protein
synthesis. and they can disrupt unrelated cell activo
ities. In C<lmmon with all nonphysiological sut..
stances. they Can exert ".ide-effects." for example.
by affe<:ting membrane properties. It is sometimes
helpful to use twO different kinds of inhibitOr>; of the
same processes (such as puromycin and cyclohexi-
mide) to minimize the importance of those other
sites of action.
In some cases, mRNAs with long half.lives are
used. More commonly. protein induction depends on
the forrnation of new messengers. Such actions re-
quire long latent periods that are measured in hours.
Actinomycin D blocb the effects, since it deforms
DNA templates by intercalating between successive
guaninoxytosine base pairs (74). Consequently.
RNA polymerases cannot bind and catalyze nucleo-
tide chain elongation. Although il is widely used as
an investigative tool. this antibiotic exerts nonspe-
cifoc inAuences. Animals given repeated dosages suf-
fer generalized ill health and loss of appetite . More-
o_cr, high concentrations can inhibit ribosomal
RNA symhesis and DNA replication. ""Amanitin is
a mushroom pOison that mOre specifically affect!
RNA I"llymerases involved in mRNA produetion.

Wbile small increments in cell of
one or a rew speciali7-cd proteins can be acbicvcd
wilbin bours. true growlh does not beI:ome apparent
until after the very long latent periods (oe<:upying
day1) have ensued. Finally, some thyroid hormone
actions associated with ulrra-Iang latent periods last-
ing WeeKS arc reccgni7.ed . They involve overhauling
of cdl machinery and the formation of new ribo-
somes, mitochondria. and otber organelles.
The latent periods and inhibitors Can be uscd to
determine wbether a metabolic process is rcgulatcd
in more than one way, Norepinephrine accdcratcs
lipol},.i. within minules by activating a pr<:<:xisting
lipase. Protei n synthesis inhibitors do 001 affect the
In C<lmrast. GH and glucocorlicoids pro-
mote the synthesis of substances tbat increase the
sensitivity to lI<)repinophrine . Their inAuenccs On li-
polysis are manifested after I hour, and their actions
are blocked by the inhibitors. Thyroid hormones aCI
in yet d ifferent ways. and thcy have longer latent pe-
riods. In addition to inducing a specific prolein (31).
Ihey oxen inAuences on calcium metabolism that af-
fect th. actions of norepinephrine (45) ,
THE SECOND MESSENGER HYPOTHESIS
Tbis hypothesis was formulated to explain the ability
of protein-peptide-amine type hormones 10 initiate
prompt response< in larget ""lis despite the fact
thaI Ihey do not readily diffuse acl'QSS plasma
membranes.
Accor<iing to the concept. I1ormones of this kind
are first messengers. They bind to specific. high-af-
FInity receptors on the outer surfaces of lhe plasma
membranes of the target cdls . This leads ,-ery rar-
idly to activation of a membrane-as.wciated enzymc
that catalyzes ge neration of Ihe u<:Qnd mes.senger
within the cytoplasm , The second messenger thcn
medialeS Ihc hormone actions (130). The hypothesis
was developed soon after it was recognized that the
small molecules generated when glucagon activatcs
the glycogen phosphorylase in the liver are
identical wilh the ones made when epinephrine acts
on sKeielal muscle. Afterward. wOrK in many other
laboratories led 10 extension or the ideas to a widc
variety of hormone actions (109. 110).
Support for the Concept Thet Pept id e -Type
Ho rmo nes Ac t at Ce ll S ur/ac es
1. have been made to ensun that hor-
mones C<lflllOl enter cell$ by covalently them
to presumably inert polymers (e.g. agarosc and se-
pharose beads). Even when the diameters or the par-
licles those of the cells. the hormones wcre
shown to rClain biological activities (25. n. 131).
MECHANtSMS OF HORMONE ACTION AND tNTERACTION
The . tudies hav. boen on $Ovcral grounds
(38. 134). includina failure to rute 0111 the possibility that
some free hormone eould be liberated from Ihe prepara-
tion., They have atso yielded some intriguing findings,
When in.ulin was lin ke<!IO so/ubi, pOIyme ... such 0$
rerritin or dextran. the potency was diminishe<!. This
could be explained on the ba,; s or aece$< of .he
hormone molecule. to their receptor site" llo"'ever. when
in, ulin was bound to iluolubl< polymers (.",rose b<ads).
the poIeney wa. actually augmented (24). Moreover. it
h.s b«n Observed IhOl there are cell typt. (e.a, ones in
mammary gland <.plants) that rcspond to bound. but""t
to free insulin presented in high eonccmrations.
11 i. likely that the increased potency is related to the
ability of Ihe preparatioll$ 10 promote
dusterina of laterally mobile hotmone receptors. (Non-
hormonal agent> .ueh as plant loolin . thaI promote clus-
terinB can mimic hormone actions,) Other possible intcr-
pr.tation. hav. b<en . dvanced. The prepa,,"ion, wuld
JIJuxiuri"" of thc hormone-receptor complex.
.nd in thaI way affoot actions of the rea"lator, Celt.
could also stick to hormone-<:ooted bc:ad, in larBe num-
bo", and thereby cngaBe in eelt_tQ-Cell inleractio". Ihal
do not occur when the hormon< i. free in solution .
2. The actions oj peptide-type hornr<NU!s a" as-
soclatrti with challges In plasma nrmrbratu's. Many
regulators depolari7.e. while a few (e.g. insulin in
some cases) byperpolarize. Agents Ihat mildly dis-
turb the membrane Can mimic hormone action"
Gentle treatmenl wilh Irypsin. phospholipases. and
organic solvents enhances hormone binding (per-
baps. in part. by exposing additional receptors). and
may even mimic SOm e hormone actions. On the
other hand. more drastic trealment with the same
lcads to loss of responsiveness.
3. /forme," aclions can be al!oli$hed by addilion
oj $pecific anlibodits against them. Presum-
ably. the antibodies bind hormones allached to the
cell surfaces.
4. Specific. high-affinity w:eptors Jor (H'ptide
hormelles have betn identified III Ihe plasma mem-
brane Jractlons of target cell, (bul nol in fractions
from cells unresponsi<-e to Ihc regulators). The re-
ceptors combine with hormones pre$Om in physiolog-
ical C<lnccmralions. with I1ormone agonislS (agents
thaI mimic hormone actions). and with specific an-
tagonists (molecules chemically related to the regu-
lators Ihat eompele for binding sites).
None of the preceding ncgates lhc possibilily Ihat
hormones of Ihis exert other kinds or actions
rollowing entry inlo Ihe cells (92).
Specific Applica tion of the Hypothes is
An)' molecule generated within the cytoplasm in re-
sponse to hormone stimulation that affects cell func_
liorn; might be considered a :second messenger. The
ooncept oould be extended to small ions Or mole· Some of the cdl types in which cAM P has becn
cules that accumulate in the cytoplasm when the
hormone alters the properties of the plasma mem·
branc,
-,
implicated as a second messenger are shown in Table

It is appropriate to preface a di5cussion of the

However. early applications of the hypothesis as·
sumed that hormone-receptor association is oouplcd
specifically to activation of adl'nylau q(/a$l'. an en.
zyme that ca taly1cs tbe formation of cyclic aden<r
sine 3'.5'-monophosphatc (cAMP) from ATP. loor-
ganic pyrophosphate (r·P) is a by·product:
_ hormones.
AlP ____ .•_______ <•_ cAMP . p.p
'"
roles of cAMP by pointing oot that (a) not all pep.
tide hormones promote generation of the nucleotide:
and (b) cAM P is found in all nucleated animal cells
that have been examined (including those of inver-
lebrates), in the erythrocytes of mQS\ mammals. and
in prokaryotes. h is generated by, and affects, the
functions of cells thai are insensitive to vertebrate
Mec hanism of Action of cAMP ( 15 )
Prolein kinDses (P Ks) are rt'gulalOry enzymes. They
catalyze the transfer of Ihe terminal b"l phosphate
of ATP to a wide variety of mole<:ules whose prop.
erties are alfe<:ted by the phosphorylation. The sub-
strates include other enzymes. components of mem·
branes, and proteins associated with the ribosomes.
nucleus, mitochondria. microtubules. and olher cdl
oonSlilUems.
$Qme of the protein are eA M P-dependent;
i.e. they arc relatively inactive in the absence of the
nucleotide because the catalyti, oomponents (C) are
masked by regulatory subunits ( R). Activation of
those teUamers can be repre"""tcd a. follows:
R,C. , + 2 cAMP _ R,{cAMP), + ), C.
(inactive (acti,·c
cn7,yme) enzyme)
Substrates for the activated catalytic subunits in·
elude regulatory enzymes.

T.bIe 4- 1 Some oIlhe largot Celli .. I'II'OctI II1teraet'" 01 thO 1100 .. """, with nl
p , :01'10< L_IO flevat'" o! CytoeoI eMAP ConoetI\,.tio<>l

Cdl Type St,mot>!in, HOt"""'" Elf."" of .A"-iP !;\o•• tioo

Hcpatocyte Gloc'loo Acti .. t;". or , ty""8oo

phoop horyl ... ,)'St.m
Adipoeyt. NOr<pi .. ph,i .. A.,i.>!;". or lip . ..
Folliool .. «It or ,h)·roHl Th)'md.-'imol .. in. S«r<lion of 'h)·roid

.
tt.od
Zoo. f.,oioul ... ,dl of Ad" """""io«ropi< S«""ion of , IUOO<OT'iooid.
• d .....1 «J""
.\!.", f>OIlOot. .1.1'' ' ' ' 1 ,..,,' m. I., ,ng Oi.I'<"ioo of pi,,,,,",
,",,,t«
Kid""y coItoc'in, d." V'",!"""i. W'IO'l""pot!
.<11
InI.",i,i.1 «11 or ""i. lotti.;,i., hor....",., $0."""", of "''''''Ct''''''
G.,,,i. m""""" colt I/i".m''''' S<o .. ,ion of ""jd

Kid .. y '.bo" «II P",.. hyroid loOt.,..,. t " ..... d 110 _ _ "<>"
Th)·""....,. 0011 of Th r)·' " ropi .... I•• ' i OJ: S<<<Ol"" 0/
p<'.i'>ry JI.od "' m.t""IOoo'_
'"
Protein kinase
Regulatory enzyme + ATP
(inactive. dephosph(),ylatcd)
The activulcd regulatory enzyme can be a CQm·
ponen! of a cascade that then aCt. on yel a different
,"',ymc.
Phosphate acceptors for ..actions catalyzed di -
1"<:olly by cAMP-<!ependent protein kinase! (or by
f<'gulalory enzymes activated by the prolein kinases)
can be membrane C(lrnponcnts inV<llvcd in control of
permeability, microtubular proteins required for in-
tracdlular traru;locations. ribosomal proteins affect-
ing peptide chain assembly_ mitochondrial conslilu-
ents, or substances within the nuclei (46, 61. 115).
A generalized scheme for eAMP regulation is sum-
marized in Fig. 4·2. Two examples are
shown in Fig, 4-3.
1. Norepinephrine is released during and
when the environmental temperature fans below lev-
els at which body temperature can be maintained
with the ongoing metabolic processes. One of the
hormone functions under such conditions is mobili-
7.ation of fatty acid fucls from adipose tissue.
The hormone combines with its receptor on the
surface of the adipocyte, and this leads to thc gen-
eration of cAMP. The nucleotide then activates a
cAMI'-<lepcndent protein kinase.
The kinase catalyzes the phosphorylation of a hor-
mone-sensitive lipase and thereby activatcs that en-
zyme. The lipase promotes hydrolysis of triglyecr-
ides to fatty acids and glycerol. The products of thc
reaction diffuse out of Ihe adipocyte, enler Ihe blood-
F«m.tion 01 HORMONE-Receptor complex ,,"
j
Act;."..., 01 adenylale eyc1a ...
"
j
Activation 01 cAMP..mpcn<\e(lt
prot",n kinase
j , • An> _
Enzyme
m<>mbrane tronspo<!.
protein synel1le'; $,
etc.
MECH.o.N I$MS OF HORMONE "'CTION AND INTERACTION
, Phosphorylated cnlymc + ADP
(ac(ivaw,l eozyme)
stream, and travel to ti .. ues lhat utilize them for the
production of ATP energy.
2. Glucagon is secreted during times of fasting
when blood glucose levels begin to decline to subop-
timal concentrations , The hormone interacts with its
receptor On the surface of the hepatocyte, and this
leads to the generation of cAMP. A cAMP-depen-
dent protein kinase is then activate<!. and it. in turn.
catalyzes the phosphorylation of a regulatory en-
zyme. glycogen phosphoryla se kinase. (The e/fects
of glucagon are amplified, since many molecules of
protein kinase arc activated. and each of them cat·
alyzes phosphorylation of many molecules of the gly-
cogen phosphorylase b kinase.)
The regulatory en7.yme then promotes the transfer
of a phosphate from ATP to glycogen pnosphorylase
(which has very 10'" activity in Ihe deph<lSphoryl·
ated state). The reaction results in the conversion of
the glycogen phosphorylase b to Ihe much more ac,
tivc glycogen phosphorylase Q. (Amplification is
again achieved.) The glycogen phosphorylase Q then
acts directly on the glycogen substrate to promote
the formation of glucose phosphate. In the hepato-
cyte, glucose phosphate is rapidly hydrolyzed to
yield the free glucose Ihat is liberated to the
bloodstream.
The glycogenolysis s)'stem is more complicated
than the lipolytic one. and it involves more amplifi.
cation. This is physiologically appropriate. since
,."
r 1 PK'
x_p· .. AOP
aetivaf.on,
4-2. e./IMP medlOlion of
. <:lions, • ""t;.,It!<! f(l<m ,
 NOREPINEPHRINE (adipocyte l GLUC"'GON

I
c",MP generation cAMP
I
g"""rao:on

j I
Glycogen
p/'IosphotyIase • AD P
(I kir\ao.Il.p'

Glycogen Gl"lcogen + AOP

p/Iosphorylaset> • ATP p/Iosp/'o<ylaS<l ,.
(p/IoS!>ho<yIate<l I

Glycogen • Pi ) Glcocose·p
("",,(/lin"
phoopl'latl) I

Fig. Ro1<l. ot cAMP in octi.ation Of..,..se.n<l

QI)'OO9&II p/lCoophofyl ..... • ... cti • • ted 1.,."1 oj enzyme.

there is an urp;cnt to rapidly correct the blood (e) moleCules phosphorylated by cAMP are con-
glucose levels, trolled by other regulators (140),

Exper lmentel Support l o r the Conc epts 01
cAMP Fun ct ions
Protein kinases that Can be activated by cAMP are
found in the cells (140) and sufficient
cAMP is generated to bring about the activation.
The cells also contain numerouS regulatory mol.,.
eules whose: functions are affected by addition Or loss
of pho&phate. The protein kinascs catalyze the pho$.
phorylations both in vivo and in vitro (46) .
Many investigators believe that all of Ihe conse·
quences of eA M P generation arc directly related to
the mechanisms just described. nowevcr, the fun so.
quenees of events initiated by hormone- receptor
binding and culminating in end rcsponSC5 have been
traced for just a rew functions.
When assessing the importance of cAMP gener·
ation, it should be '<'cogniZed that (a) whenever
ATP i. used to make that nuclcotide.there is simul-
tane<lu! formation of 1'.1' which also affects meta-
bolic processes; (b) cAMP degradation yields aden-
osine, another biologically active substance: (c)
steroid hormones and other regulators contribute to
cAMP generation and degradation (134). although
mO&t of their elTects are exerted in dilTercnt ways:
(d) many important pho&phoryiations are catalyzed
by protein kinases that arc cAMP-inde"..ndenr; and
c AMP Cen Bring AbOut In hibiti o n as well as
Activatio n of Enzym es
Although the hormone-sensitive lipase and the gly·
cogen phO&phorylasc enqmes a'<' activated by bind·
ing phosphate. other enzymes arc inoctivoted. Since
many of the second group catalY7.. reactions that op-
pose those: of the first. this provides for efficient con-
trol over metabolic The following very
useful generali7.ation has been made: En1.ymes in
biodegradativc pathways are activated by phospho-
rylations. whereas enzyme.'; in biosynthetic path ... a)'s
arc inactivated (S6A). The best'Known example of
inactivation by phosphorylation is the glycogen-csyn·
thesizing system of liver and muscle cells.
The formation of glycogen from glucose phO&·
phate is accomplished in twO steps. first . the glucose
pho&phate reacts with uridine tripho&phate (UTI'. a
molecule chemically related to ATP but containing
uracil in the place of adenine). The products of the
reaction arc pyropho&phate plus uridine diphO&phate
glucose (UDPG).
Glucose phosphate + UTP - UDPG + P- P
The UDPG then reacts with a preexisting glyco-
gen chain. and the glucose moiety is addw to the end
of that chain.
 MECIi ... NISMS OF HORMONE ... CTION ... NO INTERACTION

Glycogcn syn thase

UDPG + Glycogen Glycogcn + UDP
(n glucose) (n + I glucose)

The second of the reaetio!l5 is rate·limiting for
glycogen sy nthesis. and it is catalyzed by the cn7-yme
glycogen synthase (glycogen synthetase. UDPG·gly·
cogen transphorylase). which binds to the glycogen
cbain.
The en'_yme exists in two forms: glycogen syn.
thase D (so !l3med its activity is dependent
upon tbc presence of very high ooncentrJtions of glu·
cose-6-phosphate) and glycogen synthase I (whose
activity is independent of such substrate re-
quirements).
A glycogen synthase kinase catal)'7es inactivation
of the en,_ynte,

Glycogen synthar.e
kinase
Glycogen synthase + A TP Glycogen synthase D + A DP
(active . dephosphorylated) (inaclive. phospho rylated)
Protein phosphorylate •. and it thcr<:by ae- k llQwn a, pbQ<phor)'lue kinase-kinase . and the >e<:<>nd a.
tiva tes the glyoogen synthase kinase. ThererOf<'. glycogen .ynthase ki nos<.
when cAMP promotes glycogen degradation. it si· T he described mechanism, for acedorating gly·
multaneously shuts do"'n the opposing prO<:eS$ of cogenolysis a rc mar<: complex than the ones inhibit·
glyoogen synthesis ( Fig. 4-4), ing glycogenesis, T his i, consistent with the urgent
Before it ..... rerogni7.cd thai a 'inale en'.)"me (protein need to rapidly OOrreCl low blood glucose levels.
kinase) catal)"><:< pbQ<phoryl.tion. of both pho<phoryiase Howe_cr. additional controls arc in the
kin .." and glycogen synthase. the first en,)'me was next section and in C hapter 5.

GLUCAGON

I
"""
j
p,ot'"" kinase
(active bm)

GIyo<>gM syntflase phOSphoryIa ...

kmase (inactive) I> kina ... (inactive)

j j

Fig. 4·4. SimuIla"""". InM>ition <>I glYe<>g9n sYnthesis

and activation <>I g1yooge.-.01y.i.,
RegulatIon 01 cAMP Concentralion s crelion. f<.lr example. when glucagon restores blCKld
concenlflllions, Ihe alpha cells of the pan-
Since calalF.<:d by the cAMP..:Iepen- crealic islets decrea.\e lheir output of the hormone.
dent prolein bnases advanlageous al (The n:gulator must be continuously presenl to cxert
times but undesirable at olhers, cAMP levels must sustained actions [1121_)
be regulated, 2_ Targel ails JX>-l$tSS enzymes thai degradt her-
Cyclic nucleOlide phosphodiesterases calaly?.<: hy- nlOM previously secreted. Similar en?ymes are pres-
drolysis of to adenosine-5'-mooophosphate ent in blood and in other body fluids. Some hor·
(5'AMP), a product that lacks the biological moncs involved in processes that can require
enics of cAMP, especially mpid termination of Ihe clfe<:ts an: re-
moved in other ways_ For example. secn:tory gran·
Ph asphod iest erase
cAMP + BOH ( S'AMP) ules lake up and sequester catecholamines_
3. Correction of the condition thaI originally elic-
The en7.ymes are universally present in cells, and iled secretion of the hormone can provide Ihe stim-
Ihey play major roles in depr=ion of cAMP levels. ulus for Ihe release of amagoni,,'ie reglilalorS.
Their formalion and activities are controned by hor· (When glucagon excessively elevates blood glucose,
mones and also by cAMP ilself. insulin secretion increases.)
Other mechanisms contribute to lowering of Ihe 4. Pm/efT! kinases are itUleth·ated. As concentra_
cAMP conccmmtions. Small quantities of the nu- tions of free cAMP decline. some of the nucleotide
cleotide diffuse oul of cells. especially when the cy- bound to Ihe regulatory subunits of the protein ki_
tosol concentrations are high. cAMP is a normal nases is released. This permils the regulalory suo.
constituent of blCKld. urine , cerebro:spinal fluid, gas- units to re<:ombine with Ihe catalytic subunits.
Iric juice. and seminal Huid.
In addition. some cAMP is bound to macromole-
R,.(""MPj, 2R • 2 CAMP
cules or otherwise rendered tempOrarily inactive via
sequestration within organelles (fig. 4-S).

Terminstlon o f Effects 01 Hormon es Acting Actnoe ea"'lyIic lnacl;"" p'OIein

vIa cA MP $Coonit kin a ...

Mosl reSpOnses can be rapidly arrested.

I. Rmwval of the stimulus shuts off hormone Sf:-

In addition. cclls conlain inhifJirorr prolej'J5 that

combine directl y with (and then:by inactivate) Ihe
fro:<' catalytic subunilS_
High concentrati<>os of
I' e<! CylO$OI cAMP
c +. C-'
Active Inhibitory Inactivale
""""'"'
rIO/mor>es ar<l
olhcr 'e-gulaIOO'S
catalytic
.ubunit
protein enzyme

t Adcnylate
eyela..,
I
t
P Msphorlie .. "" . ... 5. Pho.<phoqialtd molecule., re.erl II, Ihe del'hos-
aCI;"ity pho'Ylaled Slate. While the process can proceed
slowly without the benefil of en,)'mes, cells contain
phosphat"ses that speed up the reactions.

""- ,
ar<l a'he,
6. Changes in cell metabolism can reduce Ihe ef-
ftCliW' Ms., of phosphorylated regulatory molecules.
'<>gu10100'S
Ex""""",

I
Roles of Phosp hoprotein Phos phatases
Phosphoprotein phosphatases catalyn: hydrolylic re-
moval of Ihe phosphale groups added by the kinase-
low concen"atior>. direcled n:actions. (No ATP is synlhc.'izoo.) The en-
of cytOSOl ""MP ?ymes aCI On molecules thaI arc either activated or
Fig . 4-5. of cyloool cA MP r;<>o<:enl,aliorl •. inactivated by the phosphorylations_

'"
PrOlein phosphatase
Glyoogen phosphorylase b kinase + HOH
(aclive. phosphoryl ated)
Prolein phosphatase
Glycogen synthase D + HOH
(inaclive, phosphorylated)
Insulin. an amagonist of glucagon. brings about
activation of several of Ihe pllosphoprolcin
phosphalases.
The interactions of lhe hormones and lhe enzymes
they alfe<:\ permit the operation of elegant and
highly cflicicnl mechanisms for fine control of
metabolic processes (set Fig. 4-{i). In addition,
(he'" arc substrate controls Ihal CQ/\fer spe<.:ial
advantages. High oonc<:ntralions of gluC«IC-6-phos-
phate increase the activity of glycogen synthase.
even when the enzyme is not
some glycogen will be i10red during
times of substrate abundance, when insulin
levels are low_ Thi, i, especially fortunate for
subjects who are insulin-defieient. Glucose con·
tributes to the regulation of, among other things,
the activities of phosphoprotein phosphatBses
(26).
MECHA NISMS OF HORMONE ACTION "NO INTEAACTKlN
Glycogen phosphorylase b kinasc + Pi
(inactive. dcphosphorylalcd)
Glycogen synthase J + Pi
(active, dcphosphorylaled)
Regulation 01 Adenylate Cyclase Activity
Most of the adenylale cydase activity of eukaryotic
cell. has been localized to the plasma membrane,
and only membrane-associated enzyme has been
studied in detail.
There i. evidence for aClivity in the .. r""plasmic relic-
"tum of cardiac muscle (75). cAM P i. found in all Olher
pam of Ihe ce ll . but dala , upporling the existence of the
enzyme in nuclear. miloch""driaL and mierosomat f ... c.
liom have been que"ione<i by some on lhe ground. thaI
contami""li"" wilh ptasma membrane components wa.
oot unequivocally ruled out .
The enzyme systems arc and they vary
from cell type to ceillype within the .. me individual.
Some generalized models for activalion have been
proposed (102), but concepts of the organillltion are
still evolving.
 Sinc< the hormone binds at the cell surfatt. while
the Mg-ATP and tne cAMP are in thecy-
tosol. it was reoognil.cd from the outset that the sy!;-
tem must span the width of thc plasma membrane
(Fig. 4·7 A). Hormone binding and catalytic activity
can be affected by different regulators_
It soon became apparent that the iIornlQne-rec.
ognition and catalytic clements arc separate prt>-
leinS. and that t!ley are physically and functionally
linked by a "coupler" or "transducer" (Fig. 4_7B) .
Hormone-recognition , rtgulato,y (If.nsduee,) .nd
e.lalytie dem.nts nave been separated from eaeh o1her
od I
• more of thc hormones are presented simu ltanoously •
pI •• ma "
membr"""
Ftll. 4 ·7. Model. 01 eye/. . . .
""'mone: RH, _mono _ tor s ite, Rg " Rg •. Rg ••
,ogcotltOO'y s itel: C, CIltaly1ic
RH"
S. ilUbalra t.; T.
lor hormono I; RH" receptor for
hormane 2. _ indicat... pot..,lilt for interaction with
un r,hration <:<>tum", (55). The regul.tory units (G. G /F
or N) are complex protein, ,,·ith molecular wcil\htS of
arou nd 1)0.000 th.t contain three diffe,ent kinds of S"b-
unitS(93), They can be sepanucd from the cat.ly1ic ';te.
when two diff<rtnt kinds of cell. art co-<:uh"rtd (20) ,
Moreove,. «lis that I,ck hormone reccptol'$ can bind rc·
cept"" presented in pl.,ma mcmbr .... fraction. from
othe r «lItyp<' in a mann", that permi,. hor-mOMI aeti.
• .,ion of the enzyme (121).
In "resting" cdls. eaen component may be free 10
move laterally within the plasma membrane (25.
102) (Fig. 4-7C) . The hormone evidently inV<lkcs
clustering of receptors and the linking of the three
oomponents. The ooncept is consistent wiln several
kinds of observations. I.«:tins and othcr agenu that
promote cluster ing of thc hormone receptors Can
often mimic hormQlle actions_ Electron microscopy
Sludies employing specialized techniques have pro-
vided morphological evidence for hormone-stimu-
lated rec<ptor clustering.
The adenylate cyclase! of SOme eel! type; ean be
activated by twO or mOre hormones. Each bind, to
its own receptor. When very small dose! of twO or
the effects On cAMP generation Summate , However.
when one normonc invokes a maXimal response. a
seoond cannot further activate Ihc enzyme , It is
likely. therefore.lht different kinds of receptors in·
teract with oommon catalytic oomponents.
THE COUPL( NG FACTOR
Tfllnsduccrs interact with both rc:<:eptor and cata·
lytic component< (3, 93) , The (f subunit binds GTP
(e ..,ential for ad.nylate cydasc aClivation). and its
GTPase terminates the response. Inhibilory (N;) and
stimulatory (N,) regulators have been identified (A·
7). bu t it has been suggested that Ihey are different
forms of the .ame peptide.
According to onc mood (13). the hormone inte,aet'
first with both its receptor and tne G protein to form an
",etivated oomplex."
Hormone - Rocep1or " G _ _••_ H·R·G
(""'mane (activ.te<l c<>ml)le<)
recognition
proteinl
Then. GT P binds to the complex.
Only when thiS oceul'$ can the G protein effectively at·
H, tach to and .ctivate the catalytic ';te.
H·R·G·GTP + Gatalytic unit
f
.. H·A·G·GTP
(;"act; •• ) (""waled adenylate cydasnl
". OF ACTtON AND INTeRACTION

The "li" i1y is of short duration. boca.« 'he OTPut m,

enzyme of th. G unil c.talyz., hyd,<>Iy.i. of lb. nude.,. 2,
tide and separ" lioo of the components of lhe C(lmplex. 1. C, - GTP + H - R - GTP - -- -_ ,

I I
H_A·Q·GTP _ -••_ H_R·G·GDP _ _ _ ._ H • R • G + C
H - R - GTP-GTP - C ,
(fully active .den)'la te
cyda.. )

GTP ha. additionally be." implic.ted in pTOtoction of

The '· .. m<>del" ju" d=ribcd '"ggom .hal lhe the receptor again.t eon •• roion to a "d • ..,n.iti«d'" .Iat •.
hormone aClS sole ly to r.dlilate Ih. binding of GTP 10 When hormone concentrations are low. and Iher.
th. regulatory (G) oomponen,. probably via ".8mo",a- i. 110 GTP . • mall quantities of. hormone-rece ptor com·
lion of lh. "umbers of binding ,ile, (29). II i. con,;.(en1 pl.x are formed. Such bindi", doe, IIOt liter re"'ptor sen-
with the followi ng observ.tion" $itiv;ty. but the ""mpl.xes bind to catal ytiC comport.nt.
GTP an.1ogo that ca noot be dephosphorylat<:<l (e". in their b..al "atc•• and the re.ulting prod uct> have little
, •• nosine (5'.[#. y-imido) triphosphate, Gpp[NH)p) or 110 enzymatic aClivity,
bring about pel'S;' len1 activation of adenylat. <)"<:1.""
when"" hormone is present. The effect i, pre«ded by a R. + H _ R, _ H
lag pe,;od. which i. pr<>bably ,.lated 10 Ih. mi .. ing bor· NoGTP
monal facilitation of the GTP binding. The hormone can R,- H + C. R, - H - C,
incre... th. dfec\i vc"""Of 'he analog. Different .nalog.. (low
that do 1101 " imul ate the .!fecl' of Ihe horlOOn ••. aot ivity)
pr<,umably l>ecause they form oomplexes th.t failtQ.e-
li.ale the cllalylic sil'. When the hormone concentration i. high. and there i.
A different. "equilibrium" model (I) ... to< Ihat the eilher "" GT P or .ery liul. of the nudeolido •• compared
ho,mone ca n prorn<>te bind ing of the G unil 10 the cata· wi th th. hormone. the receptor i. con,"t "od to • dnr"..
lytic one. to fo,m a ""mpl.x wilh low leli.ity (e.on when .ili:td .. ate as it binds tightly to the hormone. Ad.
110 GTP anache,). The 10w-acli.iW comple< can then dition of GT P can the n ..,"" .... the dosensiti,Olton . po$"
bind to GTP.• nd this in marked enhancement of .ibly by binding to th. receptor.
cOla I yl ie f U0<1 ioo,
HorlOOne only

"G, __ -"C'e''---_ •_G·GTP

"' '.
(receptor in
R.- H
(d=",itizod
G • basal or roceptor tightly
6 ! $Cnsiti""
.... e)
bound to hormone)

lhi9h ""t;'ityl Gn
R,H - R,-Il _ R, + H
In. reCCnt model (A.?)' H·R bind, G to form I high.
allinit)' II·R·G complex. When GTP attache, to th.
OTHER CONCEPTS OF GTP FUNCTIONS (2. alpha .unu nit of G. H-R and the bo,a , ununit ar. re-
11.110.111) leased. The alpha ,ubunit then bind. and act ivai" C. Fi-
By combining dir«lly ""ith the catalytio unit . GTP m.y nally. GTP dissociat., G from C, and the on·
fo,m an comple. Ih.t undergoe. lime- and '.)'me rever,. to it$ in.ctive "ote.
tempe,.ture-dependent.eti.ltton e.en whon 110 hormone Additional c:oncep" indud. hormone and GTP antag.
i, p, • ..,nt. (Thi, i, con.i"ent ""ith the existence of low onism of inhibilory regulato .... and GTP and/ or hor·
1..01. of .n,),me aeti.ity in "ro. ting" cell,. and with tho monal mediation of th. rei .... of.n .ubunit
direct activation by GTP analogs. The quant ilie, of from the adenylale cyclase complex ,
cAMP g.ncrat.d as a result of th i. kind of int • .,ction GTP io an establi,h.d po:Iitive mod ulator of glucagon-
would be eXpeCled to be lim;ted by the rapid Tate of GTP sen.iti ve O)"tem, of hepotQ(yt.s, .dipocyt< .. pa ncrea tio
de pbosp beryl.tion,) i.lel bet. cell •• and myocardium. of catecholami""...,n·
,iti.e .dipoeyle< and m)'oc.ordium. of ACTH-<o""itivo
Direci combin'l ion of additional GTP with the hOT'
""mplc. could thon lead to form. tion of adipoeytes and adrenocortical cell •. and of
the fully acti.e .iti.e frog bladder epithelium" HO""e'>'< r. adenylat. cy·
da ... ystem. can be Ictivlted in more than ono way. and
L
4 __ u_-_
GT P GTP hao been repOrted to ..en inhibil<Hy inn u.nees on
v."'p..... in- and oxytQ(in...,n,ili'e cell. of bovine kidney
medulla while faili ng to affect some other ceUtype •.
(enzym. in (inacti,. (parti.lly Certain of the celll)'peo .. irnulatcd by GTP ore inhib-
bu.l"ate) intermediate) activated ited. by GOP. while Oth .... are 1101. lnosin. triphosphate
(ITP). ATP. and ADP have also been obst,vcd \0 eith.r
.timulale .". inhibit en.yme ,)"S\em •. eith.r directly.". via
in\ ..... ctioo wilh GTP.
NUCLEOSIDES
Adenosine. dewyadenosine. and OIh.r nu.lcosid .. in·
......" .AMP concenlration. in lymphoC)'t ••. plal.l.t •.
Skin. boO(, and myoc.o.rdium. and a lso in brain. adren<>-
cortical. and le'lieul., lu"""'. It de .. e'iC1lhem in fal
cells. kidn<:y COrle •• li'-.r. and norm.1 b.. in .nd a,cite>
tumors (33). Mammalian fat coil. oonlain high adenooin.
de.minase activity. TIl< en.yme promot •• oonversion of
.denosine to inosine. and it. inhibilors e"ue .. te Ihe in·
fl.cne .. of Ihe ad.nosine.
Theophylline and some other "gents u,"d 10 prolonS
the lif. of cAMP via inhibition of phosphodieslerase.
have been .hown to exert inHuence, on .denosine uptake
from Ihe e"noellul. r fluid. (31).
PHOSPHOLIPIDS
Hormone receptors are a.socialcd wilh phospho-
lipids of the plasma membrane. and Ihe associalion
may be essential for maintaining adenylale cyclase
funclions. Hormones Ihal generalC cAM P can bring
about very rapid melhylalion. and Olher changes in
the phospholipids (5 1).
Membrane-bound adenylale cyclase system. of
cell fractions relain lhe hormone responsi vcness of
lhe tissues from which they were deri,·ed . lIowever.
if ancmplS arc made to solul>ilize Ihe enzyme sys-
tcrns by homogeni7.ation in Ihe presenee of deter·
gents such as Lubrol·PX (and the detergenl is then
",moved). catalylic activily is p",sc"'ed while hor·
mone sensitivilY is los\.
Highly specific cll'eets of phospllolipid addilion.
can tnen be demonstraled . For phosphati-
dylinositol ",.to"'-1 the responsiveness of myocardial
systems to calecholamines (57). whereas neil her
phosphatidylcholine nor phosphatidylserinc is effec-
Ii"". lly comrast. phosphatidylserinc (but nol 1be
others) rc.IO",. In: responsiveness of hel'alic en·
zymes 10 Ihe catecholamines. When exposure of the
enzyme .ystem. of thyroid glands to phospholipase
A Or C destroy. the sensitivity to TSH. IIormonc re-
sponsiveness is restored wilh phosphalidylcholinc
only (75).
STUDIES WITH CHOLERA TOXIN
Chole,. loxin (choleragen) promote •• uStaincd. irrevcr·
.ibl. activation of the cyclase. of .11 euk' ryolic cdl Iype,
Ihu, far c.amined (87. I D). It i, a useful experimental
100[ for 'Iudying the "If.." of persistanl "Iovalion of
cAMP coneentr.lion< .nd for probing mechani<m, of ad·
enylal" c)'cla", regula\ion.
Cholcrag.n i. an oligome, conlaining throe dill'crent
IYpe. of subunia. A,. A,. and B. The enlire molecule i,
required for .ction< on inlaCt oell •. The rlfSt Step i$ the
bi..:ling of Ihe B ,ubuni" 10 8"nllliosides on lhe cell .ur·
face. The mo!eeul .. lhen dis.sociOl. and Ihe A, subunia
interact directl)' wilh the eyel . ...y.tem. (A, i. effecti..,
alo.,. in b,oken «II preparation •. ) The A .ubunit e.lo·
I)" .. Ihe tnn,fer of AOP·ribo<e from NAO' 10 an . mill(!
acid moielY of Ihe G oomponenl of lhe adenylale cycla..
S}·stem. It dimini.he. Ihe GTP.", .etivity of the G com·
ponenl and Ihe reby ,If.. " .ustain.d aClivalion of lhe ')"i-
tern. In platelets. it blocks PGF. , $1 imulation of GTPa ..
(16).
Beca.", gl)'coprolein hormone. $haft: SOme amino . oid
>«luenee .... ith choleragen. il ha. been ,uggest"d lhal gt>-
nadolropin. and TSH e, ert 'imib' innuenee. on lhei,
13'gCI cell •. Howe""r. dilf.... fICC. in Ihe mechanism, have
been found (I I 3).
FLUORIDE IO NS
F1uorid. ion ..... fIOl •• pecially u.eful f.". the study <>f
.den )·I.I. eyclase .)'Stems of inlacI celi •.• ince they exorl
powerful inhibitory innuen... 00 enl)'mcs of the glyco-
Iylic palhw.y. 11",.·ov.r. th.y are polenl stimulanl. of .d·
enylal< eycla...y"em, thaI have been ",Iub ililed (and
have therefo ... become unrcsponsi,·. 10 hormone Slimu·
lotion). The mechani . m. of aClion differ from Ih"", 01
hormones; and F- can anl.gooi,.. the effects of both hor·
mone. and chok,agen. Binding to G componcn" lhal
have associaled I<ith GOP ... m. 10 be .... nli.1 for nut>-
,ide aClivalion (3). It hO$ also l>c<;n ,uuwcd th.1 nut>-
;"'11' prumUL< ui ph"'''l'h''''''9'''0
or dis.socialion <>f an inhibitory compo.. nl rrom Ihe C)"
cia .. 'yOlem (9).
Forskolin is a ... cently introouced pharma.ologic. l lool
that activa\ .. adenyb'e eyel .... in both intact and bro-
kcn-ccll p... paralions. This dilerpenc ... m. to inleracl
wilh a previously unrcoogni,cd ..11 eomponenl Ihat i, no\
...dcd for hormonal or cholera lo,in >1imul'lioo. The ef·
feel> are dimin i.hod ... ith inhibitors of prolcin. but not <>f
RNA .yn lh.,is (II AI.
LO NG·RANGE INFLUENCES OF HOR MONES
Several hormones affect Ihc bitlSynlho.i, of catalytic
and C<'gulalory componems. GH promotes a delayed.
.ustained elevalion of "basal" activily in adipocylcS.
a nd it also increases the effectiveness of catechol-
amines. Early reports Ihal insulin decrease. basal
aelivilies in SOme cell types (24) weC<' regarded as
controversial. bu\ mare recent work suggcsi' Ihat
some effects of lhe hormone can be linked with
depression of cAMP levels (3A).
Endorphins inhibit the aClivity of pr.. ad·
enylate cyclas. syslems in a manner thai is anlag<>-
ni1X:d by naloxone and related opiate antagonists.
Long'lerm e,posur. of cultured glioma cells 10 en·
dorphins lead. 10 "addiction" because of compensa·
tory increases in en7.yme synthesis. Afler Ihis has oc·
curred. Ihe cells tend 10 exhibit "normal" cAM P
 MECHANtSMS OF HORMONE ACTION AND INTERACTION

production when continuously exposed to the agents.

bUI excessive cAMP formation during times of
"withdrawal" (68). Cells of other types may "pro.
teCt themselvcs" against cxccs.sive elevation of
cA MP levels by increasing Ihcir synthesis of cn-
zymes that degrade Or inactivale thc nucleotide.

Pros ta g lan dins and the c AMP S yste m

Ccll perturbations by hormoflCJ;, neurotransmitters.
ions, and mechnical and other stimuli can lead to
rapid gcneration of the prostaglandins (PG.) and as-
sociated regulators (PGIs. TXs. etc.) (117). The
molecules exert effects on the cdls in which they arC
made. and they arC also potcnt stimulants for other
cdls (fibroblasts. platelet •. adipocyles. hepatocytes.
and comportems of kidney. pancreatic islets, thyroid
glands. for example) when they are released to the
surrounding nnids (43). They interact in complex
ways with other rcguahors (53). Sincc these include
cGMP. Ca" . calmodulin, phospholipids. neu",
trnnsmillers. growth·promoting hormones. and ki_
nase C. eAMP-dcpcndcnce is not easily delineated.
Three different kinds of interaction have been
found (105):
I. Augm,malion: PG& ,ynthesized in response to
a hormone that also activatC$ adenylate cyclase can
increase the quantity of cAMP generated and addi·
tionally act in other ways to augment the response.
The cAMP may also eontribute 10 PGE synthesis
(Fig. 4·8A).
2, NtgaliOit fudback: PGFs can lower cAMP lev-
els by exerting inhibitory innucn= on adenylato cy-
clase and stimulatory ones on the phosphodiester-
ases. At the same time, they can exert other acilons
that are not mediated by the nucleotide (Fig. 4-88).
3. aCliOlU: PGs generated either in
response 10 the hormone or in other way. can act via
separate mechanisms to either augment or lessen the
changes accomplished by cAMP (Fig. 4-8C).
T he roles of Ihe PGs depend not only on their
chemical nature, but also on the cell type and the
physiological oonditions. Moreover. high oonccntra·
tions can have effects that arc very different from
lower ones (53). They act on ves.sel walls to incrcase
or decrease the blood How: on plasma, lysosomal.
and mitochondrial membranes; on en,-ymes; and in_
directly by altering cytosol Ca'+ concentrations, In·
Auences on adipose tissue provide an example of the
problems involved in interpreting their importance.
When acting alone on whole tissue . they tend to el·
evate the cAMP ooneentrations. The effects are ev·
idently exmed on endothelial and fibroblast com·
poncnts. On the othcr hand. they reducc Ihe ability
of catocholamines to elevate the cAMP concentra-
Other . /
stimuti
C. cAMP.lnclepenclent ,nHlJences on the response
tions of isolated adipocyte:s by exerting direct
ito'1 infiuen= on those cells (30).
Protein Kln a ses
Animal cells contain a variety of en1.ymes that cat-
alyze transfers of the terminal phosphates of ATP.
GTP. ITP. and other nucleotides to regulatory mol·
ecules (I 5. 132. 140). They can be divided into three
groups on the basis of their activation requiremcnts:
(a) cydic nuclcotide,.jcpendcnt protein kinases; (b)
calcium-activated protein kinases; and (c) phospho;>-
protein kinase. that are not regulated by either
cyclic nucleotides Or calcium.
Most members of the cyclic nucleotide,.jepende nl
group are obviously contr<>lled by cAMP but ,how
limited responsivenes.s to cG M P. In this chapter. the
term PK is applied to them , Others prcrer kinase A.
and use kinase G for en1.ymes affe<:ted pr;imarily by
cGMP.
PKs are associated with the plasma membranes of
endocrine cell& (48) and erythrocytes. At least some
transport processes. Considerablc PK activ-
ity is found in the cytosol of liver, heart. Skelctal
musclc. uterus. mammary gland. and other cell
types. and the roles include phosphOf)'lations of met-
abolic enzymes and of ribosomal and other proteins.
Catalytic subunits of PKs are translocated to nuclei,
in which they act On histones and "acidic" nuclcar
prolein:;. Sub'llrale utilizalion ""ntrolled to a great
by onzyntC ""ntpartmentali,.ation .
Many of the are large macromolecular
enzymes with dissimilar thaI bear numer·
ous phosphate_binding A single type of PK can
calalyze phosphorylations of serine or Ihre<lninc reS-
idues at more Ihan one sp«ific locus. O nly some of
Ihe phosphate additions are directly linked with
changeS in the activity of the substrate enzyme. Oth_
ers Ca n affeci interactions with small cytosohc COm-
ponents or with other enzymes. In many cases. dif·
ferent sites on the SlIme molecule are phosphorylated
by caleium-<lcpendent Or other prolein kinasc.s.
Phosphate additions at one site can aff«t the ten-
dencies to gain Or \os( phosphates at another. More-
over. an enzyme that is activated by phosphorylation
may have a calcium requirement Or be capable of
activation by calcium alone. To funher complicate
the situation. a single PK can phospllorylate two Or
more that contribute to a common meta-
bolic function.
PK ISOZY MES
Tile t"" major iTOuPS have .imila, or identical calalytic
. ubunits. but they ha'·e different regulatory ""mpencna
and Ihc,d"", diff.,cnt propenies (140. t 4 7).
Type I isozyme> are ,mailer. more addic molecute.
that can ea.il)' be di."",iatcd inlo their subuni .. when ex·
p<»od in vi,,,,.o O.S At N.C! . hol<><n7.ym¢. bind MS-
ATP when it is pr=m in physiologica l concentration •.
Since Ihe .clivi.i. s arc inc 'eased or dee .... ed in
responselo .ma n changes in the cAMP Icvels. il ha, been
proposed that Type r isozym., cataty>e mostty '·on-off"
reactions that shift metabolic palhway. in accordance
wilh rapidty changing need. (28).
Type II iso.tyme. do not bind Mg·A TP directly. They
lend 10 undergo Ha ulophosphoryta.ion" and can pc"i" in
ccll. in phosphorylated form. (140) . The binding of phos-
phate reduoes lbe tendenci., of separaled ,ubunit< '0
...,,,,,,i.to wilh cA Mp. and it Ihe ... by increase. ··appar-
enl activity·'. Dephosphorylation. are eatalyzed by cal·
cium·<lcpcndeOi phosphatase •. Since Type II iso.ymes
are Ie .. euily affected by small change. in cAMP
they may be in,'olved in tho regulation of mctaboli< pro-
cesses Ihat .... of long dur.tion.
The Type I:Typc 11 rali05 vory with Ihe cctt type. the
phy,i<>lOjlical.l.tus. and the species. Thu •. Type 11 pre-
in rat adipose tiuue.nd Type I in rat t<Sti,.
The 1:11 ratio. arc higher for mouse and rat hea't than
for beef and iuin•• pig hear\. Type I is preSt". in lorg..
amounts in cardiac musdo undergoing hypcrtrophy than
in adull li .. ue that i. main taining a conSt.n, si7.c.
Hormono, excn differential effect. on the bios),nthesis
(36,73,8 4). For uample. estrogen, inorease PK I: PK II
ratios in the Uleru •• while FSH selectively activ.te. the
PK I in senoli cells of the (84). Although interre-
tationshipS between cAMP .nd ,rowlh processes .... only
parlially understood (34. 119). it h.s been p",posed Ihat
PK t affectS mostly cell si ... nd .t,ucture. where.. PK
r t pa!licipates in prOleCtiOn agai",l excessive celt protif.
eration (140). Many obse ..ation. ,upport the notion. but
.orne (e.g. the high lovetsof PK 11 in . kcletat muscte) do
00'.
Pho s phodiestera s e s
Each cell type contains its characteristic assortment
of cyclic nucle<ltide (PDE) iso-
zymes. Differences in amino acid S«juenc<:s account
far some of the variations in substrate specir,eities
and allinities. but the subcellular distributions and
dcgrees of association with membranes a!Tect both
the availabilities of the substratcs and the suscepti-
bi lities to activalion or dcgradation by other cell con-
stituents (91. 141). All cell s additionally contain
phosphodiesterases that dii!Tcrent kinds of
reactions.
On the basis of their cAM P-binding properties.
Ihe more common form. of PDE. have been divided
into three categaries. However. ent-ymes performing
specialized functions that do not fit into any of Ihe
groups have been deseribed for some cell types.
PDEs assume greatest importance when
Ihe cells accumulale substantial quantities af cAM P.
but they bi nd cyclic guanosine 3.5-monophosphate
(cG MP) with fairly high allinity. As discussed later
in this chapter. Ihese PDEs are regulated by calcium
and by calmodulin (77). "Low· K.. •· PDEs can hy·
drolyze cAM P that is present in lower ooncenlra-
lions. and they act mostly on that nucleotide. They
arC contwlled primarily by hormones. A third type
of PDE is activaled by low levels of eGMP. Once
this is accomplished, the enzymc evidently aelS
equally "'ell on cAMP and cOM Po(Therefore. vcry
high levels of onc of the substrate. may prolong the
life of thc other .)
Phosphatidylinositol and lysophosphatid}'lclloline
are among the additional known physiological PDE
acti va tors. Pharmacological agents used in the lab-
oralory include imidazole and ammonium sul falc .
Hormones regulate PDE synthesis as well as aC-
ti vity, and changes in the relative quantities of the
isozyme forms OC<:ur during cell differentiation and
maturation (126) . The ability of insulin to oppose
Ihe effects exerted by cAM P-generating Ilormones is
attribuled in part to insulin activation or induclion
of PDEs (63). Glucocorticoid. can exaggerate or
prolong some cA MP actions by interfering with
PDE induClion or aClivation. Long-range inhibitory
influences ar synthetic steroid analog. have been d.,.
scribed for cultured heptatoma cells and ftbwblasts
(5. 119). PG regulation of renal cell sensilivity to
parathyroid hormone has also been linked with
changes in the PDEs (10) .
In many cell types. cAMP ""ntributes to IKgativc
feedback control over ils own accumulation. espc-
 MECHANtSMS OF HORMONE ACTION AND tNTERACTION

,",
,

Catteir.e
I·MetI>y!·3-isobutyl·
X8t'I!hine IM IX. tBMX)

TheopIlyIIir>e & EtMylene<1ia....)

o " /"
" OH
"C -C-
"
""
HO-C-CH,A
\
oF
/"-Y'""N
y\"" C _ C_OH
H H H
HO-C_C'H'

" "
o
Oipyrid.moiO

FIg. '-9. Some phosphodie.t ..... ..

cially when the COOlCentraliollS a", chronically ele- PDEs arc widely used to detect small increments
vated. Cultured fobroblasts ·'comp"".."te" for expo- in cAMP generation following the presentation of
sure to cAMP analogs or PDE inhibitors by hormones, and to increase the dTeetiveness of pharo
stepping up their rates of PDE production (2 7). macological agents that elevate intracellular cAMP.

PHOSPHODIESTERASE INHIBITORS cAMP Ana logs

xanthines (including eaffciOlC and amino-
phylline) arc highly elTcetive inhibitors, and another
member of thc group, theophylline, has becn espe-
cially widely used for in vitro studies. I·Methyl·)·
isobutyl xanthine (M IX, IBMX), a synt hetic ana-
log, is mo", potent. In adipocytcs, dipyridamole and
papaverine are stronger inhibitors than the methyl
unthines, and the same agents arc highly effecti'e
in the heart (Fig. 4-9).
In co",,,,on with all pharmacological age nts. PDE
inhibitors exert actions other than the ones for which
they ar<: used (125, 129). Several inhibit the uptah
of This increases their effcctivcn= in
adipocyt<;l; (in which the nucleoside inhibits adenyl-
ate cyclase). [t also limits their actions in brain cells
sino:<= adenosine can aCo:<=leratc <:AMP generation in
neuronS.
It is difficult to a rtificially elevate
cAMP by adding the nucleotide to Auids surround-
ing the cells, because the molecules do not rapidly
traverse: the plasma membranes. There are condi·
tions under which cAMP can be used in combination
with one of the PDE inhibitors.
Synthetic analogs accumulate in the cytOplasm
because they enter the o:<=l1s at reasonable rates and
resist enzymatic degradation. They directly activate
protein kinases. and can additionally increase the ef·
fectiveness of endogenous cAMP by combining to
some extent with the PDEs. Dibutyryl cAMP (N",2'
-O-dibutyryJ..cAMP, B1r<:AMP, [).cAMP) is the
most widely used, but many others have been devel·
oped (86).
It cannot be assumed, however, that the cAMP
analogs faithfUlly mimic the effects (){ hormones that
activate adenylatc cyclase. The agents are presented
to cdl and it is common to use high con-
centrations. Many undergo metabolic reactions that
release biologkally active products. For D-
cAMP is degraded to butyrate and AMP. both of
which affect cell lipids and enzymes.
Phosphoprotein Phosphatases
The&<: enzymes catalyze hydrolytic removal of the
phosphate groups of regulatory molecules. They
comprise catalytic and inhibitory subunils thaI do
not dissociate in the ways described for the protein
kina_.
The enzymes are difficult to study for several rea-
sons (26). Four different types (I. 2A. 2B. and 2e)
have been identified. each catalyzing the removal of
phosphate groups from ils own set of substratcs.
However. some substrates are alfected by more than
one phosphatase. Most are high molecular ,,'eight
polymers that are present in limited amounts. They
arc not easily separated from other cell coru;tituents.
Each of the phoophatases can in active and
inactive forms tht differ from each other in associ·
ations with inhibitors. Three proteins that serve as
inhibitors have been found (S6A). These, tco, exist
in aClive and inactive forms, but in this case the
changcs arc brought about by phosphate tran,fers.
Protein phosphatases can aClivate (and protein ki·
nases inactivate) the inh ibitors. Therefore. the e<:lIs
contain wha t amount to phosphatase cascades. Nu-
;"""'ive
Pho6phc<yIase 1'. kjoase
&Clive
I 1- ---/
Pl\oSpho<yIase..Q. k;naS(! ""
Ftll. 4_ 10 . ParticipatiOn 01 pIIo"",""""t"" p/>o$photues
in 11M oon1lot 0_
trients delivered by the /luids, and me-
tabolites formed in the cytoplasm. interact with the
phosphatases. their inhibitors. and their substrates.
As diso:;ussed earlier. the PK activated by gluca-
gon catalyzes phosphorylation of glycogen phosphlr
ryllUic kinase. It acts at two sites within the molecule.
When it phosphorylates the fj subun it of the enlyme .
it increases the activity. When it phosphorylatcs the
'" subu nit, it changes SOffie properties of the protein
but does not inc,..,a,e the activity. Protein phospha ·
tase-I dcphosphorylates just the II $it(, The -"lime PK
phosphorylates glycogen ,ynthase; and protein phos-
phatase-I also dephosphorylates thaI enzymc. All
three inhibitors (inhibitor-I. inhibitor·2. and one
form of glycogen synthase) can decrease phospha-
tase-! activity,
The preceding complicate the work of biochemists
and physiologists. but they provide the body with
highly degant control m«hanism. (50. 74). A few
examples that apply to the glycogenolysis-glycoge-
nesis s)'stent summarized in Fig. 4-6 are cit cd,
I. The glucagon·regulated PK that acts on the
glycogen phosphorylase cascade to provide for rapid
recruitment of carbohydrate fuel. and on the glyco-
gen syntba<e system \0 inhibit opposing reactions.
performs yet II Ihird function. It assures that the gly-
cogen synthase system will not be prematurdy reac-
t;vated. It accomplishes this by activating an inhib-
itor of glycogen synthase phosphatase lsee (/) of
Fig. 4-10. J [t does so by calalyzing phosphorylation
of the inhibitor.
in""'OIe
Glycogen
-,
,/
,
'(4)
pOOsphalase ;oI'»bito< "
Gtycog"" syntl\ase
p/'>MpI>.t.se ;m;tJ;lor
"J
.J

2. Wben tbe PK the phosphorylase b ki-
nase. tbe product of the ..action further ensures that
glycogen syniha'" wilillOt be reactivated. since it in·
hibits the glycogen synthase phosphata", (s«: (2) of
Fig. 4-10).
3. The phosphorylase b kinase converts phospho-
rylase b to phosphorylase Q. The phosphmylase Q
also inhibitory inHuenees over the glycogen
synthase ph osphatase [sec: (3) of Fig. 4·10].
4. Insulin antagonizes the elfeetsof the PK on the
phosphatase inhibitor (22) [sec (4) of Fig. 4-10] .
5. When carbohydrate-rieh food is absorbed from
the intestine. glucose rapidly in the
liver. At such times. it bocomes appropriate to switch
from glycogen brcakdown to new glycogen synthesis.
The sugar itself arrestS the glycogenolysis by acting
di ..ctly on a phosphatase to promote reversion of
phosphorylasc a to phosphorylase b [sec: (5) of Fig.
4-11].
6. As a result of the preceding. phosphorylase Q
inhibition of glycogen synthase D phosphatase is
lifted [sec (6) of Fig. 4-11].
7. The liver rapidly converts glucose to glucosc-6-
phosphate. When high of the metab-
olite build up. they can accelerate glycogen synthesis
even when the synlhase is in the D (phosphorylated)
form [see (7) of Fig. 4-11] .
8. Glucose in the bloodstream provides the stim·
ulus for insulin see.. tion. The iIormone activates a
phosphatasc that converts phospilorylase Q 10 phos-
phorylase b [see (8). Fig. 4-1 1).
9. Insulin also activates the phosphatase that con-
verts glycogen synthase D to glycogen synt hase J
Phospnoryt •• e.!! pMsphata$(>
__L I _ ••_
"';'
Glycogen 'j'fllha$l!
o pMspMata...
,---,1__ "'00'"
- .ynthase
, phoop/lorylase phMphatase a""viIy.
GlI.>cose·P
IolECH",N I$ Iol$ OF HORMONE "'CTIaN ... NO INTERACTION
[sec (9). Fig. 4-11] . Addilionally. it a he.-
okinasc that conversion of glucose to glu-
cose-6-phosphate.
A further form of control (not shown in the dia_
is exerted by glycogen. When large amounts
glycogen synlhase activity dedin ...
Skeletal muscle also contains a glycogen·sy nthe-
sizing S}'lltem that is stimulated by insulin. liowever.
since the functions of glycogen in the two s}'lltems
are dissimilar. wmcwhat dilfe .. nt kinds of controls
are needed. Whereas glycogen Can account for 8%-
10% of the weight of the Ii.er of a well·nourished
individual. muscle rarely contains more than 1%.
Moreover. there are only special condilions under
which the 81)'CO{\en can accumulate. The muscle
must bo at ..st and exposed to adequale levels of
both insulin and glucose. (When insulin levels are
low. the plasma membran .. of .. muscle have
a "barrier" Ibat sha rply limits glucose uptake.)
When glucose can enter the cells. it is very rapidly
phosphorylated.
Contracting shletal musele must almOSt inSlan·
tancously break down glycogen when its ATP sup-
plies dedin •. AM P is an important activator of phos-
phorylase h. whereas ATP is an inhibitor. When the
A MP :ATP ratio is high. phosphorylase b can cata-
lyze glycogenolysis without prior conve rsion to phos-
phorylase a. Additional controls are described in the
sect ion on calcium ions.
Glucocorticoids exert long·range innuences that
contribute to the mainlenanCe of blood glucose Icv-
els. especially during limes of fasting. In add ilion to
promoting the conversion of amino acids 10 glucose.
Fig. 4-11 . Gluoose ta"mtales
glyoogero $yntl>olll by lr><:ro. U>.!
deCr<lftoirl(j inIIibilion oj i;I,OOQen
phospl1alo . • n<! prooOdlog
Glycogen gluoo..tl-phosphato .
they activatc ,;orne pllQsphatases. The)" 31,;0 support
the ability of glucagon to activate the phosphorylase
system (17).
Examin ati on of t he Importance of cA MP as
the Second Messen ger f or Most Pepllde
Hormones
In endocrinology. Ihe nolion ·· If you think Ihc COn·
trois al"<' sim pic, )'011 do nol have all of Ihc facls·'
usually proves 10 be morc useful Ihan the tenet
"Neve. a"""pl a complicated explanation if a simple
0'" seems to work.'·
The formulation of the Second Messenger Hy-
pothesis, and the research il engendered. markedly
advaneed our underslanding of the mechanisms of
hormone action. On tile other hand. uncritical appli-
calion has fostel"<'d confusion. while dogmatic accep-
tance has delayed I"<'cognition of Ihe importance of
observations inconsistent with thc concepts.
eAMP is generated in response 10 a variety of
stimuli. even when 00 hormonc is pr=nted. It can
exert numerous inHuences on cell funclions that are
unrelated to hormone functions. Therefore, the con-
clusion that it serves as the direct mediator can be
drawn only when certain criteria arc met (118).
It should be possible to demonstrat e that (a) the
plasma membrane has specific. high·affinity recep-
tors for the hormone and an adenylate cyclase sys·
tern Ihat can be aClIvated by the hormo...; (b) the
rise in cAMP prl'Ct'd.s manifestations of the re-
sponse; (c) cAM I' can dicil the same response when
no hormone is presem; (d) phosphodiesterase inhib-
itors exaggcrate the effects of subma,imal dosages
of thc hormone; the has cAMP-dependent
protein kinases that are activated when the hormone
is presented; (I) regulatory molecules arc phospho-
rylated following activation of the protein kinases;
and (g) the phosphorylated molecules are directly
involved in eliciting the
Usually. the f,rst requirement is easily satidicd.
The second is difficuh 10 demonstrate when the la-
tent period is very short, when only small cAMP in-
crements are sumcien t to achie ve the response. and
when the nucleotide binds rapidly to protein kinases.
Problems with the third arise because thcre is no
satisfactory way !O artifICially elevate intracellular
cAMP withom perturbing the cdl in other ways.
Protein kinases 3re universally prestnt. They are
easily activated by cAMP in vitro. However. Ihey
are usually studied with artificial substrates and
hiSh cAMP concentrations. Thel"<'fol"<'. the in vitro
studies provide only limited information on PK ac·
tivation in vivo.
Ma ny molecules have been shown to underso
pllQsphorylalion when the cells are exposed to her-
mones that promote cAMP generation . However.
the sequence Ihnrmone - cAMP - PK ' - phos-
phorylated motCl:ule - response] has been demon-
mated for only a few functions. Usually. it is the
links between the phosphorylations and the re-
sponses that have not becn established. cAMp·in-
depemienl protein kinases can affect substrates for
tile cAMp-<lependent ones.
In some cases. (e.g. when ACTH acts on the adre·
nal cortex), physiological levels of the hormone clicit
characteristic responses but no detectable elevation
of cAMP, while high concentrations of the hormone
promote substantial cA M I' generation. Since the nu·
cleotide alone can rnirni c the hormone actions. one
suggestion is that the physiological doses brinS about
localized changes in cAMP concentration< that are
too small to be picked up by 3""),S. No hard evi.
for such oompartmentali7.ation has as yet been
presented. Another thought is that low levels of stim_
ulation accomplish their effects in other ways.
whereas st rons stimulation recruits acccs.sory.
cAMP-<lepcndcnt mCl:hanisms.
The recruitment concept has been applied to some
different observations as wdl. Glucagon can invoke
muimal activation of the hepatic pllQsphorylasc sys-
tem when there arc just small cAMP inerements.
Higher glucagon Icvcls and greater production of
cAMP bring forth gluconcogenic responses as ,..ell.
Slill stronger hormone stimulation (and more
cAMt'J addItionally augment ul"<'a production.
The presenee of more adenylate cyclasc than
SCemS to be nceded oould also ensure that the ability
to senerate cAMP never becomes rate-limiting.
Thel"<' are diffe rent situatioM in which cAMP is
generated and is known \0 contribute \0 the re-
sponses. but for whiCh even hiSh levels are not. by
themselves. sufficient. In such cases. a search for
··third messengers·' is indicated .
The possibility that cAMP is generated as a con-
se<luence (rather than of the respons<: must
also be considered . When norepinephrine inleracts
with a ·lype noradre ... rgic I"<'ceptors of smooth mus·
cle, cAMP generation follows the contractile reo
sponse and plays a rnajor rolc in its termination.
Satisfactory demonstration that cAMP mediates
SOme effects of a horrnone docs not rule OUI addi·
tional sites of action. It has long been known Ihat
peptide hormones enter cells, but it was widely as-
sumed that such "internali7.ation" is soldy for the
purposes of degradation. Th e demonstration of high-
affinily intracellular binding sites, trans locations of
the hormones to the nuclei (38. 92). and th e long la·
tent pe:riods for some inftuenccson protein and RNA
synthesis 31"<' consistent with the Ihat pep-
tide-type: hormones exert actions inside the cells that
al"<' unrelated to cAMP generation (19. 42. 134).
,,.
TM K<XI!Irl JI'1<F'"nger <:OII«pt cmbn.ccs all media-
ton generated in response In bormo",s. Although it
is most oornmonly associaled wilh can be
applied in dill"....' nl ways.
Ca lcium plays such importa nt roles in bolh
cAMP.(\cpcndent and cAMP·independent fUrlClions
Ihal il is considered later in its own s pedal section.
IMUlin and prolactin provide examples of bar-
ITIOI>CS whose effects arc for the most part opposite
in direction 10 those e:tcncd by the cAMP-gcrw:ral-
inll regulators. l1>crc an: oondilioM ulldcr which
some inHucnc:c:s ca n be linked wilh actintion of the
phosphodiesterases (136). Il owever, the hormones
are . 1$(/ polen! when administered \0 cells that a rc
in "basa l" Jlales and ha ve very low adenylatc cy-
clase activity. It i. unlikely thaI further inhibition ()f
the enzyme is of primary important<:.
Pl'OI5la&b;ooiru can se"", IS se«>nd mcucngcn for
some procwcs regulated by prolactin (S<!, 1(8) and
ceTla;n other hormones. Altlloo&h Ihey interact wilh
cA MP or c(j MP in some « II types. they aloo neTt
actions 01 their own. PGs and tile relaled lcuko--
triCIlCS liso inieraci in several ways wilh calcium
ions (83), and PRL uses other media tor (A.I).
Since insulin opposes many actions of cAMP. il
obvtously ean""t ulilize Ihal Il$ a =<>nd
messenger. While considerable in formation on the
consequences of insulin bindillj to its receptor lias
b«n Ic:o:umulatcd. tlK: m«banisms ofletion arc sti ll
under inVUliplion. O ne hypot1le$i$ SlI.ICS tllal in-
sutin invokes some of ;IS cally effCCls by relcasing
(a nd lhereby act ivalin,). pro-
le;n kinase tllal is sequestered in pluma membranes
of unstimulated largel cells (22). Another is Ihal Ihe
insulin rec<:ptor i$ a PrQIein kinase tha i is aClivated
by the hormone (57 A). (The reo;cptor t>ccomes phos-
phorylated, but an alternale poss ibility ;' thai it
serves u • substrate for an utrinsic prOtein kinase.
Several inlracellular rnolc<:ulcs tlull undergo phos-
phorylations haye been identifl«l ( 12). These in-
clude phosphoprQIcin pbosplla\.lses thai oppose tIM:
effe<:Uof cAMP. YCt a different ooncept of insulin
action (which does not conflict .... ilh I.... preceding)
is that lhe l\ormone unde'lOCs proteolytic cleavage
afler it binds to ils receptor, and il then releases a
fragment that enters the cytoplasm and function& as
a second rTlCS$Cnger (38). T he suggestion is CQ1I$is-
tenl with observations made on pyruvate dehydro-
8('- (I mitochond..u.1 ellllyme whose activity is
enhanced by phosphorylalion). The physiologiall d ·
f«ts of insulin on 11K: enzyme can be mimicl:ed by
adding the hormone Iu buth
plasma membranes and mitochondria, but I"0OI by
treatin, mitochondria alone (122). Morcuver. ",boo
slano:u been identified within inwlin-stimu-
liled cells lhat mimic many of lhe actiUfl$..
For e.1lmple, they incrase the Ict ivilk$ uf Jlllruva le
dch)'ilroacnase, glycogen synthase, a nd low K.. phos·
phodiesterase. They also promote phosphorylaliun or
a ribosomal prolein. increase RNA polymerase I I
activity. and inhibil cA MP-depc:ndent protein ki·
nases
CYClICGMP
Guanylate cyclase lhe of eydic
guaOOlinc J',5'·munophosphate (cGMP) from GTP
by' reaction analogous to Ihc one described for fOf·
ma tion of c AMP from ATP. Both soluble and memo
brane-bou nd guanylale cydases have been identified
for a wide variety uf cell Iypc:$ (41. 91).
Cellula r concentratioros of cG MP are generally
lower than lho5e of cAMP. T his is allribu led in pan
to 8('ncn.lion of .... aller quantities; butlOITIC of Ihe
nuelC(llide phosploodicsterases preferentially inael;"
vate Ihi$ nucleotidc.
cO M P-depcndcnl protein kinases ha", been iden-
ti6ed in lhe cells. Although they have re8111al0<)' a nd
cat alytic subunils. activation by Ihe nuclcQlide does
nul seem 10 involve dissoc ia tion uf Ihe en7.yme com-
pone nlS (t40). Roles for cO M f' In supporting hor·
monal $limula tion of cell proliferalion and in media·
tion of .ctions of acetylcholinc that OppOSe the ones
obtliMd wilh catecholamines bocn described.
Small eicvations of cylOlOl Cal. art: IISUIlly re-
quired for IClivalion of adenylale cydaoe. Somewhat
higher ones can be achieved Ihat in hibil that enzyme
but Ictivate the guanylate cyclase:. Considerations of
Ihis kind led tu the formulation of an intriguing "yin.
yans·· hypothesis for reciproca l control of the direc·
tions of melabolic reactions by the lWO nuclOOl idcs.
The hypothesis is nul supported by expc:rimemal
fondillj:$- Although some pro«ssinp Ire senl in 0p-
posite d irections. otheR are affected in the same .... y
by Ihe cAM P and cOM P. MOI"CO'<'<:r, each can indio
rectly en .... nce thc effects of the other, sina: lhe tWO
n\ICleotidcs compc:le fQl" some of the same phospho-
dies/crases. cOM P also bind$ 10 kinase C.
T he funclions of cGMP nul su fficiently under·
stood. There are indicat ions Ihat low levels of some
horrllOllCS (e.g. ACTII) act;vate Ihe guanylate cy·
dase. whereas only higher ones promote cAMP gen-
eration (9g).
CALCIUM IONS AND CALMOOUUNS
Cf;llnimulation ",,-y be univ<:rsally .ssociated with
eh.ngcs in eytosol Cal. o;on«ntrations (9. 103). In
 most eascs. the ion interac ts with cK lcium·binding
protcins. the most importan t of wh ich arc the ca l-
modulins descri bed below. Many (but not an) of the
effects are linked .... ith the eAMP sytlcm. Some cal·
ciullHlependent enzymes underao phospborylations
that lowe r the ooneentrations of Cal' required for
activation.
Cakium ion conccnttltions in blood pluma arc in
the &cneral neighborhood of 2.1 - 2.6 X 10- 1 M.
They arc 10- 1 M to 10-' M in the cytoplasm of
"resting" cells. and closer to 10- 1 M after most
forms of stim ulation.
Hormones can r.lpidly cle .... tc the cytoplasmic
conccntr.ltlons by chanaing the of the
plasma membr.lllCS and thell'b)/ aeecil:rating passive
upta ke. Because of Ihe steep ooncc:nl ration gr.ldient.
a "simplc:" increase in pcrmc:abilily ....ould be
pected to aocomplish thi$. HO\Oo"l:ver. the hormone
seems to !TOO«: specifically bring about "opening of
calcium channels" and/or bcilitation of CO!r.losport
mechanisms.. (Tllere are pharmacological a&cnls
that can block the effects on calcium entry witbout
changing the rates of upta ke of ,luCO$(: and other
sUbstanees.) Hormones can also promote the rckase
of calc ium from sequeslration sites. Mit<x:hondria of
most cells contain $Ome .soo limes as much calcium
as the cyt05Ol. but endoplasmic retiCula seem to be
the major sou rces (A -6). Smaller quantities can be
libera ted from plas ma membranes.
Cytosol Ca" Ca n be rapi dly lowered by reuptake
into seq uestration sit C$. CII'/MgI·.ATPase ca l-
cium "pumps" actively lransport ions from the cells
to the su rl'Otlnding Huids. They ca n be stimU lated by
A CaM • c.1- C.-ClM
-.
•• c..c..... ,
CUi ' .....
, , . ....
...... = . ea.t
PC'''' ./
c.> . .........._
"" bindong 10 c.M
o.
f tg . 1-12. 1.. """•• tion 01 C.M. B. 1.<I;'01ion 01 C.M·
....1"". C. inhibit'" _ . Co" _ D. IrIlibilor
bloCk. C.Mtctlonl.
hormones and by other factors that elevate the cy_
losol Cal<
Ca" Interaction. with Calmodulin.
Calnl<XMins (Ca Ms) arc lhe major calci um·binding
proteins of non musele cells of vertebrales. and lhey
parti<:ipate in a wide variety of calcium-mediated re-
sponses (18. 141). They are also present in muscle
cells, in which they interlct .. ilh troponins (a MI wilh
.... lIich Ihey share both chemical and biological
propcnies).
Each of tile molecules bas foor sites for bindina
calcium. In restina cells. " 1111 low cylO5Ol Ca". lhe
sites arc unoc:<:upied. and the CaM s an: ill3.ctive.
When cell stimulalion leads 10 elevalion of the cy.
tosol Ca'·. the ions bind 10 lhe CaM. This brin"
about conformat ioll3.l changes in the protein Ihat in.
volve exposu re of sites apa bk of interaClina ",ilh a
"'ide va riety of proteins (including cAM P-dependent
proIein kill3.SC5. cA MP·independent protein kinascs.
and ot her rcaulatory enrymes).
The gencrali 7.cd seheme for activa tioo and usc of
the calmodulins is shown in Fig. 4-1 2. More calcium
ions bind per molecule of CaM as the Ca" conce n·
tration rises. and the atlachmenl5 of some affect the
affinities for others (66) . Some of the Ca·Ca M' -de-
pendent enzy mcs are more easi ly acti v"tcd than oth .
ers when therc are only small increments in cytosol
C.. ".
Calcineurin was fi rst identified as a calci um.bindin,
protein of that " "son;,,,, eff«,," of Ca·
CaM' on phosphodiesterase, (tJ9). l>ut protei .. with
C. - CoM'
"Actiwe-
"""""""" Co·CaM-E· - -_, ........
". MECHANISMS OF HORMONE ACTION AND INTERACTION

"milar proper!i., ha •• been r(}llnd in the hea" and else-
"'here. 11 is a het'rOO,mc, .,jlh 6 1,000 and 19,000 dalton
. ubunits (caldncurin A and calcineurin B. r<:<",,<lively).
It dephosphQryl.t<s ,Ile " , ubuni, of , keletal muock
phosphoryl .s. kin .... and the Type J I regulatory . ubunit
of PK- Although $/lid 10 be: idemical with tbe phospho.
1.<c-2B d.>c,ibcd .arlier (S6A), it diffell from that en·
7.}'me in molecular we ight and ;mm"nolosi•• 1 propcrli ••.
h .trongly binds C." and tner<by mak., the ion un-
... i!able for activation of el M . In addition. Ca-<:alci·
neurin form. comple... with C • .c. M th .. bl"". the
binding of Ihe activated C a M 10 enzyme. (66). In com·
moo with other C . ... limul.lcd cnzym ... calcine"rin can
b< actiyated and made Ca M·independent by limitod pro-
teolysi., The proteoly.i, afftolS the A subunit which be.rs
boIh CaM-binding and B subunil·imeracling ,i,o. (78A).
Caldosomon bind, ,nlOOlh muscle aClin. It may ",gu-
late cell .hap" art<! adhe'''''' (A.S).
Ca"/cAMP Interactions
It has been pointed out that moot hormone-respon-
sive cells ulilize both Ca" and cAMP. and thai the
IwO messengcl"5 can interact in several ways (1 04).
Some of Ihe mechanism. are summarized in Fig. 4-
13. Calmodulin is involved in many Oflhe responses.
but it is IIOt $hown in Ihe figure.
L When norepinephrine interacts wilh" ad","er.
gic reccptol"5. il elevales the cylOSOI Ca". The ions
mediate Ihe responses via cAM P-indq>endeni mech-
anisms, and the hormone effec\!; can be mimicked by
artificially raising Ihe calcium ion concentrations
(see Fig. 4-I JA). In Ihi. case. Ca" can be regarded
as Ihe second messenger.
2. CaCaM is a major activalor of ade nylate cy-
dase systems (64, 141). and calcium ion. may be
universally required for Ihe generation of cAMP.
Zona fa.deulal. cells of the ad"'nal cortex must
lake up some Ca" from the surround ing Auids to
elevate the cyclic nucle<)tide levels and respond in
other ways to ACTH (1 43). Some other cell types
can recruit sufficient ion from intracellu la r seques-
tration sites when they are bathed in ealcium-<lefl-
cicnl media . In either case. elevation of eytosol C. I.
precedes <and is essential for) accumulation of

, HORMONE • I Co" RC$POO5e

,. HORMONE
I Co' - - - i cAMP - -" Rc Sponse
/ca"
, HORMONE J I CAMP - - _ , RC$po<'l$e
D. HORMONE - - , t cAMP - -- - -•• Rospon..,

t C... •
, HORMONE
/' Response

, - •t ..
cAMP

--
HORMONE ,

HORMONE, _
• I CAMP > -

, HORMONE,
I cAMP ---------..R...pon ...
HORMONE, I ",.
,. HORMONE I Ca" Response

t/ cA MP -----•

I. HORMONE

Fig. 4· 13 . C. " -cAMP int....clion • .

" -. Inhibition Of rllld<lction.
cAMP. However. cAM P goes on to mediatc at least
some of thc response, and Ihe hormone effects can
be mimicked with exogenous nucleotidc (Fig. 4-
136). In a sense, therefore. Ca" functions as the
seCQnd messenger and cAMP as the third.
J. A somewhat different train of events has been
described for acetycholine aClivation of adl"<'nomed-
u11ary cells (104). The I"<'gulator may be capable of
activati ng adcnylate cyclase to a limiled exlent when
Ihe..., is nO change in cytosol Ca'·. However. pnys·
iological stimulation also invokes elevation of thc
calcium ion CQncentration. and the Ca" enhances
the adenylate cyclase activation (fig. 4_13Cj.
4. In CQntrast. when epinephrine interacts wilh {J-
Iyp<: adrenergic receptors in the heart_ Ihe cAMP
serves to the cylowlic Cal'. and tnc hormone
effects can be mimicked with nigh calcium CQncen-
lralions (see Fig. 4-13D). Wnile it can Inen be said
that cAMP is the seCQnd messenger and Ca" Ihe
third. it is more appropriale to regard Ihe calcium
ions as roup/us Ihat link cAMP generation with the
I"<'sponse,
5. Mosl I"<'sponses said to be mediated via cAMP
requil"<' tne participation of Ca". For example.
when glucagon aClivales Ihe glycogenolytic cascade
in liver. phosphorylase b kinase requires adequate
Ca" levels to funclion. The hormone clevales the
cylosol coneentrations of both mediators. but cAM P
can contribule 10 the changes in Ca". I'arathyroid
hormone is believed 10 acl via ""paTatc
10 devatc cytosol Ca h and cAMP (Fig. 4-UE),
(Some elTeets of ACTH on the ad...,nal cortex are
also Ca"-mcdialed [67A].)
6. Two different hormones can act on the same
large t cell to invoke a common response (Fig. 4_
UF.) Thcy may. however. be used under dilTerent
When glucagon functions under
conditions 10 maintain the blood glu-
cose levels during of fasting. its major media-
tor is cAMP. Muimal levels of glucagon deplete
only of the liver glyCOgen. The ...,mainder can
be tapp<:d under emergency conditions. e.g. when a
fasted animal Ihat has used mOSI of ils Skeletal mas·
ele as well as hepalic glYCQgcn reserves is confronted
by a pl"<'dalor. Ordinary concentralions of epineph-
rine have lillIe di=1 influence On IIlycogenolysi. in
Ihe liver. The amounts released during stress operate
via Ca" -mediated (cAMP-independent) meeha-
ni,m, 10 incl"<'3SC phosphorylase b kinllle activily
withoul alTecting Ihe glucagon·regulated PK (sec
Fig. 4- 13G).
7. Cal< and cAMP sometimes exert antagonislic
effects. Although cAMP elevates cytosolic Ca" in
many cell Iypes by facilitating its release from se-
questration sites. the nuclootide uecrellSts thc Ca"
in skeletal muscle by promoting its uptake into the
sarcoplasmic I"<'liculum. When cell stimulation ini-
tiates elevation of the cytosol Ca". the calcium ions
can bring about activation of adenylate cyclase. The
cAM P formed then becomes involved in a Iype
of negative feedback control (Fig. 4-13H).
8. While moderate elevations of the cytosol Ca "
invoke activalion of adenyl ale cyclase. vcry high
ones innibit (Fig. 4-131) .
DistrIbution and Chemfcal Nature 01 the
Calmodulins
Ca Ms have been identified in all in,...,rtebrales stud-
ied (including pn)t07.0aj . and in plant5, They arc bi-
ologically a ctive when lested on prokaryotcs_ and it
nas been suggcsled that structurally and function-
ally rdated proteins will be identified in bacleria
(58).
IntereSlingly . • lthough prokaryotc .dcnyl'lc oyol. ..
Iystem. differ rrom those of "ukar)''''e, in th.t they are
00l regulolcd by nuclco.ide l1ipl>oophales and ate inhi b-
ited by "uoride ion.. . uk.ryetic ealmodulin$ c.n incre...
the aClivilie' of the .. (8),
Before il was re<:ognized thaI ..
were sludying Ihe ",me proleins. CaM. werc kMw'n
under olher names that include calcium-<iependcnt
I"<'gulator (CDR) and calcium-activated prolein
(141).
The CaMs al"<' acidic. hydrophobic. heat-resislant
proteins with weights or 16,700. They
contain 148 amino acid moieties. including a vcry
specia l one at position 115. trimethyllysinc. AI·
though species differenccs are known. variations
secm to be limiled to seven point mutations. even
when the molecules from plan15 arc compared wi,h
those of animals (85).
The genes di=ting Ihe formation of thc m RN As
have been partially sequenced (90). Since each mol-
ecule can be divided inlo four components bearing
one calcium_binding sile each. and since the amino
acid sequences are very similar for domains I and 3
and domains 2 and 4. it nas been proposed thaI gene
duplicalions have occurred during the course of eV()·
lution , Close biochemical and physiological similar_
ities with muscle troponins suggest Ihal the tropen-
ins evolved from ancient CaM molecules (90).
The cnzyme attachment sites Can bind \0 phene-
thiazines (including chlorpromazine and triHuoper·
nine) and 10 some other "antipsychotic" agents be-
lieved to act via suppression of excessive inHuences
of dopamine. in particular. has been
used as an experimental tool to counteract calmo-
dulin functions. It is hignry potent. but it cannot be
regarded specific for Ihe purpose since it also
binds other hydrophobic cell constituents.
The subcellular location of the CaM is a major
determinant of ilS actions. Plasma-membrane-asso-
'"
cialed prmein mediates at least some of Ihc slimu_
lator)' cffe<:15 of dopamine on adenylale cyclase sys-
tems of neuronS . Chronic elevation of the dopamine
lovd. leads 10 "desensitization" that is associated
wilh a shin of Ihe CaM 10 lhc cytosol. The CaM
then becomes a phosphodiesterase activator (47).
CaMs hav. also been observed to bind to compo-
nents of submcmbranou$ aelin systems, and Ihc ITIQI·
al such sites arc implicated in funclions as.-
sociated with changes in the cytoskeleton (40),
HORMONAL REGULATION OF CaM
Generally, hormones $CI'm 10 have n<l innucnccs on
Ihc \Ola\ <xII C<)nicnt of the CaMs. They do, how-
ever, bring about changes in ils distribution (and
therefore in il! funclions) (85). On the olher hand.
some viral transformations have been roporlcd to
augment Ca.caM synthesis (90).
Some Roles of Calmodullns In Glycogen
MetabolIsm
Liver utilize mostly fatty fuels. The gly.
cogen they make is for "export". 1t is converted to
glucose and released to the bloodstream during times
of fa,,;ng. major conlT<)b OV"OT the
processes undcr physiological conditions. Very large
quamities of glyoogen can be broken down within 1-
2 min utes.
In oontrast, muscles store glycogen for their Own
use. They break it down to and
send the into ATP·yiclding metabolic path·
ways. The quantities of glycogen utihcd are small
in muscle (as compared with liver). However. the
need for ATP must be satisfied almost instanta·
noously. Obviously. different control systems are reo-
quired. Glucagon docs oot di=tly control the car-
bohydrate metabolism in muscle . Very little of the
hermone gets to th()I'.C <.:ells. and muscle lach the
ki nds of receptors found in the liver.
Physical exercise aeederates epinephrine ""cre·
tion. The IIormone activates skeletal mus<:le adenyl-
ate cyclase. and thereby initiates a cascade similar
to the one des<;ribed earlier for the liver. In common
with the hepatic en?yme. the phosphoryla.>c kinase
requires Ca>- to function.
MUs<:le kinase has a subunit strue-
lUre that can be represented as (nfj-y<i) •. The nand
fj comJlOnents hve serine groups that serve as phos-
phate aceeptors, the ""( ,ubunit bears the catalytic
SIte. while the 0 constituent is identical with CaM
(22) . When the muscle is stimulated by its motor
MECHANISMS OF HORMONE ACTION AND
nerve. the cytosolic Cal< con<.:emration rises rapidly
because calcium ions arc extruded from the !;are<>-
plasmic reticulum . To SOme extent. the magnitude of
Cal. elevation is related to the amount of stimula-
tion. When the calcium ion concentration is high.
phosphorylase kinase is activated by a ..cond mech·
anism. The enzyme mokeules bind calcium. and the
en1.yme can act on muscle phosphorylase b even
when it is in the nonphosphorylated form.
There is yet a third kind of control. The troponin-
C of the thin filaments i, a CaM ·like protein that
.. rves as the Ca" acceptor for the contractile mech-
anism. After it binds calcium. it too contribute; to
phosphorylase kinase activation. Thu" stimuli lead·
ing to conlraction simultaneously accelerate
glycogenolysis.
Regulation of glycogen synthetase activity is in
<orne wa)"$ even more complex. The s)"$tem comains
seven serine residues that serve as phosphate recep-
tors. and it is aifectcd by five different protein Ki·
nases. Phosphatase s)"$tems that include at least two
inhibitors contribute to the controls (22). Although
calmodulins are involvcrl. insulin activation via
mechanisms that require Ca " but not CaM has also
described,
Other Functions of the Calmodulins
The list of enzymes reportcrl to be activated by Ca-
CaM ' includes Ca" /Mglo _AT?uscs involved in
export of Ca" from the cells (138). phospholirase.••
dehydrogenase. some methyl transferases.
and guanylate cyclase (85). InAuenCel on prosta-
glandin metabolism have also been reported (145).
Direct contributions to endocytosis have been dem-
onstrated . However, although some involvement in
exocytosis is likely. diiferent calcium binding pro-
teins seem to be of greater (sec discu ...
.ion of synexin, Chap. 3).
Membrane Phospholipid "Cycles"
Several I'I'ptidc-type hormonel are known to bring
about almost instantanoous activation of plasma
membrane enzymes involved in phospholipid metab-
olism. The reactions can change the properties of the
membranes such as rates for Ca' - uptake_ abilities
to engage in endocytosis. the nature of the ceil-tOo
cell interactions, or the relea .. of enzymes and other
membrane components. [n many case". the hormone
exerts its influences selectively on one kind of en·
zyme and on one kind of phospholipid. (The prod·
 F'hosphoIipne A,_
f !SJ, . · l • .
R,. filly _
C.......I06.r.d' ; X. d>o" ... Iz ·..... ME. ;Zz_. _ _ ..
inoIil<ll pro, ,pilot"" p .
of the reactions may thcn the activities of
other cn1.ymcs.) Phospholipids, their metabolites.
and C," also afl"oct the properties and of
mit<xl\ondrial membrane. {99).
The hormone-medi.tled reactions <:an transiently
chan,e (a) the ratio; (b)
the of a phosploolipid containing one ki nd
of alcoholic group rdali...:: 50 tho$o: conlaining a ...
OIhcr (e.,. the phospllatidyicholine:phosphalM1yl.
Sl' riroc ralioj; (c) Ihe Cally acid composition (ex.
changes of an unsalurated for a s.aturatcd Cally acid
are CJ;peciall y to have biological conse-
quences); and (d) Ihe availability of a wide variely
of bioIojically active phospholipid derivalives, in·
duding 17"lItchidooale (which serv.:s as a precursor
for pro5tlJlandins aJ>d other rc,ulalon but addition-
ally lias elfe<;l! of its _n). lysophosphalidic acids,
pllo5pllatidic .<:ilk. diaC)'lsJ)'ttrols. alcolzolic groups
(choline. serine. elhanolamine. inositol), alcohol
phosphates. and monoacylglyo;crols.
The typical mcmbrane phospholipid is sh<lwn in
Fig. 4· 14. along with the .iles for cleavage by phos-
pholipase. A,. A,. C. and D.
Phosphatidylinosilol cycles (Fig. 4-IS) (S7) me-
diate effC(\$ of thrombin, collagen. hormones. neu·
and psyclzoaclivc agentS sucll as lith·
ium (A·2. A4) by activaling C. 1o «pendent kirwc
C. C libe7"llttes inositol pOOspItates lhal
mobili>;<: Ca" . and diacy lglycerols Ihat aUlmtnt the
, C_ _ , ; At. fally..a.s.
Ca l' afllnity. Arachidonale (A·!), ill$ulin (22). and
tumor promoters (A·S) activate the Ja me kinas<:.
MECHANISMS OF ACTION OF STEROID
HORMONES
Sltr(lid honnonCJ; ob>riously differ from those of the
peptide Iype in ph)-,.ical and chemical properties.
l"heir mosl obviou. aClions are aCrer latent pe-
riods of One or more hours. The Collowing mecha·
nism.! of action havc been proposed and shown 10 be
with many kinds of observation. (59, 60).
I. The her""",e traVel>OC$ the plasma membrane
and il cnttrs the e)'ropJasm.
2. The hormone (5) IlIen combines " 'ith a cyto-
plasmic fCCeplor ( R). 10 which ;1 binds wilh high af·
finilY and specificity \0 Corm a $teroid hormone-rc-
cepto. complex.
S+R - S·R
) , The complex undergocs a time·. tempemtu re·.
and calcium-dcpendcnt activa tion thaI affecls its
oonCormarion and possibly a lso ils ,i1.<:.
$oR -S· R·
4. The activated oomplcs is translocated to thc nu·
cleus, whtre it binds to lites'" of Ow:
chromatin.
 MECHANISMS OF HORMONE ACTION ANO INTEIlACTION
'"
"
C,NOSITOL".)
INOSITOL
CYCLIC
PHOSP HATE 1
INOS ITOL_I ·P HOSPHATE
o bH
' -- - INOSITOl·I ,2·CYCLIC PHOSPHATE

,_ / PHOS PHATIDYLINOSITOI.
FATIY ACID
•
CMF>·F>foIOSPHA TIDIC ACID DIACYLGLYCEROL

CTP ACID MDNOACYLGL YCEI'lOl

FArrY ACID
" FATIY ACYl.·CoA LYSOPHOSPHATIDIC
\
ACID

GLYCEIlOl
GlYCEROL·3·PHQSPI'ATE /

Oif>e< moIc<ules
GLUCOSE

Fig . 4 _1S. cycle. E""iOMod

inl .... l1'I<!<li.t •• con be ,,",cycled 01 roplaoed 01.,..-.,
· cal.lyzod by pI>ospI>oIipa.. C.

5. A oonsequcncc of that binding is the "unmask-
ing" of p",.iously inactive com(XInems of the ge-
nome. This leads to the production of new mRNA.
6. Some of the rnRNA goes to the ribosomes to
direct the formation of hormone-induced proteins.
7. The new proteins mediate the hormone actions ,
Experimental Support l or the Hypot hesis
HORMONE ENTRY INTO THE CYTOPLASM
AN D NUCLEUS
When the target cells are to hor·
mones labeled with lrilium, it can be demonstrated
with radioautography lhat the marker soon appears
in the cytoplasmic companment. The radioactivity
then inc,""ases for a time. and it generally pea ks in
half an ilour for preparations maintained at 3rc.
Some labeled hormone gets into the nudeus 5 min_
uteS or longer after it appears in the cytoplasm. The
nuclear COntent graduall}' rises and can peak in an
ilour, as the cytoplasmic radioactivity ,",'aneS.
Many of the steroid hormones act without them·
selvC$ undergoing metabolic transformations; and la-
beled hormone can laler be reCQVered from the
preparations.
It has been proposed that the lipid solubilities and
the conccntration gradients permit passive diffusion
into the cells (78). The concepl is sup(XIrtcd by slud·
ies demonstrating very rapid enlry of estrogens into
dispersed Ulerine tclls, linear rates of uptake r.ia'ed
10 hormone concentrations, and failure to find a Car·
rier protein (89) . However, Ihe possibility of carrier-
medialed transport has been seriously co",idered
(44.65.78). If <;aTTier proteins exist. they could be
inVQlved in with plasma proteins thai
regulate the rate of hormone entry and facililale up.
ta ke when lhe plasma concentrations arc low. Con-
ceivably, thcy could promote prcferenlial uplake of
sleroids that ael on the cells. However. it is more
probable that all sleroids cnter. but only the OIlC$
Ihat find high-affinity binding sites are relaincd in
substantial amounls.
Neilher Ihe conccnlration gradienlS nor Ihe lipid_
solubilities explain the mechanisms for rapidly over-
coming the barriers posed by hydrophilic g\ycoca-
Iycts on cdl surfaces. The importance of such bar-
riers cannot be determined when collagen is used to
prepare dispersed cells.
BINDING TO HIGH -AFFINITY RECEPTORS AND
SUBSEQUENT ACTIVATION OF THE STEROID-
RECEPTOR COM PLEX
The receptors huve been rocovcred from target cells.
but 1101 from cell types thut arc unresponsivc to the
hormone. The receptors bind to the hormones. to
hormone agonists. and to some highly specific hor·
mOne amagonists. They show little allinity for
chemically related molecules such as cholesterol
and steroid hormones that do not alfect the
functions.
When labeled hormonc is used. a labeled steroid-
receptor can be rec()\lered. Unlalx:led hor·
mone can displace the labe led one. but biologically
inaeti"e steroids cannot.
Qucstions havc been raised concerning whether
the receptors of unstimulated cells are in free form
in the cytosol. since cannot be accom-
plished with mild procedures. One .,uSgcstion is that
Ihe receplOrs are bound to macromolecules (94). An_
other is that they arc contained within organelles
tnat are disrupted during the extraction procedures.
The 5-R to S-R ' step is impaired by maima ln ing
the preparntions at low temperatures. Then. only the
initially formed complex is recoverable. According
to some observers. the activation is needed for trans·
location to the nucleus. According to others. the in·
active complex does r nlfr that compartment. but it
is not retained because il cannot bind with high af-
finity to acceptor siles of Ihe chromatin.
On the olher hand. it is by no means certain that
complex activation exclu-
sively (or even preferentially) in the cytoplasm (65).
The complex formed "'ilh estrogen ha s a sed imen-
tation constant of 45 prior to activation. and one of
5S afterward. It has been pointed OI.It that a smaller
molecule may bt: more: easily translocated (88).
Moreover. utlO<Xl'l'ied have been found
within (he nuclei (123).
According to onc hypothesis. Iysosomes conlain-
ing the "cytoplasmic" receptors cngage in uptake of
the steroid. formation and processing of the com·
plexes. and delivery of the product to (he nuclear
binding sites (133. 134). Both hormones and recep-
tors have been identified within such organelles.
Moreover. in at least some cell (Ype5. Ihe Iysosomes
tend to accumulate near Ihe plasma membrane be-
fore presentation of the steroid. and (hey migra(e to
the nuclear region afterward. The Iywsomes may
additicmally contribute to the inAuences exerted on
the nueleus. and to receptor replenishmcnt and
degradation.
ASSOCIATION OF THE HORMONE·RECEPTOR
COMPLEXES WITH THE CHRO MATIN
Thc nuclei of the target cells comain limited num·
bers of high.,.ffinity binding sites that may be di·
rectly invol""d in mediation of the hormone elfects.
along with larger numbers of 10w.,.fIinity sitcs. Aner
exposure to the 5·R· s. some of the are
easily extracted with KCI. but others arc not.
The progesterone-receptor oomplex consists of two
dissimilar sub units. each of whieh binds One mole·
cule of the hormone. One of the subun its attaches
directly to the DNA. "'hile the other associates with
a nuclear protein implicated in directing the complex
to the "correct"· nuclcotide sequences (120). The ae-
ceptor sites can be dilferent for other complexes act·
ing On the ""me target cell, (65). with binding to one
Or more of the following: DNA. nuclear Cn7.ymes
(especially RNA polymerases). nuclear proteins that
alfect the activities of the enzymes. nucleoplasm
components that regulate thc binding of the poly·
mcrascs to the DNA. or nuclear membranes .
The nucleus contains basic histoncs and a variety
of "acidic" (nonhistone) proteins implicated in reg·
ulation of access to specific DNA sequenccs. The
proteins undergo phosphorylations. acetylations.
methylatlons, and other that affect their
functions (61. 67). The protcins of the acidic group
dilfer with the ccll type. and binding to 5-R com-
plexes has been shown for some of the steroids. Sev.
eral ways tnat the S-R ' interactions with nuclc.or
proteins can lead to formation of new RNAs nave
been suggested (<)5).
FORMATIO N OF NEW mRNAs
Soon after the bioding been accomplished. Ihe
rate of incorporation of labeled u'idinc into DNA-
li ke. pre-messenger ("'siant:' "heterologous") RNA
can be demonstrated . This is associated with aug-
mented activity of RNA polymerase II. the enzyme
needed to form such RNA. For at least somc of the
steroids. this is followed aflCr a time by increased
activity of RNA polymerase I. which is involved in
the syn(hes;s of ribosomal (nucloolar) RNA. The p0-
lymerase I is not sensitive to (\'-amanitin (a poison
derived from mushrooms) . However, when the agent
is used to block the initial elevation of the polymer.
ase II activity. or when protein synthesis inhibitors
are presented. the hormone cannol increase nucleo-
lar RNA. This susgesls that small a1t1Oltnts of a spe·
mRNA and of a protein whose syn(hesis it
directs, contribule to the mediation of those hormone
ac(ions.
'"
When chick oviduct is eXp<)$ed to gonadal ste-
roids, the respOnse includes massive increases in the
production of RNAs and proteins. Many other re-
sponses 10 steroid hormones involve mQl;\ly qualita-
live changes and the appearance of molecules that
were IKlI dele<:tablc in unstimulated cells. In some
cases. it has been po:s.siblc \0 extraci new mRNAs
and to demonstrate thaI Ihey direct Ihe proouction
of hormone-induced prole ins in bacterial Or in cell-
frce systems.
MEDIATION OF HORMONE RESPONSES BY
STEROID-INDUCED PROTEINS
On. Or more hours aFter the hormone has been pre-
sented. it is usually possible to demon strate an ac-
celerated rale of incorporation of labeled amino
acids inlo proteins. T his is not necessarily associated
with subsuntial increases in Ihe prOiein cOntent pcr
cell. Some of the newly formed protei"" have been
identified and shown to be directly involved in me-
diation of the hormone actions. For example, cenain
of the aldosterone·induced proteins contribu te to
stimulation of sod ium transport in the kidney.
whercas certa in of the glucocorticoid·induced pro-
teins facilitate gluroncogcl\CSis in the her. Not all
<If the link< Mt ween, he newly <ynt mol"""I",
and the subseq uCnt hormone effects have been
defined.
W hen steroid hormones promote eel! growth. the
dfe<:ts are usually not seen for many hours afte r
stimulation . Time is requi red for, among other
things. the formation of neW ribo!;omal RNAs and
for processing and translocation of new mRNAs, as
well as for the assembly of the peptide chains.
STIMULATION OF DNA SYNTHESIS AND CELL
PROLIFERATION
AClions of this kind are not manifested until at least
18 (and more commonly 24) haurs aftcr the initial
exposure to the hormone. The)" evidently require ex-
tensive preliminary preparation of the cells that in-
cludes production of ne"· proteins.
Emogens can elicit such responscs only when Ihe
stcroi d-receptor complcx is retained within the nu-
cleus for several hours (see Cbap. 15). When uterine
tissue is presenled with a singk. moderate-si7.cd dose
of estradiol-17-fj (E,). all of the described cha<lges
in R NA synthesis can be demonstrated (21). While
very small increments in DNA may be detected car-
lier, quantitatively impressive changes first beoome
apparent aftcr (he 18,hoor latcn( !'Criod. They arc
associated with stimulation of DNA polymerase and
MECI1ANtSMS OF HORMONE ACTION AND INTERACTfON
thymidine kinase activitie! and of glu cose utili7.ation.
If agents tbat block DNA syn thesis "re introd uced.
the cells slill engage in thc preparative activities.
When aminopterin is used to block mitosis. the cells
undergo hypertrapby (128).
Estriol (E l ) binds to the receptors used by E l . and
its early influences are indistinguishable from those
of El . However. tbe E,receptor complex is retained
only briefly within the nucleus. When a single dose
is given, no delayed !Iimulatian of cell proliferation
occurs. El can invoke tbe delayed responses if it is
given in repeated doses Or is continuously presented.
STEROID HORMONE INFLUENCES ON
RECEPTOR RENEWAL
Estrogens arc among the hormones that play essen-
tial roles in regulat ion of their own receptor num-
bers. Thrc<: different mechanisms for receptor main-
tenance have been demonstrated.
I. New re«ptor is synthesi7.cd. Thc proces.< goes
On in targets Ihat have not been cxposed to the hor-
mone. and il accounts for the ability of previously
unstimulated cells to respond. When estrogen com-
bines with some of the cytoplasmic receptor and sub-
sequently promotes tmnslocation to the nucleus. (he
eytopl.smie oon tentt ronsiently dedines. Thi, is soon
followed by estrogen-mediated actions on the nu-
cieus that lead to accelera ted rates of new receptor
synthesis. The processes are blockcd in both unstim-
ulated and hormone-treated cells by "gents such as
cycloheximide.
2. S-R· that a\taches to low_affinity acceptor .it'"
in (he nucleus soon dissociates from those sites. The
liberated receptor then becomes available for
'·recycling."
3. S- R· that .naches to the high-aHinity binding
sites also di i>wciatcs after some lime . In Ihis case.
howe,.. r, the receptor is modified and is no longer
able to combine witb new steroid molecules (sec R,
in Fig. 4- 16). The modified receptor ca n then
undergo ··aetivation·' that reStOreS affinity for the
.teroid.
Process,,, 2 and 3 can be accomplished in the pres-
ence of protein-synthesis inhibitors.
Nafo,idine is a pharm acological agent th . t mimies 1he
carty cffects of cstrogen. and it can Cven elici\ ··ooe
I"0Il00'· of DNA syn,hoois. It ,ubKquen\ly act. a. an ·'an-
1iem"gen:· an effect al1ribu,wto fai tu re to promme re-
ceptor replenishment (21 ). Tamo'ifen mimics 'he effect.
of, .i ng1c dose <>f •• triol. but it th.n functions a, an an-
tie'trogen. It moy in'erfeTe wi,h 'he ability of Er R' ,,>
form the kind, of '$$OI;i3liono with nuck,T 'C<;CP'OT , itc.
required for dela)·.d estrogen action •.
 AESP<m SE
, "'.
<SHROMA11N)
,
,
Fit. 4·16. S<:h..... !Of ..,,""'. oj .... oiCI
1'\O(fI'IOnK. S. "ttOid hot",.,.,.: R. <OoOeI>lor; S·R. "",oti••
" Ac t ivation" of the Steroid Hormone.
GluC<)C<)f1iocoids. mineralocoftiroids. and es1l'Olcns
combine directly .... ith their and un-
steroid can be rcooV<:fcd at a latcr lime.
Tcw'!Icron.c alSQ bind. directly in some of ils tar·
gets. HoYo"Cvcr. in OItK:r c.:lltypc$. the testosterone
must first be mt"labolically 10 dihydrole$-
lostcronc, 10 estradiol. or 10 5OII1C other product (4.
137). Dihyd!'01cS\OSlcronc is more polent than lei>-
IOStcronc in the ce ll types in which it is formed.
However cSlradioi mimics Ib¢ "IfCCIS of andrOllcM
wlw: .c the androgen is firs! arom,uized to
Other r«agniml me\abolic chaft&CS in re-
sponses to steroid hormones inel..de intcrconv<:osiom
of estradiol OSlronc and the formalio<1 of i'l)-
duted metabolites of progecs\cronc. are
melaboli.-«i to catechol derivatives thai have
properties \Illi te di fferent from thole of the
prttllrs0r5.
CURRENT STATUS OF THE " STEROIDS IN,
PEPTLDES OUT" HYPOTHESIS
Although many asp«ts of $Ieroid and peptide hor-
mone fu""ion can be filled to the two
PflOTEINS
$·R ·
!J!J I
I
compMx; $.R·, mplex; 1\. recydMI ,,,,,,,,,,0<;
R" .--ptor.
hypotheses for m«hanisms of hormone action. the
dichotomy may be more OStensible than real.
1. In !XImmon with the steroids. peptide hormones
and their receptors enter their target cells. The
internaliuuiQn is accomplished by endocytosis.
Il>cre arc those "'00 bel ieve IlIat steroid
uptake rcqllires similar m«hanisms. Gro.... th
hormone. insulin. and othcrs
invoke stimulation of RNA and protein
synthesis.
2. Ro:ccptors for stcroid hormones have been iden·
tified al cell surfaces (100. LQ1). Estruscns elevate
the cAMP concentrations almost as soon as they
<:OI1tact utcrine cdls. and the nucleotide is in'pl icatcd
in some fC$JXMlses to androsens as well . Estrosen!
art also potent generators of prostaglandins. while
several influences of glucocorticoid! arc linxed with
inhibitory influences I:lIcned on cyc1OOJlyge!IaSC and
path""ll)'$(U. 124).
3. GluCl.IOO is ooc of several peptide! known to
aCI 00 lysosomal Gll>OOOJrlicQids are
stabi]i1.ers of the organelles in some cell types in
which cstrogen exerts opposing effects.
4. "ndrOlen re&Ulalion of carbohydrate metab<.>-
lism in.CCC$SOf)' reproduetiw= organs can pi'OU'lOd in
the prc:sentt of protein synthesis inbibiton.
 ,..
MECHANISMS OF ACTION Of IODINATED
THYROID HORMONES
The follicular cells of {he thyroid gland secrete thy-
roxine (T,) along with smaller amounts of triiodo-
thyronine (T,l. The: hormones differ chcmkally
from peplides in (hal the amino acid moieties are
held together in eilher linkage a nd ioxline i$ an es-
senlial romponcm.
II is cerlain thai T, CQII1bincs direcily with the
hormone n:«pton, and lhat the T, ctn be d.iodi-
nated to T, in both target <>rpM and in lhe
The of whether T, fu lKtioos di .eclly as a
hormone has not been adequBtely .nswcl«!.
T, acts on virtually every known <xII Iype (97,
127). II n':adily crosses plasma membranes, Iravcl'$C!l
the cytoplasm, enters Ihe nuclcu$, _nd binds direct!)'
(Qchromatin. Many of the: .:v.nu 11\;11 ....
bIc the: ones desnibcd for Slcroid """" ........... Labeled
undine is soon ITIOIl: rapidly iDWfp:>nlICd inLO
RN/\S , Afte .....·ard. prolein synthesis aceelCntles.
The cytoplasm contains prOlei", that bind the
hormone. but these do 001 funetion like steroid ,.".
They are believed to facilitate concenl
of lhe hormone fOf' fu ture presenlalion 10 the accep-
lor siles. (TIM: do not tl'llnsk>catc to the nu·
cleus in combination with the horl1lQnc.)
Some of the of the thyroid hormonC$
be deteeted aflcr latent periods of I or more hours.
Others do not reach their peaks until days or e...:n
" 'eeks ha...: elapSed. These ha...: been linked wilh •
gellCralizc:d overhauling of the cellula r machinery
that includes the formation of !lew organelles. Since
organelle turnovcr proc..,ds slowly. Ihc delayed d·
feelS pell'isl fot a considerable time afler Ihe hor·
IOOIlC is witlldrawn.
TJ may additionally interact dittttly wilh recep-
Ion of tile milochondria and other organdies 10
bring about effecls wilh very shaft latenl periods.
HOflMONAL INTERACTIONS
EKh hormone .ffeclS the bio&ynl,,"is, release. me-
tabolism. and functiOfl$ of many others. Several
kinds of inleraclion are kllOwn.
In" lIence. 01 One Hormone on the SeeretJon
of other.
l. As discusscd earlier. hypothalamic hormones
such as TR H Md LRH not only promote Ihe seere.
lion of targel cell h",mones (TS H and gonadotro-
pins. respecti...:ly), but tlley also maintain lhe mor.
phologies and fu/OC1ions of lhose cells. Additionally.
Ihe tropic regulat()nl augment lbe oensiliyilic$ 10
slimu lation (35). ITIC5lly via induction of hormone
receptors. The hermones made by lhe hypophysis. in
turn, uert si milar influcnc.:s on the IhyrOid glands
and gonads.
2. The stimulalion of horl1lQne prodUction docs
not nCCCSArily involve tropic influences. f or exam·
pic. glucagon promotes insu lin secretion, but il is IlOl
koown to affect the Siructure of the beta cells of lhe
pancreatic islets.
J. The stimulation can be dependent on othcr fae·
IOrs. As ootcd. GH prOmOIes somatomcdin tenera·
lion wilen nutrition is good, but il does oot have this
effect duri", times of food ckpriv;uion.
4. Negative feedback conlrols and other inhibitoty
influences we re disculsed in detail in C hap, 3. In
somc cases (e.g. when thyroid t on the
pituitary gland thyrotl'Ope$). i can in.
volve reduction in the numbers of receptors for p/I)"5-
ioIOCical stimulants.
Competitio n
Hormones that arc chemically similar can competc
for lhe $lme bindi", siles. USILIllly. one of the reg-
ulators binds with higher a ffinity. and the effects of
thc simultaneous presence of both are concentration
dependen!.
AldoMerone i. a hiSh)y potent nlincralocortiwid
tha! is effective in very low eoncentralionl. Proges.
lerone binds wilh lesser affinity 10 mincraloooniooid
n:ecplOfS. Therefore. when il is prcsc:nt alone. it can
serVe as a wnk mincralOClmicoid. On the Olher
hand. high cQnccnlralions of progesterone Ca n im.
pair aldosterone functions by compeling with that
steroid for the: same recepton.
ChemicaUy similar hormon.. can abo compete
" 'illl each other for binding sileson plasma proteins.
If hormone A displaces some ofhormone B, thcn the:
concentrations of "frec" B risc and Ihe hormone
temporarily ""crts greater effects than it othc""i""
"""Id at tha t ooncentralioo. Hov.'Cver. reiease from
the plasma protein can a lso aCttlerale the: degnda·
lion and ucretion of B.
and Potentiation
When tWO hormones (",eh as epinephrine and nor·
epinephrine) bind to Ihe $lime receptors, the effectS
of simultaneously p' e$Cnting small dosaces of each
Can he additive. Similar effecls may be Obtained by
combinina small amounl' of two hormones that act
on different receplors linko:<l to common cnlyrnes.
f ot example. adipocyte lip.ilSO: can be stimulato:<l in
Ihis way wilh combinations oIl1Of'C]lincphrinc and
TSH.
 It is possible For ineffective (subthreshold) dosages
to summate and thereby achieve cell stimulation_
The effects of small dosages Ihal arc above the
threshold are almosl arithmelically additive. When
quantities of one horlTlOne arc sufficient to invoke a
ncar-maximal re'ponse, lillie or no further stimula·
tion may bo accomplished by adding the other. In
fact, combinations generally inV<)kc 110 greater «:-
actions Ihan Ihc ones achieved with Ihe weaker of
Ihe two «:gulatOl"S_
Two hormones Can also utilize totally diffe«:nt
mechanisms to achieve the same end result. for e._
ample. anti-diuretic hormone directl)' promotes
water conservation. Aldosterone stimulate.< sodium
reabsorption . and a secondary consequence i. waler
retemion. When large doses of both are given to-
gether. more water is retained than is the case fol·
lowing administration of maximal dosages of cit I1cr
hormone alone. Tne response. are suP<',-.f1dd;/h·e.
Authors differ in their use of terminology. Somc
apply s}'lif'rg;sm to all additive effects. but others re-
strict its uS<: to situations in which there is simple
summation. Po/elll;a/;Otl has been used synony·
mously with synergism. but some resen'e tne term
for super-additiviIY.
HorlTlOnes Can enhance each other's effects in dif·
ferent ways. For example. one may induce an en·
1.yme affected by the other. promote cell prolifera·
tion and thercby increase the numbo rs of responsivc
01 alTccI ur ""4Ue'lraliun uf
substance involved in the response. Thus. glUCOCQr.
ticoids induce gluconeogenie enzymes aClivated by
glucagon . calciferols promole accumulation of cal·
cium Ihat can bo recruiled by paralnyroid normonc.
and estrogens incr.a'" the numbers of cells thaI
make progesterone receptors.
An tagon istic Influences
When One hormone sends a melabolie pathway in a
certain dircction. and another revers." Ihe direction.
each of the regulators usually aCts On its own enzyme
system.
If an enzymatically controlled reaction is permit·
ted 10 procced to equilibrium. a certain ratio of prod-
uct concentrations (K) will be attained.
rate I
A B
rate 2
K-
Concentration of a Usually, the permissive effects inmlve biosyn-
Concentration of A
when rale I _ rate 2
The value of K is determined by the chemical na·
tures of A and B, the bnds of bonds that arc formed
and broken. and the prevailing conditions (temper.
ature. pH . etc.) . It is independent of the speed of lhe
reaclion.
Hormones that activate Ihe en1_y me reduce the
time needed 10 attain equilibrium. Hormones Ihat
inactivate the en1_yme slow down the rcaclion, bUI
they canoot affecllhe K value.
Dual controls are achieved when One pathway in-
volves reactions that faV<)r the formalion of B (high
value of K ), whereas a diffc«:nt pathway (c_g_ B -
C - A) favors the formalion of A. (It will be re·
called thaI glucagon facilitates glyCOgenolysis by ac-
tivating the phO$phorylase sYSlem. whereas irumlin
favors glycogen synthesis by activating the synthase
pathway.)
Tne effeetivencssof dual controls is enhanced if a
regulalor aClivating One of the pathways can simul·
taneously inhibit the other
Indirect Antagon ism
liormones can Oppose each olher by acting on dif-
ferenl target cell,. Thus. paralnyroid hormone can
increa,e urine volume by inhibiting sodium reab-
""'ption. wnerea.1 norepinephrine can decrcase it via
constriction of the afferent arterioles.
PermiSSive Actions
When a hormone exeTlS no dircet effect on a rc-
'1'<'1.,e. ual creale. Ih e ""mli1ion, Ullclcr w h ich an·
other ca n aCI. it is said to perform a permissive func-
tion. An example i. shown in Fig. 4-1 7.
In intacI animals. norepinephrine invokes dCl'C--re-
laled elevation of the systolic blood pressure_ It can·
not do this in thai are deprived of glucocor.
tieoids(sce Fig. 4-17A).
Glucocorticoid. normalile blood vessel lone_
Wben adrenalectomiJed (glucoconicoid-deRcienl)
arc given maintenance dosages of tnc ste-
roid . they «!spond li ke imact controls to norepineph-
rine administration (Fig. 4·178). However. in the
presence of unvarying levels of norepinephrine. Ine
glucoconicoids do 1101 dose-related influences
on the blood pressure (Fig_ 4-17C).
G1UCQOOrticoids perform similar permissive func·
lions for glucagon stimulation of gl uconcogencsi. in
the liver and for catecholamine stimulation of lipol-
ysis in adipoolc lissue. Growth hormone also
permissive influenccs that support norepinephrine-
stimulated lipolysis.
thesis of some substance in\'(Ilved in the response. A
protein made under Ihe influence of glucocorticoids
(SCA RP. steroid· and eAM P.regulated protein)
thai supports cAM P.mediated reactions i. discussed
in Chaplers 7 and 10.
Occasionally. tne lerm P<'rm;"iVl' act iotl has
,., MECHANISMS Of' HORMONE ... Cl ION "'NO INTERACTION

,.,., TCgulators. Yet. only those of lhe thyroid gland are

uniquely responsive \0 TSH. while rona fas<:icuiala
prenure ce lls of the adrenal respond most obviously to
ACfH. When the of rco:ptors for a hor-
mone dccline. there is usually an associated loss of
sensitivity to that regUlator.
Agents chemically different from the hormones.
such as antibodies directed against the re<;eptors. can
A Dose of nor,pineph,ine
mimic hormone action!;. Some have sugge<ted that
function by activating Iheir reccptors.
while others have speculated on the possibilily thai
hormones lifl a form of tonic inhibition Ihat is oth·
erwise by the receptor.
,.,., "Spare" Receptors
pressu,e
Quantitative inleraetions bclW""n hormones and re·
ceptors vary widely with the cclltype (14) . When
angiotensin II stimulates lOM glomerulosa cells of
, Dose Of norepinephrine
the adrenal the steroidogenic re<poll';c rises
in parallel with receptor occupancy until both pa-
rameters reach maximum. In contras!. most targel
cells for peptide-!Ype hormones respond muimally
when only a small fraction of Ihe receptor siles is
occupied. The term sf'O't receptor.r designales Ihe
remainder of Ihe populalion.
AI leasl some of Ihe "exira" rco:ptOTS bind wilh
low amnlty. and It is suspeclcd that they do not di-
",.,
pressure
reclly mediale the hormone aClions (82)_ Suggested
functions include th. following: (a) aceumulalion of
the hormone in Ihe vicinily of Ihe high-atnnity re·
ceplors, thereby increasing the probability that bind-
ing will be accomplished when the hormone conccn_
tralions are low; and (b) modificalion of membrane
properties in a manner lhal supports high-affinilY re·
c Dose 01 ad renocortical steroid
ceplor
FIg. 4·17. P6rmiui • • ""'''''' of Idr..-.ooort""" .,.. oO:Is on Anolher Ihought is thllthe usua l physiological re·
blood
te
P"I""'''' "'PQo"'" to ""'opInephI1 .... .... FieS9O"se
in !llueocortir;oid-deficien1 I """" ' . e.
sponses r"'luire occupation of limiled numbers of re·
ceplOrs, bUI hormone binding 10 "eXIra" receplors
RosponMIO OOf6piMphrino in thO preSMC<! 01 • """stant invokes supplementary reactions. It is known, for ex·
Ie" .. olldre"oco.ljcal " ",<>ids. C. Rllpoese to ample, that low dosages of glucagon affect mostly
adroonocor1collleroids "",opInepM". II ""in,o;ned
glycogenolysis in the her. Somewhat higher ones
0., • con,,,nl "'....
also accelerale gluconeogenesis. while concentra·
lions approaching Ihe upper phY5iologicallimil< ad.
ditionally faci lilale ureogene<is. Minimal levels of
r.ervcd as a ta\chall to coyer up the igllOranc<: of the insulin inhibil adipocYle lipase. Moderate one< also
investigator oonccrning [he mechanism. whereby increase gluCOlse oxidation. whereas high ones accel-
one supportS Ih. actions of another. erale amino acid uptake (132).
"Spare receptors" could also bc involved in initi·
alion of negative feedback controls that protect the
REGULATION OF HORMONE RECEPTOR
cells againSI Pr(llact;n and prosta-
NUMBERS AND FUNCTIONS
glandins are among the regulators klIOwn to act in
In some respects. Ihe fe<:eplOrs are Ihe major deter- one direClion when the concentrations arc low and in
minants of cell responses. All somalic <xlls arc con- a reverse manner when Ihe pharmacological ranges
tinuously exposed 10 a cornucopia of btood-bornc are approoched.
 A dilTerent point of view is that th: "extra" recep"-
tor.. are "anticipant." and therefore spare only in a
sense (92). They could simply be waiting their
IUrn to serve as internali1.ation removes the others.
The whole concept of spare receptors has becn
qucstioned on th: grounds that the conditions used
to assess hormone bi nding are not necessarily opti-
mal for measuring the associated innuences of the
hormones On the cells (116).
Negetlve Cooperetivlty
The binding of limited numbers of some hormonc
molecules to their receptors decreases the affinitie.
of the receptors for additional hormone. Sucb "neg·
ative COOlX'rativity" has been described for insulin.
GH. TSH, catecholamine•. and other regulators. 11
could provide protection against cxcessive acute
stimulatiOll in respon.e to a .udden "burst" of hor·
mone release while preserving the ",nsitivity to low
concentrations (16 )_
Electron microscopy studies and measurements of
physical properties of the membranes suggest that
the initial binding alfocts thc locations. mobilities.
and possibly also the configurations of the IMOCi'u-
piNi receptors. Agents that interact with the recep"-
tors but fail to mimic the hormone actions can dicit
similar changes.
Pos itive Cooperatlvlty
For some hormones. the bindins of limited numbers
of molecules tnhancf'S the amnity for others. Phe·
nomena of this kind have also been described for Slu·
cocorticoid bindins to chromatin (32). and for tro-
ponin binding in skeletal muscle. Presumably. the
mechanisms provide for rapid mouming of respollSCS
to low hormone concentratio", by target cell, previ·
ously deprived of the regulators.
" Down Regulation"
Chronic of cell, to high concentration. of
most hormones leads. in time, to reduction in the
numbers of available hormone receptors. Although
the phenomena have been linked with lowering of
target cdl sensitivitie, and protection against over·
stimulation. they differ from negative cooperativity
in several respects: (a) usually receptor affinities are
not changed; (b) the responses are highly specific_
When chronic elevation of t he bl<X>d insulin le.'els d i·
minishes the numbers of insulin receptors on the ad;·
pocytes, the same cells retain their sensitivi ty to cat·
echolamine,. Agents that bind to the receptors but
do not mimic the effects of the hormone fail to affect
the receptor numbers; and (c) tlte reduction in reo
ceptor number takes time to become manifested. a nd
it is only slowly reversed after the hormone is
withdrawn.
For peptide·type hormones, the down regulation is
evidently directly related to internalintion of the
hormOl*receptor (19). Receptor replcni.h.
ment requires new protein ,ynthesi,. and it can be
blocked with protein--synthesi, inhibitors. Chron ic
overstimulation by the hormone may disrupt the
normal cycles involved in
maintaining normal membrane structure •. However,
in addition to GH, catecholamines. and several oth·
ers. steroids .uch as progesterone can reduce the
numbers of their own receptors. In such cases. the
effects may be exerted on nuclear components and
involve changes in the rates of formation of the
mRNAs that direct synthesis of the receptors,
Hypothalamic releasing arc secreted in·
termittently . Jfthe neurons that deliver LRH to the
gonadotropes are destroyed. LH secretion can be
maintained by delivering LRII at hourly
intervals. On thc other hand. continuous prc",nta·
tion of LRH invokes a transient elevation of LH se-
cretion that is followed by a steep deeline. The loss
of responsiveness has been lin ked with reductions in
the numbers of LRH receptors (6).
Maturity-<>nset diabetes mellitus is often first dc-
tec ted after a period in which excessive f<X>d intake
has led to overstimulation of the cells of the pan·
creatic islets. Typically, the patient has supcroormal
insulin concentrations in the blOCld plasma but shows
symptoms of insu1in deficiency that have been linked
with reductions in the numbers of insulin receptors.
The condition may be exacerbated if exogenous in·
sulin is given. since this can further lower the recep-
lOr numbers. In many cases, restrict ion of f<X>d in·
ta ke leads to normalizalion of insulin requirements.
fall in blood insulin levels. and restoration of the in·
sulin receptors.
Desensitizati o n
Thi, term designa tes gradual loss of sensitivity to a
poten! regulator thaI is chronically prescnted in ex·
ces.sive amounts. In addition to the mechanisms dc-
scribed , it Can involve forma tion of "tight." nonfunc-
t;onal associations between hormone and receptor.
the "uncoupling" of the processes that hormone
binding to the response , and cell changes that are not
directly associated with hormone-reecptor inter·
ac tion"
Desensi tization is observed for responses to neu·
rotransmitters as well. for example after Iong·term
presentation of high levels of acctylcholirIC to cui·
tured heart cell, (37)_
An intereSting form of "adaptation" follows
chronic administration of endorphins to cells COn·
taining the appropriate receptors. When the peptide.

'"
decrease the adenylatc cyclase aClI .. ly. the cells
"compensate" by ,yothesiling more enzyme. In
time, they can be said to be "addicted," since Ihey
Ihen maintain normal ad.orlst. cydase activity only
in Ihe prc:sc:ncc of the endorphins. "Withdra,,'al
symptoms" associated with persistent ovcraClivi\y of
Ihe adcnyla\e cyclase system arC sten when Ihe en-
dorphins arc no longer p,e:scmcd (68) .
" Up Regulation"
Changes in ",ceptor numbers haY<' been .""wn \0
occur in 3$SOCiation wilh cell differentiation. maw-
ration, and aging (114). Hormones contribute 10 Ihe
regulation. in nlany cases by promoting formation of
their own rctePlors (79).
It has long been known thaI Ihe administration of
a "priming" d():$c of estrogen to immature tissues
used for bioassay sharpens their sensitivily
10 a dose subsequentlyadminiSlered (146). II is
now re<:ognized Ihal eslrogen indU'lion of eSlrogen
reeeplors is an important componenl of the processes
in'olved in maturation of ovarian follides (106).
thai androgens induce androgen re<:eptors in matur-
ing pl'05tale glands (88). and thai prolactin promotes
formalion of prola'tin re,eptors by some of its targel
cells (79).
Heterore g ula tion
MOoSI hormones affect the production of receptors for
different honnonc:s (107). Estrogens facilitate Ihe
formalion of progesterone recepton in several differ-
ent kinds of cells. and most physiological function,
of progesterone (including the cyclical changes in
the endometrium associated with ovarian functions)
require prior of the cells to estrogens (72).
The processes are hormone and target cell spc-
ciric. Although thyroxine promotes the formation of
prolactin TCceptOrs in the kidney. it does not regulate
prolactin TCceptOrs in the adrenal cortex (80). Thy_
roxine additionally increases the numbers of cate-
cholamine receptors in m)'ocardium.
Hormones can also reduce the numbers of func_
tional reoeptors for other regulaton. For example.
glucocorticoids exert this intluen« 011 prolactin re-
ceptors in the kidney (80. gl). progesterone antago-
nius the ability of estrogens to increase prolactin re-
oeptors of the pituitary gland (49), and thyroid
hormones reduce the numbers of pituitary TRH
re<:eptors.
Me.:hani.m. for .-.gul.tion of re.:eptor number c.n be
complex. The chronic administration of lulCini,ing 00 ....
mooe-.-.leuing bQrmOn< (lRH) k.d,. in time. to loss or
MECHAt-It$M$ OF HORMONE ACTION AND tNTERACTION
lH. FS H. and prolact;n re .. ptors in the rat te'ti, ( 14),
The effects on the prOlactin re.:eptors are believed to be
secondary COlloequence, of inhibition of prolactin , ecTC·
tion. where .. the chang.. in gon.d<>lropin receptOr> >«m
to rc •• it ffOOl lRH binding to . it.. in the goo.d, ph)',.
iologie.lly re'pOn, ive to a different ,ogu lator.
O ne hormone can also affoet Ihe fum:lion.<of an-
other by exerting influences 011 nonreceptor proteins.
FSH acts on the te'lis to induce an androgen-bind-
ing protcin that concenlrates teslosterone and dihy-
drotcstosterone (84), Estrogen am on the liver 10 in-
duce rcnin substrate and Ihe plasma proteins that
associate tightly with glucocorticoids. and
other regulators. Prolactin augmenlS the effecti,"<:-
ness of ACTH on Ihe adrenal in pari via in-
hibition of an en7.yme that degrades glucocorticoids
(96). LH contributes to estrogen produclion in the
ovary by promoting the synthesis of androgens that
serve as estrogcn precursors,
SOME PROBLEMS ENCOUNTERED IN THE
DESIGN OF EXPERIMENTS
Wholc-animal studies are generally the mOSt trou-
blesome 10 conduct because of the complexities of
the systems. Inc individual variations alway. enCOun-
tered among animals of the same strain. age. sex,
and history. Ihe problems involved in duplicating en·
vironmenlal conditions if the experiments arc to be
repeated or to be conducted in other laboratories.
and the ·'nonspecific" effects of the tesl procedures.
Such studies are essential. however. for investiga-
tion, of development. maturation and somatic
growth. of behavior and learning. of the influences of
dietary manipulations. of longevity, of long-term
functions of hormones and Ihei. interactions, and of
some aspects of hormone metabolism. Oflen. they
are needed to determine the physiological relevance
of in vitro findings. since the major influences ex-
erted by the hormones on the whole animal Can dif-
fer from tbose demonslrable in Ihe tesHuix:.
In ITIOllI cases. the use of "sham"' controls permits
assessment of the effeets of nonspecific intervention.
If endocrine tissues are to be surgically excised. the
shams are subjoeled to the anesthesia. and auempl<
are made to intlict comparable trauma to the af-
fected region while permiuing the tissue, to remain
intact. It may be necessary 10 use additional unop-
crated controls. especially if Ihe tissues to be studied
are innervated Or if the trauma affects other organs.
[f lesions are to be made with eleclrodes. Ihe same
kinds of electrodes are inserted into the controls but
no Curren! is used. When hormones arc adminis-
tered . the controls ,hould roeeive Ihe same volume of
material in the sam. region-preferably empty ve-
hicle or something that inmkes C<)m parabk
irritation.
If the test substances administered affect the ap-
pctite. it is difficult to determine what shou ld be donc
with the controls. Restriction of food in take intro-
duces the complications of undernutrition. At times,
even brief periods of food deprivation invoke changes
that can not be reversed by subsequent refeeding
(39). The shams Can be "pair fed"\0 achicve a cOm-
parable nutritional status. However. the expcrimen-
tal animals are then perm itted to cat as much as they
choose while the controls are subjectcd to the stress
of arti ficially imjXISed hunger . Forc<:·fe<:ding intro-
duces different kinds of unwanted stress.
Determination of the "Corraet" Dosages of
Hormones
For mosl regulalors. Iher. i. a limited range m'er
which Ihe magnitude of Ihe response increases wilh
the dosage. Less commonly, a sufficient quanlity
"triggers" a response. whereas larger ones have flO
further innuene<:.
Since negative fmdings arC seldom as useful as
jXlSitivc ones, Ihcre is a templation to administer a
more than ad<"quate dose ('"jusl 10 be surc·· ). When
100 much is given. the OOrmone can interact with
sites thai it never affecls under physiological eondi·
tions. (This is oflen an eve n greater problem in in
vitro work.)
Commonly, OOrmone derived from one species is
injected into another, despite kflOwn differene<:s in
receplor properties. Largc slaughtered for
food can be inexpensive and readily available sourCeS
of largc quantitie, of the regulators. Smaller ones
are more convenient recipienlS , ince they arc easy to
maintain and handle. usually require only minute
amounts of test materials. and have sOOrt gestation
periods a nd life spans that facil itate the acquisition
of highly inbred strains. It cannot be assumed that
body we ight is an adequate parameter for judging
the appropria te dosage. Whcn calculated on a per
gram basis. a rat can tole rate something li ke 1000
times as much histamine as a human. and a guinea
pig succumbs 10 a fraclion Oflhe dosage tolerated by
man.
Tha Importance of Timing
As flOlCd, the effect of X grams of a hormone Can be
very different if the regulator is given all at oncc
Ihan if presented in divided dosages.
A quanti ty of OOrmone that is highly effective
under e<:rtai n conditions may be totally inadequate
at other times. The investigator muSt be aware ofin·
teraclions with othe r regulalors and of diurnal vari-
ations in the secretion pallems (69). Environmemal
faclors such as light and temperature can alfe<:t the
responses. and singly caged may respond dif-
ferenlly from ones housed in groups. When females
are used. Ihe stages of the ovarian cycles sOOuld be
ta ken into consideration. !Xason can affect not only
the hormone secretion pauerns, but also the condi_
lions of the target organs. Nutritional statu, at the
lime of testing and past nUlritional history are ad.
di tional important variables.
Routes of Administration
The sites of entry inlo the body affect the rates of
hormone absorption imo the extracellular fluids,
penetralion to targe t si tes. degradation, and exCre·
tion . They Can also have important influences on the
secretions of other rcgulators.
ORAL ROUTE
Addition of the test to food or drinking
fluids averts thc stress associat«l with parenteral in·
jection. Slow rates of absorption can accomplish
gradua l elevation of the blood Icvels and long·term
maintenance of the concentrations. They can also
frce the invesligalor from dire<:t and frequent ad·
ministrations in experiments that arc of long
duration.
Oral administration has numerouS drawbacks .
Except when fe<:ding SChed ules are highly artificial.
the animal has considerable control OVer the dosage .
Foods Or fluids judged by the animal to be unpleas-
am may be refused enlirely umil Severe hunger Or
thi rst is cxpcriene<:d. W hen bitler substances arc
wilh po"dercd foods. small rodents will some-
limes select out the usual nutrients and leave the test
subslances in the cups. Tbe investigator Can get ex-
aClly Ihe quantity desired into the animal at c,actly
the right time by using a stomach tube. However,
the procedure;s traumatic for bolh the animal and
thc invesligator who must struggle with it.
Some of the (or their vehicles) irri_
tate the gastrointestinalt""cl and Can there by affect
Mood dist ribution or the of gastrointest inal
OOrmones. Enzymes of the digestive tract degrade
most peptide-type hormones (but a fcw such as TRH
escape such destruction) . Blood drainins the gas-
trointestinal tract enters the hepatic portal vessels
Ihal lead to the liver. ThaI organ is a major site for
hormone degradation .
PARENTERAL ADMINISTRATION
Fairly largc volumes can be injected into the pt!ri-
and ml)l;t substances a rc rapidly air
sorbed. However, the vessel. also lead into the he·
'"
palic porlal syste m. Moreover. the method is not
suitable for lipids, irritants. or vaso<xmstricto.s.
While moderate volumes of Auid Can be acCOl1l<r
dated in the spalX'$ under the skin of the back. the
quantities lnal can be inje.:lcd subcuwneDus/y al
other siles a re sharply limited. Slow absorption rates
can be: advantageous. blood levels build up
gradually and they can be maintained for extended
lime periods. Hormones presented in poorly soluble
forms are laken up even more slowly. Minipumps
thai deliver the regulators at continuous, predeter.
mined rates can be implanted under the skin. T he
sites mUSI be chosen with care. (It mayor may not
be desirable. for example, 10 have the hormone go
directly to the liver, kidney, or some Olher organ.)
Strongly irritating malerials cannot be given in Ihis
way. Intradermal arc generally «,served
for special purposes. They are painful. are likely 10
sel up allergic «,actions. and can be used only "'hen
the vol umes a«' minute.
Intramuscular administration is oflen the method
of choice for lipid-soluble materials, and for OneS
that are too irritating to be ;njeeled al other Siles.
Absorplion rates are usually mOre rapid than from
skin sites. They can be controlled by varying the
physiCOChemical properties of the hormone Or
vehicle.
The im,awnous route permils almost ;nslama·
neous elevalion of the blood concentrations. and
most target organs are soon rcaehed. (So are the
degradation and excretion sites.) Great caution must
be exerted when the test substances affec t cardiac
func tion . and it is also important 10 avoid more than
minimal disturbance of the osmotic pressure. Agents
that lyse erythrocyle membranes cannot be given in
this way. Insertion of the needle requires skill. can
be and is likely to disturb the sub-
jec t. When il is especially important to avuid stress
at the time of hormone administration, a cannula
can be inserted and the study delayed unti l after the
animal has recovered from the procedure. The can-
nula method is a lso useful when repeated injections
must be given, or if the experiment calls For contin-
uous or intermittent infusions.
AGENTS ACTING ON THE BRA IN
The "blood-brai n barrier"' exdudes most s ubstances
that get into the peripheral circulalion.
into the cerebral ventricles require apparatus
and skill, and they oflen have unwanted "sidc·d-
fects." Injections also be made into parts ofthc
brain.
The problems associated Wilh injee.
MECHM·nSMS OF HORMONE ACTION AND tNTERACTION
tion ean sometimes be averted by administering pre-
cursors thai readily cross the barrier and arC after-
ward converted to the active hormones. Dopamine is
a good example . since OO?A enters the central ner-
vous system and is soon decarboxylaled. The effects
of peripheral rormation of dopamine can be mini-
mized by giving the OOPA in combination with de-
inhibitors that do not eros.. the barrier;
and the observations can be compared with on ....
made on different animals receiving OOPA plus an
inhibitor thai gelS to Ihe brain.
Organ Perfusion
Organ perfusion studies in whole animals make it
possible to study Ihe direct effects of a regulator on
a targel that retains its architecture and many of its
associations with surrounding structures, and (0 col-
lect produced in response to its administra·
tion. The hormone is not metaboli7.Cd by other cell
types before it reaches il5 destination. and it cannot
act first on endocrine glands that regulate the organ
under invC'ltigation. The method has been used . e.g.
10 eumine the of glucagon on Ihe ii'l<'r, the
roles of sugars, ions. and other agents that
pancreatic islet functions, and the quantitative
in the variou< producls relea<cd
Following injections of ACTH, prOSlaglandins. and
olher agents into vesselS supplying the adrenal
glands. It usually lakes CO/lsiderablc lime to prepare
lhe organs, and the effects of anesthesia. trauma,
brief periods of hypoxia, and Olher factors must be
considered when as:o;essing the dala. The indiyidual
variations in responses arC likely to be greater than
is the case for in vitro studies.
Specilll Advllntages lind Problems
ASSOCiated with In Vitro Studie&
In vilro syste ms remOlie some of the complexities
that must be deah with in whole animals. The reg·
ulators. syne rgists and antagonists can be directl y
presented 10 the target cells in controlled concentra·
tions. and the cell environments can be manipulated.
In many cases, it is possible to observe early re-
sponses that cannot be mcasured in "'hole anima ls
Or in perfused organs. Relatively small quantities of
lest substances Ihal a«' in short supply can suffice .
Tissues or cells From a single source can be divided
inlo aliquots for control and experimental use. so
tha t variations between the t"'o targets l«' mini-
mized. The drawbacks include loss of substances not
«,cognized by invest igalors as essemial cofaclors,
loss of physiological "activation" of some of the rcg-
ulalO1'5, and failure to recognize that the an imal
wmponent under investigation is only one of several
targets contributing to lhe overall in vivo responses.
Some prior knowledge of the hormone functions is
usually needed for interpretation of the physiological
significance of the f,ndings. For example. investiga-
tors of the roles of ealciferols in calcium homeostasis
can o btain only limiled information if they present
vitamin 0 10 inlestinal sacs. They must recogni1.e
that under physiological C<)nditions, the vitamin i.
first metabolized elsewhere to 1,25-dihydroxy vita-
min D. Mor<:Qver, thcy cannot assume that the ef-
feelS on the intestine explain the hormone's roles at
Olher sites such as bone,
T issues and organs compri'e diverse cell types.
whieh Can respond in different ways to presentation
of a single kind of regulator. For example. pituilary
glands contain lactotrope, that are inhibited by do-
pamine. and other components that arc stimulated,
Adipose tissue has adipocytes whose responses differ
from those of slromal cells. Zona faseiculata and
zona golmerulosa c.::lls of Ihe adrenal cortex respond
differently 10 ACTH and to angiotensins.
Methods have been developed for separation of
the various cell type" While this somctimes sim pli-
fies the interpretations, it also destroys the usual
forms of c.::\l·t<>-Ccll communication. Mo reove r, the
tc<:hniques used can damage Or alter the properties
of the cell surfaces.
The extent to which diffe",nt kind, of co lis interact
has been demo n"rated by oQ-Cuhuring mOuse m)'ooard;al
cell. (which lack FSIl ",ceplors) with rat ovarian gran-
"I.,.. ceU, thaI arc ordinarily unrc<pon.ive to IIQrepincph_
rine (71). Under such conditions. each or the hormones
promotes the generation or I.rge quantiti .. or cA MP.
FSH can thereby provide _<timulat ion to the my<><.roial
cells and IIQrtp;neph,ine to the ones obtained rrom the
ovary.
Mo.t cell types obtained from normal tissue have
limited survival times in vilro. h is pos,ible to get
some of them \0 proliferate in culture. but this usu-
ally requires the use of artificial environments_ The
cultured cells often acquire new characteristics thaI
can affect the response., to regulators subsequently
presented.
Endocrine tumor cells are usually easier 10 cui-
lUre. However. Ihey can respond in abnormal ways
to physiological stimulants. release hormones that
are chemically different from normal cd l products.
and display resistance to thc usual kinds of negative
feedback CQnlrols.
Some aspects of hormone action arc m(,lSt easily
in simpler syStems. e.g. isolated memo
branes. mitochondria. ribosomes. or nuclei. A serious
problem. however. i, that hormones can bind to sub-
cellular components that ordinari ly arc not affected.
Reliable assessments of Ihe physiological fune·
tions of hormones arc besl obtained by integrating
findings oblained from all of the preceding.
REFERENCES
L Abramow;t,. J .. I)'engar. R_, and Birnh. umer. L_
On the Mode or Action of Cotech<>l.mines on the
Turhy Erythrocyte Adenylyl Cyci.sc. J, Bioi.
255: 8259-65 . 1980,
2_ Aurbaeh. G, O. Hormone Receptors. Cyclic Nu·
eleotid.... nd Control of Cell Function_ Chap. I.
pp_ 1_43 of Frein • • 1. N.. cd. rht Y",r in Mtlaro-
1i'1I11975-1976. Plenum. New York. 1976.
3. G. D_ Polypeptide and Amin. I!o)rmonc
ReS"I.tion of Adenylatc An• . RoY, Phy.·
jol_ U: 6H-66, 1982.
3A . Avruch. J.. Alexander. M . C. Palmer. J. I. ..
Piere •. M. W .. N.menhoff. R, A.. BlaCkshear, P.
J.. Tipper. J, P.• and Witlcrs. L. A. Ro)leof In,ulin ·
Stimulated Pr<)\.in Phosphorylation in Insulin Ac_
tion. PNX_ 41:2629-33.1982_
4_ lia.rdin, C . W .. lIuliock. I.. P .. Mill., N. C .. Lin. Y.-
C .. and J.cob. S. T. The Role of Receptors in the
An,bolic Aetio)n or Androgen!. Ch.p, 4. pp. H3_
.,
103 of O'Malley .nd Birnbaum«. cd._. r.rerence
5. B.<ler. J. D.• and Ivark. R. Regulation of Gene
F.>pre"ion by Glucocorticoid Hormones: Studies
of ReceptOl'$ and Response> in Culture<! Cell •.
Ch.p. 10. pp_ 15t_96 or O·M.It<y "nd 8i,nru.u.
mer. ed, .. reference 95.
6. Belch.. >. P. E_. PI'nt . T. M.. Nabi. Y.. Keogh. E.
J .. and Knobil. E. II)"poph)'lial to Con·
tinuou. and I nterm;"ent Deliv.r)" or 11 YP"thalamic
Gonadotropin·Releasing Hormone. ScitfIU 1M;
631_3. 1978.
7, Benjam in. W. B... nd Clayton, N. Acti<mof In,u·
lin and Catech<>lamines on the PhOllpoo.ylation or
Proteins Associated with the Cytosol. Membrane •.
and " Fat Cake" of Rat Fat Cell •. J. Bio/, Ch"" ,
,51' 1700-09. 1978
8. Berkowitz. S, A.. Goldh .mmer. A. R.. Hcwletl. E,
L.. .nd Wolff. J_ Aetiv .. io)n or Pro'aryotie Ade·
nylate Cyclase by Calmodulin, N. Y. Acad.
Sd ]56: 360, 1982
9_ Berridge. M. J.. and Rapp. P_ Cycl ic Nucleotid ...
Calcium and Cellular Control Meehani,ms. Chap,
pp_ 65-16 af Cramer and Sobuhz. ed._. reference
n
10, Biddulph. 0, M.. Currie. M. G .. and W",nn. R. W.
Effects and Interaction. of Parathyroid !tormone
and Pr",tagl.ndi". on Aden",ine 3'Y·Monoph"".
ph.te Concentration. in Isolated Ren.1 Tubules.
l:."ndocrill()l_ 104: 1164-7 I. 1919,
II. Birnboumer. L. Regulatory E-.nt< at the Le>elof
Membrane-Bound Cyclase. Chap, 2. pp.
13-36 of Cramer and Schultz. cd, .. reference 23.
111\. Broohr. G_. Pedon •. c.. "nd B.rovsky. K. Selec·
ti>e Reducti"" of FOfSkol in-Stimulattd Cycl ic
'"
AMP Accumulation by Inhibitors of Protein Syn,
thesi •. }](J: I \69_10, 1983.
12. B"',,"'n. E. M .. and Au,bach. G. I). Receptor< and
Second Me""n,." in Cell Function and Clinical
0 1",,<1< .., Chap. 8, PI'. 247-99 of Fn: inkcl. N_. cd .
M'IO/xJIiJm. vol . 1. Plcnum. :"I.'"
York. 1982.
13. Cassel. D. and Selinger, Z. Cu¢cltol.mioc Inductd
Role"," of [' H1G,..(N H), from Tur key Erythro-
cyt. Adenyl.te Clduc. J. C)'eI;" R'J.
1:11-22.1977.
14. Can, K. J .. B.uhl, A. J .. D.-ies, T. F.• and Durau.
M. L. Luteinizing H<>rmone-R.le.Sing Hoemon._
I nduccd Regul.tion of Gonad<>lmpin and Prolactin
Receptors in the Ral Testis. EmitXFino/. 1(14: 17_
25,1979.
15. Call. K. J .• and our••. )1.\. L. Bui. Concept$ of
the M<:<;hanism of Acti"" of Peptide Hormone,.
mol. Rep' oJ. 14: 1-15. 1976.
16. Call, K. ] .. and Dura •. M. L Pep,ide Ilormone
Receptors. Ann. R.". Phpiol. 39: 529_57,1917.
17. Chan. T. M .. St<iner. K. E.. and E"OIl. J. H. Er·
fee" of Adrcnalo<t¢my OIl HOrm¢fIC Ac'ion on Hc·
patie Glueose Metaboli,m. j, Bioi. CMm. ]j4:
11374-78.1979.
18. Cheung. W, Y. Calmodulin Plays . Pivotal Role in
Cenular Regulation. Sci. "u 107: 19-27.1980.
19. Chuang. D.·M .. and Costa. £. E.idenct for Inter,
nali ... ,ion of lhe Re<:ognition SilO of Adrenergic
Recepto., Recep,o. Subsc",iti.i,y Induced
by (+Isopro .. ",no[, PI"OC'. Noll. Arad. Sd. USA
76: 3024_\28. 1979.
20. Ciment. G ..• nd Dc Velh" J. Cellul.. In ....
Uncouple /l-Adren..ak Receptors from Adenyl.te
Cycl .... Sd.",. 201: 765-8, 1978.
21. CI •• k. J. H.. Poek. E. J .. J ... Hardin. J. W .. and
Eri ksson. H. The Biology and Ph.rameology of E.·
trogen Receptor Binding: Relation.hip to Uterinc
Growth , Ch.p. 1. pp. 1-31 orO' Malley and Birn·
baum ... cd •. . reference 95.
22. Cohen. P. The Role or Protein Phosphorylation in
Neural and Horl1'onal Control of Cellular Aeti_ity,
Nalure 196: 613-20. 1982.
23. Cramer. II .. and Schult1.. J .. ed" Cydir j'j'·Nu·
c/Wf;d.$.· MtchcniJmJ o[ A(,;on. Wiley. New
York. 1977.
24. Cua"ec.!.as. P. In,ulin Receptor of Liv<f and Fat
C.1I Membra""" F,tI. Proc-. 31: 1838-46. 1973.
25, Cuat •• c .... s. p, MembfOn¢ RectplOt>. Ann, n"".
Bjorn,,,, , \69- 214. 1974.
26. CU,,,"w. R. T .. ao<l Lame', 1. Horm<>n.1 .nd Met·
abolic Control of Phosphoprotein Phosphatase.
Ac,jOll$ Horm, 6: J7 _I 19. 1979.
27. D·Armiento. M.. Johnson. G , S .. 00<1 Poston. I.
Regulation of Adenosioe ]':5'·Cyelie Monoph*
phate Die"era .... Activity in Fibrobla." by Intr.-
e<lIular Cono<ntrati,,", of Cyclic Adenosin. Mono-
ph<J5phate. Pror. Nail , Acad. Sc/. USA 69: 459_62.
1972.
MEC f1ANtSMSOF liORMONE ACTION AND tNTERACTtON
28. Doskcl.o<I, S, 0 .. Kvinn.la nd. S .. and Ueland. P.
M . Protein Kinase' Acti¥31ed by cA MP in the
Gonital Tract of Spayed Mice Treated with 0.:,.
tradiol·17/l. J . R<prod. Fmi/. 44: 207_ \6,1975,
29. Dufau. M, L.. Baukal, A, J.. and Can. K. J. U",·
mane-Induced Guanyl N ucleotide Binding and Ac-
livalion of Adcn),lale C)'clase in the I.c)'dill c.n.
PrO(. Na,l. Acad. Sci. USA 77.. 5837-41.19$0.
30. Fain, J. N, Cyclic Nucleotide, in Adipose Ti",ue,
Cbap. It pp. 207_28 of Cramer .nd SChull>. cd ...
refc.ence 23.
31. Fain. J, N .. Shepherd, R. E.. Malbon. C C ... nd
Moreno. F. J, Hormon.1 Regulation of Triglycer-
ide Bre. kdown in Adipoqt"'" Chllp. 13. Pl', 213-
28 of Oielsehy,J. M .. GOlla. A. \ 1.. Jr .•• nd Ontko.
J. A .. ed •. DiJ,urbllnctJ in u'pid and UpOprOl.in
MtiahoJism. Ame.iea" Ph)'.iologic.1 Society. &-
thood •. 1918.
32. Feiacl>on. p" Ramana.ayan. n·Murthy. L.. and
Colman. P. D, Studies on the C)'topta<mic Gluco-
corliooid Rec.ptor and its Nuclear Interaelion in
Mediating Induclion of Tryptophan O,),gon.",
Messen8er RNA in Li"er and Hepal00,". Chap. 9.
pp, 226- 49 of O'Malley and Birnb.umer. ed ... ref·
erence 95,
33. Fo x, I. It. and Keney. W. N. The Rol .. of Aden·
osine and 2'·Dcoxpdenosine in Mammal ian Cell •.
Ann, Rn'. 47: 655_86, 1978.
34. Friedman. D. L Ro\e of Cyclic Nucleotide, in cen
Growth and Diffe.entiation. Phy,jol. R,,'. 56: 652-
1976.
35. Friedman. Y.. Lang. M .. l..basseu •. S .. and BU'lc.
G, Demon>uation or a Tonk Regulalory Thyrolro-
pin Effect on Thyroid Function. Em/oc-rjrool. 1M·
467-75.1979.
)6. Fuller, D. J. M .• Bmy •. C. V.. and Ru".U, D . H.
Specific Regulation by Steroid Hormone. or tho
Amount of Type I Cydic.AM P·Dcpendent Protein
Kinase Holoonlyme. Proc. Narl. Acad. Sci. USA
7j: 223 - 7, 1978,
37. Galper. J. B.. and Smith. T. W. Properties of Muo-
carinie Acetylcholine ReceptOt> in Heart C.II CuI·
W<e$. PI"OC'. IV"'I. Acad, Sci. USA 75: 5831-5.
1978.
38. Gin.burg. B. H. The losulin Receptor: Properties
and Regulation. l/orm. )1l_
49.1977.
39. Gla",. A. R.• Mellill. R.. Vigenky. R, A.• and
Swcrdloff. R. S . Hype.ndrogen;'m and Abnorm.1
' Regulation of Gon.dotropin Secretion in Ra" Fod
a Low Protein Diet. em/or,;""I. 104: 438-42 .
1979.
40. Glennoy, J. R., Jr" Glenney, P.. and Weber. K,
erythroid Speclfin. Brain Fodrin. and Intestinal
Brush (Ior<le. P,olein. (TW·260/240) are Related
Molecule. Containing a Common Calmodulin.
Binding Subunit Bound to • Variant Cell T)'pe-
Specific Subunit. Proc. Norl. Acad. Sci. USA 79:
4002-5. 1982.
 41. Goldber,. N. D.. and Haddox . M. K. Cydic GMP
Metaboli,m .nd Involvement in Biologi<al Regu.
lalion . Ann, Rn-. Biochem . • 6: 823_96.1977 .
42. Goldfine. [. D.. Jone •. A. L.. Hrakok. G, T,. Wong.
K, y,. a nd Moone),. J. S. [ntryof In,ul in Inlo Cui·
tured lymph<>c)'lCS: EI.clron Mkl"O:5-C"P" AUlor3-
diographic An.lysi •. SdtrlN 102.- 760-3. 197a,
43 . Gorm.n. R. R .. Hamillon. R. D.. and II<>pkins. N.
K, Slimulati"" of Human FOr<.kin Fibrobl."
Ado".,.in. 3':5"-C)'dk Mon<>phosph .. e l.vds by
Prootacydin (Prost.glaodin I,), J, Bioi. Chml.1H.-
1671_6,1979.
44. Gorski. J .. arid Ganoon, F. Curren, Modols of S,e-
roid Hormone AC'ion: A Crilique. Phy,,·
;()/. )8: 425-50. 19")6.
45. Goswami, A. . and Roscnbe'l!. I. N, Thyroid Hor·
mone Modul'lion 0>1" Epinophrine.[rlduocd l.ipOly.
. is in Ra' Adipo<ytC$: A Pos.iblc Role of Calcium,
EndocrilWl, 10):2223-33, 1978.
46. Greeng.rd. p, Phospbor)'latod ProIe;n. and Ph),s'
iological Elfeclors, 1<J9: 146- 52.
4"), Il.nba"cr. I .. Pradh.n. S .. and Yang. H,·Y. T.
Role of Calmooulin in Dop.minergic Transmi,·
,ion. Ann. N. Y. Acad. Sci. 356: 292_302. 1980.
48. Hashi,.ume, K., and OeGrooI. L. J. Adenosine
3'5'· Mooophosph.le.D<pendent Prolein Kina",
AClivily in Soluble ThyrOlropin Rec<ptor Com·
pte.. ElUiocrilWl, 104: 1739- 44. 1979.
49. Haug, E, ProBe'lerone Suppression of Emogo"'
Slimul.ted Prol.ctin Secretion .nd ESlrogon Re·
oxplOr levels in Rat Pi luitary Cel l, . f.·ndocrinol,
104: 429-37.1979.
He". H. G. Th. Controt or GtyOo!en Metat>oli,m
in the liver. Ann, ReY, Biochem, 19")6.
51. fli .. la. r .. W. J.. A,elrod.}, (j.
Adrenergic Receplor Agoni"s Ine, •• se Phospho-
lipid Melh)'l .. ion . Membrane Fluidity. and (j·Ad·
renerg ic Cycl ... Coupling.
PrIX. Nar/. Acad, Sci. USA 76: 368_72. 1919.
52. Hollenbe,s, M. D. and •.,. P. Studie. on
lhe Interoction of flormonell with Pla.m. MOm·
b,ane Reoxplors. Bioeh."" Acli""" HOf"', 3: 42_
85.19H.
53, Horrobin. 0 , Cellul.. 8a.i$ of Prolactin Aeli".,:
Involvem.nl of Cyclic Nucleotid••. Polyamine,.
Prosl"-3londin,. S'eroid .. Thyroid Hormones.
ATPase. and Calcium. R.le,'.nox to
Bre." Cancer and the Mcnstrual C)'cie. Med·
ieal 5: 599-620.1979.
54. Horrobin, D. Pro/(I(,"lin 1976. Eden PreiS. Mon·
".al. 1976.
55, Howlen. A. C.SlCfnwei •. P. C .. Maci k, B. A.. Van
A"dale. P. 10.1 .. and Oilm . n. A. G, ReoonSliluti""
or Cateeholamine-Sen<i,i.e Adenylale Cyda.e . J.
B;{)/. 154: 2287-95.1979.
56. Ignarro. L. J. Cyclic Nuc1eotidC$ arid LyOOS(lmal
Enzyme Scolion. Chap, II. pp. 189-206 ofCratncr
and Sehul1z. ed •.• rererence 23 ./
56A. [ngob, it",n. T . S .. and Cohen)'. Protein Phospho.
l.oes: Prope'li ••• nd Role in Cell ular Regul'lion.
pp. 331-8. 1983.
57. [rvinc, R. F. D,W$<)n, R. M. C. arid rreinkc1. N.
Slim"laled Phosphatidylinositol T"rnovu: A Brief
A ppraisal . ChO?- 9. pp. 301_42 of Frein"l. N" cd,
Mnabo/iJm. vol , 2, PI.num. New
York. 1982
S7 A, Jacob" S.• nd Cualrec..as, P. Insulin ReceplOrs.
Ann, Rev. Phormorui. Toxieol, 23:461_79. 1983.
S8. Jami.""n, O. A .• J, .. Br""",,.. O. 0 .. Sh.ch. t. F,
H .. and Vanaman. T. C Structure and FunOlion
Rel.lionships among Calmodulins and Tropon in
C·Li ke PrOlein. from Divergent Euk .. Or·
ganisms. Ann. N.Y. Aead.Sri. 356: 1-13. 1980.
Jensen. E. v .. and OeSombre. E. R. I'..strogon.R¢.
oxplO' Inleraclion. Sdtl1ff 181: 1973.
60. Je nsen. E. V ... nd OcSombre. E. R, ",[rogcn' and
Progestin•. B;oeMm. Act;ons Horm , 2:
1972.
61, Johnson, E. M ... rId AIIl.ey. V. G. Postsynthelic
Modifioalion' of Hist01lC Primar)" StrUC1"re: Phos-
phorylalion and Acelylali"" .. Rclaled 10 Chro-
malin Confo,m ation aod F"nction, Ac-
Ii""" I/orm. 5: I-51. 1978.
62. Katz.nellenbog.n. B. S .. and Go ... ki. J. E'lrogen
Action. on S),nlhesc. of M. cromo!<culu in Targel
Cells , Bioch.",. ACI;""" liorm. 3: 188_243 1975.
63. Keirn$. J. J .. and TOlman. E. K. Nucleot idC$
in Disord .... of Carboh)'drale and l ipid Melabo-
li,m. Chap. 22. pp. 397_414 of C .. and
SchullZ, .d. .. reference 23.
64. Kelle r. C 11 .. L.Porte. D. C , TO£C:Ino, W. A .. Jr .•
Slorm. D. R.. arid Westcol1. R, C." R.gulalion of
C)'ciie N"cleotide Metabolism. Ann. N.Y. Ac"d,
Sci, J'6: t930,
6S, King, R. J. B. Inlracellular Reoxplion of S teroid
Hormone.. pp. 41_76 of Campbell. P. N. and Ald·
ridge. W. N.. cds .. Ess"y' In BioeM",;"r,-, \'01 , 12.
Academic PreiS. New York. 1976.
66, Klee. C. B... rId Haicch. J. Concerted Role of Cal·
modulin and C.loin"erin in Calcium Regulation.
Ann. N.Y. Acad, Sci, 356:43-53. 1980,
67. Kleinsm ith. L. J. I'l\o$phorylation of Non·historIC
Prolein, in the Resul.li"" of Chromosome Struc'
ture and Funclion. J. Cdl Ph,-'i"'. 8,: 459_16.
1975.
67 A. Kokt.ky, R. J.. Brown. E. M., and William •. G. H.
Calmodulin-like AClivily arid C.lcium-D<pondenl
Pbosphodiest.rasc in Purified Cells of lhe R.l
Zona Glomerulosa and Zona rucic"lala .
rooJ, 1983.
68. Krieger. 0 , T, Il )'polhalamu,. Chap. I. pp. I of
Ingbar, S, H .. ed. Th, Y,"r in EndoerirooJogy 1977.
Plenum, New Yo,k, 1978.
69. Krieger. 0 , T .. cd , t:rrdocrlM R h)-'Ih"", Raven
PreiS. New York. 1979.
")0. Lapelina, E. 0 .. Billah . M. M.• and Cu.tre ......
P. The PhOSph31idylinositol Cycle and the ReBu,
lalion of Arachidonic Acid Produclion . Nature
192: 361-9. 1981.
71. lawrence. T. S .. Beers. W. H.. and Gilul •• N. B.
Transmi"ion of Hormon.1 Stimulation by Cell·to-
Cell CommUn icalion. Natwl't 271: 501 - 6.1978 ,
'"
72. Leavitt. W. W .• Chen, T. J .• Do, Y. S .. Carllon. B.
D.. and AlTen, T. C. Biology of Prog.. tcnme Re-
.<1'100. Chap. 7. PI'. of O' Maltey and
Bi,nb,um",. cd, .. rdCI'<'n<;< 95.
13. Le •. P C, RadlolT. D.. Schweppe. J. S .. and Jung.
mann, R. A. Te.l ieul .. Protein Kinase>.
! •• julio" of Multiple Form. "ltd Onlogeny. J.
Bioi, Chrm. 251:914-21, 1976.
14. Lehoi",.r. A. 1. of B/ochtmjjfry.
W<>r1h. Ne ... York. 1982.
75. L.hotay. D. c., Lo. fl. K.. and Leve),. G. S . ACli -
valOon of Adenyla!. Cyelo",: Requirement fo r
PlKisphoUpids. Chap. I. PI'. 1-12 of C.. mer and
SchulIZ. cd •. , r.rc ... nce 23.
76. Lt.ler, H. A .. Sl .... M. l.. and Levi(,;. 1\. p",..
taglandin-St imu lalcd GTP HydrQly.i. I\",,,,iat.d
with AClivalion of Adenylote C),<:I.", in Human
Platelet Membrane>. Proc. NaIl. A,aJ. Sci. USA
79: 719-23,1982.
77 . Levin. R. M .. and Wei ... B. Spccif"'ityofthe Bind_
i", of Ttifluoperlline 10 the Calcium·Dependcnt
AClivator of PhO$phodieSl.ra .. and 10 a Scries of
the Coldum·Sindin, PrO!ein •. Biophy,'.
ACla540: 197_204, 1918.
78. Main"aring. W . I. p, Androgen Re""pt<>r.O and
Biologic Respon>cl; A Sur.ey , Chap, 5. Pl'. 105_20
of O'Malley and Birnbaum.,. ed, .. 'ercf<'n<:e 95.
18A. Manal. n. A, S .,.nd Kite. C. S, Acti.alion of Cal·
cineurin by Limiled ProteolY'Si' , P'O<". Narl. Arod,
Sci. USA 80.4291_5.1983.
19. Manni. A.. Chambers. M. J .. and Pearson. O. H.
Prolaclin I nduces Its Own Rec,pl<>r.O in R," Liver.
Endor'illO/. 103: 2168-11 , 1978.
80. Marshall. S. Bruni. J. F.• and Mei,e •. J. Effects of
H),pophysectomy. Th),r<>idcclomy .nd Thyroxine
on Specific Prol.etin Recop'Of Sites in KidneY'S and
Adrenal, of Male R.1S. t.·m/«, illO/. 11)4." 390-95.
1919.
8\ . Marshall. S .. Hu ang. H. fl.. G. S .. C.mp-
bell , G. A .. and Meil" . J . Gluc<>COI"ticoid Regula.
tioo of Prolactin Recepl<>r.O in KidtICy. and Adre-
n.l, of Male R.... t 'm/oainol, 102: 869_75.
1918.
82. Martin. T. F, J .. and T",hjia n. A. H .. Jr, Con Cui·
ture Sludie< of Thyrot ropin·Relea.i", Hormone
A<lion, Bloch'm. Aelions !form. 4: 210-312. 1977.
83. Marx. J. I.. The Leu kO!rienc:< in Allergy and In-
flammation. 215.- 1380_3. 1982.
84. Me . ... A. R .. Fakunding. J . 1... and Tindall. D. J .
Follicle Stimulating Hormone Regulation of Pro-
tein Kinase Acti.ily and Protein S)'nlhesi. in Tes-
tis. BIoi. R,prod, 14: 54-63 .1916.
85. •. A. R .. T .. h. J. T. and Chaf""I .... J . G.
Physioiogieallmptication, of Ibe Pre .. nee. Di'lfi·
bution. and Regub,ion of Calmodulin in Eu kar)"
otic Cell. , Phy.iol, Rn>. 62: I - 39. 1982.
86 . Miller, J. P. Cyclic Nuclrotidc Anaiov. Chap, 6.
pp. 11-105 of Cram" and Schuh,. cd . ..
"
81, Mou. J.. and Vaughan. M. Aeti.ation of Ad.nyl.
MECHMoilSMS OF HORt.iONE ACTIO N AND INTERACTION
at. Cyct... by Choleragen. Ann, R, •. Bioch,m. 411:
58 1-600, 1919.
88. Muldoon. T. G . Regulation of Ste rOid Hormone
Roeepler Activi,y , £MOC', Rrv, I: 339-64. 1980.
89. MUlier. R. E.. and wOli ,. II , II. Kinet ic<of Estra·
diol Entry into Uterine C.lIs. EN/oc,inol. 105:
1101_1 4. 1919.
90. Munjaal. R. P .. Dedman. J. R .. and Me.n,. A. R,
Isolation of the Slructural Gene for Calmeduiin,
A"n. N.Y. Arod. Sd 3J6: 110_11. 1980.
91. Murad. F .. a nd "u,bach. G , D, Cyclic GMP in
Metaboli.m: Interrelalioll$hip; of Biogen ic
"mi ne •. Hormon .. and Other Agenu. C hap. I. Pl'.
1-32 of Freinkel. N .. ed. y..", in MtlaooU""
1977. Plenum. New York. 1918.
92. Nolin. J, M. Targel Cell ProIacl;n, Chap . 1. pp.
151_82 01 McKerll$. K. W .•• d. S",.uu'e alUi
FUnc,ion of th' Gonadotropin<. Pltnum . New
York. 1918.
93. NOrlhrup. J. K __ Sternw.i •. P. C .. Smigel. M, 0 ..
Schleifer. L. S .• Ro». E. M.. and Gilman, A. G,
Purification of lhe Regulatory Compone nl of Ad ..
ny lat. Cyclase , P,O(:. Nail, Arad. &i, US A 77:
6516-20.1980.
94. NOtid ... A. C. Conformational Form, of the Estro-
gen Re""ptOr. Chap. 2. pp. 33-61 of O' Malley . nd
Birnbaumer.• d, .. referen"" 95,
95. O'Malley, B. W .•• nd Rirnbaumer. Led,. Rectp--
lor. amJ lIorm"'" Ael/on II. Academic Pre ... New
York . 1918.
96, Ouglc. T. F .• and Kitay. J . I. Interaction. of Pro-
lactin and Ad"IlOCOrlieOlropin in the Regulation
of Adrenocortical Sccretions in Female Rats. H".
docrinol, /04 ' 40-4.1979.
97. Oppenheimer. J. H. Thyroid Hormone AClion at
Ihe Cellular I..vel, 103: 911_9. 1919.
98. J.·P .. and Sharma. R. K. Modia1ory
Role of Calcium and Guanosine 3·,S'. MonopJ-ros.
phate in Adrenocorliemropin·lnduce<l Steroide-
gene,i. by Adrenal Cells. Sti'",... 103: 1259-61 .
1919.
99, Pfeiffer. D. R. , Schmid. P. C. Beatrice . M. c.. and
Schmid. H, 11. O. InlTamitochondri.1 Plw;pboli ·
pa$< Activill' .nd the ElTects of C. " Plu , N·
Ethylm.leimide on MitoChond rial J.
BioI. 154: 11485_94. 1979.
100. Pietra •. R. J .. and S.ego. C. M. Melabolic .nd
Proliferalivt R•• pQn$Cs 10 EsIfO/!en by Hepato-
eyt.. Selected f'" Pla,ma Membran. Binding·, ile,
10 e;trad iol.17{1, J, C,II. Physiol. 98." 145_
60. 1919.
101. Pielra" R. Land S,.so. C. M, Specir,e Binding
Site. for Oest rogen at the O UlOr Surface. of 100-
lal.d Endometrial Cell" NalUtf 265 .. 69-12. 1977.
102. Pohl. S. L The Gluca,on RC«p1Or and its Rei.·
lionship 10 Adenylate C yclase , F,d. Pro<. 36:
2115- 18. 1971.
103. Rasmussen. H. Calcium and cAMP in Stimulus-
Re,ponse Coupling. Ann. N Y. Acad. Sci. 356.-
346_H 1980.
104. Rasmumn. H., and Goodma n. B. P. Rdationship$
Btt...... Calcium and Cyclic Nudeolides in C.tt
AClivation. Ph,..;Q/. R". 57: 42 1_509, 1977.
105. Reed. P. W.. aOO Knapp. H. R. Prostaglandin. and
Calcium. pp. 445_7 of Scarpa. "-. and Car.Joli. E .•
• d •. Calcium 1,o/U!>O'/ aM fUIf</iQlf, Ann,
NY. Ac"d, Sci, j(l{. 1978,
106. Richa,ds. J . S . Hormon. R.gul alion of O .. rian
Hormone ReceptorS. Chap. 16. pp, 479_91 ofai'n-
baumer. L.. and O·Mattey. B.. cd •. OM
Hormon, AcUan III. Aead.mie Pre ... New Yo'k.
1978,
)07. Richa,d$. J, S .. and Midgcloy. A, R. PMcin Hor-
moo. Ael;oo: A K.y 10 Und.rslandinS O varian
follic ular and Luteal 1k.cIQpmenl. Bioi. R.prod.
14: 82-94.1976 ,
108. Rillema. J. "- Mech.ni.m 01 f'r"laclin Action,
Pm,. 39: 2593-8.1980.
109. Robison. G. A.• Butcher. R. W .• aOO SUlhcrland.
E. W, Cyclic AMP. Academic Press. New York.
1911.
110. Robinson. G. "-. Noh ••. G. G,. aOO Triner. L.. ed •.
Cyt:iic AMP aM Fum:tions. Ann, N.Y. Acad,
Sci. 185. 1971.
Ill . R(K!b<l1. M. Tbc AClion$ 01 Hormone.. On Adenyl_
ale Cycla.. S)",lem •. pp. 365-74 01 ThiTd »«trl-
nl,,/ Rn>i.", ("('"/'"""': (". 1/,Ti",,". aM Organ
Cull",•. NCI Mooograph 48. DliEW Publ. 71·
1441. Go,,,rnmcnl Prinlins Offite. Washinglon.
O,e..1917.
112. Rodbell. M. The Problcm 01 IMntilyinglhe Glu_
Receptor, F,d, Pm,. 12: )854-8. 1973,
113. R=. P. S .. Mos.<.J,. and Vaughan. M. Inleraction
of Cholcragen and T hymlrop;n ",jth Bovine Ade'
n}'I3le C),cl.",. £MOC,;Mi, 104: 10)6-40.
1919.
114, Roth, G. S. Hormone Reteplor Change< during
Adulthood and SetICSce nce: SigniflCanee lot Aging
.. ch, Ftd. Proc-. 38: 1910-14, 1919.
Rubin. e. S .. and Rc.scn . O. Protein Phc.sphoryl-
atien. Ann. Rev. Bioch"" . -1-1: 831-87. 19H.
116, R)'an. R. J .. and L.e. C. Y. The Role of Membr"ne
Round Receplor., Bioi. 14: 17_29_ 1976.
117. Samu.llson. D,. Goldyne. M .. Gtans"Om. E..
Hamberg, M., Hammarslr,)m. S .. and Malm'lOn.
e. P""'taslandin. and Thromoo,"nes. Rto.
8ioch'm. 47:
118. Schell-flederick. E.• and Dun""'t. J. E. Meeha-
ni .m. of Action of Thyrotropin. Bio<htm, ANions
I/OI'm, 1:416-6). 1970.
119. SOl>!)nhOlor. P. S .. and Pelers. H. D. Role 01 C)'clic
Nucleotide. in Cultured Cell •. Chap. 7. pp, 107_
12 of Cromer .nd Schuh,. cd •.• roferenee 2).
120. Schtadet. W. T .. and O' Mall.y. D. W. Moleeular
Structure'OO An.ly.i. of Progo"e",ne Receplor<,
Chap. 8. pp. 189-22401 O'Malle}' aOO Dirnbau-
mer. cds .. relete""e 95.
121 . Sehramm. M, Transler 01 GlucaB"" Rcceptor Irom
Liver Membran... to. Foro;g. Aden),I"e Cyc1a",
by • Membrane Fu,ion Pro<:edute, Pmc-. No/i.
Acad, Sci. US A 76: I I 74_8. 1979.
122, &,1 •• J, R,. and JareH. L. AClioation 01 Pyru,'ate
Ikhydrogena'" Dy Dir«1 Addition of I•• u)in 10.n
Isol, led Plasma Membrane/ Mitocoondtia Mi.-
ture: E' idcn« fOT Genera'ion of InSu)in'$ S«ond
M ... ",nget in a Subcellulat S)'stem. P,oc. /'Ial/ ,
Acad, Sci US"A J!: 77-S I. 1980.
12]. Shetidan. p, J .. Buchanan. J, M,. Ansclmo. V. C.
and Manin, P. M. Unbound ProgoSl<ro"" Rtctp-
to,.. ate in Equilibrium Btl"'een th. Nucle •• and
Cyloplasm in Cell. of Ihe Ral Uleru,. £ndocrlno/,
108: 1533-7. 1981.
124. Siog<1. M. I.. McConnell. R. T .. Portet. N , 1\.. and
Cua'tecasas. P. Arachidonatt Me10OOli$m via Li-
PQ'ygcnue and 12L-HydtopOro.y-5.8 . 10.14_1=_
atetraenoie Add Pero<id.", Sensilive to Anti·l n-
nammalOry Drugs, PTOC. Narl. Acad. Sri. US"A 77:
308_12.1980.
125. Skolnick. P.• and J, W. Daly. Regula,ion 01 Cyclic
AM P FOtmalion in Btain Tissue by PUlali.e Nc.·
rotranlminerS. Chap. Ii. pp. 289_315 01 Cramer
and S<hu l!z. ed •.• ,el.",ne. n .
12/'i. Slephe n., D. T,. Wang. J._L.. and HOIIkin,. D. O.
The Cy<ik AM I' I'ho<phodie<lerase of B<wine
Sperm.lo,,,,, : Multiple form •. Kinelic Propotlie.
and Change. Durins [X,dopmonL BIoi.
10: 483_9). 1979,
127. Sletling. K.. La",ru •. J. H.. Milch. P.O._ S"u-
rad •. T,. and Dtenner. M. A. Mitochoodrial Thy-
roid Hormone Receptor: Locali,-"Iio" a nd Phy.io-
logical Sillniflcane<:. Sc;tlW }OI: I I 26- 9. 1978,
128. Storm,h.k. F.. Harris, J. N.. and GOrSki. J. Nu_
dear E.m og.n Rec.ptor and DNA Synthesi •.
Chap. 3. PP. 63_8101 O'Malley and Birnbaumct.
.d". refer<1ICC 95.
129, Sul •• r. !" •• nd Velulani. J . P<ychotropie Drugs "nd
Cyclie AM P in lh. Central Ne"""" SY"tem. Chap.
19. pp. 331-65 of Ctam.t and Sth ult,. ed, .. ref-
crence 2),
130. Suthcr land, E- W. Studie. on th e Mochani'm of
HOtmon. AClion , ScitlW 177: 401_8. 1972.
])1. Suzu ki. F.. Daikuh.ra. y,. 0110. M,. and Takeda.
V. Sludi •• on Ihe Mode 01 Atlion 0/ I n. ulin: Prop-
ctlies and Biological Aetivityof an In,ulin-De"ran
Compte.. t:nrlOC,ilWl. 90: 1220-30. 1912.
132. S",Hlens, S .. and Dumont. J. E. cA MP_]'",,"in Ki-
na .. Inloraclion , Chap. 4. PP, 57_64 01 Ctamet
and Schult •. ed$.. refere""e 23 .
133, SlCgO. e. M, Lysosomal Function in Nucleocyto-
plasmic Communioation. Chap, 14. PI'. 385-744 of
Dinsle. J. T .• and Dean. R, T .. ed •.
Bioloty anrl 4. Elsevier. New York.
1975.
134. S,ogo. e. M. Parallel, in the Mode$ Of 01
P.ptide.OO Stcr<>id Hormones: Membrane EIr.ets
and Cellular Enl'Y. Chap. )9. pp. 431_72 of
McKetns. K. W .• cd , and Fllnc/ion 0/
(jQlU1dOlroplns. Plenum. New York. 1978,
135. Ta i. T ,-Y.. and Pd. S. Direcl Stimulation by
G rowth Hormone of G lucagon and In.ulin Rei •• ",
lrom lsoialed Rat Panete as. EndOCT;'wl. 99: 669-
17. l n6.
136. Thompson. W. J .. and Strada. S. J, Hormonal Reg-
ula,ion 01 Cyclic Nucleotide Pho<phodieslera..,.
156 MECHAN ISMS OF HORMONE ACTION AND INTERACTION
Chap. 20. pp . 353-71 of Birnbaumor. L. and
O'Malloy. B. W .. ed •. RtNplO<' "mllformo", Ac-
lion III. Academic Pie ... New York. 1978.
137. Tymo<>ko. C. L. . l.i.ns. T ..• nd l.iao. S. Androgen
Rectp!ol Inleraelion. in Targol Ccllo: Biochemic.1
F•.a lu.lion , Chap. 6. pp. 122- 56 of O'M.l le), aFld
Bi.nbaumer. cd •..•de",n •• 95 .
138. Vineen,i. F, F .• Hind •. T. R.. and Ram, B. U. Ca l·
modulin and lh. PI3<ma Mcmbrunc Ca lcium
Pump. N.Y. J56: 232-44. 1980,
139. W.llace. R. W .. Lynch. T. J.• Talla.,. E. A..• 00
Cheung. W. Y. Pu.ificalion and CharaCleri'",I;on
of an InhibilO' of B.ain Aden}'lale Cyela.. and
C),cl;c Nuc1colide Poo.pbodieslCr... , J. Hiol.
Ch,m. lH: 377_82 .1 978 .
140. Walsh. D. A.. and Cooper. R, H, Tho: Ph),.iologic.1
Regulalton and Funeli"" of cAMP.Depende nl
PrOlein Kin.,., •. 8irxhtm, Action., /form. 6: 1-13.
(979.
14\. Wang. J, H. Cakium.Rcgulolod P'Olein Modul._
lor in C)'dic Nucle01ide Syslem •. Chap. 3. pp. 37-
56 OfCramc. and S<'huh,. ed, .• •dorenee n.
142. Waue"" •. D. M .• and Vineen,i. F. F.
A·I . Kelly. P.A.. Djiane. J, . Kaloh. M,. FerlaFld.!.. II ..
Iloudebinc. L.· M .. T<),»o'. B., and Du,",n,.r·
Foun. L Thc Inl e .. ction of Prolaclin wi,h h. Re·
ceplOTS in Targel Ti "ue. and It , Mcehani'm of
Act ion . Rrc. Pmg. /l orm. RJeh. 40: 379-436. 1984,
A·2, M arx. J . L. A New View 01 Kecep,or ACHon .
""u2N:211-4.1984.
A·3. McPha il. L. c.. Claylon. c.. and Sn)'de.man. R. A
PoIenli. 1 Second Messa nger Role for Un,aluroled
Fall)' Acids: AClivated of Ca' · ·Dtpend on, Pro,cin
Kin.... 1U : 622_5. 1984,
A-t. O"'ad •. M. K.. H.kura. A.. lid,. K,. Yah.ro. I..
Sobue K.. and Ka kiuchi. S. Occuran« of Cak$-
and (",/I N.Y , Acad, Sei , Monograph
J56.198O.
14). Way, . D. K.. Mahaffee. D. D.. and On'j'" D, A.
An Adrel'lO<:Q.lic",.op;n Analog (ACTII 6--39)
which Acto a. a POlent in Vi"o Adrenocorlicolro-
pin Anlolon;" a, Low Calcium C""cen,rol;"n . nd
as a Agon,,, al ll iAh Caldum Coneenua'
lion. f.ndrxtill()/ , 1M. 1028_35. 1979.
144. Wi«. L. S .. and JungO$. R. L. E. idcnce for . Dual
Mechani.m of Lipol)'.is ACli.alion by Epineph rine
in Ral Adipo:sc Ti"ue. J. Bioi. Chem. 25]: 2624-
7. 1978.
145. Wong. P. Y.·K .. Lee. W, H.• Chao. P. H,-W .. and
Cheung. W,_Y . The R<>Ie of Calmodu lin in Pro, ·
laglandin Melaboli<m. N .Y, ANd, Sci. 356:
179_89. 1980.
146. larrow. M. x.. Yochim. J, M .. McCa rl hy. J.
L. Endoc,in%gJ'. Ac.den,ic Pre".
New York. 1964.
14 7, Zol ler. M, J,. Keda .. g•• A, R.. and Taylor. S. S.
Sl'UC,u .. 1 Con,parison. of cAMP..;Jependenl Pro-
lein K; nase, [ and I[ from Po.cine S keleta l M u"'k.
J. Bioi. Ch.rn 154: H08- 18. 1979.
",on (A Ca lmodulin·binding Prolein) in Cul1ure
Cells; Comparison of Normal and T.. n,formed
Cell,. Proc, Narl, ANd, Sri USA 81: ) 133-7, 1984,
P,enl". M,. Biden. T, J .• Janjic. D.• ["'inc R. F.•
Berridge . M, J.. and Wolheim. C. B. Rapid Mobi·
I"-" ,,on of C." lrom Ka' In,ulinom. M,C.osom.,
by IIlosi101-1.4.5· Tripoo.phalc . m: 562-4.
1984.
A·7 . Sliles. G. L . C..on. M. G,. and l.enowi".. R. J,
/l.Ad.encr8ic Receptors; Biochemical Meehani.m.
of Ph)'.ioIogical Rcgulalion, Ph,.•. R, •. 64: 661-
743.1984.
_ __ PART 11 _ __

Hormonal Regulation of
Carbohydrate, Protein, and Lipid
Metabolism
_ ___ 5
The Endocrine Pancreas
The panc",as plays key in [hc provi< ion of nu-
trients 10 all body cells during times of fceding and
fasting. The exocrine components se<:relc cn'.ymes
thal diges l proteins. fals, phosphQlipids, polysaccha-
rides. and nudeic acids. The endocrine ti .. uc affects
Ihc appeti te, governs Ihc absorption. distribution.
and uS<: of fuels. establishes and recruils glycogen
and rat reserves, regulates the forma lion of protO-
plasmic building blocks. rnain!a;n, (hc plasma 000·
cemralion! of glucose and olher important compo-
nems. and contributes to Ihc CQnlrol of acid·base a nd
waler balance.
The major hormone-producing cells are
into "islets" 1h31 are scattered within (hc exocrine
tissue and comprise 1%--2% of the \ota l pane",a!;.
mass. Most of the regulators arc released in Ihe vi-
cinity of Ihal lead into the ponal
blood vessels. and many of t he actions are exerted On
the liver. Each islet is a comple. microorgan that is
richly ,upplied wilh blood. It receives <ympathetie.
parasympathetic and pcptidcrgic innervat ion, and i1
conlains at leasl three different kind, of functionally
interrelated cell types (216) (see Fig. 2· 3 and Table
2·4).
THE VITAL IMPORTANCE OF MAINTAINING
ADEQUATE BLOOD GLUCOSE
CONCENTRATIONS
Under normal oondit ions. brain ncuron, depend al·
mQSt . xclusively on glucose metabolism 10 SlIlisfy
their energy requiremenls (I 26). Since the cells Can·
not Slore subsla nl ial carbohydrate rese rves. Iheir
functions are disrupted by even brief periods of glu-
cose deprivation. ErylhrocYleS also require a slcady
supply of glucose. The)' lad mitochondria and
Iherefore cannot fatty acid fuels. S keletal and
cardiac muscle usc fally acids IlIQSI of Ihe time. bUI
'"
they. too. require glucose when the body engages in
slrenuous activity. Since all of lhose eells take up
glucose by facilitated diffusion, Ihe blood COnCCntra-
tions mU<1 be main tained at levels Ihal provide ade-
quate ooncentration grad iems.
According 10 a popular misconception. glucose de·
ficiency lead, to drowsiness. Fortunately. this is not
the case. The eartiest signs of hypoglycemia (sub-
normal blood glucose oon..,ntration) include reSt-
lessness. irritability. and increased awarCneSS of Ihe
environmenl. as well as sensations of anxiety and
hunger. These arc actually important for su[>ival.
since they s;gnal the need loseek OUI nUlricnts. Con.
sider the fate of an animal mu't hunt for it'
b",akfasl, if failure to find food and consequent de-
pIction of carbohydrate reserves could bring on
drowsiness. The animal would gradually lase moti-
vation to chase. fall asleep. and soon Sla rve to dealh.
The cries of a hungry infant (and the nap of oon-
tentment thaI follows a feeding) are Hnked with re·
latcd underlying mechanism,.
More severe hypoglycemia causes headache.
lurban..,s in sensory perceplion (including blurred
Or double vision) . mOlOr incoordination, and sweal-
ing. and ils viclims descri\)c '"feelings of impending
doom".
If the blood glueQSe is pcrmilled 10 fall to even
lower levels. the consequences can be disastrous. In-
voluntary t",mors progr<:ss to mU$C lc spasms and
convul,ion" as higher ccnters of the brain lose tllcir
normal inhibitory influence, over lower ones. Ulti-
mately. consciousness is lost and dy,funclions of the
lower. more vital pans of the brain ma ke it impos-
sible to suslain life (45).
i\ method ror the bioass.ay or insulin (which rapidly de-
1>"'=_ th. glucose levol. ) i"volv"," determination or lh.
quantity requi",d 10 invoke convul.ion. in rasted ra!>bits.
'"
Higb dose_.,r i.,ulin have been u",d in the pas, ., ",hod
therapy" rC>l psychiatric p.li.nlo. The effec,. inciudod
convul.ions and 10$$ of con<Ci""'n ..... fo>llo",.d by mental
<:<;>nf",ion and disorientation during lhe ,.."".cry period.
Chronic hypoglycemia of a milder nature can be
the caus<: of "bizarre" or "psychotic" bc:ha.ior. It
has bun xtll,lwn to damage the neurons of aduhs and
to impair brain development in Ihe yoong.
Since there is compelling need for p'QIe<:tion. it is
not sUrprising that several bormQnes a rc charged
wilh the T<;sponsibility of elevating Ihc blood glucose
concentration, when this beCQrnes appropriate. The
group indudes glucagon. gluCOC<lrlicoirls. epineph·
rine. and growth hormone.
All cells funclion best when Ihe plasma cone<:nlra-
lions of essential molecules are maintained at opti-
mum 1.,,<=11. The quanlilies of glucose used by brain
are determined by aClivities of Ihe inlracel-
lular en7.ymes. and Ihere arc no advantage, to forc-
ing glucose enlry. The .yntptOnt. of mild hypugJy-
u mia (excessively high blood glucose) include
drowsiness and impa ired ability to perform demand-
ing mcnlalla,ks.
Occa,ional. moderate elevalion.. of the blood glu-
cose concentration, are tolerated by otherwi,e
healthy individuals. However. marked hypergly-
<:<omia Can have disastrous consequence<. e<pe<:ially
if it recurs at frequent intervals Or i, chronically
maintained.
Hyperglycemia Leed s to Glycos uria
Under IlOTmal conditions. vinually all of the glucose
filtered by the renal glomeruli is reclaimed by the
proximal tubules. The amounts that escape into the
urine are not detectable with ordinary technique,.
Reabsorption is an active. energY·Q,lnsuming. sat-
urable process. When hyperglycemia leads 10 the fil·
tration of supernormal amounts of glucose. Ihe kid.
ney handle. whal it can and Ihe excess passe. on 10
the urine.
GlyC05uria (sugar in the is nOt necessarily
an indication of kidney damage. The situation could
be compared with One in which a bricklayer does the
!.ame amount of work each day. If he is provided
with exactly the number of bricks thaI he ne<:ds.
oonc arc left over at the end of Ihe shift. However.
if he is given Iwice as many. the exIra ones will not
be used.
Glycosuria is wo$leful. since potenlially useful nu-
IrienlS are forever lost . During a subsequen l period
of fasting, body proteins must be broken down to
provide fuels tbat would otberwise have come from
glucose-derived glycogen and fat. It is possible to
lessen the protein destruction by taking frequent
TH£ £ NOOCFlINE
meals. bUI glycosuria has other serious con-
sequences.
Glycosu ria Leads to Dehydration
Thc glucose Ihat escapes into the urine osnt()/ically
draw.• walfr from the body. The blood is
transiently maintained with fluids recruited from the
extracellular spaces, but it eventually falls. Massive
fluid depiction Can invoke hppottruiQf1 (low blood
pressure). even when tile blood viscocity increases.
ReA.x vasoconstriclion counteracts some of the ef-
fects of hypovolemia (low circulating blood volume),
but it causes other problems. Renal function can be
compromised because of reduced renal blood Aow
and inadequate filtralion pressure.
When the plasma lxeomes concentrated. water is
drawn from tile cells. The hypovolemia and vaSOCOn-
striction impair delivery of oxygm and nmrienls and
the removal of metabolic wastes.
Eerly Symptoms of DIabetes Mellitus
The lerm diabele.• me/lil'" designates a group of dis-
eases eharac\C,i'.ed by hyperglycemia. glycosuria .
absolule Or ..elative insulin deficiency. "Diabe-
les" from a word that means syphon. and it is
applied to ,everal conditions in whicb the mte of
urine production is excessive. Mellitus (hone)') refers
to lhe sugar contenl of the urine. The early manifes-
tatiollS inelude (a) polyuda (increased urine vol-
ume); (b) thim and pol)'dYP${a (incrcased drink.
ing): (c) hunger and h)'(lI!I'phagia (ingestion of large
quantilies of food): (d) wea kness and fatiglle: and
(e) some impairment of mental functions. including
"inability to concentrate".
The polyuria is largely attributed to the osmotic
effects of glucose. but th e condition is aggravated by
byperglycemic suppression of antidiuretic hormone
.eer.tion (221). Osmoreeeptors stimulated by the
hemoconcentration C<lmmunicate wilh neurons Ihat
mediate thirst sensations: but falling blood pressurc
and blood volume also promote Ihe production of an·
giotensin Il (a highly potent dip:sogen). Usually,
drinking only panially compensate, for the water
10M. It can also exacerbate the polyuria and accel-
erate the "wasbing out" of essential electrolytes.
The hunger and wcak/ICSs can resull from insulin
def,ciency, since Ihe hormone regulates glucose: up-
take in skeletal musele and probably also in pam of
the brain that contain "glucoreceplors". Increased
food intake replaces SOme of the lost nutrients. but it
exacerbates the hyperglycemia. glycosuria. and
polyuria. rndividuals suffering from uncon(rolled di-
abetes mellilus usually lose weighl rapidly.
 Dlra ct Daia ta rioul Effect. 01 Hyperglycemia
Proteins undergo IIOnenzymatic glycosy)ations. and
the fC3.ction ratcs rise in paralld with the gluCQSC
con«ntrations (22). Plasma albumin is heavily aly.
cosylatcd in patienu "'itn hypcrgl)'ccmia (76).
whefC3.s only around I 0( the moIeculcs bind sug.
a", under normal condilions (' 72).
Suprs auneh 10 hemoglobins. and hemoglobin 1\
is o;Qfwerted to hemoglobin A" when glucose: at.
tacoo to Ihe N·tcrminal valine of Ihe chain. 'The re-
suiting chansa in affinity arc I'I(lI physiolog.
ically important . but the reactions serve as markel'll
for OIher events (1 0 7). Determinalions at hcmogk>
bin provide a 0( the effective-
nel$ of hormone thernpy in patients "'ho h,wc /lOr.
nu.1 glucose Ie.'cls but may upericncc
inlermillent (and otherwise: undetectC(i) boulS at
hyperglycemia.
Patients ... ilh diabeles of long standing almost in.
variably suffer a of patholo£ical changcs that
include thickenings of Ihe capillary oosemenl memo
brancs. shortened erythrocyte life spans. deteriora.
tions or the blood "esscls and of renal cells. neufOP'
athia. and ca laracts. It is suspeCted thai al leasl
wmc of Ihc arc to eXO;:(5Sivc glycD-
sylalions. Lysine allaehments lower ... rum albumin
affinity for fallY acids (11.-4). glyCCll5ylalion of lysine
residues of lellS proteillS is follo ... ed by 11M: formation
of disulfide bond. and the appcaran<:e of high.1ll()o
leculu " 'eight aggregales thai cause
while glycosylation of lOme membrane prOlei", .f.
fect$ properties such as su rface
Hyperglycemia can disruPI the funclions of cells
that do IlOl pO:!.SCs.s the kindl of barriers described
later for skeletal musele and adipose li"'lue. Under
lIO.mal oondilion$. glucose is phosphorylated as SOOfI
as il enter.; the cells. and the product is ... nt into gly-
colytic and other major metabolic pathways. When
Ihe blood arc exceed ingly bigh. phos.
phoryilitioo cannot keep pa« with the rale of glu.
CCI5C uptake. Substanti.1 quantilies of excess sugar
are then sent inlO pathways that do IIOt ordinarily
aooount fOf more than 2% of gluCC15C usage (229).
Neurons. kidney cells. blood vessel CXlnlponenu,
and lens lissue contain cm.ymes Ihal C3talyte the re.
dUction of glucose to sorbitol.
, 0 ",
1"C - QIi
I
HO-CH • NAOPH • H'
.... w
,.........,
.
, OH
tCI - Cti • N.o.oP ·
I I
IiC - OH OH
I I
I I
"CO" He · OH
"
D-Q"COOfl " Hormonal regUlation of melabolic pathways is usc.
Although sorbilol can he very slovo-Iy conven ed to
fruet+:lSC. it tcnds to ac.:umulale within the cells.
Since it does not easily exit via the pluma memo
braroes. il osmotially dr3ws water in"1lrd. In
imenlal animals. sorb,tol has been sllown to aecu.
muiate in lens tibue and to cause catarnCI$.
disruplions of arnillO acid uptake palle,os. and other
metabolie abl'lOrmalities. Sorbitol can also damagc
neurons. Additionally, the aldose reductase rcaction
lessens 11M: availability of NADPH. "'hieh would
otherwise: be used fOf processes that include
ti$.Sue rcpair.
METABOLIC FUNCTIONS OF INSULIN; AN
OVERVIEW
Although irISUlin is the oni}' hormone kllOWn to lower
blood gluCC15C concentrations. it is important 10 rw.
08 ni 7.C Ihal protection apinsl the dcvelopment of
hyperal}'cemia and 1J1}'rosuria is but one of many
functiollS scO'VW. If Ihe blood glucose levels of a ni.
mals deprived at insulin ""ere to be artificially main.
tained by presenting very frequent. very small meai$,
mosI of the $ubjccts "vuld soon slICCUmb to other
components of the deficiency syndrome.
Insulin regulates thc abi lity to store fol.
Io... ina meal ingestion. and it lhereby provides lhe
n::scrvcs that can be called upon during times of fasi.
ing. It controls Ihe transport of sugars and amino
adds me"""" plasrna membrane.. il direCI,' the
uses of those molecules. Ie augments fuel OJ<idation
and Ibe formation of ATP. It increaSC$
the efficiency of pcptide assembly on ribosomes
(evcn ... hen cells are OOthed in
media). and it provides procection against excessive
dograda lio" of body li$sucs. II growl h, pro-
liferation. and at many cell Iypes. in
part ';a influcnces on nucleic acids. It even
aCtS On oocytes (al IeUt in amphibia). and promotes
lheir entry into meiosis (43). TIM: roI"" in control of
glucose a nd fa t metabolism have profound cffcctson
water. mineral. and acid·base oolance, While it
stimulates Ihe appetile, insulin abo accelcr3tcs glu.
cose trallSpOrC in cells providina tbe saliety sig ... ",
The hormone additionally aell in major ways to reg.
ulalC the secrctions a nd functions of sevefa l olher
Despile thc compelling ncc:d to avoid development
of bYflO8lycemia. masl mammals can survive under
cootrol led conditions if they are deprived of a ny of
the hormoolC$ thai eleVllte the blood gl.""O$C levels;
yet few can ... itMlltnd insulin deficiency.
SKElETAL MUSCLE CONTRIBUTIONS TO
GLUCOSE HOMEOSTASIS
fu l only when cells "*n uMierJO pltysioiogiroJ
'" G_.1(1 )
lHE ENOOCIltNE PANCREAS

changes in funClions. e.g. when Ihey can substitute

one kind of fuel for another ()' undergo allernating
cycles of anabolism and catabolism. As discussed
earHer, neurollS have quite rigid require-
ments. If honnoncs cuuld restrict the supply Or affect II"
Fruc'ose·6·P
glucose usc, Ihey would only impa ir the funclions. In
contrast, resting Skeletal muscle and
pn:wide good examples of targelS wilh uAcxible" re-
tissue t (3)
F,uctose· 1.6·biphosphate
quirements thaI can be manipuiated by borman.s.
Since it is well equipped to burn fauy ac ids. reSI- I (4) (50
ing skeletal muscle requires very linl. glurose. Dur- GIy< ...aldohy<le-3-P -
ing times of fasti ng, when plasma insulin levels arc
low, a "barrier" sharply limils glucose upta ke. When
1(6)
plasma gluoose concentrations arc in the range of 1.3·Bi.P·glyce'a'o
80- 100 mg/dl (80-100 mg%), tile intracellular lev- j (7)
els rail to less Ihal 1 mg%. Sugar is lhen "spared"
3·P-glyCe,ate
for use by neuTOns and other cells that must have it
(8)
all the lime.
When a meal is eaten and the blood glucose levels Z·P-glyce,alu
rise. the beta cells of the pancreatic islets release in-
sulin. Some of it travels via the bloodstream to the I"
P·EnoIpyrwate
s keletal muscle, where it ·'lifts the barrier"· The 1(10)
muscle cells then la kc up glucose rapidly. and thcy
L_Pyruvale
put it 10 good usc. At the same lime. Ihe uptake sub-
stantially reduces thc dangers of dcvcl<)fling post- Fig. 5-2. GI";OOIytie poth_y . ( T) H. xOl< ......: AlP -
prandial (after·meal) hyperglyccmia. because thc ADP + Pi. (2) PI>ospI1oMxose ;"0(_ _ • (3)
mass of the muscle is so greal. Phosphof,uctOl< ...... , AlP - AOP + Pi. ( .. ) A_se.
Under IIOTmal condhloos. the glucose Is phospho- t b) r,IOIl4'I ,_u.. t tI)
rylated as rapidly as it emers. The hexokinase reac- oehydIogena .. : NAD - NADH. + W + Pi. - HOH. ( 7)
tion irreversible under in vivo conditions. and the ADP - ATIl. (8)
glucose phO:sphate that is formed is retained within PhospI>oglyce'o<oo" .... (9) 10",,1... : - rtOH. ( 10)
Pyruvate k ina..: ADP _ Al P.
the cell.

Hexokinase
Glucose + ATP
Glucose-6-phO$phate + AD P The glucose-phosphate is then uscd in several
ways (Fig. 5-1). Much of;1 goes inlO glycolysis. The
energy trapped each time a molecule of glucose is
converted to twn of pyruvate permits the formation
Gt""""" in biood of just tWO ATP from tWO A DP (Fig. 5·2). Howe"" r.

I MU$de glycogen the pyruvate can be made into acetyl coenzymc A

/ (acctyl.(:oA). Trieaholxy lic aeid cycle enzymes and

mitochondrial dectrnn transport chains then provide
for the acquisitinn of vcry substantial quantit ics of

t
Gluco ...·6·pho<;phate
(NADP _ NADPH)
- - - Py'''''.'e
1_'- - (AOP _ ATPj
P"""", .. 'uga's
AT P energy.
Smaller amounts of pyruvate are used 10 makc al.
anine and olhcr amino acids (52) (Fig. 5·3). while
some acctyl·CoA goes into lipid syn thesis.
Cells have limited abili ly to store ATP. However.
muscle has crealinc. which functions as a "sronge··
to ·'soa k up'· some of the ene rgy. It Can later be
·'.<qucc7.cd·· ,,·hen muscle contraction rapid ly con_
the ATP \0 AD P.
Creatine + ATP _ Crealinc-P + ADP
 "1 ",
,
0- 0 • ,
HC-NH,
Resling muscles abundantly with glucose
also Slore glycogen reserves. They additionally send
SQmc glu= imo the hex()SC monophosphalc path·
way (H MP, JlCnlOSC shum) (Fig. 5-4) thaI pro.ides
fivc-carhon sugars and NADPH for anabolic
reactions.
In addition \0 facilitating gluoosc uptake. insulin
induces he xokinase and slycogcn synthase, and it
augments the activities of preexisting .n>-}'mcs in-
volved in glywlysi', glycogenesis and lipogenesis. It
also accelerates conversion of p)'ruvatc to acetyl-
CoA and the use of glu= in the HMP.
INSULIN REGULATION OF CARBOHYDRATE
METABOLISM IN LIVER
G lucose is flOt an imlX'nanl fuel for hcpatocylcs.
When the supply is abundant. mOSI of the sugar is
converted to glycogen. During times of fasting. the
glycogen is degraded, and the glucose derived from
it is released to the bloodstream for use by other
cells.
The livcr "knows" whcn it should Stor<: glycogcn
because of Ihc special feature, of ils circulalory sys-
lem. During limes of meal absorption , the hepalic
porlal vessels deliver very large quamilies of the
sugar, along wilh insulin roleascd from Ihc pan·
creatic islets. The hormone accderatcs glucose phos-
phorylation and glycogen synthcsis. It also inhibit'
glycogenolysis. In addition to facilitating storage of
carbohydrate reserves for future usc, the actions of
insulin provide protcction against Ihe development
of postprandial h)'pcrglycemia
During times of fasling. gastrointestinal cells ex-
traci some sugar from the blood sent into Ihe hepalic
porlal vC&Sels, and the glucose concenlrations Iher<:
are actually lower than Ihe ones in peripheral arlcr·
NAOP · . HOt1
_
------,"""',,' ..,,..,,'--------
Gl"""",,·t>P dehydrogenase
6-P·GluCOolate . NAOP '
0.=====
Ftg. 5-4. Fa"".tion ot NAOPH a nd _p/lospIIo.le r,,,,,,
gloco06-6-phO'-I,Mle.
" HOM
Fig . 5 ·3. Co<Ivorslon of py,,,,oto to
. 1.......
ies. Al the same time, insulin scc retion decline"
while glucagon secretion is stimulated. The liver
then releases carbohydrale 10 Ihe hepalic ""ins.
The rapid exchanges of glucose are facilitaled by
Ihe suslained high perm.abilities of the plasma
membranes. There is no need for hormonal accder-
ation of glucose transport in either direction: and in-
suHn docs not affecI those processe., in the liver.
(Some f,ne controls are. however, exerled by Olher
rcgulalol'$. For example. more glucose leaves thc
liver afler meals in subjects who have recently ex-
ercised than in rested subjects r130).)
Although they use mostly fally acid fuel , (83), he·
palocytes need small quantilies of glucose for other
purposes. Their glycolytic pathways supply inter_
mediales for lipid and their HM P en·
1.ymes prov ide NADPH and pcmQSe sugars.
ADIPOSE TISSUE CONTRIBUTIONS TO
GLUCOSE HOMEOSTASIS
In common w,th re,ting muscle. adipose tissue has
insulin-regulated plasma membrane barriers and
"flexible" requirements for glucose. When nutrients
are abundant. gluCO$C is used 10 ma ke triaeylglyc-
crols (falS). Insulin then accelerates uptake,
glucose phosphorylation. and some of the SICPS in the
anabolic path,,'a}"!;. Glucose upta ke by adipocytes
provides a third mechanism for averting p<l$lpran.
dial hyperglyC<!mia.
During limes of fasting, insulin and glucose levels
are low. The plasma membrane barrier restricts glu-
cose cntl)'. Fats are Ihcn degraded to fatty acids and
glycerol. and the products aT<: releascd to the blood-
'Iream for use by other cell Iypes.
The me<;hanisms whereby insulin integrates the
functions of skeletal musele, adip<l$e tissue and liver
• 6.P_GlUWfl31<l + NAOPH . H'
'" THE PIINCREAS

Ta ble 5-1 MjusI""">tS ......... s...o6on and eorbo/>yd-.,.l.\@tOboIism",5I<..."..M..,.., A<!WrJo .. T,""", and U- Nt
ConIrOblJ!<I to M:W>t .... """, ot Bioo<I ,"""",0. eoo<>Oi,I .. otiona Roquired by -..on.

Food intak< No from ,., Suppii«

,,,,. Iin «<,.,"" Inhi bi«d

low _0'1. 1 ""go: o)'f'OIl)'ccmi •• ..,;0«1 lIiSh "", ...1 "' "80:
in part ,i.
m«h.ni,m. cilN 001"", • .,oided ;" po"
vi. m«"ni. "", <',cd ..1ow

Sk,letal ","",k Bo,n« '0 <."y: l 'OCO« ", pam!" ,,,,,.'i, lif" 1>;0";,,, tlu,,,,,, <"'f)'
ro< "s< by "0"""'" pr<,",", ly >lored ""cr. ' )'n,k<>;,cd
m. ..<I
pI ..
,Iy<o&c" ' Ur>!">f" """".«ion . tot«! ['" I.,,," ..
Banier to , 1Il00>< <""yo , I. "",", ",,,,,,cd" In"'lin lifl. banier: 110""" '""1
(or UK by ",,"roni; fat !OW," pi .... > t'u"""" ro"
o>".",ds rat . )'nlh"i<: latty oc;d, . )'nth«i"d . .. , (0«<1 (or
p<O'IiO< r.d for mo><k>; il)'cerol ","I I.te, us<
10 1;><, for ,Iuoo>< . )'nlhe,;,

Liv<r V"Y liule l lo"""" "ien ur boca.", <II lor.. of glo«>« "ke.
10... pl •• .,. "",",en".,".n>; low ;",.I i" .p ""co.", of hic k
k ,·d . J><'m;' 11)""Il" <I<, ,.d,,;o...<I 1;Qn«""..ion< in 1",,,. 1
I I."""" • y., h.. 11"0<»< '" I.... d 10 """,I" prole<" .",in"
m.i."i. pl.,m. """".""ion. hyper, I)",<m;a: ,I)",,,,,,.
. "..'"
. )-.,h<>i=l.nd >I""d f",

cells to averl 'oolh postprandial hyperglycemia and
faSling hYP<lgiycemia are summarized in Table 5-l.
The innuences exerted on mu,de cdl piasma mem-
branes make major contributions to protecli""
against hyperglycemia because Ihe uptake is rapid
and the muscle mass is very great. The ones on gl)·.
cogen synthesis in the liver are the most imporlant
for accumulation of (he carbohydrate reserves used
by neurons during times of fasting. while (he ac<:el-
eration of fat ,yn(hesi! in adipose tissue assures that
alternale fuds will be stored for later use by ··glu-
cose-iparing" cells_
INSULIN AND GLUCOSE REGULATION OF
LIPOGENESIS
Although adipocyles stOre some glycogen and have
glycolytic, tricarboxylic acid. and hexose mOl>C>phos-
phate path,,·ay enzymes similar to the one>; described
for muscle. glucose metabolism in the cells is closely
linked with lipid metabolism .
Adipocytes con(inuously engage in lipolysis (fat
breakdown) and lipogenesis (fat synthesis). The nu·
tritional status determines which of the pathways
predominates at any given time . Fat stores are built
up when nutrients are abundant and insulin is sO?
ereled, and Ih. reserveS are rolinquishcd during
times of fasting.
Triglyceride lipases ca(alYle the first step of an
overall process that culminates in the complete hy-
dro!ysis of the fal molecules. (Other eel! (ypes have
similar enzymes. but they are used mos(ly for inte r-
nal functions.)
Lipase
Triacylglyccrol + J HOH
(fat)
J Fatt y acid + Glycerol
MOSI of the glycerol diffuses out of the cells and
!ravels to (he liver. It is (he only prodUct of fat hy-
drolysis that can be used (0 make glucose_ Glycerol
can also enter into the formation of hepatic lipids, or
be metabolized to yield energy for ATP synlhesis_
The rate at which glycerol leaves Ihe adipocyles pro-
vides a measure of triglyceride lipase activity.
During limes of faSli ng. much of the fally acid
also exits. 11 combines with plasma alhumin and
journeys with i( 10 Olher parts of the body. Some is
directly laken up by other cells and used in various
ways that include incorporation into phospholipids_ Thus . glucose ntetaoolism promotes the biosyn-
Since the molecules are almost all of the long-<.:hain thesis of fats from falty acids in three obvious ways:
saluraled or mono-unsalurated varieties (stearic, 1. It provides the ATP for activalion of the fally
palmilic, oleic, and palmiloleic), Ihcy are !lO1 suila- acids
ble for direcl usc by man)' cell types_ The liver lakes 2. It provides Ihe
Ihcm up rapidly, converls Ihem 10 shorler-<:hained precursor of glyccrol-3·phosphalc
moloculos, and releases products Ihal arc more easily 3. II provides Ihe NAPH for Ihe glycerophos-
oxidized. phate dehydrogenase reaction
When nutrients are abundant. mosl of Ihc fally In addition 10 supplying Ihe glucose by acting on
acids a rC relained in adipose tissue. and similar mol- the transport mechanisms, insulin ac""leratcs Ihe
ecules arc additionally taken up al thaI lime from formation of ATp. NAOH . phos-
the blood. phale, and acetyl-CoA. It also activate, whatever
The palhways for biosynthesis of large molecules glycerol kinase is present (134).
always differ from Ihose in degradation, and
they invariably require suoolantial atllOunlS of en- A form of gc"",i. obe'ity in roden .. ,.,u lls from the
combined effoct' of too much of the en,)"",o and hyper.
ergy 10 drive the reaClions. in, ulinemi •. The animals make targe q".n,ili .. of rats
In order for lipogenesis 10 be accomplished. each (31 Ihc .'pen", of body prllt.inll. ",en .. hen 'heir food
of the fany acids must first be "activatod." in,.ke. are limi'ed 10 Ihe amounts con,umed by nonobcsc
Fanyacid conlrol., (16).
activating enzyme A!lOther major innuenec of in<ulin is inhibilion of
3 R-COOI-I + 3 ATP + 3 CoA • a hormone-scmili"e triglyceride lipase. In hormone
Fallyacids defidency Slatcs. tho fat sloros arc deplct«l. This
3 R·C().CoA + 3 AMP + 3 pop limils the fue! supply for use during the intervals be-
"Activated" fally Iween meals. and onc consequence is increased de-
acyJ.cocnzyme A .truction of body proleins. The ability to adjust to
cold environmental temperalures is also impaired,
Glyccrol-3-phosphate (rather than glycerol) is partly because of loss of natural in,ulation. but
nccded to initiate the synthesis. The overall pathway moslly because of decreased ability of the cmedol-
in which it is used can be summariz«l as follows:
3 Faoty-Acyl-Co.A • Glyte,ol-3-P Tho release of large quantilies of free fally acids
• 4HOH
into the bloodstream. combined with impaired abil-
ily 10 take up and use fally acids from other «Iurces.
The Ii""r conlains considerable glyctrok;nau ac- crcates dilTerent kinds of problems. High fally add
tivity Ihat permits il to directly make glycerol-3_ concenlrations aggravale Ihe existing impairment of
phosphale from glycerol. glucose uplake by aCling direclly on Ihe plasma
membranes. (Artificial elcvation of Ihe concentra-
tions antagoni7.<:s Ihc elTcclS of in,ulin. even when
Adipocytcs have limited quantities of the enzyme. the endocrine system is functioning normally.)
They musl therefore derive mOSt of the glycerol-)- P There are, however. even more dire consequenccs
from glucose melaoo\ism. The that arc wilh the central role of the liver in
phosphate ob laine<.! when fructose 1.6-biphosphate is the regulation of lipid melabolism.
cleaved (Fig. 5-2) thcn reacts with NAOH (also ob-
tained during glycolysis).
INSULIN DEFICIENCY LEADS TO THE
DEVELOPMENT OF KETOSIS AND ACIDOSIS
"I Hepatic enzymes converl large quantities of long-
c =o G')'C<l'<)f>/>:>SpI\"o chain fally acids 10 shorl-<:hain fatly acids via reae-
HCI - OPO'!-h NAD+l .,. W .. tions that release successive lwo-caroon fragments in
Ihe form of acctyl-CoA (Fig. S-S)_ Under normal
"
();hydroxya<:elon. Phospllote condi tions, most of the shortened molecules 3re re-
leased inlo the bloodstream, while the acctyl-CoA is
"
HC - OH
I
eilher oxidized in the liver Or is use<.! to make other
lipids.
HC - OH Skeletal musele continuously uscs the short-<.:hain
I
HC - OPO,H, • NAO ' fatty acids for fuol. and it becomes especially depen-
dent On them when Ihe glucose levels are 10w;Sxccp_1
Gtyr;e'ol-3·Pho.pMle undu cardiac musele
". ENDOCRINE PAI-ICREAS

Ii Ii Ii Ii Ii Ii Ii Ii H Ii Ii 11 Ii H H@
HC - C - C- C - C - C-C- C-C-C - C - c - C - C - c - C - Coll
HHHHHHHHHHHHHHHg

t
HHHHHHHHHHHHH@
--==-----'=-=-=---- -
NAO' FAD CoIl H,o Acetyl·eoA
NAOH . H'
FAOH,

HHHH H HHI1HHHHHg

___c"c'"='-_C'_,=,'------''''''
:::_-'',''''''_• ___ _ Acelyl.coA
•
FADH,

HHHHHHHHHHH@
HC-C - C- C - C- C- C- C-C - C- C- C- CoA
HHHHHHHHHHH "
o
.l __c":·:'C'_ --",-·o,_ _"OOw,'-------'"""'''--____ _ , GAcot;'.CoA
J" FADH,
" , "
HC - C - C - C-Co.o.
Ii H H II

l 0
1----------- -- Ace:j1-CoA

.
, .
HC - C - CoA

o
(ACeO)'l.CoII_' _ _ _ _ __
_____ • ChoIe.'ero! synthesis

F.ttyacO:l
syntllesis

"preferentially" uscs this form of fuel even when Iyrau . Or irreversibly dccarboxylated to aN'IOfIf. The
is abundant . Th. o.idat ion of Ih. molec ules lerm (ke tonemia) designales the aceumula·
to COl + HP pace with the rate of lion of exee",h·. quantilles of such molecules in the
their delivery from the liver. blood.
When the hepatic enzymes are presented with ex- Sinee it is volatilc. some acetone is excreted by the
cessive quantities of long-chain fatty acids. they pro- lungs. It imparts a '"flu;ty·· odor to the breath.
duce more molecules and more acetyl· The accumulat ion of acetoacetate and of p -OH.
CoA than can be diroctly used
poses. (This oc<:urs not only:,
'0; butyrate has several serious (a) Since
Ihe molecules are acids. they directly lower blood
slates. but also when pH. In Ihis way alone. they can invoke sufficient aci·
plelcs the sources of dosis to impair brain funClions . (b) These s mall.
lism beoomcsslrongly wate r-soluble molecules arc rapid ly cxcreled into the
I urine. They Ihcreby draw large volu mes of wa ter
ones it from the body. and the resulting dehydration is of
Much made into greater magnitude than the problems associated
ketones (Fig. 5-6). A celO<1Ulate is the firsl one with hyperglyccmi a_ Unfortunately. Ihe clTeels on
formed. It ,an be reversibly converted 10 {j·ON·bu· watc r balance a rc additive in patients wilh unCOn'
trolled diabetes mellitus. (c) TIle NaHCO,: H HCO,
ratio is a major determinant of the blood pH. In ad-
dition to dire<:tly furnishing the hydrogen ions to el-
evate the denominator. acetoacetate and {J-OH·bu-
tyrat. carry away ions. since they are
excreted as sodium salts. The acidQS;s and dehydra-
tion are major contributo,"" to the onset of diabel;c
coma .
Allempts have been made to apply Ihe observa-
tions to Ihe lrealment of gross obesity. It was as·
sumed that fast ing can markedly accelerate lipolysis
and 1= of kelones. and si multaneously abolish the
stimuli for insulin secretion. Therefore . fa t synthesis
as "'ell as degradation are affected _ It was also be-
lieved that protection against the development ()f
acidosis and dehydrali()n could be provided. More-
over. it W3$ Slated that brain [unctions c()uld be
maintained for the following reasons:
Previously well·fed subjects accumulate substan·
tial quantities of aceloacetate. but very ]illie I1-OH·
butyrate when Ihey are fasted. \-Iowever.long-Ierm
food deprivation (stafl/ation) invokes up to IO-fold
elevations of the 11·0H·butyrate level s. The brains of
experimental animals metabolize Ihal acid. and it
has been claimed that stafl/ing humans "learn" 10
substitute the /t-OH-butyrate for glucose. It has fur·
thcr been proposed that Ihe brains of well·fed sub-
jects would use such molecules if they were provided
in substantial quantities by blood plasma Ihat also
contained adequate glucose_
Accordingly. patients have been subjected 10 re-
gimes that involve ingesting II()\hing bUI water. vi-
lamins. and minerals for weeks or months al a lime.
Proponents of Ihe starvation methoo for reducing
body weight state that Ihe patients "feci well'" and
soon lose interest in food _This is difficult to roconcile

2 "
.
I-tC - C - CoA
" o

•
"
",..11><"
I-IC - C- C-C - CoA
o 0
AcetC><>C<l¥-COA

o
•
C -0><
•
• ."""
, Acelyl-COII

" "'", "

H C-C - C-CoA
" oI " 3- jJ -01-1 -3-methylglutaryl. CoA
IHMG.CoA) _ Cl>clestctol

"""
><C-C-C-COO
" oI "
"
'"
with reports by hospital pcrson"ci (hat such individ-
uals display "bil.arre. paranoid. and be-
havior or bcoomc extremely apa thetic. and thai mOl'll
oomplain of continuous preoccupation with rOC<!
both du ring waking and dreaming_ There arc good
reasons \0 suspect that brain usc of /J-OH·htyratc
represents an adaptation in which suboptimal ncu-
ronal functions arc accepted in the interests (If pro.
longing survi val.
Long_range Sludies indicate that the W<'ight 1= i.
no more rapid than when 500-600 food caloriC!; pcr
day are ta ken. and thai i1 is promptly regained after
lhe fast is terminaled. M=vcr, there is consider.
able iO)Sl; of body prolein (used to provide $Orne glu·
and prolonged food deprivation ca rries with ;1
the danger! of developing hepaiic dysfunctions, ane-
mia, cardiac arrhythmias. and other disorders that
are superimp::.sed on the melaoolie acidosis (12).
The Concept That "Ca lories Don 't Count"
II has been ad",,,,ated Ihal individual. who wi,h losafely
.nd rapidly to.c weight sllould take diet< high in fat bUI
seve,ely remioled in carbohydrale. Pre,umably. Ihen ,
Ihey will deplete body fat by ,uppr."ing in,ulin =re-
lion, inle,fering wilh lipogenesi., and I",inll polenlio l en·
• molecule. in the form of urin.f)' kelone._
Some furthe, in.ist IhOl "polyunsalurated" fally acid
,uppiclrK'nt' aid in "fat mobil i7.ation. " (Ther. are indio
calion. Ihal arachidonale Illenuales the 'limulalO!)' in-
on fat.ynthesis th.t .,.., ..en when .. 'mal. pre-
viously deprived of carbohydrate .re given some ,ug"
1223).)
The concepl. are appealinllto lbose wilh • fondne ... f",
rich foods of the kind' Ihal ar¢ "forbidden" on Ihe usual
low..:al",;. dieu. Moreover. the inge5lion of fal' pro-
moteS Ihe rde.se of ga$lrointestinal hormones Ihat re·
duce ll"'lrointe'tinal motility ond may contribute 10 a
.. nSe of " .. titty." In addition, aimOSI new Concepl
for weil\ht control is greeted with g,..,.t (if ev.nescent)
enthusiasm.
Som. weitht is. in fact. u,ually l""t at first. The mild
kelosis dra"" ,,'.Ic, from III< body. while Ihe restriclion<
on intake I.... n the inge.tion of ' Ia",hy
.naol«. • weel dO$$Crt •• and lhe kind. of fally food. Ihat
are seldom ta k.n wilhout (e.g. salad dress·
ings and bunor). Commonly, ><>m. nausea and gamoln.
te.tinal discomfort contribute to the reduction of food
inta ke.
On a k'"8· .. nge basi$, the diets .rc both ;""ffoctive
and dangeroos. Hurr..ns ·.vith IIOrmal endocrine gland. do
not ",erele more Ihan 100 food Calorie equivaion" .. ke-
IOnes. even when ta king carboh}'drale-poor food (75),
(On usual dielS. they exOrelc .round 0.1 g pcr day. Thi$
can rise to 20 g. although it approache, 100 g in palien"
with severe, unlreated diall<les mellitu •. ) When ketones
accumulate in til< blood. the high levels .ugment the ac·
tivities of hep"tie proleirHiegrading enzymes,
THE ENDOCRINE PANCREAS
Indi vidualo diffe' in their "'pOnKS to high.fot die\>.
Some break down la'ile quantities of body prolein. and
they usc Ihe gluoose they deri.e 10 support fat .yntt.c.is.
Thi, cln occur even when the food;, protdn·rich , Otll<rs
develOp mOre se •• ,.., ketosis and acidosis.• Iong "';Ih
headache. we.kness. fatigue Ind gastrointestinal dislress,
The diel' are also counle rproductive. ,inc, corbohydratc
deprivation lend. to reduce the conversion of Ihyroxine 10
triiodothyronine and to thereby depress thc
rale. Forlunately. mosl usc.. roon "cheat" on the diets
and Ihereby a.oid the " -0Th1 of lhe pOlential
con .. qu.n ....
A wc.lth of firm evidenet .upporl' the COrIC.pllhal the
intake is the major determinanl of the balallCC 11<.
tween fal .)"nlhesi. and f.1 degradati<.>n, and th.t high
carbohydrate diet. of remictcl calor ic conlenl arc jusl
a. effective fo, "'oighl loss ., ones conlaining limited
quantiti •• of sugars (I 2.84).
INSULIN REGULATION OF FATTY ACID
BIOSYNTHESIS
Carbohydrale·rich die" accelcrate thc synlhesis of
fally acids from a.etyl-CoA tx.eause they pro. ide
the substrate , the energy ""mces. mosl of the
aCli.alO", They also stimulale irt5u lin secre-
t ion. and thai hormone acts at transcripli<.>nal. trans·
laliona! and p<)Sllranslalional levels .
kinds of fotty acids. In hu
manS and many other species. the liver is Ihc major
sile for produClion of molecules Ihat are
raled into Ihe slorage depol IriacylglycieroJ., Adi·
poeylcs of rats. mice. and several other species ma ke
subslan lial amounlS of thc faUy acids. but Ihese an·
imals al"" utilizc lipids produced in Ihc her,
Most of the fally acid mole.:u lcs madc in Ihe liver
and destined ror export are incorporated inlo
prolein complexes. especially OneS of Ihe very low
den<ity (VL DL) type . Thc partides are then re-
leased to the bloodstream. VLDl5 contain subst:m·
1;31 qUanlities of triacylglycerides, along with
proteins synthesized in the liver. and some
phospholipids and cholesterol (40). Lipoprotein Ii·
pases of the vascular system free some of the rauy
acids ror uptake by many cell types. Insulin activates
the phosphol ipases.
Adipoeytes additionally use d ietary lipids. Food
rich in $aturate<! fany acids slows endogenous pra-
duetion. since pa lmi tyl-CoA and other long..:hain
fally acyl·CoAs depress acetyl-CoA carboxylase ac-
tivity. They a rc bdieved to do SO by promoling de-
polymerization of Ihe la rge complexes , Insulin Ie ....
cns the inhibition by direcling the fatty
metabolites into palhways leading 10 produelion of
triaeylglycerols (14.223.228). Mosl dietary lipi ds
undergo preliminary processing before they gel 1<>
the liver and peripheral tissues. Intestinal cells in·
corporate the fally acids into chylomicrons and
Vl Dls and deliver the products to the lymphatic
vessels. From there. the particles enter the circulat-
ing blood. The liver takes up some of them and uses
Ihe components to make VlDls of different COm·
position ( 196). h also takes up chylomicron and
VlDl "remnants" (part ides lefl Over after Ihe Ii-
pases have acted on them). Additionally. hepalo-
cytes synthesize and secrete the albumins Ihal bind
and Iransport circulaling fally ac ids.
Under mosl oondilions. Ihc ralc-limiling Slep in
falty acid biosymhesis is Ihe formalion of malonyl-
Co-A:
Acelyl-CoA + HCO,
+ A TP - Malonyl·CoA + ADP + P;
The reaction is catalyzed by a highly complex en-
1.ynte known oollectively as aITly/-CoA ca,...
boxylase. Biotin is an essential c()-factOl".
Thc enzyme is ntade 'up of subunits wilh molec u-
lar weighls of 225.000. Dimeric forms have SOme ac-
livily. whereas monomers do not. AClivily sec ms 10
be controlled to some extcnl by phosphj)r)'lalions
ealalyzed by several kinase •. and by dephosphoryl_
alions; bUI local concentralions of cilrale alkl ;.orne
other low molecular weighl substances arc believed
to be more important.
Insulin activates preexisting enzyme in sevcral
ways. and il provides subslrates and sources.
11 is also Ihe major inducer involved in long-Ierm ad-
aplalions 10 carbohydrale-rich diets. 0"" componenl
of Ihe aClivalion mechanism$ may be mediated by
Ihe phosphoprotein phosphalase-l thaI was dis-
cussed in Chapter 4. However, the hormone addi-
lionally calalyzed phosphorylation$ al Olher sites on
Ihe molecules (224A).
CilratC.OO is<>citra,. are produced in mit<>chondfi' by
Ihe tricarboxylic acid cyde enzymes , They aClivale Ihe
om.ymc by pf<>m01ing its polymefi",tion to f,l,me nIOU '
fOfms Ihal weigh 5 10 10 million daltons (21St\),
Insulin can subs,anlially i""rease hepa,ic prodUClion of
cilrale in spet ial ways (150), (lIS effects in adipose lissue
are . !>owever. variable . • nd tbe hormone can even lower
Ihe concenlralions in s\:.elelol musclc.)
The hOfmooe induC¢' and • .,iva,e$ mali<
which calalyzes Ibe reaclion .bown below. Insulin also
provides the NADPH .
Pyruv.te + CO, + NADPH
+ H' _ Malate + NADPH
Tbe malate is fOfmed in Ihe cylopla,m. It Orl)$," Ihe
milochondriol membrane. and Ihe 1,,"'0 reaclion. ,h.,
fol-
low COnvert it to eitralc;
m.l.,.
dehydrogenase
Malale + NADP' , ' O •• loacol.le
+ NADPH + II '
Oxal03eelale +
condensing
en'.ymc
+ HOft Ci,ralO + CoA
The citrale Ihen leave, Ihe mi'ochond,ion a nd aCcu_
mul.'e$ in the cylopla,m. Only somc i, "".ded 10 oCli.ale
Ihc en'.y me, Insulin aOO "u,ricnl' acoolerote. reaction
e.. aly,o<I by (citric cleo.age cn 'YOle) Ihat
pfovide, aOOlyl_CoA:
CiI"'le + ATP + CoA - Aeely t·CoA
+ oulMec,.te + ADP + P;
Insulin .Iso induct, Ihe enzyme, and il p","idcs f<>r Ihc
produclion of ATP. Tbe ace,yl-Co servCS a, an aCliva'or
a, wdl as a , ubslra'c fOf th.1 reaclion.
Somc of Ihe 51imulol",), cffecls of ;"sulin can be mim_
icked by provid ing large qu.nlilies of ,ubslralc (1681.
Fructose i. an exccllcnt source of acelyl-CoA when il i,
presenlcd direclly 10 hepalocY'e5. It also or",ses .dip<>-
ey'e plasma membranes when low iRSulin I«'el' restrkl
glucose up,ake.
A tally .cid synlh.se (,ynlheto.. ) comple. pmmoles
"ansfel'S of .celyl and malonyl group< '0 aC),1 c.rr ier pro-
lein •. and. condens.a'ion ",.c,ion fc,ullS in Ihe fOrm"lion
of ..etoocelyl-ACP.
Acetyl_AC P + Malooyl_ACP - Acc'0300\), I-ACP
+ CO, + CoA + ACP
The four-carbon dedval;"c Ihen undertlocs roaclions
requiring ATP and NADPH Ihat prep.",;1 for ,ucccs·
<j", tw<>-c.rhn" "'"'"V';"", n"",.11 1'-" h,,·.y for ,yo_
Ihesi'ing palmila'e can be $ummari'.cd a. follow",
8 Aco'yl_CoA + 14NA DPH + 14H ' +7ATP
+ HOI-! - Palmitale + 8CoA + 14 NADP '
+ 7 ADP +7 P,
Insulin i, . m.jQf de'erminanlof Ihe rate of NADPlI
produclion. In well-nourished ralS, up '0 30% of .dipos<
tissue glucose is se nl inlO Ihe H M P. Glucoso-6-phosphale
dehydrogeno .. levels fall,harp!y in fa"cd .n imals. Thcy
can be devoted as much •• 1900% over lhe b• .,IIe.d,
aftcr fcfecdina (168),
INSULIN REGULATION OF CHOLESTEROL
BIOSYNTHESIS
Choleslerol is an essential constituent of cell mem-
branes and a major determinant of their fluidity. It
is the precursor of vitamin D and 'teroids hormones.
and of Ihe hile salts that arc needed for the absorp-
lion of fally acid,. fat-soluble vitamins. and OIher di-
clary lipids. It is present in free form in the bile.
where il funelions as a lubricant (213). While it is
indiSl"'nsable for survival, eholeslerol is also a major
componenl of alherosclerotic plaques and of SOme
kinds of gallstones (74A).
The liver plays key roles in cholesterol metabo-
lism. It .ynlhesizes the lipid from acetyl-CoA for use
by Olher 0011. , [I also ta kes up cholesterol from Ihe

bl(>(>(btr<:am. uses some of il for spc<:ial purposes.
and degrades or excretes the remainder.
Under roormal condilions. something like 80% of
hepatic cholestcrol goes into the manufacture of bile
salts. The huma n adult produces around 0.5 g daily.
C(lnjugales the salts wilh taurine Or glycine. and
sends them t(> the gall bladder for Storage. COnCen·
tration, and subsequent discharge into the duo.
denum (91). Substantial quantities arc returned to
liver wilen the lipids are absorbed. but Ihere is
also limited. regularly recurring excretion wilh
feces. Around 0.8-1.2 g of free cholesterol also en-
ters the bile (74A), and much of this is SOOn ex·
creted. Loss via the gastrointestinal tract protects
against c,ccssive accumulation of eholeslerol in the
bloodstream and in the tiSl;ues .
The diets of carnivores and omnivores often con-
tain considerable quantities of free and esterified
cholesterol. Intestinal celli have eholesteryl esler·
ascs. and they package free chole,'terol inlO chylo-
microns and VLDLs. The liver up some of
lOOse particles from the blood. and it al50 gets
choleslerol from circulating high density lipopro-
leim (HDLs), chylomicron remnants. and VLDL
remnants.
Intestinal uptake of die ta ry cholestcrol is incom·
plete. and in mOSt mammals thc percentage "b-
"",b<:J val i"" >ely wiill III" !cvd in the fOCld. Ao-
cording to somc observers. Ihe plasma cholestcrol
concentrations of healthy humans rise in parallel
with the dietary coment of that lipid when the food
contains small to moderale amounts. but maximal
blood levels are attained when 400-500 ms/day arc
ingested (74Al. However. othcr componems of the
diet alfcctlhe intestinal processes. and the blood lev-
els arc affccted by additional factors (74A). For ex-
ample. VLDL eholeslerol is transferred to low den-
sily lipoproteins (I-DL.). and many eelllypes take
up LDL cholesterol. They also give up eXcess
lesterolto H Dls. There are large individual varia-
lions in cholesterol absorption and metabolism
(131). Some subjects maintain normocholesterole-
mia when Ihcy cat heavily enriched food. Olhers de-
velop and sustain much hiS her levels when are
on restricted diets. In eontTast with humans. in
which tile levels ra rely rise above 300 mg/dl in in_
dividua ls free of cenain relatively rare genelic dis·
orders. rabbits arc among thc sp«ies Ihat develop
truly severe hypercholeslerolemia when they arc fed
very large quantities. ( It is probably worlh noting
thai the nalural diet of the rabbit contains very lillie
of the lipid.)
Most of the chOlesterol releascd from the liver is
imo lipoprotein particles. bul some eholes·
teryl eslers 3150 enter the bloodstream. 1.ow density
Tl-lE ENDOCRINE f>A NCRl':A$
lipoproteins (t Ols) are the major carriers in
mans and many other mammals.
Cholesterol Bi osynthe sis
The liver can synthesize enough cholesterol 10 salisfy
body requirements when the diet does not supply any
of the lipid. In humans eating ordinary foods. endog·
enous produclion often provides 80% of the 100ai
amount usc<i. The precursors are always available \0
well-nourished subjects. since all 27 of the carbons
arc derived from acetyl..coA. Some of Ihe interme-
diates in the melabolic pathway are shown in Fig.
5-7.
The synthesis begins with the formallon of 3{J-
hydroxy.J.melhylgl utaryl..coA (liMG·CoA). This
part of pathway resembles Ihe one deseribed for
ketogenesis. bul il utili7.cs enzymes associaled with
the e ndoplasmic retiCulum.
The ne xt step is catalyzed by liMG·CoA
reductase'
IiMG·CoA + 2 NAOPH + 2H' - Mevalonate
+2NADP' +CoA
Th is is the major control Sile for cholesterol bio-
synthesis. since both the act ivity and the production
of the en7.yme are monitored in several ways.
,ellulali"" i. via
phorylation-dephosphorylation rcactiom (8). A
cAMP-dcpendent cascade brings aboul rapid inac-
tivation (Fig. 5-8). The nucleotide directly affects a
HM G..co reductase kina..,..kinase. Thai cnzyme. in
lurn. activates H MG-CoA reduclase kinase. The ki-
nase then cataly1.es the ph(lSphorylalion of Inc
HMG..coA reductase. and it thereby .lhUIS down
NAOPH
'"
ChoIeSielol
Fill. 5·7. Shot! $1_ in the 110lI"l .... lyt-CoA 10
0 _1",<>1.
 A.v<l,n

,, ,, -
i n7iP>

I
kinase _'--_ R"""Clase kinase·P·
,, ,,
,,
_ ___ ' - -- ,,
,
HMGCoA I.......... • • ___ ,. fiMG.CoA reducIase-P I
,

I - -.-- _' -
INSULIN

5·S. 5t>orI'I"" 01 HMG.coA IflduCl...

ldMty, p. Iorm, • MIh«> lor ... , - .
S _.;or" " . _;or"

mcvalonatc production. One Of more plloo:tiphoprolcin
opposes the: cffects by calal Y7jng de--
phosphorylalioN lhat direclly activale Ihe HMG·
CoA reductase and inactiV"Jte the roouclas.c kiM >e,
The phosphalase 2C cited in Chuptcr 4 mu)" be Ihc
m..jar regulalor of Ihis I)"pe. The cells also contain a
phosphalase inhibitor thai is activated by cAMP.
mediated pl>a!.phorylalion.
When presenl in high
or of iUi metabolilC$ can activa tc the: cll.M p·rcg·
Ulalcd cascade. In rats. the effects haY(: bttn denr
wilhin 1 hour afler a meal f;OflIa'n'ng 2%
eholeslerol. and within just 20 minules afte r a pharo
maC()logieal agent (mevalonolaelonc) is admin's--
teredo Phosphoprotein phospl1atascs can rapidly re·
y(:1'IC the early etTecls of choles!crollooding.
II. second phase of inhibilion ..... hic h begins 2 bours
afler a cholesterol meal (and I bour after mevalon·
oIaelone). is allribulcd 10 a different kind of cn>:yme
inaetivalion. It not oppQIICd b)' phos.phatMCS. The
mechanisms arc Evidently. Ihey do not i....
voIve Iov."(r;ng of the cdlular coo«ntraiion
(211.).
A third form of inhibil;"n takes longer to develop.
It is linked "'ilh changes in enlymc levels, and it
probably depends on interfercoct with the synlhesis
of n-c .... enzyme. However. it may additionally involve
facilitation of more rapid degradation.
Theil' a", u...,u!ed conlnM:t"Sics O'ICr 1M chemical na·
lu", of I"" ",P';YC focdboc k rel"lalor. When cholesrcrol
is .dded.o ..."".. 1kind. cell. i. cuit ure. and "'M" il
0(
is perfused .b,oorlb isoIa.ed li"" .... . M ral. of rw;,. c"""
lt$lCroIo)'nIMoi. d.di...... Ho-o"""r. coo"".....,.,.o. me·
laboli,e rnay be ..... uired. In culiured cani .. inteslinal
nluC(ll.l, bile salt. ar. morc pOOcnllnhibiton than cbole.·
I.rol. 7·kelo-<:lIQlc"crol, or 2i-hydro.yc hol."crol. but all
of the pr=dinl .how some "Iivily 163\.
All anima ls seem 10 "lien at leasl some negative
control H1>lG..coA reductase. Dogs
can completely shut (\oo,o'n their llepatie s)'nt1lcsis of
cboleslerol .... lIen Ihey arc fr:d eholesterol-rich diets.
T he H\/(CIS of rats respond prompt I)' and vigorously
10 dietary manipulations. and al$O 10 the administ ra,
lin ot cholcstyramin-c ( .... hich dfilws cholesterol into
the bile) (I %). This partiall)' aC<XIun t$ for tbe abilit),
of rats to maintain 10.... blood level s despite efficient
intestinal absorption. Humans undergo meal· related
circadian variations in biosynlhetie rates. .... hich arc
rdkctr:d in the: changes in plasma eonecntrnlions at
mevalonic acid (1 62).
ClIok>t.roI n n be syn. hor;si,.ed in ... hol"nl ..1"""nlili ••
in I"" inl... i",,; and lip;.! "'1....., rrom 'M'" ""'y make
_ contribulion IQ IIw; circula.ing lev. I•. Some ani mal>
.how poorer melabolic control in .Mn liver
...Iw;n the diet i. nlanipulat.d.
Roln 0 1 Ins ulin
Insulin dir«ll)' aClivates IIM G-CoA re'
ducl ..... evidently by incrcuing pllasphoprotein
pho:sphalase act ivity. It indir«lly contributes to the
,clivOIY by facilitating tM provision or acctyl-CoA.
NAOPH. and AT P. High C(ItIttnlrntlons of oicate
and of othe:r Iong-chain fally acids clio-
'"
I.sterol synth",is. probably by forming esters and
thereby lowering the f= cholesterol concentrations
(81). As discus$Cd carlier. insulin promotes the syn_
thesis of those fally acid"
Insulin also induces the .""ymc. mcr;tly via inOu-
one", exerted on pl'Qlcin _,ymhcsis; and such action'
arc believed to ma ke major to the diur-
nal cholesterol rhythms (38). Moreover. it stimulates
lh. appetite. It can thereby oountcracl1hc inhibitory
effecls of undernutrition On H MG -CcA production .
AI! of the preceding would suggest thai insulin-
deficiency states should be associated wilh subnor.
mal cholesterol production. Howeyer, Wille palients
with inadequately controlled diabetes melli tus have
high plasma concentrations. Many others have val-
ues within the oormal rangc but develop pathologi-
cal conditions thal are associated with hypercholes-
terolemia in individuals producing adequate
quantities of insulin. Evidently. disturbances in cho-
lesterol use (ralher Ihan in ils produClion) prcdomi·
nate in diabetic paticnts. Somc problems with trans-
jXlr! and distribution hu,'c been described (53A).
The high incidence of atherosclerosis is probably ad-
ditionally linkcd with defects in the blood vessel
walls.
Pharmacological Manipulation 01 Chole sterol
MataDOlism
Because of stati51ical associations betwcen high
blood eholC5terollevels and the incidences of alherc>-
sclerosis and myocardial infarction. there has been
considerable interC5t in agents purported to lower
the levels. However. it has not be<:n demonstratcd
that hypercholesterolemia. per se. causes the dam·
age to the vascular system. There arc ind ications
that lesions of the blood vessel walls precede the for·
mation of cholesterol plaquC5. Morcover. the med·
anisms for diS(ributing cholesterol may be more im-
portanl Ihat the total plasma concentrations. HDLs
are beheved to carry into the liver.
and good prog!IQSes ha"e been associated with high
TlItios of IiDL: LDL cholesterol. On tile other hand.
adrenocortical hormone-producing cells of many
mammals obtain much of their cholesterol from
LDLs. Fibroblasts arc among the additiona l extra'
hepatic cell types that have surface re<:eplors for
LDLs. They internalize the particles. and the lipo-
proteins al"<' imjXlrtant negative feedback regulators
of Ii MG-CoA reductase biosynthesis. In at least
some kinds of cells maintained in culture , 25·hy·
droxycholcsterol has greater on lowering
thc cell enzyme content than on direct inhibition of
preexisting HMG-CoA (SIA).
Some plant sterols and their analogs interfere with
THE ENOOCR1NE PANCflEA$
the intestinal ab<orption of dietary cholesterol. but
tncy scem to have limited therapeutic 6-Dc·
mcthylmevinolin (compactin) is a jXltent compctiti"e
inhibitor of I1MG·CoA reductase that Can lower the
total blood cholestcrol, and also the quantities
carried by low density lipoproteins. A re<:ently
described steroid. 5",·Cholest·8( 14 kn·3{J-<lI·1 5-<lne
is rejXlrtcd to additionally elevate the cholesterol
content of HDLs. as it lowers both the amounts
within LDLs and the total plasma content (l90A).
INSULIN REGULATION OF PROTEIN
METABOLISM
Insulin is a major anabolic hormone that is required
for growth and repair. It most obviously stimulates
prolein synthesis by accelerating amino acid uptake
and peptide chain assembly. Its indircet actions arc
essential for supporting thc direct ones. since protein
synthesis can proceed only when there are adequate
supplies of building blocks and energy sources. In-
.ulin facilitates their by sharpening the
appetitc. by diverting amino acids away from deg·
radalivc path ..-a)·s. and by promoting the genernt;on
of AT P. In addition. augments RNA synthe-
sis. and il contributes to the maintenance of normal
ribosomal structure and composition.
The Importance of Maintaining Intrac ellular
Amino Acid Balan c es
Proteins can be only wilen all of the
amino acid "'building blocks" arc simultaneously
present in proper within the ce lls. Young
rats do not grow at normal rales if they are fed a diet
divided into aliquots that supply some of the amino
acids in thc morning and the others in the e,'(ning.
even if it is otherwise fully adequate. Moreover.
when the food satisfies caloric I"<'quil"<'ments and has
a moderate or high tOlal protein content , but there
are deficiencies or gross excesses of certain amino
acids. the consequences are impaired protein synthc-
sis and aecderated protein degradation (23).
Some kinds of amino acids are easily
from others. For tyrosine is made from
phenylalanine. whi le alanine can be obtained by
transferring amino groups to pyruvate. Other amino
acids are said to be "'essential"' because they must be
supplied by the diet. Thel"<' are species differences in
the reqU;l"<'ments; and young, growing animals have
special needs for substant;al quantit ies of cena;n of
them. Most mammals must eat histidine. methio-
nine. tryptophan. phenylalanine. lySine. threonine.
valine. leucine, isoleUCine. and arginine. Some of the
esssential amino acids al"<' pr=nt in low coru:entTll'
lions, Iheir availabilities can beoome ratc·limit-
ing for prolein synlhesis. Each cell Iype uses amino
acids in unique ways to make ils own special pro-
teins. It maintains a characteriSlic intracellular mix-
lur<:, and il sequeslers the various molecular types
into "pools" that dilTer from each other in the case
wilh which they can be recruited. Thus. cardiac
musele maintains free taurine levds Iwice as high as
the oncs in the diaphragm and up 10 11·fold grealer
than IhQ:I.c of thigh muscle. while ils gl)'cine Content
is low i 133).
Amino Acid Upteke
Since Ihe inlmcei1uiar levels arC higher than the
ones in blood plasma. amino acids must be tmns·
ported againsl their CQnC(:ntralion gradients. The
processes arc carrier mediatc<.! and cnergy-consum-
ing. Howev<:r, Ihc participation of ATP is indirect
(82). Although gluwse oxidation usuall)' supplies
much of Ihc energy. Ihe uptake can proceed u'hen
cells are bathed in nuid, thai do not contain the
sugar.
Ail ceils wntain oombinations of carriers with
overlapping properlies (176). These ha"e been clas-
sitic<.! in sev<:ral ways (117) An "'A" type ("alanine-
preferring"') system. which is sodium-<lependcnt. is
widely diWibuted . It transports small neulral amino
acids ,uch as glycine. and threonine (in ad-
ditiulL tu alaILiILc). AIL "L" Iyp';
ring") $)-,;tem is Na1 >·independcnt. It carries phe-
nylalanine. tryptophan. Iyrosine. methionine. valine.
and isoleucine. as well as louein •. It Can usually be
distinguished from an "L '''. which handles the basic
amino acids argini ne. lysine . and histidine. At least
some cdls have a separatc carrier for acidic amino
acids such as glulamie and asparlic, and a dilTcrent
one for cystcine and proline. However, an "ASCP"
Syslem thai performs the functions of Ihe "A" Iype.
but addit ionally car'ies cY"eine and proline. has
been deseribed for tumor cells.
Two chemio:ally similar amino acids can compete
with each other for the s.ame carrier or engage in
cQunreriransporl phenomena. (For example. u'hen
Ihe Auid bathing Ihc cells is rich in Icucine but poor
in methionine, the carrier Ihat brings in the leucine
can take the methionine out .)
ROLES OF EXTRACELLULAR SODIUM IONS
Sodium-<leflCient fluids. and Ihe administration of
agents such as ouabain that interfere with function-
ing of the Na' / K+ ATPase "sodium pumps". im·
pair Ihe uptake of some of Ihc amino acids. The fol-
lowing mechanisms hav<: been proposed for sodium
facilitation (117).
When the amino acid binds with Na+ al lhe cell
surface. this increases Ihe affinilY for the amino acid.
Since extracellular Na+ is high, Ihe sodium ions
have a sirong tendency 10 enter Ihe cells and 10
"drag" Ihe amino-acid-laden carriers with them .
The low intracellular Na+ facilitate. dissocialion of
bolh Na + and amino acid from the carrier. and this
leaves the carrier free 10 return to lhe cell surface .
It is lechnieally diffICult \0 assess the elT<:<:ts of
hormones on trampon. since each amino acid is used
at ils own rate. Insulin specifically alTecls the upla ke
of just certain ones. However. il acts in other ways
to promote protein synthesis. and it thereby indio
r<:<:tly acC(:ler3tes the uptake of Ihe others (23). Soon
after il is administered 10 whole animals. Ihe 10lal
amino acid ooncentralion of Ihe blood plasma falls.
Insulin also accelerates the usc of all of the amioo
acids for peptide chain assembly. Therefore. mea-
sU'ements of changes in plasma Of intracellular oon·
centrations of Ihe various amino acid types cannol
be used alone to obtain information on transport.
Protcin synthesis inhibitors can be used 10 block
amino add incorporalion into proleins, but they in-
lroduce variables of their own. Although Ihey do nOl
dirCClly alTeel operation of the transpon systems
(23). they can interfere with Ihc production of thc
amino acid carriers and other protcins thaI support
normal cell functions. Invesligators have thcreforc
turncd 10 studies of amino acid analogs such as ami-
noisobutyrate (A I SA. AI B) and cyclolcucine. These
are Iransported b)' Ihc carrien;. bUI tho}' arc not
metabolized .
The data must be interpreled wilh c,ution. It w,s a..
.um<d for, long time Ihal AlB was transported by the
"A" system in enclly the same way as alani"". Howev«.
more reOCol "udies ha,'e dernon;tr.. tcd ,h.1 some .I,nine
(but 001 A IB) upt.ke moy be aC<XImpl i<hod by lho No >·
indopcodonl"L" 'Y'lom . Unlike the .rtiflcial analog. 0.1·
anine competes wilh leuo ine. Mo.-Moor. in lhe presence
ohmino-oxyacelale ("'hid perm ii' tran'port lo proceed
but block. sub,equent mClOboti$m). al,n inc aeeumolates
in cell< rou, limes as rapidly as AtB.
Insulin is said to accdemte Ihc lransport of only
glycine. alanine. serine. histidine. and methionine in
skelelal muscle (133). I-!owcver. the specific amino
acids alTccled by insulin are not the same for all lis-
,ueS Or for the same kinds under dilTercnt physiolog-
ical conditions. Moreover. While findings wilh AlB
secm to be wnSi!tenl, data on upta ke of the natural
amino acids are oo\.
Insulin lnl1uences on Peptide Chain
Assembly
Although Ihe hormone acede rates the uptake of
only eerlain of Ihe ami no acids. it enhances Ihe use
of all nalurally occurring ones for peptide synthesis
via mechanisms thaI arc not direclly linked wilh

transport. (It is effective. for example. "'hen cells arc
bathed in media that do not contain sufficient amino
acids 10 support protein synthesis. and alw when
amino acid concentrations can no longer be ratc_lim_
iting because their levels are artificially elevated.
Ribosomes i>O!aled from tho museloo of insutin-defi·
cienl animal ...semble I"'p'ide chain, more .Iowly than
or",nelle. ta ken from control •. Fewer art incorporaled
inlo poly""mes.• nd fewe, enll.ge in protein ,ynthesis. In·
.ulin does rM)1 directly Ih. funetion. when il is
added 10 such preparations, Howe"",. the defect. can be
correcled if the hQrmone-deficienl a nimals are pretrealed
with insulin for only 5 minule. prior to ... ,rifie<:.
The ribosom •• can be di."",ial.d inlo ,ubunits. and the
large and small eomponent> from different a nimal, Can
be recombin.d. Peptide chain .... mbly pr<><:<:ed. al . im-
iI.. in prep..,nion. containi ng .ither both ,ubunil<
derived from eonlr<>1 animal •• or large subunil' from e<>n-
tr<>l' and . mall one. from in,ulin-dc{,cientanimals. Ho"'·
ever. onOO th.t eontain jmoll subunits from in.ulin-dcfi_
cient animals .how ,ubnormal ra,es, e"<n ,,'hen combined
wilh large ,ubunits from the e<>ntrol, (2H).
Sinee Ihe ,mall . ubunits from diabelie rat ribosomes do
not ,hQw defect. in mRNA binding. pcpl idyllr.n,fcra",
activi,),. or prolein e<>mposil;on. il has been p"'l'O"'d th,u
in.ulin rapidly change. the chemical n.luro or e<>nfigu-
ration of ribisomal proteins involvcd in lhe: in;lialion of
peptide chain formation (176.2)5).
·rhe effects may be related to insulin inftuenees on
depbosphorylations of regulatory proteins. Insulin is
known to oppose many cA MP actions. while phos-
phorylations of initiation factors ha"e been shown 10
impair protein syn thesis. On the other hand. al-
though bigh cAMP levcis and insulin deficiency in-
crease Ihe phosphorylation of ribosomal prote in S.,
it has not been possible to link this with Ihe hor-
monal functions (234).
Imulin Slimulation of protein synthesis has been
dcmonstrated for cultured s keletal and cardiac mus-
cle (2). In long-tum studies. hormone deftciency ac-
cderates protein degradation, and it also impairs
pept ide chain elongalion (227).
fa l cells synthesize lipoprotcin lipase. and they
export il for transport to the capina.y endothelium.
Insulin accelera les Ihe sy nthesis, evidently by acting
3t both transcriptional and translational levels. Its
innuences can be partially bloc ked "'ilh agents Ihal
impair RNA synthesis. and totally abolished wi th
cycloheximide. Insulin may additionally facililale
secretion of the enzyme, The efi"e<::u can be enhanced
with calcium ionophores and inhibile<l by chdalors
thai interfere with the upta ke of Ca " from 'u.-
rounding Huids (223A).
In the liver, Ihe major inHucnees of insulin on pro-
tein synthesis are amibuted to augmenlation of
RNA synthesis, whereas Ihe inhibitory effects on
THE ENDOCRINE PANC,qEAS
protein degradalion result from actions on the Iyso-
somes (176). However. illSul in is one of Ihe hor-
monCOi that accelerates amino ac id uptake (145).
Although cffccls of insulin on nucleic acid melab-
olism arC well recognized (121.188).liuic is known
of the mechanisms. It is likely Ihat the hormone acts
at multiple sites. Innuences exerted on Ihc plasma
membranes can increase the availability of RNA
building blocks. nutrients. and ions. while ones on
the ribosomes would be expectcd to augment pro-
duction of RNA polymerases and other proleins that
support RNA $ynlhesi$ more directly. "Se.:ond mes-
senger!<"' that affcct nuclear functions may also be
released. It has observed Ihat phy$iologieal con-
centrations can increasc Ihe aClivity of a nucleoside
tr iphosphatase of the nuclear membrane. even "'hen
insul in is dirCClly prcscnted 10 nuclear envelopes in
vilro. The enzyme is implicated in provision of the
ATP energy for transport of mRNA$ from
the nucleus to the cytoplasm ( 176).
INSULIN REGULATION OF CARBOHYDRATE
METABOLISM
In addi lion \0 promoting glycogen and fat storage.
in,ulin aCtS at several sites to acccierute glucose ox-
idation. A major funClion i. p",oi.ion of ATP
energy .
Influences on Glucose Transport
Under physiological C<lnditioos. glucose oxidation by
skeletal muscle. cardiac musclc, adipocyle. and some
other cdl t)'pes is limited by the ratc of sugar cnlry.
Insulin acceleration of glucose transport begins very
soon aftcr the hormone is presented. All of the ob-
servations are consiSlent with the helief thai the
sugar enters via passive. facilitated diffusion, and
that the hormone actions are exerted on glucose
carriers.
The effects are srereospecific. Whilc insulin pro-
motes Ihe uptake of D-galaclose as well as D-glu-
cose, it has no di,cernible effects On the transport of
Ihe L isomers of Ihose sugars. or on fructose and sev-
era l pentoscs. The processes arc saturable , Thi, can
be demonstraled only when the sugar conccntralion.<
are above Ibe physiological ranges, However. the af-
fected sugars compote with each othe. for transport .
IIISUlin also accderates countertransport (143).
The uptake rate increascs linearly over low con-
eent.alion ranges. and it tapers 01T when higher ones
arc presented , The quant ities of glucose transported
in a given time period a.e diminished by Ihe simul,
laneOuS presentation of gulactose.
 34M.lhyl glucose (3·MG) c'"rIOl Ix mct.boliwi.
but il doe< cr«lS tbe plasma m.mb .... nes in bolh dire<:·
lions. It i, • useful tool. linco il apparently utiii'e> Iho
giuco«: ca"ier to CrOSS Ihe plasma membran.s. When
cells bathed in a ",Iulion containing J·MG hav<: been p"r-
milled 10 accumulate •• bst •• tial <oo<e.ltalion. of the
mol.eule •• addilion of glucose to the medium a<xcicrale<
3·MG .gr.... Thi, i. believed to occur beeau.., glucose
"an.(>Om Ibe carrier to thc cell interior. bUI SOOn disso-
ciate< from it. The carrier is Ibc. frce 10 combine .,ith
Ihe 3-MG and tran'porl il to Ihe pla.ma membrane. In·
IT.celiular glueo«: levels .re nc .. er high "rIOugh to clfee-
liv<:ly e<)mpete witb th. J·MG for Ih. c;lrricr . • ince glu·
c,... is phospOOrylated almosl as soon 85 il cntcrs,
Howe ..... under the experimenlal condition, im!l'<"e<l.
there i. more glucose Ih.n 3·MG "' the c",erior surfaces
or the o<ib. In.u lin .ceeler'le. Ihe COunteHran.port
(143).
Insuli n Regulatio n 01 Hexokinases
\Vhen hiSh level. of both insulin and Slucose pro-
mote rapid upta ke of the ,usur in cells with lIor·
mone·resulated plasma membranes. and when mcal
absorption leads to rapid delivery of Slucose to Ihe
hepatocytes. thc hexokinase reaction becomes rate·
limiting for glucose use along all major metabolic
pathways. In most cell types. insulin augments
hexokinase proouetion. In thc liver. it additionally
some influences on the activities of
enzymes.
Several ;sQzymesthat dilfer from each
other in amino acid oonlposilion. charge. af·
nnity for glueClSe, and susceptibility 10 inhibition by
gluoose-6-phoophate and glu<;o<;e. have been identi·
fied in vertebrale tissues (98.189).
J is univer.;ally present. It is the dom.
inam form in neurons and in mOSI uther cell Iypes
thaI do nol have insulin·scnsitive glu= barrier.;. In
sensitive cells. it maintains basal (Lc. unstimulated)
glucose mClabolism (150). The isozyme binds glu·
cose with high affinity. but it has low activilY and is
easily inhibited by glucose-6-phClSphate.
Hexok;nast /I predominates in muscle and other
lissues with insulin·,ensitive transport systems. AI-
Ihough its activity is greater than that of hcxokinase
I. fairly hiSh glucose ooncentralions arc required
(K., 2.1-4.1 X lO - 'M. oomparcd ""'ith 3.0-8,0 X
IO - !M for hexokinase I). Insulin increases Ihe
hexokinase lI:hexokinase I ratios. and the values of
thooe ratiClS are positively correlated with insulin
sensitivity,
The 11: 1 ratios are especially high in the fat pads
of well· nourished animals. The)' fall following either
insulin or food deprivation. and they can be restored
by insulin administration Or refceding. Glucose also
promotes hexokinase II synthesis in insulin .. ensitive
cells maintained in culture, In oontrasl. the 11:1 fa·
tios are low in brain and they arc unaffected by
insulin.
lIexok;'wse III is present in small amoonts in
most or all cell types. but it is mClSt easily identified
in the liver. It has an extremely high affinity for glu·
cose (K. 70--9.0 X 10-OM). but its activity is rap.
idly inhibited by low inlracelluar concentrati<ms of
free glucose. This isozyme seem$ to be impoortant for
sustaining the minimal rales of glucose mttabolism
that keep the cells viable during times of gluCOllC
deprivation. In the liver. it probably es""dally
netded when glucose release to the bloodstream de-
pleles glycogen StOreS.
Hexokinase IV (glucokinase) functions best at
very hiSh glucose concentrations (Km ... 1.2-2.0 X
IO-IU) . for example. when large quantities of the
sugar are delivered to the liver via the hepatic portal
vessels. Since this iS07.yme is 100 times less ..,nshive
to gluc0sc-6-phosphate inhibition than the other
he xokinase .. it is especially suitable for cells that
must rapidly synthesi ,.e glycogen. It has heen staled
Ihat glucokinase is unique 10 the liver . but a similar
isozyme is present in the bela cells of the pancreatic
islets (79).
Insulin induces hexokinase IV. and Ihis is one of
Ihe mechanisms by which il aSSures that gl)'cogen
will be synthesized rapidly during meal absorption.
High le.els of the cnz)'me build up in individuals
diets rich in carbohydrate. There is !lOme
evidence poinling to insulin aetivalion of preexisting
enzyme. as well.
In sulin Regulation of Glycogenesis
Glycogen is synthesized from glu<;o<;e-6-phospha\e in
three steps (Fig. 5·9). The firs1 involves liuie enersy
exchange and its direction is determined by sub-
strate levels. The glucose·l·phosphate formed dis-
places a pyrophosphate groop of "ridine triphos·
phate (UTP) to yield uridine diphosphate glucose
(UDPG) ,
The third .. ep of the reaction. which is rale lim·
iling. involves the transfer of Ihe glucose of the
UDPG to the end of a preexisting glycogen chain.
The chain i. then elongated. and UDP is libcMed,
Insulin acts rapidly to enhanC<' the activity of pnx:x.
isting enzyme, and it promoles the biClSynthesis of
new enzyme. High levels are attained in individuals
ingeSling dietS rich in carbohydrates.
[nsulin al!lO facilitates gl)'cogen storage by inhib-
iting phoophorylase systems that promote gly<;:ogen.
olysis. In musele. effects on the plasma membranes
that augment glucQSC enlry oontribU1C substantially
10 Ihe stimulalion of glycogen synthesis.
The phosphorylnlion-<:lcphosphorylation meeha·
nisms fOT regu laling the activities of both Ihe glyco:>-
gen synthase and glycogen phClSphurylase systems.
n.
GIJ<O ...·I·P - UTP -::
(U/ aciI·ribose-P·P -PI
(Utidine·lr;'P)
UOPG +
(u<idine-<li.P·Gtuoose) (n moieties)
Fig . 5·g. Formalion 01 glycogen Jrom gioco..s·
pI\oophot •.
and the hetw".n insulin and the cA MP
syStem, were discussed in detai l in Chapler 4.
Insulin further augmenls hepatic glycogenesis by
shunti ng glucose-phosphate away from lhe foliowing
reaction (which is accelerated by gl ucagon):
G lucose-6-phosphate
gl uco:sc-6-phosp ha lase
+ HOH Glucose
In insulin-dcficicncy SlateS, glycogcn synthesi' in
the liver does not totally shut down. because enough
glu c0se-6-phosphatc accumulates to di'e<:dy aClivate
glycogen syn thase in Ihe absence of the hormone.
In muscie.howe'-cr. glycogen storage is severely
impaired because (0.) very little glueo<e enter< tho
cells: (b) there is not cnOllgh hexokinase [I 10 rapidly
phosphorylale the glucose that dotj ente r: (c ) gl}'-
cogen synt hase is not activated: and (d) hormo!'H:S
thaI promote glycogenolysis arc nOI opposed by
insul in.
Insulln Regulation 01 Glycolysis
Glycolysis directly providc;s some AT P. It converts
glucose to pyruvate, whiCh is used for several pur-
(XlSes that illC lude formation of acetyl-eoA a nd gen·
era tion of much more ATP. Addilionally, it s upplies
phosphoglycerate a nd othe r intermedia tes.
Fructose--l.6-l>ip!>osphate kinase
__
(p/>osphorylate<l. inacIiYtI)
- - - -- - - - - - - - -,(, _ .
Phospholruc101<inase _ _ _ _ _ _ _ _ _ _ _
(inactr.-.)
Fruelow.6.P _ _ _ __ _ _ _ _ _ _ _ _
Ftll.5-10. F,_.
glyOOly .... ( I) A<:CftIO<II6d by insulin. (2) ReverS6d I>y
cAMP an<! by phoophotylose·!>-kina"",
THE ENDOCRINE
.
UOPG p.p
(uraciI·_· P 'gluCose)
Glycogen .ynthas:
Phosphofructokinlsc (PF K) eatal}'?e. the ralC-
limiting ",action. Insulin activates PFK . regulates
t he functions of a physiological stabilizer that rc-
la rds PFK degradation (39). and promotes the for_
mation of new enzyme. The hormone al"" incrcascs
the availability of glucosc-6-phospha te.
PFK is an allosteric enzyme that is modified by
several factors. It has long been known that enzyme
+ P; aClivity is increased by high levels of fructose-IS-
phosphate (the substrate ) and by high level, of AM P
(an indicator thaI mOre ATP shou ld be synthesized).
It is lowered by AT P and by cil"dte (OOth of whiCh
arc expected to risc when the rale of glycolysis ex·
ceeds Ihe need). Recenl ly. it has been demonstrated
that fructa<e-2.6-bipho<phate is major phy<iologi_
cal aCl ivalor that can syncrgizc wilh AMP (222).
Glucagon. which anlagon;'.cs insulin innuonces On
glycolysis and on several other aspects of glucose
metabolism. markedly decreases the levels of the
fructose--<.6-biphosphale: and Olher hormones that
inhibit can exen inAuences in lhe same di-
rection (86). Glucagon aClS in pari by promoting
eA M P-depc:ndent phosphorylat ion of lhe IS-phos-
phofrueto-2-kinasc needed to generate the regulator
(Fig. 5-10). This reduces the aninity of the enzyme
for its fructosc-6-phosphate substrate. It may addi-
tionally aCli"ale a fructose-2,6-biphosphatase ( 44).
A second mechanism for phosphorylation of the ki-
• Fructose-l.6-t,;phosphate kinase
(dephospllory1ate<l, active)
,r_-_
(act;"")
Jr,_"_-.. .6-t>iphosplla'Q
''''lu1o.100n of
naSC (and therdore rwuction of the amount of frue-
tose-2.6-biphosphatc) in the liver is via phosphoryl-
aSe b kinase and Ca" . It has been proposed that this
mechanism is especially useful when there is a strong
need to elevate the blood glucose oonccntrations.
Then . the glucose-phosphate formed during glyco-
gen breakdown will be shunted away from glycolysis
and become available for conversion to free glucose
that is relea,ed imo the blood,tream (59).
I n>ulin augmentation of phosphoprotein phospha·
tase aetivitics is (he most likely mechanism for in-
creasing the fructose-2.6-biphosphale and thercfore
for acceleration of glucose·phosphate entry into
glyoolysis.
The fructosc·I.6·biphosphatc cleavage is cata·
Iyzed by aldolase. Although this is not gellCrally re-
garded as a oontrolling Slep (and thc reaclion can be
sent in the opposite direction under some in ,·ivocon.
ditions). ;1 has recently becn demon mated that he·
patic aldolase le"cls fall during faSling (170). Roles
for insulin in regulation of the levels of Ihis en'.yme
have not been cstablished.
It is sometimes stated that PFK "pushes" glycol·
ysis by facilitating the formation of fructose-1.t\..bi·
phosphate, whereas the reaclion catalyzed by pyru·
vate kinase (which is strongly exergonic) "pulls" the
pathway to completion.
Insulin the biosynthcsis of Ihe pyruvate
kinase. It also promotcs dephosphorylation. and
thc",by aClivation. of Ihe liver enzyme (110).
Insulin further accelerales gl)'oolysis by reducing
the at which intermediates are shunted to other
palhways. for example. il lowers the activity of frue·
tose- I .6-biphosphatasc. and therefore the conversion
of fructose-biphosphate to free fructose. This action
also s«ms to be accompli'hed by an en1.yme de-
phosphorylation (110).
Insulin Regulation of Pyruvate Co nversion to
Acetyl·C oenzyme A
ado", il can enter Ihe tricarboxylic acid cycle. py-
ruvate must be converted to acelyl·CoA.
Pyruvate + NAD ' + Coenzyme 1\ - -- - cepts have been presented (A·!. A·2. A-6).
Acetyl·CoA + NADH + H ' + CO,
The pyruvate dehydrogenase oomponent of Ihe
mitochondrial cnty,"c oomple x Ihal cataly1.cs Ihc
reaction provides one more sile for insulin activation
via a deplK:>;phorylation mechanism. When insulin is
incubated with preparations oon\aining bolh plasma
membranes and mitochondria derived from adipo-
cytes. Ihe phosphorylation of Ihe pyruvate dchydrt>-
genasc is decreased as the aetivily is increased. The
hormone does nOI affect Ihe enz)'me if it is presented
di",ctly to just mitochondria. Since surfacc-aeting
agenlS such as concanavalin A. and also ATP. can
exert similar influences. the findings arc consistent
with liberation of a "scoond messenger"' that acts on
the mitochondria (24.(94).
The pyruvate dehydrogenase oomp\ex plays key
metabolic roles. It may therefore be activated in dif·
fcrent ways as well. Alternate mechanisms have
been described (164).
MECHANISMS OF INSULIN ACTION
Although the problem has intrigued for
several decadcs. definitive informalion on the mech·
anisms of insulin aClion is just beginning to emerge
(28.I09A). We now know something about the rc-
ceptor struetUTe and Ihe changes thaI occur when
the hormone binds.
Insulin receptors are oligomer> of dissimilar gil"
copeptides. According to one modcl. there are IWO
large a subunits (M, 120.000-135.000) and two
smaller {J subunils (M, 90,000) arranged in series
and held together wilh disulfide bond,. QIIC or bolh
of the components can be cleaved 10 yield a /J, deriv·
alive "'jth a M, of 45.000:
{J·s·s....·S-S-«-s·s·/J ./I·S·S.....S.s-a-S·S-./I ,
uncleaved one small com]l(lnent
./I,·S.s...... S·s..,.·S·S·/J I
two small components
The" subunits bind insulin. The ./I sunbunits af·
fcel the proc<:ss by either modifying the aninitics or
associating with additional hormone molecules. Ev·
idently. the plasma membrane, also contain regula·
tory comrollCnts thaI alTeet the binding aninities. A
problem with the model is thc appmcnt molecular
weight of 300.000-350.000 obtained for assembled
complexes (29. 171).
Rccent pholoaflinity labeling studies suggest Ihal
the insulin receplors exisl in multiple form" and thai
the one which predominatcs has a molecular weight
of 300.000. It appear. to be up of four dissim-
ilar components with molecular weighls of 130.000.
90.000. 40.000. and 40.000. The Ia>t tWO differ
chemically from each Other. and neither is believed
to be a degradation product {236A). Diverse con·
Insulin associates rapidly and rever.ibly with
high.."ffinity siles. Some observers state thaL Ihe
binding shoW!; negalive coo]>Crativily. but others do
not agrec (92). Hormone-receplor interactions may
lead 10 changes in Ihe rceeplor properties thai arc
essential for initiation of the hormone functions. [t
has been proposed Ihat the receptor can assume
eilher of two configurations lhat are in equilibrium
with each other. and thaI inSUlin stabili,..s one of the
forms. Insulin is also known 10 promote receptor
clustering. Plant lectins (97). bivalent (bul nOI
monovalent) antibodics dir«ted against the receptor
(92). and some other agenls chemically unrelaled to
'"
that promote clustering. can elicit many of
Ihc aClions of the hormone. Those same agents may.
however. also change the configurations of individual
receptor moltcules or ael in yet different ways.
There is good reason \0 believe that proleoly.•is oc-
CUI"$ soon after hormone binding. Some of Ihc reac-
tions may accomplish receptor-mediated insulin deg-
radation, and perhaps protection of the cdls against
over_stimulation. However. olhers have ocen linked
wilh hormonal functions.
Mild treatmenl of the target cells with trypsin can
inVQke respo"<cs similar to the ones thaI follow io-
sulin pre""ntation. Moreover. Ihe a subunit is re-
poned \0 undergo proteolysis soon after insulin
binds: and cleavage,; of OIher membrane components
have been described. Th. reaclions may be initiated
by Ihe fr<:e energy released during the binding (29).
or as some direct conS<':quence of reccptor aggrega·
tiOll( 113).
Prote<Jlysis could lead \0 (a) releaS<': of second
messengers othcrwise S<':questered in thc plasma
membranes; (b) unmasking of the catalytic sitcs of
plasma membrane-associated en'.ymes that arc in-
active in unstimulated e<:l1s; (c) changes in
membrane properties that affect transport: (d) func·
tional alterations in the receptor: or (ej cleavage of
the hormone to release fragments that enter the cy·
toplasm to act as messengcrs. Substantial evidence
for the lir.;t idca is pr<:sented below. Since so many
agent! chemically unlike insulin can serve as ago-
nists. the last concept is least likely 10 explain the
mechanisms whereby insulin invokes ils early
responses.
Some time after the horl11<.lnc is first presented. a
dilfer<:nl kind of binding (which is nol easily revers·
ible) can be demonstraled. It is believed to initiate
endoeytie inrerna/izalion of horl11<.lnt-re«ptor rom·
plexes (II). Some reduction in surface receplor
numbers Can soon be demonstrated. Prolonged ex·
posure of the targets to high insulin concenlralions
inV(lkes "down regulation" and cO!lS<':quenl loss of
sensilivity to the horl11<.loc.
Allhough the insulin and ils reooptor seem 10 be
simultaneously internahed, the comple xes disso-
ciale; and the IWO components fOllow separate path-
ways (73). Most or all of the hormone may be dc-
graded. whereas some reccptor molecules are
retained and later recycled to the pla,ma membrane .
Lysosomcs may be the primary sites for degrada-
tion . Chloroquine interferes with the actions of ly-
sosomal enzymes. In its presence. receptors are
translocated to the ecll inleriors, but they arc nOi de-
graded (65). The receptorsean be identified in crude
0011 fractions ronlaining Iysosomes and golgi rom-
ponenlS. It has ree<:ntly been reported. however, Ihat
THE ENOOCRINE
the inlernali,-"d receptors bind to a special kind of
vesiclc that possesses properties intermediatc be-
tween those of lysosomes and golgi components
(102).
Some of the delayed innuene<:' of insulin on pro-
tein synlhesis and cellgrowlh arc not mimiCked with
the surface·aeting agents menlioned earlier. The
possibility that thcy are mediated via binding of the
bormone to intrae<:lIualr organelles been eonsid.
er<:d (67,70,174). High-affinit)" binding siles for io-
sulin have been idenlified in targel cell" and it has
been suggested that at least some are involved in
hormone·regulated synthesis of thc receptors and in
the transport of those molceules to the plasma mem-
branes (113). Insulin is chemically related to ocrve
growth factor. which also exerts long-range inHu_
ences that involve protein synthesis and receptor reg-
ulation. Nerve growth factor must enter Ihe cells be-
fore it can act (15).
Insulin-like growth factors arc discussed in Chal'"
ter 18. Some hind to insulin receptors and mimic
many of th. insulin actions. They haoc be\:n shown
to affect the same glucose transport systems in adi-
pocytcsand in some other kinds of cdls (169). How·
ever, Ihey have receptors of th.ir own. and not all
targets ar<: sensitive to both regulator.;. Whcn pre-
sented in high concentrations for extended time pe-
riods, insulin binds 10 somc of the growth factor re-
ceptors. and cerlain long-range insulin inAucnces
may be thus mediated . Insulin also regulates reccl'"
lor numbers for some growth factors (A-I).
In s ulin Acti o ns Med iated by
Pho sphorylation-De ph osphorylatIon
Reactio ns
Many examples of insulin regulation of the activities
of preexisting cnlymes via phosphorylation Or de-
phosphorylation have been cited. Innuences exerted
on phosphoprotein pllosphatases ( I 8,27) at least par-
lially explain Ihe aClivation of glycogen synthase.
glycogen pl>osphorylase. pyruvate dehydrogenase,
HMG·CoA reductase. and some other enlymes . On
thc other hand, insulin is known to increase the ac-
livilies of a variely of protein kinases. Some arc
cAMP-<!epcndent, some are Ca " -<!ependent. and
yct differenl ones are not controlled by either of
those regulalor<. Proteins phosphorylated in re_
sponse to insulin include ribosomal components, as
well as acetyl·CoA and citrale lyase:
and it has been suggcsted Ihat activation of cyclic
nuclootidc phosphodieslerases is also accompli,hed
via phosphorylation (l09A) .
A roncept that is gaining wide acceptance is that
in.ulin-receptor binding leads to clcavagc of a
plasma membrane-<lssociated glycoprotein and the
consequent releQ.'e oflWQ small glycopeptide media-
/()f'S of the early effects of the hormone. The larger
of the IWO, which is more basic, is implicaled in the
dephosphorylation.ll$SOCiated functions (113). The
smaller glycopeptide. which has a molecular weight
of 1(l(l(}-1500, is said to exert SOme opposing innu-
enees. [n addition to probable involvement in protein
kinase activation, it may participate in some form of
negative feedback control and provide an explana·
tion for the observed biphasic actions of the hor-
mone. One possibility that has been considered is
that the larger glycopeptide gives rise to the smaller
one (89). Other investigators have described differ·
ent insulin-generated mediators (I09A. (93) .
Studies with pyruvate dehydrogenase lend strong
supporl to the conoxpl. This mitochondrial en7.yme
can be activated in -everal ways ( 164), one of which
is dephosphorylation. rnsulin cannol increase the aC-
livity if il is pre-entcd dircc;tly to isolated mitochon·
dria. However, it is effcctive in vitro when thc prep-
arations contain plasma membrane components as
well. Agents Ihat act on the target oxll surfaces, 'uch
as concQrlavalin A, mimic the insulin actions. All of
the preceding arc consistent with the liberation of a
·'second messenger" from the plasma membranes
(24,195). Low molecular weight substa"""s with
pcptide-like propeni.. ha'·e been extracted from the
plasma membranes of insulin-treated oxll •. They arc
direelly implicated in mediating the hormone func-
tions, and the quantities generated rise with increas-
ing irn;utin dosage . Very high insulin levels invoke
production of molecules with opposing effects (I 85).
The receptor beta subunits catalyze tyrosine phos-
phorylation of histones, angiotensins and other pcp-
tides. The activity is augmented by hormone bind·
ing, and the subunit undergoes autophosphorylation.
The modifioo pcptidc activates kinase C (which ar-
fects serine and threonine residues and may thereby
mediate some response.). Kinase A acu on either
the receptor or a regulatory peptide to decrease .in-
sulin binding (A-I).
The relationships between phosphorylation-<le-
phopshorylation reactions and mechanisms of hor·
mone action are not .Iways easy to interpret. There
are situations in which all of the data poim to an
influence of the hormone on a protein kinase, but the
affectoo regulatory molecules have not bc<:n identi·
fied. There arc others in which molecules phospho-
rylated under the innucnce of the hormone can be
found, but no links have been made with the ob-
servoo ccllular responses (166).
Even when hormone·regulated molecules clearly
involved in the functions arc known, this docs not
rule out other actions that arc quantitatively mOre
imponant. For example, the hormone may simulta-
neously release other mediators, promote ATP gen-
eration , provide substrate, or accelerate the removal
of reaction products.
When insulin invokes dephosphorylation, it can do
SO by, among other things, activating phosphatases,
inhibiting phosphorylases, activating cyclic nucleo-
tide phosphodiesterases, Or impairing cAMP gen-
eration.
Since most protein kinases and phosphatases act
on more than one substrate within a single celltypc,
it is sometimes difficult to assess the consequeneesof
their activation or inhibition. There are proteins that
are phosphorylated by both insulin and glucagon, al.
though the two hormones invoke opposing response.'
(202). In some (but not all) cases. it can be demon·
strated Ihat different sites on the same enzyme arc
affecloo. There are even proteins that are phospho-
rylaloo by hormones in vitro, but not in vivo. Thi s
has been attributed to denaturation under the arti_
ficial conditions (202).
The popularity of the concept that insulin exerts
important inAuenees by changing cytosol Ca" levels
(28) has waxed and waned repeatedly Over the paSt
few decades. it i5 oot necessarily in connict with
other findings. Changes in cytosol Cal> can affect,
among other things, the activities of adenylate cy-
clase, cyclic nucleotide phosphodiesterases, and the
binding affmities of siles for phosphate uptake. Some
major actions of i",;nlin On adipoc)"tes that were de-
scribed earlier Can be augmented with ca!cium iono-
phores and Inhibited by chelator.; (22JA).
long-range, "adaptive" roles of insulin arc often
allributed to en1.yme induction. rn SOme cases, other
possibilities (tnat inetude interference with enl.yme
degradation) musl be considered. As noted earlier,
the hormone contributes to elcvalion of ?FK activity
by controlling an cn7.yme stabilizer; and at !cast
",me effects on citrate lyase arc accompli,hed in this
way (39).
Ins ulin Regulatio n 01 Glucose Tra ns p o rt
If a prile were to be awarded for the topic in endo-
crinology that has generated the largest number of
hypotheses, it ..·ould surely go to mechanisms
whereby insulin accelerates glucose uptake. A recent
concept that seems to be more widely accepted than
its predecessors is considered next. This is followed
by a summary of carlier thoughts and observations
on thc subject. it is included here because (a) there
may be morc than one mechanism (4), and (b) the
history of endocrinology is laden with description' of
hypotheses that went through the SlIme phases of en-
thusiastic, almost universal approval, transient rejec-
tion, and resurrection in somewhat modified form.
h has been proposed that insulin promotes the
translocation of glucose carriers from an intracellu-
lar site to the pla,ma membrane (109A,207). The
'"
resulting increase in the numbers of carriers then ac-
celerates the transporl. Substances capable or pro-
moting glucose transJIOrl ,,'hen incorporate{! inlO Ii·
posomcs arC prescnt in concentrations in goIS;'
rich cell fractions of unstimulated adipoc)'lcs. When
the cells arc pretreated with insulin. the aClivity de-
clines in such preparations as it rises in plasma memo
brane fmotions. Insulin increases the V_ . value
without alfe<:ling the K.. (4.25), a f,nding consistent
with the avai lability of mol"<' <.:arricrs of the kinds
present in "resting" adip;:>eytes. Cywchalasin B at-
taches 10 glucose carriers. and insulin augments its
binding 10 plasma membranes as it decreases it in
microsomal fmClions. Ho",cvcr, insulin may rotale
the carriers so that sugar_binding siles face
cell surfaces (A-I).
Stimul"i.,. <>f glucos. uptake ",Ust .tan with a cell
.u,face p!le1lOtt1enon, since (I) it begin. within minutes
afler Ihe hor"'one i. presen",d, (b) il Can !Ie invoked
"'hen in, ulin is covalenlly linked 10 polyme .. thaI sub-
slantially (if nol lotally) block in, ulin enlr)' into the
l<:>pla,m; (c) it can be mimickcd with planl leclins, biva-
lenl antibod ies dirC<:led ag.in" Ihe f¢C<PlQf. and low
concentrations of su,fa",""clivc agen,", inciuding phos-
pholi pases and Ifyp&in; (d) higb<r C(lncenlf31ion. of lho$<:
sam. agents are known 10 damage pla,,,,a membrancs
and 10 abolish insulin senSilivily; and (el chalti.es in Ihc
,urface propenies of Ihe cell . have been observed . For e.-
ample. pi..",. memb .. ne hyperpolari,alion and m<>re
rapid uplake of pota .. ium ;Q!l$ have been reported f",
skelelal musete. even when the botmone is presented 10
cell. bathc<l in gluCQ»derocienl media (1 43.238),
Both insutin molecules and Ih.i, receplo" h..e disul-
fide bridges Ihal are nceded for roali>otion of biological
aetivily. It has been prop<l5Cd lhal disulrode inleraclions
belwcen l\'le lwo lead 10 ch.nges in plasma membrane
configurations lhat "open Ihe channels" for glucose entry.
O bservolioM lhal Ihiol blOCki ng agcnl • • uch IS N·
ethylm.leimido (NEM) abolish in.ulin aClion if lhey are
presenled btfore (but 11(11 after) 'he hormo,.... lhal NEM
alone can mimic >Ome insulin aClion •• and lhat o.ylocin
has. disulf,de ring 'imilar in ,ize to <>ne on Ihe A
chain of insulin). a ugments the gluC<JSO uPlake <>f .dip<r
cyle •• ha,e aU been cited as evidence for such S-S inler·
.ction, (177), Howe,·er, il i'lI(Iw rCC(lgni1.. d thaI t"EM
can ael inl .. c.llularly. Ihal oxylocin docs 1101 affccl glu"
cose tran'pOrt in musele. and lhat tyrosy) and histidyl
(ralher th.n cy$linyl) m(lielies of the hormollC are in·
vol_ed in binding 10 Ihe r=pl"'.
Tilero have been related ,u"e$lions Ihat in.ulin pro-
moles o. idalion of $ulfhydl)'l grou]l$ (28).
Hydrogen peroxide and some olher o. idanlS can accel-
craIe glucose uptake.
It i, OOvious. bowe_er, lh .. insulin does IIOl ,impty "en·
large lhe pores" of the pl3<ma membrane. A, di.eussed
above. lhe effects of Ihc hormone are stcreospecific and
satu .. ble _ Moreove r. Ihe processes of binding and Slim·
ulalion of glucO$. lran.port are separable (149). Neur-
aminida .. (roalment of adipoeyle, .ff.. t< iU' l lhc tra""
pon (4). Cooling Ihe cells 10 2 ' ' C permits binding. bu(
tran' porl i. nol accderaled, If cell . Ife.wi in thi. w.y
arc wa'hed to remove unbound hormone. and lhey .ro
lhen ,,-. rmed. Ihe effc<:lS of lhe bound in, ulin on lfllnsport
are manifested. It c.nnol be argued lhal cooling " nd re-
w.. ming exert their elfcclS by influencing glucI)SC melat..
ali ..,. sinc. similar phenomena can be demonmaled with
galaclose (which is "'" metaboli,ed by musele cells)
(14) ,
A somewhat more sophi<!icated concepl. which Can
be .ccommodated 10 lhe ,....d 10 'pecifically .lfcel glu·
cose carri .... is Ih.t in.ulin·in_Ok¢<! proteolysi, bring;
about redistribulion of mcmbrane phospholipid, (I I 3).
Changes in mcmbrane fluidil)· (165) that lead 10 reori·
enlation, of glucose corrie .. and consequcnt increa,e. in
lhe numbe .. c.pable of funclioning. coold .100 result
from hormone-invoked falty acid d.s:lluration. choles-
lerol depletion. ph<><pholipid melhylalion. Or calcium
binding. In adipoe}'to$ from human, a. ,.-cli as from cer·
lain other species. form ation of microviili and aceetetal¢<!
pinocylOSi. arc reporlod 10 be a$$OCtaled V.-ilh in, ulin·in·
vo,od elevation of lh. V ... .
The mechani,m, for acceleraling glucose "anspor,
may 11(11 bt lhe same fa, aU cell lypes. T, •• kinelics aro
dilferenl for . k.klal musele comj>arod wilh adipose
lissuo. In ral epidid)'mal fat pad •. gt""""" is taken up
more 'lowly lhan in some other depots. and in,ulin hO'
"'t n .o"""M 'n Inw" ,.., K_ i " n <.IT,et ",","<I"n,
a chang. in c.rricr .ffinity) (4). Change. in aHinit)" have
also bten described for earoisc musele (143).
M.inlenance of the hormone«n,ili, . barrier when in·
.ulin I._cts a,e low i. ATP-<kpendenl. Agents such as di-
nilrophenol (hat bloxk ATP .ynthe.i,. and hypo.ia. ae·
c.terat. glucose uptah in cells tha, aro 001 e.poscd 10
Ihe hormones. The ob'CrVOlions spawned se,eral hy.
pothcse. linking ;n.ulin Slimutalion wilh ATP depriva·
lion. It ",-as suggcSted. for example. thaI iM"lin "diven, '
ATP from the pla,ma m.mbr. ne and send, it into ana-
bolic
Re«nt re-e .. mination of Ihe roles of ATP (I09A)
provides more logical concepts. Cells ",ildty deprived <>f
o.ygen Or AT P hav. higber bo.<al (i _e. not botmone-slim·
"I.. ed) rates of glucose uplah , This mak.s good "sense''.
since Ihe .hortagc. increase the dependcnce on gl}'C(liy,i$
fM fu.l , In contrast. ATP deprivalion and hypoxia le=n
in'ulin .. imulation.
Two intriguing hypolhe"" linking in,ulin action, with
phosphorylalions arc WOrth menlioning, although lhe)-
aro 001 roadily recondl.d ,,"'ith 50me other f,ndings. It has
be.n proposed lhat lhe glucose carricr e.ist. in aNi". (de·
phosphorylal.d) and ;IUI("/;"e (pbospbotylat.d) form.
lhal differ f,om each other in IIluc""" affinities (177). II
has be.n pro[>OS«l th .. in. ulin bring • • boul depbospho-
rylalion (and Inerefore oClivalion) of Iho ca .. ier. vi.
moehani.m. opposed by ATP.
An al(ernate eoncepl i.lh .. in. ulin "aeli'alcs" lhe Car·
rier by promoling oxidalion of its . ullltydr)'1 groups.
If Ihe "activo" form has ' ery low .mnil), fM glucose,
the "'p' is rapidl)' .. leucd Iu Ihe con inte,;'" ("'hofC
f... 11- le.els.", ,cry low dOle lu ..pic!
The a";e . is Ihno freed 10 u l al Ihe colls-doce: (where
low .ll\fIily is no dioadnft..,e';""" u n_n"la. 11"""",,
<:<)ftC<fttralicms ... hi8h).
INSULIN INFLUENCES ON CARBOHYDRATE
METABOLISM OF NEURONS
Most neurons do oot have insuliNegulaled plasma
membrane ··barriers··. hclWkinaSd. or aly«lgen syn-
Ihases. I nsuli n activalcs tyrosine ( A.J), but
neurot rans.milltl"S wntrol CAs and
VU(IIct;ve intcstinal peptide a re beljco,ed \() stimu-
late llIe PIOCCSS via. cA MP generation. histamine by
increasi ng Ca" upta ke. and serotonin through in-
te.lctions with receptors thatBfc coupled to eA MP-
independent p. otoin kinases (175) .
E.ceptions to this gelll'.al rule illl'l ude limiled
numbe rs of «lis with in the amyg-
dala. and certai n Qlhe. pam of tile brain that If<'
implicated in tile wnlrol of food inlake.,amoinlC5-
tillal functions. and the !leCn:lion of carbo/l)'drnle--
regulali", hormones. The spoolanrous fi.ing rates of
tiles\: neurons undergo rapM! c hangeJ when Ihc glu·
cose conc<:ntralloos of the «f<'brospinal fluid a",
vari.d, and when they.", exposed to nonmctaoo1i7.-
substances such as 2-dco.y,lucose that arc
by
The .. ntral nervous system is protected against
mom.nt.to-momenl nuetua lions of insulin levels. A
·':Iood·brain barrier" formed by spccial i7.Cd ClIpil.
!aries re$lricts con<;CIItrations of Ihe 1Iorrnooc to.....,.
fourth lhose found in periphera l blood. Although
chroni<: hyperinsulinemia cvc:mually rai_ the lev·
cis. s}l temie vein injections of insulin do not invoke
aeule changes (233). The ",qui",ments for such pro-
leetion may be linked wilh the fUn<:tions of the Sen·
, ilive neurons Of wilh ""me long·range ClTeCls of in·
sulin deficiency and
Excbangcs of hormones and OIhe. kinds of
molecules between the blood and the cerebrospinal
fluid .'" accoillplisbcd by cin:umvcnu-;cular organs
(226), $peCializcd stroct ur<:S outside the blood-brain
barrier. The cells have ins\llin receptors (68.220)
and very bigh gluIUC «XIuiremen1S, and (hey Slore
substantial quanlilies of glycogen.
Hypo 'h"amlc "Feeding" and " S.lIely"
Cenler,
Many mecbanisms for assessi ng nutritional stalus
and a pplyi", the information to ",gulatc food inta ke
ha..., been ptopo:wsro (n. 105). The h)'llOlhalamus has
1orI& been rqardcd as llIe major wnlrol sitc
(16.1 55 ). since pa(iCnlS wilh tumors impinging on
thai part of the brain. and animals wilh lesions al
certain loci an become hypo- or hyperp/lagi,. Al_
though human obesily is only linked wilh hy_
pothalamic dysfunction (1 2). some a Ulhors ha,..
drawn parallels bet"'ccn lhe behavior pattc.ns of
ovc:rwcighl humans aoo t hose of Iesioned animal.
(186).
A widely disseminated concept Ihat glucose·sen·
silive hypolhal amie neurons Me g.ouped into ",eip-
rocally innervated ventromedial "$II ticty" centers
and more laIc rally Iocaled "fc«ling" OMS i. based
on many kinds of obse ...... tions ( 16,155, 159). Al-
though il <;a n no longc. be: ae«pled in ilS original
form. the h)'pothcsis is still being presented in eic·
menta ry biology te.tbooks.
When adult animal. of many mammalian (and
""m e avian) species are subjected 10 extensive de--
S\fuction of Ihe hypothalamus, includes the ven·
tromedial nuclei. Ihey .apidly develop ··bypotha·
lamie obesity'·. They have been obse.ved to head for
100 food cup while still .ecovering from 100
anesthetization. If pa.ialable food is readily availa·
ble . llIey can soon double lhei. body weighls. h lias
been proposed lhal kM Qi tile &lucosenslli\I(C neuroJrS
.... ilhin the nuclei a bolishc$ 100 inhibitory inn\ICn<;Q
normally exerted by the ventromedial "s.a(iety cen-
ler" on the laleral hypothalam ic "feeding ce:nter".
In con trast. animals with latem l hypothalamic Ie-
.ions ",fu$(: food and waler. eycn when mo;sl. pal·
atable subslances Or liquids di.e,tl)' into
Iheir mouths. The)" soon rapidly Io5c weight and die
of SIIn'8tion and dehyd.ation if they 8", not fon:e-
fed. Some suffer permanent loss of Ihe abilily to at-
ccpl nourishmcnl. but others will in lime swallow
tOmC foods directly A fcwean rqain self.
feeding functloos. One interpret.1tion is that I"CWY'
cry is possible only when subslantial numbers of
"feeding neuTO!I$" a'" spared. Another is thai "fC.
ca n ,""cu •.
Additional su pport for the ..oncepu comes from the fol·
Iow;n, obu .... t;..,.:
L. HunlJY animah lhat have elc:ClAldcs ;mpbnlod iRl0
but.", OIhe ..... iH intaol. will promplly
s.op fcedi., ir tbe unlr<)modial "'gion i...im.lata!.
Fully fed ones "'ill take "",", food ifille 10leral region is
stim"laltd (and fCpelIted t"'almenl 0( Ibis kind co.. l<;ad
to the deyelopmenl of m..si ve but reversible abc';ty).
2. Anatomical evidence has bc:cn prosc:nlod for reeip-
,oxal\n"".vation of the two hypOt halamic . egions. More--
over.spontaneous eleelfieal aetivilios ha .. e bc:cn obu,ved
10 unde'IO r«iprOC. l eha..os in rc>ponsc: 10 fcedinl-
fa"ina, slcop-a"",.. I. and acti.ity-rosl rhythms.
Eleetri ..1 diJcha'l\C of ve,..,orncdi.1 ""ul"O<l$ is d.,..
pressed by fpli"" by hypoclyccmia. _nod followi",.he
a<!mh,;"ration '" 2-dcoxnl ....... (2·00), wbich com-
petU for the Ilu"""" ca.rie. bUI ean"", be metab<tl;ffi!.
11 acceleratcs in.-espome to fccdi"lar.d II ........ Lat.....1

'"
hypothalami. neurOIlS are inhibited by glucose and reed·
ing, and they are stimulated by and 2·D(; .
The finding$ have been .. id l<} indicate that glucosc
stimulate. _."lromedi., r.eunln$ and thaI 'hoot cells, in
,u,n, .,ert inhibitory inftuen ... 0".' the I.teral ones.
(The ini,;al ob",rvalion, were made On la rge neuron clus-
te ... When the technique, ,",'.r. refined. il lOa. discovered
thaI bolh hypothalamic rcgion$ 00"\". limited n"mbcrs
of neuTOns that respond in opposing way •. The new dOla
we ... not ",g..dod 0$ s<riou. contradiotion. of the
hypothesis.)
3. Some ob",'valions made with gold-lhi<>-glucosc
(GTG) have also been dIed in $uppon. When the agt.,
is given to inl.OI a duh animal • . th. con'equence, inc lude
damage to the ventromedia l hypothalamu •• 00 to the
fiber 'ro.I> that Ii. 1.' .....1 10 the region. 31008 ,",'ith de-
,.topment of the hypothalamic Qbesity .yndromc_ The
damagc is 1101 in,oked by gQld .. h. that do not ha"eglu-
cosc: componenl>,
Roles of Insulin In Hypothalamic Feeding
Center Funcl10ns
The concepts have been further utended to inel ude
roles for insulin, which is known to stimulate the at>-
(16,32). When given insulin depresses
"sa tiety conter" However, it enhances glu-
cose stimulation. Insulin..:leficien t animals, and pa-
tients with poorly controlled diabetcs mellitus often
suffer from hunger, which has been at-
tributed 10 impaired glucose uptake by the "saliety"
cells. Animals fail to de"clop hypothalamic obesity
when they are given GTG: and sensitivity to the
toxin restored by hormone pretreatmcnt.
Modified Forms of the Hypothesis
It has been proposed that ventromedial and lateral
hypothalamic neurons work together to regulate
"scI-points" for body weight (99). Animals with ven-
tromediallesions do not continue to gain weight in·
definitely. After a time. they establish and maintain
"plateaus". They develop less severe postoperalive
hyperphagia if Ihey a re ove rfed for a time before the
surgery. They also "defend" their new sel·points
when certain changes arc made in the caloric den-
sities of their food.
Similarly> animals Ihat "reoove r" from lateral hy-
pothalamic and resume feeding defend a
body weighl set-point that is very much lower than
the ones of u!lOperated controls. When animals have
been deprived of food prior to surgery. many eal dur-
ing the postoperative period before developing hy-
pophagia . Moreover. animals with one form of dam-
age have been known to establish new "set-points"
THE ENDOCRINE PANCREAS
that are closer to the normal range if the second kind
of ksion is subsequently inflicted.
The hypothalamus surrounds (he third ventricle of
the brain. Studies inwlving long·term infn,ions of
nutrien15 into the ventricle have provided some
plcmentary concepts (311), Greater sensitivities to in-
/ractrebral than to systemic administration have
been interpreted to moan than Ihe neul"O/1.S respond
directly 10 Ihe availability of fuel, for their Own use
(rather than to changes in the plasma nutrient lev-
els). Dose-rdatcd of body weight can be in-
voked when either glucose Or glycerol is given in this
way. Curiously. howe,-cr. although slycerol provides
fewe r calories than an cquimolecular dose of glu-
cose. il is more potent for appetite depression: and
its effects On body weight arc sustained for longcr
time periods. Both fuels are highly potent if thcy arc
administered during the niShl (when rats normally
consume their largest meals), but they have litt le in_
flucnce on daytime food ingestion_ Another interest-
ing finding is that ,6.()H-butyrate can bring about
weight loss without affecting food intake
Some Problems with the Concepts
As diseussed in Chaptcr 19. the kinds of hypotheses
ju<! described nre inconsi.tent with currenl
of the highly oomplex nature of hypothalamic func-
tion. A few specific fmding' that suggest the need 10
the ideas (1,16,1 18) arc presented here.
It i, now that amyg-
daloid, and other brain regions oontribute to the reg-
ulation of food imake (178); that "hypolhabmic
obesity" can be invoked hy lesions that do not in-
dude the ventromedial nudei: and Ihat receptors in
the liver, gastrointestinal tract. and elsewhere se nd
signals to the brain. Cholecystokinin. catechol-
amines, a nd calcitonin are among the hormones thai
affeci food iutake by mechanisms not directly re-
lated to glucose uptake by neurons_ The cffem of
GTG are now attributed to damagc inmcted ()n
brain blood vessels; protection against it can be pro-
vided with anti-inflammatory drug<_ Some agcnts
that affect endothelial membrane permeabilitie<
(but not gluc05e metabolism) can didt similar
symptoms. Insulio and glUC05e seem to exert wmc of
their effects on vascular endothelium . These proba·
bly include regulation of gluoo>e transport carrier in_
duction. (Patient, with diabetes mellitus often
play signs of hypoglycemia when they first begin to
establish normal gluC<l:'le le.cl. in response to insu lin
therapy (66J.)
Eating is a ootnplex I:>ehavior that in"oh-cs moti-
vation and motor activity as well as perception of sig-
nais. Laboratory animals that maintain normal body
weights on stoc k diets can easily be persuaded to
overeat and b<:come obese when they are offered
"more interesting" food. They will take exce.,ive
quantities of the stock diet if they arc subjected to
some mild form of stress. such as tail pinching (144).
Sectioning of the vagus ncrves Can abolish th. erreels
of endogenous and exogenous peptide·typ" "satiet y
factors" (199) and also of pharmacological agents
widely believed to act centrally as hapP"tit. depres-
sants" (2IS).
"Hypothalamic obesity" in rodents is associated
with learning and behavioral changes that include
The Iesioned animals have exagger-
ated tendencies to refuse food that has ahered lIa·
vors. (Whereas intact controls gradually lcarn to ac-
ccpt suffident quantities of diets tainted with bitler
substances to maintain their body weights. the Ie-
sioned animals do TIOI.) Lcsioned animals al>.o dis-
play suboormal locomotor activity. and they are re-
luctant to press bars. lift heavy lids. or do other
forms of "work" to obtain their food . They suffer
metabolic dcrangements that can iead to changes in
body composition. even when thc animals are pair.
fed with in tact controls. Young animals subjected to
ve ntromedial lesions eat the same quantities of food
as controls. bUlthcy acquire high fat:iean body mass
ratios. Human " hypothalamic obesities" usually in·
yolye disturbances in the function s of several pitu_
itary gland hormones (190).
The ventromedial nuclei are now sp"cifocally im·
plieated in stimulation of glucagon secretion. inhi·
bilion of insulin release. and regulation of growth
hormone levels. Hypolhalamk obesity is invariably
associated wilh hyperinsulinemia Both the hyper·
phagia and the weight gain can be pre"cntcd by de-
stroying thc beta cells of the pancreatic islets or the
vagal inputs thcy rcceiYe from the hypothala mus
(::17). "'en when animalS arc given functioning islet
cclltran,plant • .
GLUCOSE TRANSPORT AND METABOLISM
IN THE INTESTINE AND KIDNEY
Glucose \f"Jnspon acro&! the cells of the small intes-
tine and proximal convoluted tubules of the kidney
is accomplished by active. energy-consuming. Na ' -
and ATP4ependcnt processes that can oppose con·
centration gradients. Under optimum conditions. all
of the available glucose is scnt into the bloodmcam.
No additional transfers can be accom plished by hor_
mones (and no useful purpose would b<: served if
tl10sc regulators could limit the transport rates). The
hexokinases arc mostly type I. and their acti"itics
arc closely linked with the rates of glu= uptake.
The kidney is an important site for gluconeogen-
esis. and the reaction rates accelerate during times
of food deprivation. However. although gluconeo-
genesis in the liver contributes to glucose homeosta·
sis. the processes in the kidney provide ammoni um
iol1$ and contribute to the regulation of acid_base
balan<:<:. They are regulated by aldosterone and
parathyroid hormone .
Insulin does. however. exert some inlluene<:.< on
those organs. For example. it can affect the renal
tral1$port of phosphate (153) and the intestinal
transport of calcium.
METABOLIC FUNCTIONS OF GLUCAGON
Glucagon protectS against hypoglycem ia when (a)
the blood sugar level falls during the intervals be-
twcen meals; (b) food rich in protein but low in car-
bohydrate content is ingested; and (c) the demand
for glucose rises, e.g. during exercise. Falling blood
glucose concemrations provide the direct stimulus
for glucagon secretion by the a cells of the pan·
crealic islets. The hormone is transported by the he-
patic portal blood vessels to its primary target. the
liver.
Under resting conditions in wen'flOUrished ani-
mals. glucagon functions primarily to ae<:elerate Ihe
conversion of glycogen to glucose. When these ac·
tions do not effectively maintain c"glycemia. larger
quantities of glucagon arc secreted. The hormone
then additionally stimulates gluconeogcnesis. Sttll
higher conccntrations within the physiological range
promote lipolysis. fatly acid oxidation. ketogenesis.
and urcogenesis.
Conversion of Liver Glycogen 10 Glucose
The mechanisms whereby glucagon activates a
cAMP-dependent cascade. and thereby simulta·
neously accelerates glycogenolysis and inhibits new
glycogen synthesis. were described in Chapter 4 .
Glycogenolysis results in the production of glucose-
I·phosphate (Fig. 5· 11). Phosphoglucomutase then
catalyzes a readily re"ersible reaction whose direc-
tion is dete rmined by the substmte concentrations.
When glucagon act,. glucosc-6-phosphate is formed.
The final step in thc pathway is catalyzed by glu·
c0se-6-phosphatase. an enzyme whose activity is
augmente<i by glucagon.
Glucagon-stimulated elevation of blood glucose
levels requires the support of other hormones. Insu-
lin acts most obyiou,ly to provide the glycogen
storts. G lucocorticoids play several roles. only some
of which arc cited here. They (a) synergize with glu-
cagon to increase glucose-6-phosphata .. activity; (b)
promote conversion of amino acids to glucose; (c)
antagoni?e insulin·stimulated glucose uptake by
,. Falling blOOd glucose
I
GlVCAaON secret<>n
Ac'ivation 01
I ...,.,•
Ir'I<ICti.aliot1
synthase
i>I1<>SpI"Io<)ot .... easc_
I
Con'efl jon 01 gl ycogen 10
r phOSph<>\l lucomutase
glucose·6. phosphale
I gIucose.6.pho.pMl.<e
F,ee g1l.ocose
skeletal musde and adipo:se tissue; (d) aced.rale li-
polysis and provide alternate fuels; and (el
act in Olher ways to facilitate glycogen st(lrage
(203).
In adrenoconical iTlSufficicncy Siaies. glucagon
can generale cA MP, but the effects of (he nucloolide
a re severely bl unted. The steroids are said (0 per-
form "permissive" that arC for reali-
zation of cAMP functions (71). These have been
linked witb phosphorylation Of SCAR P (steroid and
cAMP regulated phosphoprotein), which is also
phosphorylatod by glucagon. There are indicat ions
that SCARP is the regulatory subunit of the cA M P-
activated protein kinase . GluCOC<lrticoids little
innucnec on adcnylate cyclase, but can dec",ase
phosphodiesterase activity somewhat.
Phosphorylase b kinase activation is calcium-dc-
pendent. and the steroids may contribule by mobi1i7.-
ing Cal<. Glucocorticoids also increase the produc-
tion of glYCQ8cn phosphorylase in <keletal muscle.
and they may do the same in Ihe liver.
LIMITATIONS TO GLUCAGON-ACTIVATED
GL YCOGENOL YSIS
Although both prompt and impressive in magnitude,
the influences of gl ucagon 3re limited 10 recruitment
of (Only SOm e of the liver gly«lge n .Ior ••. Special
oonditions under which cate<:holamines. vasopressin,
angiotensin, and other hormones utilile cA MP-in-
dependent mechanisms to recruit much of Ihe rC-
mainder (5,13,61) a re considered in Chapter 8. Min-
quantilies mUSI always be retained . since the
act ions of glyoogen synthase require attachment of
the enzyme 10 Ihe glycogen.
Ftg. 5_11. GIo.>ce.Qon
<:0.,._ 01 live. glyCOlI"" to (/I"""",, ,
cAMP-mediated activat ion of phosphorylase b kinas<:
is aCC(lmplished by the binding of pho$phale gro"ps 10 the
enzyme. SubK<juenlly, .ddil ion.l ph<»phate a",
addoo at other . ite. on Ih... me enl)'m. molecules. The
second addil;on perm;ls Ihe enzyme 10 serve as • sub-
,Irate fur a ph<»phatase thaI brings .bout inor,;"",;"".
Thus. cAMP ;s involved in both iniliation and le ,m;n.-
tion of the re.ponse (225), It has 1)«n proposed that the
need f'" Ine .. <ond phosphorylation "ssurn Ih.1 en,yme
inaCtivation will 1)< delayed until at ka" a minimum
quantity of glucose i. made.
Prolonged presentation of high glucagon concen-
trations leads to "down regulation'" of Ihe receptor
numbers.
Importance of Restricting Glycogenolytlc
Actions to the Liver
The liver ma kes the glycogen primarily for "cxport."
II is Ihe",fo'" appropriale thai the glycogen be bro-
ken down when Ihe need for mo", glucose arises, In
contrast . muscle makes glyoogen for iu; own usc, and
il would be physiologically undesirable for the stores
10 be lost during limes of fasting.
Very lillie glucagon ever reaches Ihe muscle. It
g"", directly from the pancreas to the liver, and
much of it is degraded Ihere. Muscle cells a'" insen-
silive to the hormone. Moreover, when muscle is
stimulaled to COntracI, Ihe glycogen Ihal is degraded
is made into glucose-6-phosph'lo (whi ch cannol
leave the cells). Muscle does nOi oonta in a gluOO!;e-
6-phosphatase. The glucose phosphate is senl into
the glyoolytic pathway. and it Ihereby provides the
ATP energy needed to support muscle work. $Qme
diffe ren""s in mechanisms for regulation of glyco.
genol}"is and some differences in the propenie. of
the enzymes (184) were discussed in Chapler 4.
Glucagon Stimulation of Glueoneogenesls
W hen glyoogcn reserveS are inadequate for support-
ing blood glucose levels. the influence. of glucagon
on the formation of glucose from otne. rrKllcculcsas-
sume imporlane<:. The processes arc activated by
cA M P-<lcpcndcnl prolein kinase!. and they depend
on the "permissive" actions of lh. glucocorticoids.
II igh •• oonccmmtions of glucagon and grealer eI·
evations of the cAMP levels arc required than for
glycogenolysis. The actions are "IOS1 easily demon-
strated when glycogen slOres run down. There arc
both carly and laIC components. and the ianer can
be continued for hQurs when this is required
(37.48). The effects arc potentiated by the glucocor-
ticoids (41 . 216), and they are diminis hcd by insulin.
Studies on p<rfuscd li>cr< have s!town that glucagon
promotes BIYCOienoly,is when pre.. ntod in conoonlr._
tions of 5 X 10- " M. but al leait I X 10- 1• M i. needed
for glueoneogencsis. Further dc'O,ions to I X 10-' M
and 5 X 10-' M promote "rOOilenOi;i and kClOgene,; •.
ft.pte lively.
Allhough carly clrcels are reialC<.! to aCl ivation of
preexisting enzymes. the later ones r.::quire cn7.yme
(4"d tltey al "itlt plotei" >llltlt..,..
sis inhibilors). The glucocorticoids are believcd to
act on the chromatin to accderatc transcription and
to thereby increase the availability of specific
mRNAs, cAMP has been implicated in facilitating
the processing of m RNA prccursors. stabililing the
promoting transloc3tions of the molecules
to the ribosomes. and aeeelera ling the Hanslation
(46).
'",
, "'
PyrU'late
c .. bo,ylase
c =o · CO,- ATP
boo
C=O
'00
O,aIoa<:elate
'",
",
HC - QPO,H -
coo-
Phosphoenolpy'U'l3Ie
GLUCOSE SYNTHESIS FROM PYRUVATE AND
LACTATE
When muscle contracts. the rate of dcgradJlion of
glucose-phosphate to pyruvate excecds the rate al
which the product Can be converted to acctyl·CoA
and senl into the tricarboxylic acid cycl e, Under
such oonditions. much of the pyruva le formed is rap-
idly wnverted \0 lactic acid.
,
'", '",,
,coo-
c- o • NADH ,coo- - NAD '
PY'U'l3Ie
Although the reaction i. reversible, it tend. to go
\0 the right in Ihc muscle because (a) large amounts
of NADH arc formed during glywly'is: (b) hydro-
gen ions accumulate: (c) Ihe lactic dehydrogenase
isozyme of muscle has high affinity for pyruvate: and
(d) lactate exits from the cells_
Laclate formation accomplishes several objec·
lives. Firsl. it reduc<:s the acidity of Ihe cells. and
thereby delays the onset of fatigue. Second. it is as·
sociated with oxidation of the NADH. and it there-
fore provides a coenzyme needC<.! to sustain the gly·
oolysis, Third. unli ke pyruvate. laclale can easily
CrOSS the plasma membrane,.
Somc lactate is excreted in Ihe urine. but much of
itt,a .. e), tu tlte li>er fa.o,,,blc
for oonvcrsion of lactate to pyruvate. This is attrib-
uted to the presence in liver of a lactatc dehydroge-
nase isozyme with dilTerent properties. the hiSh lev-
els of lactate that accumulate in the liver during
muscular aetivily. and the rapid rate of pyruvate
cnlry into me labolic pathways ,
The pyruvate is ta ken up by liver mitochondria.
and it is carboxylated to oxaloacetatc (Fig. 5-12).
W,
- AOP , Pi
,
FIg. ,s., 2. Conv... ...,., of py,,,,,ate '0
pttosphooonoli>'ft\Nale (F'EP) . ( 1).
( 2), I nd (3) if>dioate proposed siles
for IUIl,,*,lOtior>,

This reaction is ratc limiting for pyruvate conversion
to phosphoenolpyru_ate (PEP).
Glucagon both activates and induces the pyruvate
carboxylase (36). It also hepatic levels of
acetyl-CoA (which activates the enzyme). and it
may additionally facilitate mitochondrial uptake of
the pyruvate substrate.
The oxaloacetate is decarboxylatcd in the pres·
ence of GTP to PEP via a reaction c3taly7.cd by PEP
carboxykinase. E_idence has been presented for
stimulatory influences of glucagon on a "f.rroacti.
vator" of PEP carboxykinase (37). In addition, the
hormone opposes insulin inhibition of both enzyme
activity and biosynthesis.
The formation of PEP .. ia an indirect pat hway is
necessary because the pyruvate kinase reaction of
glycolysis is irreversible. Thus. glucagon hldirectly
oppooses the stimulatory influences of insulin on the
pyruvate kinase (5g).
PEP is then used for the synthesis of fructose-l.6·
biphosphate. via reversal of the reactions of the gly·
coIytic pathway {see Fig. 5·2).
The key role of phosphofructokinase (PFK) in
regulation of glycolysis has been diseussed. The reo
action is not reversible in vivo. and a fruetosc bi·
phosphatase is needed to convert the fructosc bi·
phosphate to fructosc-6-phosphate (sec Fig. 5·10).
Glu,",gQII illdu."," the .nzyme. and il also inhibits
PFK activity.
Fructose-6-phosphate is rapidly made into glu-
_
Gi)'ce<oI • ATP ____________o,,""""·c·'"'·"·,·'-________ •
_
HOH ________-'0,..
" ..
,,-,.""'0'..
Ftg. 5· 13_ Blosynthoor.ol gluco.. trom 11>"",01.
THE ENDOCRt NE PANCHEAS
cose-6--phosphate, and the glucose-6·phosphatase ac-
tivated by glucagon and glucocorticoid, catalyzc.s
the final step in prodUction of free glucose.
GLUCOSE SYNTHESIS FROM GLYCEROL
lipOlysis is accelerated during both fa,ting and mus·
cu lar The fally acids that arc liberated can
be utilized by many cell types for fue l. but only the
glycerol portion can engage in net synthesis of new
glucose.
Hepatic glycerokinase acts first to catalyze phos-
phorylation. The product of the reaction is then
made into dih)·droxyacctone phosphate. of
the aldolase step of glycolysis yields fructose-l.6--bi·
phosphate (Fig. 5-13).
G lucagon acederates sugar production in this way
by (a) augmenting lipolysis in the liver (an action
attributed 10 influences exeTlC<:! on the lysosome,);
(b) deereaiing the shunting of gl)·cerol-J-phospbate
into patbways for triaeylglycerol synthesis: a nd (c)
probably also increasing the activity of the glycerol
phosphate dehydrogenase.
GLUCOSE SYNTHESIS FROM AMINO ACIDS
Glucagon enhances gluconeogenesis from amino
acid, by (al cooperating wi1h glucocorticoid 1",,.·
mones in induction of enzymes that catalyze deam·
inalion (212): (b) shunting the amino groups liber.
GlycerQl-3·P + AOP
".''',..
,,____-00-
• Glucoso ' Pi
lIed inlo pal hwa)'S of urea synthesis (and therefore
a way from ones in which derivW interme_
diales can bt made into new a m ino Kids): (c) labll-
and Ihercbyacceleraling
prQIcin d<:.radaliol!; (d) of .milK! acids
ror protein synl hesis; and (e) aCling on lite: hepa .....
cyte plasma mcmbrantS 10 accclcmlc the uptake or
glucogenie (>ugar-yielding) amino acids.
G lucogcnic amino acids Can be oblaiocd from the
die\. However. during times of fasling. the major
$OUrccs are tissue proteins. Skelelal musde contrib-
Ults consid<:rable quantities of alanioc for lhe reae-
lions .... ilhoul suffering PrQIein desl",elion. Gluco-
«II1icoids make additional amino acid. by
dec:rcasinglhe rates at ... hieh they incorporated
inlo proccins in muscIt and seve".1 other ccll types.
GllICagon has lillie inlluence on heP0lic uptake of
ketotcnlc amino acids. II docs. howevcr_ promote
conversion of fally add' 10 ketones. which $Crvc as
positive modu lalOrs of Ihe cn •.ymes that cataly'",
amino acid dcam inalions.
Glu cagon Stimulation of Fetty AcId
Degradat ion and Ketone Format ion
Glucagon acu via cAM P 10 IClivate triglyceride li-
pase Ind to affect the Iysosomcs in I manner thaI
leads to either ",lease ollhe enzymes to the cylosol
or augmentation of intra lysosomal enzyme activity
(31). II aelS on the mitochondria loacccicrate fatty
acid degradation (101) and in the cytoplasm to in-
hibil acctyl-CoA carhox)·lase. All of the preceding
increase Ihe availability of Ihe acclyl-CoA substrate
for kelogenesis (sec Fi,. SoI4).
t f'ynN... ..,...., inIo " .........
t catbo>;yIa ... 8CIWity
P-,oruva[C
I Pyruvat. <;OI1v.,sion 10 at ......

Ureogen ..ia
I C·.......·pbosphaQ. .
The potcntially toxic of ammonium ions
formed during glu<:vncog<:nesis arc averted by the
rapid incorpCllll.tion of the nitrogen groups into urea
(201). G lucagon induces of the pathway. us. 01
l,uCl""'·p.'>:><pha!O "' gI\'COIYM
When urea concentrations rise in the livcr. they aug-
ment the .et;v;lie. of glueonoogcnie ketogenic
en'.ymes.

o -c
........-Mlt
lit..
c:
The diversion of amino groups Inlo urooacnesis
also reduces lhe uSC of such Irou PS fIX 11M: s)'nthesis
of tleW amino acids from carbon formed
during the metabolism of glucOS<,: (Ind other ruels.
LipoIysi • . lormalion
Inflllencel on Glycoly,l,
cells ma ke only limiled IISC of gl)"a:lI)"sis. Glu·
cap tends 10 fu rther mluoc: th is by
the $1imulatory innuenct" or insu lin. Mec:hanisms I GIy<:efot use lor t.. oyn/>noI
wllcrcby il inhibits the formation or rfllCtoso-2.6--bi-
phosphatc (a positive modulator or Ihe rale-limiting 1 t t'('y<;'. Iorma"Oon ot Iroe tal!\' _ )
for entry of glucose phosphate into the gly-
colytic pathway ) have been disc u!l<ed. "0 SOme e x- 1 fatty acid oon_oion 10 acotyI-CoA
ICM. glucagon al"" indirectly relurds extrahcpatic I IIc.....>is
glycolysis. since it elevatcs the: con<;en t rJtions of frtt
fally acids within the blood . This sro...'S glucose up.
tate by muscle and other iMulin . artc"t (On Ihe
other hand. glucagon ravors lhe transpon by elevat-
inl blood Ilucose collOCnt rat ions ,nd 11)' promoting Fl!iI.'- '4. _""r "; ...... li(:rt..... _ ... gIr .. 'Y'"
insulin s«re.ion.) _ _ _ 01 gIr ...... produelion.
...
Acetyl·Co" carboxylase catalyzes the rate-limit-
ing in fally acid symhesis. and th is leads to the
formation of malonyl·Co". Carnityl transferase
transportS fally acids into Ihc mitochondria fot dcg-
radation . Malonyl-CoA is an inhibitor of Ihc trans-
ferase (a nd therefore of fallY add o:\ida\;on)
{138.231}. By interfering with Ihe formation of mal-
onyl-CoA. glucagon indirc<:tly accelerates fally acid
degradation.
D<:SpilC the many sites of action, glucagon does
n()! seem to invoke sever. kelosis. except in insulin-
deficiency state, (53). Howe"er. ellOugh of the rrKll·
ccules are made in the Ii....:, to SCrve as activators of
gluconoogcrn:sis.
Influences on Ch o lesterol Blo8ynthesls
Glucagon lends to accelerate cholesterol syolnes;s by
providing the precurwrs. The influcnces arc opposed
10 some by inhibitory effects exerted on the
synlhesis and aClivalion of HMG-CoA reduclase
(38).
Extrahepatic Act ions of Glu cag on
At I.ast ,,'h.n pres<nt in high conc.ntration •. glucagon
can accderat. lipoly'i' in .diposc tissue. Phy.iologic.lly
"dev.n t infiuonce. of thi. kind h.ve boen domon",.tcd
for birds. but thtir importance in mammals ha. not ade_
quately been assessed . Theoretic.lly, at I..". glucagon
could act in this "'.y to provide ruel. during .xcrcise.
, ince the hormone levels are de>'atcd then,
PharmaCQlogical d()SC. raise thc pla,ma.free rauy acid
concenlrations. but Ihey lower the level, of ..,me olher
lipid •. CI.i"" hO"e been made Ihal glucagon exer,. ben-
eficial .ffeea in pat ienl. with SOme lipid melOboli,m de-
feclS of go""tic origin (I (6),
Pharm.!X>logical d"", •• I.., inhibit p'lroint¢$tinal mo-
tility and depress the appetite (62). The hiSh glycerol b-
els r•• ulting from accelerated lipolys;s may 'CCOUnt for
the effecl$ QlI food inta\;e. Si""" palientS with glucagon-
secreting tumor> usually lose .... iSht. large doses of the
hormone hay. been to obe$( The "eal-
m.nt ho, proven to be both ineffective and dange",u"
Glucagon promote, in,ulin ",.rellon. au .. v.t .. 'Iomach
ule .... and "".,..timulat.. the heart. All of the preceding
haye been hnked wilh cAM P gt""ralion .
Although glucagon and cAMP labiliz. I)'oosomal
membra"", in the liver, ".bili,. the organdle. at
other .;tes, "llempts 10 toke advantage of the potentially
"anI i-inflammatory" action. of ,Iucagon ha"e not prov. n
•uccessfuL Other age nt. or. avail.ble Ihat arc more p<>-
tent and e..en fewer .. ts.
[nfluerlCes exerted w;lhin the pancreat;e i,lets that af-
fect the s<c"'tion. of other hormone. are eonsidered lalc r.
Intera.tiQllI with thyroid horm""e' that .1f«1 fuol me--
toboli.m hI .. boen dcscribed (160).
THE ENDOCRINE PANCREAS
In some of thc poikiloth.rm •. glucagon has little innu·
ence on blood . ugar levd •. but il antagon;,,,, the effects
of in,ulin on water and elec trolyte bal.n« , It has been
speculated th.t the incr .... d urinar)' excrelion of water
and doctrol)'tes that folio"-. the admini.tration of larse
doses to mammal, repre.. n" nothi ng mort tha n an "eYG-
lutionary carryover" dev<>id of physiological rclc,"nce ,
Pharmacological doses ha". al'" been reported to co,-
reCI h),pereatcemia in both intaCt and Ihyroparathyroid.
o<lomiud animals. and to inhibit bone ,e",rption (205) .
Glucagon-like Immunorea ct ivity (O Ll )
The chemical and biological propertie, of peplides
thaI shar. immunological features ""ith "truc" glu-
cagon wcre diseussed in Chapter 3. GLI. haye been
found in Ihc brain. salivaI)' glands. colon. thymu,
gland. and olher parts of Ihe body. Isle t cell. <Xlnlain
gly«ntin (O L-I) (37). which scems to be Ihe hor_
mone P"'CUTSQt". The quanlilies of enterolucagon, ro-
leased into thc bloodstream vary wilh bolh the spe-
cies and the physiological status. T hey are made in
the gastrointe"inal traci. and Ihe plasma conCentra-
tions rise afler meal ingestion in pancrealcclonli7.cd
dog, and pigs (219).
SOMAT OST ATIN S
SomatOSlali n (S5) was inilially identifted as a [4_
amino acid hypothalamic peptide Ihat inhibils Ihe
=retion of growth hormone (somatotropin), II is
now called SS·14. sin"" longer molecules that con-
tain tlte sequen<;e, ,ueh as S5-28. arc widely distrib-
uted to structures, induding the extra_hypothalnmic
brain and ncuropophysis, Ihe gastroinlestinal tract,
and the thyroid gland. (See Chapter 18).
All pancrealic islets havc delta (il, 0 , A t) ""lis
that make lxuh S5-14 and SS.28. The receplors on
Ihe alpha (a. A. A:. glucagon-secreting) cells prob-
ably dilfer from lhose on Ihe beta!p. B. insulin-se-
creting) ones. sin« S5-14 appears 10 be more polenl
for suppressing glucagon secretion. whercas 55-28
exe rlS prolonged inhibitory influcn«s on insulin re-
lease (21 0). Synlhclic analogs Ihat act preferentially
Q1l just one of thc cell types have boen madc and
lested fOT therapeutie usc (209). T he peptides exert
m(lSt of their aClions close 10 their , ites of synthesis,
Thus, hypothalamic SS acts primarily on Ihe hypo-
thalamus and pituilal)' gla nd ( 163). and islel cell SS
acts On the endocrine cells of Ihc pancreas .
The 55 Ihal accumulates in Ihe blood plasma fol-
lowi ng meal ingestion is said to origi nate in the
stomach (191). It is a potenl inhibitor of the secre-
lions of gastrin . motilin. I-iCI. and pancreatic en-
zymes. II depresses gastroi ntestinal trael rnoIilily
 and <klays slomach emptying. It al50 dimi nishes
splanchnic blood 11010' and slows the ab§orption of di-
clary and
It has been proposed Ihal SS funclions as a major
component of a lhat works in
ronceTi with ins"lin to provide prOiectiQJI against Ihe
dcw:lopmenl of hyperglycemia al limes of meal ab-
sorption (217). Although lillie di",ct inAuenc., on
"basa l"' glucose proouttion by the li""r i$ found. 55
polentiates Ihe glycogeoolytic aelions of glucagon
but 0JI1l0SCS 11>05<: 0( epincphrine (lg3).
PANCREATIC POLYPEPTIOE
The insulilKCCreting cells of Ihe typical mammalia n
islel occupy the imlCnnosl paru oftltc organ and ae·
count for around 65% of Ihe endocrinc population.
Many in dose to the mo", periphcrally
located delta cells that make up an additional 10%.
The Other occupants of Ihe i.let peripheries differ
wilh the panc",atic "'gions in wh ich they ",sidc.
GlueatOn (n. A,) cells predominale in the tail ",.
&ions and Ihey CO/lSIitulc some 25% of lhe endocrine
cells. "'hile pIlnercatic polypeptide (PP)-5ttrcting
(F) ccll$ ,Imost complelely replace Iltcm in the head
"'gions. Some species di /fe reoces ha" e been found .
for the islets of ce rlain Strain< of normal
mice have c lose 10 80% beta cells. while obese ani-
mals can ha ve mo", than 90% of the insulin'so:<::"'t·
ing ones (19).
Although blood from a ll of the islets passes
Ih rough the pancreas. head and tail organs
are dra irtcd by different Y(Cins. a nd they ma)' perform
slight ly d ifferent functions. Those wilh large num-
bers of F cells $CCfCte relatively more insulin. a l-
l/tough t he relati ve numbers of beta cell> a'" not
greater (79)
Ma mma lian islets ma ke more insulin a nd PP than
glucagon. Allhough glucagon performs important
funclions. dc:.struction of Ihe organs lead$ 10 the de-
' clopmcn t of hyperglycemia anti other symptoms of
instllin defICiency. In COOtrast. bird islets make more
,Iucagon and PP tban insulin •• nd their 105$ is fol·
lowed by lhe development of hypogl)'«mia. These
OOsef\\ltions u nderlie the beHe( lhat PI' perforlm
SO/11C important funclions that are linked wi th those
of the other e ndocrine ""lis of the paocreas.
PP is also made in the panerea. and in
pa rI! of the gastrointest inal lraet. a nd it is probably
releaKd from Ihere into the bloodstrcam. Although
Species differences have been fountl (SS). all the
mammalian PPS thus far siud iod Ire sim ilar in siu
.ntI .mioo acid scque!lCel (T. ble 5-2). Avian PPS
are somewhat different. both chemicll l'y a nd
biologically.
Factors alfecting the sc:cretion of PP are simila r 10
the ones that ""i!1 be d escribed for glueagon (31).
n.. ingestion of mc:3 t provides a potent stimulus.
and the plasma PP ",mains eleva ted for a t least 2
hours. The e/fcelS arc probably mediated via the
valUS nerves. Intravenous injectioo of ami"" acids
only sH,ht ly slimulates PI" relcasc:. whereas dlOlin-
erlie stim ula tion e'vhs a brilk rcsponse. Hypergly_
cemin. exercise. and prolonged food deprivation all
increase: the blood levelS. Inhibitory e lfeet. are '-Cen
with hyperglye<=mia a nd high roocen tratioru; of frec
fally acids in the bloodstrea m (80). and wilh high
levels of 55 (167).
It lias been proposed lhat PP rontribules 10 the
regUlation of food intake and 10 the distribulion of
body fuels. NZO (New Zuland obese) mice SIIffer
gcnctie defect. lhal include the paucity or absence
of F cells in their pancreatic isleu. Their obesilY i<
attribut able at least in part 10 h)'perphagia (3 pos.
sible indication that Ihey do 110\ elfcet ively ut ili1e
their food). When injected into huma ns and other
animals. PP depresses the Bppctilc, and it is said to
do 50 without in,ding malaise Of other Hnoosl»"
H
eirlC effects. There are some prOblems wilh the . ug·
gcslion that it acts in coojunction " 'ith other peptides
as I Hs.:tticly factor:' As has been dise:ussc:d. CC K·
PZ okpresses the appelite. and it reduces intestinal
motility when it;s injected into the brain (2! ). Sioce
PI' ac ts peripherally to antagoni7.c the effects of
CC K. I'Z on the release: of pHncrea tic enzymes. it be-
comes necessary to consider that (he intcraction
mechanisms arc dilferent in the brain. Of that I'P
p.omotcs the release of CCK·PZ by lICurons.
EKOIe nous PI" bas a lso been found to
lhe of FSH a nd L H b)' tlte I'ituilary gland
(21 . ). It is not k"",,'n whether .weh OOsel"V;)tions
haw: pbysioiOSical relevance.
No obvio\ls inlluences of PI' on carbohydrate Of
lipid have been found for mammals.
Some effects coosisten t with inhibition of lipolysis or
acceleration of triacylglycerol s)'ntbC$is have been
reponed for birds PP accelera tes hepalie glycogcn-
oIysil wit/toul raising the blood glurose coocentra-
lions. elevates circulating triacylgl)"CCroIlevcl.. and
Ic!wers tho5t: of free fatty acids and glycerol.
recent findi ngs",ise lite th,U PP
is I by·product released d uring synt hesis of a differ.
ent reg"lator. Of that it acts in conj ullCl ion with a....
other peptide. (This has been contpared Ihe re-
lease: of "connecting peplide" when proi n. uli n is
converted to insulin.) A high molecu lar weight pre-
c ursor of PP gi,'cs rise to cquimolu aRlOUnU of a
pelMidc with the following amino acid SC<jl>Cnte
( !92):
Asp-A rg-Gly-Glu-Mcl_Arg_Asp- IIe-Leu-Glu·
T rp-G ly-Ser_f'ro. l l is-Ala-AIa-Ala· Pro- A rg
 THE ENDOCRINE PANCREAS

r_ S-2 .....,....., Acid 01 FO<.o' P8n0r...1ic PoIypep_

with Seqoonoo !or Porc;n. f"{Y

Po..,;""
I!.mon
Il0)0,'' ' ' Potc i"" 0.,,,,, Chick," en
,, ,.
,,,
,, u, "' '" '"
, ,.", "'
", '"
'"
•, '" T)',
", ", ,", G"

•• G',,,"._, '"
'"
.'",
(;1.

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"" ,.
,",
"'
" G," ."
"" ",
M"
M,
u, ",
"" ''"
'""n"
''"
.
G"
'",
.
,'"'" "'
'"
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'" '"
""
M,
u, ", G" ", M,
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"" '" ",
"'. G', Ili,

,."" '"
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M,
L," M,
u.
'"" ""
u,
,",
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'" ."
"" ,.'" IIi. ",
,."" '"
Ty,.NII,

The large nombers of peptides made in exocrine,
endocrine. and neural components of Ihc gUi. the
overlapping chemica l structures. the abilities of OIlC
regulator \0 oompclc with albers at some rec<:plOr
siles (and \0 thereby either mimic or anlagon;,_e),
and lhe activities of Ihc same or relmed mole.:ules
within Ihc oxnl.al nervous system. all contribute to
Ihc diflkuhics of defining the functions. The roles
may be even more oomplicated than has been antic-
ipated, and it is not known IIow many new regulators
,,<,main to be discovered.
A peptide first found in endocrine cells of the
tal portions of Ihe gul in pigs was gi,·cn Ihe name
pyy its silc or origin and the presence of
a carboxy terminal tyrosinamide and an amioo ler·
minal tyrosine moiety. (In Ihe soon-hand sYSlem, Y
is the symbol for tyrosi ne.) It has 36 amioo acids and
is chemically similar to avian p p (2 1!) Table 2-
2). PYY inhibils Ihe release of secrelin and CC K-
PZ. deprcsses jejunal and colonic motility. and ele-
vates Ihe blood pressure by promoling vaSOC<lnstric-
lion (n?).
OTHER ISLET CELL PEPTIDES
Gastrlns
Gastrins arc produced mostly by glands of Ihe £10m-
3ch. and they exert Iheir mOSI obvious intluences On
the secretion of Hel and on the maimenanee of Ihe
epithelial cells of Ihe gastrointestinal lraCI (Chaps. 2
and 3). Although they are found in felal pancreatic
islets and in islet tumors of adults. there are con·
troveni .. concerning their consistent presence in the
normal adult panereas (139). The peptides found in
adults may come from the nerve endings. Inhibitory
inHuenees on insulin secretion have been observed.
but no physi(}logical role in regulation of beta cdl
functions has been established.
Nauromodulatora
The islets contain small quamities of several pep-
tides implicated as either ncuromodulators Or partie·
ipants in the paraerine cOlltrol of hormone secretion.
These include p-cndorphin (20). ga'IToim.stinal in·
hibitory peptide (GIP) (which also elsewhere
and may comribute to meal·associated insulin r.,.
lease). thyrotropin-releasing hormone (37). and va·
_Clive intestinal peptide.
NSILAS AND OTHER FACTORS AFfECTING
INSULIN FUNCTIONS
Blood plasma contains peptides that exen insulin·
like actions. but whose activities are nOt blocked with
antibodies that interfere with insulin. Two that were
formerly known as NSI LA (nonsuppressib!c insulin·
like activity) have been characterized and arc now
called insulin·like growth factors I and II (IGF·I
and IGF·II ). The liver=ms to be the pr imary site
of origin. The growth faClOrs are induced by pitu·
itary growth hormone. They are discus.cd in Chap-
ter 18.
T he blood of 'lOme patients sulTering from insulin·
resistant diabetes mellitus contains substances that
reduC<' the elTectiveness of exogenous hormone . The
term .pm/bumin designatcs an uncharacteriled fac-
tOr that associates with (but can be separated from)
the plasma albumin (45). There arc those who be·
lieve it is identical with Or is derived from the insulin
B chain. Antireccptor antibodies have been found in
small numbers of patien1s.
M(lSt patients receiving insulin therapy develop
some antibodies against both insulin and noninsulin
components of the preparations. It has therefore
been advocated that highly purified insulin. be
given. The laller are. however. expensive and in
shon supply. MOSt pa1ients requiring exogert<)us hor-
mone retain sufficient sensitivity to the cruder mix·
tures. despite the antibody proouction. Some benefi t
from switching to insulin. obta ined from a dilTerent
species.
BIOSYNTHESIS AND METABOLISM OF
INSULIN
The formation of proinsulin from a larger precursor.
and the cleavage of the proinsulin (molecular weight
approximately 90((1) to insulin (monomeric weight
approximately 60(0) plus a connecting "C" peptide.
were diseussed in Chapter 3. Some proinsulin. along
with the enzymes that catalYle its cleavage. and
some zinc. are packaged into tne secretory granu les .
Equimolecular amounts of insu lin and of C peptide
are released into the bloodstream by normal individ·
uals. but the C peptide has a longer half·life in the
circulation.
Currently available bioassays do oot distinguish
bet"",en exogenous and endogenous insulins. A spe-
cial procedure for detecting C peptid.. (which are
not contained in the insulin extract) is therefore use-
ful for assessing the islet cell functions of patients
receiving replacement therapy. It also can provide
information on tumor activities. since at least some
of the cells release large quantities of the C peptide.,.
High circulating C·peptidc levels have been found in
patients with hypokalemia. and th= are corrected
when the electrolyte balance rC!)lOred (182). The
C·peptides are not known 10 possess biological
activity.
Usually. proin\ulins constitute 15%-20% of the
product of the ccll\. Some variations related to en·
docrine status have been found. The molecules can
bind to insulin receptors and exert weak actions
qualitatively similar to those of the hormone.
The hormones associate with plasma proteins and
travel from the pane,""atie veins to the hepatic portal
blood ve.'<Se t<. The tiver. therefore. receives the high.
est concentrations. Proteolytic enzymes. glutathione
insulin dehydrogenase. and probably al50 glutathi.
one n:duetase. contribute to intrahepatic degrada·
tion of approximately one·half of the insulin and a
smaller fraction of the proinsulin that enters. rnsulin
that gets into tbc extrahepatic blood "essels is
picked up by many kinds of cells. The kid ney
degrades around one-third of the sec'""ted insulin.
along with a higher fraction of the proinsulin. Some
injccted insulin can find its way into the urine.
especially when the doses are large. but very little
of the bormone is found in the urine of healthy
subjects.
Plasma concentrations of radioimmunoassayable
hormone arc around 5-15 " Uj ml in fasted humans.
and 5%-30% of this is proinsulin. The levels rise
sharply soon after meal ingestion. When 100 g glu·
= is taken orally. substantial elevations are seen
within 15 minutes. and pea k concentrations of to
eight times the basal levels are attained in l> to I
hour. It has been estimated that the basal output is
in the order of I UI hour (171).
The values are usually expressed in units. since
botb blood and therapeutic preparations comain
other substances that can alTectthc assays . One unit
is approximately equivalent to 0.04 mg of purified
peptide.
 ...
METABOLISM OF OTHER PAN CREATIC
HORMONES
Alpha cell "true" lllucagons of all kllOwn mammals
(except the auinea pial llav<: a mQlocular wdght of
3485. Ahhouah si milar pcplides arc ma<k in the
stomach and intestine (and tile)' may be rckased in
substamial qUMlilies when a lpha cell functions are
depressed), mOSI of Ihe circulaling glucagO!l 3SOO
seems to come from Ihe islets under normal condi-
tions. Glucagon 2000 i$ probably a bioIogiully in-
a<:liv.: degradat ion pl"Odocl . Since lite: ciml laling
aJucagon 9000 can be dcaved \0 yield 1/w: JSOO "".
ricly. it may be a prccUI'$OI', Usu ally. only small
a mountS of "biS" a nd "big-big" glucagon. a rc pre,;..
ent in the blood. They are believed \0 be either poly.
mers of the smaller molecules. or smaller peplidcs
' WV';.aleO wilh nonbormonal Proteins wilh
we ights or SO.OOO. 65,000, and 180,000 haV1) b«n
found in salivary glands and SOffil: pans Qf the gul
(217). bul few arc rcleaud into the bloodstream.
The high potencies of glucagons are attributed in
part to low for the plasma protein!;. MOit
of the islet cell glucap enlers lhe li.-cr. in which
enZYrr>e$ that also act on insulin degrade around
I,...,..thirds of the quantity delivered. The kidney is a
major site for degradation of the hormone thaI en-
len the ex". "",-""I. high gl" <::1&"" Io.v_
el$ can build up in palients with 5e.-cre renal insu f-
ficiency). Small amOu nts are into lhe bileor
arc allaeked by eirculalin!
Since 5e.-cra1 varieties $hare immunolotical prop-
ertics with "truc" gluclgoM, the plasma levels re-
ported depend upon th e specificit;csof the amibodics
employed in the a ssays. After an overnighl fut, hu-
mans are said 10 have 50-1 SO pmol/ ml, but the val.
ues tend 10 rise: during 11M: Ihird d<=dc of life (10).
Although tIM: fall rapidly to around
15 pmol/ml afler the ingestion of 100 g of glucQ5C,
there are only small diu rnal variations when bal.
anced meals Ire taken al conventional intervals (53).
Fasting ,Iucagon dellflldation. and this ac-
counts for much of lhe elevation during that lime.
"Basal" levels of somatostatin-like immuooreac_
livity (SLl) at(: in the general neighborllood of 150-
200 pg/mt. The diurnal variations follow thc pat-
terns described for inrolin.
Plasma con«ntrations of PP in heatthy humans
rise from around 54 pgjml in IIIe third decade LO
mean values close r 10 297 pal mi in the seven th
do:eade.
REGULATION OF ISLET CELL SECRETIO N
TIle iskt arc Il'glilated by (a) constituents of
Ihe bl""'" plasma Ihat ir><:lude not only glucose. bUI
THE EHDOCRINE PANCREAS
also a mino acids. fallY acids, circulating hormones.
and inoraanic ions; (b) adrencrgic. cholinergic. and
pcptidcrgic innervation. and a wide variCly of ncu·
romodulalors; and (c) pamerine control s operating
locally. These probllbly involve both diTC(:t
cell communicalion via &liP junctions. and lite seqe.
lions thai onc cclltype releases in Ihe diTC(:1 vieinity
of another,
Interrelationships among the regulators all' nu·
merous and complex. Glucose is a major stimulant
for tIM: insulin-sccll'tin& bul il the ac-
tivilies of ,II of IIIe others. It also modifIeS the sen-
sitivities to different Il'gulalors. Some amino acids
stimulate both alpha and beta cells, but olhel':! arc
more selcctive (50),
G lucose promotes CAMP generation. and some of
its actions an: mediated by that nucleotide. Ho,.,_
ever. gl ucose stimu lation of the bela cells
requires uII'lI""lIular Cal •. cA MP can be effective
in its absence. Higb tontcn tratlon$ of Ca lo Can di.
rectly promote imulin secreLion, They also act On the
alpha cells to both augment arginine stimulation and
el<llucmte the glUOJlSC inhibi tion.
CholillerJ,ic slimulation directly augments both
insulin and glllcagon secretion. It also promotes tIM:
release of gastroinleStinal hormones Ihat travel to
the islet cells via the bloodstream. a,·Adrenergic re-
ceptors mt(\'ate Insulin InhIbition. ,.'her.'" bela ad·
Il'ncrgic receptors all' involved in stimulat ion. In ad.
dition 10 promoting the relcuc of catccholaminc:s
thai act on both types. sympathetic nervous s)1tem
stimulation affects the blood supply to tilt islel$ in
special wayllhal do not paral lcllhe .ffectson Olher
parts of Ihe pancTC3-1 (140) . Bombesin is a peptide
formed in both lhe gUI and cenlnol nel'\lOUs system
tha t can act via tile inno:rvation and also dirtttly 10
promote glucagon sccll'tion (19). Serotooin. d0pa-
mine. substance P, neuroten.in, TRI!. VIP. G IP,
prostagland ins. endorphins. and cnko phalins are all
found in the islets. and all are implicated in Il'gula-
lion of their functions. Hormoocs prodlKed else-
"'hell' additionally modulate both basal secrelion
and Ihe responses 10 $Iimuli.
INSULIN SECRETION
Beta act' V11lion is associated ,.ilh plasma mem-
brane dcpolariulion. forma tion of microvilli. uptake
of CI '· and Na - from tile su rrounding fluids. intra-
cellular redistribution of Ca". phosphate efflux
("'phosphate flush"), and phosphate binding to thc
plasmalemma and (51). I-Iypoxia. fuel dep-
rivation, and agenll lhat impair A TP ,eneralion. all
blunl responses 10 p/lysiological and pharrrnleologi-
cal stimul i.
Roles of Glucose
Glucose is by far the most important regulator. It
stimulates both prompt and delayed insulin rdease.
new hormone synthesis. growth and proliferation of
the beta and induttion of glucose receptors It
is also said to perform a "'memory function··. sincc
brief 10 the sugar enhances the sensitivity
to glucose and other stimuli that are subsequcntl y
pf<:sented .
The secretion falls off sharply during overnight
fasting, and minimal ('"basar·) ratcs of hormone re--
lease are established after three days of food depri_
vation. The quantities released by
tells vary with the endocrine status. (Even further
reductions can be achieved with catecholarnincs.
whereas high estrogen levels $Iimulate !691.)
NATURE OF THE SIGNAL THAT INITIATES
SECRETION
Somc obse,,·ers believe that the very prompt rC·
sponse seen after glucose pf<:sentation invah.. s dire<:t
intemction with "glucof<:ceptors·· of the pla'rna
membrane. and that sugars capable of mimicking
glucose effects interact with the same or similar re--
ceptors (151). A mOf<: widely held opinion is that all
effect. of the sugar require entry into metabolic
pathways. There seems to be universal agreement
that the delayed actions arc associated Wilh accel.
eraled glycolysis .
Glucose is taken up by facililated diffusion . It is
rapidly phosphorylated and convened 10 trioses .
Mannose. whith is similarly transported and metab-
olized, exerts effoxts not readily dist inguishable from
those of glucose . Mannuloheptose and deoxyglucose
interfere with glucose phosphorylation and they
block the stimulation (237). Galaclose is takcn up
but il cannot be metabolited. MOSI observers statc
Ihat it docs not activate Ihc cells (60). bUI effeotson
electrical activity of a limited number of cell, have
been describe<! [161 J.
Anempts have been made to define a specifIC me-
tabolite that is directly responsible for thc stimula·
tion. Among many others tested. phosphoenolpyru-
va te (PEP) has emerged as a candidate.
Glycerol-3·phosphate is rapidly oonvertcd to PEP,
and it is a potent Sl imulant. ,,·hereas pyruvate is
ineffective.
Gluc0se-6-phosphalc has b«" ruled ou l for ,e.eral
re.","" (a) il;' nol made when manno:« i, phosphoryl.
"ed and senl inlO glycol>"i'; (b) iodoace,.,e (1-<:11,·
COO-) i. a potenl inhibitor of th. glyccratdeh)·d... 3·
phosphate dehydrogenase n•• ded 10 make PEP from both
glucose and gl)·coratdehyde·J·phosphal • . It does not in·
lerfere with the formation of bUI;1
btock, "imulotion by bolh glucose and gllc ..... ldehyde
phosphale; and (e) mannuloheptO$< prevenlO Ihe f",ma·
lion of glyce .... tdehyd. phosphate PEP) f,om glu·
cose. but it doc. rIOl les .. n Ih. stimulalory .lfccts of th.
glyceratdehyde phosphale.
Other con,ideral;ons have led to the eliminati"" of 6·
phosphogluconal' (of Ihe h..ose monophosphate path·
way) "nd of dl .... le (oblained ..·hen PEP undergoes fur·
thcr mctaboli,m (19).
An entirely different conccpt is that thc stimula·
tion is not relaled at ali to thc formation of some
specific glucose mClabolite. Rather. thc u!'C of glu·
cose leads to changes in NADH:NAD' and
NADPH:NA OP ratios. ,,·K etoisocaproic acid
brings about similar changes. and it mimics both in_
s ulin·releasing and '·memory"· aClions of glucose.
According to some authon; the resulting acceleration
of oxidative phosphorylation is then linked with the
Slimulation (74), but others believe the major cffects
arc changes in extramitochondrial redo. potentials
that affect membrane tltiol groups (1)2).
Roles 01 Cslelum Ions
The elfects of glucose are believed \0 be mediated via
elevation of the cytosol Ca". Although some early
effects may be accomplished by redistributing intra·
cellular calcium. the sustained ones absolutely re-
quire ions supplied by the environment (103). High
glucose ooncentrations increase total cellular cal-
cium while glu",""", deprivation (and Slar-
vation) lower both the calcium <:antent and the sen·
sitivilY to glucose stimulation.
Higb e,traceliular Ca" alone is an effox\ivc Slim·
ulant. The calcium ionophore A 23187 promotes in·
sulin secretion when extraceliular Cal> is available
for transport into Ihe cell, bUI not when the Auids arc
talcium depleled . Verapamil (a calcium channel
blocker) obliterates the effects of high extracellular
Cal>. DantNle"e sodium interferes with the recruit-
menl of Ca" from intracellular stares . It blocks the
stimulatory effects of glucose. mannose. and glye-
erol-3·phosphatc. but it does not slow glycolysis
(MS).
Afler prolonged gtucose Itimulalion. C." ,ff/ux ....
cel ..... t••. It i, believed tha t •• c.... ive elevation of cylosol
C.'· aCli •• ,., ptum. m.mbrane C."/ATPase ··cal·
cium pumps·· (232). Th. pumps ","ork 10 mainlain <>pli·
mum intr:lecllul3r catcium jon le""t,. but tbey do oot
overcome the force, tha, tead to tOlal cell co.kium
.coumul.tion.
Ca" is needed to activate some enzymes and to
maintain the funct ions of the microtubules and mi-
erofilaments involved in transporting secretory gran-
ules to the cell peripheries (112). It also interacts
with proteins that promole fusion of the granule and
plasma membranes (see discussion of sync.in. Chap-
ter 3). High intracellular Ca" facilitates the growth

and proliferation of many cell types (94). and it
probably has similar effeCls on the beta cells.
Pharmacological agent. that impair microtubular
functions block insulin 'ecretion. However, some mi-
crofilament poi5O!l$ have complex effects on the cells
(195).
Roles of Cyclic Nucleotldes
Glucose raises beta cdl cA MP concentrations (64) .
This is probably accomplished indirectly. via cleV3-
tion of the cytosol Ca2+ and activation of calmodulin
(218) . TriAuoperazine (which binds 10 the cal""""
dulin and prevents it from interacting with cnzymes)
blunts glucose stimulation of insulin release and of
cA MP generation.
Exogenous cAMP and ils analogs. and cyclic nu'
clcotide phosphooieslera", inhibitors such as MIX.
promote insulin retease. but only in the presence of
glucose . It has therefore been proposed th"t cAMP
contributes 10 glucose-depcndent stimulation but
that it is Mt. of itself. sufficient to activate thc se.:rc'
tory process. One role seems to be redistribution of
thc intracellular calcium StOres. (Unlike glucose,
cAMP can augment inSUlin secretion in cells previ·
ously exposed to the sugar even when the surround·
ing do not ""ntain Ca' · .) cAMP alto impli.
ca ted in activation of protein kinases that catalyze
phosphorylations of regulatory molecules. ( Phospbo-
rylations have becn demonstrated, but thc proteins
h"ve not been identifoed. Kinase C activation is now
believed to contribute.)
One function of ATP could therefore be provision
of the substrate for the adenylate cyclase. Another
would be participation in the phosphorylations cat-
alyzed by both the cAM P-dependent protein kinases
and the hexokinase and
Glucagon is a potent stimulator of the fJ cell adc·
nylate cyclase. It and some other peptides are be·
lieved to promote insulin sccrction in this way.
Only early effects have been linked with cAM P.
The deeline in insulin se.:rction and the loss of sen·
sitivity to stimulants that result from fasting arc not
associated with lowering of adenylate cyclase activo
ity. In fact, a brief discharge of insulin can stili be
accomplished with theophylline (but it is of much
smaller magnitude than when the agent is presented
to islet celis receiving gluCO!<e) (123). (On the other
hand, the augmented ratc of insulin relcase by preg-
nant rats is associated with high cyclase activit)'
[122].)
The whereby gluc= preferentially
accelerates proinsulin synthesis (as it exerts lesser in·
fluences on the formation of other proteins) are not
known. The effects are not mimicked with cA M P> its
analogs, or the phosphodiesterase inhibitor:;.
TKE ENDOCRI NE
Sustained presentation of high glucose concentra·
tions leads to cell growth and proliferation. The pre-
cesses are ev idently separable from the one. inVQlvcd
in hormone release. Dia1.oxide is one of the agents
kn<;lwn to interfere with hormone secretion but not
cell division. (It i. believed to act at the level of
cxocytosis [ 104] .)
The effects of the strong glucose stimulation may
include calmodulin'mediated activation of phospho-
diesterases. (Thcophyliine and dibutyryl cAMP in-
hibit thymidine incorporation into beta celi DNA.
and they are known to inhibit proliferation of othcr
kinds of cells (104].)
The "memory" effects seem to depend on stimu·
lation of metabolism and the accum ulation of cal·
cium. They are not affected by cAM P.
No involvement of cGM P in the stimulation by
either or acetylcholine is known .
TIME-COURSE FOR INSULIN RELEASE
When the beta celis arc exposed in vitro to concen·
trations of glucose within the "physiological range,"
2%-5% of the insulin contcnt is dischargcd within 2
minutes. A "refractory perioo" then ensues in which
further insulin rcicase cannot be provoked by either
<"Qntinucd exposure to the '"gar or the presentation
of dilTerent kinds of otherwise potent stimuli.
If a !«Ond Slucose stimulus is prescnted (or if the
celis are continuously surrounded by sugar conce ....
trations of this magnitude), a dc1ayed. sustained
phase of secretion can deplete up to 20% of the islet
insulin content. Vcry high glucose concentrations
can inVQke even 8reater and more sustained elcva-
tions of the secretory ratcs (Fig. 5·15).
The acute response is belicved to contribute sub-
stantially to thc of normal "glucose tol-
erance," and to provide immediate protection
against sudden bout. of hyperglycemia (e.g. when
carbohydrate food is taken) (72). A brief "spurt" of
insulin release can also ,erve in an "anticipatory" Ca-
pacity when food intake i, contemplated but no glu-
cose has yet arrived. The endocrine system is pre·
pared to aven (rather than correct) hyperglycemia.
In somc forms of diabetcs mellitus, rapid ci·
in blood glucose associated with food intake
(or the diagnostic administration of glucose), but
reasonably good control at other times. arc associ·
ated with blunting of the rapid responses.
It haS been suggested thaI the refractory phase
that follows provides proleetion against a "hypogly-
cemic overshoot," such as might OCCur if only a smali
amount of gluc= were ingested. or if the "cephalic
phase" of vagal nerve activation in rcsponse to ant ic-
ipation of food .ntry stimulated some insulin rekase
but th e meal waS then not taken.
 @pe.k
-.•
R.:.
" ®
-
ReI'""tory
5 period
'ateQ) ®.
-
Laten!
Fig . 5-15. l .... <:Ou,'" ot be.. ","I ","""'"" 10 gfoc<>S&
stimoJlul.
Thore has been <1"'OUlalion a. to. bUI no rully .. I·
i,factory explanation of. thc me<:hanisms . One idea
that a limiled number of secretory granulcs is es·
pecially sensili.e to the Slimulation. or is located
close cnough to the plasma membrane for rapid fu·
sion . Time may be required 10 translocate other
granules to the <;:ell periphery or to accomplish actio
.alion of the less acutdy sensiti.e insulin ·'pools_'" A
similar release pattern is seen when insulin secretion
is augmented by addition of calcium 10 the extracel·
lular fluid.
Another suggestion is that the <econdary phase is
pre<:eded by redistribution of the intra""lIuiar cal.
eium StoreS. (The acute rise requires extracellular
Ca". but the secondary one can be accomplished
withoUl il.) A third notion is that the early discharge
of small amounlS of hormone sctS up SOme kind of
intracellular negative fe<=dback control. possibly as a
result of signals received from Ihe plasma mem-
brane. Yet another thought is that the fITst '·bum"
of insulin rdease provokes localized discharge of so.
maloslalin. (This is difficull 10 rcconcile with obser-
vations lhat glyceraldehyde. which also elicits the bi -
phasic response. Can inhibit somatostatin secretion
[228J.)
The later ,tagC!l of insulin se<:rction depend On
new hormone syn(hesis. and the)" can be blocked
with cycloheximide_ Unlike lhe sitUalion described
for other kinds of :;ccretory cells, there is no evidene<:
that newly synlhe'lizc:d hormonc is preferentially sc-
EHectS of
....-----------
Plateau
®
cretcd. API"'r. "tly the pmcc..",,, of packaging the
prohormone into granules and granulc maluration
must f,rst take place (79).
INDIRECT EFFECTS OF GLUCOSE
Oral ingestion of glucose is more effe<:live than par-
entcral adminiSlralion of thc same quantity. The 0b-
servations that both the prompt and delayed re-
sponses to glucose feeding are abolished by eilher
atropine or abdominal vagotomy arc consistent with
the belief Ihat the effects are mediated via choliner-
gic nerves.
The "burst'· or
insulin discharge Ihat almosl im-
medimdy follows glucose ingeslion is attributed 10
the of ae<=tylcholine from nerve endings lhat
terminate On lhe beta e<=lIs (125). When isici cells
a re transplanted to dilferenl sites within the same
animal. they retain the ability to cUrl long-range
conlrol over carbohydrate metabolism. but the rapid
insulin discharge following glucose ingestion is not
=..Denervated islets do show the secondary re-
sponses. These are believed 10 result from vagus-
nerve-mediated slimulation of Ihe "'lease of gas_
troinlestinal hormones thai tra.eI 10 the beta cells
via the bloodstream.
The term iw:relin de'lignates gut faclor medialors
of lhe delayed increase in insulin :;ccretion that fol-
lows glucose ingestion. There are conlroversies rC-
'"
garding iI, nature. The lis\ of hormones '""wn 10 be
released and to stimulate lhc isle! cells (at least
when presented in high concentrations) includes gas-
lTin. secrelin. CCK·I'Z. cmerogiucagon. and gas-
uoimcslinal inhibitor}' peptide (GIl') (111); Hel
may also have such ClTcCIS (50). CCK·PZ is highly
potent. It has been suggested that it acts both di-
reclly and via pronlotion of glucagon rclease
Several invcstigators have been impressed with the
promptness of G Il' release. and with ils mong stirn.
ulation of bela cells. Olhers have observed, ho"",,vcr.
that i1 "ct,only in the prc$C1ICC of high glucose levels
in thc blood. and that il has no innucnces on lhc
alpha cells. A mechanism of aClion similar to that of
arginine has been proposed (42). Galactosc can be
slowly ronverted to glucose in the liver. It is a poor
insulin stimulant when gi,'en in vivo. but it releases
as much GIP a, glucose (60). Evidence for se<:retion
of an incretin of different (but unknown) chemical
ma keup thm ausmenls insulin relcase when nonnu·
Irients arc ingcstoo ha. been pre<enlcd (119).
An altcrnate explanation for Ihc less vigorous rCo-
sponses to intravenous, compared with oral. glucose
administration has been offered. T he plasma glucose
rises mO«' rapidl y, and provides a Slimulus for
thc rcleas<: of SS and of PP (both of which in-
hibitory innucnces on the beta <;<:lIs)_ A faclOr com -
plicating Ihc interpretation is that 55 also inhibits
PP secretion (167).
Inftuenee& of Amino Acids
Insulin is needed to promote efficient utili7..ation of
dietary amino acids. even when the meal does not
contain carbohydrate. Carnivores and others eating
mostly prtXeins are e,o;pecially dependent on such
stimulation.
A rorm of negative feedback control has been pro-
posed: Dietary amino acids promote insulin secre-
tion. The hormonc lowers the plasma concentrations
of the amino acids, s ince it accelerates their uptake
and in protein synthesis. The fall in eircuiatins
levels of the amino acids then removes the stimulus
for furth.r releasc_ Glucose indirectly oon-
tributes. When its plasma levels rise. insulin is se-
creted. This is SOOn followed by the lowering of the
amino acid concentrations (50).
Some species in the relative sensitivi-
ties to the types of amino acid, have been
described. [n humans. th. a1"<' reported to
be Arg > lys > leu> Ph. > Met Oil 11. Oil Trp
Oil Tn T, All of these are "essential" amino acids. His-
tidine. which is also essential. has little effect. and no
stimulation has been found with the other dietary
amino acids.
THE ENDOCRINE PANCREAS
Not all amino acids have thc same mechanisms of
action. Arginine Can stimulate only in the prcsence
of glucose. [t is slowly metabolized. and it s deriva-
tives arc ineffective. lysine and some nonmetabo-
hnble amino acids have similar effcets on the beta
cells , In contrast. leucine docs not require glucose to
stimulate. It is rapidly metabolized to o-keto-isoca-
proic acid (which is also potent). and the conversion
may be necessary for the effects on insulin release
(232) , Sulfonyl derivatives such as chlorpropamide
potentiate Icucine. but not arginine. stimulation
(SO). Mixtures of and glucose-in_
dependent amino acidS exert greater effects than th.
sums of their individual potencies.
Unlike glUCQSe. amino acids a", bener ,timulants
when they are given intra"cnously than orally. This
SUggCl;ts that their direct innuences on the islets 31"<'
more important than the ones mediated by the vagal
nerves. In addition to interacting with beta cell rc-
<;<:ptors, thcy indirectly ausment insulin secretion by
promoting slucagon ",lease , Protein meals arc. how-
evcr, mOre effeeti,'(: than amino acid miuures. prob-
ably because they arc good releasers of gastrointes-
tinal hormones. The observation that mixed meals
arc even beller hs been explained on the basis of
syncrsisms with carbohydrates.
Effeets of Fatty Aci ds
Ruminants (cows. sheep. goats) derive most of their
energy from thc short-chain fatty acids produced by
the microorganisrru; witni n their gastrointestinal
tracts. is a potent stimulant for insulin se-
cretion in these animals, and at least some observers
find that propionate i. effective.
Dogs usually ingest oonsiderablc amounts of fat.
Their beta cells show some st imulation by both bu-
tyrate and the Iong..:hain fatty acids. In contrast.
healthy humans On mixed diets fail to increase their
insulin secretion when siven long-chain fatty acids,
This is probably physiolosieally desirable. since the
fatty acids accumulate in the blood during times of
fasting and too much insulin would then invoke hy-
poglycemia. Some obese humans do not appropri-
ately lower theif rates of insulin .ec1"<'tion during
fasting or glucose depri.ation. and thcre have been
suggestions that th.ir beta cell receptors resemble
those of Other species.
Inftuences of Neurotransmitters and
Circulating Catecholamlnes
Acetylcholine aCts very much like glucose. but it is
effective when the blood sugar levels arc not ele-
It the plasma membranes and ae-
 celerates Ca" uptake. Release in response to fe<:d·
ing has been ciled .
The dominant effects of eatecholamines are ex·
erted on ..,.... drenergie The inhibition in·
voI.es hyperpolarization of the membranes and in·
terference with dcpoiari'.ation.
Since higher concentrations are needed to interfere
with Cal' uplake or to depress adenylatc cyclase ae·
ti_ity. it has bc<:n suggested that catecholamines act
at sites beyond glucose-mediated Ca" uptake and
cAM P gcneration (232). The inhibit ion ocrvcS usef"1
functions during times of exercise. stress. and food
deprivalion.
There are SOme indications that the beta cells arc
kept unde r tonic inhibitory control that is lifted in
Ihe presence of specifjc stimuli. The 'o<t'al nucleus
ambiguus of the brainstem (Amb) sends vagal f,bers
to the pancreas and abdominal _iscera. Direct stirn.
ulation there (but not at other braimtem sites) lead'
to prompt secretion of insulin. even when blood glu-
COSe levels arc low. Participation of GAB A in Ihe in·
hibilion is indicated by fjndings that bicucullinc (a
GADA antagonist) administered to the Amb pro-
motes insulin se<:retion if the ,....adrenergic control is
blClCked with phentolamine (9).
In the presence of ,....adrenergic blocking agents.
the elTeets of catecholamines on /J.... drenergic re<:ep-
tors of the islet cells can be demonstrated . Insulin
secretion is Ihen augmented. probably via activation
of adenylalC cyclase.
The ventromedial nuclei of Ihe hypothalamus arc
10 tonically inhibit insulin se<:retion. but 10
excrt stimulatory influences on glucagon and growth
horl1l()nc release. As already noted. thc "hypotha·
lamic obesity'· that develops after destruction of
those neurons is associated with hyperinsu linemia.
While bolh the hyperphagia and wcighl gain arc
blunted by abdominal vagotomy. More late ral parts
of thc hypothalamus arc implkated in stimulation of
the insulin-sccreting cells.
Several of the islel peptides are believed to origi-
nate in neuronS. Their effects can vary wilh the e<:11
environments. Substance P seems 10 inhibit insulin
secretion in the presence of glucose. Neurolcnsin
may 1101 exert direct influences. but it can potentiate
eholinergic stimulation (129). Endorphins are gen·
erally regarded as facililators of other stimulants.
Influences 01 Some Other Hormo nes
Intcrrelationship5 with growth hormone are multiple
and complex. Some of the amino acids Ihat prol1l()te
insulin secretion also stimulate GH release. The twO
horrnones work together to acromplish am ino acid
uptake and protein synthesis. but GH antagonizes
many of the elTe<: ts of insulin on carbohydrate and
lipid metabolism: and ;t thereby increases thc need
for insulin (93).
Insulin hypoglycemia augments GH se<:retion.
GH can di rectly increase insulin release by isolated
pancreatic islets. and it elevatcs hepatic porlal insu-
lin concentrations when thc blood glucose level. arc
high (198). GH also increases the se nsitiviliesofthe
beta cells to other stimuli via glucose·independent
mechanisms: and it indirectly augments insulin se-
cretion by elevating the blood glUCose . The insulin·
otropic elTeets of estrogcns arc allributed in part to
their stimulation of G H secretion. Estrogens also
prol1l()te prolactin secretion. and that hormone ex-
erts some G H·li ke actions. High prolaclin levels rna)"
account for the high levels of beta cell S1imulati()ll
during pregnancy in many species.
Acromegaly is ",id 10 reduce the nurnbers of in-
sulin ree<:ptors. but to inc rease th. affinities. This
could result in apparently normal insulin binding
when Ihc levels of that hormone are low. with blunt·
ing of the ciTe<:ts of high insulin concentrations
(146).
Glncocorticoid, elevate blood glncose concentra-
lion •. amagoni1e many insulin actions (84,146), af-
fect insulin and elicit indireci effects on
insulin secretion. The bela cell, generally show signs
of strong stimulation when glucocorticoid"'Sccreting
tumors arc present. or when high doses of Ihe Stc-
roids arc repeatedly administered. Chronic eAcessive
administration can exhaust the beta e<:lIs.
Sustained high eSlrogen concentrations increase
both insulin requirements and insulin secrelion ( 11).
In addition to promoting Gil secrelion, direci pan·
creatolropic actions have been described (45). Al-
though pregnanc)" and the use of oral contracept;.c,
have been known 10 bring about earbohydrale imol-
crance and hyperinsulinemia. the belief that the COn·
tracepti'·es increase the risk of developing diabetes
mellitus has becn challengcd (230). Progestins op-
pose many actions of estrogens. Some a ulhors state
Ihal they tend 10 reduce insulin se<:relion (11). but
olhers find Ihat cerlain of them increase it . The
numbers of insulin receptors have been shown to
vary with Ihe phases of the menSlrual cycles (33).
Angiotensin II can decrease insulin .ecretion _ia
several mechanisms that include vasoconstriction
and catecbolamine release . The plasma levels are el-
evated during some forms of st ress.
It is unlikely that either PTH or ealcilonin plays
impOrlant roles in regulation of i,let cell functions
under normal conditions. Caleium infusioRS may
slimulate insulin secretion in paliems with insulino-
mas, but they seem 10 have lillIe effect in healt hy
humans. In dogs. amoums Ihat markedly augmented
glucagon secrelion were found to have lillie or no ef·
fcci on insulin release (180) . It is not known why
infusions invoke changes opposite in direction to the

effects of bolus injeclions Or in vitro presentalions.
Marked bypercalcemia augments. and marked by·
pocalcemia depresse.. insulin secrelion. Palienls
wilh hypercalcemia lend 10 have high insulin
whereas ones wilh hyJXlparathyroidism generally
have poor carbohydrale tolerance and hypoinsulin.
emia that can be corrected wilb vilamin D admin_
istration. The effects of the low Ca" are seen in suI>-
jects with otherwise normal pancreatic islets (51).
Insulin . in turn. is necessary for normal calcium mc-
tabolism . Reduced bone mass is a cOmmOn finding
in bolh juvenile and adult palienl.l with diabetcs
mellitus (51).
An early clTeCt of insulin defIciency seems to be
impa ired abil ity 10 vitamin D to 1,2S-di-
vilamin D. and ther<:fon:: to absorb calcium
(187). The .lcvated PTH levels an:: attributed to the
resulting hypocalcemia_ There scems to be "app..,
priate" lowering of Ihe calcilonin concentrations.
After some time, ralS thai ar<: made insulin defi-
cient with streptOlOlocin acqui re thc ability to
achieve a jlO&itivc calcium balance de.pite persistcnt
impa irment of calciferol metabolism. T hey eal large
quantilics of food. and the high calcium content of
stock diets permits absorption of the mineral via ras-
sive (calcifcrol-independent) medanisms. They can
ingest sufficienl calcium to develop hypercalcemia
and hypercalciuria. Kena i excret,on of ca lCIum '$ cn_
hanced by the 05motic diuresis resu lting from hyper.
glycemia and kel05i$, and probably because the hy.
percalcemia inhibits PHI s""relion (85). The
metabolic acid05is facilitalCl; both calcium absorp-
tion and calcium excrelion,
[n addition to Iheir influences on intestinal absorp-
lion and plasma mincral content. calciferols promotc
intracellular sequestration of calcium and phosplJo.
TUS. The minerals can be recruited by physiological
regulators tbat promote calcium redistrihution. It i.
therefore no! surprising thai vitamin D deficiency
impairs insulin .""retion (152). Receptors for 1.25-
dihydroxy vitamin D, and a eakiferol..:lependcm cal-
cium-binding protein, have been identified in the
cells of chick pancr<:atic islets (18 1).
PP has bc.::n var iously r<:ported to inhibit (129) or
to have no elTect OJ) on insulin release. Prostaglan-
dins may stimulate under some conditions, but they
can blunt the elTects of glucose_
Effe cts o f Pharmsc o logic a l Age nts
Insulin musl be adminiSlered parenterally (since il is
degraded by gaslrointestinal en1ymes). In addition
to the associated pain. inconv.nience. dangers of in-
fcetion, and formation of antibodies. ther<: ar<: usu-
ally localiwl and occasional allergic r<:actions. Some
THE ENDOCRINE PANCRE AS
palients have difficulties estimating thcir r<:quire-
ments. and hypoglycemic episodes ar<: not uncom-
mon. Tl105e with visual and motor impairments have
special problems.
For all of these reasons, it would be desirable 10
have orally effeclive agents for controlling the insu-
lin deficiency. Two kinds have been used to treat pa-
lienlS, bUI problems have been encountered with
both (124) (Fig, 5·16).
SULFONYL DERIVATIVES
These agents arc inclTective in palients Ihal cannot
sc;cr<:tc insulin. and in pancreatectomilcd animals,
The most obvious initial effect is augmentation of
the sensilivily to glucose stimulation. The mecha-
nisms include activation of adenylate cyclase (232).
In common with cAMP, these agents fail \0 stimu-
la\e insulin symhesi s or i.let cell growth and prolif-
eration (171).
After some time, other cffects become evident.
Fasting hyperglycemia continues 10 be controlled.
bUI insulin levels decline to pretrcalment valucs_ At
Ihe same time. target organ sensitivity to tile hor-
monc increasc;s. and it is i\.';sociaied with Ibe acqui.
sition of larger numbers of insulin r<:CCpIOrs. How_
evcr. Ihe dangers of developing hypoglycemia are nO!
as gr<:at as with insulin injections.
The agents th.t have been devdoped differ
from .ad oth.r in their lim< cours« of action . Tolbtl'a-
mi<!e (Orina.e) wa. among 'he finl to be tesled, It i, de·
graded in Ihe liver and Ih .... fote is rIO! .lfeetive for mOre
Ihan 4-10 hour$. Acetohexamide and \(.I",.amide arc al$O
aCled upOn by hepatic enzyme •. bUI Inc metabolites bave
hypoglye.mic pOteneiO$. (Therefo,. ,ingle d.il)' dosc.
u.ually .uffice.) Chlorpropamide h.,the longe" duration
of aClion because it bind. 10 pla,ma protein •. uoderg""s
liUIe degrad.,ion, and i•• Iowly «.re,ed. Two ne ...er
agent. b.>e much gre ... r pOl.nci ...
Co"ltoversie. have ari .. n concerning Ihe ",fety. since
Ihe ... bave been rCpOm Ih .. Ihe inciden«.s of death from
cardiov.ocular failure are g ... aler i" patient . ... e.i.ing
the 'ge"IS Ih.n in th"", I,e",ed by diel alone (lOS).
The ... arc also numeroo. sidcxlfccts. Many patienlS de-
velop gaslroi.,csti.al problem. (nau .... diarrbea. >om·
iting. and cramp.o) and ' kin ra.hO$. and a few ba>e more
..,iooo problem. (li.er damage, agr,nulocyl""i'l. Chlor_
propamide can act On the kidney in much Ihe ,.me way
as anlidiurelic hormone, The effeel' are amibuled 10 ac-
liv"K," of renal adenylale cycl .... Chlotpropamide also
inleract' wilh olher medication, frequently prescribed for
palienlS wilb di.bete. melli,",
Preparalion, wilh Ihc dcs"ibed actions are of no
value in Ihe tr<:almenl of severe. insulin-<lepcndenl
disorders Ibat arc associated with kel05i"
The big.anides can lower blood glucose levels in
 ,,0 0
" 5-N
" Ii - C-N
H H,
8

,,0 0 H H IiH Ii
""HUHHH
5- N - C- C - C - C -CH, C - C -H - C- H-C-NH.
o" H Ii Ii HH
""
II "
,
Ph..,lormin (OBI)
"
o
H,c-C "

Oiazol<i<lO
,",
,
o
ou H H H ' N
j
,,0 0
,,,HuH
C- N-C - C - S-H-C-N-(

" " 8 \.-J

"o
1--f0H /N=O
HN-C-N-CH,
alit>u<ide (Glibenclamid)
o"
\\ 0, S-N-C
, H,,0 - N....(
H
o" ' '---J

0"" NH

" o"

5-16. .o.g.nt. aclio1Q on beta cell. oj patlCfoatiC j....,.

ond .,wlin feI ge' 0<\lIl"'.

panc!"<'3tectom;zed anima ls and in palients unabk 10
PrOOuce much insulin . H(}w ••-••. they are IIOW gen-
erally regarded as 100 IOxic for human Us.(!. In pa.
(icnlS with diabetes mellitus. pyruvate dehydroge-
nase acliv;IY;5 subllQrmal, which probably accounts
for the tendency (0 ac<.:umulalC lacti, ac id. O ne con·
seq ue nce is exacerbation of the melabolic acidosis
invoked by Biguanidcs ;n,,,,sse the lac_
toacidosis. e'I"'cially when there is ooncurrcm renal
insufficiency ( 49).
Methyl .. nthine< ele,oto cAM P le_.I. ond acl in ot he,
10 ' Iimul .te in.ulin They are oot useful.
ho'"" ..... r. fo, controlling hyperglycemia.
Di"""id. i.,encrally used 10 lower the blood pressure.
lt can decrease in,ulin .. eretion by promC>ling the relea,e
of cat ccllolamine. and by ,cling d;,oetiy on lhe .Ipha ad-
reccpl<>rS of thc inlul in... crelin, cells, Its effect.
are enh.nced by beta bl",,' in, a,ent. , ueh as prop""""
101. S I,epIOW\ocin i•• widely use<lexpcrimenl.1 toollh.t
damage> both ,Iuc.gon- and i",ulin«cfct;n, coli .. It ha,
been given 10 pati.nl, "ith in,ul iflOmas. AlIo .. n is • toxic

agent used to destroy the beta cell. of cq,.riment.1
animal •.
REGULATION Of GLUCAGON SECRETION
In .. well.nourishcd humans taking regular.
glucagon secretion continues
throughoul the 24-hour period al a fairly
basal rate. The diurnal variations in plasma concen·
trations are of limited magnitude when the diet COIl·
tains moderate amounts of carbohydra te. The small
changes observed are a(( ribuled moslly to Ihe inftu-
ene.:: ofT) rhythms on glucagon rales (37).
If blood glucose levels rail below 50 mg/dl. the re-
sulting of release varies di·
rectly wilh the severity of hypoglycemia. Rising
blood glucose concentrations inhibit glucagon secre·
tion. and maximum suppression is atlained at con·
centrations of 150-200 mg/dl. Hyperglycemia also
increases the sensitivity to other depressants. Insulin
is a major inhibitor. but its aClions on the alpha cells
require the presen"" of some gluC<lSe .
The roles of calcium ions vary with their eoneen·
!rations in the ex tracellular flui d. and with the
amounts a nd kinds of nutrients in cell environ-
ments (115,128). Some Ca" is absolutely required
to maintain secretion. probably because it plays roles
in exocytosis of the kinds described for mOSt other
cdltypes. Ca" is also needed 10 ,uppon stimulation
by other regulators. Glucagon release is blocked if
the cells are bathed in Ca" -{\efieient Au ids, or if
agents such as verapamil (which impair Ca" up"-
take) arc presented. On the other hand, moderatc
of Cal. support glucose
inhibi tion. and very high ones directly interfere: with
glucagon rei case.
Allhough physiological concentrations of Ca"
contribute to adenylatc cyclase activation, the en·
zymes of the alpha cells share some special proper·
ties with those of the cells of tbe
thyroid glands. The adenylate eyda... are inhibited
by small elevations of the Cal' cone<:ntrations above
the TC<Iuired for stimulation .
Glucogenic amino acids direclly stimulate the
alpha cells when they a'" to isolated islclS.
They are Ifl()!"e elfcctive physiological condi.
tions. since they enter the bloodstream along with
other components of protei n meals thaI invoke vagal
stimulation and the ",lease of gastrointestinal hor-
mones. CC K·PZ and VIP are among most p0-
tent of Ihe gastrointestinal stimulants.
glucagon promotes ketoge""sis and lipoly-
sis. il is physiologically appropriate that ketogenic
amino adds do nol stimulale secrelion of the hor·
mane. High free fally acid concentrations a rc alpha
THE ENOOCRINE P.o.NCf\E.o.S
cell depressants. and it has been suggested that they
engage in direct negative feedbac k control. Secretin
can synergize with mher regulators to inhibit glu·
eagon secretion, and thc levels are often elcvated fol.
lowing the ingestion of lipid·rich foods.
Acctyleholine stimulation is probably important
during times of meal intake . It does 001 secm to be
involved in alpha e<:11 responses 10 falling blood glu-
cose levels (54).
The cells may receive tonic
sympathetic stimulation that inwlves both alpha-
and bela·type adrenergic receptors. Glueagon out-
put diminishes when the splanchnic nerveS are cut.
It can be increased by stimulating th e nerves of in-
tacl animals (37).
Hypothalamic ma nipulations that affect insulin
release generally extn opposing inAuences on glu-
cagon secretion.
PARACRINE CONTROLS
The specialized architecture of the isicls. and the
presence on each cell type of re""ptOTS for hormones
produced by the others. support the operation of
highly sophisticated, localized controls within each
organ (216.21 7). Gap jWICIiOllS facilitate
of ions. cyclic nucleolides. nutrients. and small pep-
tides, while Ijgnt jlmclions Hmil or block such com-
munication as they favor release of horfl1()l\Cs to the
adjacent environment.
The beta cells arc clustered within the ""nters of
the islets. and neighboring ones arc cou-
pled. It has been demonstrated that fluoreseent dyes
arc transported from one cell to the (lOti), and
that number of gap junctions inc reases following
gl ucose While such arrangements
can enhance the effccti of stimuli. they probably
function more to protect aga inst the discharge
of excessive amounts of the hormone. The rates of
insu lin release accelerate if the cells are a rtificially
dispersed. and they return 10 control levels following
reaggregation (78).
55 has a shen biological half·life thaI makes it
especially suitable for functioning over short dis·
tanees. Gastrointestinal 55 cells have long processes
that terminate on the gastrin-secreting cells and con·
tribute to their inhibition. The SS cells of th. islets
may communicale in similar ways with alpha
and beta ""Ils (11 4). As discussed in Chapter 2, 55
is a highly potent inhibitor of glucagon secretion.
When present in high concentratioru;. it also de·
creases insulin release.
The beta Cells situated along the peripheries of the
cl usters are contiguous with delta (SS), and also
with either alpha (glucagon). Or F (PP) e.::lls: and
 they can transport dyes to them (141). Some delta
""lis are always in direel contact with alpha Or f
""lis.
Hyperglycemia inc reases Ihe activities of beta a nd
delta cells. as it inhibits the alpha ones. It is then
appropriate to decrease the !'dte of gluo.gon s.ecre·
tion. and the SS contributes to the response.
Very high glucose con""ntrations also increase the
numbers of functioning SS re""pton on the surfaces
of the beta ""lis, The process does not 1"<'quire protein
synthesis, and it is not associated wit h decreased
rales of receptor internalization . It has therefore
been propoSed that when insulin is released. the se-
crelOry granules carry SS receptor.; from the edl in·
teriors to the plasma membranes (206). SS can then
more effecti vely \:ccp the bela ,,<,lis under control.
Acelylcholine augments the seerelion of both in·
sulin and glucagon. The ,"".ponse is appropriate
when protein-rich food eaten. since insulin then fa·
cilitates diversion of ami"" acids into anabolic path.
Wa)'s. while glucagon protects against the develop-
ment of hypoglycemia. Cholinergic ne,"e endings
a re most numerous in islet regions that permit dircct
communication among alpha . beta. and delta cell
types. Some of the effeels of the neurotransmi tter
may be accomplished via inhibit ion of SS
Insulin is believed to act loeall y to inhibil gluca-
gon release. whereas glucagon acts within the islets
to stimulate insulin secretion.
The role! of PP remain 10 be defined. It ha. been
noted. however. that islels in which F cclls replace
the alpha cells SCC1"<'te more insulin, Prolein.rich
meals, acetylcholine. and CC K-PZ are among thc
stinmli that affect both the alpha and F ccn •. This
raises the possihility that PP or a peptide associated
with it aSsu meS some spec ial importance when the
food contains ketogenic amino acids along with
enough carbohydrate to maintai n cugl)'ccmia.
The existe nce of islets with few alpha cells. and
the inhibitory effects of "oth SS and insulin in the
islets in which alph edls are abundant. suggest that
mammals have a necd to prolect themselves against
glucagon release.
EXP ERIMENTAL ISLET CELL HORMONE
DEFICIENCIES
Although much of the early work on insulin was per·
formc<J on pancreatectomized animals. the surgical
procedure for crealing deficiencies has numerous
drawbackS, especia lly for 10ng_lerm studies. In many
of the mammals, th. pan<:rea$ ;s a diffuse organ. It
is therefore difficult to excise. Evcn skilled surgcons
inflict considerable trauma to blood vessels
neighboring stmlu rcs. and il is often impossiblc to
remove all of the endocrine cells. There is simulta_
neous I<:ISS of all of the islel cell regulators, and no
satisfactory method has been devised for replacing
all but the One to be investigated. The net results of
the surgery are determined by the relative impor.
tance of the various peptides. Carnivores and olhcrs
that usually ha'·. long intervals between meals suffer
most from insulin deprivalion. Ruminants also de·
.'clop insulin-defoeiency sym ptoms. but Ihey arc bet·
ler able to lo\erate the loss. (In contrast. bi rds gen-
erally develop hypoglycemia and other sym ptoms of
glucagon deprivation.)
A very $Crious problem in most verlebratcs is the
removal of Ihe exocrine cells. The pan·
creatie juicc contains en7.ymes essential for Ihe
digestion of most foods. II is also suspected Ihal Ihc
acinar cells release other physiological regulators.
and •• ""rine compooents of the pancreas
ore >cpa rated in some of the fi,he" .t udiO' on
tbo$c . nima!> provide only Hm;ted in, illha into in,ulin
functions in other vertebratcs.
Pharmacological Des tru ction of the Islet
Cells
Chemical techniques eliminate Ihe undesirable COn-
sequences of surgery inelude pain. trauma. pro-
longed anesthetiration. loss of exocrine tissue. and
nonspecific slress. A major disadvantage is Ihat all
a_ailable agents invoke unWllnted "side effeels".
Alloxan transiently stimulatcs. and ultimately de·
.troy•. th. beta cell" but the component. a re
preserved. It is difficull to determine appropriate
dosages. Even when linermales of highly inbred
strains arc used. a quantity Ihat fails to accomplish
adequate destruction in one animal can be leI hal 10
another. Alloxan i. a lso toxic to Ihe bone marrow.
Strept07.oloein is in SOme way. more useful. since
graded dosages can be given to achieve the desired
degree of insulin deficiency. Howe\·er. effects are
a lso exened on the alpha and delta cells. On the kid·
ncy. and often on Ihe immune s)'stcm.
SS. long-lived SS analogs. mannu loheplose. and
dia7.oxide arc among the agents used 10 transiently
suppress insulin sec1"<'tion . Some of thc analogs show
high spec ificities for just Ihe beta cells. bUI SS-14 is
a potent inhibitor of glucagon release. Since Ihe ef.
fects are 1"<',·ersible. the animals can be studied while
suffering aCute deficiencies, and also during the reo
covery period. They can be resled and subjected to
different experimental conditions when they arc
given a second course of treatment. A disad"anlage
is that the su ppression is incomplete.
Agents used to "sclec ti vely" destroy the alpha
cells include cobalt chloride. neutra l red. and syn·
thalin A (decmethylene-<iiguanide).
Excessive caloric or glucose inlakc and several
hormones that increase insulin requirements can 0"-
erslimulatc and e_.nt uany "exhaust"' Ihe beta cells.
,.,
"Meta hypophysial diabetes" hu been invoked by re-
peatedly administering large doses of growth hor.
mone that elevate the blood glucose levels and
antagonize insulin actions on largel cells. Glucocor-
ticoids also elevate blood gluoosc and antagonize in-
sulin effects. They additionally lower the numbers of
insulin receptors. Chronic overdosage leads to the
development of "steroid diabc:tes", Forced feeding
and administration exacerbate the hormone
effect •.
Immature an imals are generally quite resistant \0
such treatments. This has b«n attributed 10 their
high food intake under normal conditions. their re-
sponsiveness [0 growth normone, and Ihe "resil-
iency" of young tissues. There arc marked species.
strain. and individual differences in susceptibilities.
All of Ihe hormone trealments are with
thanges not !dated to insuhn
Antibo dies
Specific antibodies directed against of the hor-
mones have proV<'n useful for many kinds of inves-
tigatiom;. A problem is that the: proteins combine
only with the hormone mole<:ules with which they
COme in contact . and the deficiency is thus
incompl"c.
It is also pOSSible to get animals to mount autoim-
mune attacks against their own islet cells. Usually.
there are associated disruptions of other functions
that complicate interpretations of the data.
DIABETES MELLITUS
This tum is applied to a heterogencous group of dis-
orders with certain common features. Glucose tol·
crance ;s subnormal, ther<: are at leas t intermittent
bout'; of hyperglycemia and glycosuria. and other
symptoms of insulin dcficiency are manifested. M()St
patients eventually s uffer pathological changes that
can include thickening of capillary basement mem-
branes. microangiopathy. renal damage, arterioscle-
rosis. and cataract formation. Two major categories
and scveral subgroups are recognj'.ed (49).
Juvenile Onset Dlebetes Mellitu s (JOD J
This form is associated witb absolute insul in defi-
ciency, and with the development of severe hypergly·
cemia. ketosis. and acidosis if the treatment is
inadequate .
The first symptoms commonly appear soon after
initiation of the preadolescent growth spurt. proba·
THE ENOOCf1INE PANCREAS
bly because this is a time of increased insulin re-
quirement. However. they can ()C¢ur ocfore the age
of 2 years or during young adulthood. Some inves-
tigators therefore prefer tbc designation
diobetes melli/us (100), or type r diabetes.
Environmentally.imposed factors such as viral ill-
fcetions can bring about beta cell destruction in in·
dividuals with inherited immune system dysfunc-
tion, ( 154). Tbe genetic defect can involve impaired
ability to rid the body of viruses and cells damaged
by them. exaggerated tendencies to mount autoim-
mune attacks against previously healthy tissue. un-
usual susceptibility of the islets to invasion or de-
struction. or combinations of the preceding.
EVIDENCE FOR INHERITED PREDISPOSITION
Although there is a highly variable age of onset in
unrel ated subjects. identical twins living in the same
household often acquire the symptoms of JOD
around the same time. Such concordance of onset is
less common among nonidentical twins.
Certain combinations of histocompatibility alleles
occur with high frequencey among patient.l with
JOD. The patterns do, however. vary with race and
gwgraphicallocalc (51). It is therefOr<: considered
likely that the genes coding for those molecules can
inIN".' in .... e. ""'Y' with other dromo<om,,1
components as well as with environmental factors.
Autoimmune diseases occur with high frequencies
in some families, and hereditary pr<:dispositions have
been demonstrated for some of them. JODs and
their ,..,Iatives have greater incidences of Hashimo-
to's thyroidi tis, Gravcs· disease. rheumatic fever. and
other disorders than populatiom; of nondiabetics
matched for age and other parameters (191).
Insulitis, lymphocytic inftltration of the beta cells.
and other signs of immune system involvement have
been found in some recently diagnosed cases. a nd
autoantibodies directed against human pancreatic
cell proteins that impair glucose·induced insulin re-
lease in rats have been recoV<'re<i from diaoctic chil·
dren (6). There are strains of rats in which it is rei·
atively easy to stimulate tbe immune system to
destroy the islets cclls. and others that are highly re·
sistant to tht same forms of treatment.
Through selective br<:eding. colonies of rats have
been obtained in nearly 30% of the population
develops hyperglycemia. ketosis, and the other met·
abolic derangements SCen in JOD. Neonatal thy.
mectomy usually blocks development of the disorder
( 120). while the injection of antilymphocytic sera
ca n reverse the insulitis and reStOre euglycemia in
intact animals that have become ill. The insulin de-
fICiency can be corrected with transpla nts from
healthy animals, but disease-prone rats mount au-
toimmune attacks against the tissue within a few
days. The destruction differs from the usual types of
foreign tissue rejection. The animals will remain cu-
glycemic if they are given bone marrow cells from
healthy rats along with the transplants (1 4S).
EVIDENCE FOR VIRAL INVOLVEMENT (154)
Most viral infections OCCur more frequently at cer·
tain times of thc year than at others. There are sea·
sonal variations in the timing of the first onset of
JOD symptoms. In northern temperate wnes. the in·
cidences increase durinS the fall and winter. and
they peak in December. Clusters of cases have been
known 10 emerge in a geographically limited area at
defmed time intervals following epidemics of mumps
and other infcctions. In many young patients. it has
been possible to identify antibodies directcd against
certain viruses. and there is sometimes of
hepatitis or Coxsackie virus B, inf""tion. Some
young patients not known to have suffered discases
of this kind are victims of congenital rubella.
When identical twins are reared apart. they do not
show the tendencies to aequire the laD at the same
time. In fact, one may beCQme severely ill while the
other shows no symptoms.
It has been possible to inV<lkc beta cell destruction
in some strains of mice by exposing the animals to
enccphalomyocarditis virus and other agents. The
insulin deficiency that develops in experimental ani·
mals treated with streptol.otocin has been attributed
by SOme observers to changes in the {J cells that reno
der them mOre vulnerable to viral attack. and byoth·
ers to effects of the agent on the immune syslem that
facilitate the mounting of autoimmune re,"ctions.
Recently. it been dcmonstrated that both strep-
tozotocin and alloxan cause DNA strand breaks that
lead to augmentation of the islet cell nudear poly
(ADP·ribose) synthetase activity with oonscquent
dcpletion of intracellular NAD and impairment of
proinsulin biosynthesis. Some viruses may de'troy
islet cells in the same way (236). ([nf""tions can aloo
permit leahgc into the bloodstream of proteins that
are normally sequestered. Immune systems will
reaCt to them if they are perceiv.d as ··foreign.'· Vi·
ruses can also change cell proteins in ...ays that ren-
der them more strongly antigenic.)
UNUSUAL FORMS OF INSULlN·DEPENDENT
DIABETES MELLITUS
Some patients may have autoimmune problems un-
related to viral infeclions th"t CauSC them to make
antibodies directed against their own insulin recep-
tors (147). The receptors can show perfectly normal
binding properties. but the hormone is pr<:vented
from acting. Such individuals are especially ditlicult
to treat.
In very limited numbers of patients, thc metabolic
problems are allributed to the formation of abnor-
mal proinsulins and impaired ability to convert the
molecules to insulins (157). Responses to exogellOlls
hormone may then be similar to those of healthy per_
sons (A·5).
TREATMENT
Some form of insulin therapy is essential for JOD.
Often. it is uscfulto employ mixtures of preparations
with varying absorption rates. so that too frequent
injections can be avoided. While most patients do
,,·ell on the widely available extracts obtained from
bovine. ovine. and porcine sourees. some dinicians
believe that those who will require lifelong treatment
can benefit from highly purifted insulins that contain
fcwer antigenic conlaminants. Thc purified hor·
mones are expensive and in short supply. Iluman in·
sulins Cotlld provide further advantages. and some
progress is being made in techniques for synthesiling
them in bacterial systems (131). Devices that can
scose blood glucose changes and then deliver just the
amOunts of insulin nceded at that time 10 maintain
metabolic balance arc currently being developed.
There is also hope that islet cell transplants will one
day replace injections and artificial devices.
Maturity On set Diabetes ( MOO, Type II
Diabetes)
Disorders in this category are usually of a milder na-
ture. The symptoms indude hyperglycemia, glyco-
suria . and insulin resistance, but no ketosis or aci·
dosis. The plasma insulin levels are frequently
supernormal (but inadequate for the exaggerated re_
quiremenlll). Although MOD has been diagnosed in
adolescents. most patients have thcir first symptoms
after the age of 40. The incidence inc reases with ad·
vancing age.
Evidently. genetic and environmental factors in·
ternct . but thc hereditary pallerns and aggravating
conditions are different from the ones described for
100. Autoimmunc problems can be involved.
they do not play the prominent rol es suspected for
insulin-dependent diabetes mellitus.
It is estimated that close to 90% of the victims are
obese at the time of onset. and thcre i. good reason
to believe that )·ears of eXC<'SIlivc food intake aggra·
vate an underlying inherited def",,1. Obese identical
twins living in different cities and engaging in differ_
ent kinds of activity have been known to come down
with the symptoms at almost thc same time. Casc
histories reveal MOD in obese relatives. When One
identical twin remains lean and Ihe other becomes
,,.
obese and hyperglycemic. the lean sibling may retain
the ability to melabolize glucose in an app:lrcntly
normal manner. However. "chemical diabetes" (i.c.
defective response 10 hyperglycemic challenge) is
of len dete<::table , In contrast. humans with healthy
endocrine systems can remain obese for years wilh.
OUt showing signs of insulin deficiency.
THE HYPERPHAGIA HYPOTHESIS
According 10 this hypothesis. the following 1rain of
event!; lXX'urs in susceptible individuals: (a) Ih. di-
clary habits ;nc...,ase insulin requirements and pro-
vide potent stimuli for release of the hormone; (b)
lhe plasma insulin levels be<:ome chronically ele-
vated; (e) Ihis leads \0 "down regulation" of insulin
receplor numbers and blunting of Ihe responses to
the hormone; (d) therefore. there is a further in.
Crease in insulin requiremenls. and yet larger
amounts of the hormone are seeretoo: and (e) after
some time. even very high plasma insulin levels can·
nol maintain the hornwne funclions. In many of the
patients. dietary restrictions ameliorate Ihe condi_
tions. As Ihey lower insulin requirements and the in-
tensity of islet cell slimulation. plasma insulin levels
retu rn slowly to value;s approaching the normal
.... nge . The I'reel cell. 'hen er.,j".lly hn;!rl " I' ,h,.;r
hornwnc r=ptor numbers. However. in some indio
viduals the beta celi. become "exhausted". Or they
undergo changes that rcnder them hypersuseeptible
to injury.
The concepts Can be supported by several kinds of
observations. The blood insulin levels of most MOD
palients who have not received hormone therapy arC
high, and insulin resistance is easily demonstrated if
auempts are made to normali7.e the blood glucose
values by injecting insulin. Much larger doses are re-
quired than the ones given to patienlS with JOD and
islet cell destruction.
"Simple" obesity tends to elevate the blood insulin
levels and to invoke insulin resistance (135). Previ-
ously oormal cells maintained in vitro undergo in·
sulin receptor loss when they arc exposed to high
concentrations of the hormone. Adipocytes. lympho-
cytes. and other cell types laken from obese MOD
patients usually have subnormal numbers of insulin
receptors.
The increased insulin requirements imposed flrsl
by 0"er-<'3ting and later by «,ceptor down-rtgulalion
may not, however. tOlally alX'oum for the hyperin_
sulinemia of obesity. Hepatic clearance rates of the
hornwne are also tower than in normal subjects
(139A).
Dietary restriction alone is often effective for al·
leviating the symptoms of MOD. Interestingly, im-
THE ENDOCRINE PANCREAS
provement OCCurs when only a small fraction of the
excess body weight is lost. Women who deposit most
of their surplus rat on the upper parts of the body
arc mOre prone to development of MOD, and nwrc
likely to benefit from "'eight reduction if they ac-
quire the discasc. tlmn arc women who store mOSI of
their fat below the waist. This has been attributed 10
the much greater tendency for fal cells in the upper
part of the body 10 enlarge when food intake is ex·
cessive. and 10 shrin k when the diet is more moder·
ale (135). Lower body obesity is more commonly
linked with the presence of large numbers of adipc>-
eytes that arc normal in size and fat COntcnt.
PROBLEMS WITH THE HYPOTHES1S
T here arc findings that cannot be reconciled with the
preceding. It has been poinled QUI that maximal ef-
fects of insulin on normal adipocytes are achieved
when only 10% of the receptors are occupied by the
hormone (157) . (Other target cei ls have similar 1"\:'
quiremcnts.) It should therefore be possible for the
high levels of circu lating hormone to interacl with
sufficient numbers of receptors even when the total
population is low. The patienls should also display
full responses to exogenous insulin if the dose is suf-
ficiently laree ;, n<l' c-""" ("",", tMN
discussion). Unimpaired carbohydrate metabolism
has been described for some patients with a form of
museular dystrophy, despite reduclions in receptor
numbers (34).
In healthy persons. small increments in blood glu·
CQ$C concentra tions are rapidly corrected. mostly via
prompt suppression of hepalic oUlput of the sugar. "
stronger hyperglycemic challenge invokes acceler-
ated inward transpon of glucose aC rOSS the insulin.
sensitive plasma membrane "barriers" of the hor-
mOne target cells.
Some patients with MOD are unable to substan.
tially accelerate glucose transport when given
enough of Ihe hormone to correCI the hyperglycemia
(224). The observations indicate that there arc
poslreceptor defects thaI impair coupling of hor-
mone binding to cellular responses. The defects may
actually be caused by chronic insulin deficiency,
since they can sometimes be correcled with hornwne
therapy (158). S imilar postreceptor defects have
been described for streptozotocin-treated rodents
(95).
Ther. have been recent indications that high in·
sulin levols do nOt always bring aboul down regula·
tion of the receptors in vivo. and thaI effect.s of the
hormone on receptor regulation vary with the car_
bohydrate and fal contents of the diet as wdl as with
the caloric value (I 42.158). In fact. it has been sug·
gested that some of the "down regnlation" of insulin
receptors in patients is related to cooditions imposed
upon them during their stay in hospitals (142).
POSlree<:plor defects probably account for Ihe fail·
ure of some MOD 10 respond 10 dietary restriction.
There arc also limited numbers of MOD patients
who are of normal weighl Or even lean (224).
Clearly. the "down regulation of receptors" concept
cannot be applied to them.
A common defe\:t is within the islet cells. AI·
though the ability to synthesize insulin is retained.
the cells do not release adequate amounts of hor.
mone in response to a hyperglycemic stimulus. Pa·
tients with this kind of problem can have fasting
blood gluoosc levels within the normal range but su f.
fer bouts of hyperglycemia when they eat
Hormones that antagoni?.e insulin actions and in·
crease insulin requirements account for some fo,ms
of diabetcs mellitus. Glucagon may be a particularly
important offender. especially if the insulin sec relion
rale is subnormal. When there is insuHicicnt insulin
to support glUCQSe-mediated inhibilion of the alpha
cells, enough glucagon can be ",leased to invoke Se-
Vere hyperglycemia and also ketosi s, It is suspected
thaI some individuals put Out tOO much glucagon be·
cause somatostatin depression is defective. Glucagon
receptor antagonists have been shown to very sub-
stantially ameliorate the metabolic problems of in·
sulin-deficient rats (90). and long·acting somato-
statin analogs have had beneficial in some
humans.
Growth hormone. glucocorticoids. and thryoid
hormones all raise blood glucose level s, increase in·
sulin requirements. and affe\:t receptor functions.
Chronic oversecretion aoxounts for limi ted numbers
of cases of diabetes mellitus.
TREATMENT OF MOD
It has been strongly adVQCated that oOcse patients
with MOO be treated by dietary means and exercise
programs whenever possible. and that the limited
numbers of patients who do not respond adequately
should be given minimal amounts of insulin
(136,137). There is a growing tendency to include
substantial quantities of "complex carbohydrates"
and fiber in the calorie·restricted meak
Grains and vegelables are included because of some
evidene<: that carbohydrate deficiency and cxcessivc
of fats contribute to the metabolic prob-
lems. It has been assum«l that starches do not rap-
idly elevate the blOXld glucose because they arc ab-
sorbed slowly. This concept has recently been
challenged. but higl1-fiber diets may provide a dif_
ferent kind of advantage. They can supply traCe
metals (espceially zinc and chromium) that are
needed to maintain normal glucose tolerance.
The "oral (s,", above) were
widely used for a time. Some have suggested that in
addition to possibly aggravating the tendency to de-
velop severe and even fatal cardiovaseular problems.
the agents can be harmful because tbey initially el-
evate the insulin levels. This can nacerhat. the in-
sulin resistance and increase the appetite. Moreo''';:r.
insulin itself has been implicated in st imulating the
proliferation of the smooth musele of arterioles and
of thereby increasing the tendencies to develop
atherosclerosis .
Somc clinicians defend the use of the sulfonyl urea
derivatives, both in conjunction with dietary thcrapy
in MOD patien\\, and for "stabiliunion" of glucose
tolerance in patients requiring insulin. They question
the validity of statinical findings that point to larger
numbers of deaths from cardiovascular problems in
patients receiving the drugs and point oUi that oral
therapy is especially needed by who are
very young, elderly. blind, or unable to give them-
selves injections because of motOr impairments.
Relation ships between Insulin Deficien cy
and Patho logical Changes In the Tissues
lnsulin-deprived animals do not develop the kinds of
pathology commonly seen in patients with diabetes
mellitus. It has tbcrefore been suggested that the ti,·
sue cbanges result from hereditary defects that arc
acquired along with the beta cell problems, bUi that
they are not dire<:tly rela ted to insulin deficiency,
t.......... defic;eI>CY me'8b01i<: problems
<
Gcnelic
defects
changes in 'he tinue.
A second CQncept is that the primary defect is
thickening of the capillary basement membranes.
This impairs both insulin release and the normal
processes of tissue repair. It may also account for
some of the insulin resista nce.
I"'U"" ooficieocy
<
Ge .... tic Thickening ot
defect - - basemen'
membranes
Disrupte<1 metabOlism,
tissuo damaQc
A third idea that has long been conside",d and is
now widely is that insulin per se.
along with the bouts of hypergl)'cemia it leads 10.
accounts for all of Ihe clinical fingings.

It is rerognizcd that most laboratory animals ,ut,.
jeeted to insulin deficieo9 do not survive for the
time periods requir<:d for acquisition of the patholog-
ical changes. Recent demonstrations that hypergly-
cemia leads \0 accelerated glycosylation of macnr
molecules and disturbances in cell metabolism have
provided some indication, of the way, that insulin
deficiency can cau,e tissue damage. Ther<: has also
been r«'ent recognition that the hormonc performs
previously unsuspected roles. For e xample, il is
needed to su pport normal renal glomerular function
(11t).
Receptor defects and postreceptor disorders can
CQntribute 10 insulin deficiency al the celtular level
when the plasma concentrations are within the nor-
mal range or elevated. Insulin resislance may be a
cause, as wen as a consequence: of Ihc hyperphagia
of MOD.
REFERENCES
1. Ahl.kog. J. E,. Randall. p, K .• and Hoebel. B. G,
HypOthalamiC H)'perph.gio: Dissocioti(>!l
ing De'lruction of Noradrene,gic Neuron •. Sd-
Oil« 19Q.- 399_401. 19H.
2. Airhart. J" Arnold. J, A" Sti,e"'alt. W, S., arid
Low. R, B. In.ulin Stim.lo tion of Prot.in Synthe_
,i, in C..I",rro S1<o1el>1 .nd C.ardi. c Mu",le
Cel l•. A .....r. J . Ph,'';''', 141:
2A. Ar.balo. R. E .. Torm.nen. C. D.. H.rdgrave. J .
E.. NOland . B. J.. and $catlen. T. J. In Vivo Reg-
ulation of Rat Live, )-Hydro.y-J-Melhylglu-
t3ryl-Coentyme A Reductase: Immunotitr""'n
of the afler Sloon·t.rm Mev.lon.te 01"
Choksterol Fe.ding. Pro<:. Nail, Sri, USA
79: 1982.
3. Avruch. J .. Aleunder. M. c.. Palmer. J. 1...
Picr(c. M. W .. Ncmcnoff. R. A .. Blael:.h""f. P.
J .. Tipper. J . P..• rId Wilters. l. A. Rok of I"".·
lin-Stimulated Pfotein Phosphorylation in 11IS"lin
Action. Fod. Pro<. 4/: 2629-)).1982.
4, AVfueh. J .. Cartef. J. R .. and Ma rtin . D. B. The
Effect of [",ulin On the Metabolism of Adipose
Tissue. Chap. H. pp. 545--<>2 of Stei""r and
Freinkel. cds .. refefen"" 204,
Babcock. D, F.. Chen. J .,\.. J .. Yip. B. P.• and
Lord),. H. A. Evid.""c for Mitochondri.1loc.li·
,.,Iion of the Hormone-Respon,iv. Pool of Cal,
cium [on ;n Isolated Hepatocyte •. J. Bioi. Chom.
2j4: 81 17-20.1979.
6. BaeHe.l:ov. S .. Neilsen, J. H., Marnef. B.. Bild •.
T .. ludvigsson. J.• and lornmark. A. Aut.,.nt i·
bodies in Newly Diagnosed Oi.betie Childr(n 1m_
munoprecipilat. H.man Pancreatic Islet C.II
Prolein'. 167_9. 1982.
7. Ball.r. J, D.. and Rou"". u. G. G .. cd,.
(tNlit(JiJ ANion. Springer_Verl.g. New
York. 1979,
THE ENE>Oa;INE PANCREAS
8. BOll. Z. H .• Ston; k. J. A., and Brewer. H. B., J r.
Characterization and R.gulation of Reductas.
Kina.e, 3 Protein thaI Modulates the En,ymic
Activily of 3-Hydro,y-3-Methylgl.laryl·Coen·
,}'me A P'IX. Nat'- Acad. Sri. USA
76:4315_9.1979 ,
9. Bereile" D. A.. Berllooud. H._R .. Becker. M. J.
A.. and Jeanrenaud. B. Bra;n Stem lnfu,;on of
th. Aminobutyric Acid Antagonist Bie.culline
Ine,ease, PI .,ma In,ulin level, in the Rat. En-
doc,i""'. 111.- 324-8. 1982.
10. Berg.r. D.. Crowth.r. R. C .. Floyd.J. C .. Jr .. Pel: .
S .. and Fajans. S. S. Effeet of Age (>!l Fo'ting
level, of Paner.atic lIorm""., in M.n . J, Clin.
Endoc,irwi. MtI"b. 47: I 183_9.1978.
I I. Berhanu. P.. Olef,ky. J, 11.1 .. T.. i. P.. Thamm. p ..
S.und.... D.. and B.... nd.nburg. D. Inte rnaliza_
tion and Moleeula, p,,,,,,,.. ing of In,ulin Recep-
ton in Isolated Rat Adipocytes. PrIX, Nail. AroJ.
Sci. USA 79: 4069_73. 1982 ,
12. lIiermon. E , l.. and Glomsel. J. A. Disorde .. of
Lipid Metaboli,m. Chap. 18. pp, 890-937 of Wil _
liams. R. H .. ed. T fXIOOoJ;. of f:MorrinoioKY.
ed. Saund.rS. Philadelphia. 1976,
13. Blackmore. P. F.. Dehaye. J.- P.. and Exton . J. I L
Stud ie< On a-Adrenergic Activation of Hepatic
Gluoose Ou tp"1. The Role of Mitochondrial Cal -
cium Release in the AdrenergiC Aetivat ion of
Phoshorylase in Perfus.d Rat Live" J. Bioi.
154: 6945_50. 1979.
14. 1Iloch. K .• and Vance. D, Control Mechani,ms in
the Synthesis of S.turated Fally Aoid •. A"". RfV.
Biocht m. 46: 263_98.1977.
15. B.... d.haw. R. A. Nerv. Growth Factor. Ann. R fv.
Bioch'm. 4 7: /91_216. 1978.
16. Bray. G. t\., and York, D. A, HypOthalamiC and
Genetic Obe,;ty in E,pcrimental Anim.lo: An
Autonomic and End<oerine H)'pothesi •. Phy.iol.
Rn. j9: 719-809. 1979,
17. BriU$. M .• and Brigg •. M. 0,,,1 Conlraaprivts.
Eden Press. Montreal. 1977.
18. B","'n. E. ,1.1 .. and Au,baeh. G. D. Rec.ptors .nd
Secorld Messeng.rs in Cel! Function and Clinical
Diserd .... Chap. 8. pp. 247- 99 of Fre;nkel. ed ..
vol. 2. reference
19. B"''''n. ,1.1 •• Toehe . Y.. and Fi,her. D, Central
Nervou . S),.t.m Acton of iJombc,in: Mechanism
to IrId.e. Hyperglycemia. EndIXri'lOi. 105: 660--
5.1979.
20. Brun i. J. F. . Wat kins. W, B.. Y.n. S. S, C. 13-
Endorphin in the Huma" Pancre ••. J. Clin.
doc,;"')I. Melab. 49: 649_SI. 1979.
21 , Bueno. 1... and Ferre. J.,P, Ce ntr.1 Regulation of
Inte'linal MOIil il)' by Somatostatin .nd Chole·
e)'Slol:inin Oc tapeptide, Sci'flrt 116; 1411_9.
1982.
22. Bun". H. F.. Gabbay. K, H.. arid Gallop. p, M,
Th. Glye,,"yl.tion of Hemoglobin: Relevance to
Di.hete. Mellitu" Srifl!<:f}()(): 21_7. 1978,
B. Cohill. G. F.. J, .. T .. and Marli$<. E. B. In_
 • uUn and Mu.cle Prolein, Chap. 36. pp. 563-77
of Stei ner.nd Freinkd .• d.,. rcr.rene. 204.
24. Cato. R, L.. and R<>che. T. E. Funetioo and Reg·
ulalion of Mammalian Pyruvate Dehydrogenase
Complex.}. S.oi. Chern. 24j: 1659-65. 1979.
25. Ciaraldi. T. P.. Kolterman. O. G .• Siegel. l . A"
and J. M, In,ulin-5limulaled Glucose
Tran.port in Human Adi"""yt ... PhJJ-
;oi. 236: E621-E621. 1979,
26. Crisp. A. H.. and Stonehill. E, Siup. NUlri/ion
and Mood. Wiley. New York. 1976.
27. Curnow. R, T .. and Larner. J. HortnQnal Control
of Phosphoprolein Phospha ....., Biochml, Ac-
,ions oj Horm. 6: 77_1 19. 1979.
2S, C •.• eh. M. P. Molecular Ba.i. of Insulin Action.
Ann. Rey. 46: 359_84. 1977.
29, Czech. M. P.. and Massague. J. Subunit Strue·
lure and O),namie, of the In,ulin Receptor. f"d.
P,oc. 41: 1982.
lO. Davis. j, D.. Wimhafter. D.. Asin. K.E .. and
B'ief. D. SUStained Inlrocerebrovenlrieul., Infn·
. ion <>f Brain Fuel. Roduce. Body Weight and
Food Intake in Ra,.. &imu 212: 81 - 3. I,
31. Debeer. L. J .. Thomas. J .. DeSchepper. P. J .. and
Mannaer ... G. P. Lysosomal Trioeylglyctrol Li.
pa"" and Lipoi),.i. in Isolated Hep.loe)'I ••. } ,
Bioi. Chem. 2H: 8841_6. 1979.
n. Debons. A. F.. Krim,'y. l.. . nd FrOOl. A. A Di·
'ect Aelion of Insulin on thc Hypolhalamic Sa·
lie,), Center. Am. } . PhJ"i()/. 219: 938-43.
1970.
33. 0.. Pi,ro. R .. Fu,co. A .• Bertoli. A .. G,oco. A. V..
• nd Lauro. R. In. ulin ReceptOD During the Men·
stru.1 Cycle in Normal Women, J. £do('f;-
47: 1387_9. 1978.
34. De Pirro. R.. Lauro. R.. Te., •. I.. Ferreni, G .. Dc
M.rt;ni$. C. and Dellonlon ;o. R. Dce'e'<Cd In·
• ulin Receplors bUI Norm.1 Gluc= ),i"taboli. m
in Duohenn. Mu""ula r D),"1Oph)'. Sd",,,", 216:
311-13.1982 .
H. Dio"ehy. J . M .. Gono. A .. Jr .• • nd Ontko. 1. A.
ed., DiJlu,lH>ncr.' in Upid and Upopmlrin Melab-
o/ism, Am.,ie.n Phy.iological Soc;"t)·, Bethe.da.
1978.
36. Dobb •. R, E .. and Unge,. R, H. Gluc'gon and $0-
m.,ostalin. Chap. S. PI'. 307-57 of Frein kel. cd .•
1'(11, 2. rtference 56.
37. Dobbs. R, E.. and Unger, R. H, Glue_goo Secre·
tion, Funclionand Clinical Role. Chap. 2. PI'· 61-
liS of Frein'el. cd .. vol. 2. refere",e 56,
38 . Dugan, R. E.. and POrte , . J. W. Hormonal Reg·
ulalion of Chole"erol Synlhe.i •. Biocht"" Ac-
lions oj lIorm. 4: 197_247. 1977.
39. Dunaway. G. A.. Leund. G. L.·Y .. Thra.her. J.
R. , and Coope,. M, D, Tur"""e, <>f HepatiC Pho<-
phofruclokina", in Normal and Diabelic Rats. J.
Bioi. ehtm. 2Jj: 7460-3. 1978.
40. Ed.r. H. A. Plasm. Apoiipoprolein, and Lipop,o-
lein Recepto". Chap. 4. PI'· 145-75 of Freinkol.
ed .. '01. 2. ref.re",e 56.
41 . Edmondson.J. W.• Lenng. L., .nd Li. T.· K. Com·
parativ. Sludie. of Alanin. and ",Aminoisobu·
tyrie Acid Upta ke by Freshly 1",1,'ed Li'er C.II •.
J. BIoi. Ch'm. 154. 1653-8. 1979,
42. Elahi. D .. Raizes. G. S .. Andre •. R.• Ile",bcopf.
R. J .• Muller, D. C .• Tobin. J . D., and Andersen.
D, K. Interaclion of "'iinine and Gastric Inhib-
itory PoI)'p<ptide on In.ulin Release in Man.
Ame', J , Physi()/. U2: E343- EHI. 1982.
43. El·Et'. M. , $ehorde'CI-SI.t kinc. S., and Bauliou
E. E. MeiOlic Maturation in Xt/l0PUj latvi. 00-
cytes Iniliated b), In$ul in. lIJ5: 1397_9 .
1979,
44. EI.Maih,abi. M, R.. CI.u •• T. H.. Pil ki" J .. and
Pilkis. S. J . Rogulalion of 6·Phosphofrueto-2 · Ki·
1\(1", Ae' i, i'y by CycliC AMP.Dep<ndent PhO$-
phorylalion. P,oc. Nml. Sci, USA 79: 315_
19,1982.
45 , Ensinek, J. W.• and Williams. R. H. Hormonal
and NonbortnQnal factors Modifying Man', Re·
'pon"" 10 In.ulin. Cnap, 43. Pl', of Steincr
and Freinkel. ed$.. reference 204.
46. Ernest. M. J .. and F.igelson. P. Multino,monal
Control of T)"",inc in Isolated
Live, Colis. Chap. 12. pp, 219-41 of B.xler and
Rousseau. ed •.. ,efe,eno" 7.
47. hlon. J . fl , Regulalion of Gluconeogenesis by
GluC«<lrtioOid$. Chap. n. pp, 535-46 of 6."..
and Rousseau. cd . .. reference 7,
4g. Exton. J. H.. and Park. C. R. Interaclion of !n-
,ulin and Glucagon in the Control of U"'" ),ie·
taboli$m. Chap. 28. pp. 437-55 of Steiner and
Freinkel. ed, .. reference 2M.
Fajan,. S. S, Di"I><t., Molli," •. Chap. 2. PI>.
71 of Freinkel. N.. od. Th, Y,a, in .
Plenum. New YOrk. 1976.
50, Fajan •. S , S. Stimulalion of 1, lel Cell Socretion
by Nut,ients and G.moimestin.1 Hormone •.
Chap. 30. pp, 473_93 of Steine, and Froinkcl.
ods .• ,e/e,cnce 204 .
51. Faj.n •. S, S .. and Floyd. J . C .. Jr.. Diabetes Mei-
litus. Ch.p, 7, PI', 235-305 of freinxel. ed .. ,01.
I. roferonce 56.
51A. F. ust. J . R .. Luskc)'. K. L. Chin, D. J .. Goldstoin.
J. l.. "nd Brown. M. S. Regulation of Synlhesi,
and Degrodation of 3-H)'droxy-3 ·),iethylglutaryl·
Coenzyme A Reductase by Low Density Lipopro-
tein and 25-Hydroxychol..,erol in UT-I Colis,
Proc. Na,'. Acad, Sci.. USA 79: 5205-9. 1982.
52 . Felig. P.. and Koi,isto. V, Recenl Ady.n .., in
Body Fuel Met.bolism. Chap. 9. pp. 359-84 of
froin kel, ed .. vol. I. refere""e 56.
S3. f.lig. P.. Sherwin. R. S .. Som.n. Y.. Wah'"n. J..
Hendler. R.. Sacca. L.. Eigler. N .. Goldberg. D..
and Wal.. ky. M. Hormonal Inte ,aetion. in the
Regulalion of Blood Glucose. R«. Prog. /lor""
Huh. 35: 501_29.1979.
53A . Fklding. C. J .. ReO"en. G.. and Fielding. P,
Human NQninu.lin-<iependent Di.bet.., Identifi-
calion of a Defecl in Pla,ma CboIe".101 Trans-
port Norm.lized In Vivo by In.ulin and In Vitro
by Sel¢clive Immunoadsorption <>f Apolipoprolein
E. P,(X. Na,l, Acad, Sci. USA 79: 6365_9,1982.
54. Findlay. O. M.. Omond. S .. Alford. F. P.. and
'"
Chi,holm, D. J. Hyperglycemia and Glucagon
SUPP'c>$ion: I'o$$iblc Importance <>f lhe Vagus
and Enlcric Unmoral Fact""', J. Gin. Endocri-
noI.
48: 13_16, 1979.
H. Floyd, J. c.. Jr .. Fajan" S. S .. Pd. S.. and
Chance, R. E. A Newly Recognized Pancreatic
P<>Iypeplide; Pla.ma Leve]. in Health and Dis.
. .... R«. P,og_ lIorm. R$ch. JJ: 519_56.1977.
56. F.. inkel. N .. cd. C()l1/tmporary MtlalxAi,,,,.
Plenum. New Yor. , vol. I. 1979. 1'<>1. 2, 1982.
n. F,einkel. N .. Pedley. K. c., Woodi",. P.. and
DaWSM. R. M. C. Local i"'ti"n " Inorganic
Phospha!e in the P'ne",";c {j Cdl and 11> Loss
on Glucose Stimulalion. 201: 1124_6.
1978.
58. Fril>. I. B. Insulin Act;"", on Carbohydrate and
Lipid Met.bolism. ACliOlU HOTm. 2:
1b6--214.1972.
59. Furo)' •. E_. YokO)'Mna. M_. and Uyeda. K. Reg-
ulation of Fruc! .... -{>.Phosphale 2· Kinase by
PlIosphorylation and DephO$phoryl.ti<>n: P=ible
Mechanisms for Co-ordin.ted Control of Glycol.
)'$i\ and Glyoogeoolyi\, Pro{". Nail. Acod. Sci.
USA 79: 32S-9. 1982,
60. Gaoda. O. P., Soeld""r. J. S .. Glc.5On. R. E"
Ck.lor. J. G. M" and Reynold,. C. Motabolic Ef·
feel> of Glucose. Man_e. Gal.close and Fruc-
lose in Man. J. f:ndoaino/. 49: 616_
22.1979.
61. Go"i",n. J . C" il<>rlond. M. K" Flotk>, V. A"
T,,·ible. I). A. The Role of Calcium Ion ... Me-
dialor of lhe Effeeu of A",iolen,in II. Calechol -
aminC$. and VaooprC$$in on the Phosphor),lation
and Actiyily of Enzyme. in 1",lated Hepalocyte<.
J. Bioi. 1979.
62 , Goary. N" Langhans. W" and S<har",r. E. Met-
abolic Conoomitantl of Glucagon.lnduced
Supp", .. ion of Feedi!\i in lhc Ral. J. Phys-
iol. 141: R330_RBS, 1981.
63. Gebhard. R. L. and Cooper. A. D. Regulalion of
CIIoIC$lerol Synthe,i, in Cultured Canine Inte ..
Mucosa. J. 8iol. CMm. ]5J: 2790-6. 1978,
64. Gerich. J, E" Charles. M. A.• and Grodsky. G. M.
Regulation of Pa"""e'lic Insulin and Glucagon
Soorel ion . Ann. Rtv. Ph)-'slol. 38: 353-8S. 1976,
6S. GiMberg. B. H. T he In,ulin Re""plot: Properlie.
and Regulalion. BiorMm. A<li01l.f /I&m, 4: 313-
49.1977.
66. Gjedde. A" and Crone. C. Blood-Blain Glu=
Tran,fer: RcprOO$ion in Chronic Hyperglyoomia.
2H: 4S6- 7. 1981.
GOldfine. I. D .. JortC$. A. L,. Hrodd. G. T ..
W"",. K. Y .. and Moon-cy. J. S. Enlry of Insulin
inlo Human Cuilured Lymphocytel' EIe<>lrO<l Mi_
croseope and Autoradiographic Analysis. Sclmu
}()2: 760--2 . 1978.
68. Goodner. C. J .. arid ikrrie. M. A. Tho Failuro of
Rat Hypothalamic Tissues 10 Tako Up Labeled
Inlulin In Vivo or 10 Respend 10 Insulin Vjt,o,
End"",j""" /01: 605_1 2. 1977.
THE ENDOCRINE PANCREAS
69. Goodner. C. J .. and Po"e. I).. Jr. Determinanl, of
B••• I Islet Cell $coretion in Man . Chap. 38. pp.
S97- 609 of Sleiner and Freinkel. ods .. ",fe",ncc
'"'
10. Gordon. P.. Carpemier. l.-l .. Freychel. p ..
LeCam. 1\ ., and Orei, L Intracdlular Translo-
cation of lodino_IH_Labelied Insulin: Direcl
Demonmalion in 1",lated HepatocytC$.
100.782_5.1978.
71. Gr.nner. D. K. The Role 01 GluCOC<>rtiooid sas Bi_
ological Amplif,ors. Chap. 33. pp. 593-611 of
Ba"er and R""SSClIu. eds .. relerc"",e 7.
72. Grcoo. A. II .. Mann •. R .. Ghirlanda. G .. Aha-
mOnte. L , Rebuni. 1\ . G .. and Bertoli, A. Early
Insulin and Glucatlon Response to Subsoqucnl
Pulses of Arginine. GluCose. and ToIhutamine in
Normal Man . Am. l. Phy,iol. 236: E85-E89.
1979,
n. Green. A .. and Olor,ky. J. M, E_iden"" for in'u-
lin_Induced Inlernali7"lion and Dogradalion of
In,ulin Reeeplors in Rat Adipocyte>. P<or, NOli.
Acad. Sci. USA 79: 427_31. 1982,
74. Grill. V. Nutrient-I nduced Primitll! of h"ulio and
Glucagon S<cretion, Effecls of «-Ketoisoc'pfL)ic
Acid. Endoe,j/tl)/. /lQ: 1013-17. 1982.
74A, Grundy, S. M. Absorption and Metaboli,m of Di_
etary Cholestorol. Ann. Rtv. NUI<. J: 71-96.
1983.
IS. GUlhrio. H. A. Im<O<101cl&y NUI<il/on. 41h cd.
Ch4p. 20, W<iSh' Con,,,,!. M",by. S,- lou; •.
1979.
76. Guthrow. C. E., Morri,. M. A.. Day. J. F..
Thorpe. S. R .. and Bayne •. J. W, Enhanced
Nonenzymatic Glucosylation of Hum.n SeTllm
Albumin in Diabelos Mellitus , P,or, Natl. Acad.
Sci. USA 1979.
77. Guylon. A. C. Talbook of M. dir(11 PAysioiog)'.
5th cd. Chap. 13: Dietary BalanLX'. Regul'lion 01
Feeding: Obesity and Star.. lion, Saunders. Phil_
.delphi •. 1916.
78, Halban. P. E.. Wollheim. C. B.. Blondel. B..
Mcda. P.. Nic<Ot. E. N,. and Mint •. D. H. The
PO$$iblc Importance of Contacl Between Pan_
creatic ]s]el Cells fot lhe Control of Insulin Re-
lease. 1:;"aor,i""l. 111:86-94. 1982.
79. Hedc,kov. C. J . Mech.nism of Glucose_Induced
Insulin $ccretion. Phy./oi. Rt>. W: 442-509.
1980.
80. Hedo. l . A., Villanue_a. M. L.. and Mar<:<>. J. In-
Huence of Plasma Free Fally Acids on Pa"",re.tie
Polypeplide $ccretion in Man. J. c/in. Endor<i-
nol. 49: 73-7. 1979.
81. Heimberg. M .. Goh. E. H .. Klausner. H. J .. SoIer-
ArsH.ga. C .. WeinSlcin. I .. and Wilcox. H. G,
Regulation of Hepalic Melaholism of Froe Fally
Acids: Inletrelalion.hip< Among Secrelion of
Very_low_De",ity LipoprOl< ins. Ketse..s;, and
Cholesterogene,;s. Chap. IS. pp. HI_67 of Diet_
$Chy et .1 .. eds .. reforonce 3S.
82. E .. Geck. P .. and Pielrz),k. C. DriYiog
 FOr<e5 of Amioo Acid Tra"'port in Animal Cells.
Ann. N. y, A'ad. Sd. ]64: 428-4 1. 1975.
8). Hers. 11. G. The Control of GIYcosen Metat>olism
in the Liver, Ann. R,y. 8i«hom. 45: 167-89.
1976.
84, Hood, C. E. A.. G<X><Iharl. J. M., Fletcher. R. F.•
Gloster. J .• Bertrand. P. V.• and Crooke, A, C.
Observation, on Obese Patients Eat ing l«>caloric
Reducing DietS .... ith Varying Proportions of Car·
boh)'dratc. 8" J. NUfT, U : 39_44. 1970.
S5. Hough . S ,. Ru.sell . J. E .. Teitelbaum. S. 1.. . and
A.ioli. L. V. Calcium Ilomeosta,i< in Slreptom-
t""in_lnduced Mellitu. in the Rat.
Am. r. J. Phy'io/, 24 2: E451 - E4 46. 1982.
86. lIuc. L.. Blackmore. P. F., and Exton, J, II . Fruc_
t= 2,6- Bi poo..phatc. Hormonal Regu lation and
Mechani,m of Formation in Liver. J, Bioi, ehe",.
81 , Inoue. 5 .. Bray. G. A., and Mullen , '1'. S. Tr.n>-
plantatiOn of Pancreatic fj CellS Pro"ent' De.d·
opment of Hypothalamic Obe,it)" in Rat< , Am , J.
PhyJiol, 21'" E226_E211. 1918.
88, Janjic, D.. Wollhdm. C. B,. and Sharp. G, W, G,
Selective inhibition of Glucost.stimutated In, u_
lin Role.", by Dantrole ... Am". J. PhyJiol, 24J:
1059_1061.1982 ,
89. 101"<''', l.. Kicchlc. F, l.. .nd P:orket. J. C. Chem-
ic.1 Mediatot or .\ lediato" of lns.l in Ae,ion: Re-
'I'On"" to In, ulin and Mode of Action. F. d, Pr«.
f l: 2736-41.1982.
9'0. Joh nson. D. G.. G""bel. C. U.. Hruby. V. J .,
Bregm .n. M, D., and Trivedi . E. Hyperglyce mia
of Diabetic R." Deerea",d by. Gluc.gon Recep-
tor Antagon i,!' Sdt/lU 215: 1115-16. 1982.
91 . John"on. J. M. Esterification Reac'ion; in Ihe In_
te>!inal Mu"""" and lipid Absorption. Chap. J.
pp. S7 -68 of Diet""hyel aL. cd ... 35.
92. Kahn, C. R,. Baird, K. L.. Flier, J. S .. Grunfeld,
C., H.rmon. J, T .. Harrison. L. C , Karl s<on, F.
A., Ka,ug.t. M., Ki ng. G. L. , Lang, U. C., f'od ·
,kalny. J. M.. and Obberghen. E. Insulin Re-
eepto", Insulin Anlibodie •. ,nd the Mechanism
of Action, RH:. Prog. /form. IIsch. 37__
411_533,1981.
93 . Kahn. C. R., Goldfine. E. D.. Nevill • . D. M.. Jr .•
and DeMe),,,. P. Alterations in I",ulin Bi nding
Induced by Change' In Vi l'O in the Level,of Glu_
cocorticoids and Gro •.-th Hormone, f:nd«r;noi.
103: IOS4-66, 1978.
94. Kapla n. J. G. Memb rane Cation Tun.port and
the ConlT<>I of Proliferation of Mammalian Ce ll,.
Ann, II .., PhysiQI. 4(J: 19_4 1, 1978.
95. Kosuga. M,. Akan"ma. Y., ]wamOlo.Y,. a nd K,..
• aka. K. I n,ulin Rinding and Glucost Mel,boli.m
in Adipocyte$ of SlTeptoIOl""in-ciiabetic Ral1,
Am, J. 13.1: E I H_ E I 82. 1978.
%, Knut., M.. Karlsson, F. A,. and K.h n,C. R. ln-
.ulin Stim"lale, the Ph,..ph<>rylotion of it> Own
Re<;eplor. 215: 185-1, 1982.
91. Katzen, H. M. Carbohydrate Inh ibitorS of Con_
canaval in A that Inhibit Binding of Insulin Se·
ph.."", to Fat Cell, and Anlagoni,.e and Mimic
In,uli n's Biooeli.ity. J. iJjol. eh,,,,. 254: 298) _
92. 1919,
98. K.l7.en. II. M,. Soderman. D. D.• an d Crillo, V.
J . Ti"ue Distribution and Phy,iologic.1 Signif,-
ca n<X of Multiple Forms of Ik.okinasc, Ann.
N.Y. Acad, Sd, 151: 351_8.1%8.
99. Kce,e)', R. E .. and Powley. T, L H)'l'Olhalamic
Regulation of Ilody Weight. Am. Sd. 63: 558_65.
1915,
100. Keirn •. J. Land T<>Iman, E. L. C),clic Nucleo-
tide, in Dioorde" of Carbohydrate and lipid Me-
tabolism . Chap. 22. pp. 391-414 of Cr.mer. H.,
and SchUltl. ed •. Cyclic 3'.S'-Nuclro/idu'
tmi.ms o[ A",i"". Wiley. New York, 1977.
101 , Keller. U., and Shulman, G, Effec' of Gl ucagon
on Hepatic Fatty Acid Oxidation and Ketogc=i,
in Conscious Dogs. Am. J, Phy.iol. 137: E121_
EI29.1919.
102. Khan. M. N,. Po:<ner. 9. I. . Ve,m •. "- K.. Khan .
R. J. , and Ikrgeron, J, J, M. Intr.cellul .r Hor_
mone ReceptorS: Evidenc<: for Insulin and l act,..
ge n Receptors in • Unique Ve.iclo Scdimenting in
LYiiOSOme Fract;on,. Pr<x, Nail. Acad. USA
78.4980_4.1981.
103, Kikuchi. M,. Wollheim. C. 8.. Siegel, E. G.. Ren_
old, A. E. , and Sharp. G. W. G. Bi ph.sic Insul in
Relea", in Rat 1,lels of Langerhan, and the Role
of intracellular Ca '· Store,. t:nJocriool. 10.1:
1013_19. 1919.
104. King, D. L.. Kitche n. K. c.. and Chick. W, L
Pane reatie D-Celi Replication: Relation to Insulin
Secretion , f:ndocrir/Ol, 103: 132 1_7, 1978.
lOS Ki .. ikff, It R... nd Van It .llie. T. B. Ph ysiology
of the Cootrol of Food I ntal<e. Ann. 11m NUlr. 1:
371-418. 1982
106. Kohen. E,. Kohen, c.. Thorell. D,. Minll, D. H.,
and Rabirw)vi'eh, A. Intercellul., Cornmunica-
lion in Pancreatic Islet Monolayer Culture<: A
MieroHuo.-omelrie S'udy, Sci, net 204: 862-5.
1919.
107. Kola,., G. B. Blood Sug.tr and the Complication.
of Diabetes, Scitnu 203: 1098-9. 1919.
108, K<>Iota. G. B. Con'roversy Ovcr Stud)" of Diabetcs
Drugs ContinuC$ for N•• rly a Decade. Sci",u
2OJ: 986-90. 1979,
109. Kolata. G. B. Polypeptide Hormones: Wh at Are
They Doing in Scitnct )()I: 895_7. 1978.
100A. Korw). T. Ae,ion' of In,ulin On Glucose Transport
and cAMP Ph,..phod ie.terasc in Fat Cells: In-
",I. ement of Two Dis,inct Molecular Mech.·
ni,m,. Rtc, P,og.lform, RtJ. 39: 519_555.1983.
110. Krebs, E. G., a nd Bea.o. J. A. Phosphorylation·
Dephosphorylation of Enzyme.. Ann. Rn',
8iochtm. 48: 923-59. 1979.
I II. Kre isberg. J . I, Insulin Requil"<'mcnl fo r Contrac·
,ion of CultuI"<'d R.t Glome",l.r Mc..angi.1 Cell.
in Re'ponse to Angioten,in 11: P<mible Role for
In, ulin in Modulating Glomerular Hemodynam_
ics. Pro<:. Nail. Acad, Sd. USA 79: 4190-- 2. 1982.
112. Lacy, P. E., and Matai"e , W. J . Microlubulo.
and Beta Cell Secretion. Rrc. Prog. l/orlnOM
R.ch 19: 199-228, 197J.

'"
II). Larner, J .. Cheng. K., Schwa"._ C .. KikuchI. K ..
Tamu," , S .. Creacy. S .. Dubler. R.o G.I.sko. G .•
Pullin. C .. and Kall. M. A Proteolytic Meeha-
"i1m fO)f the A<tiM of Insulin via OlillOPCptido
Mediator formation. F,d. Prot:_ 41: 2724-9.
1982.
11 4. Larsl¢n. L.-I.. Gollerman". N .. Do Magistr; •. L-.
Rehfeld. J. F.. and Schwartz. T. W, Somatostatin
Cell PrOC<:$50' as Pathwa)" fOT Paracrinc Sccre-
tion. XU: 1393-5, 1979.
115. led.rcq-McY"" V" Marchand. J.. and Mal .i,..,.
W. J. Calcium Dependencyof Glucasoo Release:
h. Mooulation by NUlrilioMI FaC[(>n. Am, J.
Physlal. ]36: E98-El04. 1979.
116. lcr.b¥r., P. and Luych, A . S. The R<>Ic of
Glucagon in Clink.t Medicine. Chop. 20, pp.
J I 5-S I. of Foa. P. P.• ed. ACli(Nl.j 'if HOI'-
",,,,,,,s. Thorn ••• Sprinllficld. 197 1,
117. Lehn ingCT, A. L. Blorh,mi",y. 2d ed. Worth.
New York. 1'}76.
118. l eiboYit •. S, F. Brain Catecholaminergi. Mech·
anism. for Control of Hunger, pp. 1-18 of Novin
.. aI., Qk. refere""e
II'}. Levin. S. R.. Pohlevanian. M. Z .. La..,e, A, E ..
and Adachi. R. L S<.relion of an I",u linotropic
Factor from Isolated. Perfuoed Rat Inte .. ine. Am.
J. £7Io-E720. 1979.
120, Like. A, A.. Kislau,ki •. E.. Williams. R, M .. and
RO$$ini. A. A. Neonatal Thymectomy Prev.nt.
Diabetes Mellitu, in the BBj W Rat,
Sd",« )16: 644_6. 1982.
121 . Linebaugh . B.. and Rillema. J. A. Action, of In-
,ulin and Hydrocortisone on Macromolecular
Synthesi, in Primary Epithelial Cell Culture,
from Moo", Mamm.ry GI.nd,. E"docTino!. 105:
806-11.1979.
In Lipson. L. G .. and Sharp. G. W. ln,ulin Rdc.",
in Prellnanc)"; Studi • • on Adcnylale Cycla",.
Ph<»phQdic$teT''''. Protein Kin.« . and Phospho-
protein Phosphata .. in Isolated Rat Isle!.<of Lan-
llerhan •. /:;ndoc,i""I. /OJ: I 272-80. 1978.
123. Lipson. L. G .. Siege l. E.. Wollhcim. C. B.. and
Sharp. G. W. G. Insulin Reka", During Fast in&;
Stud ie, on Adenylal< Cycl .... Phosphodie'ter ....
Prolcin Kina", .• nd Phosph<>pr01C in Pbo<ph.ta",
in hoi "cd I5let. of L.",erhan, of the Rat.
doc,ino/, /Q5: 702_7.1979.
124. Loub31ieres. A. Therapeutic Mooifieat ion of I,tet
Cell Function . Chap. 42. pp, 653-64 of Stcincr
and Frein..!' eds .• reference 204.
125. Louio-Syl"","e. J. Ret.tion,hip betw«n Two
St.ge, of Prandial In,uli n Rde.", in R.ts. Am.
J. Ph)'jiol. 135: E 103-E I I I. 1978.
126. Lund.i\ndersen. H, Tr.n.port of Glucose from
Blood to Brain. Physiol. R. y, 57: 305-52.1979,
127. LUndberg. J. M .. TatcmolO. K.. Tereniu,.
I... Hcll"nlm. P. 0\1.. Mutt. v.. HoHelt.
T .. and !lamberser. D, l ocali7.ation of Pcp-
tide YY (PYY) in Gastrointestinal Endocrinc
Cell' and Effects on intestinal Blood Flow and
THE ENDOCRtNE PANCREAS
Motility. Pr{)(", Nail. Acad. Sd USA 79: 4471_5.
1982.
128. lundquist. I .. Fansk•. R.. and Grod,ky. G. M. In·
t.. action of . nd Glucose on Glucagon
Secretion, £ndoc'ino!. <19: !J04-12. 1976.
lundquist. I.. $undler, f .. Ahren. B.. Alume ... J .•
and IU kanson. R. Somatostatin. P.ncreatic Poly·
pep1ide. Substance P. and Neurotcnsin: Cellular
[}i"ributi(>ll and Effeel& on Stimulated In,ulin
S<crction in the Moo",. I:."ndoNino!. 104: 832_8.
1979.
130. M.chlum. S .. Felig. P.. and W.hren. J. Splaneh.
nic Glue""e and Mu><le Glycogen Metaboli,m
aft .. Glucose Feeding during POIIte.erei", Recov_
ery. Am, J. Physiol. 235: E255-E60. 1978.
131. Mahley. R. W, Alteration. in PI •• m. Lipop,-o.
teins Induced by Cholesterol Feeding in Animal,
!ncluding M.n, Ch. p, II. pp. 181 - 97 of Steiner
and Fr.inkel. ed$ __ reference 204.
132, M.I.iss<:. W. J .. Malai ... -L"-3-'e. F.. and Sencr.
A. The Stimulus«eretion Coupling of Glucos<·
Induced Insulin Release: Effect of i\minoo,yaco-
tatc upon Nutrient..$timulated In,ulin S<crction .
l-:ndoc,iflOl.III:392_7.1982,
133. Manchester. K. l. Insulio arid PrOiein Syothc.i •.
Bloch.",. AolI"", /I",,,,, I: 267_320.1970,
134. Masoro. E. J, Lipid, and Lipid Metabolism. Am',
R ..... 19: 301_21.1971.
1l5. Maugh. T. H.. Ii. fI New Marker for Diabetes.
ScI.nu)J5:651_2.1982.
136. Maugh. T. H .• II. Diet: Drug Free Thorapy f<><
Di.be .... Th.Sdtllu. 17; 16- 19.1977.
137. Mau .. r. A. C. ne Therapy of Diabetes, Am. Sci.
67:422_31. 1919.
138. MeGa,,),. .. and Foster. D. W. In Support of
the Roles of M. lonyl·Coi\ and Ca,nitine i\cetyl-
transferase I in lhe Regulation of Hepat ic Fally
Acid Oxidation and Kelogencsi., J, Bioi. Chim.
)54: 8163-68.1979.
139. Mc(iuig.n. J. 10, Pancreatic and E'<".p" ncrc.tie
Ga,,,in. Chap. 16. pp. 279_87 of Steiner and
Fr.inkel. cd, .. reference 204 .
139i\. Hypcrln,ulinem;a of Obesity i. Due to Decreased
Cle.rance of Insulin , Am , J. E155-
EI59.1983.
140. Me)'e,. H, 1·1.. Vencrlein. F.. Schmidt. G .. . nd
Hassclb l.tl. A. Mea, urement of Blood fkl", in
Pa""reatic Islets of tile Rat ; Effect of l",prOler-
enol and No'epinephrine. Am. J. Physiol. Ul:
E298- E304.1982,
141 . Miehaeh. R, L .. ond Sheridan. J, O. hie!> of l.:ln·
gerhan" Dye Coopting Among ImmunocytO-
chemically Di,t;nct Cell T ypc •. Sd'rIff 214: 801_
4.1981.
142 . Mi.bin. R. I.. O·Leary. J. P.. . nd Pulkkine n. "-
Insulin Receptor Binding in Obesity : A Rc • ...,ss-
ment . Sd,nc, XU: 1003-4.
143 . Morg.n. II. E .. and "'coly. J. R. In,u lin and
Membrane Transport. Chap. 20. pp. 323-31 of
Steiner and Frein"l. ed, .. rererence 21)4,
144. Morley. J . E.. Le,ine. A. S .• Murray. S . S .. Kneip.
1.. and M. Peptidergie Regulation of
Str"..· lnd"ced Eating. Am. J. PhyJiol. 11):
RIS9_RI63.1982.
145. Mortimore. G. E. I.Hu.nce of 1",,,li. on th. He·
patic Uptake and R.I •• ", of Glu<:<;:« and Amino
Acid •. Chap. 31. pp. 495- 504 of St.iner and
Fr.ink"l. ed •.. rderence 204.
146. Muggeo. ,1.1 .• Bar. R. S .. Roth. 1.. Kahn. R.• and
Gorden . P. Th. In.ulin Resi'tane. of Acromeg-
aly: bid.nee fOT Two Alt.rati ...... in the In,ulin
R.ceptor on Circulating Monocyt •• , J. E".
docTinoi. Mt llJh. 48: 17_25. 1979.
147, MuU.o. M .. Kahn. C. R .. Bar. R. S .. Rechl ...
M,. Flier. J. S ..• nd Roth. J. The Underlying In·
• ulin Receptor in Patient. with An1ir<ccptor
AU1oantibodiC1: of Normal Bind·
ing and Immunological Properties. J. C/in. /:'".
drx, ino/. Mtlab. 49: 110-19. 1979.
148. Naji. A.. Sil,e ... W. K.• &IISr.u. Do> and Borker.
C F. S]Xlnlane"" , Di.bett.. in Rat,: Do:,truction
of 1.1.1. i. Pre""nted by Immunologic.1 Tolcr'
ance. Sdtnu 111: 1190-2. 19S1.
149. Narahara. H. T. Binding of In,ulin 10 Ti"ue. in
Relation to Biological Action of the Hormone.
Chap. 21. pp. 333-45 of Stei..,r .nd Frein. el.
cd ... rde.-.:nce 204.
Ncwsholme. E, A.. and Start. C. Gener.1 A'pect'
0[ the R.gulation of En1.yme Acti vit)' and the Ef·
fects of Hormon.s, Chap. 23. PP, 369-83 of Stei·
ncr .nd Frein • • 1. ed •.• ,deren<e 204.
A,. 1'I11;i. II .. • nd Mlw • . I. [If", Qf Ao'
om ... of D-Man"",. on In,ulin R.I .... from
Perfu",d Rat P.""r.... 1::ndoaillOl, /Q5: 1051 -4,
1979.
152. Norman. A. W .• B. J.. Heldt. A. M.. and
Gro,b' y. G. M. Vitamin D Inhibits
Pancr.atic Secretion of I n.u lin. Sci,net m : 823-
25. 1980
IS3. Northrup. T. 10,. Krewwski. P. A.. Palumbo, P.
J.. Kim. J. K,. Hui. V. S . F.. arid Dou$ll.. T. P.
Insulin I nhibition of Hormone·Stimulated Protein
Kinase of Rat Renal Am. J. i'h,-, ;o/. 1J6.-
E649-E654. \979.
154, Not kin •. A, L. The Ca . ,.s of Diabetes, Sri''''ifir
Am". UI:62-73. 1979.
155, Novin. D .• Wyrwic\:a. W .• and Bray. G. A.. ed,.
Basic M« honiJnts ond Clinkallmp/ic-a·
';OIU. R.",," Pr .... l'Ie'" Vork. 1976.
156. Ceh.,.. S .. and Do: Haro. C. Regulation of Protein
Synthe.i, in E.uryocytes. Ann. II.", Bioch'm,
48: 549_80.1979.
157 , Ol.fsky. J. M,. Kolterman. 0. G .• and Scarlell. J,
A. In, ulin Action .nd Resistance in Ob.;,it)' .nd
Type II Diabetes Mettitus.
Am". J. PhYjio/. UJ. EI5-E30. 1982
158. Old,ky. J. M.. and Saekow. M. The Effect.of Di·
elary CarbohI'drate Content On In. ulin Binding
and Glu= M.taboli,m by lsolaled Rat Adipo-
cyt ••. £ndrx,iN)/. 10)' 2252-63, 1978 .
159. Oomura . Y. Sisnir.ca"". of G\ueose. 1",.lin. and
Free Fall)' Ac id on the HypOthalamic Feeding
and Sati.t)" N.uron •. pp. of No,in et al ..
ed ... r<fere.ce 155.
160. Oppenheimer. J, H. Thyroid Hormone Action at
the Ceil.l.r l evel. 103: 971 - 9. 1979.
161. Pace, C S .. and Price. S, Bioelectrical Effect. 0[
H.x""",, On Pancr.atic Islct Cells, £ndocrino/. 94:
142_1.1914.
162. Parker. T. S,. McNam.ra. D. J .. Br",",'n. C. Gar.
r igan. 0 .. Kolb. R.. Batwin. H .. and Ahren •. E.
H .. Jr. Mev.lonie Acid in Huma. Plasma : Rela-
tionship of Cone.ntration and Cireadian Rhythm
to Cholesterol Synth",i. Rat'" in Man. Prrx,
Nail, Arod. Sci. USA 79: 3037 - 4 1. 19S2.
163, Patel. V. C,. Hoyte. K .• and Mani •. J. B. Effeet
of Anterior HypOthalamic !."'io'" On Neuroh)' .
pOphy.ial .nd Peripheral Ti .. ue C""cen1ratLons
of Som.toslatin in Ihe Rat, Endocr;""I. 105: 712_
15, 1919.
164. Peuit. F. H.. Humphrc}' •. J .. and Reed. L- J . Reg·
ul.tion of Pyruvate .. Kin.", Acti,·
ily by Prot.in Thiol.Di,ulf,de £>'ch.ngc . Pro<:.
Nail. Acad. Sci. USA 79: 3945-8. 1982.
165. Pilch. p, F.. Thompson. P. A.. and C,eeh. M. P.
Coordinate Modulation of D·Glu<:<;:« Tran'pOll
Aeti'ity and Bilayer Fl uidity in Pla.ma Mem·
bra nes Derived from Control .nd In,ulln·treated
Adipoeyt .., Pro<:. Narl. ,tcad. Sci, USA 77: 915-
18.1971.
166. Pilkis. S . J,. EI-M .ghr.bi. M. R.. McGra ne. M .•
Pil ki•. L and Claus. T. H. Regul'li"" by Gluca·
son of Hepalic PyrU""t. Kinase. 6--Phospbo.
f ruw,..t·Kioall<.
Ftd. P,rx 41: 2623-8, 1982.
161. Pipel.e ... D,. Some... G .• Cepts. W .• De Nulle.
N .• and De Vrocde. M. Pla.ma P.nereat;c Hor·
mone le'el. in a Ca", of Somatostatinoma; Di·
ag""'1ic and T herapeut;e Impli'"t"' ••. J . Gin,
t;ndQuillOi. Me/ab. 49: 512_9 . 1979.
168. PilOt. H. C, .• nd Vatvi n. M. B. Interrelation.hips
of Mammalian Ito,mon •• and En')'me Le vel, In
Vi"". R",. 53: 228-325. 1973.
169. PosSi. c.. Lc Marehand-Bru.tel. Y .• Zapf. I ..
froc-.. h. R.. and Freyehet. P. •• nd Bind ing
of In,ulin·Like Grow1h Factor I in the Isol"ted
Soleu. Muscleof Le.n and Obese Mice: Compar.
ison with In.ulin, End«rinoi. 10j: 723-30. 1919.
170. Pontrcmoli, S.• Melloni. E.• Michelli, ,1.1 •• S.I·
amino. F.. Sparatore. 8.. and It","ecker. B. I..
Limited PrOteol),si. of !.iver Aldolase and Fmc·
tose 1.6--Biphosphata", by Lysomal Protei ..se"
Effeet on Complex Form.tion. PrIX. Nail. Acad.
Sci. USA 79: 2451-4. 1982.
171. POrte. D,. Ir .. and Halt.r. I. B. TIte End"",ine
raner<a. and Diabet •• Me llitu., Chap. 15. Pl'.
/16_843 of William •. R, H,. ed. Ttxrbook oj to,..
drx,iIWlogy. 6th cd. S.unde... Philadelphi •.
1981
172. Porte. D,. Jr .. It alter. J . B.. de C . Palmer.
J. P.. C M.. Graf. R. 1.. and pr,d. r• M.
A. Diabete. Mellitu" Se lected Aspects of Patbo.
phy.iology lnd Clinieal Practice. CMp. I. pp. 1_
59 of Fr<inkel. ed .. ",I. 2. reference 56.
'"
173. Po..., . B. I., Ikr,c'on, J. J. M ., Jo.erbcrg. Z. o
Khan. M. N .• Khan, R. J., Patel. 1\ .. Si); S!r<Kl1. R.
1\" and Verma. A. K. Polypeptide Hot"""''': In·
Iracellul.r Rocopl"" . nd Regula'ion . R«. P'og.
I/orm. 37: 539_79 . 1981.
174. Purr.lio. F.. ViSnc,;, R., Clawson, G. A., and
Goldf",o. I. D. [Mulin Stimulation of Kuclcoside
Triphosphatase Activity in Isolated Nucle .. En-
velope •. 1/6: 1005- 7. 1982.
175. Quach. T. T .. Duchemin. A. M .. '..:I Schwart" J.
C. GI),cogcnoly.;. Induced by Serotonin in Brain:
Identification of. Ne" Clu$ of Reccpt<>t. Naru,e
198: 313_5.1982.
176. Rannel •. D. E" McKco, E. E.. a nd Morgan , H. £.
Regul'l;on of Pro,ein Synthe,i. and Dcgrodalion
in He.rl and Mu.cle. ANi"",
lIorm. f : 135-95, 1977.
177. Rie$<', P. I",ulin. and M"ai>olism.
William. &; Wilkins, Bol1imore. 1%7.
178. Riner, R. C. SI."",. P. G" and SlOne. S. G lu·
corccepl<>rS Contrelling Feeding and Blood Glu·
C<IIC : LQcation in 'he Hindbrain. 1/3.-
1981.
179. Robinson. T. J.. Archer, J. A .• Gambhir, K. K. ,
Holli •. V. W .• J, .. Carler. L.. and Bradley. C
Er)"hrocyles: AN.", C.II Type for Ihe E'alua-
Ii"" of the Insulin Receplor Dcfoet$ in Diaoclic
Hum.n$, )OJ: 1979,
ISO. S .. [,hid •. T .. Bloom. G.. Chou. M. C
Y .. and flel t!, J. 6. f.ffOC lol In,raporlal CalClOm
lnru,ion on [n,ulin and Glucagon Secrelion and
Hepa,ic G lueos<: OUlput in A nes,helized Dogs.
£""o<,ilWi, 104: 1979.
181. ROth , J.. Bonnor.Weir. S .. Norman, A" and O rei,
l. Immunocytochem istry of Vitamin D-Depon·
denl Coldum Bindi", Pretein in Chick Pancrea"
E.du,ive lAcali7.lllion in B-Ccll, . """oe,;""I.
110:2216_ 18.1 982 ,
IS2. Ruben.,e;n, A. H .. D. F" Horwit<, I). L.,
Ma.o. M. E .. Block, M. B.. SUitt. J. I.. Ku,.ya.
H., and Melaoi. F. Clinical Signifie.nee or Cir·
eulati", Proinsulin and C·Pcplide, Prog.
I/o<m. 33:435-68. 1977.
IS3. Sacca, L., Sh,r",in. R" and Feli,. P. Innuence <>f
Somatoslalin on GI"c.gon ....
Stimulaled Hcpatie Glucose Outpul in the Dog.
Am, J. PhYSic!. 236: EIIJ-EI17, 1979.
IH. Sakai. K., Manumu,", S .. Okimu,., y" Yama·
mura. H.. and Ni'hizul:a. Y. Li •• r Glycogen
Phosphorylase Kinaso. J. Bi()l. Ch.".. 254: 6631_
7.1979.
185. Salli.l. A, R .. S i.gel. M. I., Jacobs. S .. and Cu •.
lree . .... P. PUlaliv. Medialors of Insulin ACliOn:
Resulalion <>f py",v:lle Dehydrogenase and Ade-
nylale Cycl .. e AC1i,ili ... Pro<. Nail, Arad. Sci.
USA 79: 3513_17, 1982.
186. Sehachler, S .. and Rooin. J. OMu I/uman< and
Hats, Wiley. Ne,,", York, 1974.
187. S<:hedl. H- p .. Hea1h. 11 .. [1 1..00<1 Weng... J,
Se,um C.icitonin and Parathyroid Hormone in
THE ENDOCflINE PANCREA.S
".perim .. I.1 Di.bc,cs: Effect of Ill$ulin T.-.:at·
menl. EndIX'ino/, 103: 1368-73. 1978.
IS8. Scheying,l .. A.. Sch.ving. L. E .• T"'i. T H.. and
Pauly. J, E. Circadian Slage-Dependeni Elfem
or IrI$"lin and Glueag"" on Incorpora,ion of ' H
Thymidine into Deox)'ribonucleic Acid in Ihe
Esophagus. Stomach, Duod.num. J'junum.
Ileum. Caecum, Colon. Rectum. and Spleen of
the Adult Female Mouse. t:ndor';no/. III: 308_
IS. 1982.
189. Schimke. R. T .. and Grossbar<!. L. Studi",on Iso-
'.yme. of Hexokinase in Animal T; .,.c>. /Inn,
N,Y. Aead, Sci. Jjl: 332_50.1968,
190. Schneider, B- S ., and Hirseh,J. Hypo1ha lamic·Pi·
l uilary Funclion in Obesily. Chap, 3, pp. 1 19_44
of Frein kel. cd .• reference S6.
I90A, Schroeprer. G , J " J, .. Parish. E. J" Kisic. A.•
Jackson. E, M" Farley. C. M .. and Mo\\, G . E. 5
a-CboleSl-S( 14"'n-3/H>1-1j-<>ne. A Potent I "hib.
ilor of Ster<>1 Bios)'nlhesi., LQwc" Ser"m Chole$-
leroland Alters Di'tribulion of Cholesterol in Li·
popro1ein. in Babo<>n •. Pmc. Na". Aead. Sci.
USA 79: 3042_6.1982.
19 1. S<:hu,dziarra, Y .. R<>uillcr, D.. Harrio. Y .. and
Unger. R. I·!. Plasma Somaloslatin-like Immu·
noreaCtivily in Depancre.ti,<d DQgs. EndIX,inol.
10$: 595-9.1979,
192. Schwan,. T. W., and Tager. H. S . Isolation and
Biogenesis of a New Peptide from Panerealic 10-
leIS. Nalu" l'J4:
193. Seals. J, R.. McDonald. J. M .. and Jaren, L. In·
.ulin Eff«1 On Pr<>tein Pb<>$phorylalion of Plo&ma
M.mbran .. and Mitochondria in a Subcellular
S)'Olem from Ral AdipOC),le'. !J. CharaCleri,..·
li<>n or Insulin-Scnsiti.e Phosphoptoleins and
Condili<>n. f", Obsorvat ion of the Insuli n EffocL
} , Hi"', eM... 2H:6997-7001, 1979.
194. J . R., and bren, l. ACliv.,ion of Pyruvate
Dehydrogena.. by Direc I Addilion of Insulin to
an holated Pl.sma Membrane/ Mitochondri.
Mixlure: Eviden<:<: ror Goncr.tion or Inoulin',
Seoond Me""ng" in .. Subcellular S),<lem, Pro<:,
NaIl. Sd. USA 77: 77-81. 1980,
195. Shah, J. H., Udomphonkul, N .• Ed .... rd$. G .. and
Hurl:s. C The Diphasic Effec1 of Vincri'line ""
Glucosc-Indu""d Insulin SccreliQn and Glu"",""
Tolerance in Ihe Inlact Ral, EndIXrilWl. /OJ:
1041_7.1979.
196. Shorrill, B. C Kinetic Characteri'ties of Ihe He·
palic T rall$PQn of C hylomicron RemnanlS. Chap.
6. pp. 99-109 or Dietschy al .. ed ... rererence
"
197 , Silverberg. J .. and Volpe. R, AU10immunily in
Endocrine Di"" ... Chap. II. pp. <>f Ing-
bar. S. H .. ed . Y.a' in "ndoc,,'noltJgy 1977.
Plenum, New York, 1978.
198, Sirek, A.. Vranie, M.. Sire k. O. V.. Vigas. M..
and Policoya. Z. Effec I or Gro... th Hormone <>n
Acule Glucagon . nd !nsulin Rdea... Am, J.
Physi<>l. 237: E I07_EI12. 1979.
199, Smith, G. P.. Jerom •. C. Cushin. B. J" Et<"'o.
R .• and Simansky. K. J. Abdominal Vagol"",y
BI<>eks Ihe SatielY Effecl of CbQlceY'tokini n in
lhe Rat. Sci,,,,,, 113: 1036-7. 198 1.
200. Smilh,J . D..• nd liu. A. Y.-C . Leeti n. Mi mic In·
sulin in Ihe Induc lion of Ty,osine .. n.·
ferase, Sci."", 799-800. 1981.
20 1. Sno<lgr .... P. J .. Lin. R. C .. MUlier. W. A.. and
Aoki. T. T. of U,ea Cycle Enzyme< of
Rat by Glucollon. J. 8101. Chm•. 253: 2748----53,
1978.
202 , Soderl ing. T. R. Role of 1l0rmooes and Prolein
Phospho'ylation in Metabolic Regulation. f-'M .
PI'O<:. 41: 2615-17. 1982.
203 . S"lm'''-'. W .. "nd L.loux. M . Glu<:QCQn ieoid,
and Hcpatic Glycogen MClaboli<m . Chap. 27,
pp, 517-33 of R. ",cr and Roo"c,u. cd, .. refe,-
ence 7.
21)4. Sleine,. D, F" and Frein..!. N. V()l. ed •. /land·
boak af Physlolag)" .. c, 7. V()J. I. Ame,ican Phys-
iolog ical $ociety. Washington. D.C. 1972.
205. Stern. P. f I.. and Ikll, N. fI, ErreclS of Gluc.gon
on Sorum Calcium in the Rot and on Il<lnc Ro-
5O,plion in Tissue Culture. Endocrinol. 87: 111 -
17. 1970,
206. Su«man. K. E.. Mehler. P. S" Leitner. J . W" and
Draln;n . B. Role of the Socrelion Veliele in the
T,an,port of Receptors: Modulation of Somalo-
Itatin Bind ing to Islct$. End<>c,ino/.
111:316_23.1982 ,
207. Suzu ki, K.. and Keno. T. Evid ence that Insul in
Cau .., Tran,location 01" Glucose Transporl Activ·
ill' 10 the Plal ma Membrane from an Intr.cellu·
lar Sto<.,e Site. PI'O<:. Nail. Acad. Sci, US A 77:
2542-5.1980.
208 . J .. Lin" P. E".nd Efend it. S, Effects
of Choielcyl\o kinin, Gal tric Inhibito,y Peptide.
• nd Seetetin on In,ulin and Gluca,on Seerelion
in Rats, f:ndocdnQ/.IW: 1268-72. 1982.
209 , Tabonl<y. G, J .. Jr" Smith. P. H.. and Porle. 0 ..
Jr. Differential EffeC1l of SomatO&ta lin An.I08$
On ". and jl'<:ells of the Pancrea" A",. J , Ph}·.;ol.
236: 1012)-10128.1979,
2tO, Tanncnb.um. G , S .. Ling. N .• ond Draleau. P.
Somalosmin·28 i. Long., Acting and M<>rt So·
Icclive tllan Somatostatin-14 on Pilu ila,y and
Pa ncreatiC Hormone Relea... t,'nd<>cdno/, 111.-
101_7.1 982.
2tl. Tal.motO. K. 1$OIation and Cha,acteril3.tion of
Peplide YY (PYY) . • Condidate GUI Hormone
Ihal Inhibil$ E,oc,i ne P,<>c.
Nml. Arod. Sci. USA 79: 2514-1 8. 1982.
21 2. Thom pSon. E. B. Gluo«orticoid Induction of Ty_
rosine Aminolranlferase in Cultured Cell •. Chap.
II, PI', 203-4 1 of Ba".' and 1I.ou$.SOau. cdl .. ref_
erence 7.
213. Thom5On. J. M. In\eSlinal Abso,ption of Lipid "
(nftuence of the Unstirred W.ter La)'.. and Bile
Acid Micelle. Cha p, 2, Pl'· 29-55 of Diet.. hy et
• 1" eds .. reference )5 .
214. Ti,;er·Vidal. A" and Gourdji. D. Moehanilm of
Action of Synlhelic Hypothal.mic Pept ide. on
An!Crior Pituitary PhyjiGI. Rn'. 61: 974_
1011. 198 1.
215. Tordoff. M. G .. Hopfenheok. J.. Butch<,. L L.
.nd Novin. D. A Peripheral Locu, for Amphel-
amine Anorexia, 197: 148-50. 1982 .
215A. Smilh. 10 , L. Hill. R. L. Lehm.n. I. R.. Lell<ow-
;1', R. J.. Handler. P .. and W hite. A. P'il!dpl••
of BiorMmiS/,y: AS()«ls. 7th ed, Mc_
Graw.Hill, Ne", York. 1983.
216. Unller. R. H " Dobbs. R. 10" and Orei. I.. In,ulin.
Glucagon and Som.."'tat in in tho Reg·
"Iatioo of Motabolism. Ann. Rn'. PhYjio/, 4():
307_43.1978.
211. Unger. R. H.. Raskin. p" Srikan!. C. 8" and
O,ei . L. G lucagon .nd the A Cd l•. R",. Prol.
Harm. iU'h. 1917.
218. Val,wd •. L. Vandermeer>. A.. Anjanoyul •. R..
and M.lai.... W. J . Calmodu lin Aoti .. ,ion of
Adonylat. C)'clale in IsklS. Sdt n«
206: 1979.
219. Van Hoarn. W. A.. Vini k. "- I., and Van HOOt'n·
Hiokman. R. The Metabolic Cle.",.-.c<: of rondog-
enou' Immunoreacl i"e Glucagon and bogeno-u,
Glucagon in Pancrealoclomi,ed and Sh.m.()p-
e, aled Pigs. EndO<'rino/. 103.- 1084_9. 1978.
220. Van Hooten. M" P",ner. B. I.. Kopri"'" B. M ..
. nd Bra",o,_ J. R. Insulin· Binding Sit« in Ihe Rat
IIrain: In v;"" Localizal ion to tho Circumventri-
<ular O,gan$ by Quanlitat ive Radioautography .
t:ndO<'r/no/. /05:666- 7), 1919.
221. Van hallie . C. M.•• nd Femst,om. J. D. O<molal
Effects on V.sopre,,;n Secrel/on in Ihe Slrepto-
ZOlo<:in· Diabetic Rat. Amu. J. PhJ.iol. 141:
E4 11 _E417.1982 ,
222. Van Schartingcn. E .. Jett . .1.1..1'., Huc. 1... and
fle rs. H.--G . Control 01" Liver 6-Phosphofrucloki-
n.se by f,u.,,,,,, 2,6·Bi pllo$ phat. and Olhe, Elf.
feclors. /'rO<', Nail. Acad. &i, USA 78: 3483- 6.
19 81.
223. VoIp<. J. J .. and Vase los. P. R. Mochanilm. and
Regulation of Biosynthesis of Fatty Acidl. Ph},-",
;01. 56: ))9- 411. 1976.
223A. Vydelingum. N.. Drake. R. I.. . Ettonne. J ... nd
Ki$.SOba h. A, H. [o."li n Regulation of fat Cell
Ribosomes. Synthesi" and Lipoproloin
Lip.... Am. J . Physiol. US: E12I - ll. 1983.
224. Wajngot. A.• ROllY., •. A .. V.. nic. M.. Luft. R ..
and Efendic. S, (n,ul/n R.. i51ance .nd .. d
in$ulin Respon .. to Glu"<>;<: in Le.n T)'p< 2 Di·
abelies, PI'O<:, Nail, Acad. Sci. USA 79: 4432- 6,
1982.
224A. Wakil. S. J .. SlOOps. J. K.. and 3oshi, V, C. Fauy
Acid S),nlhesis .nd itl Regulation . AMI. R.v.
Blorhem. 51: 537-79.1983.
225. Walsh . D. A. . a nd Coope,. R. H, The PhY$iolog'
ieal Regulation of cAM P·D'p<ndont Prole/ n Ki·
naseJ- Bioch"". A"i(MS /lm-m. 6.- 1-15. 1979,
226. Weindl. A. Neuroend()Crine AspeCII of Circum.
•• mricula, O,gao •. Chop, 1. pp, )-32 oI"G.noog .
W. F.. and Martini . L.. ed •. Frtmfi." in Neu,orr1-
d<>cr in%gy 1973. Odord Uni.orsily P"",. New
York. 1973.

227, William •. I. Ii .. Chua. B. II. L.. Sahmi. R. H ,.
Si.hl. D .• and Morgan. H. E. Effcc\S of Diabct«
on Protein Turoovcr in Cardiac Muscl •. A""". J.
Phy,iol. ]]9' 1980.
228, William •• R. H.. and Porte, D .• Jr. ne Pa""rca •.
Chap. 9. Pl'· 502-626 of William$. R. H.. cd.
T'x/book oj EndlX'ri/lOJogy. 51h ed, Saunde ...
Philadelphia. 1974.
229. Winegrad. A, I., Clements. R. 5 .• Jr .• ,nd Mor·
rison, A. D. In$ulin.indcpo;ndcnl Palhway. of
Carbohydrate Motabollsm. Chap. 29, pr. 4H_71
01 Slciner and Frcin kel. ed ... relcrcne< 2(14 .
230. Wingrove. S. J .. Kay. C. R....d Vessey. M. P.
Oral Conlracept i,..,. and Diabele, Mcll itu$. Brit,
M,d. J. I: 23. 1979. ",viewed in r' ''r«uw, in
Family Planning II: 120-2. 1979.
231. Wi"e ... L. A.. and Traiko. C. S. Regulation of
Hepalic Free Fally Acid MClaboi;,m by Gluea·
gon and Insulin , Am. J. Physiol, 217: E23_E29.
1979.
232. Wollheim. C. B.. and Sharp. G. W. G. Regulalion
01 Insulin Rele.", by Calcium. Rh'.61 :
914-73. 1981.
213. Wood" S. C .. and Porte. D.. if. In$ul;n and the
A·I. C'c<h. M. P. Now Perspeclive.on Ihe Mechani.m
of Insulin Action. R«. Prog, I/IKm. Rsch.
347-B. 1984.
A·2. Jacob<. S .. Kull . F. C .• Jf. . and Cuatre.cua. P.
Moo<o, in Block, Ihe Malu,alion of Roceplo,", fo r
Insulin and SomOlomedin C: IdonlificOlion of Re·
C<pl"" Precursors, Pmc. Nal/, Acad. Sci. USA 80:
1228_31. 1984,
A·3. Rees-Jone,. R. W.. Hendrick,. S, A .. Qua,um.
M.. and Roth. J. The In,ulin Recepl<>r of Ral
Brain i. Coupled \0 T)'rosine Kina", ActivilY. J .
Bioi. n9: 3470-4. 1984.
A-4. Shakl,'i. K. Garlick. R.I... and Bunri. H. f .
NQnCnT.)'malie GI),eos),lalion 01 Hum.n Se,um
THE ENDOCRI NE PANCREAS
SeI·Poinl Regulation of Body Weighl. pp.263_8O
or Novin et al .. ed •.. ",Ierenee 155.
234. Wool. I. G. The Slruclure and Funclion of IOu·
karyotic Ribos(lmcs, Ann. R<>. 719-
1979.
235. Wool, I. G.. Castl«. J. J., Leader. D. P.. Fo,.
A. rn,ulin and the Funclion of Muscle Ribosomes,
Chap. 24. PI'· 385_94 01 Sieiner and F ... inkel.
e<ls .. refe ... nce 204.
236. Vamamoto. H.. y .. Okamolo.
H. St ... plO1.otocin a nd Alloxan Induce DNA
Strand B",.ks and Poly (ADP.Ril>o$e) Syn·
Ihet.", in Pancreatic 1,let., No/un }94: 284_7.
T
236A. Vip. C. c., and MOllie. M. L. In,u lin Recept.,..:
It, Subunil Struclure as Delermined by PlIot",f·
£nity Labcling. Pro<. 42: 2842- 5. 1983.
237. Zawolich. W. 5.• Dye. E. S.. Rogn$lad. R.• and
Matschins ky. F. M, 00 the Bioclk:mieal NOlure
of Triose· and Hex"",-Stimulaled ln$ulin Seer.·
tiQn. EndotrirlOi. 103: 2027-34. 1978.
238. Zi.rler, K, L. In,uli n. [on. and .\ lembran.: POlen·
tial •. Chap. 22. PI' . 347-68 of Slein.:r and F... in·
kel. eds .. reference 204.
Albumin AiterS its Conlormaiion and Function. J.
BiO/, Chm•. 259: 381 17. 1984.
A·S. Shoclson.S.. Hcko... 1.1 .. Nahum. A .. Mu ..... G.•
Ka i,er. E. T .. Ruben'tein. A. H .• and Tager. H.
Identifieation of a MUlanl Human In,ulin Pre·
dicled to Contain a Serine-for· Phenylalanine Sub-
SlituIKln. Pmc. Ndli. Arod. Sri. USA 80: 7390-4.
19M.
A-6. Van Obberghen. E.. Ka,ug •. M .. Le Cam. A..
Hedo. J .. I.. in. A.. "od H.rri<Qn . L. C. Biosyn·
Ihetie Labc ling of In,ulin Receplor; Studie, of
SubunilS in Cullured Hum.n lM·9 I.ymphoe)'te"
Proc. Nml. Arod. Sri. USA 78: 1052-6. 1981.
_ _ __ 6
The Glucocorticoids
Glucocorticoid! support Ihc glycogenolytic, gluco-
neogenic. ketogenic. and ureagenic aClions of glu-
cagon. They also innucnees of the ir own on
carbohydrate. pMcin, and lipid metabolism. In ad-
dition, Ihey perform many funClions that aT<' 1101 di_
rectly related to such processes (29).
The steroids sharpen the appetite, mod ulate gus-
talOry and olfactory perception (62) . affect the
d igeslion and inleSlinal at>sorplion of nUlricnI'. and
promOte thc slorage of glycogen . Thcy induc<= glu·
cone<lgcnic enzymes. provide substrates for thcm by
diverting a mi oo acids away from p;lthways for pro-
lein synlhesis, and excn "sugar-sparins" effects by
slowi ng glucose uptake into cells that hllve insulin-
regulated plasma membrane barriers.
They also play important roles in the regulation of
(a ) myocardial contraction. vascular permeability.
the tone of vascular smooth musc le. hematopoiesis.
and leukocyte translocation; (b) Water. monovalent
ion, calcium, and phosphorus metabolism, and acid-
ba$e balance; (c) clectrical activity in the nervOus
system . t he biosynthesis and lurnover of neurotrans-
mi tters, learning. behavior. and mood; (d) immune
system functions and inflammatory responses; (e)
the ability of skel etal muscles to engage in sustained
effort: (0 the secretions of several hormones; (g) skin
pigmentation: (h) reproduction, lactation, embryo
onic development. and both prenatal and postnatal
cell proliferalion. differen ti ation. and maturation,
and (i) Ihe ability to cope with
Most oflh. actions are man ifested after latcnt pe.
riods of I Or mOre hours . The re<:eptors havc be<::n
characterized (A·) . and factoN; that alfe<:t their
stabilizal ion (A·l) and activalion (A-4) have be<::n
identified.
'"
GLUCOCORTICOID DEFICIENCY IN WHOLE
ANIMALS
Glucoconicoid receptors have be<::n identified in vir_
tually every known nucleated ceillype of the ,,,,rIC-
brates (22). The importance of thc hormones can be
demonstrat:d by performing adrenalectomies and
providing protection against mineralocorticoid dep-
rivation ( IH).
Even when all kinds of pr<:caulions arc taken.
mortality rates arc high for most species, and this is
:specially Irue for infants and juveniles. Rats arC
among the hardicr Iypes tbat can survive for long
periods onder carefully controlled laboratory condi·
tions_ They most be continuously supplied with
moist, palatable food and water. and they require en·
vironmental temperatures that never deviate by
more than a few degrees from the optimum range.
They can not cngage in sustained phy<ical
and they havc poor resistance to infeClions. Rela·
tively mild forms of " nonspecific me,-.," c_g .• loud
noises. can cause death.
The animals display low levels of motor activity.
and they tend to havc subnormal body temperatures
when kept in rooms suitable for the housing of un·
operated lil\ermatcs_The eleclroencephalogram pal-
lern, and thresholds f()r stimulation are abnormal,
the re arc i>Cnsory defects, learning a nd memory are
impaired, and there is reduced tendency to e ngage in
exploratory behavior.
Circu latory system impairments include low blood
pre.ssure, reduced blood volume. poor cardiac func_
tion. inability to cope with water loads, inerea>cd
vascular pe rmeability. delayed coagulation. and dif·
ficulties in adjusting to sudden postural changes Or
'"
Ihc loss of small amounts (If blood . Anemia be
",vere. and the plasma albumin levels arc inade_
quate: but the lymphocyte ooun\;s high and .osirl()-
philia may develop. The thymus gland is enlarged,
and ;\ fails to inVQlutc in response to stress.
Adrcna lC:<:l()mized animals usually cal only lim-
ited quamities of food . especially when offered stock
laboratory diets. They further decrease their intakes
if they 3re required 10 "work" for the food (e.g .. by
lifting heavy lids on fceders. crawling Ih rough lun-
nels . Or pressing bars) , Gastric acidity.
tina) motility. and ralCS of nulr;cnt absorption arc all
depressed , Although the sensitivity \0 Ihc hypogly_
cemic effects of insulin is glYW&cn stor-
age is inadequate, The limited num!>' .. of you ng an-
imals thai survive .how poor groWlh rates.
The problems Can be averted by instituting glu ·
co<xmiwid replacement therap)" soon after the sur_
gery. They are less easily corrected after two Or more
days of deprivation.
Addison's disease is a clinical disorder in Which
inade<juate amou nts of adrenocortical hormones are
secreted (78) . Usually. tl1c gluoocorticoid deficiency
syndrome is aggravated by the simultaneous depri.
vation of mineralocorticoids.
Many of the symptoms resemble the ones just dc-
scribed. Skelelal muscle wea kness is pronounced.
and sleep offers lillie relief from the chronic fatigue.
The patients are apathetic and ps)'chologically dc-
pressed. They suffer sensory impairnlents, and some
enga ge in what has been labeled "paranoid" or "psy-
chotic" behavior. The gastrointcstinal symptoms in·
clude anorexia . nausea. vomiting. abdominal pain.
and sometimes diarrhea. Inadequate food intake
ac<:rbates the hypoglycemia caused by metabolic dc-
fe<:ts. In formerly fair·skinned individuals, there i, a
'bronzing" of the skin that is especially marked in
normally pigmented regions (e.g .. Ihe nipples), attd
in parts that are exposed to sunlight. (Da rk ... kin'lCd
patie nts may develop patches of poorly pigmented
skin. or vitiligo. This is probably related to autoim-
mune processes that are also responsible for the de_
struction of the adrenal cortex.)
GLUCOCORTICOID EXCESS
Cushing's syndrome is a clinical disorder in which
excessive quan tities of adrenocortkal hormones are
secreted. Similar problem. arise when pharmacolog·
ical dosages of synthetic steroids are given for their
anti·inflammatory properties, or for other purposes
unrelated to correction of a deficiency_
Only some of the consequences Can be predicted
from krlOwledge of the defIciency problems. The ..
inelude hyperglycemia and glycosuria (which is
THE GLUCOCORTICOtDS
often mild because of "compensatory" hyperinsulin.
emia). The "ruddy" appearanec r<:sults from poly-
cythemia and elevated blood pressure.
The appetite is sharpened. and this sometimes
leads to the development of oocsi ty. l'lowever, oot a ll
of the fa! depots aro affected in the Same way. Li·
polysis tends to deplete those of the append icular
structures (arm. and legs). whereas execs,ive 'tor_
age of falS On axial structures (abdomi nal region,
face. and back of the neck) accounts for designations
,uch as "moon face" and "buffalo hump".
Inhibition of protein synthesis is a major problem .
This. too, is selective. Ther<: is usua lly "wasting" of
skeletal muscle Ihat is aS$OCiatcd with weakness. The
dermis of the skin becomes and a depressed
rate of fibroblast proliferation contributes to the for-
malion of pink or purple striae ("stretch marks"),
delayed WQIInd healing. and defective walling off of
sites of inFection. Thinning of thc bones (osteopo-
rosis) i. amibuted to both faulty collagen synthesis
and influences of Ihe glucocorticoids On vitamin D
and calcium metabolism. Catabolic influences On the
thymus gland and aS$OCiated lymphatic tissues in-
crease the susceptibility to infections. On the other
hand. the synthesis of certain hepatic proleiM is ac-
celerated. and too many red blood cells are made.
Glucocort icoidscxert early influences on the brain
that tend to elevate mood and increase the sense of
"well-being". Larger amounlS can bring on tempo-
rary euphoria. However. the se<:ondary effects in-
clude psychic depression. Patients with chronically
elevated levels tend to have mood .wings. They have
also been known to display bizarre behavior and to
suffe r hallucinations . Before the dangers were fully
appreciated . some individuals given very large doses
became suicida l. Effe<:t s on the brain arc manifested
by individuals with no previous history of psycholog·
ieal problems.
The steroids reduce fever mostly by decreasing
prostaglandin synthesis and inhibiting the release
pyrogens; but som<: innuences are also exerted on the
brain.
INfLUENCES OF GLUCOCORTICOIDS ON
THE LIVER
Glycogen SyntheSiS
The dose-related augmenlation of glyoogen storage
in fasted. adrenalectomized animals is the basis for
one of the methods of bioassay.
Glyoogenesis. glycogenolysis. and the roles of in·
sulin, glucagon, nutrients, and metabolites. in the
regulation of glycogen metabolism, Were discussed in
detail in Chapters 4 and 5.
 G LUCOCOATICOIOS

1 Gluconeogenesis
j Glucose oxidat"'"
'"
t Poripheral glUCOSe uptaKe
4,-t.o.,.

• Glyeog<>n
, synThase
achvity
! fiepaTic __
-;-
-
I
t Gly<:ogen _ __ _ __ _ _ __ _ __ _ _ _ _ _ ; G._d,...

""'ag"
Fig, 6- 1. O' .... H of glucoeott;ooO:Is or> glyoogen
motobol;om.

Glucocortiwids promote Ihe produclion of glyCQ- conyersion of phosphorylase 1/ to phosphorylase b.

gen syntllase, and they aClivate preexisling en'.ymc.
They provide the liver wilh glu=-phosphate by a,-
,derating gluooneogencsis and by limiling extra_he_
palic use of glucose. They also e.erl inhibilory inAu-
enee!; over th. phosphorylase 'ystem. especially
when glucose i. abundant (Fig. 6-1).
The actions require the support of in,ulin, and the
steroids indirectly augment insulin secretion. How-
ever. their metabolic effects can be acoomplished
without rai.i"$ the blood in.ulin 1e",1•.
The livers or glucocorticoid-treated animals oon-
tain a phosphorylase: regulator that cannot be de-
tected in the tissues of untreated adrenalectomized
oontrols (140) .
The induced pMcin gradually decreases the aCliv-
ity of phosphorylase b kinase. Consequently. phos-
phorylase II roYerts 10 phosphorylase II. and glycogen
degradation is slowed. Glucocorticoids may al so pro-
mote Ihe of thaI calalyze
MOf<'Q\ler, when high glucose ICYels build up in Ihe
li ver, the sugar binds 10 phospho')'lasc 1/ and thereby
f<'nde .. Ihe en,-yme morc yulnerable 10 auaek by Ihe
phosphalase (Fig. 6-2).
Glyoogen synthase aClivity is indirectly aug-
mented by thc reactions. sillCe phosphorylase II is an
inhibilor of that enzyme.
Newly fornted glyoogen granules associate with
Ihe tubules and vesicles of the smooth endoplasmic
reticulum. The hormone promote. proliferation of
the membrants and accumulation of enl.ymes within
them (85). Some of the slowly developing influences
of the glucooorticoids may be on such
processes.
GLYCOGEN SYNTHESIS IN THE FETUS
During late felal stages, promOle Ihc
formation of gluooki nasc and of large amounts of

Pho.pMl3se

Fill. 6-2. 1'r<>PQM<l mechaniom.!<>I'

Aeli • • u"" o! glycogM syntha".
'"
glycogen synlhsc (8). This is nec=ry for aCCu-
mulation of the glycogen thai will be """de<! to
maintain Ihe blood sugar CQlICentraliollS during lhe
perinatal period.
In ralS with 22...Jay geSlalion period" plasma glu-
cocorticoid levels rise during day, 18-20, while gly-
cogen accumulation rapidly during daY' 19
through 21.5. Precocious onset Qf glyoogen storage
can accomplished by injecting the steroids on day
16, whereas lh. normal processes are impaired in
hormone deficiency stalcs. The fctalli"., is insensi-
tive 10 Ih. steroids berOT. day 16. probably because
il Ihen has rew hormone «<.pIOrs.
The r<:sponses 10 glucocorticoid, decline rapidly
after birth (140). This has be<:n variously auributcd
to (a) cell differentiations thai aITe<:t post-receptor
events; (h) delivery of nutricnts via Ihe hepatic por-
tal =sel, when the infants begin to feed; and (e)
influences by othcr hormones . {Changes in
thyroid and growth hormone functions occur during
the perinatal period; and thyroid hormone aCIS on
glucocorticoid-sensitive pituilary cdls (86J,)
Although in. ulin i. tho major inducer of glyooson .yn·
Ih""" and glucokinase arter birlh. il doe. not ...,m 10 be:
"fprimary impOrtance during tht late fet. 1.lagtS, II o.n
aocelor.t. gl)'cogen .ynlhesis by "oli\'3t'1\3 glycogen .)'n·
th .... but il cannot roplace the gluCOCOrtiC(>id,. Insulin
may requiT. Ihe >yneTgi>lie elfee" "r Ihe hi$h glu<=<: le,-
el.that are no! .ltai.cd until .fter r«di1\3 bogin •.
Glycogenolysis
Blood gluwse-maintaining roles of glucoconicoid.
include support of glycogenolysis during times of
fasting. In addition to providing Ihe glycogen sut>.
'trate. the .teroids promote the biosynthesi, of gil"
cogen phosphorylase (56). The livers of untreated
rats comain subnorma l quantities
of the inactive form of the cnzyme (phosphorylase
b). The levels are slowly restored by hormonc
replacement.
RELATIONSHIPS TO cAMP
Slcroid.deficient animals secrete glucagon. They
thereby build up high levels of cAM? in the liver.
and thcy activ.te the cAM?.dependenl prolein
kinascs. However. the)' C<lnnot e/foxtive ly usc
the cnlymes to accomplish The
mechanisms glucocorticoids may exert
'"pcrmissive'" influences at silcs beyond protein ki·
nase activation (56) werc discussed in Chapter 4.
The glucocorticoid. do not exert important inllu-
ences on hepatic adenylate cyclase. Some small ef·
fects on phosphodiesterases may prolong the biolog·
THE GlUCOCOIlTICOtOS
ical life of Ihe cAM P, but these do not Seem to be of
.ub,tantial physiological imponance.
Thc glycogcnolytic aClions of cateeholamines and
of certain Olher regulators on the liver arc largely
cAMP·independent. Glucocorticoids may support
Ihcm by providing glycogen, by promoting phosplHr
rylase synlhesis. and possibly also by facilitating el-
evation of Ihe cylosol Cal' concentrations.
Gluconeogenesis
Adrcnale.:\omizcd animals can ulilize dietar), nU'
tricnts. but they soon become hypoglycemic when
food-deprived. One problem is that they cannot re·
cruit amino acids from extrahepatic sources for usc
in gluconeogenesis.
The glucocollicoids '"mobilize" Ihe lissue protein,
in several ways, (a) They inhibit the uptake of amino
acids by skelctal muscle .nd other extrahepatic tis·
sues. This leaves larger amounts for the her. (b)
They inhibil glucose uplake at those same .itc •. The
extrahepatic cells are Ihereby deprived of sources of
ATP and other substances needed to support the in-
oorporation of amino acid, in to protein •. (e) By se·
lect ively accelerating degradation of SOme rate·lim·
iling aminQ acids, imbalances arc created that
funher depress protein ,ynthesi •. Con..,qucntly.
amino adds leave the cell, to enter Ihe blood'tream.
Skeletal mu",,\c i. an e.pecially rich SOurCC of aia·
nine and of branched-<:hain amino acids,
INFLUENCES ON INDUCTION OF AMINO·ACID·
DEGRADING ENZYMES
A lan ine a nd smaller amounts of serinc. proline, thre-
onine. arginine. glutamate. and aspanate are the
major direct precursors of glucose in the liver (38),
Glucoconicoid, have liltle influence on the en"ymes
thaI directly promole dcaminalion of those .minQ
acids, The steroids aCI most obviou'ly on tyrosine
transaminase and on tryplophan oxidase .
Tyrosine aminotransferase (TAT, TA tyrosine
ketotransferase . TKD promotes Ihe transfer of
amino gr()Ups from tyrosine (and relaled moleeuk.
such as phenylalanine) 10 (t--kctoglutarate .
Tyrosine + Ketoslularate-
+ Glutamate
The hydroxyphenyl'pyruvale is further metabo-
lized to fumarate (which is glucogenic) + acetoace-
tyl-CoA. The glutamate can be used 10 make glu·
cose. to provide amino groups for the synlhesis of
amino acids from carbon ,keleton proxursors. or for
other metabolic purposes,
 Tryptophan oxidase (TO, tryptophan pyrrolase,
TP, tryptophan dioxygenase) catalyzes the oxidation
of tryptophan to formylkynurenine, which Can be
metabolized to alanine or used for the formation of
nicotinic acid,
Glucocorticoids are potent inducers of both of the
enzymes when they are administered to either intact
or adrenalectomized animals_The latcnt periods thai
precede accumulation of the and the aoo.
lition of the effects with «_amanitin or actinonlycin
D, are consistent with the belief that the hormones
act primarily 3t the level of transcription. Tbc
mRNAs that arc made have very Short biological
half-lives (only 1.5 hours for TAT mRNA).
Only modest clTeets arc obtained in the absence of
eA M P. This has been demonstrated by in vitro stud-
ies of isolated liver cells (and ,,-ith hormone-respon-
sive hepatomas thai arc more easily maintained in
culture) (37, 38).
It has b.:cn proposed by various investigators that
cAM P (a) facilitatcs the processing of m RNA pre-
curSOrS into forms that can be used by the ribosomes:
(b) accelerates thc transport of the mRNAs from
the nucleus to the cytoplasm: (e) st"biH,-e, the
m R NAs and prote<:I' them again.t degradation: and
(d) augments ribosomal use of the mRNAs for Ihe
dire<;tion of en?)"me bio.;ynt he'is_
There is evide",e f<>r cA M P 3cede'. tioo of the rate of
etong."on ot the tAt n• .oCnt cha,", (t l t).
elTcet' of cAM P on ,tabili,-,uion of the m RNA for PEP
c .. box)'kina<e haY< l><cn demoMlmtod (37)_ A cA.\lP_
depeodent pf<)tein kinase i, kno"'n to promote poo.pho-
,)'l.lion of $CyOml kind, of molccule!. Thc... <x>uld in·
dude an)". or a combination. of the following: clong"t ioo
f.ctorl. pol)'som. l.mRNA .... ssociated protein,.• nd nas·
cenl (121).
The cA ." !P is not effective by itself. (Small incre-
ments in en'_ymeconlcnt seen when dibutyryl cAMP
and pho:;phodiestera.'iC inhibitors arc presented to
preparations prc.iously exposed to thc are
attributed to interactions with the very limited
amOunts of mRNA, made under basal conditions.)
If the cAMP is presented firsl. and the glucocor-
ticoid i, added late r, the full latent period for the
steroid action muSt elapse (pre,umably because
stimulation begins with Ihe mRNA symhesis).
However. if (he glucocorticoid alorte is given. and Ihe
cAMP is added at (he end of the latent period. the
clTects of the nucleotide become apparent alrtl(lSt
immediately_
High eoneemrations of tyrosine. leucine. and cer-
(ain other amino acids Can increase hepatic TAT
(141): and tryptophan has similar innuenecs on TD
(42). The eITec1s a'e attributed 10 stabiliwtion of 1he
enzymes_ Although insulin opp:1<Cs many glucocor-
ticoid aClions.;t increases hepatic TAT_ Thi5 is ac-
complished via generaliud of protein
synthesis and slowing of the degradation, The effects
can be seen within 6 minutes (SO)_
In the glucocorticoids contribute to cell dif_
ferentiation and initiation of mRN A "ynthe.is.
Early administration of Ihe steroids Can inV<lke pre-
mature appearance of the en'.yme (8).
"DE INDUCTION ," "PSEUDOINDUCTlON," AND
"SUPERINDUCTIO N"
Hormone wi1hQraw.( leads to "dcinduelion," Or roturn of
the en,.yme conte.1 to basal leyOls. It is associated with
diminished rosponsiveoes' to cA ,\ lP and is attributed to
degradation of the induced mRNA •.
When insulin " nd other serum components slow dei'
rodalio. of thc protein •• the amounts of en'_ymCli
,..ith Shorl h.lf·livcs tend 10 increase, Such "pseudoi •.
ductioo" is not lin ked with ne'" cnzyme t;jooynlOcsi,
(141).
If the hormooc is permitted to . Cl and is t!>en with_
drawn. aC1inomyci. D bring> about i","a,,_r in h<>rmone
synthC$i, (superinduction). T he elfects .re .bolished by
c)'clohe.imide . Dne pos,ibility i, thaI lhe antibiotic intcr_
rere, wilh lhe formation of . hiihly labile inhibit<>r th. t
aclS pos1lran. lotion.lly. Anothor is th.t aClinom),ein [) in
..,mc ,",'.)' acceleratC$ protein ' ynthesis via mechanism,
unrelated to it.' «peeled .frCCl! 00 the DNA
ADDITIONAL INFLUENCES ON
GLUCONEOGENESIS
Glucocorticoids accelerate from
glycerol, p)·ru.ate, lac(ale. and other substrates a.
well. They increase the aClivi!)" of glucose-(,-phos-
phatasc_ probably by promoting transloeation of the
cnl.yme from the rough to the smooth enoplasmie re-
ticulum and thereby changing either the ph)'sical
state of the protein or the microenvironment (8).
They induce PEP carboxykinase (Chap. 5). and they
increase thc a,'ailability of glycerol by contributing
to lipolysis.
Other Influences on the LiYer
Although they do not promote increase.!
in protein synthesi,. the steroids accelerate the pro-
duction of certain specific substances. e.g .. some of
the plasma proteins. The mechanisms include ele-
vation of hepatic amino acid content_ ( 1I owe.er, glu-
cocorticoids can decrease amino acid uptake by hep-
atoma e<:Us [49]).
The fctal liver is an imror(anl site for hemato-
poiesis . Glucocorticoids promote transfer of the
function to bone marrow under physiological condi_
(ions_ T he maturation can be accelerated by inject_
ing fetuses Wi1h the steroid,.

'"
Influences on Adipoc yte Plasma Membranes
Glucocortiooids act on adipocy\c plasma membranes
10 inhibit glucose uptake. They thereby interfere
wilh production of the glycerol·3·phospha\c required
for incorporation of fally acids into \riacyglycerols.
Since the effects develop slowly and can he blocked
by inhibitors of RNA or prolein synthesis, they may
involve production of a labile prolein thaI inlerferes
with transport. (fructose utilizes a dilTercm
carrier (I I). and ils uptake is not affected .)
Glucocorticoid! increase the sphingomyelin oon·
ten! of the plasma membranes of adipocyle5. skeletal
muscle. and other insulin targets. "'hile adrenalec-
tomy decreases the adipocytc sphingomyelin and in_
creases Ihe cholesterol comcnt (107) . The quantita_
live correlations with changes in basal glucose (bUI
not fructose) lransporl are attributed to influence..
on membrane f1uid ily. Such effee\-' do not Ihe
ability of high glucose conC<'ntralions plus insulin to
sugar uplake (41).
Ph armacolo,ical eoncentrali.,... of sever.1 '[e,<>ids
•• erl rapid, non.pecifie "deterge nt_like" clfeeto <HI Ihe
membrane. that affee1 transpon funclion •. The obsc".-
lion' are probably IIQt physiologically r.levant (103).
Glucocorticoid, a lso decrease hexokinase II activ-
ity Th •. reJ"re . i, incfficicnl ,,'" nf cV'.n lim_
iled amount. of glucose that do entCr thc cells.
(Fruclose phwphorylation is 001 affectcd (13IJ.)
GluCOC<lnicoids further impair glycerol -3-phosphatc
production by inhibiting PE P carboxyki nase in adi-
pocy tes (altoough they increase lhe activity of Ihal
enzyme in li. cr and kidney). The effeclS on the en-
zymes are separable from the ones on tran'port
(123).
When glycerol-3-phosphale producliO!! is im-
pai red , adipocyte, release large quamilie' of fatly
acids !O Ihe bloodslream. Glucocorticoids can ac-
complish this when acting alone. The effecls are aug-
mented by epi nephri ne and other lipolytic hormones.
The fally acids arc la ken up by the liver. and high
levels of lhc hormone can promote the a«umubtion
of execssi'o'<' quantities of lipids in that organ.
Ad ipose tissue release, mostly long-chain fally
acids. Hepalocyles conven them 10 short-chain fany
acid" and they release the product, to Ihe blood-
stream for u .. by rest ing , kelelal mUScle, cardiac
musele . and some Ol hc r cdlIYPCS. T he processe, ",.
Sume especial importan« during fasting, .ince high
glUcocorticoid levels. decreased rates of insulin re-
lease. and blood glucose levels in the 10w-norm"1
range all limit the ava ilability of carbohydrate fuels.
The deli very of excessive quanlitics of fally acids
to hepalocyle. accelerates ketogenesis. However.
only mild ketonemia and ketonuria follow in other_
THE GLVCOCOATICOIOS
wise normal individ uals. since glucocorticoids also
ael indirectly 10 promole insulin release.
Allbough the lipid-dcpleting effects arc extensive_
they arC also selective. Most of the reserve, arc re_
cruiled from appendicular StruclureS (arms and
legs), while fat tends to QITumular.. on the axial Ones
(fac ial, cervica l and abdominal regions). The
change. in fal distrihution may be related to the
richer sympathetic innervation of arm and leg mus-
cles. a nd to greater insulin sensilivity at other sites
(4 1).
GLUCOCORTICOIDS AND RESPONSES TO
NONSPECIFIC STRESS
Pe rhaps Ihe most inlriguing (but the !cast under-
stood) of all glucocorlicoid functions is the protec-
tion they afford during Ihe early rcsponse$ to non-
specifIC stress (29. 12S).
When healthy. inlacl animals arc exposed to any
of a wide variely of noxious or Ihrealening slimuli,
they pour OU I IWo 10 Ihree times the quantilies of
glucocorticoids rclease<l under mOre usual cittum-
s ta nces. If the Slress is severe and prolonged. the gl u-
cocorticoid .... creti ng cells can be strongly stim ulated
for days Or weeks. The adre nal conices unde rgo hy-
I"'tlr<lphy, .mi Ihe <icmid chroni_
cally elevated.
Th e effeets of lhe high steroid levels on lhe ani -
ma ls include shrinkage ("stress in"olulion") of lhe
thymus gland. some hyperglycemia and glycosuria.
increased renal eXcrelion of nitrogenous waste" in-
creased glycogen deposition in the liver. some "wast_
ing" of ti.,ue prolein" and possibly also mild hyper_
tension . However, the metabolic effects arc far less
seve rt than would be the ea,e if the Same gl ucocor-
ticoid leve ls we re II) be .ustained in nonmessed
animals.
Whe n lh. offensive slimuli a re withdrawn. lhere
is us ually rapid recovcry of Ihe norma l metabolic
status. (It is possible. howeve r. for animals
to severe stress for long rcriods to evidence signs of
Recovery then involve.< more
rcpair.)
In contra't, unprotected adrcna lectomi,ed ani_
ma ls succumb rapidly if exposed to same slimuli.
Death u.ually results from cardiovascular collapse,
but ..condary re na l failu re can develop if there is
sufficient time. Hypoglycemia is COmmon in some
specie" a nd it can have fatal consequences. How-
when art ificial meaSures arc taken to keep up
tho blood glucose levels, survival is prolonged only
brieny. The same animals can be fully protccled if
they are given glucocorticoid, before imposition of
the stress.
 Imerningly. animals ch ronicatty expOSed to a spe-
cific form of IIQxious stimulaHoo prior to adrenak;(:.
tomy In: much more <eswant than " umr.aincd" COft.
trois to tllat pani<:ula. form of stn:s.s. They are.
hovo'ev.:r. futty susceptible to unrelated da maging
stimuli. Previously unlrained adrenalcctomized ani·
mals can also grad"oll" a«ustomed tOSOIm
adve rse conditions,
GIUCOCO r1 lcold Influen ce. o n the Cir c u lato ry
Sy. tem
G lucooortiooid«l'icient aninutls ha\'t reduced car·
diac outpu t. very limited cardiac 1'CKm:. and i....
paired delivery of oxygen and nutricnts to
tissues. The blood volume tends to be low. with tto.:
defect more obvious in some speci es than in otto.:rs.
T he total hemoglobin and red cett content are re-
duced (a lthough hemoconcentration mask this
c!fcct if only <.juamities per mittiliter nre measu red).
Cardiovucular reRcxes lead to some gc nc ralized va-
sooonstriction. but this is usually for pro-
ttaioro agalMI development of hypotension. The va·
can aggra""'te elfeets 0( low card iac
QIItput a nd aroemia on delivery to some of lhe
tOSMIes. There is also impaired ability to
adjust the blood flow (via va:lOOOllstrlction
and vasodilation) to changing body needs. Capittary
permeability is usuatty increased (74).
RESPONSES TO CATECHOlAMINES AND
RELA TEO PHYSIOLOGICAL STIMULANTS OF
THE CARDtQVASCULAR SYSTEM
I'.::rm issive innuenccs on cat«holamine functions.
were dis<.:usscd ea rlie r and in C hapter 4. GluCOCOl-
tiCXlid4efic icnt animals can mount brie f. limited re-
sponses to administered epinephrine or IIQrepincph·
rine. T hey a re not only una ble to s usta in such
activity. but they soon lapse into hypotension a nd
o;ardiovascular insufficieney. Prelre3tlmnt with glu-
woonicoids restores the ahility to respond in a more
normal ma nner.
Although adn:naleclomi:eed animals laCk
medullae. they release CQn$idel'll bk: <.jua lll ilies of
norepinephrinc from tto.:ir sympathetic !lCrve end-
ings, Tto.:re ale reasons to believe that they succumb
to toxic clfects of endogcnous Ci t« holamines (29).
T hey a re e xq uisite ly sensi tive to stimuli that pro-
mote diseba!"ie of the molecul es. and they can be
protected witb cate<::boIamine a ntagonists. More-
O'ICr. animals repeatedly inje.:ted with epinephrine
prior to are resi$tant to post-
su rpeal sttuS.
Angiotensin II (A·I1) is an even more pOIent va-
that contributes to the physiological
rrn.inlen.anee of vascular tane. Adrenalectomy abo!·
the responses (74). Glucocorticoid deficiency
a lso impairs A-II generation. The hormone induces
the ewymc that catalyles con' l'rsion of angiotensin
I to A, II (45). The same en1.)'1m iNJt;fil'(Jla
kinin. " 'hich (unctions as a vuodilator.
Adrcnalectomiled a nimals are O'ICr-seru;;li"e to
vasodilators (73 ). They succumb to cardiovascular
when ai "en "" the dose of histaminc toler-
a ted by intact con trols (126). They Can be fully pro-
tected against this by pretreatment with glucocorti.
coids and catecbolami ncs.
Left preS$ure during sys.tole is sub,..,r·
ma l. This is associated with changes ;n the dtaro-
cardiogram ( .. hieh ca n procrc:ssivcly worsen) and
with a ltered Na -/ K '_ATPase aet;vity. Doth the
cardiac " 'eight and its glycogen content d«line.
The heart has glucocorticoid rec<ptors (4 1). and
injcctions of the hormone restore myo<:ardiai c0n-
tractile force. normal electrical activity panems.
weight. and Illycogen content. However. all naturally
QC<:urring g1ucorortiCXlids have some mineralocort i-
coid potency. Aldosterone (the major minera1oeor_
tiCXlid) can impo ore the cardiac function. It probably
acts in pan by exening influences on tto.: ATPase.
but it also 1o"A-ers plasma K ' and a lfcas the mi neral
content of the heart . (T he hearts of adrenaleeu)-
miled a ni mals are $erGitivc to ouabain and
otber acting On the AT P-J$e ,)
"'<j,... i. k nown 'Q i"", ..... a od gt.""".,..,i ·
coid Idminimation 10 deereue. tOo numbe .. of e..,Ii.c
adrencr,ie receptors. The phj'$iol"licat .iPlifi·
e.onte oftM observatio ... is 1101 clear (2).
CARDIOINHIBITORY FACTOAS
Whu animal!; of di""rsc mamll'Ulliu species .n: .u\).
jcelt<! to procedurC$that culminate in the onset of fatal
circulatory substance. thaI depress lhe my""'"
dium ."umulatc in the blood. Some of tile lalter aOO act
on v..c u1 ...mQOth muscte 0011 inc, •• capillary
I bility. Tile I,ent. include myocardial depr . ..... nt factor
(MOF. • peptide that ori,illlles in tbe ",,""rca'
pS.1201). p..sively tra ... f.rable leI""t f.ctor (PTLF. a
tQfIK","'hat larger pqn;ru; tibetllt<! by el)'tll_ytcs pSI).
leuci"" (S I). I nd addit iona.l .. tha. """'" from
.he intcst;"" (S8).
Thoe flClOr$' u eff«ti", when teslt<! in ';' ro. and wbe n
Injected into ani mIl. in which bl.e been taltn
to overt 10",.,; •• of the body t<mper.tu,,, a..:l tbe blood
pU . (Correction of the a.idoli. docJ. !\o.... ""r. IlIcviate
.he Iccomp.iinyin, bradycardia {120). )
It i. betieved thot Iocali.ed ischemia of the re,ions in
wh ich th. &ienll . .. produced Iud. 10 labiliitltion oft}.
_ _ J membra".. wit h C<II' '"Q'''''Ol r,lea .. of h)"droly.
tie '"'ymes. The lauer caWl'« cleaoqc or bioIogicatly
i!\lClive prttunon to y;.,ld tbe tQ.lie Igent .. Prot«tion
........ development of the myocardial depression is .f·
f<mk<l by I pn>l inin . nd retl ted inhibiICIn..
tre.tmcm "'i1 h .ynthcti<: .hKoco"icoids tan p"'",nt

'"
on,et of .hock, "nd lh;. i, .tt,i!)u!<;d 10 ".bili ....tion o>f
lysosomal membrane •. The inuavenoo. inru,i<>n of p=
laglandin E, (PGE,) is benefic;al. probably beO"."'. in
addition to . l.bili. ing the membranc" it pron..,.e... _
dilat;on and thereby ",duct. ;",hemia.
HYPOXIA
Impaired o'ygen doli .. " 10 lhe coli. imposed by ca,di ••
in,ufficiency i. aggravated by inability to ,elec1ively COn-
'lricl some blood vessel, while dil ating olhers .• nd by he-
most.,;, thai e •• ctrbat.. the 10$1 of pla.ma fluids via
leaky c'pillarics (120). The", also s•• m !O be imbalance,
in the n\ln of PfOOUClion of p'(>It.gl.ndin. of the E and
I type. (whkh art vamil.,.,...) and those of the F 1)'1""
,hal .timola,e the va",ul.r , mOOth mU$(;ic.
Severe ... mia contributes .ubolan(i.lly to the hypo.ia.
The causes include inadequate food in'3ke, dogencrati ..
ch ange, in tbe ",mointe.tin.1 mUC<>:'la tbat reduce Hel
and production and probably account f<lr dc-
pressed ratel of iron and .itamin B" absorption. and
some direct elTects of Ibe borlll(lne deficiency on bon.
marrOw and erythropoietin "'lease (971. (WuCO\XIr-
ticoid injection, promole "'ticulocytosi, [ 146 J.I
Patients with Addison', disease oftcn have bout. of
vomiting and diarrbea that "Ura.. te the nU!ritianal de-
ficicnci.,.nd disrupt Hcid_baSl: balance. In addition. au_
toimmune damase 10 the bone marrow i, known to occur
in some (141.
Thymus Gland Re sponees to Stree.
In "scnsilive'- species such as Ihe rat and mouse. the
oulpouring of glucocorlicoids leads 10 rapid and
massive involution of the thymus gland. Up to 95%
reduclion in organ weight can occur within 24 hours.
Consislenl. bUI less dramalic changes lake pl"ce in
olher Iymphocyle-Iaden tissues. and Ihc blood Iy m-
phocyle counl falls. Resloralion commences soon
afler I be blood glucocorticoid level, I"<:turn to control
values. In ·'resis\am" speci.. that include humans
and monkeys. smaller changes of a similar nature
occur.
By COntrail, unprotected adl"<:nalectomi7.ed ani.
mals fail 10 undergo thymic involution when
stressed, and the blood lymphocyte COunt may even
riso(125) .
The thymus gland comprises mostly lymphocytic
elemenls (thymocytcs and prethymocytcs) tlmt arc
associated with an epithelioid Somc roles
of the Ihymocytes in immune and innammatory rc-
actions are considered latcr. The reticular cells arc
believed to make hormones thaI regulate thymocyte
maturation and proliferalion, bUlthey probably syn-
thesize other regulators as well (98) (sec Chapter
20).
GluC<.>COrticoids selmively deplcte certain of the
THE GlUCOCORTlCOtOS
lymphocytic compOnents. There is much speculation
but lil1le information on relationships of (he phe-
nomena to the resistance to stress. Hypotheses con-
cerning the physiological signiftcanee include the fol-
lowing: (a) The steroids aClivalt components of the
immunc system (despite the faClthat some cell, may
be destroyed in the process). This enhances the re·
sistance to infections that might follow stress .itua-
lions involving lis,ue trauma . (b) The glucocorti-
coids seircliveiy (/epff55 aC(lv,lt« of those
thynlOCytes capable of mounting altacb against
··seJr' or autologous (as opposed (0 "non-self." for-
eign, or heterologous) antigens. Therefore, the)' pm-
vide protection against the mounting of autoimmunc
I"<:actions that could destTO)l normal tissues. (Such
prote<:tion could be espc<:ia1\y important if !iSj;oc in-
jury leads to the "leakage" of ecllular proteins that
are normally sequestered (111), since the immune
cells may treat them as '·foreign" sUhstances.) (e)
The reticular ""lis play special roles that contribute
to stress I"<:sistance. They are usually under tonic in_
hibition by the lymphocytic clements, and the thy_
mocytes must be removed to permit them to accom-
plish their missions. (dl The lymphocytes that leave
earry nutrients and I"<:gulators to peripheral cell<
( 132). (Thymocytes are rich in nucleic acids and
protein •. They may transfer the molecules via '"CI"<:_
tory processes, direct cell-to-<:ell interactions, or
when Ihey
Since has been supported
by experimental it may be premature to
rule out the that the sIT=-associated
are i th"n exaggenllions of
events tbat proceed under more usual circumslances
(and that they arc not nccessarily benertcial). Glu-
cocorticoids eAert tonic inhibilory innuences on thy-
mocytes (and Ihe thymus glands of adrenalecto-
mi;reci animals enlarge). The tbymu, gland
undergoes circadian variations in weight (129), and
the timing i. related 10 the diurnal changes in glu-
cocorticoid hormone secretion.
EFFECTS OF THYMECTOMY
If thc thymus gland does. in faCl, play an impoT1ant
role in Ihe resiSiance (0 SlI"<:S$. it is I"<:ao;onable to seck
evidence that animals deprived of that organ suc-
cumb morc I"<:adily than intact ones when exposed to
noxious sti muli . This is not easily demonstrated,
since animals deprived of their thymus glands during
juvenile or adult Slages survive and cope with mOSI
environmentally impascd problems.
Th)'mectomy ha, drastic elTec," jf it i, performed al
carl)', erilical ".ges of devtlopment. In rat>. mie,. and
oth.r ,peci.s born aft.r ,hort ge.tation period •• ""onal.1
thymeclomy permanemly cripple' the immune system.
Animal. that .urvive ha .. limit.d ability to cope "'ith
viral and ""rtain b.oterial infection .. or 10 reject lumor
cell. Ihal h... acquired ab"",mal •• rface Ch"raCleristic"
flowevor, if the .urgery i. delayed for just a few da)", tit<
• lfeelS on the immune 'y ..em are highl)' limit.d. (Some
dopre ... io. oflhc blood lymphocyte COUnt i, $Cen in time.
and ,ublle defo.," in re'pon,es to some antigen, can be
demon'trated). T ho only major eon<C<1.uen= . eem 1(> be
in.bility 10 restore the funOlion. exposure 10 X·
'"yo or the .dministralion of antilymphoc)"lie sera (98).
No dirCOI relalionship' belween ,uch observati""" and
the rtspon$C' to non'pecifie stre .. ha.e been eslabli'hed.
Role. of the gland at a later time may be associaled wilh
Ih. markod growth th.t il underg<>c • • ftcr the immune
funclion, have e" .bli,bd. The of Ihe
young adult i. ","erallinl'" la'ller and heavier than the
neonatal "ruOlur. (II It al<o display, exqui,ile ",nsi·
livity to ,everal hormonts, The", include e""'ien,. an-
d"'i0n. , and growth hann'me.
Sublle elTecl. of Ihymus gland deprivalion c.n.
however. be demonstrated .
THYMUS, REPRODUCTIVE SYSTEM, AND
STRESS
The <x>n<cptlhat the thymu, gland pia)" role, in repro-
duction is not ""'" (27,108). for beth andro-
Rcn. and emORen. arc pre",n!. and tho:;e . t.....id ' e,ert
CIf.ClS that are dilferent from the onc. from Elu·
COC()rlioOid,. Thero arc indication. that the Ihymu, is
ncedod for no'nlat dilf",olialioo or the ",·",ic' . • t l<a<1
in ",mc 'pecies (S 1.99.1 ()\I), Females injected perinatally
with androgen, devetop a form of $torilit)". It has t>ccn
reported Ihat injeotion' of Ihymu$ cells provide protectioo
' E.in" thh (69). wh.r.as thymeCloot)" increa"" tho "'n·
, ilivit)' to gonad al stcroids (156). (On the oth<r hand.
neonalal lhymcclomy doc< not ..enl to impair testicular
dovelopment or .cqui.ition of tbe .b ili!}' 10 engago in
II I J.)
Surgkalth)'mcclon,y per '" constitute, • ' ''CS< al least
comparable in stverily to any of tit< procedure. com-
monly utili led for lest purposes. In addition 10 elfee" of
the general ".osthetio. the anim.l •• ulfer inci, i<Jn of tho
sternum and e,,,,,,,u," of contonts of the lhoracic ca,··
it)" to atmospheric pressure and room f\ , ;,.
.ble maS$ of ti .. ue i. removed (ot lea.>1 in ),oung "ni"'al. ).
and the .ubjec" endure eitbcr a mechanic.1 <h.nge in the
thomcio cavit)· or pre'lencc of ",me (pre,umably
i""rt) foreign malter. ElfccIS of Ihymu, gland depri"lion
e. n Iherdor. be '>S<:.'led onl)' whon 'ham opcrated ani-
mols ar. u,.d for comparison . The . h"m coolrol, arc ,ub-
jected 10 Ihe "nosthc.i. and Iraum •. but tho)' ore permit·
ted to rotoin thdr Ih)'nlu, gtand •.
The .ninlal. rCOO"Cr r.pidl)' when th •• urge,y i. per-
formed with ea,". Many drink W"ter wilhin 10 nlinute>
.ftor a .. from ttl<: an."hetie. and mO.l begin to
food an hour or Iwo aflerward. Bod)' wcights of both
thymeclomi,ed " nd sham thymcctomi,.od an imal' or.
u,ually comparable to those of uooperat.d oonlrol. t",o
day< after Ihe procedure. Young animals ooon resume
normal growlh. (Th)'nlCCIOO1izod animals m.y cven g.in
"'eigbt more rapidly th.n the others during lhe first few
po>(operati.e days ,) However. the crouched position . ..
,umed by some of the operated animo l. durinE Ihe flrsl
hour of reco"ery ,uU0sts thallhere i, considerable di..
comfon. and <ufiieal healing rcqui ••• several day'.
When the . urgery i. perrormed at s{Wialllfm" during
the tife of the " nimal, some <:free .. of thynlu, gland del'"
ri.ation are ca. ily demOll>!rated.
!n a s"ain of hooded rats that begins rapid growth of
aecc>SQry rCproduolive "ruetures ., ,i, and a half week>.
pe,formance of ,urgery just before Ihe ch.nges i. fol-
lowed by a period in whiCh Ihe animal$ temporarily delay
reproductive maturation. When examin.d I g days .fter
Ihe operation. sham thymcot<lmi>ed rot. have .m.lIer
proslate gland .. seminal "esides. and coagulaling glands
than unoperatcd O"",'roi> of tbe age. The effects of
the , urgicol SIre .. are maximal 21 d.ys aflcr Ihe proce-
duro. The operated .nim.ls ooon "c.teh up" and h.ve
organ weights <:<>mparabl. to lhose of unoper.led control.
by 28 day. post<urgery. Simitar observations ho"e been
made for alb ino rats of the Wi>!'r ' lrain Ihal undergo tbe
reproductive organ maturation wb.n th.), are one week
oIde,. Then . •urgery performed al ,,>V<n and a half (but
not at .ix .nd a halD wcoks ho> Ihe sa me (88).
The del.), in maluralion "'.nlS 10 makc "phYSiological
.. n'... ·, The melabelic energie, and ,"<Ource. are tem ·
I"lrarily directod loward the proc . .... of r.cover)' and
rcpair.
By contrast ..'ith .ham operaled "oim.I •. thost de-
prive<J of Ihymus Sl.nd. fail W exhibit the maturational
dol.y (88). (If organ weights are comparod wilh those of
unoperal.d control<. on<: mighl ga in the erroneou,
imprc .. ion Ihal thymeetomy wa. "'ilhout influenct.) l'he
defect in tbymectooti,ed animal • •ho"', up in del.yed
"'ound healina, Dilference. belwccn lhe", and 'ham op-
eraled animal. arc e.aggeratcd by admini<lerinE ¢.ose·
nous gluco<orlico;d, 10 both (87).
Whon yVl"'!'T animal. are ,ubjecled to 'levere (but not
overwhelm ing) <1re'$. they often undergo preeo<:iOU' pu·
berty. Sham thymeelOmy provide, an effeclive .. im"lu,.
If lbe Ih)'mu. gland is removed in the hooded animol.
,..hen thc}' arc 31-33 day. old. the growth of reproductive
structU .... i, aceelerated 10 a grealer "'tont than in .ham
operated OOOtrol' if the . urgery i. performed during the
late sprin\l. 'Ummer. or fall. but not when il is done
in the winter. Pas.ible implication' of Ihe •• a",nal dilfer_
encos "re di",u>s<:d later in conjunction with con,idcr·
'Iion of pineal function.,
Older rats display ,ubtle change. rel.l.d 10 long·tern>
'urviv.1 follo"'ing lhymu, gland deprivation, For ",.nI-
pie. Itrey show dilferenee, in pa"ern$of ,ino UplOke by.
• .,iely of body (i .. ue •. and in re'pon"" 10 e'''8enou, go-
n.d<>1ropin, (122) , They al<o h..e oon$idcrably large.
prost.te gl.nd. Ihan 'ham opcrated animal. ",verol
month, after Ihe ,ufie ry (92).
Severat dilferenl "udie, indicating influenCe> of Ihy·
nlectomy on function. of lhe piluitary gl.nd
' Url"lrl the h)'pothesis that tho de'<ribe<! cbanE'" are rc·
lated to altered seor.tion of hormones.
'"
THY MECTOMY AND CALCIUM METABOLISM
The calcium ion concentration <>f the blood plasm •• IfOClS
g",""n and proliferation of many <:<:11111'<' _Chronic h}'.
pocrcale<;m i. lead, to dCjlOIIilion of calcium .. It. in ooft
,issue •. The me,aSlatic c.lc ific.,;on and 'S$OOi31cd tissue
clacerbated by .imult ...o", de .. ,ion of lhe
ioorganic phosphate level •.
Dirt.l i.",h'ement of the thymus gland in lh. regula-
lion of plasma calcium conce"lral;OnS is ,.ucSled by lhe
or cakitonin and olher hypocalcemic racl<>r$ Ln
lhe thymus gland (83). (Til< ."i.. on"" of. ",ctan)'_pro-
dueini subslanco" in glands of salamander larvae "as
,ug8m"" half. centu,y .s<> [148 ). )
Whon .. IS are ,ubjected 10 ",na l ob,n.ucti.,.,. lflcy r.-
l.in pMsph.,c and thi' leads 10 ..",,"dary h),perS<"",'i,,"
of parathyroid hormone. A ,ub".nt;al percenlage of
adult male, develops cardi"".",ula, ncc,,,,,i, in response
10 the hypt:re.leemi, and parathyroid hormone. The ten_
dende, 10 develop exten,iv. dant.ge doc direclly wilh the
ag'" of the r31, at Ihc lime of imposilion or Ihe
renal obwuct ion . In young adult malo., th}'mo<lomy
greatl)' increa"" both the incidence and severily of
,uch Io.ion, (91). Th}'nteclomi,,ed anim.l, al<o .how
abnormal ,espons", to tho injection <>f vilamin D,
(lJ_90) .
SODIUM, POTASSIUM, CHLORIDE, AND
WATER METABOLISM
Thymo<tomy .1<0 chan8e. renal eleclrolyte ",cretion
pallern. (in .nimal, withoul .. nal d.mage). Thc e!fcclS
are very much "'8&.rated if th. "nimals a .. additionally
.drenaleclomilCd or ..It loaded (66). Thymeclomi,.cd.
animal, ",c .. t. 'mailer amOun" of s0-
dium, po"",ium. chloride_ ond water than do .ham thy-
moclomi,ed-ad .. nalcclOmi'.ed .... u d.rinll the wintcr
moolhs (when all .nimal. have low value.), bUI excrete
)a'ger .mouna than the control, during Ihe 'prinBtime
(when all .. Iu •• are high) (g9). The finding< rna)' hc re-
lated to lho>< on caldum metaboli,m. ,inco it ha, been
omcrved thaI parathyroidectomy ,nd injcct>On. of vila-
min 0, increUt ch loride e.cretion (33), and marked in_
Aue ncc. of cakitonin on chloride .xcre-tion have hcen
known f(>r """e , ime ('ee Chapter 12). Thymoctomy.l",
alfcclS food and Huid intake and renal cxcrelion rhythm,
of ra .. maintained in continu"". IiBht (60). The findings
sugge" th., gland deprivation re-mo ... <orne kind
of fi ne control.
The thymus ,ynthe,i>... and $Urn. 10 a hepa_
rin-li ke ' ulra1<d mucopolysaecharide (26,28). The Ihy-
mu, also regUlates plasma heparin concon"Olion, .i.
m«,hani<m. alfocted by glUCOCQrlicoid. (40).
When hepa,in and related substanee. arc iivcn in
pha rmacological dosages 10 palients (for protection
against intrava",ula, clot formatioo). Ihe excrclions of
sodium and waler are increased (130). The elfects have
b<:<:n al!rii>uled to inhibitory innuence, on .Id""'eron....
cre, >On. HO\>'.v.r. heparin promote, wa .. r and
THE GlUCOCORTlCOlOS
..",.. ion in adr.naleclomize<! rats .• nd the re.ronses are
altered by thymeelomy (89).
S<veral other observa,ion, SUMe" link' bet"'een hep-
arin and lhe Ihymu, IIland. Thymec,omy markedly alters
'he tolerance to e.ogenous histamine (126), while hepa_
rin bind, histamine and e.ist. in combinati.,. with it in
rna" cell granules (43). Heparin bind. .al<:ium and i, be_
lie"ed 10 be a COraCIOr f'" Ih. hUm",al r.llulalion of bone
r.sorp'ion (61) . It anlOSMi>.•• IIlucoconieoid innucnc",
on oosinophil movement out of the v.",ular oompar1mcnt
(while thymectomy .!fcclS blood eosinophil counlSl. Hep-
arin also aeli'ates lipoprOtein lipase. and the thymus ha.
hcen proposed to partic ipate in rcgulalioo of ,uch activilY
(39),
In add ilion. lhe .. a .. indicalion. Ihat thc Ih}'mu,
gland .ffee.. develOpment <>f Ihe adrenal c(>rte. (113)
and also Ihe secretion of some of Ihe ste,oid !Iormone,
(21). and ,hal some mineraloc(>rlicoid. promolC lh)'mu.
gland cnl.rgem.nl.
All of Ihe preceding observalions arc consislcnl
wilh (but do not eSlablish) roles for Ihc thymus
gland in mediation of gluCOCQrliwid innuenoxs dur-
ing limes of stress.
Actions of Glucocorticoid$ on Lymphocytes
Humans are among the mammals Ihal make cortisol
(hydrocortisone) as Ihcir major glucocorlicoid. They
ar<: .\aid 10 be "glucocorticoid r..,i"ant:· bccauo.<
,heir lymphocytes arc not easily kil led by high con-
centra,ions of Ihe sieroids. When the hormones (or
highly polent analogs) arc injccted inlo re-
sistant species. mosl of the reduclion in Ihymus
gland .i7.e and weight resulls from Iranslocalion of
lymphocytic componenls 10 olher siles wi,hin the
body. Grossly pharmacological levels do. hoW<'ver.
killlhe colis in _ilro.
Mice, ralS. rabbils and other species make moslly
COrliCO$lerone. They arc said to be
sensitive," since Iheir lymphocytes are much mOre
vulnerable 10 anack by Ihe s'eroids.
II is perhaps "n(Ortunale Ihal most of Ihe sludies
designed to elucidale Ihe mechanisms of glucocorl i-
coid aclion have employed cortisol -hke analogs bul
cells from ",nsi,ive animals. Further confusion has
arisen because Ihe steroid concentrations have usu-
ally far exceeded those oblained in viv<) ."OCn when
pharmacological dosages arC injecled (I (l).
Guinea pig. ma ke corlisol. and Ihey have betn u.ed 10
SOme e" enL Howe .. r. they are unu,ual in Ih.llhey gen-
erally Itave high cireuiating glUCOCOrtiCOid levels. and
t heir receplors bind tho>< regulal<>r> wilh low amnily
(72).
Although there are indications Ihal Ihe g lucocor-
licoids act mostly on only corlain kinds o( Iympho-
cyles, and Ihal immature cells may be more alfoeted
Ihan older ones (46). $Orne investigators have de-
scribed inAuences on all groups of such cells ( 105)_
The mechanism. whereby glucocorticoid, kililhe
cells are only partially understood (104), Sieroid-re-
ceptor complexes Ihat enter the nucleus accelerate
the I}'nthesis of $Orne mRNAs and there is an aSso-
ciated rise in RNA polymerase II (RNA polymera,e
S) activity. Evidently. new prOlein, Ihen aceelerate
the uptake or glucose. amino acids. and RNA pre-
cursors. "Scnsitive" cells show changes in transport
rateS within 15-20 minules. and this suggcsls that
lhe dd.cts are mediated in part via dilTerent mech-
ani.m .. (Resistant cclls require closer 10 an hour.)
Delayed changes include intraccllular accumulation
of falty acids (pos$ibly because oxidation is im-
paired). and signs of nuclear fragility. The elTects
arc blockcd by aClinom}'cin D added during the firsl
15 minules. Or if cycloheximide is presented eilher
along with the steroid Or 15 minUlc:S later.
According to SOmc observers. a prolein dilTercnt
from Ihc ones invoh·.d in the plasma membrane d-
fects is formed some 60-90 minutes after accelera-
lion of mRNA production. It has been called "lethal
prolein" (13). because its inhibitory elTeets on RNA
polymerase 11 have been linked wilh subsequenl
chromatin disaggregalion and cytolysis. Steroid-in-
duced. dose-dependem increases in the ratcS of
RNA degradation are seen within I); hours aflcr
hormone presentation (25).
Other finding; suppo,t the cort"'pt that ",II death
is the final event when H serics of widepsread
changes disrupt melabolism at multiple sites. and
that the glucocorticoids aecelemtc ordinary aging
(104).
Some changes thai occur when whole anim,d. are
given large doses of glu=rticoids cannot be repro-
duced in vitro_ In the animals. inhibition of DNA
synlhesis and of cell proliferalion have becn attrib-
uted 10 interfer<:nce w;lh the production or uSC of
growth slimulants that are normally pr<:scnl in thc
blood plasma. Elevated protease activil y is a delayed
phcnomenon that has becn lin kcd with secondary in·
vasion of damaged cells by lissuc macrophage' (95).
ANTI-INFLAMMATORY AND ANTI-IMMUNE
EFFECTS OF GLUCOCORTICOIDS
Pharmacological dosages of cortisol. and high ly l»-
tem. long·aeting synthelie analogs. are uscd in Ihc
treatment of patients with allcrgies. bronChial
asthma. aUloimmune disorders. and "inflammatory
diseases" such as rheumaloid anhrilis. In conjunc·
tion with other agems. the steroids provide protec·
tion against Ihc rejeclion of lransplants. Patients r<:-
ceiving them for extended periods invariably develop
signs of Cushing's disease. sinee all anti·th}'mic Slcr-
iods have high gluconeogenic potencies.
Acu te Inllamm ato ry React ion s
Acute inflammatory reactions develop rapidly. and
they Can be maintained for a few da)"s, The four
signs sel forlh in the first cemury by thc Roman phy-
Celsus are still ciled today: rubor (erythema).
calor (heat). tumor (swelling. localized edema). and
dolor (pain).
The reactions are usually initialed by SOnIc form
of locali7.ed injury such as skin puncture. Or by re-
lease of a bacterial They can be anificial!y in-
voked wilh irritants. They provide mechanisms for
pre"eming dissemination of infections and toxins 10
other p<"IS of Ihe body. for extrusion or deslruction
of thc offensive agents. and for restoration of the nor·
mal Stale of Ihe affeeted tissue.
Each component of the response alTecls others.
and Ihere is a "snowballing" or cascade during Ihe
aCute phase. More than 50 different mediators have
been implicated.
The ...cl number;' not known, The ,.,clions differ
from Me locate to .OOlhe,. a nd they are affecled b),
preexisting condition •. Sub'lanc", made in large quan-
titie, in tbe tungs arc differenl f,om the ones that aceu·
mulate in gr.aleSI amounts in th. skin or 8UI, The agenls
h.ve o>ertapping prGP"nie. _A mediator ,,"died in " c<:r_
I.in ""'Y in on. laboratory and giv<" a nante related to
in propcnie$ Can be identie.t ... ith anOthe, observed .... ith
dilferenllechniques cl.. where. We 00"" '"0"" that. m. -
omphaie activ.till.ll fae,o, (MAf). which incre.""
phagocytic . ct ivity. i. identical with macroph.ge inhib-
iting f.cto, ('>ltF). which retaro, "",>ement, of edt.
a.... y from the affe<:led . it. (t39). It diffcrs from
cJt< inhibito,y faCIO' (Ltr). whieh reg"tate. Othe, Cclt
t)'pcs (118).
The earhest change is increased blood flow from
usually .... armer. deeper regions. This partially ac·
counts for the erythema and the rise in lemperature.
Prostaglandins (PGs) and related molecules gcner·
ated by injured cell s are the first vasodilator •• but
other mediators soon join in.
The blood brings in polymorphonuclear leuko-
cytes (PMNs). monocyles. lymphocYlcs. platelets.
some baso[lhilic leukocyles. and several proteins.
PMNs phagocytose .xrtain bacteria. and thcy can
immobilize others, PMNs also release chemotaxins
that auract wandering tissue cells including macro-
phages and mast .xlls_ Thcy r<:lcase pyrogcns -and
protcolytie cnzymes. and also agents that alTeet the
aClivities of other cells (e.g., a neutrophil immobili·
zation factor. NTf. that promotes adherence of Ihe
leukocytes to the alTecled r<:gion and reduces mn·
dom movements {II SJ). "Bursts" of o;o;idative me-
tabolism. and the associated generalion of NADPH.
arc involved in their bactericidal activilies (67).
Masl cells. basophilic leukocytes. and damaged
cells of other kinds release histamine. and also en·

'"
zymes thaI let QII precurson prllSCnt in
blood plasma, Masl cells additionally release hepa-
.in. which activa tes several of Ihe enzymes. and
Ihcf<'by promotes the formation of kinins (describ\:d
in Chapler 9) and differenl media ton.
Histamine. PO$, and kinin$ all tile
perrneabililM:s of small blood vessels. As a resu!!.
proteins leak into Ihe perivascular spaces. AlbumiM
osmotically drJw wa ler from the vessels. as fibrino-
gen pOlymerizes 10 f,brin and forms .loIs Ihal block
lhe lymph drainage channels and " 'ca ken "",lis th.u
enc:1oM: fluid·filled cavities. PGJ aClivate pblClclS
and accelerate 0( coagulation factors.
SerOionin released from blood pia Ie leIs is a pow-
erful stimulant of the smooth muscle of Ihe small
blood vessels ( 110). and it lett in oonjUlII:lion wilh
some of the PGs 10 00", about SlDlM1ioo and
JIO'lia. This leads 10 Ihe build-up 0( acid metabolites
Ihal directly kin $(N1lC of the bacleria and a«:e1en.IC
leu kocytic release of other bactcricidal
PGs, histamine, kinins. thc pressurc buill up by the
accumulated fluids. and the acid metabolites C()II-
tribute to stimulation of nerve libers and pain per-
ception (63.76,IH).
Interlcu\in I (\ L-I. Iympho<:ytc act i"luinS factor.
LAf). 3 macrophage acts on the e<ntral
nermus s)'stem 10 dcvatc body tcmperature and
thcrt;loy .,,,, .. ide c,""i'<M,,,,,,m thm i, highly u"fn'
vorable for some micrOOO"ganisms. It also stimulates
synthesis of Il·2 (T celt ,rowth factor) (A.o).
PMNs form phaaolysosomcs. in which they d.igest
some bacteria. and. the)" also main bacteria for sub-
sequent destruction by macrophagcs. In the proccss.
many PM Ns die. and pus pockelS or abscesses form
when they aIXumulate in the Auid·litlc4 cavitl«. Tile
weak "1I1Is aroulld tile eP<:lowIU first f0rrnc4 by Ii·
brin are wilen fibroblasts in the vicinity
arc &timulatcd to proliferate.
Most of the macrophagcs derive from blood mon-
ocr tes. but some wander in from the surroondingtis-
SllC. These cells pMBOCyt05C bacteria. lissue
debris, alld PM Ns that have inaested bacteria or arc
They kilitulOOT cells. and lhey some-
limes allack healthy ones as well. Scvcralt)·pcs sub-
servi ng diverse functions have becn identifIed (I ij).
Some of the "K" (killer) celts may be macrophagcs
(64).
When acute inflammatory re<lctions currecl the
conditions, healing begins. This involves .dditional
proliferation of fibroblas". and lhe formation of new
blood vessels. Macrophages fibrinolysin. thin
digest fibrin (SS). and they ronlribu tc to the reestilb-
lishment of the circulation by Kercling other agents
( 138). "The blood flow Ihen away dcbl"is, as il
provide'l nutrients. fibrinolysins.
THE GlUCOCOATlCOtDS
Chronic Infl llmmalion
Acute inflammatory reactions progress to chronic
if the conditions a rc !IO\ cOTrected within a
few days. PG. may play important roles in accom-
plishing the trnnsitions (157). The region :soon be-
collle'lilcavily infihrated ""'th Iymphocytcs and. mac-
"'IIhages. The lauer coalesce around p,articles too
large te be ;ngeoted by a single cell. The multinucle-
ated "giant cells" thus formed Can aggregate and be-
corn<: major components of nodules or 8ranulomata.
"The macrophagcs ingest antigens. process the
molecules, and present the prod\ICIS 10 lymphocytCi
in a manner that leads to lymphocyte activation
(119). The affected cells then release a varie ty of
Iymphokines. These include macrophage. neutrophil.
and rosinophil c hemotactic faclors. MIF and L1 F.
which promote retcntion of cells at the site. phago-
cytc enhancers, st,mulants of lymphocyte proMe,.,.·
tion. rubstanees affecting membrane pcrmcabiliti"".
and interferon (which confcrs nonspecific rcsistance
against 1'0111. viruses).
Different kinds of lymphocytes produce humoral
antibodies. Some antibodies directly immobil i7.c bac-
teria. and others render lhem ""'"' suxtptiblc to
pMBOCyt05is. Certain antige .... antibody complexes
serve as activators of blood components. collectively
known .s complement. that destrcy foreign cells.
E;l)$i1tOphllJ usually associatcd "'ith
reactions.. and with ddcnse against parasitcs. They
....'" implicate<! in ingestion of histamine. an-
tige .... ntibody combinations. and other components
of the inflamma tory renction that could ot hcrwise
Cause tissue injury.
Immun e Response.
By contrast wilh the nonspecific inflammatory re-
actions, immune responses arc by highly
sp«ir.c interactions between ly mphocytes a nd anti·
gcns. However. the pro«sses o"criap in III,lIIy "ays.
and they involve the same kinds of cells.
lYMPHOCYTE POf'ULATIONS (46,119)
"8" Iymphocylt.• originate in the bone marrow. In
birds. a sma ll structure at the end of III<:
pitroinlcstiflal tract (the bursa of Fabricius) sc-
factors that promotc 1TIlIlUralion. and the «lis
arc ... med for thi$. Mammalian 8 cells probably
also need maturation stimuli. but the equivalent of
bursa has not been identified. Til<: candidates in·
c1ude the Pcyer"s patches of the intestine. the appen-
dix and other lyml'lIlnic tissue
(GAln. the tonsils. the spleen. and the bone
marrow.
 Once they anain maturation. the B cells travel via
the bloodweam \0 the spleen. lymph nodes. and
other organ', to form colonies. Most do not re<:ir<:u,
late. and such lymphocytes account for onl)' a small
fractiQn of the blood leukocytes (I).
B lymphocytes have immunoglobulins on Iheir
surface. that function as receptors for specifIc anti_
gen •. When they bind such molecules. thcy enlarge
and become transformed into rapidly prolifcraling
"blast cells." S<lme of the progcny become "memory
cells" that spring into aClion if the sa me antigen is
pr<:semed at a lalcr lime. Mosl develop into plasma
cells that synlhesize large of immunoglob-
ulins and release them into the bloodstream. Tho B
cells are therefore said to be mediaton; of humoral
immunily , (Sera takcn from animal. p""viousiy cx-
posed to the speeific antigen can confer "passive im-
munily" on thc re<:ipients.)
Some B cells are known to release Iymphokincs. A
few. called "B suppressor cell<," contribute to regu_
lation of the immune re,!'Onscs and protection
against the mouming of allacks againsl normal
tissue.
"T" lymphlXyles mature and proliferate within
the Ihymus gland. and thc)' emerge as cells "com·
milted'" to perform "cellular immunity" functions.
The substances made by reticular of the th)'mu s
that r<:gulate the maturation and proliferation in-
clude th),mosterin. and thymu, protein
In addition 10 making the hormones. Ihe
reticular cells ma), provide a speeiali1.cd microenvi·
ronment that supports the maturalion (98).
The T cells are oot belicved tosc<:rcte humoral an·
tibodies. The receptors on their surfaces interact
with amige", hound to membranes of other
cells. especially oncs thaI ha''C been changed by viral
infcctioltS Or have altered surface properties that
permit them to enter into tumor formation.
T cells also bind to specific proleins. the " ,·mi·
croglobulins that arc either ''''''ponent. of Or arc in_
timately associated wilh hi stocompatibility (li LA)
antigens on the surfaces or normal body cells. Such
binding is involved in aetivation or most. if not all. T
cells. The antigens expressed on the surfaces differ
from individual to individual, and the Iymphocytc.'
can recognize ones thaI arc "foreign".
When activatcd (under natural conditions by an-
tigens Or artir,eially by some planl lectin.). T cells
enlarge to form proliferating blast cclls. The progeny
mature imo activatcd Iymphocytcs that affect other
cclltypcs by releasing Iymphokine. and I'O"sibl)' alS<)
via di""ct interactions (17) .
Several subclasscs have been deseribe<!. The oncs
most obviously involved in the lysis of other cells arc
Tc' (cytotoxic) or '"killer cells". (These differ from K
cells. which may originate from macrophages
[133] .) The)' attaek plasma membrane. ,;n part by
releasing lymphokincs that include Iymphotoxin
(LT) ,
T" or '"helper" cells cooperate with B lymphocytes
and permit them to fCS!'Ond to T ccll-<lcpendenl.
monomcric antibodics. (B cells are dir«rly aetivatcd
mostly by large. polymeric, T cell·independent anti-
gens.) The helper functions seem to include innu-
cnces on B cell maturation. Macrophage' simulta-
neously bind the Band T" cells and they thereby
foster cooperation.
T or "amplifier" cells augment immune re-
sponses and seem to be especially important for pro-
motins ma1uration of tho&e of the Tc type.
T s or "'suppressor"' T cells have re<:eivcd consid-
erable altenlion in reccnt ycars. since they are im·
portant regulators of both T and B cell functions
(68). They have surface markers similar to those of
the Tc type (but different from ones found on the
hclper and amplifier cells). They arc believed to play
critical roles in protection against de,'Clopmcnt of
sutoimmuno disease. Their relati"e numbers decline
with advancing age (as thc incidence of autoimmune
disorders increases). and some clinical disorders
have been directly linked with inadequate numbers
of Ts cells (137.152).
Yet another type. the Til cell. has been spc<:ifically
implicated in mediation of '"delayed hypersensitiv.
ity'" reactions. that is, the mounting of rapid re-
<ponses against cell antigens to which the individual
has oo<;ome previously sen'itized.
CONTROL MECHANISMS
It is obvious thm mechanisms are required for oolh
activation and suppression of innammatory and im·
munc processes. Ddensc requires rapid and ",assive
reeruitmem. and much of tni s is accomplished by
'"cascades" in which onc response leads 10 activation
or amplification of the ncxt and via participation of
"helper" cells. Conditions with generalinn
of cGMP lend to enhance the processcs. GH and
thyroid hormones promote grow1h of lymphatic tis·
sucs, and they prooobly play important roles in the
prcparation for subsequent acti"ation .
Protection against damage to normal tissuc de·
mands rapid subsidence of the response> at the car-
liest appropriate moment and prevention of Over'
reaction to offending stimuli. "Built·in" controls
include the negative feedback influence, that high
concentra1ions of humoral antibodies exert Over pro-
duction of morc molecules of the same kinds. Sub-
stantial quamities of cAM!' arC generated during
the active phases. and the nucleotide laler becomes
involved in :lOme forms of inhibition, Substances rCo
leased b)' normal pituitary glands that antugoni1.c
Gli and thyroid hormone actions havc also been im·
plicated in limitation of the responses (32). Gcnetic
".
factors affect the ability \0 terminate as well as
mollnt Ihc reactions (57). Serious
problems arise when the me<:hanisms fail.
Influences of Ihe Glucocortlcolds
When given in pharmacological dosages. Ihc steroids
can inhibit every known aspect of the reactions.
Their inHucnces 31"<' on macrophages. Iym-
pllocyles, fibroblasts. neutrophils. and maSI <:<:115.
and also on Ihc capillary endothelium and basement
membranes. They alTee! cdl migration and adher.
ence. phagocytosis. cell proliferation. the production
of certain antibodies. and the release of various me-
diators (139). AnemplS have been made to formu_
late a unifying hypothesis. but no satisfactory one
has bot n found. At least some effects are directly
linked wilh stabilization of lysosomal membranes,
and with inhibition of the rei case of fal1y acid pre-
cursors of prostaglandins and related lipids. Exces-
sive quantities of the steroids can markedly redue<:
Ihe resistance to infections. A recent hyjXIthesis
states that their primary rolc during mess is limi·
tation of (he jXItemially deleterious consequences of
the defense mechanisms (A-6).
GLUCOCORTICOID INFLUENCES ON
SKELETAL MUSCLE
Adrenoconical insufficiency is associatcd with sevcre
muscle weakness and inability to cngagc in .us-
tained. demanding physical activity. The functions
can be restored within hours by treatment with
gluCOCOf1icoids.
Although the circulatory system problems, the
anemia, and the defects in gluoose metabolism Cer·
tainly contribute to the difficulties, they do OOt
provide adequate explanations for many of the ob-
.. rvations-inciuding impaired performance of
muscles studied in vit ro. Elcctrolyte imbalances can
exae<:rbate the muscle weakness, but mineraloc<>rti-
ooids do not restore normal function.
Glucocortiooid-deficient animals have blunted re-
sjXInses to all koown C3tecbalamine inAuences on
muscle. including lijXIlysis and glycogenolysis . They
cannot elfectively inc,"<,ase the blood supply to sit""
of active con traction, and they fail to mOUnt normal
shi 'ering and piloerection resjXlnses to cold environ-
ments. Untreated hamsters made h)·pothermic be-
come limp and unable 10 rewarm. whereas ones pre-
treated with glueoconiooids prior to cold exposure
retain muscle tOne and the ability 10 regain normal
temperature (30).
While excessive amounts of the hormoncs inhibit
protein synthesis and .. tissue "wasting." phys-
iological ones secm to be needed to support normal
THE GLUCOCORTICOIOS
processcs. Young adrenalectomized animals that are
well fed and kept in very sheltered environments can
grow. but they do oot to "training·· that
stimulates intact animals to gain in muscle strength
and endurance. (Animals Ihat are ··trained·- forst
and subsequently adrenalectomized IlCrform almo<t
as well as intact animals if they arc kept in good con-
dition.) It has been JXlinted out. howe,·er. tnat ,ub-
jecting animals to in which they are
forced to engage in dcmanding activity constitutes a
form of ··stress·· (116). The observation that Over-
working limb muscles on one side of an ad'"<'Mlcc-
tomized animal impairs subsequent performance of
muscles on the other side (125) is consistent with the
release of humoral mediators. Glucocortiooid recep-
tor numbe .. are increased in .. veral oonditions as-
sociated with redue<:d muscle maSS (A-2j.
GLUCOCORTICOID INFLUENCES ON aONE,
CARTILAGE, AND SKIN
High concentrations of glucocorticoid. exert both di·
rcct and indire.;t catabolic effccts on bone. skin and
cartilage _ Chronic overdosage (or excessi,·c Secre-
tion) leads to "thinning·' of the bane (ostcopenia and
osteojXIrosis), and it impairs skeletal growth in ju-
veniles. Evidently, only twO \0 three times thc OOr-
mat ra le.< cxen inAuencc • .
The steroids have been reported to dircctly inhibit
enzymes that catalyze glycosaminoglycan biosyn-
thesis, and to bring about disruptions of the ultra-
structure of chondrocytes and of the utraedlular
matrix (lSI). They exert stimulalory inAuences on
bone-resorbing cells (144). and they may addition-
ally depress th. activities of the osteoblasts (6). They
ac t in several ways (including suppression of phos-
phodiesterase activity) to augment cAM P responses
to parathyroid hormone. They also slow intestinal
absorption of calcium and interfere in se'·eral ways
with both the metabolism of vitamin D and the ae-
tions of the hormones derived from the vitamin.
On the other hand, they protect skeletal SlructureS
against destruction by medialors of inAammation
and immune reactions. They a<x:omplish thi, in part
by inhibi ting thc release of proteases and other sub-
stances Ihat promote bone resorption. Physiological
level s of the glucocorticoid, also contribu te to the
control of G H ""cretion and to gastrointestinal fune-
tions that provide the essential nUITients.
The thinning of the skin . dola)·ed would heali ng.
impaired ability to wall off sitos of infcction and in-
flammation. and some of the loss of bone mass ay
sociated with h)·pe radrenocorticalism, have all bet:n
lin ked with inhibition of growth. and
functions of fibroblasts (5).
 By oontrast with the mostly catabolic effects on
tissues of mesodermal origin (bone. cartilage, der-
mis. and muscle), high levels of glucocorticoids Sl;m-
ulalt many ectodcrmally dctived structutes. Some of
the ioA uen""s on skin texture. sebaceous gland activ-
ity. and hair growtn involve interactions with and .....
gens. The glucocorticoids can be metabolized to an·
drogens. and this assumes importance when the
steroid le"els arc high.
The hyperpigmcntation characteristic of Addi.
son's disease is 3llributcd to loss of normal negative
feedback control Over thc pituitary gland. and the
consequent release into the bloodstream of peptides
that act on tne cclls of the skin.
GLUCOCORTICOID INFLUENCE S ON THE
NERVOUS SYSTEM
Glucocorticoid receptors are widely distributed
throughout the brain. Especially high levels have
been found in thc amygdala. hippocampus. septum.
and emorhinal cortex (96. 143). Neurons in those re-
gions arc implicated in regulation of the diurnal vari-
ations in glucocorticoid secretion.
The .tcroid, affect electrical activities of neurons,
thresholds for stimuli that can cause convulsions.
neurotransmiller biosynthesis and turnover rales.
and sleep-waking rhythms. ney innuence mood and
behavior. and they contribute to the regulation of
hypothalamic IIormone secretion. T hey may act at
several sites to affect food inta ke (31).
Innuences on learning and behavior depend. in
part. on effects exerted on the hypothalamus and pi-
tuitary gland that affect the rekase of ACTH·ro-
lated pcptides.
There are reasons to believe that there are diverse
rcceptor Iypes. Certain responses take time to de·
velop. and they scorn to result from "'classical"'
mechanisms for steroid horlllQoc action that involve
entry into the formation of complexes with cy·
toplasmic proteins, and translocation of the com-
plexes to the nuclei. Others arc seen after only brief
latent periods. and direct interactions with neuron
plasma membranes have been suggested (96). Some
of the effects on the release of oorticotropin·rcieasing
hormone (CRH) may depend on such direct
interactions.
Sensory Pereeption
Adrenalectomized animals, and patients suffering
from uncontrolled adrenocortical insufficiency. have
mikingly lowcred thresholds for perception of odors.
tastes. sound, heat. and pain . The olfactory sensitiv-
ity may be increased lOoo·fold Over Ihat seen in
healthy ind iv idual5 (or after gluCQCorticoid replace-
ment). and gustatory sensitivity can be elevated 100-
fold. Simultaneously. the ability to interprw the sen-
sations is seriously impaired (62). Patients recciving
inadequate hormone Substitution therapy readily de-
teCt differences between pure water and extremely
low concentrations of sodium but they may
statc that sodium chloride solutions taste biller (even
when the presented are within the
range reoognized as salty by oomrols).
The defects have been allributed to a combination
of rapid axonal transmission and p .....
longoo synaptic delay. Consequently. the liming pal-
lenu for arrival of the stimuli in the parts of the
brain that process the information are disrupted.
The oonditions are easily corrected witb exogenous
and there arc iO\'e= relationshi,
between the dosage and the time required for resto-
ration of normal function.
Patients with Addison's disease often suffer con-
currently from mineralocorticoid deficiency. How·
ever, although aldosterone affec\., ",It appetite and
bebavior. administering that steroid Or maintaining
mineral balan"" in other ways fails to correCt the
sensory defects.
The changes in sensory perception may be t.ag·
gera tioru; of glucocorticoid controls exerted in 001"
mal individuals. Circadian variations in perception
Ihat arc lin ked with the diurnal secretory rhythms
have been described .
GLUCOCORTICOID ROLES IN
DEVELOPMENT
InAuenees On matu ration of the liver were cited ear·
lier. The hormones also act on the developing cells
of the stomach . intcstinc. skin. brain. retina. exocrine
and endocrine pancreas. and elsewhere (8). The ac·
tions arC exerted during "'critical," time·limited I»
riods. and the dTeclS persist when the hormone is
withdrawn.
Especially important roles in lung maturation
have been deseribed. Glucocortiooids widen the air
spaces by causing flattening of the epithelial
and thinning of the septa. They also induce .rur/ac--
tan/. which lowers surface tension in the alveoli and
thereby against collapse during
Fai lure to aceomplish the changes is a major cause
of respiratory distress in premature infants.
The hypothalamo-hypophysial-adrcl\QOOrtical sys-
lem itself may be influenced by ooncentratioru; of
steroid IIormones that cireulate early in life. There
are indications that of animals 500n after
birth to "handling" or to relatively innocuous stimuli
reduces reactivity of the system when the animal.
a rc later e.poscd to novel environments or mild elec-
tric shocks (4). Responsivity is maintained for longer
times than is the case for most developmental
changes with well-def,noo critical periods.
'"
InAuellCe! On water. mineral and cltttrolytc bal·
ane<:. On calcium and phosphorus metabolism. on se-
crelo,y fUlIClions of the pituitary gland, and on lhc
reproductive and lactation arc described in
other chaplers.
ANATOMICAL ORG ANIZATION OF ADRENAL
GLANDS AND RELATED STRUCTURES
The mammalian arlrenal (or suprarenal) glands de-
rive their name from the loca tion at the anterior (su-
perior) poles of Ihc kidneys. Each is surrounded by
a CQnncclivc ti .. ue cap$wle and C<lmpriscs ouler
COrlH and an inner The CQrtex is broad.
and it varies in enlor from light brown 10 pinkish
beige 10 yellowish (depending on the lipid content),
It contains lhc cells that synthcs;1.C and release ste-
roid hormones (35.36). The medulla. which is darker
and smaller. OOnsiS1S mostly of modified symp;,tiletic
ganglion cells Ihal makc and sc.:rcte catccholamine
hormones. Steroids traveling in blood ,'cssels from
Ihc cortex to Ihe medulla exert regulatory innucne.:s
on catecholamine biosynthcsis.
The term. adrenal glomi and odrm<l/ eorU.' ar. I""",t)"
applied to of nonmamm.lian vertebrate< ,hal
.yn.hesilC related hormones. The de.ign","'" mighl be
considered appropri.,e in bird •.•1Itoougb 'be catecool·
• mine-secre,ini cell. are ",ually di.pe .... d within the
Illand.oo that no medull. i, defined . In poikilo,herm •.
cell, produei"3 the st.roid hormooC$ can occur anterior
to. embedded within. Or belw""n ,he kidocys . C.,c<;IIoJ·
amine-secretini cells can be anatomically separ. te (a, in
oome of Ihe fisbes). Or ,hey can ,u,round Ihe ' Ieroido-
ienie cell' (as in lizard.). In oome spede •. steroidogenic
cell. occur in S<:atlered elumps. ralher Ihan in organi,ed
. lTuclure. (10).
Teleost fi,he, have paired Corpu.eles of Sianniu•• ,.
SOCi".d wilh Ihe kidneys. The", ,.,or. Once believed to
make steroid hormones. bUI Ihey are 00"" implicated in
Ihe regulalion of calcium. mooo,"lenl ion and waler
melaboli'm.
The term chromaffin refers 10 the brown color
taken on by calechoiamin..,;ccrcti"3 cells when they
are exposed to chromale dyes. All vcnebrdtcs p0s-
sess chromaflin cells thaI arc not associatcd with ste·
roidogenic lissue. The)' also have gonads that make
steroids chemically identical wilh somc produced in
adrenal cOnex.
Functional Zona tion o f the Mammalian
Adrenal Corte x
The cells are organized inlo oonccntric regions (sec
f ig. 2-4) (82). Those of Ihc z<»W glomeru/osa are
closest 10 Ihc capsule. Thcy arranged in whorls
THE GLUCOCORTICOIDS
(glomeruli). and they contain the enlymcs requ ired
for the biosynthesis of aldosleronc (Ihc major min·
eralocorlicoid). The zona fosdctdata lie. just below
Ihe zona glomcrulosa. and it usually ma kes up the
bulk of the cortex. The cells arc grouped into cord,
Or fascicles. and they are lhe major sources of glu·
cocorticoid hormones. The region bordering the mc·
dulla i< thc wno rfl;cularis. in which Ihc cell. form
a nclwork or reticulum.
Fine Structure
Large quantities of lipid precursors for hormone syn·
the,is are stored in droplets or Iipaooml'S Ihat are
morc prominent in some specicsthan in OIhers (Fig.
6-3). An extensive smOOlh reliculum
providcs altachment site. for many important en·
zymes . The milochondria (which contain dilferent
enzymes required for hormone synthesis) arc nu·
merous. and havc vesicular cristac. Small inmgino-
,ions of lilt surface membrane hvc becn linked with
processes of choleslcrol uplake. The ly.w.<Qmt.' par.
ticipale in cholesterol metabolism. and they al'"
sccm (Q be involved in adjustments of secrelory fu nc·
tions to changing physiological nceds.
granule. are promincnt in some species. but lhe celts
lack secretoT)' granules of the types that store lhe
amine and peptidc hormones (84) .
FunctIonal Significance of the Zonation
Thc zonation is more apparent in conain spec ic.
(c .g., humans, monk.}.... rat'. ra bbits. and guinea
pigs) than in othe'" (hamsters. cows. sheep. and
horses), and additional 70nes have been described
for a few. Since it is virtually impossible to com·
pletdy separate one region from anothcr, mosl of Ihe
information on functional diffcrences has been ob-
tained indirectly.
ACT H adminislration promolcs hypertrophy of
the zona fasciculala . morphological changes in the
mitochondria and other organelles, and induction of
enzymes thaI catalyze lhe synthesis of glucocorti ·
coids . Hypopltyseclomy Itas opposing clTccts. 8y
oontrast. tlte zona glomerulosa retains its structure
and functions afler hypophyseclomy. Tlte cclls Cn-
large and increase their rates of aldostcrone seCre-
tion whcn animals arc saIHicprivc(\. and they
undergo atrophic changcs following chronic salt
loading.
If both adrenal glands of a mammal are excised.
thc contcnlS of the glands scooped OUl. and tlte cap-
sules returned to thc animal. only somc zana glom·
c rulosa celts thaI adhere to tltc capsulc arc rctained .
Such "cnucleation" is followcd by a bricf period in
 4
. '. - "".

,
4
,
,,
..•.'
,

4
_' 0

6·3. oj cell from ,at totN> •.• d ...... '
corte' , eleclron mleto?Oph. ( 1) In' ...""I ...... ' SPlIce, (2)
ClIIIIlTl\HTlbr.".,. (3) rnitochoodri. with "".iclJl., e"o'n,
( 4) lipid' drople1' ... iIfI matrix won pre_, (5) intert"".
lipO:j dtople1 ICytoplasm, (6) p<olI l•• 01 ag,"",,'.'
6MOp1ll""" ,.tieu!"", '<lh&ring to interlace membra.. ot
&;p;d (7) pI"""'I.,. glyoogM, (8) ,, ... ' ;00""""0.
(9) 01 OOI".n"'" . r><IopIa..".. '.Iieu!"", lr... in "'"
cytOplum, X60.000. (ROOdin. 'ot. 117)

which glu=rtiooid deficiency become< apparent.
However. Ihc con, returned to the animal r-Jpidly
undergo hypertrophy. hyperplasia. and in
organelle content: and glucocorticoid function. arc
gradually regained. It is therefore widely believed
(hat both zona giomeruiosa and fa,ciculata
cells originate in the subcapsular region. The con-
cept is supJX)rlcd by obse rvations (hal (a) thc zona
glomcrulosa oonlains whal appear 10 be young. un-
differentiated celh; (b) cens in thai regi(ln undergo
mitoses under r.ormal conditions; (e) >.ona glomeru-
I_ e<:1I. cuhul"<'d in thc of ACTH undergo
ro",,;"ont with transformation into ZOna
fasciculata_typc cells (t (0): and (d) wna fas<:iculata
e<:lIs given alono fail to support the hormonal needs
of adrenalcctomizcd animal.,
The conccpt has been challenged on se.eral g,,,"o,k
First. Iud den 10$< of all (or rnOSI) of lhe inntr regions of
ltlc adl"<'nai corle, and bolh vascula, alld neu,al connce·
tion. of fernaining ",III i. to sa)' the
least, The c,'ent<Qf ""'lIcntration'" rna}' not be ,dated 10
procc.... lhalgo on in normal glands. Mor.:ove,. rlCu,a l
influc"" ... r< not ,cost.bli,hed. Sec<.>nd. milose. oo:;cu, in
all of thc ",nes. and they seem to proc<>ed .1 ",pocially
high , ..e. at the glomc,"""",.r.seieuiot. and at 111< fa ..
eieulata·rcticula,i. borders. Third. OOrne .. 'oue'"
ing thaI mitotic rate, of the inn", ",nc, arc insuftieienl to
",'Cou nl f", physiological cell renewal have been per·
forme<! du,ing daylight hours on fIOClu,nal ao;m.l. (io
wbich po. x milOtic ratC, OCCur dur ing the timo. of da, k·
ness), Fourth. observation. made by I,beling outer cell'
witb dyes alld ,ubseque nl ly following migr.tion of the
label do not fully support lbe glomerulo.. 1origin for the
bulk of the cell' of lhe inner '-On"'.
Since complete separation of '.ona fascicul'ta
from zona I"<'ticularis cell' has not been accom-
plished . and since there arc indication. that disrup.-
tion of normal fasciculata·reticularis interactions af·
fects functions of bolh cell types. there is
considerable controversy concerning the roles of the
innermost l.one of the adrenal conex.

Because necrotic cells have been found in this re-
gion (but not in the others), it has been PfOIXISCd
that adrenoc<Jrtical cells arise from periphcral sites,
migrate inward, and finally die in the zona retieu-
laris_ This "graveyard" concept is difficult to recon-
cile with observations that the cells undergo mitoses,
and that they grow and accumulate lipids when ex-
p<)SCd to ACTH (12)_
T he fetal adrenal gland contain5 a large inner re-
gion that produces considerable quantities of sul_
fated steroids, and especially ones with androgenic
properties (94). The fetal zOne involutes rapidly
aFter birth in most species. and the Wna reticularis
may represent its remnant. The reticularis has been
reported to be enlarged in some patients who make
excessive quantities of adrenal androgens. (How-
ever, interpretations of the findings arc complkated.
since such patients also have other endocrine
imbalances.)
Diffe rent views include the following: (a) Optimal
ad renocortical function depends on interactions be-
tween the various "'gions of the adrena l cortex, and
(b) all adrenocortical ""l\s have similar potentials,
but their morphologies and secretory activities are
affected by their microenvironments. (The reticu-
laris ceUs border the cateeholamin,...;ccreting ones of
the adrenal medulla. the fascieulala cells make con-
tacts with those of both the Wna reticularis and zona
glomcrulosa. whereas some zona glomcrulosal e<:lIs
arc in direct contact with the capsule.)
BIOSYNTHESIS OF ADRENOCORTICAL
STEROIDS
T here arc two major glucocorticoids. Rats. mice.
rabbits, birds, and make mostly corticoste-
rone. Humans. mon keys. hamsters. guinea pigs, and
fishes seerete mostly COrtisol. Dogs. ferrets , <XlWS, sea
lions. and many other species make varying propor-
tions of both . Cortisol is. by several critcria . the more
potent hormone. It is made along with corticosterone
by the cyclostomcs. The fishes have
l",hydroxycorticosterooc. which may be unique to
that group of vertebrates (10,1 27).
Aldosterone is an eX!remety potent mineralocor_
ticoid that seems to be uniw=rsally prese.nt. Small
quantities of a variety of androgens. and lesser ones
of estrogens. a", found in adrenal venous effiuentsof
mammals.
T he amounts of pathway intermediates and of
degradation products relcase.d vary with the species
and with the physiological Stalus. Some arc biologi-
cally active di",etly, and certain others can be me-
tabolized to hormones .
Progesterone released by both males and fe-
THE GLUCOCOPiTICOIOS
males_ In at least a rew spe<:ies. adrenoconical secre-
tion of that steroid is ",gulated by other hormones
(114). and roles in reproduction h3\'c been demon-
strated. Progestcrone can bind to aldosterone
tors and function as a wea k mineralocorticoid. De-
oxycorticosterone (DOC) is a much more potent
mineralocorticoid than progestcrone. and the
amounlS se.crcted can vary with the I\CTH levels.
18·0H-corticosteronc ;s an intermediate in the path-
way to aldosterone. It is not usually released in large
amounts by mammals. but it is present in the blood
of amphibians and reptiles. II_o.,oxycorti""l is an
aldosterone precursor secreted in substantial quan-
tities by marsupials. Cortisone ;" a major fetal ste-
roid. It must be redu""d to cortisol before it can act
on ITIC)St target cells.
In all. some 50 different steroids have been found
in ad"'noc<Jrtical extracts . Several are artifacts
formed in vitro. A few othcrs are degradation prod-
ucts that are present in normal glands.
Some aspects of steroid hormone chcmistry. n0-
menclature. and biosynthesis we", discussed in
Chapter 3. 1\ few of the molecules commonly called
by their trivial names. along with some older desig·
nations. arc shown in Fig_ 6-4.
Pree urtlore
The hormones are made mostly from cholesterol
supplied by the blood. The glands contain en"yrn.!
that catalyze biosynthesis of cholesterol from acetyl-
CoA, but in most species the pathways arc employed
only when uptake from the plasma docs not mcet the
needs. (The hamster is One of the few animal types
known to synthesize la11\e quantities of cholestcrol in
the adrenal cortcx.) Fetal adrenal. use considerable
amounts of cholesterol-sulfate. and small quantities
are hormone precursors in postnatal glands.
The liver makes low-density lipoproteins (LDts)
and releases them into the bloodmearn. The parti-
cles have inner "cores" filled with cholesterol held in
ester linkage with long-chain fally acids (mostly lin_
oleate. along with smaller quantities of palmitate
and oleatc)_ The cores arc surrounded by rings con-
taining apoprotein B, phcspholipids. and SOme free
cholesterol.
Adrenocortical plasma membranes have specific.
high-affinity LDL receptors that bind thc apoprotein
(10). These. are located within "coated pits" that
open to the surfaces. By a process involving invagin-
ation. vesicles containing the LDLs arc formed. in-
ternalized. and transported to lysosomes. Thcre. en-
7.ymeS catalyze separation of the protcin and
hydrolysis of the esters. The liberated cholesterol can
be incorporated into pla.ma membranes, rccsterifed
 CH,oH
, ,c=o
CH,oH ,
'""'"
C=O C =O
1 1 -- 1 1 ""
"0
"" 0,
1
, ,
+
o '" o '" o" '"
CORT ICOSTERONE IS) CORTISOl. IF) CORTISONE IE)
lHydrocor1iWM)

o ,
I
'""'"
C =O
"'", <

0' 0'
ALDOSTERONE lELECTROCORTIN)

,
CH,oH
"""'"
, ,c =o
'"","
c=o c=o
0,
1 -1 -1-- - 0«

, -./
o '" o" '" o,
, l·DEHYDROCORTICOSTERONE 11·DEOXYCORTICOSTERONE \ 1·0EOXYCQRTISOL

'" Ftg. &-<t.

(0. DOC! (5. 17,..OH·OOC)
idenlified", ad,e-nooorlic.1 e,IfaOI •.

and stoT<'d in lipid droplels. or sent direelly into
pathways for hormollO biosynthesis (20).
Cdls cultuT<'d without LDu have low basal rales
of steroi d biosynthesis (although Ihey ma ke choles-
terol from acetyl·CoA). They also display markedly
blunted responses to simulant.< such as ACTH. The
glands of animals given 4-aminopyrawlopyrimidinc
(which blocks hepatic lipoprotein secretion) show
sim ilar characteristics (11). Cells exposed to chlor·
oquine (which imerfe"'s with lysosomal functions)
cannot utilize the cholesterol that is taken up. Rats
dilfcr from most other mammals in that they can
utilize high-<lensity lipoproteins (HDu) as wen as
LDLs.
Free cholesterol (or one of its metabolites) regu·
la tes cltQ!esterol synthesis. storage. and uSC in thrce
ways: (a) It indirectly reduces activity of the Tatc-
limiting enzyme of thc biosynlhetic pathway
(HMG·CoA reductase); (b) it activates microsomal
acyl·CoA:cholesteryltra ns fc rase (ACA T), which cat-
alylCs recsterification of the free cholesterol; a nd (e)
it suppresses the forma tion of LDL receptors. The
control mechanism.! permit storage of some hormone
precursor. but they protect against excessive lipid ac-
cumulation and against un necessary diversion of
melabolic resourees inlO production of cholesterol.
Controls by ACTH and other pituitary horm<Jnes
that are superimposed over these and other aspcclS
of sleroidogenesis aT<' considel"<'d in Chapter 7.
Conversion of Cho lest e rol to Pregne nolone
A Cholesterol-binding protein facilitates transport of
the pre<:ursor to the mitochondrial matrix in prepa-
ration for wha l is usually the rate-limiting slep of
,,.
steroid hofmonc: and the major .ile for
hormonal
The side-chain deavage (IKe, pregncnolonc: syn-
Ihelase, desmolnc) is a
oxidase s)'stem" Ioc:aled 0f1 lhe inner mitochondrial
(2),24). It Qlalyzcs <)):.idalion of QrOOns
2(1 and 22 of tIM;: cholo$lCroi. TIM;: molceulc is tllen
split inlO and (sec
Figs. l-23. )-24). The ddehydc i$ $OOCI widir.cd 10
isocaproie acid.
The complex comp.isa .....'heme ;fOOI- .ulfu.·
COI'Illininl .. (a4,enod,»;n). on NADPII·
spocific ftavoprolrin (ad •• lIOdc>Jin ,eductase) aftd .... b-
""""Hp«ifi<: heme: proiIcin (C}wc:hromc 1'""50...).
AI""",,, ....... 2().bj'dfWr- .... 2O.21-dih)d_ydll).
Ies,.rd an be ioobltd fTOm . t;'n,,101cd cclh ulOde, ""'-
la in condit ...... JllCh mol ,ut.. ""'y no! be formed """",
....... h """ b«n pt<lpOS«Itha, functional
unil> .... d. up of subo1fa,c and ."'ymc complc>.. intlan.
la"""".ly "o,,,.rl inte.medi.l.. 10 pr.lncl'l<>lonc. (Cho-
lestcrol '111101" Ihal II ••• 1M " •• bon at p<:IIIilion 22
blocked $(l ,hal it '."!'IOt .".(h o.o.Ylicn arc .Iso el....d
]6S] .)
Very ,mall amou nts or 17,...QH.pre,n."",kmc may b<
form.d >;. o.;dot;<)I\.t POO;lion> 17 and 20.
Calcium cyclic nucltolidcs. prostaglandins.
and Olher regulators contribute to ACTI-! control
ovcr the reaction' (124).
Metabolic Fate 0 1 the Pregnenolone
Ahhough minUle amounu exit from Ihe gland. moll
of Ihe ;s made inlO biologically acti""
molecules. Sine<: some of the en7.ymcs for
furtl>cr melabolism are on the inner mitochondrial
membrane. and otl>crs ore "socialed ..ith II>c
smooth endoplaunic ret;culum. il boen .. idely
assu med tbat the inlermediatcs are freely $hulIkd
across the mitochondrial membranes in bach dim:·
lions. HOIO"CVCr. some sludies of ullrastructure and of
adrenal VCIlOU$ dfllKnts. Ind ocnain """,id-
erations. support the SUagesiton thll rca<;lions are
a<;l;Olllplished by substtliular p;lrticlcs lhat function
35 Un;IS (SO. A-S).
CONVERSION TO PROGESTERONE
ProgC§!crone;s the major intermediate . The convu-
sion ;nvolves two "micT05Ol!\al"' cn7.ymC$ that func-
tion togethe r. A 3t1·hydroxystcroid dchydroscnase
catalyzes oxidation of the alcoholic gTOUp at position
3 to a ketOl\C. A pyridine nucleotide cor.cter is
qu in::d. and NAO ' is prden"Cd over NAD!' -.
Tfotf GLUCOCORTICOIOS
BIOSYNTHESIS OF CORTICOSTERONE FROM
PROGESTERONE
The progesterone i. then usually acted upon by a mi·
crosomal 21 ·hydroxylasc. and it ;s thereb)' madc into
DOC. The reaction requires NADPH and a cyto-
plasmic.• ubslratMpc:cific cytochrome P450.
The fiul slep in the palhway utili7.es mitochon_
drial I IP-hydrox)"lase. molecular oxygen. NAOI'H.
and anotl>cr subsualOHpeciflC P-450. Addition vi
the Ol-! g.roup confers g1ucoconicoid potency.
Birds make use of an alter ..... path .... y. in " 'bich th.
"""....ronc: is 6n. h)""""'yllnc<i positiol'l It. The
is then actod upon by the 21·
hydrmylasc. Small a"-,, .. 01" II/J-hyd"")"pn::!lCSt.ronc
"'" also found in mammalian glands.
BIOSY NTHESIS OF CORTISOL
In .... e;es ma king this pt"egrw:noionc
serve .. a SUbslrJte lor mic rosomal 17.... hydrt)xyl.
asc. When il docs. the product (!7a-OlI-prcgncno-
lone) is then oonvert.d 10 17",-OH·progestcronc. AI_
ternativel)". pregncr.olone can form
which then undergocs 17.... hydroxylation. The 2 1_
h)'dro,ylase acts on \ 7",·OU -progc_teronc rormed in
either way to yield I I-<lwxycorl''''1. The f,nal ,top
in produc tion of cortiSOl is an \ Iff·hydroxyla tion
(Fig. 60S).
The adrena l gland. of cortiCCl'ller<>nC-<ICercters
ha'"C a 17C\"-hydrox)"I ... enzyme. IxIt it docs not uCI
on the 21-carbon intermediates.
BiosyntheSis 01 Aldoele ro"e
This hormone derives il5 name from the aldehyde
g ....... p at p<J5ition 18. A hc:mi''"tal forms when it in-
tenclll "';th the alcoholic glOOp Of! carbon II (SCI::
Fig. 6-4). Huma .... se<:l"Qte only L as much aldoste-
rone as Normal blood 1e,"CI. arc only around
0.01 "g/m l (compared "ith 10 "g/ ml vi f;Of\oo).
The minule 'luanlilies "",ke it dillku!tto ckfinc Ihe
palh.... ys.
While il is like ly tltal 18.QII<o<tico.ucrone is the
major intermed;ale. rat adn::na l glands are known to
make substant ial of IS.Q II·DOC (ISO)
(sc. I'is. 6-6). An lS·h)·dro:cylase io roond in the
mit<:<.:hondria or all WAC' of the adrenal cor-
tex. IxIt only glomcrulosa oxlls contain the I 8-hydrox-
)·steroid dehyd rogenase that Ihe nn;:tl
",ep in the palhway. Recently rcvio.c:d hypotheseo
for the path,,·a).. arc described in Chap-
ter 9.
CHOI.ESTEAOL - -- - - - - - - -- - -_

PAEGNENOlONE--------""_

1"'
c=o
'-II
-
--
o• '" A

PROGeST EAONe,....- - - - - -..... 0<, d'

,
""'"
' -0
L - 00

, I
11·oeOXVCOATJCOSTEAONE- - -- -_
d'
if'
1 •. oeOXVCOATISOl

',".0<>
c=o
L -00

CORTICOSTeRONE - - - - - , ' - - - -_ ._
, d'

COOl lSOl

no. u . PI_fYt 10< _ . ' ....... 01 (Ih' ,.'"w.

... _ ....... 1nGicI,,,,, by .... '-"<J ....Ows.
 THE GlUCOCOATlCOlDS

,
CH,QH
c=O
,1
• T
" '" " '"
,=,
,,·DEOXYCORTICOSTERONE CORTICOSTERONE

"0 CH,oH
,
", CH,oH

"0"t 1"0 "0"'1=0

0
1

"0
,
,, .I

,,,
o" '"
18·QH·DOC
,,,
,,,
o' l
"'"
18·QH·CORTICOSTEAONE

,,
I
o 0"","
, o 0".0><
,
I c=o I c=o
J.
"0
,
- - - - - -----
"0
"0

" '" '"

l'·OEOXYALOOSTERONE ALDOSTERONE

Flg.li-(!. Biosynl"<o. i. ot . 'cIo$le,one.

Bi osynthesis of Adrenal Androgens bly to by a l7-kel(lSlcroid de-

are made along palhways idenlieallO the
ones seen in Ihe gonads. (Tho leSles and ovaries,
however. lack the 21·hydrmylasc needed 10 make
gluCOC<lrticoids and mineraIOC<lrticoids.)
The precursors are molecules.
Corticoste rone secrelcrs begin wilh l7a-OH·proges-
Icrone. When a cn. C20 lyase (dcsm<>iase) cala·
Iyow; cleavage of Ihc carbons al po5ilions 20 and 21.
product i5 ,., 17-<1ione. This mole-
cule po5sesscs and il is «,vcrs;-
hydrogenase-<;alaly,.d reaction (Fig 6-7).
Species ma king oorli$Ol secrete substantial quan-
titie. of several 19..:arbon steroids. In these, the
major pathway begins with l7a -OH-prcgnenolone.
This !t.riotl is directly shortened 10 dehydrocpian-
dr<l:$lerone (DHEA, DHA), a "weak'" androgen that
is secreted. It and its sulfated derivative (de hydro-
epiandrostc rone sulfa te (DHEAS. DHAS) are
major products.
DHEA can be oonvcrted. both in the adrenal
oortcx and oUlside the gland, to lestosterone.
 CHOtEfTEROL '7fl.QH-PREGNENOtONe
PREGNENOLONE •

I
PROGESTERONE ---- - • 17,,.QH·PAOGESTERONE

j
" fl-OH-PROGESTERONE
0
,",
,
j C=O
><0 I -'--

><0

A' ,
I , II. ' 7,, ·OIHYORO)(VPROGESTERONE

><0
I Jl
o 0
, 0

,, '+
A'

, '/!·OH·.l'·ANDROSTENE·3 , ".DIONE
A'

17·010NE
0
'l
'"
6 5 ·ANOAOSTENE-J.l1·0 10NE

j "
o "
"0 -'
, A' ,
o• A'

1 ' /J-OH.TESTOSTEAONE TESTOSTERONE

Flg. &-1. Biosyntt>e.i. 01 odr"",,' . ndrOQliMlo. Double

. "OWI """" ""i.O<I
by cc>rtiSOlMCreror._

Some <l'-andrOSlcncdione is also made by oortiSOI
sccr<:tors.
Adre nal Es trogen s
Under ordina ry conditions. the adrenal glands are
not importa nt direct SOurCeS of estrogens. However,
(he androgens rcleasW arc in liver. adi.
pose tissue, and elsewhere 10 estrogens. In paslrne""
pausal women. and,oslene-dionc: is the major pre-
(Fig. 6-8).
All nalUrally occurring estrogens have 18 carbons
and an unsaturated A ring. The biocbemical path.
way involves firs! hydroxylation and then remova l of
". THE GLUCOCOATICOIOS
.
,
TESTOSTERONE

j
",
0 19.()H ·TESTOSTERONE

"' j o"
»
,
0
0"" HO, II

19-OH·ANORQSTENEDIONE
A

0 " "'
19·CARBOXYTESTOSTERONE

"
o"
19-CARBQXVANDROSTENEDIONE
r-
0"
" '"
17{J-OH -ANDFlOSTA-l,4 -0IENE. 3-0NE

'0 NO'HESTOSTERONE

o "
o

-
I
ESTRONE ESTRAOIOL·17f1

FlO . 6-8. """enol e.tfog&n'. Pfecursor •. a oo ",O!><>Wd

int"'mlJdi.tel .

carbon 19. An aromalase system then acts on the A
ring. The details of the aromala5e reactions arc only
partially known.
Sulle ted Steroid s
Different enzymes conve't limited amounts of cho-
Icstcrohulfatc to sulfated steroid hormones. It has
been suggcslcd that the processes assume especial
importance when the supply of free cholesterol is in-
adequate. ACTH lowers the DHEAS:DHEA ratio
in the ""'<>Qus emUCn!. possibly by augmenting sui·
fatase activity.
The glands also contain sulfOlransferaus thai in-
crease the production of sulfated h(mnones. In ad-
dition to DHEAS. they secrete pregnenolone-S.
DOCS. testosterone-S and SOme estrogen sulfates.
The enzymes have only recently been rcoove red from
adrenooortiealtissue for study by affinity chroma-
tography (3). and there is limited information on
their functions. The activities rise whcn large quan-
tities of cholesterol and of certain other steroids ac-
cumulate within the adrenal glands. Sulfated hor-
mones released to the bloodstream are rapidly
degraded by hepatic microsomal reduetases (I 36),
GluCOC<lrticoids, estrogens, and pituitary gland hor.
mones all regulate production of the liver enzymes
(134, (35). T he observations are consistent with sug-
geSlions that sulfotransferases contribute to mecha_
nisms that prevent excessivc elevation of the hlood
steroid hormone levels.
r.tal adrenal ,land. a,. very larg. relative to body
si"". and Ih.y relea,e .ubstanl;'] <lu.nlilie. of ,ulf.. ed
I'\o,mon ... The possibilily thal lhes. "' rV. 'peeial func·
lion. i. COI1.idercd in Chapler 16. The mOlhe r m.)' lhen
require proleclion ag.inst the dev.lopm.nt of hyperad ·
rcflO<OI'ticali,m. ,inee lhe steroid. enler Ihe malernal cir·
culalion, Shc rapidly degrades sulfaled 'I.roids. becau",
her hitlh e.l<og.n level. invoke marked ele,"I;OO of Ihe
hepatiC micr<>eoomal en,),me ,clivilie •. The adrenal
gland, of noonale. undergo "involution" a, Ihc)' gradu.
ally .cquire more malure melabolic mechani.ms,
Somc observation. on ,uinca pig. ar. of intete.t in thi'
conneclion, Thooe animal, have e ...edingl)' high drcu,
IO ling gluCOCOrlicoid concenlr.lion. . Their .drona!
gland, arc .ery large relative to Iheir bod)' ,i",. bUI Ibe
,ulfot ... n,fer ... activity i. v.ry low (1]6). It has been
.uggcsled tha1 those condition, are required 10 ,uslain
normal end<>erine function. becau.e the glucocorticoid
r.'""plon bind Iho hormone. wi1h vcr)' low .flinil)' (72),
Howe""r, it hos also been .peculated Iha1 lOe gland' are
SO large becau,e fOlal remnanls arc retained poslnalally
(142). Thi. raises Ih. possibility that the ,«--
acquir. low aflinili .. ,,'hen the .ulfotransfc ras<
acti.il)' declines aft.r birth,
The 'ignificance of Ih. high circulating I<vel. of ,ul·
fa1ed .teroid, in patient. "ith mineralOCOrticoid·rel.led
h),perten,ion i. lIOt kllOwn . It could rCfieel un,u,""e .. ful
.n.mpts to limi1thc Prod"C1ion of hormoncs Ih.1 elevale
Ih. blood pressure. Abnormal sulfo,.a"sferase activily
ha, be.n demon'lraled in palien1' ,,·ilh some forms of
•• ncer.
ENZYMATIC DEFECTS OF THE ADRENAL
CORTEX
Under normal conditions, s lucocorticoids act on the
hypothalamus and pi(Ui'ary sland to limit the secre-
lion of ACTH. When enzymatic defeclS impair Slu-
cocorlicoid synthesis, ACTH levels rise
Then, the adrenal glands undergo hypertrophy, and
large quanlities of cholesterol are made inlO pres·
nenolone. Since the pregnenolone cannot be used to
ma);;e glucocorticoids, il is shunted into olher me.a-
'oolic pathways. The consequences can indude ex-
cessive prodUClion of androgens or mineralocorti·
coids, as well as glucocorticoid insUllieiency.
Problems of this kind arise when genetic defects
impair the functions of the adrenal glands. "'hen tu·
mors wilh abnormal enlyme make·ups de"clop, and
when Olher kinds of tumors relea", 100 much
ACTH. They can be mimic ked wilh pharmacologi-
cal agems Ihat selectively inhibit certain of the en·
zyme. (Fig. 6-9). 11I<;to;e agem, are sometimes used
for diagnosis of the disorders. and there are condi·
tions under which SOme Ca n provide eifective
Iherapy.
Cenain of the inherited disea>eS aifect steroido-
senesis in gonads as well. Adreoocon ical tumors
have also been known to impair reproductive s}'!ltem
functions.
Deficiency o f C-20 Hydro)(ylase
This is Ihe mosl ",rious of the genetic defecls, since
il rctards formation of pregnenolone and Iherefore of
01/ steroid hormones, Life can be suslained only
when glucocorticoid and mineraloconicoid therapy
i. instituted soon afler birth. Male fetuses unable to
ma ke testicular androgens fail to undergo differen-
tiation of the reproductive organs, and they acquire
anatomical structures similar 10 those of females
(Chapter 13). The eifects cannot be reversed lalcr.
Females may appear normal al flrsl. bUllhey
estrogens at the time of puberty for devdopment of
tile secondary characteristics.
Aminoglutethimide (AG. Eliplen) is an anticon'
vul""n( Ihal !la. be<:" u""l in p-4.1 rur Ito" (",al-
ment of epilepsy. It inhibits activity,
and thereby promotes a<xumulalion of cholesterol
within adrenal slands as il halts the use of Ihe cho-
lesterol for sleroid hormone synlhesis, W hen given 10
intac. animals. it also increases ACTH secretion
(,ince il impairs negative feedback conlrol by Slu-
cocorticoid,). AG is useful in several ways for inves-
tigalion of mechanisms of action of ACTH (sec
Chapler 7). and it has also been tried in regulated
dosages in patient' ",c'"'ting quantities of
steroids (79). I n high dosaS.... it additionally inhibits
11.8.hydroxylase aClivity. the peripheral mela'oolism
or steroid hormones. a nd possibly also hypothalamic
regulation of ACTH ",eretion (48),
Deficiency o f C-21 Hydro)(y lase
This is Ihc most common of the spontaneously 0c-
curring clinical disorders. If the cnzyme defect is se·
vere. neither slucocorticoids nor mineralocorticoids
can be synthesized. However. pregnenolone forma·
tion is augmented. and much of it is converted to
DHEA. Smaller amou ntS of tcstooterone. and also
some estrogens are made. The high cireulating levels
of androsens cause masculinization of female fctuses
(and the infants look like males with poorly devel-
oped reproductive organs al the time of birth).
'" THE GLIJCOCORTlCOlOS

'",
,

""
CYANO!<ETONE " 0
f"'
l' '\ ,-, r "'\
" I
,", -
"",ETVRAF'ONE
AM INOGlUTETHIMIDE (SU.46/15)

-;/?';yl f
l' '\ , 'I \:>--CI
'0

" SU·905S "" 0

(l,p'.DOD

'\

,
Y"
MEA -29
,", I I I
"-
SU·8000

u,_o
o
,'",
I
"",
I /
CuD \==/
I h
'",
AMPHENONE·B
o
TESTONQlACTONE

FI'l. 6 ·9. PIIIrmaoological IQ81110 d..,ting .,nll,..i5 <>f

-.I'.nocorIlal ho<mor>e$.

Latcr, the androgeru; pr(lll'lote premature onSCI of
puberty in male children and virili>:alion of the
fcmaks.
Mineralocorticoid therapy is required 10 correct
the aldosterone deficiency. GlucocortiCOid replace·
ment must be provided to maintain metabolic fune-
lions. Since;\ also negative fccdback conlrols
over ACTH, it 1eSS<'1l$ androgen producliQn.
There arc mild form5 of the disorde r, in which
limilc<J amoun(.S of are made. Fe-
males with this ",(,"dition usually rC$pond faVQrably
to early administration of glucocorticoids. Although
they commonly undergo precocious puberty. many
achieve fertility.
No specific antagonist of this enzymc is known.
17,,·hydroxylase deficienC)' can coexist. When it
docs. only minute quantities of androgens and estro-
gens are synthesized. There are also individuals in
whom the lIP-hydroxylase and IS·hydroxylase lev-
els are subnormal.
3p-Hydroxysterold Dehydroge nase
Defic Ienc y
In this disorder. the large amounts of pregnenolone
made are converted mostly to DHEA and rc1atoo
tJ,' "weak" androgens. liowe\w. since progesterone
and its dcrivatives cannot be synthesized. there is
both glucocorticoid and mineralocorticoid def,_
ciency. The androgens promote masculini7<1tion of
female fetuses and of female children and theyac-
celerate puberty onsct in boys; but they arc not ef-
fective for supporting normal differentiation of the
reproductive organs of male [etu",s. (See also adre-
nogenital syndrome. Chapter 13)_
Cyanoketone and WIN 24,450 "s[>Cciflcally"
block the enzyme (78) . When given to rats, thcy in·
VQke glucocorticoid and mineralocorticoid deficien·
des. The masculinization is minimal because ratS
make "cry liule DHEA .
11p·Hydroxylase Delfclen cy
This disorder permits the biosynthesis of progester-
one, and it can increa", androgen (and sometimes
estrogen) prOOuction. Much of the progesterone is
converted 10 DOC, IS.QH -DOC, hydroxylaloo do.
rivative:!' of progesterone, and also to II-<!eoxycorti·
sol in humaN and others_
Metyrapone (metopironc, mepyrapone. SU-4885)
inhibi!l; thc en7_yme. [t is a u",ful diagnostic agent.
sin"" it is sMrt-acting, In individuals with normal
ACTH-adrenocortical "reserve." glucocorticoid
suppression leads to increased secretion of ACTIi.
and this is followed by proouction of largc amoun ts
of Il-<!eoxycortisol. (Patients with cxtrapituitary tu·
mors that release ACTIi and ACTH·like peptides
do not display such responses.) However, the agem
also inhibits that catalyze hydroxylations at
carbons IS and 19. and it therefore does not have the
same effects as "pure" IIp·hydroxylase deficiency
(48).
17,.-HydroxylaBe Deficiency
[.QSSof this enzyme blocks the formation of cortisol.
androgens. and C!itrogens. In humans. larger
amounts of ACT['I are then secreted. and this leads
secondarily to ....""ssive production of mincralocor-
ticoids. The usual consequences arc salt ",tent ion
and hypertension in addition to the glucocorticoid
and gonadal steroid deficiency problems. SU·9055
and SU-8000 arc inhibitors.
Daflc1encles of Enzymes Affecting Oxidation
of Carbon 18
SU-8000 and SU·9055 also inhibit IS-hydroxylase.
Patients with I Ip·hydroxy lase defIciencies some·
times make inadequate amounts of thi, en7_yme as
well , Aldosterone synthesis is impaired, but usually
there is enough £XX: to support mineralocorticoid
functions_ Since £XX: synthesis is not regulated in
the same way, fine control' are lost.
When the IS·hydroxylase functions but there is a
deficiency of the l8-hydroxysteroid dehydrogenase.
aldosterone cannot be made, but large quantities of
18.QH-£XX: and of 18-0H-oorticosteronc may be
released , The consequences are sodium and wa ter re-
tention. potassium depletion. and hypertension.
An analog of I g.QH·DOC (I g.2O-cycio-20.21-di·
hydroxy+pregnen·3·(lne) has been usoo to decrease
hy[>Crtcnsion in rats undergoing ·'adrenal regenera·
tion" (77) (sec latcr discussion).
Other Agents Affect ing SterOidogen esis
Amphenone B cau... fairly selective nec""i. of the
wna fascieulata and zona rctieularis. but permits
the ..ona glomerulosa to mainain its functions. It has
been largely replaoxd by DOD (dichlorodiphenyldi·
chlorocthane) and its mote active isomer. o.p'·000.
Thc agents have been used in patients making ex·
cessive quantities of corticosteroids, but they have
numerous undesirable sidc-cffects. Testonolactone
inhibits conversion of androgens to estrogens and has
been used for this purpose in patients with breast
cancer (9).
Zo na Fa sclculata Stero id s Implicated In th e
Et io logy of HypertenSio n
$Qme patients with hypertension and associated salt
and water retention have low aldosterone levels
(since the condition invokes inhibitory inAuences on
the ZOna glornerulosa). The problems are often ag-
gravated by high ACTH coneentrations.
It is therefore believed that the", individual, se-
crete excessive quantities of mineralocorticoids from
the zona faseiculata. In some cases. sterioos made by
normal glands may be involved. but in others differ-
em steroids Seem to aCcount for the sodium retention
(44) (sec Fig. 6-10).
Cortisol has only the mincralocortiooid po-
tcncy of aldosterone. However. hypertension is com-
monly associated with high cortisol and low aldoste-
'" THE GLUCOCORTiCOlDS

K
CH,oH
1
c =o
1 '"""
H C: O
o 1 oJ-
-
I

o"
'" o" '"
CH,ott
,
'".
1
c=o c=o
J- L -0<;

4
o" '" o"
19-Not·OOC

o
c'- 1

0'

17". , 6/j·hy<ltoxy·Dt1EA

Fig. 8 - 10. Som& <otIIlascicula ta oorticosto..,ids .truc1ur&a o! DOC. 111-OH DOC . • oo 111-OH CorticostOfOM,
impicIled;" In. e1io1ogy 01 (3M a loo

rone concentrations in patien ts wilb Cushing's
syndrome. Repeated inje\:lions of pharmacological
dosages of cortisol can also lead 10 clevation of the
blood pressure. Corticosterone is 15 limes more p0.-
tent than cortisol. DOC (a wna fascicuiala m iner-
alooorticoid) has 100 limes the sail-retaining effects
Qf an equimolocular quanti ty of oort;soI.
When previously healthy rats are subjected \0 bi-
lateral adrenal enucleation (removal of all glandular
tissue except the few cells that adhere to the capsule)
or to adrenal compression. they develop "ad renal re-
generation hypertension" during the time when they
form new adrenocortical cells. The condition is ag-
gravated by unilateral adrcnal«tomy and by salt
loading, The steroid implicated in etiology of the hy·
pertension is 19· nor·DOC (54.59).
Some patients may also make large amounts of
steroid . In others. high levels of IS-OH·DOC,
IS-OH-corti<;OSterone, hydroxylatcd derivatives of
progesterone. or hydroxylated derivatives of OHEA
have been found (?7). Stress (which augments
ACfH secretion) usually aggra vates the oonditions.
METABOLISM OF CORTICOSTEROIDS
A88oclati ons with t he Plasma Proteins
Glucocortiooids. 11-<1ooxyeortiooi&. steroid sulfates.
and the gonadal steroids travel through the blood
plasma in oombination with proteins secre ted by thc
liver (1.154).
Around 76% of the oortisol in human blood
 plasma i. associated with Iral1SCQrthl (corticosteroid
bindi ng globulin, C BG). T he protein present in
low concentrations (7 X 1O-' M), but it binds with
high affinity. It has similar affinity for cortieo&te-
rone. and it binds progestero"" even more avidly (7).
Limited amounts of testOSterone and sma Ucr ones of
estrogens associate with CBG. but most of the cit·
eulaling gonadal steroids travel with a different pro-
lein, TeBG (Iestosterone-eslrogen binding globulin.
SSW. sex steroid binding globulin).
Albumins have low affinily for hormones.
However. concentrations of around 5.5 X 1O- 'M
explain the high capacity. 13% to 15% of plasma
cortisol is bound 10 them. An additional 2% aUachcs
to .. ,-acidic glycoprotein (AAG), which is present in
COncenlTations 20 times those of CBG .
Glucocorticoid. are pOtent stimulants for produc-
tion of CBG. When large quantities of the steroids
are se.:reted, elevated CBG levels it possiblc to
have high circulating glucocorticoids with(>nt ineur.
ring loxicity (since only unbound hormoncs rapidly
gain access to the target cdl recepton;) . Adrenalec-
tomir.<:d animals are exquisitely sensitive 10 exoge-
nous steroids. and One reaSOn is their subnormal pro-
duction of CBG ,
Estrogens arc also pOtent stimulants. In most spe-
cies. females have high IOtal circulating glucocorti-
coid and CBG levels. and Ihere are further increases
during pregnancy. Since fetuses have low CSG, ,te.
roid hormones are easily transferred 10 the maternal
blood. In some spe<:ies. glucocorticoids play major
roles in thc initiation of parturition, and the CBG
levels fall pre<:ipitously shortly before that time.
In rats. there arc only small increru;es in CBG pro-
duction during pregnancy. but very substantial
quantities of glucocorticoids arc nceded to suppOrt
lactation. The CRG levels in these animals fall soon
after parturition. and both the magnitudes and du-
rations of the respOnses vary with the numbers of
pups (156). Thyroid hormones stimulate
glucocorticoid and ACTH sceretion and CBG pro-
duction in rats. In humans, th)·roid hormones ha,·e
lilt le influence on the levels of either ACTH Or CBG
( 19).
In guinea pigs. production of a CBG that only
loosely associatcs with glucocorticoids. along with a
separate protein OOt found in most other mammals
that 10 progcsteronc (36) may be adapta·
tions to the low·affinity glucocorticoid receptors of
this species.
TranSfer of Glucoco rtlco lds from Bloo d to
Target Cells
Several proteins that lake up glucocorticoids but do
not function as rec<:ptors are prescnt within the cy-
toplasm (34). They may serve as buffers that protect
the against rapid changes in blood hormone
concentrations. The binding affinities arc lower than
those of the receptors. and this fac ilitates transfer.
Metabolic " Activation "
Gonadal steroids are known 10 undergo several kinds
of metabolic conversions that are essential for inter-
action with their receptors at somc sites. For
pIc, testosterone is made into dihydrotcstostelOllc in
Ihe prostate glands. and into estradiol in certain of
the neurons.
Sleroids with II·keto groups are convcrted to ones
with II.()II groups before they Can act. (For cx-
ample, cortisone and II-dehydroconicosteronc are
made into cortisol and corticosterone. respectively.)
Some low_potency steroids released from thc adrenal
a rc changed into ones with greater activity in the
liver.
At least some of t he cortiC<t\terone. cortisol. and
aldosterone seem to bind directly to Ihe receptors.
The 10 which metabolic transformations at
other sites are of physiological imporlallC( is not
known. Numerous metabolic products have been
identified. and at least a rew have demonstrated
pharmacological activity.
Degradation
The li""r is the major site of degradation. but the
kidneys and other organs participate. Hepatic en-
"ymes that catalyzc reductions of lhc A ring and b ·
tone groups, and promote side<hain cleavages, arc
the most widely The products arc for the
most part neutral steroids that have tittle Or no biG-
logical activity and greater water solubility than Ihc
parent mole.:ules , Some cleavage products are. how·
ever. androgenic. and SOme reduction products (e.g .•
S-<lihydrOCOTtiso1) have mineralocorticoid potency
(149) . Conjugations with sulfate. glucuronate. ace-
tatc. and OIher small anions further increase the
water solubilities.
Different enzymes catalyze oxidations and the for·
mation of acid metabolites (10 I). Some of the prod·
ucts have demonst rated pharmacological activity
(e.g .. they inhibit infiammatory respOnses). The pos.
sibility that they $Cr"" physiological functions re-
mains to be invcstigated.
The better known metabolites of cortisol are
shown in Fig. 6-11. More recently discovered deriv-
atives are shown in Fig. 6-12.
Androgen, estrogen. and progesterone metabolism
are diseussed in Pan V. The include ca-
techol estrogens that are present in brain as well as
liver and blood plasma (112), Such molcculesaffe.:t
neurolransmitter turnover. and they ha,'e been im-
..
, THE G LUCOCORflCOlDS

'"''''
I

"0 k - -l- - -0"

, ,
""
20. ,·OIHYDROCORTI$OL
""
20., ·OIH\' DROCOR TISON E

laRTISOL "'''''''''''''''''''''''''''''''''''''''''''-, COR t iSONE - - _ ,

1 I CH,oH
I
c =o C=O
"0
.1 0>< .1- - 00 1 " 0
---OH

, , •
"
Si!-OlftvQAOCORTISO L S,.·OIHYOROCORT ISOL S/J-DIHYOROCORTI$ONE
/

I
S,,·DlHYOROCORTI$ONE
CH,oH CH,.o1i
I I I
I
c =o
-l-- -QH HO
c =o
- --OH
'"''''
I
c=o
"0
OV -OH

- - •

3 ,,·TETRAHYDAOCORTISOL
"
AllOTETRAHYOI'IOCOR TISOL
J
[TETRAHYOAQ.F) "
ALLOTETRAHYDROCORTISONE
[TETRAHYORQ'E)
I
TETRAHYDAQ'
"0 CORTISONE
- - - OH
ALLOCORTOLONES

CQRTOLONES

COI1101.

ALLOCORTOL

"'" 1_.
Fig. e· ,!.
,&dUC!ion "
Produc!. of c<>rtiOOI """abolism reOlJIt;ng from
'<:1iono oftectitl; ca,bons 3, 4 . S. 0 0<1 20. Cory
pr_noting ;" humans .... sIIown. Some
$peCiM mok. I"' ge """nlilies 01
2'(l/,l.oH 01_ •.
_ i,.li.....""
 P
,
HC=O
,
f1C=D
,
C-OH
I1C - 0 11 C=Q C=Q
.h-- 1-_ - - - 01-1
"' 00

T
"' , "'
ISOCORTISOL 2' -OEHYDROCOflTISOI.. COFtTISOUC ACID

, .
", ,
HC-OI1 "
eo -- -- -'" - - -OH
"'
,• .,
"
ISOTETRAHYORO·f "
CORTOI.IC ACID CORTIENIC AC ID
,
,,"-,," CH,OH
He - 011
I
C= O
+1_ "'
h-

,, , "'
6
" "
17·0EOXYCQATOLONIC ACID

Fig.
CORTOlONIC ACID

e· 12. Add;t;""'" cortiSOl mfllab<>liles.

"
s.,.IWOROXYCORTISOl

plicate<! as "'Sulmors of brain funclicns and of go-
nadotropin secretion (93).
AlthQugh all mammals release the metabolic
product!; into both the bile and urine, there are spe-
cies differences in the relative amounts sen. 10 each
of the excretory Outlets. Hormone. contribute to reg_
ulation of the biliary excretion of hormones and their
metabolites (102).
SY NTHETIC CORTICOSTERO IDS
Natu!'l\l1y occurring corticosteroids have only lim·
ited usc in therapy. especially when large dosages
arc ne.:ded or when the molecules must be retained
at a localized sile.
Agems that are to be administered intravenously
to invoke prompt responses must be water-soluble.
Lipid solubility is required for prolonged actions and
topical applications in the form of creamS. Absorp-
tion raleS can he comrolled by conjugating steroids
with acetate, pivalatc. cipionato. succinate. and
other substances. and by modifying the .. chicles.
Naturally occurring hormones are not suitable for
oral administration because they are rapidly de-
graded by enzymes in the liver. Small changes in
molecular structure can provide protection against
attack by hepatic enzymes and in olher ways prolong
Ihe biological half·li,'e$ . Different modifications have
been allernptcd to sele<:tivciy increase the binding to
certain of the targets. Only SOme have proven sue·
cessful. (For example. there are synthetic steroids
thai can SOflie as potent anti·inflammatory agents
without invoking se rious salt retention: but satisfae-
tory IiCpa ration of anti.inflammatory from anti.im·
mune or glucocorticoid polencies has 001 been
achieved (128).
". THE QtUCXX)ORTKX»DS

'"","
I '""'"
I
C=O C=O

0, I k- -0" "0 k-
r

o -J' ""
PREDNISONE PAEONISOi.
CH.<JH CH,.oH
I I
C=o C=O
-l--
"0
-
,,
r ,
0"
, A'

'".
f)".METHYLPREDNISOi. T RIAMC INOlONE

I
C=O

*-- "0
- --
,, ,,
,
r , r

o -J' o
""
DEXAMETHASONE
BETAMETHASONE

CH,oH

C=O
I '""'"
I
C=o
),- .1.- -
,,
r
,
o
'" , ,, A'

FLUOAOCOfITISONE
PARAMETHASONE
(S".FLUQRQCORTI$Ol)

Some of {he more widely usW synthetic steroids
ar<: shown in Fig. 6-1 3
Insenion of a second dooblc bond in the A ring
carbons 1 a nd 2 leads 10 enhanced gluco-
corticoid and a nti-i nflammatory activities bUI it
markedly rcrlUIX'S minc,alOC<)rticoid potency. Thus.
prednisolone has four limes {he glucoconicoid and
anti.inflammatory effectiveness of an cquimolccular
dose of corti$Ol. bUI only 0.4 limes ils sah'r<:taining
actions. It binds wilh only half the affinity 10 CBG.
This may aoxount in small part for ils greater p0:>-
tency, but more a.id binding to glucocorticoid recep-
tors is of much greater importan<;<:, Prednisone. the
related analog of cortisone, associates to a lesser
tent with CBG (7), It must be reduced to predniso-
lone before it can interaCI with th. receptors.
Addition of a fluoride atom in 01 lin kage at posi·
tion 9 enhancc$ all of the corticosteroid actions. Stc-
roid, with this substitution bind with .ery high allin·
ity to receptors. resist degradation by hepatk
enzymes . and show negligible binding to CBG. 9,,·
fluorinated d.rivatiyes with 1.2 double bonds arc
among the most fX>tenl kn<lwn glucocorticoids and
anti·inflammatory agents. 9"..fluorocortisol (fludl'Q-
cortisone) has 125 limes the salt·retaining elfecti.c-
ness of cortisol . and it is used in patients with ald<>-
stcrone deflcienc),. ( It is also 10 times stronger for
anti·inflammatory and glucocorticoid activities. but
its effects on sodium and water balance prcclude its
use for such purposes.)
Substitutions at position 16 further increase the
anti·inflammatory fX>tcncy. Dexamethasone is 25
times as active as cortisol. Substitutions at the 6 p0:>-
sition usually augment the gl ucocorticoid actions.
but Ihe r•• ultil1$ changes are affcctcd by other fca·
tures of the mole<:ules.
REFERENCES
l. Abramoff, P..• nd L. Via, M, F.. cd•. Biol08yof
rhi I",,,,ull<' Rtspo1lJi. McGra ..'·Hilt. New VCK k.
t 970.
2. Abras •. I. 8" and Scarpace. P. J.. Glucocorticoid
Reg"l.,ion of /I.Adrenergic Ree<:ptors.
F,nd"", iol. 108: 977-80. 1981.
3. Ad ams. J. 8 .. and McDonald. D. En"ymOlie Syn-
the. i. of Steroid Sulphates, XII. Isolation of l)e-
h)'drocpiandrosterone SulphotfOn.fefO$< from
Human Ad",nah by Aflinil)' Chromatography.
Died;",. Biopny., Arid 567: 144- SJ. 1979.
4, Ader. K. The Effects of Early Ei;pcricncc on Ihe
Adrell<Xorlical Rcspon.c to Diff.rent Ma8nitudes
of Stimulation. Phy./ol. ,{ 8iho,'ior 5: 8]7_9. 1970.
5. Aranow, L Effccts of Glucocorticoid. on Fib,o-
bl . .... Chap, 18. pp. 127_40 of Ba... r and Roo ..
..au. cd." ",f.",ne<: I I,
6. "u,bach. G. 0 .. Mar>. S. J .. and Spi.goi. A. M.
Paralhyroid Hormone. Calcilonin. and Ihe C.lci·
fcrols. Chap. 19, pp. 922-1 03 I of Williams .• d .. ref·
erenc.155.
7. Ballard, P. L. Ddi""r)' and T .... pe'l of Glucocor·
ticoid. to Targ.t C.II,. Chap. 2. pp, 25_48 of Bax_
ler and Roo ... au. .. rde rortee I l .
8. Ballard. P. L. Glucocorticoid. and DitTcrenti.,ion.
Chap. 26. pp. 493-515 of Baxter and R"".",au.
cd . .... ference 1\,
9, B.rone. R, M" Shan,,,,,k i.1. M" Siit.r'. P. K. . • nd
Judd. H. L. Jnhibilion of Periphcr.l Aromalilation
of Androst.nedione 10 Estrone in Poslmcnopau""l
Women with Bre.. t Cancer U.ing ':"Te'lOnol.c·
t1>l1e, J. C!in. Erul"",/noi. M,"'I>. f 9: 612_6. 1979.
10. Barrington. E. J. W. An In/, odu('/;on /0 Gmudi
alUf C""'I"',ollw: End"",'noiogy. 2d ed. Oxford
Univtrsi ly p"'$$. Ne ... York. 1975.
I!. B.xter. J. 0" and Roo ...... G. G" cd •. Gi.,ONJr-
/iaAd iI(NmOM /krion. Springer.Veriag. New
V""k. 1979.
12, Bell. J. B. G .. Gould. R. P.. Hyalt. P J . Tail. J. f .•
and T.il. S. A- S, Properties of Rat Adr.nal Zona
Reliculari. Cell.: Preparation by G ... i..,ional
Sedimen1ation. J E"Joc,ilkJl. 17: 25-41. 1978.
I) , Bell. p, A.. and Bor1hwick. N. M . Glucocorticoid
ElfeclSon ONA·Depcndenl RNA Polym..... Ac-
livity in Rat T hymu , C.II,. j , S",oid /1iO(hml, 7:
1147_50.1976.
14, Bethell. F. 1·1. Blood Di ...... a nd Malignancy ,
Chap. 12. pp, 464_92 of Lu kens. F. D. W ., ed .
MNlkal of C()I'UWII<'. Blakiston. N .... VO(k.
1954.
15. Biartehi. E., Pierapaoli. W .. and Sor kin. E. Cytoloi-
ieal Change. in the Moo .. Anterior Pituilary .ftcr
N<X>Jl.tlal Thymeclomy : A Light and Electron Mi·
croscopic.1 Study. J, £nd",,'/noi. 15: 1- 6. 1971.
16. Bla.ehke, H .. S.)'e .... G .• and Smilh. A. D.• cd •.
Handbook oj Physiology • .. c. 7. vol. 6. American
Physiological SocielY. Wa<hington. D.C., 1975.
l7. Bloom. B. R. MQlecul .. Mech.ni.m. of Mononu-
clear Cell function. lntroduclion to Symposium.
PrO(: 37: 2741-42,1978.
18. 81<x>m. B. R.. Diamond. B.. Musdlcl. R.. Roscn. N.
N.. Sehneck, J,. Damiani. G. .'01 .• Rosen, 0 .. and
Seh.rlf. M . Gen.lic Approach •• to lh. Mechani,m
of Macroph.ge Funelion. P,d. P'O(. 37: 2765-71.
1978.
19. Bray. G .. and Jacobs. Ii , S. Thyr<>id Aelivily a nd
other Endocrine Gl.nd •. Chap. 24. pp. 411- 3) of
Greer. M. A .. and Solomon. O. Ii.. cd •. ilondbook
of Ph;'j /%gy. $<C. 7. yo\. 3. Amcric.n PhJ"iological
Soci.ty. W .. hinglOn. D.C .. 1974,
20. B,ow •. M . $ .. Koy,nen. p, T .. and Gold,,,,in. J. L .
R=ptor·Modi.ted Uptake of LipoprOlein-Cholc,'
leroland ilO Utilization for Ster<>id Synlhc<i. in Ihc
Ad",,,,,1 COrtex. R« , Prof. I/o"""", Rsd,. 35:
215-49.1979.
21. Bunlner. B.. and S>ym ik. N, Elfecl ofThymcclomy
"" Sleroid Secretion in Adren.1 Venous Blood in
Male R.l •. End"",i""l. Exp. B: 31_7.1914.
22. C.ke, M . It .. and Lilwac\:.. G. The Glucocorlicoid
Rccepto, . Bi""hrm. A",ion; /form, 3: 319-90. 1975.
23. ChurChill. p , F .. deAlv.,e. L. R .. and Kimur •. T.
Topological Studies of Ihe Steroid Hydroxylase
Compl.xe. in Bo,ine Adrell<Xorlical Mil""hondria.
J. Bioi 153. 4924_9. 19 78
24. Chur<:hilt. P. F.. and Kimura. T . Stud·
ies of Cylochrome P4)(1_ and P4)(1, ,, in Bovine
Adrtnocorlicallnner Mitochondrial M.mbrane,. j.
Bioi 154 ' 10443_&. 1979.
25. Cidlo.... ki. J. A. Glucocorticoid. Slimulate Ribo-
nucltie Acid Degradation in 150la1O<1 Rat Thymic
Lymphocyte. in Vitro. t:ndO(,;no/. III: 184-90.
1982.
".
26. Clark. S. L. J r. In<»rpor •• iQn of Sulfate by the
Mous< Thymus: It, Relation 10 by
"liary IOpilbcli.1 Cell. and 10 Thymic Lymph,..
poeisi •. J. f:xp_Mea. 18: 927_49, 1968.
27_ CmUi . A. Vistou. Thyroid, P"rolh}-roIiI and
Thymus, Lea &: febig.,. Philadelph ia. 1938.
28. Csaba. G .. T6ro. I.. C. Ac •. T.. and Mold.
K. Thymus and SlrtlS. J. /Oml{J(:,in(>/. 1J: 423 -3 1.
1962.
29. Dea"". H. W .• ed. AdnrlOrorlitalllortnl>M•.
Spring.,N"I." Berlin . Par, 1.1962. Deane Ii. W.
and Rubin. B.• ed •. Par, 2. 1964, P." 3, 1968.
)0. Deave", D. R.. and Musacchia. X. J. The FunClion
of Glucocorlicoid. in Thermog...,is. FNi. Pro<:. 38:
2177_81. 1979.
31. Debon., A. F.oSiclari. E.. Do., K. C.• and Fuhr. B.
Gold T hiogluCQS<:· lnciuc<d Hypolhalamic Damage
and Obesity: Dependence on the Ad ..... 1 GI .nd.
110: 2024_9.1982.
32, De nckla. W. D, Inleracli"". bclw«n Age and the
Neuroend""rine and Immune Syslcms. F,d, Pft)(".
37: 1263-7. 1978.
B. Desroches. D.. and Marlin. C. R. Seawnal. Vi,.·
min D and Thymu. InOuence. on Renal Elccl rol),le
E,creli"" Pallern., fed. Pro<. 3913): 661 (abm.).
1980.
34. Do. V. S .. loos", D. S .. and Feldman. D. Hew ...
g" neily of GluCQCOrticoid Binders: A Unique and a
Classical De, amethaw"",Bi ndin& Site in /J.o.ine
Ti"" .... ;.:",j"",i",-,J. 1Il.1: 19H .
35. Dorfman. R. L. Vama .. ki. I.. ond [)Q.fman. M"
ed •. 8iogentJis dnJ Action of SUroid Hormonn
Geron·X. lo$ Altos. Calif., 1968.
36. Eisen.,ein. A. B.. cd. n. Adm",1 C"'rtx, liuk.
Brown, Boston, 19(;1.
37. Ernesl. M. J .. and Feige l""". P. Mul!ihormonal
Conlrol. of Tyrosine Ami ootran.ferue in Isolalcd
liver Cell •. Chap, 12. pp. 219-4 1 of B.. ,cr and
Rousseau. ed." II.
38. hum, J. H. R"8ulalion of Glucort«>g< nesi. by Glu·
cocorticoid.<. Chap, 28. pp. SH-46 of Ba.tcr and
Rou",cau. cd, .. refert..,e II.
39. Fachet,J .. Szabo. I, K.. and Cs<:h. G. Effect ofThy.
mectomy on Lipoprotein lipase Acti.ity in the
Serum and Hearl of RatS. Exp"i.nrj" 10 (708/: \-
3.1964.
40. Fachel. J., Vallenl, K., and Stark. £ . The Effect of
Thymectomy. AdrenaleclOmy and Olrticoid
ment on lhe Ser.m Hep.ri n L••el in th. Rat . Acta
Physiol. Acad. Sci. Hung, Suppl. T J6: 64-5. 1965.
41. Fain. J, N. Inhibition of Glucose Tran'porl in Fal
Cell. and ACli •• ti¢n of Lipoly.i$ b), G lucoc,,.,i·
coid •. Chap. 28. pp. 547---60 of B•• tet and Roo ..
s<:u. cd •.• 11.
42 . FeileliOn. P .• and Killewich. L A. Hormonal and
Developmental Modulation of Tryploph.n
aso mRNA. Chap. 13. pp. 243-SI of and
Rou«ca •. cd.,. r.ference I I,
43. Fer nex. M. SY'ltm. William. &;
Wilkin •• B.ltimote. 1967.
44. Ftaset. R .. Brown. J, J .. Brown . W. C .. Fen;",. J.
B.• Ken ned)'. A.. Lc.er. A. F.. Ma$Qn. P. A .. Mor·
ton . J . J" Nicholl •. M. G .. Ram .. y. L E .. Roberl·
$Qn. J, L S .• Schalchmp. M. A. D" and Wil..,n. A.
The Ad .. nal COrle. and Hyperten.ion: Som.
""""lion$ on" Possible Role for Mine",l"""rlicoid,
Other than Aldosterone. J. SU,oId BiIKMm. 7:
963_10.1916,
4 S. Friedland. J" Sctton. C.. and $ il.ersl"in. E. Angi.,.
ten.in C",,".rting Enz)'me: rnduction b)' Sl.roid. in
Rabbit AI.eolar Macroph.ge< in Cultu re, Sci. ",.
197: 64-S. 1911.
46, Ftiedm... H .. cd. Tn",,,u, Factors in Immunity .
Ann. N.Y. Mad. Sci ... ol. 249. 1975.
47, Fund.,. J. W.• Ouval. D" and Mc)'ct. P. Cordiac
Glucocorli.oid Receptor>: The Binding of Tritialed
Dexamelhason. in Rat.nd Dog H.art. End«'illCl.
93: 1300-08. 1913.
48. Gaunl. R.. St.inetz. B. G.• and Charlo J. J. Ph.t·
macologie Aheralion of Sleroid Hormone Funo-
tion .. Clin. & TM",p. 9: 6S7-81.1968.
49. Gelehrl ••. T. D. G1UCOCOtlicoid. and lhe Pla'ma
Membrane. Chap. 30. pp. S61-7 4 of Ba>!er and
Roo"e ••. ed." tefet .... II.
50. Gelehrlcr. T. D. Syncrghlic and Antagoni.tic Ef·
feclS of Glucocorticoid. on Insulin Act ion. Chap.
32. pp. j83-91 of BUler and Rou$$eau. odl .. ",f·
etcrlCe 11.
51. Goldfa.b. R, D.. Weber. P... nd 8 ,C'. J. E. Char·
of Cirell\ ",in, Shock·lnclllcod
odcprO<$ln' Sub,tances, F<d. PrIK. J7.. 2724_8.
1978.
52. Gold.l.in. A. L. and W hile. A. The Thymu. o. , n
End<)Crinc Gland: .. and 'heir ACli"" •.
Bi«htm. ACfions Harm. I: 465-S02. 1970.
Sl. Gold'lein.G"and Mad ay. L TM Human Thym •.,.
G reen. 51. loui •. 1%9.
54. Gomez·Sanchez. C. E,. HOlland. O. B.• Murry. II.
A.. lloyd. H. A. •• nd Mil.wich. L 19·Nor·Deo,l"
co.-tiCO$lerone; A Po,.n, Mineralocorticoid l<oI.,cd
from the Urine of Rats ,,"'ilh RegetlCral;ng Adr.·
nal., £ndlXrillol. 105: 70s- II . \919.
55. Gordon. S. Regula,i¢n of Enzyme Sec"'lion by
Mononucleat Phagocyte.: Sludi •• with Mac,.,.
ph,ge Plasminogen Acti • • ,oo- •• d LY$O>:yme. Fro.
Pro<, J7:2754-8. 1978.
56. Granner. D. K- The Role of GlUCOCOrtiCOid ••• Ri·
ological Amplifiers, Chap. 3l. pp, 593-61 \ of Box·
Ie' and Rool'.'u .• d •.• ref••• nce 11.
S7. Greenberg. L J ... nd Vuni •. E. J. Histocompatibil·
ity Det •• minants. Immunc R.spon.i.cneM ,nd
Aging in Man. F.d. Pro<, 37: I 258-61. 1978.
S8. Haglund. U.. and LundBten. O. Inlestinal r.. bemia
and Shoek FaOlo.... p,«, J7: 2729_)3. \978.
59. Hall . C. E.. Gom.z·Sanch." C. E .• Holland. O. B..
and N'<SClh. D. Influ."'. of 19.Nw·[)<0')'<:Orli.
costerOllC on Blood .. ure. Saline C"".umplion
and Ser.m Electrolyte.. CortiCO$I.ronc. and Renin
Ac\ivily, end«,;,,"i. 10':600-4. \979.
60. Halpetn. C. C .. and Martin. C. R. Effe<:t of M.la·
 tonin and Thymectomy On Food Intake and Ronal
bOrelion Rh),lhm. of Adr<nalectomized Rats.
Pro<:. 31.]27 (3MIr.). 1912.
61. H.ocox. N. M. Bio/OIlY Cambridge Uni-
versil), Pro.,. New Yor\:. . 1972.
62. Henkin. R. I. The Role of Adrenal Corlicosteroid,
in S.nsor)' Procc..... Chap. 15. p, 209-30 of
Blas>;h\:.o el al.. eds .. referenco 16,
63. lI.n""n. p, M. M.chani.m. of M.dialor Rd . ...
from Innammatory Cell'. Chap. I. pp. 9-50 of
Abramolf and L. Via. reference I.
6-4. Hood.l. E.. W.iuman. I. L. and Wood. W. B. Im-
mulKliogy. Benjamin/ Cummings. M.nlo Par\:..
C.lif., 1978.
65, Hoyle. R, M ... nd Il ochberg. R, B. En'ymatic Side
Chain Clc..ag. ofC·20 Al kyl and Aryl Analog, of
(20-Sj.-2I).Hydroxycbolo"erol. J. 8iol, Chern. 254.-
2278_86.1979,
66. J aanu •. S. D .. and Mart;n. C. R. An Eltra·Ad",n.1
Re.pon"" to Sodium I.oading Revealed by Th)'mec'
lomy. <I COII'f'O" I(J: 147_54.
1965.
67. johnSton. R. B.• Jr. Oxygen Metabolism and th.
Microbicidal Activily of Macrophagc>. PrO<'.
37.2759_64.1978.
68, Kapp. J, A.. Pierce. C. W.. ThOle. J .• and Ben.cer·
raf. B. Mod ul .. ion of Im mune Responses by Sup-
pressor T Cells, F.d. ["0<'. 37: 2361_4. 1978,
69. Kincl. F, A.. OrioL A.. Pi. A. f .. and Maqueo. M.
Prevenlion of Steroid-I nduccd Slerility in Neonatal
Rats "ilh Th)'mic Su'J>Cll$ion •. Pro<:, Soc, f:xp.
8iol. 1;0: 252-5. 1965.
70. Kovanen. P. T., Ba,u. S. K ., J. I..
B,o"m. M, S. Low Den.ity Lipoprolein Rccept(}fS
;n Bovine Ad",nal Cortex. I I. Low i)cll$it)' liP<'
protein Bindins \0 Membranes Prepared from
fruh Tissue, £nd""..-IKli. 61 0-6. 1979.
71. Kovanen. P. T.. hust. J . R.. Brown. M. S .• and
Goldstein. J. L. Low Den.il)' l.ipoprOlein Receptors
in Bovine Adren.l Cortex, I. Rcceptnr-Media",d
Uptake of Low Ocll$ity Lipoprotein and Utili7.ation
of 11$ Cbole$lerol for Sleroid S),nthe,;s in Cultured
Adre""""rtical Cells. £nd""riool. UU: 599_609.
1979,
72. Kraft. N" Hodgson. A, J .. and Fund ... J. W. (;Iu·
cocorticoid R.ocp1<>r a nd Effector Mechanisms: A
Comparison of the Cortic05Cn,itive Mou"" wit h Ihe
CorlicoresiSlanl Guinea Pig. Endocf inol. 104: 344 _
9. 1979.
73. K,a"'czak. J. J.. and Brodie. B. B. Effect of Adf<>-
nalcclomy and Complele Blockade of Adrenergic
Funclion on MOfla!;ly from Hi'tamine. Endotoxin.
Forma lin and Tou rniquel Slress in Rats, Pha,,,,,,"
co/. 3: 65-15. 1970.
74. Lefcf. A. M. Corlicoolcr<>idund CifCulatory Fune-
tion. Chap. 12. pp, 19 1_207 of Blaschko el al.. cd •.•
refer.""e 16.
75. Lefor. A. M. Pwperies of C.rdi<>inhibiIOfY hCIQf's
Produced in Shock. F<:d. PfO(. 37: 2734-40. 1978.
76. Le.y. D. A. Histamine and Sorolonin. Chap. 5. pp.
141 -6 1 of Wcissman. ed .• fefe"'nce 153.
77. Li. M. P .. Chan. T. H.. and Birmingham. M. K.
AnlihYJ>Crlensive ACl ion of 18.2I).C),cI,,20.2l-
Di byd roxy.4--pregnen-3-On.. A St ruel Uta IAnaiog" 0
of 18·H),droxydeo'ycorticoolerone. J. Sitroid Bic--
chern, 7:949- 51. 1976,
n . Liddle. G. W. T he Adrenall. Chap. 5. pp, 249-92
of Williams. ed .. ref.rence 155.
79. Liddle. G. W.• Hollifield. J. W.. SI.ton. P E.• and
Wilson. H. M. Effects of Various Adrenal Inhibi·
lot'S in L"",_Rcnin 8«:nlial Hyp-crlell$ion . J. SI ..
Told 7: 9)7-40. 1976.
80. Lieberman. S .. Gurpide. E.. Lipsett. M.•• nd S.I·
ha"ie\:. H. Steroid Hormo"e Secrelion. , Chap, 4.
pp. H_9 of G.-e¢P. R. 0 __ and Koblin.ky. M, A..
ed .. FTontitTJ in R'p'od"cIiOlt and FUlilily Con-
1,0/. MIT Pr.ss. Cambridge. Ma.s .• 1977.
81 . Lintorn·Moore. S. Elfeclof Athymia on th.lnilia·
,ion of Follidar Gro •.-th in Ihe Ral Ovary. mol. R ..
prod. 17: 155-61. 1977.
82. Long. J. A. Zonalion of Ihe Mammalian Adrenal
Cortex. Chap, 2. pp, 13-24 of Bla.chko et .1 . cd . ..
",f.rene. 16,
83. lwc\:.cy, T. D .. cd. Thymic \tofmone.<. Uni"ersity
Park P..... Baltimoro. 1973.
84. Malamod. S. Ultra",uclure of the Mammalian
Adrenal Corle< in Rel.lio" to Socrelnry Function.
Chap. 1. pp. 25-39 of lIbschko .1 at. cd ... ",fer·
onee 16.
MarSOlis. R. N .. Garfield. S. A.. and Cardell. R. R .•
Jr. EIf.. ts of Glucocorticoid.on Mic,osom.1 Mem-
brane Synlhe.i, in Hepalocyte. from Adrcnaloctc--
mi:ted Rats. £ndoc,ilWl. /04: 1722-32. 1979.
86. Marti,l. J, A.. Soeburg. p, H.. Malulich. D. T ..
GOOIl m.n. H, M .• and 5aXlcr. J. D. Regutation of
Growth Hormone M.... ng.r RNA. Chap. 15. pp.
279_89 of Baxter and Rousseau. t<l •.• reference 11,
87. Martin. C. R, Adrcnocotlicallnfluenee.on Oro"'lh
of Repnxluolive Sltueture. of Thymeclomi,.ed and
Sham Thymectomized Rats. 75: 161-
72.1964 ,
88. Martin. C. R. I nfluenoc of Thymcclom)' on Growlh
of Sooondary ReprO<iuclive Structures in Rats. A",.
J, Physiol. 206: 193-7. 1964.
89. Maftin, C. R. Thymu. Gland and Heparin Influ·
enee. on Ren.l Electrolyte E.cretion in M.1e
Hooded Rats. Gen. & Compar. End""Tiooi. 1$:
339-51 ,1 970.
90. Martin. C. R .. . nd Desroches. D. T h)'mus Oland
InRuence. on Calcium and Phosphorus Metabolism
and on Re,po"",s 10 Vitamin D Admini"ralion.
hd, Proc. 36: 296 (aM".). 1977.
91. Marlin. C .. and Lehr. D, Interrelationship of lhe
Thymus Gland. Oonad. and Adrenal Cortex in Ex·
perimenlal Cardi!)v•• c"l.. Necr""i •. Abslracts of
lhe Twenlielh Inlernalional Physiological Con·
gfe ... Bru=ls. 1956.
92. Martin, C. R .. Rosoff. B.. and Miller. l. K, Effect
of Age On the Ven".1 Pn)!.lato Oland ReSpOnses 10
Thymeclomy. PhYJiololIiJIIO: 243 (aM".). 1967.
93. Martucci. C. P.• and fishman. J. Impact of Contin·
uousl y Admini"ered Catechol Estrosens on Utef'
ine GrOWth and Luteini,ing Hormone Secrelion.
£ndocTilKli, 1M: 1288- 92. 1979.
'"
9 4. Mason. J. I" and Hcmsell, p, G. Cb<llest.rol Sulfale
Mel.botism in Human Fetal Adrena l Milo<lIon·
d ria. EnliQCrifl(>/. III: 208_13. 1982 .
95. Mayer. M.. Gailli. U.. and K.i,.,. N. Intracellular
Prole.", Acti. ity in GluCOCOrtiooid· Mediale<! Thy-
mol),i$, EMoulllOl. 110: 2131 1982.
96. McEwen. 9 . Influences of Ad",noc",",ic"i Hor-
m.,., •• on Pituitary and Brain Function. Chap. n.
pp. 467_92 of But., and Roo ... au. eds .• r.r... "".
"
97. MeirlCk., H. A .. and Feleppa. A. E.. J r. Incn:a<e<I
Erythropoietin U .. is in Serum of Rals with Trans-
plant< "'" an Adrenal C<>rlical C. ",ioom •. Pro<.
Soc. Exp. Dim. 118-944_8. \968.
98. Metcalf. D. Tht Thy",,, •. Springer'Yerlag, New
York, \ 966.
99. Mich •• I. S. D.. Taguchk 0 .• and Nishi,"" •. Y.
Chang.. in HyPQpby$<al lIormonc:, Associated
wilb Accelerated Aging and Tumorigene.is of the
Ovaries in Neon.tally Th)'mCOtomi,ed Mice. ErI-
doc,;IIQ/. 108: 2375-8(/.1981.
100. Milner. A. J. ACTIi and the Oirrerentiation of Rat
Ad ... nocortical Cell' Grown in Primary Ti .. uo Cui·
tu .... Endoe,ino/. 88' 66-7\. 1971.
1(11. Mondor. C. and Bradlow. II. l. Cortoic Adds: E.·
pIO'"tion, at the Prontier of Cortieosteroid Met.t>-
oli,m. Prot. lI()I"m. J6: 345-92. 19S(I.
1(}2. MonU. D. J., T .. i. R., and DeConti. G. A. Regu-
lation of Pla,ma Lovel, of Aldosterone and its Me·
tabolites during the Latent Period of Aidootemn •.
J. Sruoid Bjoehmt. 7: 971-8. 1976.
1(13. Munek. A. Tho Interfacial Acti'ily of Steroid lior·
mone. and Synthetic Estrog.ns. Biochim. B;ophrs.
Acta 14: S07-1 4. 1957.
104. Munck, A.. and C,abu.e. G. R. Glucocorticoid·ln·
duced Lympho<:yte Death . Chap. I I. Pl'· 329-359
of Ilowen. I. D .. and Lock.hin. R. A., .d.
£He/h. A$$o<ialed Book Publi,h .... London. 1981.
I(lS. Munck. A.. Crabt"' •. G . R .. and Smith. K. A. Glu·
c<>OOrtiooid Reeeptor$ and Action, in R.. Thymo-
cyl<' and Immunologically Stimulated Peripheral
Lympho<:yl<s. Chp. 19. Pl'. 341_55 of Ih"er.nd
Rousseau •• d •.. refcronce II.
1{)6. Murray, D, K.. Ruhmann.Wennoold, A .. and Nel-
son, D. H, Adronalectomy Dccrea.e. Iho Sphingo-
myelin Content of Fat Cell GOOm. End"",jllQ/.
III: 452- 5, 1982,
107. Murray. D. K.. Ruhmann·We nnhOld. A.. and Nel·
son. D. H. Dcum.th."""e Err""l on lhe Phospho-
lipid COntent of Isolated Fat Cell GhOSt1 from
Adrenalecl<>mi1.cd R." , /:'·ndoc"IIQ/. 1M: 774_7.
1979.
108. Nolson. W, O. The Rclalion olthe Thymus and Pi·
neal Gland. 10 Genil.l Funclion. Cbap. 21. pp.
1 ! 21-48 of Al1en, E .. ed. Su: In"",,,1 Stat-
r'()II$. Williams&: Wil kins, I!.altimQre, 1939.
109. Nishizuka. Y.. Sakaku ... Y.. Tsujimu ... T .• and
MatSum(>to. K, SterOid BiOll)'nthcsi< in vilf(J by
DY'ienic Ovaries Induced by Neonatal Thymoc-
tomy in Mice . End"",j""', 91: 786_92. 197).
THE GlUCOCOOT1C01D$
110. Page, I. H. Stf(JI(N! jn, Book Medical Publi·
calions. Chic_so. 1968.
I I I. Parrillo. J. 13 .. and huci. A. S, Mechani,m, of Glu-
cocorticoid Action on Immun. Proc.sses, Ann, Rn".
Pha,mlU'Oi. Toxj,."l. 19: 119_201. 1979,
112, Paul. S. ,1.1 •• and A.elrod. J. Catechol Estrogens,
Pre.ence in and Endocrine Tissues,
197:657-9.1977.
113. Pie'l'"Oli. W.. and Sorkin. W. Aheral i"", of Adre-
nal Cotte, and Thyroid in Mic. wilh Congenital
Absenc. of the Thymu1-
282-5.1972.
Bj()./. lJll:
114. Pi...... F.. Gagliano. P.. Motta , M., and Martini, L.
Adrenal Pros.. teronc: Flctors Controlling it1 S<:-
.... tion. Endocrinol. 93: 1178_8 4. 1973.
115. Plagge.], C. The Thym., in Relalion 10 Se, Itor·
moFlCS and Reprodocti .. P""'e= in tOe Albino
R.I. J. Morph()./. 68: 519-45.1941.
116. Ramey. E. R. COrliCQIteroid."nd S kelclal Muscle,
Chap. 17. pp. 245-61 of Blaschko et .1.. eds .. rd·
ere""o 16.
111. Rhod in. J, A. G. l/isrology. Oxford University
Pross. New York. 1974.
118. Rocklin. R. Human L.ukocyte Inhibitor)' FaOtOr
(LlFJ : A Lymphocylic MedialOr with E"eratic
Properties. Ft d. Pro<". J7: 2143- 7.1978.
119. Roe.el. C. E. Immwn%gy. McGraw-lIill. New
York. 1978.
120. Rogd. S .. and HilewilZ. 11. Cardiac Impairmenl
and Sho<:k Faclors . Fd Pro<". 17: 2718_28. 1918.
121. Roper. M. D.. and Wick<. W, D. E,idence for Ac-
ocloralion of Ihe Rale of ElongatiOn of
inotransferase N .... nt Chains by Dibutyryl Cyclic
AMP. Pro<". Norl. Awl. Sci. USA n · 140-4. 1978,
122. Rosoff. 9.. and C. R. Martin. T he lnfluc""e ofThy-
meclomy and Sham Operalion on Prostate Gland
Response. of liooded Rats 10 GOnadolropin •. Gm
& Compo', EnJ"",'no/. 484_92. 19,1.
123. Roth, G. S .. and Uving"on. J. N. Di5SOCiation of
Glucocomicoid r nhibilion of Glucose T ran.pert and
Metabolism by Inc ...... in Adipocyte Ago and/or
Si,.<: . £ndlX';no/. 1Q4:423_8. 1979.
124. Robin. R. P. Calcium·Phosph<>lipid InleraCl ion, in
Sc<:rclory Cells: A New Pe1'lpeelive on Stimulus·
Secretion Coupling. Fro. Pro<", 41: 2181-7. 1982.
125, RU$$<Il. J. A .. and Wilhelmi. A. E. Physiology of
the Ad ... nal Co"e • . Chap. l. pp. 1-45 of Lukens.
F. D. W.. cd, UJ.. BlakistQn.
New York. 1954.
126. Sadler. A. M.. Sae kle r, M. D.. Martin . C R.. and
Saokler. R, R. Thymectomy and Hislamine T<>Ier-
ance. Pro<", 12: )63 (almr.). 1963,
127. Samuel •. L. T .. and Nelson. D. 11, Biosynlhesi. of
CortiOO$tcroid •. Chap. 5. pp. 55-68 of Blaschko et
al. .• d... reference 16.
128. 5o'pagnini. U.. and Seouo. P. On lbe Correlation
bel,.een En>yme Induction. Anti.inflammatory and
Thymolylio ACli, it}, in a Fa<t.Actin8 .n<! Lon,.
Acling Bet.metha""ne Esler. 1'h,,'mlU'Oi. J: IU-
21. 1970.
129, Sche.ing, L E.. Halberg. F" and Pauly, J. E-. cd •.
Chronobloiog)', Igaku Shain. Tokyo. 1914.
130. Schlatman n. R. J . A. F. M.• Jansen. A- P.. Pre",,".
H.. and Majoor. C. L H. The Natriu,etic AClion of
Heparin and Some Re l.led $"1>$"11«$. Lo""r I:
314_17.1%0.
131. Sehocnlt, E.• Zapf, J.. and Fnxsch. E R. Tran,porl
and Metaboli,m of Frocl"'" in Fal Cel l. c.r No,m.1
and HypophyscCllHni..d Rats. Am. J. PhJ'slol. 137__
E125-EHO.19,9.
132. Sh ield', J . W. Trophic Fun<rian of rM Lym-
phoid Thorn.,. Springfield. III .. 1972,
133. Silverberg. J.. and Volp<. R. AUlGimmunily in En·
docrine Di..a .. , Chap. II. pp. 345_86 of (ngbar, S.
H.• cd. Yt", in EndO<;rillhiog), 1977. Plenum,
New York. 1978,
13 4. Singer. S . S. Sulfarion of SI<roid •. IV.
Conlrol of Ihe Hepatic GlucocorticGid Sulfor,"n ...
f",.", Aclivily and tho Individual GlUCOCOrticoid
SulfOlran,fcrase. from Male and Female Rals by
Adrenal Gland. and CorliCO$leroid •. EndO<"rlM/.
/OJ: 66-73. 1978.
I H. Sin8er. S. S .. KU"tr. T .. and I.ee. A. h,.ym.tic
Sulralion of Sieroids, VI I I, Control of Hepalic Cor-
lilOl Sulfalion and Gluoocorlicoid Sulro<r.. ,rc...."
of RalS by Ihe Piluilary Gland. Endoc,fM/, 1()4:
S71_S. 1979.
136. Singer. S. S .. and Syl'csler, S, Enl}'malic SulraliM
or Sleroid •. II . The Conlrol of the Hepa,ic Corlisol
Sulfetran'f..... AClivil)' . nd of Ihe I ndividual
potie Steroid Sulfolran,rera.., of R.tS by Gonad.
and Gonadal Slimulalion. EndocTiltOi. 98: 1346--52.
1976,
131. Singhal. S. K .. Rod<r,J. c.. "nd Duwe. A. K. Sup-
presSOT Cell. in Immunostnesccno< , P"x. 37:
1245-52.1978,
138, So'g. c.. and Klinkert. W. Chemic.1 Ch.raCl.. i,.a.
lion c.r ProdUC1 ' of ACli .. led LympOocYles. Frd.
Proc. J7: 2748_53 . 1978.
139. Spain. D. M. Conkooleroid.<. Inflammalion a nd
Connecti,'e TiMuc. Chap. IS. pp. 263-70 of
BTuch ko el al .. ed,., ,"ferenee 16.
140. S,a lm.ns. W .. and Lalo.... M. G lueoc(>rli<>:.>idsand
Hepolk Glycogen Melabolism. Chap. 27. pp. 51 7-
n or Baxter and Rousseau. cd . .. refer.nee I I.
141. Sleinbe'g. R, A.. and I.arie. R, D. Pool1ransc,ip-
lional Regulalion of GlucocorJicuid·Rcgul'led
Funclion" Chap. 16. pp, 291_31)4 or BUle, and
Rousseau. ed •.• refcrence 11.
142. Stroll. C. A .. GoIT. A, K.. and Lyon •. C. D, Func-
tional DiIT,,"ne« Bel"een lhc OUler and Inner
Zones of the Guinea Pig Adrenal Corlex.
noI. /09: 2249_51. 1981.
143. Slumpf. W. E.. and S ... M. Sleroid Hormone T ..-
Addilional reference, added in proor will be (cmnd on page 893.
gCI Site, in Ihe Brain: The DiITe,enlial DiS\ribUlion
of Estrogen. Prog..,in. Androgen .nd GIUCOCO'li·
"a ileroid. J. Biochcm. 7: 1163-70. 1976.
144. Teilelbaum. S . L.. Malone. J. D.. ond Kahn. A. J,
GluCOCOrJieOid Enhancement or Bone Resorplion
by Ral Peritoneal Macrophage. in Vilro. J::ndoctl-
ItOl 108.' 795_9.198\
14S. Thompson. E, B. G lucocorticoid, and Lysosom ...
Chap. 31. p, 5S-81 of Baxter.nd Rou>$Cau. eM.
rererenee 11.
146, Thorn. G. W .. Jen kin •. D., Laidlaw. J. C. GOOI1..
F,C .. Dingman. J . F.. Arons. W. L.. Stnxlen. D. H.
P.. and McCracken. S. 1-1. Pharm.colOgica l A,pcel>
c.r Adrenocorticalliormones in Man. and lhei' Er·
Adrenal In,uffieiency. Chap. 2. pp. 46_176
c.r Luken •. F D W.. cd . Uu s
SlakislM. New Vo'k, 1954.
147, Travis. R. Ii .. and Sa}'.... G. Adrenocorlicotropic
Hormone; Adrenocortical Sieroid, and their Syn.
lhelic Analogs. Chap. 27, pp. 1608- 48 of Good·
m.n, L. S .. and Gilman. A .. cd •. Tht Phormocolog-
iral Bo;i, of TMrop'ufir,. 3d ed , Macmillan. New
Vork.1965.
148, Uhlenhuth, E, Furlher Proof of the Exi<lenee or 3
Specific Telan)" Producing Sub'lance in lhe Th)".
mus Gland . J. Phy<ioi. I : 33-6. 19 18.
149. L.:lick. S .. levine. L. S .. P.. 7..;1neon",0.
G .. Ramirez. L c.. Wolfg.ng. R.. Rosier. A.. 8rad·
low. It l.. and " ew. M. A Syndrome or Apparenl
Mineralocorti<>:.>id E«e," wilh Defect> in the Pe-
r;pheral Melaboli.m Qf Cortiro!. J. Ciln, t 'ndlX,i_
noI. Utlab. 49: 751-64. 1979.
Ulid. S .. and RamiTe'.. l . C. Adrenocortical Fae·
tors in Hyp<rlen,ion , I I. The Signif,canceor 16--0.-
ygen>led CI9 Sleroids. J . Surold 7:953_
61. 1916.
l SI- Underwood. L E .. and Van W}');. J. J, Ho,mQnC$
in Normal an Abc".nl Growlh. Chap, 28, pp.
j 149_91 of William•. cd .. reference IH.
152. Weigle, W. 0 .. and Parlos. E. Effcci of Aging on
Immune and TQleranl Sla'cs. Ftd, PrIX. J7.- 1253_
7.1918 .
153. Weir.sm.n. G .. ed. oflnj/om"'OIiOll .
Plenum. New York. 1974.
I S4. Wwphal. U. Sinding or COrtieO<leroid. by Plasm.
Protein•. Chap. 9. pp. 117-25 c.r Blasch ko 01 al.
cd, .. reference 16.
155. William •• R, II., ed, Tt Xlbook of F.ndorc/noioty.
Saunders. Philadelphia. 1981-
IS6, Zbu7.kova. V.. and Kincl, F. A. The Inftucnce of
Thymcclomy and Ste,oid Hormones in Neonatal
RalS. PI"Q(. Soc Exp, BioI. M,d. /3j: 874_7. 1970.
IS7 . lurieT. R. II. P""laglanrlin. , Chap. 6, pp, 163-80
c.r Wei" man, cd .. reference 153.
 7
Adrenocorticotropin and Corticotropin-Releasing Hormones
Adrcnocortkotropin (ACTH) promotes growth and
spec iali zation of Ihe cells oflhe wna fa%icula\3 and
wna reticularis of the adrenal cortex . It is needed on
a regular to maintain the si,.c. finc slruclure,
cn'.ymc components. and ",<,cr"tory funclions of
those regions. When presented in high dosages. il
acutely augments glucororliooid secretion byaccel-
erating steroidogenesis. blll il probabl y docs no!
exert important influences on the discharge of pre-
formed hormone. Although the cells have :1eclron-
dense ori3nelles (95). they lack "true" secretory
granules and they therefore store very liUle of the
final prooucls.
ACTH also transiently stimulates the zona glom-
erulosa. but the long-range efTeCtS are mostly inhib-
itory ( I,S,39). In fact. studies of cultured e<:lIs sur>-
(Xlrt the concept that ACTH can promote
transformation of glomerulooa cells into ones resem-
bling the kinds found in the fasciculaUHeticularis
zones (72). Animals chronically depri.e<! of ACTH
can maintain reasonably good electrolyte balance.
The physiological im(Xlrtance of can be
appreciated from oi.«rvati()lls of the effects of hy_
(XlphySCCtomy. It should be (Xlimed out. howe.er,
that adrenocortical functions are affected by several
regulators. Some are produced by the pituitary
glands. and the secretions of others are controlled by
pituitary hormones other than ACTH. The pituitary
gland also contributes to the maintenance of nutri-
tiOMI status. Therefore. hY(Xlphyscctomy cannot be
equated with simple deprivation of ACTI-!.
The adrenal cortices of untreated hY(Xlphysecto-
mize<! animals undergo involution. loss of the ability
to secrete glucocorticoids in quantities that sustain
metabolic balancc. and reductions in the numbers of
ACTH receptors. W hen ACTH is then presented.
the forst detectable effect is augmented blood now to
the adrenal gland. Soon a fterwa rd. the cell' begin to
aceelerate their rate, of cholesterol, glucose . and cal_
cium uptake from the surrounding Auids. Some in·
creases in steroidogenesis follow.
ACTH stimulation of R NA and protein synthesis
become apparent after approximately 3 hours. The
neW molecules indude enzymes nse<! for Ihc produc-
tion of glucocorticoid, and new hormone receptors.
One consequence is sharpened sensitivity to ACTU
presented at a later time.
After prolonged exposure to ACTH. 1.ona faseic-
ulata-reticularis cells undergo morphological
The mitochondria and the tubular
cristae of the unstimulated cells aSSume vesicular
forms as the enzyme oontem increases. The effects
Can be bloc ke<! wilb chlorampbenicol (an antibiotic
that impairs protein synthesis in mitochondria but
does OOt act On cytoplasmic ribosomes). Lipids aC-
cumulate in cytoplasmic droplets, and the smooth
endoplasmic reticulum becomes more elaborate.
Since the ACTH-sensitive regions normally acoount
for the bulk of thc structures. the gland as a whole
increases in size and weight when Ihe cells undergo
growlh. T he enlargement is evident within one day
after the first exposure to ACTH.
ACTH REGULATION OF STEROIDOGENESIS
The production of.glucocorticoid, requires the c0-
operation of several cell oom(Xlnents. Certain of the
dfeets of ACTH can be demonwated for iSOlated
mitochondria. but only when the membranes are in-
tact (l07) . Supernatant fractions taken from stim-
ulated cells can act in vitro to accelerate hormone
production (75A).
Acq uis ition snd Binding of the Precursor
Cholesterol that is delivered by li(Xlprotein particles
of the blood plasma serveS as thc major hormone
precursor (52). ACTH facilitates precursor upta ke
by ae<.:eierating blood flQ'" to the gland. and by e,-
erting inftuenco:.s on the plasma membranes thaI af-
fect transport. On a long.ra nge basis. It increases the
formation of lipoprotein receplon (34). When the
bIo<.ld dQeS not supply adequate amounts of eholC$-
t.rol. ACTH also induccs enzymes that
production of the molecules from aeety!-CoA. Under
normal conditions. much of tile cholesterol is used
for steroidogenesis. and OIlly limited quantities arc
stored. Prolonged. Io.... intensity 5limulation by
ACTH can augment lipid a«umulation: acute.
SlronJ slimuloltion uwally dcpl¢les the 1'CS(:fYeS.
Aminoslutelhimide permitS the cens to take up or
synlhesize ehOleslerol, bul it blocks the to
hormones. In ils pl'CS(:I\CC, ACTH promotC:S choles-
terol acwmulltion (66).
The lipoprolei ll$ deliver mosdy cholesteryl csters.
bUI the mitochondria can use ooly frtt cholcstcrol.
ACTH may somewhat increase the activities of cho-
Iestc,)'1 cstcrascs. but a different hormone made by
Ihe same pituitary gland ceUs is a more impol1anl
lctivllor (6.8JA).
The cholesterol muSI be tralllOporlo:d to tile inner
membrane of Ihe mitochondrion (13), and it is be·
lieved that ACTI I aeccle ratu the process by in·
creasing the Icvcl s of a carrier protein (107),
Although long'Tllng. influenco:.s can inV(llve induc·
lion. the aCute effects of ACTH on mitochondrial
accumulation of cholesterol ore oot alTcctcd by ac·
tinomycin D. Therefore. the hormone probably ac·
livales preexisling molecules.
W ilhin minutes after ACTH is presented to ceUs
previously deprivo:d of Ihe hormone. the binding of
cllolesterollo the mitochondrial c)·tochron><:
cnzyn><: syslcm accelerates. Tile pl'OC\:$! is
TIlle-limiting for cholesterol cl¢avage, and thercrore
for sieroidogenc:sis. ACTI I drectS the en1.yn><: .ctiv_
il)' only illdi",etl),. by faeilitat;n, the: bind·
ing( l lO).
The rapidity with which the bindinll occurs. and
lhe obscmot;on Ihal tile r<:SJlOIIK can be blocko:d or
";th cydohuimide (bul not "'ilh aClino.
mycin D). are cons;stenl with the propoKd 5limula·
lion of lhe produelion of a labil¢ prote;n differenl
from the cholesterol carrio:r. wl'Klse synthesis is di.
rected by a siable mR NA . A basic peptide ",ith a
molecular weight of 2200 that build, up in the cy_
toplasm and aC1$ directly on isolated mitochondria if
NADPH iJ prc$Cnt, meetS tile q\LI.liflCation! of the
hypothetical medialor (83). It can be: distinau isho:d
on the basis of size and heal stability from a previ·
ously described peptide of 3500 daltons that accu-
mulates in stim ulalo:d cells.
Th. bindin, cln be monitored in both intact c:etu and
isolated mitochondria. since it i ••• Klcilled with chan80S
in uhn.ioIettightabforption panernslnd in the electron
parama,nenlie reSOnance (EPR) ,i,nat gener. ttd by th.
iron CQmpOn<ont of th•• CQmp\e. (n), When mi-
t()Chond,;", taken from zona fasciculatl cells of I\CTH·
deprived "nim.t. are prc<cntcd with .holesterol. they do
not .how th. rapid changos choracter;'tic 0( O<lanelics
from <XlIItrol:s. and . hey do I'lOl rapidty
deave the chol .. tcrQ\ .
ROLes OF CALCIUM IONS, MEMBRANE
PHOSPHOLIPIOS ANO PROSTAGLANDINS IN
STeROl OOGeNeSIS
Extracellular Ca l - docs not SCCm to be absolutely
c:ssc:nlial fOf ACTH bindi", to IIIe rt«plOfS on Ihe
plasma membranes (48.1 18). bUI Ihe prcsc:ncc of
chelatOT'S in the utracellular fluids ean impair t he
process wilen the hormone ronccnlralions are low
(8).
Afler the binding hiS oc/':urred. utracellular Cal-
is for Ihe stimulation of steroidogenesi5. If
the iort$ are r.mo....'d after ACTH stimulation has
begun, glucocorticoid productioo falls oft' sharply. 11
can be rcslOfed by replacing th. Ca" only if ACT H
is concomi tantly (presumably because lhe
hormone is to promoIe uptake). Supra-
physiological concentrations of extracellular Ca",
and calcium ionophores such as A 23187 8iven in
combination ",ilh physiological oonce ntrations. C(In
accelera te stcroidogcfIC!is in the absencc of ACTH .
Some of Ca ' - an> oMrtcd on tho
membranes (26.95). One of thc earliest is dosc.<Jeo
pendent activalion of a ealcium.<Jependent
lipase A,. Although il can affecl Other membrane
lipids. the enzy!TIC acts preferenlially On arachidon-
alNieh phosphalidylinositols (P Is). and it eataly7.es
lheir cleavage 10 lysophosphatidylinositol and free
arachidonate. Some of IIIe libo.:ratcd fa\l)' acid is
used to ma ke proslaglandirt$ ( PGs ). bUI much of it
is ",incorporated inlO ne'" PI (94). Tile Ca' - c0n-
centrations influences tile rates of PC s)·ntllcsis.
Phospbolipa.se A , facilita tcs lranslocalion of
membrane-bound ki""", C to the cytosol. aetivalion
of that enzyme. and general ion of its calal)'tie prod.
UCI. kinase M (A·IO). L)'SOIipids and arachidonatc
a ffect membrane Huidily. and both may be inYOlved
in the opening of calcium channels and in the f\lsion
processes associated ",ilh sleroid hormone
The vasodilator activities of PCE, and PC I, proba-
bly contribute to ACTH augment.ation of ad",n.1
blood flow. but many Olher vasodilator'S do IlOl I.e-
eelerale hormone: synlhesis. ACTH also increases
prodUClion of pc; F:.. which is a vasoconstrictor.
When ACTH is prcscnlcd 10 adrenocortical cells.
PCE,and PGF,. production raleS Can increase up to
IHoid within minuto:.s (63). Although they alTcct
membrane permeabilitics. Ihe PGs probably exerl
their important actions inside the cens. Exogenous
PGs ean directly a=lerate steroidogenesis in th e
 ADRENOCORTICOTROPI N ANO CORTICOTROPIN-RELEASING HORMONES
absence of ACTK (2\). Indomethacin. ETYA (oi·
cosalctrayooic acid). and other inhibitors of PC
synlhelase blun! the resroniC!; to ACTK . Chlor-
promazine. p-bromophenyl acylbromido. and other
inhibiwrs of the phospholipase A, simultanoously
depress PI arachidonate \Urnover and the steroido-
genic responses to ACTK (104) .
Cyclic nucleotides Can stimulate steroidogenesi, in
the absence of ACTH. and they promote PG syn·
thesis. It has been reported that PGE , elevales
cGMP levels promptly. and cAMP concentrations
after 15-30 minutes (34). The nucleotides and PCs
may W<lrk together to support ACTH stimulation.
but neither seems to be absolutely essential. NPS-
ACTH is an a-nitrophenylsulfonyl derivative of
ACTH that imitates the actions of thc pituitury hor-
mone on PG production and steroidogenesis. but it
doe>; not increase the cAMP levels. Its effects on glu-
cocorticoid secretion are only partially blunted by
PC synthetase inhibitors (63). Moreover. thc ability
of PGs to promote cAMP generation may be rC-
stricted to the 7_ona glomerulosa (108) .
usually either lowers cAM P levels or has
00 cffcct on them. Sevcral "growth factors" that pra-
mote proliferation of cultured cells (including insulin
and fibroblast growth factor) promote PGFt, gen-
erntion mol""ule< pby ""me
roles in adreoocortical cell renewal. can Con-
tribute to maintenance of cell size after hypophysec-
tomy. but it docs 001 promote growth [93J .)
Although PGs affect the secretions of other pitu-
itary hormones. theydo not seem to function as stim-
ulants for ACTH . Contribution. to the regulation of
cortiootropic releasing bormone nave been ,uggested
(58).
It is virtually certain that calcium ions act intra-
eellularly. ACHI aceclerates Ca' - uptake across
plasma membranes (91) and aCross the membranes
of microsomal vesicles taken from the adrenul glands
of hypophysectomized animals (62). It facilitates in-
traceHular translocations of the ions. and it increases
Ihc calcium content of the mitochondria. It also pro-
motes localization of calmodulin (a major calcium-
regulating protein) to the nucleolar regions of the
cells in a manner consistent with influences on RNA
biosynthesis (37) . Since chlorproma1.ine binds to cal-
modulins and thereby impairs their functioIlS, it. in·
hibitory influences on steroidogenesis may be ex·
eTled at mu!tiple sitos.
Ca" alone can acederalc cholesterol side-chain
cleavage when il is presented to mitochondria laken
from ACTH-deprived animals. High cholesterol
concentrations also stimulate. and the ion s enhance
their cffeelS. The mitochondria from ACTH-pre-
treated animals are much less affccted by the addi_
tion of Ca'· . probably because they already have
high calcium contents. However. even for these. it i.
possible to demonstrate calcium<holesterol s),ner-
gi sm (110).
Calcium ions also increase the rates of mitochon.
drial oxidation of substrates other than cholesterol.
and they have potent influences On mitochondrial
IIJl-hydroxylase aClivity. It has been proposed thaI
Ca" promotes dissociation of reduced adrenodoxin
from adrenodoxin reductase and reassociation of Ihc
oxidized form with that enzyme (60).
Unrelaled effcels exerled on plasma mcmbranes
may be essential for u/eo5t' of the steroids . When
isolated glands arc perfused with ealcium-deficient
media that contaiM ACTH, Ihe hormone conlent of
the cells increases (41 ).
Roles of Cyclic Nl,lcleotldes
In many cell types. moderate concentrations of Ca'-
act in conjunction with calmodulins to increase ad-
enylate cyclase activilY. Higner ones interact with
the same protein to augmenl cyclic nucleotide phos-
phodiesterase activity. and sometimes also to innibit
the cyclase.
Similar proc",,,,, seem 10 o!",r"e in .drctlO<"OTli_
cal cells. Within the low-ta-moderate rangc of Ca"
concentrations. cAMP generation is accelerated _Su-
praphysiological levels of the ion depress cAMP
accumulation.
cAMP probably exertS SOme of its effects by pro-
moting mobilization of Ca l< from intracellular se-
questration sites. It can accelerate steroidogenesis in
tne absence of extracell ular ion . Interactions "'ilh
Ca H may be needed for its roles in promoting hor-
mone release from tne cells.
Several findings arc eonsisten! with the COIlcept
that cAMP functions as the "seeond messenger-' for
ACT H. First . the need for a second mcs.<;enger is
consislCnt with observations that ACTH exeTlS its
characteristic effects when it is prevented from en--
tering the cells (e .g .• when it is diazotil_cd 10 p-ami·
ooben7.O)·1 cellulose [!03J. Second. when presented
in high concentrations . ACTH exerts dose-rc1atcd
stimulation of cAMP generation. and the binding
curves for a labeled analog rarat\cl Ihose of adenyl-
ate cyclase stimulation (9). Third. cAM P. its ana-
logs. and phosphodicsterase inhibitors all mimic
many of the act ions of ACTH_ Fourth . adrenocorti-
cal cells COIltain cAMP.,jependent protein kinases
thaI are activated by thc hormone_ Fifth. mutant
cells maintained in culture show parallel losses of
prolein kinase activation and of steroidogenic re-
 sponses to ACT li (88). Si11h, phosphofylations of
cdl components follow ACTli presentation. ThCiC
include ribo&omal protei'" that may cootribute lO
tM formation of Ihe labile proIein already men-
tioned ('.II). lbe cytochrome P-45Qs (88) needed for
steroiqenesis. and po:!Sibly also ellolcsleryl ester-
ases. finally. ACTH promotes glycoge nolysis in Ihe
ad renocortical cells of al leasl some spc:cics.
Ol her fin dings are less convincing. Physiologica l
concen lrations of ACTH can steroidoge n-
esis .... ilhoul bringing abou l deleclable increases in
cA MP When adenylale cyclase;s obviously
act iva led. accu mulation of the does not
0"lC0' nrily pre«de (and often follows) 0Mc\ of the
steroiqenic response. Moreover. as noted. N PS-
ACTH is sierotdogenic but it has lillie intlucnce On
adenylate cyclase.
Since only high concentra tions of ACT H seem to
promote cAM P genc ra lion. il oce n proposed
that the hormone m oSt interact .... ith "spa re" recep-
tors 10 e licil Ihe effects. Therefore. Ihc nuclco!idc
may be involved only during limes of stress and
olher ronditions associaled ...·ith Slrong stimu-
lalion of the adrenal glands.
loIo"Cr conccnu-atio", promote Ca-dcpc:ndcnl ae-
tivalion of guanylarr C)·clase . Thc edb contain
eG MP.(\epc:ndent kinases implicated in production
of the labile prolein req uired to s limulate ste roido-
genesis H igh concen lralions of ACTII ca n
lower the cG MP le,·els. probably via augmenta tion
of the phosphodieslerasc activily (86).
THE GL YCOGENOl. YSIS HYPOTHESIS
eA MP-depe"""'" kin ......, e impona." .e. i",,·
Ion or llrcosenoiylic in liver. musck. and ...".
I. in Olhe, pam all he body. The IluC«otlicoO:!·..,.relinc
cell. of some .pecie. w .... •ub$lanlial 1100II"10 or glyco-
gen. Ind Ih. p<>1Y""cch. ,id. level. dcdine "'hen ACT H
"rongl)' l1im ulale •. Since the liber.led glueo>e-P can
prO'Iide Ik. ATP. NADH. and NADP H nced<:<l rer . Ie-
il hI. been provad lhal phosphoryta"" ae-
li •• lioft is • majot eompone'" of CA M P "im.. lal;oo.
SUgeo.I lhal Ikis ,ile of ac'ion is
or limiled im"",tan«. ACTH does IlOl , .. bsllnlially au*,
menl ,IYCOlenolYsU;n .... ny.pecies., Ind il .. n promote
.le'oidoat .... i. in gl)'COtCn-dcpkled •• n.. M<lR:O<'er.
major eontrot. over slycogc n dc'nldalion in lite adrenal
COtI • • arc ..etled <HI pho<ph<>rylase pho<ph.,ascs . .... ' her
Ih. n on Ihe phosphorylase kin.se (l8). It h .. a"o bc<:n
pOinled 001 Ihal Ihe NADPH lenerat«! wilhin Ike cyto-
pl •• m docs nol pin a"" ... 101h. milocllondria (1 J).
THE PREGNENOLONE EGRESS HYPOTHESIS
Tlte _ p l lhal Mrcsli ..MMlrenoxonial cell< eonl.in
endo::os<_ inhibitors or ".roidosenesi. is ... pporlo«! by
cbservllions lhal (a) cortiCO$leroid secrelion 'all. 10 u""
dclccuoblc 10...11 during certain lime. of 1M day in inlaCl
i""ivid".I .. and (b) " _ In 'rell ...."I Mor 1M cells (c.&..
llu.. ·;ng) 10.... 10 .=ko;IIed steroidoce<te-
.... Prqncnolonc .... i.bibi. ,ide-elu.i. e .......p: ",b ... il
is I"$C'" in hilh roneenlnllions. 0 .. 1M t>asis or .uch ob-
$Crvalions. il h.. bet .. prGpOlltd lhal ACTII .timul"IOS
110<_ producl ion by Pt<>rn<)linl P«l""""ionc ..
from Ihe mi lOChondria. Arsunlenls 18. in'l the hyp<>lhe-
,i, inelude Ihc somewh.1 ""Cak inhibilory c!feets 01 pre,.
ncnolont. and the r.i lure of eyanckelone 10 block . ide-
eha;. elu •• ,c . hboulh il '"el1illlOS pregn.noiooc ac-
cumuillion by inhibi'i., il$ oonvcrsion 10 ptOge$1O<onc
(I J).
ACTH Inth,e nee. on Adrenal A, eorble Acid
Content
Thc concen lration5 of ascorbic acid a rc highcr in the
adrcm,1 gland tha n in a ll othe r tissues in vestigated.
and amounts in the region ex-
o;eed those of Ihe ZOna glomcrulosa. ACT I! invokes
prom!". dosc-related deplelion, and Ihis effect is
lhe basis of widely used bioassay procedures
(11 . 24.122). Yet. liuk: is known of ascorbic acid
fu/tCIions in 1M adrelt31 cortex (33).
eA M r simila , ly promotes ascorbic acid depiction.
blocks the responses to both cA MP
and ACT. !. but it has 00 effcc i on the vitamin con·
centrations under basal cond it ions (24). Aminoglu-
lethimidc docs nol change or stimulated levels
(66).
Since ascorbie acid can decrea:;c the rates of re-
actions catalyzed by miet"O$Ofllltl P-45Qs ( I I).
ACTH could be: lifting an inhibilion othc ....ise pres-
enl. The very lIigh glllcocOtticoid t;l1C$ of
scorbutic gU;l\\:a pip has b«n ciled in support.
On lhe other hand. it bas been proposed Ihal a,..
corbie acid is needed to maintain physiological se·
erelory function$.l'roponents of th is notion a m ibute
Ihe augmented glucocotl ieoid outpul af scorbUlic
guinea pip 10 the Stress imposed by the dietary rc-
Slriction. They suggest Ihat tl>c animals ordinarily
U$C the vilamin. bUllhey ma nage 10 s)'nlhcsilC SOme
kind of substitute .... """ of;1.
Another concept i.thalthe adrel\lll cortex st0rc5
ascorbic acid for lranspotl 10 the adrena l medulla
during I;mes of stress. Blood vesscls draining Ihe fa,..
ciculala·reticulari. cout":SC Ihrough thc medulla and
they are known 10 rolease regula tors. The calcchol·
anline-RC reti ng ""II. a rc ga n·
glion cells. They ascorbic acid a. a cofaclOf
fOf 01\\: 0( the steps in the biO$)'nthcsis of norepi·
nephrine. They also incorpol"luc the vitamin into so-
granules and tMy rekuc il along witb the
bormone (18). A ncuromodu lalory fullClion for as-
corbic acid has b«n proposed.
". ADRENOCORt ICOTflOPlN AND CORnCOTROPIN_RElEASJNG HORMONES
ACTH Influences on Protei n S ynthesis
Ea rly effects on formation of a labile pl"Qlcin thaI
mediales stimulation of steroidogenesis have been
discussed.
Delayed effecls indude generalized incrca.e. in
R NA and protein synthesis, alcmg with preferential
induction of several cn7.ymc •. Accumulation of a
protein wilh a IllQlccular weight of 54.500 has been
demonstrated for \xlvine adrenocortical cells incu-
baled with ACTH, It is believed 10 be a precursor of
the dalton (23). There is also acecl -
",",Hed synlhcsi$ of mitochondrial I Iii-hydroxylase.
and of extramitochondrial cnlyme. thaI calalYlc the
synthesi' of cholesterol from acelyl-CoA. The de-
layed elfects have all be. n linked with influences on
R N A .ynthesi•. They can be elicited with cAMP_
REG UL ATION OF ADRENOCORTI CAL CELL
PROLIFERATI ON
Glucocortiooids exert '"'&ativc feedback controls
Ovcr ACTH secretion. When large dooc! arc repeat·
edly injected into intact animals. the ACTH scere·
tion declines and the adrenal glands undergo
atrophic changes that involve reductions in both cell
sizes and cell numbers.
Unilateral adrenalectomy transientl)· de<:reascs
the glucocortiooid concentrations of Ihe blood. and
the ACTH levels rise. The gland that in the
body undergoes "compensatory hypertrophy" in·
volving cell growth and proliferation.
Hy pophysc<:tomi7ed animals show only limited in·
creases in tbe Sil.c and ..·eight of the untOUChed adre-
nal gland after unilateral adrenalectomy. However.
the gland grows in response to injections of an
ACTH-cnriched piwitary gland extract (76)_
Considerations of this kind account for the for-
merly popular belief that ACTH promotes prolifer-
ation of the fasciculata-retiularis cells. It is now rec-
ognized Ihal Ihere are problems wilh the ooncept.
and it is inlerC!lting to nOie thai some astute observ-
ers were aware of them three decades ago (11 I).
Generally. when cells be<:omc high I)· specialized
they their ability to engage in DNA synthesis
and mitosis_ ACTH actson immature adrenocortical
cells to change their fine structure and cn7.ymc con-
tent. SO that they become especially adept at manu-
facturing large quanlitiC!l of glucocorticoids. After
oompleting their spccialil-l1tions. the edls flO longer
divide (36). Therefore> there i, reason to suspect that
ACTH cell prolifcration. The prediction is
borne out by 'lUdies of fasciculata-retitularis prep-
arations maintained in culture and exposed to oon-
ccntrations of ACTH that promOte steroidogenesis.
protein syntbesis. and growth. DNA synthesis and
cdl proliferation are inbibited undcr tl10sc conditions
(90).
Fibro blas t Gro wth Fa c tor
The anabolic actions of growth hormone. insulin.
prolactin, and other hormones arc believed to play
roles in adrenocortical cdl renewal ( 16). I·!o",<:ver.
their combined actions do not explain the magnitude
of adrenal gland growth under oondition, associated
with accdcratcd release of ACTH. This suggests
that SOme other pituitary factor is involved.
Fibroblast gro ..·th factor (FGF) is a polypeptide
with an apparent molecular weight of 13.400 that
has been identified in pituitary glands (32). It is a
powerful stimulant of DNA synthcsis and for
certain eelltypcs derived from the embryonic mes-
oderm. Elfcels on the adrenal cortex can be demon-
strated both in vivo and in vitro.
Adrenocortical cells have high-llmnity receptors
for FGF, but not for certain of the other milogens
present in blood sera. for example. epidermal grow1h
factor (31). The mitogenic responsc, to FGF arc an_
tagonized by concentrations of ACTH that promote
steroidogenesis.
While roles of FGF in adrenal glaod growth "",m
to be established. some in vivo observations require
explanation. ACTH can bring about some cel l pro-
liferation in whole animals. Since it is secreted in
accordance with circadian patterns. it has been
proposed Ihat ACTI! "prepares" cells for respon-
siveness to FGf during certain times of the day by
promoting growth and protcin sy nthesis. FGF can
then act on the prepared cells at times when ACTH
levels The inability of hypophysectomized
animals to renew adrenocortical cell populations is
probably attributable in part to loss of the prepara·
tiveeffeclS of ACTH. When the hormone is
cells may provide FGF. A peptide
similar 10 (or identical with) pituitary FGF has been
found in brain tissue ( 119).
The inhibitory influences of ACTH on cell prolif-
eration may contribute 10 maintenance of optimum
cell numbers and glucocorticoid secretory responses .
A problem with this ooneept is that the adrenal
glands enlarge when ACTH levels are elevated by
stress and !;Ome olher oonditions.
POSSIBLE ROLES FOR GLUCOCORTICOID$ IN
MEDIATION OF THE ACTH EFFECTS ON
PROLIFERATION
Felal adrenocortical cells do not display prompl ste-
roidogenic responses to ACTH when studied in cui-
lUf<'. The pituitary hormone promotes growth and
d ifferentiation during the f,rst few days. and it tran·
sientl y increases DNA synthesis and ecll prolifera·
tion (99). ACTI! may therefore have different ef-
fect. (preparative ones") when the glucocorticoid
levclsare very low. (ACTI-J is not the major mitogen
in thc fetus. Its effect' are small compared with ones
exerted by other components of fetal serum.)
The concept that glucocorticoids mediate the in·
hibition is consistent with the existence of glucocor.
ticoid receptors within the adrenal COrtex (96). and
with the hypertrophic responses of adrenal glands to
ACTH in thc presene<: of aminoglutethimide (97).
Glucocorti<:Oids ha"<' also been soown to suppress
the proliferation of some cell types. (However. the)'
can syncrgize with FGF to e"hane<: growth of others
[321·)
INFLUENCES OF cAMP
The influences of ACTH on cAMP generation (27),
and the effects of cAMP on Sleroidogencsis and cdl
growth (16) have been cited. High concentrations of
the nucleotide inhibit the proliferation of many cdl
types. including tbose of adrel\OCorticaltumors (28).
However. NPS-ACTH inhibits cdl proliferat ion al-
though it has linle or 00 innuencc on cA MP accu·
mulation (90).
EFFECTS OF ANTI·ACTH SERA
Intact animal$ injected with antibodies directed
against ACTH suITer a decline in blood glucocorti_
coid concentrations. alterations in the protein cOm·
position of thc adrenocortical cells. and loss of the
ability to markedly augment glucocorticoid secretion
du ring times of stress. However, their glands do oot
show the reductions in size and weight that follow
hypophysectomy. and they retain the ab ility to
undergo compensatory hypertrophy when unilateral
adrcnalectomy i, performed (89).
ROLE OF THE ADRENAL GLAND INNERVATION
When otherwise intact animals arc su bjected to bi·
lateral adrenalectomy. and a small portion of one
adrenal is reinsuted. the fragment grows and SOOn
becomes competent to secrcte sufficient glucocorti-
coids to sustain metabolic functions. It is obvious.
therefore. that humoral factors alone can promote
growth and proliferation.
Neverthelcss, observations of the kind cited below
indica ted that both afferent and efferent nerves. and
their connections with components of the hypothal.
amus. arC involved in at least early events of the pm-
liferative processes in whole animals (16.25).
l. Unilateral adrenalectomy kad. to almost in-
stantaneous release of corticotropin·releasing hor-
mone. The response is morc rapid than those toother
form$ of stress, and it OCcurs long before the blood
gluCOCQrticoid concentrations dedinc.
2. "Manipulation" of one adrenal gland (brief
clamping of the pedicle) doc, 00\ obviously impair
glucocorticoid secre tion by the alTected struCture.
HOwever. the undisturbed gland on the opposite side
undergoes a growth response while the manipulated
one docs not.
J. Pretrealment of the pedicle with a local anes·
thetic block..! the growth responses to manipulation.
4. Unilateral adrenalectomy is followed by in·
creases in nucleolar volume. nuclear size, and rale of
uptake of labeled leucine by cells of the ,,<,ntromedi"l
nucieus of the hypothalamus on the side of the un·
disturbed gland.
S. Unilateral lesions of th. ventromedial nuclei
impair compensatory hypertrophy of the adrenal
gland on the same .ide.
The findings are consistent with the transmis$ion
of information from alTerent nerve. of the manipu'
lated or excised adrenal to the hypothalamus. fol.
lowed by neural sti mulation of the gland that sub-
sequently undergoes "comperu.atory" growth.
Related slUd ies suggest that humoral factors other
tha n ACTH arc inV<lh'ed in the proliferative aspects
of compensatory hypertrophy. When hypophysecto-
mized animals arc subjected to unilateral
eetomy. the undisturbed glands are larger during the
first few days than the corresponding ones of hy_
poph)'sectomizc:d controls that are sham adrenalec-
tomi7.cd. Morea_cr, injections of ACTH blunt the
rise in DNA tonteot of the undisturhcd glands. and
they lower DNA, R NA ratios (16).
GLUCOCORTI CO ID INFLUENCES ON
STEROIDOGENESIS
In intact animals. glucocorticoid! limit their own se·
eretion mostly by exerting influences on thc hypo-
thalamus and pituitary gland that alTett the secre·
tion of ACTH and of other adre nal gland stimu lants.
It has been proposed that they additionally actio-
cally, after combining with glucocorticoid receptors .
The anti-innammatory clTects of high concentrations
of the hormones arc att ributed in part \0 inhibition
of prostaglandin synthesis (96) (sec Chap. 6), and
simila r clTeclS may be exerted on the membranes of
adrenocortical cells.
Some in _itro evidence for localized inhibitory
actions of the glucocorticoids has been presented
(10.99). The findings have been
supra physiological concentrations werc used (121).
On the other hand. thc cone<:ntratioos may 00\ have
exceeded those achieved within the adrenal cortex.
 ADRENOCORTICOTROPIN AND
'"
EXTRA-ADRENAL ACTIONS OF ACTH AND
RELATEO MOLECULES
Supraphysiological dosages of ACTH act di=t ly on
several cell types, but it is not known whether the
findings 3rC related in any "'3y \0 normal funClions.
It has been observed. for thai ACTH can
accelerate lipolysis (probably via aClivmion (If adc-
nylate cydase) and thai i( can lower the blood 81U-
C05C concentrations of adrenalC:ClOrni7.<:d animals.
Palient.s with Addison's disease and certain other
disorders in which large quantities of ACTH are s.c-
crete<! often have skin hypcrpigmcnlation. Supra-
physiological amounts of the hormone can stimulate
the melanocytes. but il is believed thai other pcp-
tides produc<:d by the same cells UC<Xlunt for the
symptom. As discussed in Chapler 3. pro-opiomclan-
ocorlin (POMC) serVes as the pre<:ursor of numer-
ous peptides in addition 10 ACTH_ includillll some
mcian{ltropins. II is II{lt as yel known which assume
grealesl importance in humans (4,61) . Peplidcs Ihat
bind antibOOies directed against -y,-mclall{ltr{lpin
have been detected in human tir.sues. bm linle (lr II{l
1',-mclanOlropin-like activity(which is present in tJo.
vine tissues) ac<:umulates (113,1.).
",-MSH. a peptide amide with 13 amino acid
moieties that are identical with the first 13 of
ACTH , is a major pigment cdl stimulant in mam-
mals with well developed intermediate lobes. It acts
on sebacCQus glands as well as on mcianocytes. and
it several other actions when it is inje<:led into
animals (1 14) . Pharmaool{lgical doses
given f{lr st"eral day< reversibly darken human skin
and hair, butlinle (if any) of that P"Plide is present
in human blood plasma.
tI-MSH is a somewhat larger p"ptide made up of
amino acid sequences nf thc tI-lipotropin . It shows
species specificity and is present in almost 50 times
Ihe ooncemration of ",-MSH in human pituitary ex-
IraCtS (gO). However. SOme investigators doubt thaI
il is synthesized (4).
",-MSH is made in Ihe extrapiluitary brain. and it
may function as a neuromodulator. When inje<:ted
intracerebrally inl{l experimenta l animals, il affects
learning, memory, electrical activity in Ihe brain.
neurotmnsminer release. and some forms of behav-
ior. Sylltemie injections have been reported to influ-
ence gonadotropin secretion in humans (114).
Several peptides that share immunological prop--
erties with ACTH have been identificd in various
parts of the brain (79) . S<lme travel upward from tbe
pituitary gland (5). and their levels are affectcd by
hypophySC<;tomy: bUI others are evidently made in
neurons (55). Most arc small molecules made up of
segments of ACTH (20) . Changes reported folk>w-
HORMONES
ing their injection into animals include implOved vi-
sual attention. memory and maze perfor-
mance. delayed extinction of condilioned reHexes_
exaggerated responsivity 10 some forms of
lion. stretching and yawning. al{lng with certain
forms of behavior generally attributed t{l other reg-
ulators (106) (c.g" the ar.sumpti{ln of unusual p0s-
tures. "wet dog shakes:' squealing. grooming. and
teeth chattering [42l). The .ffects have been linked
with changes in brain adenylate cyclase activity.
Some may result from interactions of ACTH frag-
ments with re<:eplOrs for opiate peptides (50). (Op--
iates potent inHuences on the gut. and both
ACTH and mclanotropins have been identified thcre
as welL) A few of the responses are modified by ad-
renalectomy. but most are 1I{lt.
REGULATION OF STEROIDOGE NESIS IN THE
FETUS
The fctal adrenal COrlex is diseur.sed in Chapters 6
and 16. It utilizes plasma lipoproteins as substrates
f{lr Il{lrm{lne prodUCli{ln ( 109). bUi it also takes up
substanlial amounts of cholesteryl sulfate; and
DHEAS is a major secretory product. Some observ-
e", believe thai ACTH is a major regulalor (11 7).
Otbers find insensitivity to ACTH durini some de-
velopmental slageS. However, maternal stres> ele-
vates the ACTH levels (A-II).
The fetus Ilas a pars intermedia thaI can cleave
CUP and ",-M SH from POMC. and the maternal
blood plasma alw then contains a-MSH (36). B<lth
prolactin and n-MSH have been reported 10 promote
cortiwl production. However. ACTH ' - 1' (whid
acts like the natural ACTH ' " ) promotes proges-
terone release as well (30). It;s possible Ihat ACTH
performs certain functions during fetal life, whereas
{lthers arc subscrved by thc ,,-MSH (49). The
adrenal glands of fctal sheep show steroidogenic
response. 10 a_MSH at an early developmental
stage and {lnly later beoome seo.,ilive to ACTH
(64).
CLI P is also implicated in the regulation of ste-
roidogenesis in fetuses. and il may additionally stim-
ulate insulin release (67 ). n-MSH probably plays
roles in the regulation of fetal water balance.
Prolactin and growth hormonc are believed to pro-
mote growth {If the adrenal glands. ney also evi-
dently function after maturation has been com-
pleted. Tbe zona fascieulata has prolactin receptors
(77). PRL enhances glucocorticoid responses to
ACTH. probably to a great e<tent via inhibition of
the activity of a 5",-reductase that eataly7.<::s COnver-
s ion of glucocorticoids to biologically ineffe<:live 5a-
dihydro derivatives (! 5.78).
 Chorionic gonadotropin doe, not exert known in-
fluences on glucocorticoid secretion_ When added to
preparations of human felal adrenal corte._ it does_
however, stimulate the release of dchydrocpiandros-
terone (30).
Arginine vasopressin (A V P) is a peptide made in
large quamities by the neurohypophysis. In phar-
macological amounts. it exerts ACTH-like effe<:ts on
the adrenal cortex (121). and it may play some re-
lated roles during limes of stress. Arginine vasotoci n
(A VT) is a chemically related neurohypophysial
hormone of nonmammalian vertebrates that has
been stated to be made in human fetuses and to eon-
tribute to the regulation of their adrenal glands. The
findings have been questioned. Minute amounts of
A VT made by neurons in adult brain are said to
exert indirect (but highly potent) inhibitory influ-
ences on ACTH release (81).
REGULATION OF ACTH S ECRETION
Cir<:ulaling ACTH originales moslly in Ihe piluitary
gland eorlicotropes. The various forms found in
blood plasma were described in Chapter 3, ACTH-
secrcling cells also release .8 ... ndorphin a nd other
PCPlidcs.
Gastrins haY<: different amino acid seq uene<:,. but they
hAY<> ban idcn,ifoed in eo"ieOt.-op<" ,.bile hCTIl and
a--MSH are pre..,nl in s.. trin .... crcting e<:\I, of tho stom-
ach (61).
The major posilive control. over ACTH ..,crct;on
are exerted by hypothalamic eorlit:Qlropin·relea.ing
hormone. (CRHs). whereas major negative modu-
lators are lhe glucocorticoid •.
Corticotropin-Releasin g Ho rmone s
is oe<:ded 00 a regular basis 10 maintain the
struclUres and secretory activities of the corlica-
tropes. The kinds of studies Iht
of Ihis kind were ciled in Chapter 2.
It h.. Ion, I>c<:n known ,h.. the contain'
cortieotro"" 'Iim"l.nl ' whose aCI;,itie. arc demo)"ed
with proteolytic enzyme' ( I02. 115). P,og,,$$ in defining
lite chemic.l nature wa, hampered for many years be_
CaUS< (a) Ihe peptides seem to be unslable "'hen sub-
jecled 10 the kind, of procedure, u'cd to purify Other hy_
pothalamic horm" .., (43); (b) only minu'e amount. of
Ihe hormone are made (100): (c) CLIP. ,,·MSI!. """'"
pre""in, norepinephrine. f'a8men" of hemo81obi n and <>f
myelin ba.ic protein. and some amino acid. are among
the component. of hlpOlhalam ie .,"aCI' ,ha, c.n .Iso
Ser-Gln-Glu-Pro-Pro-Ile-Scr-Lcu-Asp-Leu-Thr-Phe-His-Leu· Leu_Arg-Glu_ v al-Leu·Glu-M cl-Thr)
N H TAla-l ie-Asp-Leu -Leu- Lys-A rg-Asn-Ser· H i,_AI a -G In-G In-A la-Leu _G In·As p-A la- Lys
promote ACTH rolease (115. I (6); (d) tho p'Oo
«d"res are not wholly Oltti.faeIOl")'. and the e.tracts con-
tain substances ,hat interfere wi th on.. that have b<;en
widely used; and (e) ;1 is not known how many ··true'·
CRlls arc made. Some 01»<:",." b<;lieve ,h.. Ihe "high
molecular "'eight form,·' are either precursors (102) or
peptide oligome" (68). It h.. be.n both proposed (82)
and denied (105) th.l. coflClot '"'lu;red for Ibe aClivity
is ..,para'ed f,,,m 'he hormo .. du,ing the •• "action WOo
«dures, Several imp"",ement' in the techniques have
bcen mado (29).
Recentl y, a 41 amino acid peplide wilh the se-
quence shown below has been identified , It meets all
Ihe crileria ror a "true'· CRH, and il promoteS the
release of .8-endorphin as wcll as of ACTH (116).
(The .tarting malerial required 490.000 hypotha-
lamic fragments. Only pieomole quantities Can be
obtained from each animal [liSA].) A further dif-
ficulty involved in ;t, isolation was rccogni7.cd when
the <1rllclllf<' WlIS since the similar sizes
of C RH and ACTH hamper separation of Ihe twO
kinds of CRH has noW been synthesi7.cd.
Some CRH-likc act;vity Wa& found. however. in
discarded fractions. and other CRHs have been de-
scr;bed (29).
The peptide promoles almost instantaneous gen-
eration of cAM P (I 00% incf<'ases within 60 seconds
for rat corticolropes. and 400% within 4 minutes).
This. plus observations cAMP mimics the
mone actions. prOvides "'Idence tbattbe nllcleo\lde
serves as a mediator of CRH_Slimulaled ACTH re_
lease (58.59). Some obscrV<'rs rind that
coid antagonism of CRH aClion, on tbe cortico-
tropes involves inhibition of CRH-medialcd cAMP
generation (liSA). Many peplide hormones that
promole cAM P generation also exert other effects on
the plasma membranes, It has been demonstraled
that CRH accelerates phospholipid mClilylalion and
Ihal inhibitors of the reaction impair do fIOt to-
lallyabolish) Ihe CRH influences on ACTH secre_
lion (38A). Extracellular Ca" is required to invoke
the ACTH secretory resjXlnse ( 115A).
Although no effcclS on thc release of other pilu -
itary gland hormones ha.-e been described, CRH
prompily behavioral changes whcn
cenlrally (but not peripherally) into rats , The re-
sponses differ from tlK: ones seen after administra-
lion of endorphins and ACTH fragments, The rals
are said to show locomotor aCI;valion and "increased
emotionality," both of which could contribule to
their immediate responses to imposition of stress
(112).
The mechanisms whereby CRH promotes ACT H
synthesis may differ from those involved in hormone
'" AORENOCORTICOTROPIN AND CORTICOTROPIN·RELEASING HORMONES
discharge. Only the ones on synthesis 31"<' blocked by
cydohe ximidc.
Arginine Vasopressin
Although beSt known for its influences on the kid·
ney, arginine yasopressin probably makes substan-
tial contributions 10 the regulation of Ihe "CTH·
glucocanicoid system (29.121). It is released in rc-
spon..>c to several kinds of siress. it directly stimulates
tlte cortiootropeS.;1 has some direct influences on the
adrenal cortex. and i\ potentiates Ihe cffccls of
CRH.
There were early suggestions that A Vi> might, in
facl. be Ihe CRH. The concept bas been abandoned
for several reasons: (a) Brattleboro ralS Canll<)i make
A VP. but stress elevates the ACTH levels; (b)
water·loading inhibits A VP release in healthy ra(,.
but Ihe ACTIi response 10 stress is no1 impaired
(98): (c) hypothalamic extractS devoid of A VP pro-
mote ACTH release: and (d) the dose·response
curves for the two hormones differ. A VP is a potent
stimulant when it is presented in very low concentra·
tions, but only lim ited stimulation of ACTH release
is ach ievcd at any dosage , Very high concentrations
of AVP may be totally ineffective. In contrast. the
amounts of ACTH released in reSlX'nse to CR H rise
in parallel with the concentration of the hypotha·
lamic hormone (115) , On the other hand. addition
of A VP to CRH invokes greater ACTH release than
a maximal dose of C RH alone (115A).
Some of the A VP synthesized in the paraventric-
ular nudei of the hypothalamus is released ncar cap.
illaries of the median eminence . and it can travel .ia
the portal blood vessels to the adenohypophysis. Thc
pituitary gland may. in turn. send as yet unidentified
growth factors to the hypothalamus (2.3). When rat
para.enlrieular nuclei and adenohypophysial cells
are c<xultured. much more ACTH and AV P are
m"de than when either of the t<'lItypes is cultured
alone , Glucocorticoids inhibit AVP release. CRH
stimulates (A-8), but moderate dosages do not affect
posterior piluilary gland function, (1\-1 ),
Influences of other Peptl des
Angiotensin I[ is synthesi7ed in the hypothalamus.
It is a sympathetic system stimulant that
can promote AVP release. It seems to act directly on
the pituitary gland (69). (The observation that an-
giotensinogen and CRH contain a common 4-amino
sequent<' (116) is probably not physiologically
relevant. since only One of the moielies goes to an·
giotensin when the gly<:oprOtcin i, cleaved.)
Unlike A VP, arginine vasotocin is a highly potent
inhibitor of ACTII release. When injected into the
third ventricle of the brain in extremely minule
amounts. it invokes a very rapid decline in cortiC\»
sterone conccntrations in rats. It also com-
(>Cnsatory hypertrophy of the remaining adrenal
gland following unilateral adrenalectomy. It is be-
licvcd to act indirectly. via serotonin-secreting ncu-
rons (5 1).
" Ti ssue CRF"
Ventral hypothalamic lesions abolish the ACTH re-
sponses to aeute <1ress, presumably because they de-
stroy the CRH-secreting neurons. However, if ani-
mals with such lesions arc given time to reCOver from
the procedure. and they are then exposed to p"'"
longc<:l stressful procedures that invoke tissue dam·
age, (e,g" laparotomy Or hypoxia). thcy exhibit a
sustained elevation of thc plasma ACTH and glu-
cocorticoid levels starting 4-6 hours after imposition
of the insult,
The delayed response is associated with the ap-
pearance of a circulating "tissue CRF", If the sub-
StanCe is administered to recipients with hypotha-
lamic lesions but intact pituitary glands. it invokes
sustained elevation of the ACTH levels_ Sint<' re-
fractoriness to CRII develops rapidly, il has been
proposed that tissue CRF functions
under C<.lnditions that demand continuous stimula·
tion of the ACTI-I-glucocorticoid system for long
time periods (7.8)_
Liver. cerebral cortex. and thymus gland arc
among the proposed sources of tissue CRF. but other
cell types probably contribute. Unfavorable condi·
tions in volving tissue damage ar(: known to lead to
labilization of lysosomal membranes and consequent
release of proteolytic enzymes. The may
then deave the regulator from inactive
Tissue CRF is not released in detectablc amounts if
the animals are subjected to different forms of stress.
such as immobilizat ion. that do not involve tissue
damage. Such procedures do. however. aU8ment
ACTII release in inlacl animals.
G lucooorticoids stabilize the lysosomal mem·
branes of many cell types. ACTH or glucocorlicoid
pretreatment of animals with hypothalamic lesions
blocks CRF release in response to laparotomy
or hypoxia,
PARS INTERMEDIA HORMONES
T he intermedia persisls Ihroughout life in m30y
of the mammals , The melanotropes within it process
POMC in special ways. Li potropios and endorphins
identical with the oncs present in corticotropes are
fTIllde. but much of Ihe ACTII clea.ed to ""MSH
and C LI P. (As diK\lS$Cd in Chapler 1. the amino
acid for mctenkepllal in .;an be fOlioo in
endorpllins. but tlM:K pC1Itapeplides evidemly
formed from prcCUf'SOl'S (40.51l-
The pars intermedi. lias few capilluic:s. bul it is
richly suppl ied with nerve cndings. release
seems 10 be controlled predominantly by catc<:hoI-
amines (22.75). In mts. it hs been obser"cd thal
ACTH is released in response 10 "neurogenic SlresS"
(1 4). but noI following of man)' of the
stimuli Ihal a!fOCl tbe: CVTticoh'opcs. Neilbe:. adre-
naleclomy nor glucocorticoid 5U,,"
Mantially innuences the pars inlermedi. of
ACTH.
REGULATION OF CRH SECRETION
CR. II secrelion undergoes diurnal cycles Ihat COn-
Iribute 10 lhe mainlenance of glucocorticoid
rhythms. Neurolrammilters Ihal can aCI direclly.
via synapses., or as neuromOOulatOTS, major reg-
ulaton of Ihe c)..:les. Neuroh'ansm;lIers aloo mediale
sl .esHelated stimulation. Hormones inlo
Ihe $YSlemic bIoodsueamnn bind directly to neuron
re«pton. or affcct neurolransmillcr lurOO>· • •.
C RH o$CCfeling neurons diffusely distribuled
within the hypothalamus. and Ihey are intermingled
with olhcr cell Iypes in Ihc magnocc1lu lar nudei.
Only minule quantilies of the hormone arc presenl
within the variou, loci . many of the re-
lease studies involve of , tSp<JllMS to
CR H. All of the pre«ding f;Ofllpikale tbe: problems
of delinin, the physiological medt.ani$JnS.
Knowledge in this field was ",bs!.lnlially ad-
vanced by the inlrooiu"ion of Icchniques for lTI.:lin-
!.lining hypothalamic fragments in media closely ro-
cerebrospinal l1uid. since the cdls can be
directly 10 purponed regulators and 10 phr-
maeolollieal agents (44). !t must be r.cognized.
thai syste ms of Ihis kind do rKlI provide all
of the controls that opcnue in
Acetykholine seems 10 be Ihe major slimulanl.
There good reasons to believe Ihat il is released
by IlCUrons lhat synapse wilh the CRH«<:reting
cells. 100 that il aeu; directly.
The ,_ptOtS r« lcelykholi ... Ire evidently ()( Ihe ni·
cotinic Iypo. bloclu lhe nicot<H11c (SI ...
i lionie.ly"a p1ic) actions of a""lyleholine. "nd it 0PPOS<'
acetylcholine·modi.lt<! . Iimulotion ()( CRH ,clusc_
Alropj ....ffeclS """'Ily mu","rinle (pa, •• ympalhelic)
Ictm of lhe: "'.'01,.",mill". but il hn limilcd effects
"'" sy.. p1 ie tno ...... iu;.,.,. It impairs """tylc",,"
IllIt .. i","lItioft. Iklh.....chol is • •. m...a.rinic
block.... It is illtff... in Ibis ')'Ile",.
Serotonin (S--hydroxylryp!.lmine. S--HT) .Iso pr0-
motes dosc-depcnd.nt CRH reluse in vitro. It pro\>-
ably cholinergic neuron .. H IT agon;.ts
ekVllle plasma ACT H in humam (A-7).
The effects or S--HT a,. blocked ..itb InCthYSC:'aide."
S--tlT r«CptO< .",.,...;.t.
The melhysc'p!e docs not in-
1II'lh acclykholillC .timulolion. IIcUmel"""ium
blocks S· IIT $lim.l.t;on.
In animals. agents Ihat impair HiT synthesis dis·
,upt tht .irc.adian rhythms. but they do not block the
C RI! response. 10 SIre... It is likely. Iherefore. Iha\
C RH cells synapse: ,,-ith IWO kinds of cholinergic
llCurons. only OTIC of which is affctled by serotonin.
Norepinephrine Clertsonly minimal depressant ef·
fect$ on basal C RH secrelion in vitro. HO"'..,vcr. il
abolishes Ihe stimulalOf)' of 3CClylcholi ....
IlallO depresses CR H sccn:tion in vivo. T he dala are
C(lnsisten! ,..ilh direct influenees on the CRH neu·
rons thaI impair lhe ability to respond 10
acetyleholine_
Nore pinephrine evidently acts on ,,·type noradrc-
nergic Its effects arC abolished ,,·il h pbe:T>-
lolamine (an ""blocker). bul noc the: prOpranolol (a
/kc«PIQr .antagonist).
Gamma-aminobutyric acid (GABA ) is a highly
polenl inhibitor " '00sc elTws blocked "" Ih a
GABA·r«Cplor anlagonist. picrotoxin. Since it im-
pairs nim ulatory of both acetylcholine
and ,erolonin. GABA probably also acts direcll y on
Ih. C RH $"c"'ting no" rons.
equipped wilh collaleral uons that re·
kaK GABA have been identified in the hypothala·
mP$ (45.92). They believed 10 rele:r.se lhe GA BA
"'hen slrongly amino acid Ihcn e.-
em a kind of Iocaliud negalive f«dbaek conlrol
oYer ntUfOf\$ thaI prOduce il.
neurons may have .imilu CQllatcrals.
Phonlol.mine doc. nol affcci GAai\ Influ.nces. and
pieroto,in doe, not lcuen the nor<:pinephrioe in hibilion .
Pineal ,lands 'ynthesi>c melatQnin (Ml T) f'om .. ro-
lon;n . They p'.bly ",lea.. nIOfl 01 il 10 lhe blood·
.. ,111m. bul MLT is also p ..... nt in nrebro<pi .... l fluid.
Ahhoolsh Ihis bofmone hat liltle effect on bo,..l CRH TO-
leaK. It ,,"," diminish the tomc: "'mulants.
and modify Ihe rf:SpoMC$lO inhibitors. T10c observalm
.... oonsislenl wilh direct inHueneetOOII Ihe CRH "'u..-.
ML T may also COIIl,ibute 10 feedback oontrois.
Ii ..,. repealed injeC1ion. into ani"",11 havehe:cn obse".d
to invoke ,ro,,·,h of Ihe .dren.1 corto. and to augmen,
gluCOO<)'tieoid secrelion_
IHnaminc may stimulate in part .ia its vasodila-
tor aClivity. However. it also promotes cA MP gen-
enllon in Ihe hypothalamus. and its effecls arc.n-
taaoniud by his!.lminc r«CptOf antagonists.
Substance P has been proposed lOaffcct CR II secre-
lion indirectly. via interactions ,..ilh histaminergic
neurons (54).
'" ADA£ NOCORTICOTROPIN A ND CORTICOTROPIN·RELEASING HORMONES

Accty\chol ... _ _ __

PGF •• - - - -- CRH tffluton

",
,,
\,
,, ,,
,,
! ,,
"" ,,
,
GIt>c<x:o<!icoic1s

- - - - -_ IMIt>tioft

Fig . 7- 1. . genl$ "' tn. reguIob""

oJ CRH HCl'etion .

Other vasodilators thai either promote CRH re.
tease Or cnhance ils effectiveness include bradykinin,
epincphrioc and PG Es. Epinephrine stimulates bolh
CRH neurons and corliCQIropes (1\-9). POEs and
epinephrine activate adenylate cyclase. Morphine in_
hibits {he cn1ymc and antagonizes Ihe effects of
PGEs (58) . However. POFI. stimula te, without el-
evating the cAMP levels ,
Somatostatin is a major regulalor of pituitary
gland hormone secretion. h seems 10 have 1'10 influ-
ence On CRH. 31 least when tested in vitro. Dopa-
mine is another imporlant pituitary regulator found
to be inactive in the in vitro system.
A diagram consistent wilh rn<):'j\ of the preceding
observations, and especially wi th the in vitro
is (Fig. 7·1).
NEGATIVE FEEOBACK CONTROL OF THE
CRH ·ACTH-GLUCOCORTICOIO SYSTEM
GluC(>C<lrticoids inhibit the at several levels.
Their effects seem to invotve interactions with a va·
riety of receptors that differ in steroid amnities and
specificities (70) and in the consequences of the
binding. Two general kinds of responses have been
described (101): (3) rapid. ·· rate·sensitive·· OIleS that
arc invoked by sudden changes in steroid concentra·
tion even when the absolute levels do no! markedly
deviate from prestimulatory ranges. and (b) dctayed,
sustained '·proportional" reactions to high concen·
trations (34.121).
Rapid responses arc $Ccn in both pituitary and hy·
pothalamus. The glucocorticoids may exert stabiliz·
 ing effects On the plasma membranes of the CRH-
secreting neuron' and tbereby clevate their tbresh-
old, for st imulation (44). (The time course rules out
the "dassica l" kinds of steroid hormone actions that
involve translocations of receptor to thc
nudeus.)
The addition of glucocorticoids to the aforemen-
tioned acetykholillMlimulated hypothalamic prep.
arations leads to almost immediate mppression of
CRH release. Corticosterone is an eSjlCcially potent
in vivo inhibitor, even in cortisol seCretors. Cortisol
and dexamethasone arc: also effeclive in both corti-
costerone and cortisol prooucers. However. SOme
synthetic steroids that act on peripheral glucocorti_
coid receptors are inelfeetive. DOC_ I S.QH-DOC,
and ll-deoxycortisol arc adrenocortical secretory
products that interfere "'ith glucocorticoid suppres-
sionofCRH release.
"I ntermediate type" feedbac k develops in 45-120
min. It "ffects ACTIi rele3S<:. but hormone
is OOt inhibited. The effects probably depend on pro-
duction of a short-lived prOlein. They are easily
blocked by aelinom)'ein D in adrenalectomized ani-
m"ls and in cultures (A-6). The responscs probably
require ent ry of the steroids into the C(:II, and trans-
locations of the hormone-receptor complexes to Ibe
nuclei .
When the steroids arc injected 4 hours before re-
moving thc hypothalami. DOC_ I I-deoxycortisol .
corticosterone. and cortisol afc "II cllective inhibi-
tors. In 24-hour tests. deumethasone and progester-
one also inhibit,
Adrenalectomized animals receiving no steroids
are extremely sensitive to CRH-releasing stim-
ulants.
At least some influences are on neurons
that communicale with thc CR H_producing cells,
Certain forms of slress markedly stimulate ACTH
secrction when thc blood glucocorticoid levcl s are el-
evated. but othe rs do not.
CR H stimulates the release of ,B.. ndorphin as well
as of ACTH (34), In humans and monkcys. small
doses of dexamethasone lower plasma and
,B-lipopotropin without affecting the ,B...::ndorphin I..•
cis (46). but la rge OneS also suppress ,B.., ndorphin r..
lease. (Endorphins contribute to the responses to
stresS [19], but thcir differ from those of :he
glucocorticoids.)
Delayed responses at the pituitary le,'cI evidentl y
depend on formalion of a peptide Or protein that re-
duces ACTli biosynthesis. Structural genes that
code for the biosynthesis of POMC and DNA se-
quences and arc repressed by glucocorticoids. have
been identified (1 4).
Pituitary gland involved in inhibition of
ACTH biosynthesis dilfer from the hypothalamic
It has been staled that they are more se nsitive
to dexamethasone lhan to cOftiOO:lterone (in both
corticosterone and cortisol se<.:retors). sys'
tcmatically injected dexamethasone soon enteTS the
conicotropes, but it does not rapidly cross blood-
brain barriers (A-6). Pituitary cdls have a Iransoor-
lin-like protein that may serve as a "bulfcr" to pro-
tect the ce\ls against sudden changes in plasma glu-
cocorticoid levels (70).
CIRCADIAN RHYTHMS
Under normal conditions. the plasma glUcocorticoid
levels peak around the lime of awakening. They arc
hig:ltest in thc morning for daylight"",ctive species,
and highest at the onset of darkness in nocturnal
ones. Evidence for involvement of the suprachias-
matic nuclei of the hypothalamus in regulation of
the rhythms (45,73) was presented in Chapler 2, and
the proposed neural palhway< are discussed in Chap.
ter 20.
If the timing of "lights on'" and "lights off"' is
sh ifted in the laboratory. but the lotal cycles have
periodicities not tOO different from 24 hours. thc glu-
cocorticoid rhythms adapt 10 the ncw
Peak glucocorticoid secrelion can be invoked at any
boor of the day, and most animals easily maintain
23 or 25 hour cycles. However, althougb thcy arc
usually "entrained" to external signals. gl ucocorti-
coid rhythms are They occur in animals
$ubJectcd to orbital enucleation «JOn after birth
(113). in humans who have alwa)'s been blind. and
in animals maintained in continuous darkness. Inter_
nal factors will be the major determinants of cycle
lengths if light and dark periods alternate with fre-
quencies that arc nol physiologically compatible
(e.g" if shifts are made at 8 or 15 hour interval,).
Continuous cXp<J6ure to bright light ean abolish the
rhythms. espedally in albino animals. (This is anril>-
uted to destruction of parts of the relina a nd hrain
[53],)
Animals tend to eat and drink soon after awak-
ening. Feeding-fasting and slecp-activity rhythms
play important roles in entrainment to the cnviron-
ment (87). Light-deprivcd animals can adjust Iheir
glucocorticoid rhythms to feeding pancrns. If ani-
mals that are nocturnal by nature arc .. posed to the
usual day-night alterations in lighting but are pre-
sented with food only in morning. they can have
peak glucocorticoid levels during the morning.
(However, it Can be demon'trated in several ways
that they retain re'pon,;v;t)' to pootic stimuli
[120]. )
The nature of Ihe driving signal is not known. It
cannot be a component of the food or a gastrointe.;-
tinal hormone releas<:d in response to eating. because
the plasma glucoc:orticoid concentrations rise shortly
/Hjort thc meal is presented. The elevations are ex-
.
, ADRENOCORTICOTROPIN AND CORTICOTROPlN·flELE,",SING HORMONES
aggerated if animals accustomed to frequem meals
are provided with food JUSl 2 hours per day.
The mechanisms underlying meal-invoked phase
shift, dilTcr from the oneS associated with cbanges in
lighHlark stim uli. Adaptations to fceding schedules
persis! if the suprachiasmatic nudei arc destroyed.
but they can be abolished by lcsioning the ''Cnlro-
medial nudei of the hypothalamus. TIle observations
support the bel ier that the brain C<lnlains more than
One "biological clock" (55).
CRH Cyc les
Under normal conditions, the timing of CRH cycle.,
follows the paHerns thai WQuld be predicted from
measurements of the blood glucocorticoid levels
(56). However, there 3r<: no obvious relationships be-
(ween CRH rhythms and Ihe changes in blood
ACTH leycls. Circadian rhythms (A-3) and exag-
gerated sensitivities to CRH (A-4) have been dem-
onstrated in patients wilh Cushing's disease.
ACTH Cycles
The factors controlling circadian vanat,on5 in
plasma ACTH arc not known. The cyde!5 can be out
of phase with thc CRH rh)·thm •• and tlwy persist in
adrenalect"mize<J animal. (12,56). Tho h"flJJ<JIIC loa,
a half-life in the circulation 01 only 2-4 minutes, and
changes in ciearance rates may be imp'}f(ant. The
kidney takes up ACTH rapidly, but it does not di-
rectly send much of the hormone to the urine. It
deaves ACTH to a product that shares immuoolog-
ical properties with the biolOgically active peptide
(34).
G luc oco rticoi d Rhythms
The adrenal glands obviQllsly receive important sig-
nals other than ACTI-!. The steroid rhythms persist
when the pituitary glands are excised and replaced
by implanted pellets that deliver ACTH at constant
rates. AdrellQCOrtica l cells undergo diurnal changes
in sensitivity to ACTI-!, e,'en in animals !reated with
dexamethasone (17). In rats. the greatest sensitivity
is seen around the time whcn lights arc turned otT in
the laboratol)'. and the lowest occurs in thc morning
when lights are turned on. Differences in affinities of
ACTH receptors, Or in coupling of the hormone-re-
ceptor effects have been suggested (47).
Some component of the periodicity may be int rin-
sic to the adrenal thcre h.>e bttn re-
ports that cells maintained in ti ssue cultol"(: undergo
diurnal variations in the rates of
«,lease,
Several hormones outside the CR li·ACTH·glu-
cocorticoid system may contributions in intact
animals. Thyroxine seems to be nceded in hypoph)'-
seetomized animals (71). The effects arc blocked
with atropine, and they have therelore been attrib-
uted to influences of the thy roid hormone5 on cholin_
ergic neurons. Adrcnomedullary POMC-like pcp-
tides may contribute to early m()rning elevationi of
glucocorticoid levels (A,2j.
The adrenal glands of lemale rats arc larger than
those of maics. This may result in part from estrogen
stimulation of both prolactin and ACTH secretion
(78) , Castration can disrupt the glucocorticoid
rhythms (12).
Although a prompt increase in CRH release me·
diates the effects of acute stress on the adrenal cor·
(57), the magnitude of change in thc glucocor·
ticoid levels varies with the time of day.
REFERENCeS
l. Aguilcra, G.• and Catt. K , J . Loxi of Action of
Regulator< of Aldooterone Bios)·n,he'i' in 1<0-
I.tcd Gtomerula» C.lI,. l::ndo<TiIW/. 1M: 1046_
52. t979.
2. BacrtSCb. A. 1.. Beny. J.-L . and Gah .... iler. B.
Hypothalamic P....entrieular Kudc., is. Priv-
ileged Site for Brain.Pituitary tnte raction in
Lens-Term Ti .. ue Culture. Naruu 19J:
1982.
J. Baemchi. A. J.. Vallet. P.• Baumann. J. 8. . and
Girard, J. Neurat Lebe of Pituit.. y Modul.te.
Corticotropin Release in the Rat. t 'ndoxTiIW/.
11Xi; t98().
4, Baral. E,. Pallhy, A.• and G,ar. L Action of
Cathep,in D 00 Human P_Lipotropin: A Possible
Soure<: of Human ·'P·MelanOlropin··. P,o<. Nat/.
Arad. Sci, USA 76: 6t20_J. 1979.
5. Bergland. R.. Blume. H" Hamiltoo. 1\.. Monica.
P.•• nd Pate""". R. Adrenocortic<>tropie Hor_
mone May Be TranlpOrted Directly Irom the Pi-
tuitary to tbe Brain. 110: 54t_3. t980.
6. Be"",n'. X., Girard, F,. Seurin. D" Luton. l .-P,.
Bric.ire. II.. Mains. R, E,. and Eippcr. 8. A. h·
ide"". for a PcptideS imitar 10 the 16K Fragment
in Man, It, Relation,hip to ACTI!. j, Clin, Eft-
JI: 182_4. t980.
1. Brodi.h. I\. Tiss ue Corticotropin Relea.ing Fac·
t"". F,d. Pro<. 36: 2088_93, t9n
8, Brodi'h. A" and Lymangrovcr, J, R. Th. Hypo-
thalamic,Pituitary-Adrenocortica l Sy$lem. Chap,
3. pp. 93-149 of McCann. S. M.. ed . t-ndo<r/M
Phy.to/ogy /I, University Pork Pre ... Baltimore.
1917.
9. Buckley, O. Land Ramacha nd"n . J.
ization of Corticotropin R.e<:ptors on Adrenocor-
tical Cell" Prot:. Nail. Arud. Sol. USA 78: 743t_
5.1981.
 \0. Carsia. R. V.. and Malamed. S. AC"le Self·
Supp"".i(>n of Co,l ic"'te,oidogcn.. i. in lsolaled
Adrenocorlical Celi •. t·ndocr;l!Oi. 105: 911-14.
1979.
II . Cha)"en. J .. Daly. J. R.. Loveridge. N .. and Bilen·
,kyo l . Cytoclt<mical BiM."')' of Ho,mones, R«.
Prog. /fomWfte RJcA . 31: 33-72.1976 .
12. Cheifet'.• P.. Gaffud. N .. and Dingman. J. F. Ef-
feci. of Bilaleral Adrenal..lomy and Cominuou,
light on Ihe Cireadian Rhylhm of C"'tiCOlr<>pin
in Female R.I •. Endocr;/IOI. 81: 1117_24. 1968.
13. ChurchilL P. F.. deAlvare. L. R.. and Kimura. T,
Topological Studies of Ihe S teroid Hydrox)'l"e
Complexe. in Bo.ine Adrenocortical Mitochon·
dria , J. Bio/, Ch'nt. 153: 4924_9.1979.
14. COChct, M .. Chang. A. C. Y.• and Cohen. S. N,
Charaelcri .. lion of the Siruclural Gene and Pu·
lative 5'-Regulatnr)' Sequence< fnr Human Pro-
opiomela!lOCQflin. 297: 335-9.1982.
IS. Colby . H. D. Mcoh.ni.m of AClion of Prolacli n
on Adrenocorlical Sieroid Secrelion in Hypoph)'.
$COtomi>ed Female R.t,. Endoc,;noJ. 104: \299_
1303.1979.
16. Dallman. 101, F.. Engeland. W. C ... nd McBride,
M, H. The Neural Regulation of Compcnsato'}'
Adrenal GrolO.'lh , N. Y. Arod. Sri. 297: 373-
92.1977.
17. Dallman. M. F.. Engeland. W. c.. Rose. J. C ..
Wi\ki=n. C. W.. Shin",ko. J.. and SiMenbull!,
F, N),cth emcral Rh)'lhm in Adrenal Respon,ive-
ne .. 10 ACTH. Am. J. Ph},J;{}I. 235: R21 ().. R2 IS.
1978.
lJO..,el,. A. J .• LJ. . n. G .• v,.ell)<. U. H .. aM LJ"
liberlo. E, J.. J r.. Secrelion of Newly T. ken·Up
Ascorhic Aeid by Adrcoomedulla,}, Ch,omaffin
Cells. Sci.1IN 216: 737-9. 1982,
19. D.ugh.day. W. H. Ante,ior Pituitary, Chap. 2.
1'1'.21- 76 of Ingbar. S. 11 .. ed. C{)fllrmpo;Q'Y Ell"-
d()CT;fI(}IOf}-', ,'01. I. Pl enum. r>ew YO'k . 1979.
20. Dc Wied. D. Piluil',}, Ncuropcplide,.nd Ben",',
io'- PI'. 297_3 14 of F",e. K.. HOkfelt . T .. and
L"ft, R. C. mrol (}f Ih. f:1I(l""r;nt Sys-
r.m. Plonum. New Y"'k. 1979.
21. Diamond, E. J.. Manin, C- R., ar><! Monde,. C-
Effeel of Proslaglandin and Indomelhacin 00 Cor·
lioo$1eroidogene.i, in the lsolat<d Perfu""d Rat
Adrenal , TA. PAy#%g;J1 1j: 119 (abm,). 1972.
22, Dcugl••. W. W.. and T...,kevieh, P. AClion Po-
in Gla nd Cell. of Ihe R.I Pil"it.r), Pars
lntermedia : Inh ibition by Dcpam inc. and Inhihi·
lor of MSH Secretion. J, PhYJiol. 185: I 71_84.
1978.
23. DuBois. R, N .. Simpson. E. R .. Tuckey. J.. Lam-
bclh. J . D.. • ,d Wate rman. M. R. for.
Highe' Molecular Weight P,ecursor of Chol ....
terol Side-Ch.in-Cle.vage Cytochrome-P450 and
[nduclion of Mitochondrial and CyloooUc Pro-
tein. by CorliCOlropin in Adult 8();'ine Adre nal
Cells, Proc. Nail, Acad. Sri. USA 78: 1028-32.
1981.
24. urp, H. S .. Il l. W"$OT(, B. S .. and Ney. R, L.
Ade"",ine 3',S'.Moooph"'phale os the MMi.lOr
of ACTH·lnduced Ascorbic Add Dcplclion in
Ihe Ral Adrenal. f.-ndoc'inoJ. 87: 118- 23. 1910.
25. Engel.nd . W. C.. and Dallman. M. F. Neu ..1
Medialion of Compensator)' Adren.1 Growlh.
EndtX'il!Oi.99: 1659-62. 1976.
26, Farer.c. R, V.. Sabir. A. M.. and Vando,. S . L.
Adre""""'ticotropin Acutei), Iocr•• "", Adrenal
Phosphoinosilide •. J. BjO/, Ch,m, 254: 6842-4.
1979.
27. Free. C. A.. and Paik, V. Adrenal Steroidogenic
AClion. of C),clic Nuclcolide [)c,ivative< in the
R.I . EndtXril!Oi./OO: I 281-9J. \977.
28, Fricdman. D. L. Role of C)'elie NudCOlides in
Cell Gro",·t h and Differenliation , Phy';ol. Rn'. 56:
652-708.1976,
29 . Gillie<. G .. and Lowry. p, J. Co,licolropin-Re-
leasing Hormone and il' ValOpre .. in ContenL
F"(NII;tT. I'\'"""",ndocr;no/, 7: 45- H. 1982.
30, Glickman. J. A.. Carson. G. D" and Challi'. J. R.
G. Differenti . 1 Effects of Synlhelic Adreoo-
corlicOlr<>pin ' -" and ,,·Mclanocylc-Stimub'ing
Hormone on Adre nal Funclion in I [um.n and
Sheep Fetu .... 1Q4; 34_9. 1979.
31. Gospodar,,",,'icz. D.. III. C. R.. Horn,by. P. Land
Gill, G. N. Conl,ol of Bovine Fibrobiasl
Fae,or. Lack of Elfecl of Epidermal Growt h Fac-
to,. £ndoc,jrwl. 100: 1080_9. 1917.
32. Gospodarowicz. D.. and Mnr.n, J. S. Gr,,",,'th
faclors in Mammalian Cell Cuhu,e, Arm, R.v.
B;tXhe1t!. 4j: 531 - 58 . 1976.
n. Guthrie. It A. Mosby. SL
Loni •• 1919.
34. IJwynne. J. I .. "nO Noy. !t. L. The ,\deenal Cor-
te • . Chap. 6, PI'. 173-231 of lngb." $. H .. ed.
Conumpora,y Plenum. New
York,1979 ,
35. G wynne. J. T .. and Ney. R. L. The Adrenal Cor-
tCx. Chap. 5, PI'. 161-89 of l!I,Ilbar. S, H .. cd,
Y oar £OO(><:,,-noJog),. 1977. Plenum. Ne", Ynrk,
\ 978.
36. Halmi. N. $ .. and Moriarty. G. C. The Celi, of
O rigin (}f ACT H in Man. N Y. Arod. Sn'.
197: 167-81. 1977.
37. lI.rpc'. J. F.. Che ung. W. Y.. Wallace. R. W..
Huanj:. H,-L.. levine, S. N .. and Sieiner. A- L.
Loo:.liution of Calmooulin in Rat Tissues. Pror,
Nail. Acad. Sc;, USA 77: 366-70. 1980.
J8. Hayne •. R. C .. k Tbw,ie<on Mode of Act ion of
ACT H in Sli mula ting Secretory AClivil), of Ihe
Ad'enal Corte,. Chap, 6. pp, 69_76 of Bla""hlo,
Ii .. Sayers. G .. and Smilh. A. D.. ed,. Handboo1l
{}f PhyJi%/!J'. ""c, 7. vol. 6. American Phy,iolog·
ical Society. Wa,hington, D,c.. 1975.
38A. Hook. V. Y. H .. \lei,Ie,. $ .. and Axelrod. J. Cor-
licotropin-Rele.. ing Faclor Slimul'les Phospho-
lipid Melhylalion and CorliCOlropin Secretion in
Mou .. Piluil'ry Cell •. P'oc. NOlI. A({}d. Sci.
US A 7P: 622()..24. 1982.
39. florn,by. P. J.. O'H.re. /1.1, J .. and Neville. A. M.
Func,ional and Mo,pholo!ieal Observalions on
Ral Adren.1 Zona Glomerulola Cells in Mono-
layer Cu lture , Elldocr;l!Oi. 9j: 1240-51. 1974,
 AOIlENOCORTICOTFIOPIN AND CORTICOTROPIN·RElEASING HORMONES
4fl. Hua",. W._Y .• Chang. R. C. C. Kastin. A. J ..
Coly. D. H .• and Sehally. A. V. l$Clation and
Slrycture of Pro-Methionine--Enkephalin: Polen-
ti al Enkephalin PrecurSOr from Porcine Hyp<>-
thal.mu,. Pro<:. NaIl. Acad. Sci. USA 76: 61
SO. 1919.
41. Jaanu •. S. D.• Rosenstein. M. J .. and Rubin. R.
P. On the Mode of Aetion olf ACTH on the I$()-
lated Perfused Adrenal Gland. J. Physlol. XJ9:
539-5-6.1970.
42. Jacquet. Y. F. ,6-End<>rphin and ACTII-Opialc
f'<:ptide. witb Coordinl ted Rolle. in the Regula-
tion of Beh •• ior? T-md. in N. urosdtll<tJ 2: 140--
3.1979.
43. Jonos. M. T .• Gillham, D.. and lIilIhouse. E. W.
The Nalure of Conicotropin R.I .... ing Facler
from RII Hypothalamus in Vitro. Fd. "'lX:. 36:
2104-09.1977.
44. Jon... M. T.. Hillhouse. E .. and Durden. J. Se<:re-
tion olf Corticolropin_R.le.sins Hormolne in
Vitro. Fromi, rs in N.wo,ndlX:rinol. 4: 195-226.
1976.
45 . Joseph. S. A.. and Knigge. K. M. T he Endocrine
Hypothalamus: Reo.nl Anatolmical Siudie<. pp.
15_41 of Reicblin, S .. Daldeuarini. R. J.• and
Manin. J. D.• cd •. 1M Hypolhalamu•. R'''''n
Pr .... New Yor. 1978-
46. Kalin. N. H .• RiSCh. S. C .. Cohen. R. M.• In<ol,
T .• Ind Murphy. D. l. Deumeth..one Fail. te
Suppress II_Endorphin Plasma Concentratioln> in
Human, and Rhe,u, Monkeys. S,i'II('109:
8.
47. Kaneko, M .. K.. Shinsako. J., and Dall-
man. M. f . Adren.1 Sen.itivity to AdrollOCOrti_
<:Q\ropin Varies Diurnally, f.:..a(>(:'inol. 109: 10-5.
1981.
48. T. Cyclic NuciWlid .. and Hypotnailimic
Hormone" C hap. 16. pp. 2H-SS ef Cramor. H.•
and Sehuh. J .. ed •. 0'('/10
M«hDmJms 0/ Ae/ioM. Wiley. New York. 1977.
49. Kapl.n. S. l .. and Grumbach. M. M. Develop-
ment of Hormonal Secret;on by th. Humin fetal
Pituitary Gland. F'()I!fl.rs In . •:
255-16. 1976.
,;(), Kendall. J .• and Orwoll. E. Anterior Pituitary
Hormone. in the Brain .nd o.her E'lr.-Pituitary
Sitos. Itt N,u'otndof'inol. 6: )3_65.
1980.
SI. Knisht. M .. and Kke. W. A. Enkephalin Gentr_
aling !\Ct ivily ef Rat Brain Endopeptid ..... J.
8io/, Ch,,,,. 254: 10426--30. 1979.
52. Ko>anen. P. T., Fausi. J . R .. Brown. M, $ .. and
Goldstein. J. l. Low Den.ity Lipoprolein Reccp-
lOll in Bovine Adren.l Conex. L Reoeptor-),1e-
dialed Uptake of Low Den.ity Lipoprotein and
Utili"tion o f its CholeSterol for Steroid Synthcsi,
in Cullured Adrenocortic.1 Cell •. t·ndoerlllGl.
I()I: 599-609. 1979.
53. Krieger. D. T .. cd. £ndoaiM Rhylhms. Raven
Press, New York, 1979.
54. Krieger. D, T. NeulOCndocrinoiogy, Ch.p. I. pp.
1-19 of Ingbar. S. H .. ed. Endo-
crinology. vol, I. Plenum. New 1979.
55. Krieger, D. T. Ventromcdial Hypothalom ie le-
sions Aboli.h Food-Shifted Ciroadi.n Adrenal
and Temperalu", Rhythmicity. Endoc' i..m. 106:
649_54.1980.
56. Krieger, D, T .. lioltta. A. S .. Hauser. H.. and
Brownstein. M. Elfec," of St ...... Adreoocortico-
lropin or C<lTIiCO$ltfolid Treatment. Adfcnal«_
tomy. or Hypophysectomy on Hypolhalamic
[mmunore.Cliv. Adrenocortio;Qtropin Cencentr,-
tion •. EndlX:,IItoI, /05:737 - 42. 1979.
57. Krulich. l .. and Fa,..e1t, C, O. The Hypotha-
lamic Itypophysiotropic Hormone,. Chap. 2. pp.
35-92 of McConn. S, M .. ed. EndOCriMO Physiol-
ogy fI, University Pre ... Daltimore. 1977.
58. labrie, F.. Pelletier. G ., Borgeat. P .. Dreuin, J..
Ferland. l.. and Belanger. A. Mode <>f Action of
HypOthalamiC Regulatory Hormones in t he Ade-
nohypophysis, FT()I!fi.,s in 4:
63-93. \976,
59. Labrie. F .. Veilleux. R.. Lefe.re. G.• Coy. D. 11 .•
Sueiras-Dia •. J .. and ::>Chally. A. V. Cort icOtro-
pin.Relea,i", Foctor Slimulat ... Accumulalion of
AdCOO$ine 3',Y-Monophosphate in Rat Pituitary
Corticotrophs. Sci'II(' 216: 1001-8, 1982,
60. umbelh. J. D., Seyben. D. W., and Kamin. H.
Ionic Elfects on Adrenal Steroidogenic Eleclron
Tra .. port . J. 8iol. eh"". 154: 1979.
b l. Larsson. 1..1. and Rehfeld. J . F. Piluitary Gas-
trin. Occur in Colrtio;Qtroph$ ond Melanolrophs.
...u 2/3.- 768- 7fl. 198 1.
62. laycboc., S. G.. l andon. E. J" and Hardman. J.
G. The Elfect of Adrenocorticot'opin and Nueleo-
lid .. on Ca" Uptake in Adrenocortic.1 Micro-
oomal Ve.icle •. £ndlX:ri""'. /OJ: 2198-221J6.
1978.
63. La ychock. S. G .. W. rner. W.. and Rubin. R. P.
Funher Studies on the Mechani'ms Colntrolling
Ptostagl.ndin Biosynthesi. in tbe Cat Adrenal
Colrtex: The R<>Ie of Calcium "nd Cyclic AMP.
t·ndocrlnol. I(}(J: 14-81. 1977.
64. llanos, A. J .. RamaChandran, J.. CrCO$y, R. K..
Rudolph. A. M .• and Scron-Ferr<. M. .,·Melano-
cyte-$timulating Holrmone and AdrollQCOrt icOtro-
pin in tho Resulation of Glucocorticoid Secretion
during Ihe Perina .. 1 Period in Shtcp. End",ri""'.
IOj: 613_17. 1919.
65. loh. Y. P .. and Ga iner. H , The Rolle ef the Car-
bohydrate in the Stabilization. Proce .. and
Padaging of the Glyccsyl31ed Adrtn()(:Qrtio;Qtro-
pin.Endorphin Common Precursor in Toad Pitui·
lari ... Endocriltol. IOj: 474_87. 1919,
6(" Loscalzo. D.. Nislko. G .. and Pre,ios;. P. A Pos-
$ible Dissociation of ACTH Elfects on Ihe Ad ....
nal Gland, a, RC'uled by Amiooglutethimide,
Rsch. ("0"''''. 1.- 55_62.1970.
61, Lowry. P. J .• Silman, R, E .. Hope. J .. and Scott.
A. P. StruCtufC$ and Biosynthe$i, of Peptide. Re_
 la1ed 10 Cor1iOO1ropin, and II-MciMOlropin •.
Ann. N. Y. Sd. 197: 41-60. 1977.
68. Main •• R. E., and Eippo:r, B. A. Coordin .. e Sy'"
Ihoois and Rei •• ,. of Cor1icotropin .nd Endor-
phin. Chap. 13. Pl'. 143-57 of Usden. E. Bun""y.
W. E.. and Kline, N. S ,. eds. l:."ndorphillS in M....
ia/ Odord Uni.e .. i!}' Pro",
N.w Vork. 1979.
69, M.ran. J. W" and V•• e•. F. E. Coni$Ol Seerelton
during [ntrapilui.ary Infusion of Angioltn,in II
in Conset<>U' Dogs. Am. J. Phy.iol. 133: E273-
E285. 1977.
70, McEwen, B. S. Influence. of Adrenocor\ka l Hor-
mone. On Piluil.ry and Brain Fun.,ion. Chap. 25.
pp. 467-92 of Bax1er. l. D., and Rousseau, G. G"
cd., Glut:IX(JTtkoid IIDrmOM Springer_
Vcrlag. New Vork. 1979.
71, Mei.,. A. H. Daily Varia,i"" in Concentral ion of
Plasm. COrtiCOSleroid in Hypophy><ctOll1il.ed
Rats. Emi{)(:rinol. 98: 1475_9. 1976.
72. Mi lner. A. J. ACTI! and lhc Differen1i.,ion of
Adrenal Conicol Cell. Grown In Prim..}'
Ti .. ue Culture. l:."nd{)(:rinol, 88: 66- 71. 1971.
73. Moore. R. Y. The Analomy of Central Neural
M.chani,m. Regula1ing Endocrine Rhylhms. pp.
63-87 of Krieger. D. T. ed. Emi",",;n< RhYllrm•.
Ra.cn Pre ... Ncw Vork. 1919.
74. Moriany, G. C He1.roge""i1}, of ACTlI-Con-
1aining Cell. in Ihe Ral Pilui1ary. wilh Emphasis
on Ihe Slruelure and FunClion <>f 1he I nlcrmediale
Lobe. Ann. N.Y. Sci, 197: 183-204. 19n.
75. Munemura . M.. Co.e. T. E-. T,urU1 •. K.. &kay.
R. L.. and Kebabian. J. W. The Dopan,ine R.-
ceplor in Ihe I nlermediale Lobe of Ihc Rat Pilu-
itar), Gland: Pharmacologic.l Characleri'Ation.
EmiQujJt()/. 107: 1676-83, 1980.
75k Neh ... R .. Milani. A.. SalllM. A. R.. and Po-
desl ' . E, Compartmentalizalion of Corlic<>lropin-
Dependen. Sleroidogenie F.et()l'S in Adren.1 Cor-
le" for a Pos1·Trans lalion.1 Casc.de in
Stimulalion of tile Chole.sl.r<>l Side_Chain Splil.
PT{)(:. Nail, Aead. Sci, USA 79: 1727-31. 198 2.
76. N,,),. R. L. Effects of Dibulyryl Cycli. AM P On
Adrenal Grow1h and S1eroidogenic Capacil)'.
d{)(:Tinoi. U 168-1 70. 1969,
17. Nolin. J, M. Inlf.cellu lar Prolaclin in Ral Corpu,
LUleum and Adrenal COrtex. End{)(:TiJt()/. 101.-
402-6.1978,
78. Ogle. T. F .. and Kitay. J. I. lnleraelions Of Pr(>-
I,clin and AdrcllOCQl"Iico1ropin in lhe Regul.lion
of Adrenocortical Secrelions in Female Rats. f;If-
drx,jlW/. /()4: 40_4. 1979.
79. Orwell. E.• Kendall. J. W.. Lamoren •. L and
McGilvra. R, Adr.nocor1icotropin and Mclano-
cylc-Slimul"ing Hormone in the Brain . f:nJcTi-
noI. 1()4: 1845 - n. 1979.
80, Parker. F. S.in and HormMe., Chap. 2) . pp.
1080-98 of William •. R, H .• ed. oj Elf-
d{)(:Tinolog)' 61h cd, S.und.... Phil.delphia. I.
81. Pavel. S .. Cristo.can". A.. Gold ... in. R... nd
C.lb. M. Inhibilion of Cortic<>lropin Rel • .,ing
Hormon. in Ca" b)' E"remely Small Amounts of
V'$(lI.ocin I njeel.d inlo the Third Ventric le <>f Ihe
Br.in. Evidence for Ihe I..olvemem of 5-Hy-
dro'ytryptamine-COn1aining Neuron •. EmirxT;_
noI. /0/: 672-8.1979.
82. Pearlmuller. A. F .• Rapino. E.• and Saffran. M .
The ACTH-Rele •• ing Hormone of Ih. Hypothal-
amus Requires " Co-Factor. Emi{)(:,inol. 97:
13)6-9.1975.
8) . Pederoon. R. C. and Brownie. A. C. CholesterOl
Sid • .ch.i n Cleavage in lh. Ral Adrenal Cort."
1$Olalion of a Cydohe, imide-ScnS ilive ACli.alor
P.plide , P,{)(:. NDI/. AClld. 5<-;, USA 80: 1882 - 6.
1983
83A. Ped.tsOn. R, C .. Browni • . A. c.. and ling.
N. Pro-Ad re nocort iCOl ropi nI Endorphin-Dc ri.ed
Pep1ides: Coordinate AClion on Adr.nal S.cr<>id_
ogene"i •. 108: 1044_46. 1980.
84. P.,ch.llel. l.-P .. Shanl-.cr. G .. and Sharma. R, K.
Regulalory Role <>f Guanosine 3'S-Monophos-
phale in Adr.nocorticotropic lIormone-lnduced
Steroidogcne,; •. Scienn 1<;<;: 3 11-12, 1978,
8S. Perohell.l. J ,_P.. and Sharma . R. K. Med i>lory
Role of Calcium and Guanosine ) ', S'-Monoph"".
phal. in Adr.nocorlicotropin-Induced St.roido-
gc"".is by Ad« .. 1 Celi>. Sdencr 203: 12S9-61.
1919.
86. Perchell.I, J.-P .. and Sharm •. R, K. Slimul"ion
of GuallOlline 3',5' -Monophosphalc Ph<>sphodies_
Ie,.", ACli.i1y by Adrenocortico1ropic lIormo",,-
Aeti.aled I"",.a ", of Guanosine l'Y_Monophos-
ph.,. in 1$Olal.d AdroJlOC<)n;cal Carcinoma
Cell •. EmirxTint>i, 105. 879_83. 1979.
87. Qui,ley. M. E.• and Ven, S. S , C. A Mid-Day
Surge ,n COrli$01 l,,'el •. }, EnJouinoi.
Metal>. 49: 94S-7. 1979.
88 . Rae. P. A., GUlmann . N. S .• Tsao. J .. and Schim_
m.t. B. P. Mu.ations in C)'dk AMP-d.pendenl
Protein Kin.,. and Corticotropin (ACTH)&n.
.iti", Adcnyl.,e Cyd.", AlTecl Adron.1 Steroid-
ogenesis. PTQ(:. Nail. Aead. Sd. USA 76: 1896-
1900.1979.
89 , Ram.chandran. J., Roo. A. Land lilcs.S. S, ud-
i.. of th. Trophic ACl ion of ACTfl. Ann. N.Y.
Acad Sci. 197: ))6_47.1977.
90. Ramach andran. J .. and Su)'am •. A. T. Inhibilion
<>f Repliealion of :>!Qrm.1 Adrenocorlieal Cell. in
Cullure b)' Adrcnocorlico1wpi n. p,{)(:, Nail,
AClld, Sci. USA 7]' I 13-17. I 975-
91. Rasmu.",n. H .• and Goodman. [). B. P. Relalion-
.hip$ be1ween C.lcium and CyClic ]'; ucleoo.id.. in
Cell Activalion . Ph),Ji"', R<v. j7: 1977.
92. Renaud, l. P. Neurophr>iologic.1 Organi7l11ion
of tbe Endocrine Hypo1halamus .• pp, 269- 300 of
Reichlin. S" Balde... rini, R, J .. and M.rtin. J . 8,
Th, HYP<',haIDmu" R.. cn Pr .... N...' Vork.
1978.
9) . Rcos. B. A. Effect of ACTH and cAM P on
Human Adrenocorlical Growth and Funclion in
V;tro. Emi{)(:,int>i. W: 6NS_90. 1974.
94. Rubin. R. P. Calcium-Phosph<>lipid [0lorac1ion in
Secrelory Cells: A Ne.· PerSpecl;v. on Slimulu,_
Secrelion Coupling. Fd. hoc. 41: 2181-7. 1982.
'"
95. Rubin, R. p" and Lalch<>ek, S. G. Prost3g1andins
and Calcium·Membrane Interaction. in s.c*
lory Glands. Ann. N.Y. Acad. Sri. )07; 377_89.
1978. (O;,c"uion. pp. 389-390,)
96. Rusw-),1.,ie, F.. Paing. M .. and Duv.l. D. In·
""I.omen' of Glucoool'I;co;d R=ptors in Steroid·
Induced Inhibition of p",.taglandin Secretion. J.
Bioi. Chtln. 254- 8498-8504. 1979.
97. Sa.,. J. M .. Mor<,a. A. M ..• rId G.llet, D. Op-
posite Effect, of ACTH and GluCOCQrliCQid$ o n
Adren.1 DNA Synlbe.is in Vi.o, i::nd"nloo/. 100:
1268_75.19i7.
98. Saffran. M. Hypothalamic Comrol of Ihc Socr.-
tion Qf Melaoocyle-Stimul",ing Hormone (M$H )
and AdrcrIQC()rticOlropin (ACTtl). Chap. I L pp.
225- JS of Pon.r. J. c., cd. HYfXJ/h{J/amir
HOI'f>umtS and PilUiM'y Rrg.lalion. Plenunt.
New Y,.,.k. 1971.
99. S.ito. E.. Mukai. M .. Muraki. T .. lehik.", •. Y ..
.nd Homma. M. In.ibilory Effoo" of Coni<:<»'c-
ron< on Cell Proliferatioo and St.roidogenosis in
lhe Mouse Adren,l Tumof Cell Lioc Y·L Endo-
crine/. 487-92. 1979.
100. S.)'ors. G. Nature of Cortiootropin Rele •• ing
FaOI(lf. Fd Prcc, 16: 2087.1917.
10 I, Sayers. G .. and Portanova. R, Regulation of the
Soof.' '''y Aelivil),of lhe Adrenal Corte" C"'liwl
and Corticosterone, Chap, 4. pp. 41-H of
H., Saye .. , G .. and Smith. A. D .. ed.,
J/Q"dl>ook of Ph,.sio!0fJ)' • • e<:. 1, V<J1. 6. Amerieo.
Phy$iological Society. Washington. D.C.. 19H.
102. Sch.lly. A. V .. Arim.ra. A .. Coy. D. H .. K.Sl i•.
A. L Meyers. C, A .. Redding. T. W., Chi'ara.
K.. Hua",. W. Y .. Chang. R , C, C. Pedroza. E..
and Vil.hoz-Maninez .. J. Hypothalamic 110r·
n",ne$ Regulating I'ituitary (.nd other) Fu(\O.
tio",: neir Phy$iology and Biochemistry. as ,",'ell
a. Re«n' Studies wilh 'heir Synth.,i. AnalQg$.
pp, 9- 29 of Fux<, K.. HOHell. T .. and Luft. R ..
cd • . Rtr ulmlon of Sy",,,,,
Plenum. New York. 1979,
103. 5chimmer. B. p.. Ueda. K ... nd S.to. G. H. Site
of AClion of Adrenocortic"'-ropic Hormo ..
(ACTH) in Ad",n,1 Cdl Culture •. ... , 8i.,.
ph,.•. Rt'. Com .... 12: 806_10. 1968,
11)4. Seh«y. M . P.. and Rubin, R . P. Ch.racterizatton
of. Calcium-medi.ted Ac,i"lton of Arachidonio
Add in Ad«nal Ph<l>pholipids by Cor·
liCQIropin, J. Bioi, ('htm. 11234_41. 1979.
105. Seoli8. S .. and Sa)·ers. G . B<wine Hypothalamic
CoriioC>tropin Releasing Factor: Chemical and 8i·
oIoric. 1 ... Ft<!. PlCC. 36: 2100-03.
19n
11)6. Segal. D. S., Browne, R . G .. ArnSten, A .. a nd
Derri",lon, D. C Characler;'lia of p.Endor.
phi,..!nduced Beha.ioral and 1m"..,.
biliz.a\ion, Chap, 28, Pl'. 107_124 of U.din, E..
Bunney. W .. Jr., and N. 5 .• cds . End(N'-
pM'" in Oxford Uni".r·
. ity Pres •• New York. 1979.
AND CORTICOTROPIN-RELEASING HORMONES
107. Seybert. 0, W" Lancaster. J. R" jr" Lambeth. j ,
0" a nd Kamin. H. P.nieipalion of lhe Mem·
br.n. in the Sid. Chain Cl<a'a8e of Cholalerol.
J. Bioi, Ch,m. 154. 12088_98, 1980.
108. Shima,S .. Kawa,hima. Y .. Hirai, M .. and A •• k·
ura. M. S,udies on Cyolio Nuelootid« in the
Ad«nal Gland. X. Elfecl.of Ad«nororli<:olropin
and PIWlaglandi. on Adenylote Cyola" Aoti,i'y
in th. Adrenal Cortex. Endl><rillOl. 106: 948- 51.
1980.
IW. Simpson. E. R .. Cm. B. R .. Parker. C R.. J r..
Milo,.ich, L.. Port ... J. C .. and Macdonald. P. C
The Role of Serum Lipoproteins in Sieroidogen.
esis by the Human Fotal Adrenal Corte,. J. Clin.
Endcc,,·nol. Mtwb. 49: 146-8. 1979 .
110. Simpson, E. R .. McC.rth)', j, L. and J.
A. E.idence that the Cyciohe,imide·.... ilive Sile
of AdreoocotlicOlropic Ilormone AClion i, in 'he
Mitochondrion, J. 81a1, Cht... , 253: 3 t 35- 9. 1978,
I II. SI.ok·Du"no. M . p, The Action of PilUi'",y
Preparation. on Ihe Adrenal Cortex. pp. 133-43
of WoI".nholme. G. E. W.. ed. BiOlJsj(lY of All<-
te,ior Piluilary and Ad"''''''''''ica! HQm",,..•.
Ciba Found.lion Colloquium on Endocrinology.
LillIe. Brown. Boslon. 1953.
I I 2, S"lIon. R. E.. Koob. G . F .. t. Mool, M" Rivier.
J .. and Vale. W, Corticotropin Rdea.i", Fa.lor
Produces Beha,ioural ACli'alion in R.... oVaiur.
]<;7: 331-3,1982
11), Tohh •• hi. K .. lIoudo, K.. K .. Ib),_
afuji. C" Otani, S ... nd Takah .. hi. V. o.:.dol>'
ment of the Circadi.n Adrenocortical Rh)'lhm in
R.to: Studied by Delerminat iOn of 24· or 48-
Hour p.tlor .. of Blood C"'li<:O:lt.,onc Level. in
Individual PupS. ,,'ndcc,illOl 954-61. 1979.
I I lA. Tan.ka. I" Nakai. Y.. Nakao. K .. Oki, S.. Yo<h·
imasa. T .. and ImUl't. H. l,_Melanolropin.like
Immunoreacli'ily in B<winc and Hum.n Ad,-e..
oocotl iCQtropin.ProdUCing Ti"ue., J. Clin. Ell<-
dl><r;no/. Mtlab. 56: 1080-83. \981.
\ 14. Thody. I\. J. MSH
N.,. York, 1980.
II S. Vale. W" and Ri,ier. C, Substances Modul'ling
Ihe Secretion of ACTH by Cultured AnteriOf Pi_
lui!ar)' Cell •. FNi. Prcc, 36: 2094-9.1977.
1151\. W .. Ri.ier, C , Brown. M, R .• Spit$<, J ..
Koob, G" Sw.nson. L, Bil.zikjian. L.. Bloom, F..
and Ri.icr. J. Chemical and Biological Chorac-
te,iUlion of Corticottopin-R.le •• ing F.Clor.
PrOf. HOT .... Rts. 39: 245-70, 1983.
116, Vale. W .. Spi •••. J" Rivier. C. and Ri,ier. J,
Cha .. elcriUtion of a 41·Residuc O.ine llypoth •.
lamic Peptide th.t Slimulata Seerelion of Corti-
cotropin and p.Endorphin. 5,it"'-" 213: I 3<f4_1,
1981.
117. Wtl.h. S. W .. Norm.n. R. L. and Nory. M, J.
In Ute,o Regulalion of Rhesus Monkey Felal
Adrenal l: Effec" of Dexamelh • ..,ne. Adrenocor·
ticotropin. Thyrotropin·RoIe • • ing Hormone. Pro-
laclin, Human Chorionic Gonadotropin, and
 a- Molal'lOC),le-Slimulaling Horrrt<>n< on Felal and
Malernal Pla,ma Sleroids. f.·ntlocr;I1O{. 1M:
18CS-IJ.1979.
118. Ways. D. K.. Mahaffee . D. D .. and Onljcs. D. A.
An Ad renocorticotropin Analog fACTI! (6-39)]
which AC\5 .s a Potenl In Vitro Ad renoconicotro-
pin Anlaioni" al Low Calcium Concentralions
ond U a Weak Agonist at lIigh Calcium Conecn.
ualion'. Endocrino/. 104: 1028-3S. 1979.
119. Westall. F. C .• Lennon. V. A.. and Gospod.ro"-
iez. D. Brain·D<rived fibrobla. , Growl h Faclor:
Idenlity ,,"'ilh a Fragmenl of Ih. Ba,ic Prolein of
Myelin. P"",. Norl. A cad, Sci. USA. 75; 4675_8.
1978.
A·1. C""aglen. J. V,. Dooald. R, A.. E.pi ner. E. A..
Livesc)'. J . It..nd Nicholl•. M. G. The Elfeelof
Ov;nc Cortlcolropin·Releasing Fa"", on Calc'
eholamine. Vasopressin. and Aldoslerone $cere-
tion in Normal Man. J. elin. J::ndocrino/,
58.46 3-6.1984,
A·2. Fehm . H. L and Kle in. E" Holi. R.. and Voigl. K.
II. Evidence for E''''piIUilary Mcchan ;,m s Me·
di'ling Ihc Morning of PI.,m. Corti sol in
M.n, J. Clin. J::ndocrino/, Mtloh. 58: 41 0-14,
1984.
A·3. Glo,,-'. A. R.. Za,-.dil. A. P. I II . Halberg. F. Cor·
neli..., n. G .•• nd Schaaf. :>'1. CiTCldian Rhythm of
Se rum COrli<Qi in Cush ing', Dise ... , J. elin. En-
docrino/. Mttohl. 59: 161-S. 1984.
A-4. Ilermu •. A. R, M, M.. Pieters. G, F, F. M.. Smals.
A. Ii .. 110:", . au. T. J.. a''''! "1,,,,1'<"""');'
C. Plasma Adrenocorticotropin. Cortisol. and AI·
dOSlero"" Respon.e. to Corlieolropin. Rclea$ing
Factor: Regulalory Elfect of Cortisol l.eoels. J.
Clin, Emiouino/, Mnab. 58: 187- 91. 1984.
A·S. Jadson. R. V.. DeCher"e),. G. S .. Ddlold . C. R ..
Sheldon. W. R.• AI ... nder. A, N.. Rivi.,. J..
Vale. W.. and Orth. D. N. S}'ntbeli. Ovi nc Cor·
tlcolropin-Relea.in$ I!",rrt<>n<: Simullaneous Re--
loa", of ProopiolipomcJanOCOrt in Peplide' in Man.
J. Clln. Endoc,i'lOl. Mnab. 58: 740-3 . 1984.
120. Wilkinson. C. W .• ShiMa'o. J .. and Dallm.n. M,
DaHy Rhylhms in Adren. 1 Respon.ive n... 10
AdreflOCOrliCQtropin arc Determined Primarily by
the Time of feeding in lhe Rat. cndocr;no/, {(H:
350----9. 1919.
121. Yate •. F. 13 .. and Maran, J. W. Slimulalion and
I nhibilion of Adreoocorticotropin Release. Chap,
36. pp. 367-404 of "n<>biL K.. and Sawyer. W.
II .• ed •. Hondbook of Ph,·s;ology. sec. 1. vol, 4.
ParI II. American Societ)'. Wa,h·
inglon . D,C .. 1974,
122 , Zarrow. M. X.• Yochim. J. M.• and McCarthy, J.
L EX!"rim,nlal Endocr;l!()/oty, Academic Press.
New York. 1964.
A·6. Keller-Wood. M, E.• and Dallma n. M. F, Curt i·
casteroid Inh ibili"" of ACT H Secrction. t:"Jocr.
5: 1- 24. 1984.
A·7 . Le"'i •. D. A, and Sherm.n. R A. $crt(Hlcrgic
Stim"lati"" of Adreooc",liootropin $ccrelion in
Man, J. Clin. f.·miocri",u. M rlab. 58: 458_62.
A--8 , Mele}'. E.• Kiss. J. Z .. S kirboll. L R.. Goldstein.
M .• and Axdr<>d. J. lncre.se of Corticotrop in.Re·
lea,ing Faclor Slaini", in Ral Par. ventricular
Nucicu, Neu ron •• by Depletion of 11ypothal.mic
Adreo;,li ... JIO: 140- 1. 1984.
A·9, )'1e,C}'. 10 .. Reisine. T, D.. Pal kovilS. M .• Brown·
"ein. M, J.. and Axdrod . J. Direcl S,imulat ion <>f
IJ,.Adrencrgie Reeeplors in R., Anterior Pi,u·
itary Indu"., the Rele.", of Ad renocortiCOtropin
p, w. in Vivo. !'roc. NUll. Acud. Sci. USA 80:6128_31 .
19H
,\ · 10. Vilg,.in. I.. Cochet. C .. and ChamN,. E. M, Hor-
mon" 1 Regulation of a Phos·
pholipid·Dcjl<ndont Protoin Kin""" in
Ad,enal Corle> . J . 8iol. }59: 3403_6.
1984.
A- II. Wood. C. E.. .nd Rudolph, A. M. Can Malern.1
SITe.. Alter Fetal Ad reooconieotropin Secretion'
cndocrino/. 115: 298-301. 1984.
 8
Catecholamines, Serotonin, and Related Regulators
The major catecholamine! arc norepinephrine (N,
nomdrcnaline). epinephrine (E. adrenaline), and do-
pamine (DA). The minor OI1CS include cpinine. oc-
lopaminc:. and related "false transmitters." All have
a dihydr01)'phcnyl (catechol) group and an amine
CQmponem, wilh Ihc following common structural
features.
, ,,"
',7 ' ,
C-C-N / hormone, since most of it is made in the adrenal
."'-, I, I I "-
"0
Same calechol. Ihal are not amines (c.g. dihy-
droxyestrogens) interact with receptors for thc
amines and wilh the enzymes catalyzing their
SITES OF BIOSYNTHESIS AND STORAGE
In mammals. most of the N is made in sympathetic
neurOnS. The fibers arc distributed to blood vessels,
and to a wide variety of organs thai include lite liver.
kidney. and pancreatic isicls. The heMt. spleen, and
vas deferens receive rich innervations (33). Human
lu ngs and skeletal musele arc major sources of blood
N (A-3).
N is made in discrete regions of the brain. and it
accounts for approximately one·third the catechol·
amine (CA) content of that organ. Thc highest oon-
centrations arc found in the paravcntricu!ar. peri-
ventricular. dorsomedial. arcuate. and supraoptic
nuclei of the hypothalamus and in the prooptic re-
gion. The amine gets there from cell bodies in the
locus e<:rulcus and neighboring regions of the brain
stem (25).
Brain N is used and degraded locally. Peripheral
ncrves release substantial quantities of N into the
sj"'Jtcmic circulation. and the nerve endings also take
up N from the blood . However. much of the plasma
N originates in distinct populations of adrenal med-
ullary c<:lIs (63). The concentrations vary widciy
with the physiological status. Under "resting" con-
ditions they arc in the gencral neighborhood of 0.3
nglm l in many species (26).
Epinephrine has long been regarded as a "proper"'
glands and released into the bloodstream. h was the
first humoral regulator to have its chemical nalUre
defined (81). The plasma concentrations under
"'resting" conditions are approximately 0.05 n8lm in
humans. The levels vary markedly with the species
as well as with the ph)'1iologieal state.
Epinephrine is prescnt in the hypothalamus and in
the medulla oblongata. It acoounts for only 5%-17%
of the total brain CA (33), but imporlance is
greater than the relative concentration suggests
(51). In frop,$ and e<:rtain other species. E (rather
than N) is thc major sympathctic system neuro-
transmitter (133).
DA i. a precursor of both Nand E. and a very
important regulator. It is continuou.ly re1ea..d from
adrenal slands and peripheral nerves (A-Il). The
plasma ooncemrations a rc usually higher than those
nf Nand E (26). It is present in substantial amountS
in the small intensely fluorescent (SIF) cells of thc
superior cervical ganglia. in the carotid a nd aortic
bodies. and in the intestines. kidneys. and lung.< (33).
DA distribution in the brain differs from that of
Nand E, and it accounts for a good half of thc total
CA content . Especially high concentrations are
found in the caudate nucleus. in the nucleu, aCCum_
bens. in the hypothalamic tuberoinfundibular sys-
tcm. and in the mcdian eminence. Some DA is also
present in the midbrain and amygdala. and in re-
strietcd fIelds of the frontal cerebral Small
quantities are additionally found in parasympathet·
ic ganglia (106). in the spinal cord. and in both cen·
tral and peripherally located mast cells of most
Sf"X'I<:S.
Melanin pigments art: made from DA. and the do-
pamine precursor accumulates;n the pigmented re·
gions of the nigra, the retina, the iri ., and
the middle ear, as well as in skin and hair (112).
EXTRA-ADRENAL CHROMAFFIN TISSUES
Fetuses ha'"C widely distributed dump. of cells CQI-
lectively known as ·'chromaffin tissue'· in which CAs
are made. The name derives from the brown oolor
that develops when the cells are exposed to diehm·
mates Or chromic acid (10). Beeause of Iheir ap-
pearance and locations, the tissue groups have also
been called paraganglia . The cells originate in. and
migrate from the embryonic neural crests and ncural
tube. The mammalian adrenal medullae seem to
form via coalescence of such cell groups. As the
glands mature in neonates, much of the chromaffin
tissue degenerates (144). Glucocorticoids play im.
portant roles in the maintenaoce of the fetal cens
and in organi7.3lion of the adrenal gland, I3xogellO\l$
stcroids retard the involution and they may increase
the total coli numbers (18).
Clusters that persist in adults include aggrega-
tions found near the aorta (the para-{lortic bodies or
organs of ZUcXerlandl), the enterochromanin li,-
sues of the gut, and clumpl; of ce1l, in the skin. kid-
ne)"ll', heart. prostate glands. and gonads.
The .ites of CA accumulation Can be identifIed in
chromatographic fractions, and by radioimmunoas-
say. The amines nuoresce when they arC treated in
suita ble way' with formaldehyde. Minute portions of
the brain have bc.:n punched out and used for anal-
ysis by bioassay. Agents that interfere with CA pro-
duction can be inje<:tcd into thc brain. and compar·
isons can then be made wilh control tissues. The ,ites
for CA biosynthesis arc studied with antibodies di·
re<;ted against en7.ymc.. needed to male the
molccuics.
RELATIONSHIP OF THE ADRENAL GLAND
TO THE CENTRAL NERVOUS SYSTEM
The adrenal medu1la is, in fact , a modified sy mpa-
thetic ganglion. and it is therefore an extension of
the «mral nervous sy,tem (82). The cell' rctain sev-
eral neuron-like properties that include loss of ability
to divide. They do not haye axon, or dendrites, but
they can be persuaded to acquire them if nerve
growth factor (NGF) is administered during early
developmental stages (64). The CAs arc stored in se-
cretory granules that art: in many ways similar to thc
synaptic vesides of the sympathcie nerve endings.
Acetylcholine-releasing splanchnic nerves serve as
the preganglionic clements. They originate in the
thoracic region of the spinal cord and COurse through
(but do not synapse within) thc celiac ganglia. Sep-
arate terminate on N- and E-se<: reting cells of
the adrenal medulla. The gland cells haw: acetyleho--
line receptors that resemble those of " truc·· postgan-
glionic sympathetic neuron, (4).
HORMONAL VS. TRANSMITTER FUNCTIONS
The adrenal medullae release small quantities of CA
on a regular basis (8, 89, 149). The hormone con-
tribute, to the maintenaoce of autonomic balance.
mostly by opposing effects of exees.,;ve acetyicholine.
Exercise, exposure to cold environments, and stress
lead to the release of much grealer quantitie:;. High
hormone Ityels invoh coordinated responses that in-
volve many target organs.
In contrast. each of the sympathetic nerves has ils
djscTelt targets (120). Thus. for cumple. if N is re·
leased by cardiac nerves. there is 00 obligatory con-
comitant release of the amine into the gut. Con-
certed responses are seen only under conditions in
which there is simultaneoos activation of widely dis-
tributcd s)'mpathctic componcnts. Thcn. tne CAs re-
leased postsynaptically and postjunctionally act sy-
nergisti,ally with the ones secreted by the
adrenomedullary cclls.
The sensitiyities of the targets vary inversely with
the distances from the souree, of the amines (20).
The postsynaptic and postjun<;:1ionaltar8Cts respond
only when the concentrations are fairly high. Therc-
fore, they are not affected by the Clls in the blood
plasma under '-resting" CQnditio/lS, T he lower sensi·
tivi ties are allribUied in pan to some ··down regu·
lation" of receptor that follows repeated ex·
posure to the regulators and 10 other mechanisms
described later. Injection of CAs into the blood·
stream therefore cannot wholly mimic the effects of
sympathetic nerve stimulation , D<:nervated organs
be<;omc hypersensitive to exogenous CAs.
Same apprc<oiation of the relative importance of
slandular compared with neural control can be ob-
tained from experiments in whiCh one component is
selectiyely affected. The proc<:dures include (a) sur·
gical interventions; (b) administration of cytotoxins
that impair <xII growth a"d survival. or interfere
with the biosynthesis, release. and mctabolism of the
CAs; and (c) presentation of antibodies directed
against either nerve growth Factor or specifIC
en7.ymes.
ADRENAL DEMEDULATION (ENUCLEATION)
If both adrenal glands arc excised , the soft materials
within the capsules are scooped oUi and discarded,

and Ihe emply capsules are "'turned to thc animals.
a slate of permanent ad"'lI\Imedullary deficiency de-
_elolX_ The'" is no "'generation of the inner com-
ponents of the glands. However. thc few cortical cells
that adhere to Ihc capsule soon grow. proli ferate.
and undergo maturalion. Within less than twO
weeks, the animals reacquire almost II\Irmal adr.·
noconical functions.
The animals ",main in reasonably good health
when kept under the usual laboratory conditions.
They compensate in pan for loss of the medullary
cells by increasing the release of N from sympathetic
neuron5 (67). and the consequences of the depriva_
tion become apparent only when special demands
arc made . Loss of the adrenal medull a impairs the
abilities to engage in strenuOUs physical activity. to
adapt to exposure to cold environments. \0 cope with
the injection of moderate doses of insulin. to sustain
blood loss, and to make the necessary cardiovascular
adjustments to sudden changes in posture. The ani-
mals show tendencies to develop hypoglycemia
under St"''' conditions. although they can still rc'
lease and utili ze glucagon.
IMMUNOSYMPATHECTOMY
Ne,,,,, growth fQctor (NGF) WQ. described in ChQP.
2 (43.86). It is essential for the growth and differ_
entiation of oomponents of the embryonic neural
C"'SIS and cspecially the sympathetic system and
dorsal root ganglion neuronS (I3S). Although it has
been suggested that NGF promotes proliferation of
very you ng neuroblast!. the major functions are pro-
lcmgation of ce ll survival. stimulation of neurite OUt·
growth. and induction of en,.ymes and other
proteins.
When antisera to NGF are gi"cn to very young
animals. thc development of the sympathctic system
permanently impaired. Transmi$$ion in the gan·
glia is affected wi th in hours after presentat ion, and
the longer-range effccts incl ude destruction of the
neuron •.
In older animals, impa irment is serious bUi at
least partially rc""rsible. Since the a ntibodies can
act only On structures they reach (21.33), the dam·
age is oonfined mostly to Ihe peripheral nervous sys·
tern. The "blood-brain barrie'" proteCtS centrally 10-
catcd cells. The anlibodies do not enter malure
ad",nal In faci. thc adrenal medullae engage
in "oompensatory" hyperfunction after the sympa_
thetic neuron, havc boen damaged (64: A.I).
The animals suffer disruptions of funetions depen.
dent on reHex discharge of N from the sympathetic
neurOnS. These a", especially marked for the ca,d i(>-
C.o.TECHOlA MtNES " NOFlEtA TED REGUlATORS
vascula, system. but the abilities \0 adapt to oold en-
vironments and to engage in sustained motOr activi-
ties a re also affected. I nnuences on the kidneys havc
addi tionally ocen demonstrated (39).
A milder. more rapidly reversible form of ··im·
munosympathectomy" can oc inV<)kcd by adminis-
tering antibodies di,«:ted against dopamine /I-hy.
droxylase. the enzyme needed 10 conven DA 10 N
and E. The antibodics do not jot.rfc", with the syn-
thcsis of new
CHEMICAL SYMPATHECTOMY
An especially useful agent for the study of CA dep-
rivalion is 6-hydroxydopamine (),4.6·trihydroxy_
phenylethylamine.6.QH_DA).
It select ivdy promotes acute degeneration of nor-
adrenergic nerve lerminals (39) and cau<;cs almost
total depiction of N in sympnlhetieally inncn'atcd
tissues. but has lillie effect on the ad renal medulla.
It does not CrOSS the blood-brain barrie r when given
systemically, but it can bo administered intracere-
bra\!y to accomplish destruction of brain neurons.
Compensatory increases in the activity of tyrosine
hydroxylase (a rate-limiting cn'.ym. for CA biosyn·
thesis) usually occur in surviving neurons (2). In
very young animals, 6-O H· DA can dcstroy thc sym-
pathctic system: but in olde' oncs it tcnds to affect
mostly ncrve terminals.
6.QH_DQPA does cross the barrier. and it is rap-
idly oonvenerl to 6-OH_DA both centrally and pe-
ripherally. The",fore. brain ne urons a'" affected if
the age nt is administe",d syste mically.
Guanethidine i5 one of se_eral agents that block
the release of CAs from ncr"" endings. It more tran-
siently interferes with the functions of
neurons. and it has been used to t"'at Ihe hypenen.
sion of patients with N-secrcting tumors (70l_

Guane\hOj;ne (Oclal"""n)
EFFECTS OF EXCESSIVE
CATECHOLAMINES
Pheochromocytomas are spontancoosly developing
tumors that pour out massive quantities of N. The
symptoms invariably include either persistent or in_
termittent hypertension, and usually also
mal tachycardia (37). Headache, sweating, elevated
metabolic rate. decreased gastrointestinal motility.
mild hyperglycemia. weight loss. and poor appetite
are other common findings.
Special techniques must be used to invoke cxper-
imental excesses. because CAs injected into the
bloodstream arC taken up by nerve endings. Or are
deslroyed by enzymes in the bloodstream and tis-
SueS. Usually, the heart is the most obviously af-
fected. and eardiotoxicity limits the ability to study
effects of CA overdosage on other organs.
Systcmically administered CAs do not get to the
brain. Thc central effects Can be obtained by admirt-
istcring the CAs into cerebral ventriCles, or by giving
DOPA or dihydroxyphenylserine (OOPS). both of
which are metabolized to norepinephrine.
Many of the consequences of E overdosage or hy_
persee""tion resemble the Ones described for N .
However, the"" arc SOme important differences in
the biological actions of the tWO amioes that are COIl-
sidered later.
DA alfects the heart. dilates blood vessels that
supply the viseera. plays major roles in central ner-
vous syStem regulation of motor functions. and ex-
erts in Huenee. on behavior that arc very different
from the effects of Nand E.
CATECHOLAMINE REGULATION OF
CARBOHYDRATE METABOLISM
As discussed in detail in Chapter S. resting skeietal
muscle cannot always ta ke glucose from the blood-
stream, because speeial properties of the plasma
membrane impede sugar entry. Feeding leads to the
release of insulin . The hormone aclS On the plasma
membranes to facilitate glucose uptake. It a lso pro-
moteS thc storage of glycogen reserves in both muS-
cle and liver.
When the blood glucose and insulin levels are in
the low-normal range. ""sting skeietal muscle de-
rives its energy from oxidation of fally acids that a rC
delivered by the bloodst""am . I r the blood sugar COn-
centrations fall, glucagon is released. and this leads
to the conversion of liver glycogen to gluOO5e. Mus-
cle glycogen is not used to maintain the blood glu-
CQ6e levels for several reasons. The <xlIs are insensi_
ti.,.e to the glycogenolytic actions of glucagon.
Morcover. they lack a glucose-6-phosphatase.
Therefore, when glucose-phosphate forms in the
muselc. much of that metabolite is sent into the gly-
colytic pathway. (Unli ke free glu= , the phosphate
doe. not CrOSS the plasma memhranes and enter the
bloodstream.) Growth hormone further facilitates
preserva tion of the glycogen reserves of resting mus-
cle. since it exerts "glycostatie" innucnces on muscle
when it facilitates glycogenolysis in the liver.
In contrast with resting cells. vigorously contract-
ing musele requires a very rich supply of ATP. Fally
acid oxidation can no longer meet the demands, and
glycolysis muSt be accelerated. This i. especially true
for the "white" or "fas!" fibers thai contain smaller
amounts of m}'Olllobin and fewer mitochondria than
the "red" or "'low" fibers (131.147).
At such limes, the muscle glycogen StOrCS assume
major importance. The need for the reserves is es-
pecially obvious after an overnight fast when the
time comes to scek out breakfast.
Neuronal stimulation of thc muscle cells leads to
the elevation of cytosol ea", which directly acti_
vates glycogen phosphorylase (32). Therefore, the
fuel supply automatically inc reases.
The adrenal medulla accelerates its rate of E re·
lease. not only during exereise, but also when vigor-
ous activity is anticipated (151). Relatively small in-
crements promote cAM P generation. The nucleotide
stimulates glycogenolysis in musde in much the
same way that it docs in liver.
When the glucose-phosphate goes into the glyro-
lytic pathway. pyrUVa\e is formcd more rapidly than
it can be converlCd to acetyl-CoA and used in the
acid cycle. Much of the exCeSs is OOn·
verted to lactate:
cm- coo-
I ,
I
HC - OH + NAO -
+ NAOH . W
I I
"C"
"
PynNate "
'"
The reaction tends to go 10 the right because: of
the low pH of vigorously conlracting muscle. the
high levels of NADH. the high levels of pyruvate,
the special properties of Ihe muscle-type lactale de-
hydrogenase. and the exil of lactate via Ihe plasma
membrane.
Several purposes are S<:1'V<'d. First, the acidity of
Ihe cell s is lowered. Thi. delays the onset of fatigue,
Second. Ihe NADH is oxidized to NAD', which can
be reutilized in the glyCQlytic pathway. Third. unlike
pyruvate, lactale readily nosses the plasma mem_
branes. FOIITlh, although SOme of the lactate is lost
into the urine. much of it is laken up by the liver and
is used 10 make new glucose.
In addition to raising circulating lactate concen-
trations. E augments blood now \0 the liver. It
thereby provides hepatocytes wilh a glucose precur-
SOr. Ordinary levels of E do not 3e<:elerate cAMP
generation or glycogenolysis in the liver. However,
very high hormone concentrations can recruit a frac-
tion of the liver glycogen that is not affected by glu-
cagon. The mechanisms. which arc cAMP-indepen-
dent. are linked with elevation of the cytosol Ca".
N has little inHuenee on the phosphorylase s)'Stem of
muscle. but it is more potent than E in the liver.
The sympathetic system can elevate bkx>d glucose
in additional ways. N and E act on the pancreatic
islets to ,timulate glucagon release and 10 inhibit in-
sulin secretion. N released from sympathetic nerve
endings augment' triglyceride lipase activity in adi-
pose tissue. It thereby "spares" glucose by providing
fany acid fuels for cens that do nOl require the
,ugar. It also accelerates the release of glycerol.
a glucose precursor. E opposes insulin-mediate<! glu·
C01<C use (A-S).
Stimuli other Ihan the Ones directly related to ex-
ereise can trigger additional CA release, Brain glu·
ooreeeptors that make functional connections with
the adrenal medulla are activated by falling glucose
levels and by the administration of agcnts such as 2-
deoxygluOO5e that interfere with glucose metabolism
(127).
Fasting augments adrenal. but dopres.c< $ympathetic
CA (A· I J). The rogulat"'" .dju.t mctabolic pro-
ce .... to food int3ke (15t). and there are conditions
which CA, can pronJOlO insulin release.
THE " FIGHT OR FLIGHT" CON CEPT
The provision of carbohydrate fuel for mu,cle con-
tmction is but one of an almost bewildering array of
actions of tlle CAs. Most of the effects of rapid and
massive adrenomedullary discharge of E and N can
be fille<! into the concept ,hat the regulators prepare
C'" TECHQlAMtNES AND Fl€LA TED REGULATOA:S
the individual for effeetiw: responses to threatening
situations (27.2 8).
The CAs improve the blood flow to the brain
(I02)-and thereby facilitate arousal-via influ,
ences on neuron metabolism (139) a nd on the ear·
diovascular system. Dinx:t effects on the eyes (114)
aid visual perception. These include stimulation of
the radial muscles (and therefore dilation of the
pupil to admit more light), and relaxation of the cil-
iary muscie. to aeoommodatethe eyes to distance vi-
.ion at a time when a search for escape routes and
awareneSS of other dangers is surely more relevant
than fine detail. In SOme species (e.g. cats and ral>-
bits). there is also retraction of the nictitating mem-
brane (Ihe '·third eyelid'·),
Direct effeels on the heart include inc",ase<! rate
and force of contraction. and more rapid conduction
(102). The effectiveness of tho ·'push·' on the circu_
latory .ystem provided by the rise in s)'Stolic blood
pressure is augmented by selective influences On the
smooth muscle of the vascular system. VaSOOOllStric-
tion on the arterial side limits the blood supply 10 the
skin. viscera. and mucous membranes. thereby per·
milling the shunling of the blood to the heart, brain,
liver. and skeletal museles. Venoconstriction hastens
return of blood to the right atrium. One consequence
is distension of the ventricles and therefore further
augmentation of cardiac contractile force,
Ga. exchange is improved in several wa)'S (73).
The respiratory center is stimUlated, and there is a
consequent increase in the rate and depth of breath·
ing. Relaxation of the 'mooth muscle of the trachea
and bronchioles dilates the air passages, and venti-
lation is further benefited by constriction of the pul-
monary venule •. Blood Hows through the capillarie.
al a faster rate because of the effecls exerted on the
heart , In SOme species. oontraction of the spleen re-
lcases substantial numbers of erythrocytes to the cir·
eulating blood . Influences on platelet aggregation
and on blood can be useful if the emer·
gency leads to trauma, as vasoconstriction further
lessens the dangers of hemorrhage.
When oxygen and nut rients arc diverted to the
skeletal muscles for a fight or night response. it
makes ··physiological sense"" to tcmporarily suspend
activities that need not be continued at that time. In
general. the elfects of the CAs on the viscera are in·
hibitory. Blood flow to the gut, especially to the mu·
00&31 lining, is diminished. This indirectly reduces
the secretory of the gastrointestinal glands.
In most species, the tont and motility of the stomach
and intesline are depressed via both direct actions of
the CAs On the smooth muscle and inhibition of do--
lincrgic neuron act ivities. There are, however. '1-""
eies variations in the responses of the gut \0 CAs. In
 some cases. sphincter mUs<:les are oontracted. bUI in
othcrs they are nOi. The preferential slowing of blood
flow to thc mucosa may play some role in the ulcer-
ation that occurs in chronically stressed animals of
some specics (53).
Urine formation is transiently depressed . partly
be<:ausc of sympathctically controllcd changes in the
hemodynamics. but also becausc of more dirc:<:t ef_
fects On the kidney (39,60.151). Reduced water loss
via this route facilitates augmentation of Ihe cireu·
lating blood volume and the of thc tlnra
hea t generated by actively contracting mus<:lcs. [n
dogs and ..orne other species. the CAs are major reg-
ulators of Ihe sweat glands. [n different mammals.
including primates. the sweat glands involved in
thermoregUlation are stimulatcd by acetylcholinc,
but they are innervated by the sympathetic systcm
(108). (Despite the adjustments. the body tempera-
ture tends \0 rise somewhat. Small elevations arc fa-
vorab[e for muscle contraction [67. 68) .)
More blood is shunted into the actively contract·
ing muscles. This is accomplished in part by con-
stricting the vessels of the skin and viscera. However,
epinephrine also dilates thc vessels of contracting
muscles. and thus facilitates thc presentation of ox·
ygen and fuels as it removes thc excess heat and mct-
abolic waSteS. Small amounts of lactic acid do ac·
cumulate, and this is useful (since the lactic acid is
a vasodilator) . Some of the lactic acid that leaves the
muscle scr.·es as a vcry acceptable fuel for the hean.
CAs also directly affect the skeleta[ mus<:[e (\ J 1).
They facilitate neuromuscular transmission. in part
via inOucnces cxerted on the cholinergic
(125). Relaxation of the "slow" fibers is useful to
some species in situations that call for
responses.
Piloerection can makc animals appear larger and
more ferocious to would·be predators. In animals
with long fur. it may additionally provide some pro-
tection against injury to the body surface. (It is
doubtful . however. that the "gooseflesh" response of
humans has any value.)
Slight modifications of Ihe reaction pallerns Can
provide for effec tive responses to emergency situa-
tions that do not call for rapid locomotion (e.g. sud-
de n exposure to cold environments),
Since Iher<: is considerable "anticipatory" r<:lea""
of tho CAs, difficulties may be created if the Ihreat
does oot materialize (e.g. if a potential predator sim-
ply cro»cs Ihe path). Some of the feelings experi-
enced when the dentist announces "No drilling will
be necessary" can be allributed to releasc of CAs in
amounts that thcn prove to be inappropr iate, In
some humans. excessivc adrenomcdullary discharsc
in respons<: to persons or situations pereeivcd as
threatening may contribute to the ctiology of
vascular di..orders.
The Continuous Need lor Catecholamlnes
CAs are nceded on a regular basis to perform less
dramatic bu t equally imponant roles. Many of the
actions oppose those of acetylchol ine. and fine ad-
justments of the sympathetic:parasympathetic ra-
tios are made many times each day ( 120), Unop-
posed actions of acctylcholine would [cad to
problems such as bradycardia. hypotension, ovcrae-
tivity of the gastrointestinal tract. and accommoda-
tion of the eyes for near vision.
A sudden change from supine to upright position
calls for the release of norepinephrine. The conse-
que nces of a delay in such adjustment are apparent
to anyone who has jumped out of bed to answer a
telephone located some distance away. A return to
th. supine position requires increased vagal (acclyl·
choline) activity to avoid "O'o'Crioading" the hcad re-
gion with blood.
EXCITATORY VS.INH[BITORY EFFECTS
CAs stimulate smooth muscle in some parts of the
body (e.g. the blood vessels supplying tbe skin), bu t
they inhibit it in the broncbioles and in mOS! of the
gut. It was at one time proposed that the "cxcit·
atory" effects are mediated by onc type of regulator.
"sympathin E." whereas thc inhibitory oncs result
from release of "sympathin I" (99). The "dual me-
diator" hypothesis implies that the nature of the re-
sponse depends on the chemical makeup of the
regulator.
When some informat ion on differenccs in rCaC-
tions to norepinephrine and epinephine began 10 ac-
cumulate, altcmplS were made to equate norepi·
nephrine with sympathin E and epinephrine with
sympathin I. This seemed to make sen$C, since nor-
epinephrine cxens only stimulatory influences on
vascular smooth muscle. whereas pro-
dilation of $Ome blood and it. alone.
relaxes thc bronchioles.
It soon became appa rent that the concept did not
"work." Bolh Nand E stimulate the heart . and bolh
cootribute to relaxation of the gul. Morcover. me/-
abo/if" effects are not easily put into cxcitatory and
inhibitory categories. (It is illogical. for examplc, to
apply one of the terms to glycogenol}'sis and the
other to gl)'eogenesis.) Table 8·[ summarizes ..orne
of the established differences in responses to the two
CAs. (Effects on thc hypothalamus and on Ihe se·
cretions of pituitary gland hormoncs are discussed in
the chapters devoted to those subjects.)
A much more useful idea is that thc target organs
for the CAs arc equipped witb two or more different
kinds of receptors. and that thc nature of thc ro-
spo11sc is related to the kind of receptor affected.
This concept is oonsidered in detail later in this
2711 CATECHOLAMIN ES AND RELATED REGULATORS

Tabla 11-1 Coo'r9arison 01 Soma EWocts 01 wiIh _ 01 .....

Elfe« of Epinephrine

For<c "f ",)v<.tdi., loc, • ...,d

"""tr.e'ion
S),""';< blood I"=. ,e In<'eased
lle.rl .. ,< DeOf"oed b«,.", of .. lie,"" Inc",.oed
Di.stolic pr=ure In<r<>><d llsu.lIy littl< ""I,rreOl
Cordi.oout"", Moy..,. be .1f<C!<d Inc ... >«1
Blood 0.,.,.
S ki" Decruoed
Mu<"", mcmbran<. Decr.. oed D« ..... d

'"'
Kidr.cy
li.or
Deore, oed
Deo ... oed
\.Iou.,ty "'" ''''"",0<1
D«,uoed
Dco,,"ed
loc" ... d
O.. in M . y to< ,,,hlly i"",....d loc' ....
Skclot. 1m"",1< lilli. or no elfeol Inc, .... d
Som<wh .. ;""".>«1 Inc, .... d

-
lie."
l."n&, V..oco",triolion bul ropid Co"'tri,,""'. ropid I\ow

Pupil of <)'e Dil .. e<I Oil.,ed

CiI;.,), n,.",k of 'ye Rei .. e<I (S<OmC ..) .. ed ("""" 'p«i<s)
lI,oochiol., mu",1e No elfcct .. ed
Venli l...", Incr,.",d Inc". ",d
Slom"h. i""'lill< . .. ,I bl.dder
MOIilily. ' .... D«"as<d De.",_
Sph;n<t<r> S,im.lated S,im.l>led
5e<,clion D«rc..ed D«,e..ed
Urinary BI,dd"
DeINiIOT ",.",'e liHI«rr'<1 Rei .....
Sphioc,er Slim.I.,«I S,imuloted
UI«.' Nonp", ... I.,",lIy Pt",n'.1 "",,,Uy ",..«1
st;mulat«l
Skin
Pik>o:'<Clor muscl .. Conl .. clcd Conlrocl<d
S"","inl Inc .. _
Mel. 1>01>/>0«'
S kole,., m.",k
Con'roe"ion Pi'PC"'''''
","romuocul.. transmi .. ion Facilil>l«I Some f""iIi"lion
C""''''<lion of ··f." m..... •· E.""n«<I Enhonc'"
Fali,ue Reduced
.. ion of ··,Iow f,l:>< ..•• Li!H. ,lfoe! Fa.ili"" ...
Blood compone""
GI.=< Uttle .1f«1
I.oolio .dd Slightly inc ... oed Markedly inc,caoed
ooids Iner .... d Somcwh>1 inc ... ",d
E')'throc)"le< May l:>< little ,If.."
F.QS; """h;
O,)'",n "",,""mplion
No elfoe!
Inc, ..",d '''''' ....
O' .... oed

,
Sen..
.
"_ l""" of ' n,""y No .If..,t
F•• ilil.,«1
!"",ea",d
I'•• ili .. t«l

chapler. To avoid Ihe problems of classiFying al1 re· MaJOf Dlfferencea between Epinephrine and
sponses inlo slimula tory or inhibitory types, Greek Norepinephrine
Ittlers were (4.99). Norepinephrine was E is Far more potent For elevation of the blood glu-
Ihen shown \0 interact mostly with adre nergic recep- cose. Its effects on glycogellOlysis in muscle and on
tors of \he a type in thc heart). whereas epi- dilat ion of the blood vessels of Ihe liver hay. been
""phrine can affect both {J and a receptors. described. This am ine also exerts long-range inftu-
ences On hepalocyle membranes Ihal lead 10 accel.
eraled rales of amino acid uplake from Ihe blood
plasma (83). The processes provide subl;trotes for
gluconeogenesi'l in the liver. E acts on the plasma
membranes of other cell types to limit the uptake
and "none=ntial" of glucose, especially
during limes of stress (123) . (Glucagon also does
this. and the effects of the two hormones are super-
additive [461.) A hypoglycemic stimulus preferen·
tially augments the rdease of E from the adrenal
medulla .
Hypoxia also preferentially promotes E release.
The hormone is thcn useful be<:ause il provides glu-
cose (which ean be melabolized anaerobically). and
because it dilates the respiratory tract muscle (146) .
(E is used as an emergency treatment during al\ack s
of bronchial asthma. 1'1 is ineffective.) often
leads to increased se<::retion of glucagon ( 11). Epi-
nephrine contributes 10 thi s, but N i. also a good
stimulant for the pancreatic glucagon-;;ecrcting
cells.
Humans subjected to anxiety-provoking stimuli
secrele more Ethan 1'1 , and E is put out in larger
amounts during times when mental (rather than
physical) tasks arc performed (89). Systemic injoo-
tions of E (but nol of 1'1) elicit restlessness and sen·
satioru; of anxi .. y. It is not known bow they act. since
the amine does not readily gel 10 Ihe brain (139).
[n contrast. norepinephrine is much more potent
for elevation of the diastolic blood pressure (since all
effecls on vascular smooth muscle are stimulatory).
It Iherefore provides belter protection against the
development of hypotension. and it is preferentially
released after a hemorrhage.
Both of the CAs promote lipoly.is, bUI N is more
potent. Much of this activity is elicited when the
amine is released from sympathetic nerve endings.
Localized impairment of fat mobilization Can result
from destruction of the nerve endings at specific
siles. Adipose tissue plays major roles in the adjust-
ments 10 cold environmentallemperalures. and N is
Ihe more important CA for this purpose (68).
Both of the CAs exert positive inotropic, chrono-
tropic, and dromotropic actions on the heart . These
[cad, respectively, to increased contractile force, ac-
celeraled heart rate, and more rapid electrical con-
duction (102) . The elTeets arc easily demonstrated
for isolated hearts. In intact animals, both increase
the systolic blood pressure . Epinephrine also in-
creases the heart rate and cardiac output of intact
animals.
Both of the CAs also promote vasoconslriction in
the skin, mucuous membranes, and viscera. Since all
of the actions of 1'1 On blood vessels are stimulatory.
the diastolic blood pressure is consistently e[evaled.
This invokes Ihal lead 10 slowing of the Car-
diac rale. Usually, Ihe increased peripheral resi s-
tance and bradycardia are suflicient to prevent a rise
in cardiac output despite tbe increased stroke vol·
ume. The heart then works efficiently and has ade-
quate time to rest and fill belween the beats. (The
reflex nature of the bradycardia is easily demon-
strated. [t is not seen when N is presented to iSOlated
or denervated hearts, and il Can be blochd with
atropine.)
By contr3llt , E dilates l'Qrne vessels as it constricts
others. The receplors Ihat mediate vasodilatioo re-
spond to small elevations of the CA concentrations.
Although there are times when E eilher lowers or
elevates the diaslo[ic pressure, usually the vasocon-
strictor and vasodilator effects are balanced and
there is no net change. Therefore, reflex bradycardia
is nol invoked, and the cardiae OUlput is generally
increased.
ADRENERGIC RECEPTORS
There arc times when it is useful to distinguish be-
lween adrenergic (E) and noradrenergic (N) recep-
tors. In this section, the term adrenergic refers to all
receptors responsive to E. N, Or both.
The "dua[ receptor" hypothesis developed
during the course of studies of the relative potencies
of epinephrine. norepinephrine. and some synthetic
analogs for stimulation or inhibition of the contrac-
tion of .moolh lllu",lc laken fr<llll variou> site> of the
body. It was obl;erved that the target organs could
be grouped into two categories on thc basis of their
responses to the various agents (4) (Fig. 8·1).
The <r receptor was defoned as the cell component
most responsive to phenylephrine (an amine chemi_
cally related to N that stimulates) and to phentola-
mine (a receptor amagonist). A[though many of the
of phenylephrine Can be oblaincd with both
N and E, N is usually far more potent when mod-
erate conc.ntrations are used (3).
The p receptor was defoned as the componcnt most
responsive to isoproterenol (which is chemically re-
rated 10 E) and most easily blocked with proprano[oI .
The pharmacological agents initially used were
found (0 have limited specificities. Furtllcr work Icd
to the development of better receptor agonists and
antagonists. The are all chemically related
to thc naturally occurring CAs. has
been called a "purc" <r stimulant (16).
H,c - O "oI H /H
C-C-N
H [ 'H
,",
0><
 CATECflOLAM INES RELA.TED AEGUlATORS
'" ,, ,,
I fl .... CH .. , ,
,C-C-N-C H..-CH,

I,
C-C-N P
H Ii 'H H 'CHI

'" l$Oproterer»l
(Isop<enaline, ISuproQ
Ii agorrist

,, ,,
,, "
,, ..... CH,
" " , , -,
C _ C_N
" " I , , -,
C-C _ N

" "" Nort!pinephriroe "' '" Epineph<ine

Il'IyNHI ,,
H I H H H ...... eH,
O-C-C-C-N-C
H 1"1 Ii 'CH,
'"I "'-
" ,r
"
" I
",c
"" ""
Phentolamine (Ae<jIine)

Fig. 8·1. SI""'i"'" 01" agon;. t and " ant&go<'li.1

compar.d "'ill> no<ep;nepM.... (lo ll). a r>d 01 lQOf'IO' arod
J compo,"'; with ep;oep/'If;"" (r\gI>I) .

The {J blocking agenu exert mostly competitive fieilics. These include dobutamioc. "'hich is a sele<:-
type actions, and they chemically resemble epineph- tive p, agonist; pmetolol and aleoolol. which are se·
rioe (Fig. 8-2). By COW.,!, '" blockers act dir· lective P, antagonists; salbulamol. a selective P,
ferem mechanisms. and they generally sbow lesser agonisl; and whkh is a selectiv<: P,
specificities. antagonist.
The "specificities" are. however, limited, espe-
cially when the agents are presented in high coneen·
Subclasses 01 Receptors lrations_ Thus. acebulolol is classified as a selective
The rec<:plors of the myocardium were initially clas- P, bloc ker, but it can some effccts on lhe liver.
sified as {J, sinc<: Ihcy arc stimulated wilh isoproter-
onol (but not phenylephrine) and they are blocked
wjlh propranolol. E is as effective as N for thc
stimulation. ,,
However, E and isoproteronol also bronchiQ- H I H H H C H,
o - C-C-C - N-C/
lar muscle. whereas N does no!. It was therefore pro- HHH .... CH,
posed that Ihe heart has an adrenergic receptor of a
special kind. now called P,. whereM the bronchiolar
musele has a different. P,. type. This idea gained
wide aCe<:ptance when newer pharmaoological By COntraSI, Del. pronethalol. and limolol .."
agents were synthesi>.ed that showed greater speci- "nonspecific." i.e. Ihey block both p, and P, aCliorIS.
 II
DoI>ut.mine: (I, agonts, ($\;mulales 11'10 !lean)

o "
o
" "
H,c-C-N O-
H I H H H .... CH,
C-C-C -N __ C
II H H H 'CH,

Pr8 Ciolot
(Eral,,",,) II, onla9O";SO

H t
o"
H H H .... CH,
O- C-C-C-N-C
II H H H '"- CH,

IJ. M'ag<n,st

"o
IHHI
CH,
"o CH, CH,
I I H I
C - C-N - C-Ot,
II H H 'cH,
C-C-N-C-CH,
H H 'CHI

Sabulamol: I" ogoni.. (brOIlChocIilato<)

(AltlulCfol. Sulla""'l

while isopMerenol is a "nonspecific" fJ receptor ag-
onist. (Fig. 8-3).
"", and "", TYPES
Some adrenergic agonisls aCI,v,tles that
have been associated with sympalhe tic system stim-
ulalion. Evidcnlly> they exert their innucnces on pre-
synaplic receplOl'S involved in negative fecdback
control over neurotransmitter releasc.
The carli.. t ol.>:servations indicated that the pre-
synaptic receptors had binding propertics dilfcrent
from the poiStsynaptic and poiStjunctional ones. The)"
were called a, receptors. and the OneS initiaily
known simply as a were renamed a, (15.12S).
Further investigation re"ealcd that the binding
properties cannot alway-, be predicted from the an-
atomical location (36). Now. the lerm a, is applied
to rc<:<:ptors that are mostly (but nOI exclusively) a t
the presynaptic sites and have the binding charae-
Icristics of the ones initially designated as «"
Phenyicphrine and methoxamine are a,
agonists.
When administered in the usual dosages. they mimic
the conventional effects of N at the postsynaptic and
postjunctional sites. Their actions are blocked wilh
phentolamine. tolazoline. and prazosin.
Clonidine and a--methylnorepinephrine are "1 ag-
onists. They bind to presynaptic sites and they in-
hibit release of catc<:holamines. Yohimbine is an a 1
receptor blocker (Fig. 8-4).
Additiona l a, receptors have been found On SOme
cholinergic and serotonin terminals. It is known that
long-term administration of the presynaptic agcnisto;
can bring about increases in Ihe numbers of )XIStsyn-
artie receptors (36).
'" C,\TECHOlAMINE$ANO RELATED REGULATOO$

CH, - CH, - CI
HIH
H C- N-C-O'''-O
1"0.
I
,",
E. OichloriSO!>'OC."'noI
(DCI)

A. F'I>eno' VOOnUlmi""
(Oit.enty1enel
"o
oII
I "-
C-C "-<,",
N

H
H
C- N
H,
0,,/
"
o H H CH,

"' F. P'ooel .... 101

,0';-- ' 0
"'/'--.<<""'H 'eH, H I "
oIHHH/CH,
-'" -'" 1 " C-C - N - C

",- -' o I H f1 'eH.

G. $Qtalol

C . Tolazol ....
(PriSC<ll)

I ""
O. ....apel;""

Fig. 8·3. Some CA. B. C,.nd O) and 8

(E. F. G, and H) adronorg;c _;ng agent•.

The existence of presynaptic re<:eptors of Ihe p,
type has b«n described for lhe brain (87). These
exert jtJdlilalil'l! inftuences on CA release (125).
Both fJ types pronlQte adenylat. cyclase aCI;_a_
lion. whereas cr, ..,COplOrs mediate inhibition. a, re-
ceptors invoke phosphatidylillOi'litoi hydrolysis and
changes in cytosol ca' · .
The term autore.:eptor nOw designatcs a, !"(X:Cp.
tors that inhibit N release (A-2) . The ones on sym-
pathetic ganglia hyperpolaritc. Tlt<:IM: located so-
malodcndritically on central nervous system neurons
inh ibit fIring. Non.neUl1l1 0:, receptors a"" foond on
platelets. adipocytes. and pancreatic Ixta cells. Neu·
romuscular junctions arc depolarized by CAs but in·
sensitive to both a and (J antagonists and may I'<"'"
sess yet different ("() type re<:eptors (A..t;).
It should Ix pointed out that, although the oon·
cepts are very widely accepted. some investigators
doubt that neurons are regulated by presynaptic
receptors.
 " "
LY " , ",

Pra,os'"
". an",(/O<'Ii'"

Ii Ii Ii Ii/CH,
O- C- C- C- N
H I H 'eH,
o
" ."""thylnorellinephrine
h ag<>!lis" AJp<enoiol "
.ntagoni.,)

"
H?HHH/CH,
C- C- C-N- C
O/H H H 'eH,

,, ""
o
... Yoh<'n\>ine
('" lIntagonOSlI
"
Fig. 8-.. Adc!it;onal ageot. tha t _
to a"'_g;c recep1ors.

Down Regulation 01 Receptors Receptor Induction

Proiooged of larget cells to {J agonis(s such One kind of adrenergic agent can affect the recep-
as isoproterenol leads in time to reductions in the tors for another. It has been shown, for example,
numbers of fJ receptors and diminution of scnsiti_ily that fJ agonists increase the numbers of (t', receptors
to sub:>equcn( Similarly. prolonged ex- in th. ce",bral cortex (93, A-12) , The drects are
posure to '" agonist. I.ads to "down regulation" of rapid in onset. and they can be blocked with sotalol.
tho '" Pharmacologica l 1M! affect Interactions with cholinergic neurons do not al -
the rales of CA upta ke into nCurons and their ways inv<>ive changes in ",ccptOT numbers. For ex-
qucslration into synaptic vesicles or socrelory gran- ample. a influences on gut smooth muscle contrac-
ules can also affect roccplor numbers. The time tion. and on neurotransmission in skeletal muselc,
courses are very different from the cffe<:\s of presy- have been linked withfunclional (rapidly reversible)
naptically drugs. Prolonged administration of changes in the rateS of acctylcholine release (131).
anlag()nists has effects (84). a, and fJ, types In some of the sympathetic ganglia. acctyicho]ine
do not down regulate (A-(i). stimulates OA interneurons, and the consequent rc-
'"
lease of dGpaminc lead, to hyperpolarization of cho.
lincrgic neurons (16). GluCOC<lrtiooids can induce (J
receptors and alter affinities (A-9).
Classification of Metabolic Responses (109)
GL YCOGENOL YSIS
The CAMP·mediated activation of Ih. phosphoryl-
ase system of skeletal muscle by E is mediated by
the {J, type receptors (and it Can be opJlOSed by both
"oonspedfic" (J and mor. specific p, antagonists bul
not with the", blockers). However. the Ca" ."jcpcn-
dent clTecls of N on Ihe li,,<,, involve "'I rcc<:ptors,
LlPOL Y$IS
Similarly, E {l, receptors when it gcncratcg
cAMP and thereby activates lrigiyceridolipascs in
adipose tissue. N accomplishes the same end via
cAMP.independent mechanisms when ;1 bindS 10 <W I
receptors,
CALORIGENESIS
Both N and E rale . Th< mecha.
nisms. which involve accelerated ATP degradation
and intcractions with ,B,-t)'pe receptors, are only par-
tially understood (67).
INSULIN AND GLUCAGON SECRETION
a, type receptoN predominate on the plasma mem-
branCl< of insulin-secreting cells, and E with
them to inhibit hormone sec",tion. Stimulatory in-
fluences mediated via ,B, reeeptON are difficult to
demonstrate except in the presence of blockers.
Sympathetic system stimulation activatcs " , recep-
toTS on the glucagon-secreting cells to promote hor-
mone release.
Secondary changes in islet cell functions mediated
by paraerin. mechanisms were described in Chapter
5. These include glucagon stimulation of insulin re-
lease. and insulin inhibition of glucagon secretion .
Regulation of gastrin secretion by stomach glands
follows the patlern deseribod for insulin, The /'I_type
receptors mediate stimulation and the "'-ty]l'C inhi_
bition (116). Both ki nds of adrenergic receptors e<.II>-
tribute to the control of gastric motility.
There are controversies concerning the as£ign_
mentS of ",ceptor type! in some cells. A "majority
opinion" clas£ifieation is presented in Table S·2 .
CA TECKOLAMtNES AND REUITEO REGUUI TORS
Problems ASSOCiated with Attempts to Apply
the alp Concept to All Adrenergic
Responses
Difficulties arise because (a) pharmacological agents
do not exert "pure" ctTocts. In many cases. unwar-
ranted as£umptions concerning their actions have
botn made. and the assumptions have then been
Uscxllo draw conclusions. (b) Cells, which are under
no obligation to function in an orderly manner, oflen
respOnd in ways that defy simple interpretations.
Propranolol is a potent local aneslhetic, "nd some of ilS
elfe.t,.re re'al.d 10 Ihis, The property is oot ,h.red by
some olh.. "bet. block ....... for • .,"'pl•. sot.lel. Phenyl·
ephri"" was OnCe cMsidered to represent Ihe prolotype
for .,...reec]>Ior ' Iimulanl" It is a tso a ..... k (!l aIlOni.t (t 3).
(Thi, should have been suspected from the presence of.
methyl group auaehed to Ihe nitrollen (16J .) Phonlol .·
mi"" faih to block some of lhe "ctio"" that .re "ron&ly
anlagonized by phenox)'ben,"min. (t44). It inhibits
some to ser<)1onin. e,cTt S hi""mi",,·likc aOliollS
00 Ih. stomach . nd blood vessel •. and h•• sonle "para-
. ympathomimetiC" properlies that aro bl<;.cke<l by
pine, Phonoxyben23mine is one of several "llont, aCling
on" roccpt<)r$ that at$O releases CA from . ynoptic ve.<i·
cl •• (tH), Erllo>t.mine ,Iim"'ate. smooth musele vi.
u"rdoted to lhe "",droner,ic fCceptOr<. La·
belolol i•• re.sonably good blocke r of bolh" and (!l re-
P)·
Hli H H H H II \\
C-C - C-N-C-C - -f' ' ,- 0"
HH I H I
CIi, 0 - /
/
"
F"rther compli.ali"", becau.e In end re.ull Can
be accompli.hed in moT< than one woy. Dilation of a
struelure conlrolled by ,mOOlh muscle ¢.In re.uit from in·
hibit;on of COntraction of lh. circular muscle, .Iimulation
of the radial fibe .... '" interference wilh tM influences e,·
med by other StimutanlS and depressant" The activit)' of
an .o'yme ean be affected by allosteric modift¢.ltion •. • d·
ditiOn' or ddtliOIl$ of pbo<phate group:! in ways Ih.1 .f-
fect affinities for .ubslrates. pr•• ent.tion Gf differenl con·
centr"tions of substrates or cofactOr<. ehange. in Ihe N. ·
concentration' (A·I!) or ,ale, of product removal.
Some peri Iou. of "circular reasoning" have
been indulged in (lOO). The scenario can proceed as
follows: (a) A respOnse is attributed to activation of
/l·type receptors boeause it can be inhibited with
"beta blockers." (b) A new agent is found to hlock
 StruOtu,o St'mul.tod by (."ehol,m'''' «-11.«"""",

Va""ul" """""h m"",k

S);,n C""'''itt'''
M"""", .,.,mb<one, C"",tri""",
Sal",,)' ,land. C""'triction
Moo;t ,I>dom'n.1 ""'''' C""'trio<'"
1.,,<, C.",. .. ic,'" Oil""'"
S);OI01.1 mu,1e (C"",trict"",) Oil",'"
Lun8 C""'trie, ion
Otlte, "oo"t h m",de
B,,,,,,,h;.,ic<
Sph ;oct, ...: i"'troi .,," iflli. ",i no,)' C",,".c,ion
Pih>root .. (.);in) C"",,,<,ion
l(.di,1 ",u", lo of i,i, C"",,,, .. ,,,,,
Ci l,,,), m.,,,lo (0)'0)
S">nl1ch K<I ..""",
Inte<1,n< (Rei.","",)
Spice.
Heo"
C""''''«'''''
SillO.u,"( nOOc (S"mul .. ion) Rate i"''''l<d
Atria J""",ued oond ..,,,.,. " "
""",raOt ion
V,n" ick; S>.,., .s .tri.
Skel<1.1 ",u",k
White IF..!) F."c,. compl...
too«
>10 ... "I.... "'"
Rcd ISIooo') Oppoo"c '" "hi"
;o.;curomu",.Io, ",n,m",,,,,, Incr",«d
I. ""I' hoJre, OJ,pe ... ion
GI,nd,
Seer""",
5. 'i...". V i",,,,, ..«,,,,"," Growth, .m)W< ... ',,,.,.,
E.""""cr.,, , Eo,)'m, «<,et"'"
P''''''''';'; "k" (1",.1,. ,,:0,,'''''')
Pi ....1 SetolQnio. mol""",. ')'n''''''i'
Kid",,) R,nin .)' nlh ..i•. "''',...
Plaid,,,
1.,.l.oc)',<> An"son·indurnl h'".mi""
"'I.... inhit>;"d
C.lori,enc,i, loc",.",d
G 1)'''''1;' "",,"i' (Ioc'e>sod) loc" ... d
UfIOI),>" (Inc" ... d) 1"""• .00
Tood 'bdJc, Redu«d water permeability
Tood , );i. I"",."ed sodium, '..,"
pe,.,.,.bili,y

Ih( r(Sponsc. It IherdOr<: dassifted as a "beta
bl(lCkcr." Tit. new agent is now lesled in a dif·
ferent "Y'tem. The secondary rc.'ponse i, assumed 10
be medialed via fJ receplOrs . (d) Totally differenl
substances tlml elicil the second response are now
cla!.Sified as fJ agonislS.
When $Cveral agents of a pharmacologic.1 8muP are
tested. th.ir .".de" of poleney for one cell tyl'< differ f rum
lhose fo' anotner. Such finding> h.we prompled ""me 01>-
.. rver> to suggesl thaI Ih.ro aro as many dirTeron, kinds
of receptors as Ihere are cell Iype, (4), The
responses are affected by the physiQiogieal SIalu, of Ihe
.ubject from which Ihe coU. are They vary with
'be microcnvironmenl.the pa.t n"trilk'nal and endocrine
history. the environmental lemperature. and often w,th
,he ,ime of d.y_&'.•ge. ".d . pecie. difference. are teC-
ognized. and .arialions have beon encounl<ted .mong
., .. in. of laboratory rodenl .. The p"r it ie •• conecnlta·
I'ons. and "obiel.. f.". Ihe pharmaclog;cal agents must
.Iso be cOMidcred.
The presence of more Ihan <HIe kind of re<epICr per 0011
ma), be the rule rather Ihan the oxccpt'on. The existence
of both <> and IJ «ccP'Of$ in Ihe pancreatic i,lel oolls.

li.or, and adiP"'< tissue ha •• been cited. Th. intestinal
mu",I.,. til< coronary blood .e$$<I$. the brain. and the
beart arC among the other ,it.. wh.re the phe""me""n
h.. been enwuntcr<d.
Can One Kind of Adrenergic Receptor be
Transformed Into Another ?
In many spoci.,. CAs stimu lat. the ,mooth mu",le of tbe
.irgin uteruS but rtlax the m"",le during pr<gtlllncy. Vir·
gin uteri tr.at.d wilh estrogen. beha.e like the those <>f
pregnant animal. D). Studi", with phorm.cok>gic.1
agentS are ",,",i... nt ... ith th. concept tbal « receptCKS
medi ... Slimulotion, and P typos relaxation. The
ins four interpr.tation, of the findi"iS have be.n
ad.anced.
I. There is. singlt o[ whose pwporti.,
ar< a lfected by the e,troson . (Differen.e. in roccpt'"
function have be.n .bown f'" other .y"em,. FO)!" ... mple.
wdium ion conc<:ntralio", affect the affi niti.. of opi...
receptors. dcn.rvation chans'" DA rtteptors IA-4J.)
2. Hormones .nd other r<S"I.tort control til< rat« of
[ortMlion and JtJlruction of . podfic receptor t)'po'. or
affect their acccS$ibihtieo. (In ,hi. .•Slrogen COUld be
f..",ing formation of tbe ll·typo receptors Or conferring
... bilily upon them. as it ' uppr ...., the f",mation <>f u'
Lypo rec.ptors Or ace. I. rate. thei, degradation rat ... )
). Th.r< ar< '''''' kind. of .... ptors. e.ch of which Con
undergo chang.s in sen.itivity 10 the CA, wh.n llerman.,
arc administerod. (Estrogen< coold increase the
fU"'tions <>f the II receplors. dep", .. those of the «'. or
both.) Thc belief that hormones c. n act in this w;>y i.
. upported by some unrelated studies. h ho. be.n re-
ported. for ."mple, that thyroid hormones enhance <>
Lypo respon.ivity in Lhc myocardium and depresoll sen-
.itivity. witbout ehangins the tissue CA conlent (II I).
Problems C<lmpliCaLing the interpretation .r<: possible di-
reel effects of the thyroid llermoncs and innuen... <>f
fUn<lional st.tu. of the tiss ue on reactions to the 1Ior-
mOne. Cardiovascular insufficicncy may faeihtato eo",cr-
$ion of triiodOthyronine to Irii¢dOthyraminc. a n agent
tbat lead . 10 II re .. ptor dominance and possibly also to
increases in tb. numbers of dopami ne r«eplors (65).
4, On. kind of receptor con be conv.rted into thc other
(10). A related idea i, that a ,ingle receptor has lwo (or
more) binding .it ... only on. <>f which is ••• ilable at any
given time, Hormone, could Lben be ehanginll the aeee,-
sibiliti ... (Frog hea rts ,h.".. Lempor. tu.-...lependcnt
change, in ""pOnseslo CA. and related "Ilents, One in-
terpretation hos been th.t cold environmen.. 1 tempe .. _
Lures "Iock"" cardioreceptors in lhe u state; bowe.er. this
notion bas n<>t been universally accepted 1131.)
Some of til< questions raised will probably be an,,,.-eN<i
... hen it becomes possible to ioolat. and f""y cbaract.,i.e
the ""ptors. The technical problem. en"",-,nt.red in
,ucb ...o,k include the •• ry bigh rates of nonspecific bind_
ing of labeled r..,eptor agoni,,, and .nlagonim, and the
chemical in'labili tie. of the comple.eo formed , Recently
•ynthuiu:d .,en" that bind with vuy high ,ff,niti.' and
CATECHOLAr,{tNES ANO RELATEO REGULATORS
specificiti« include I' H l-aminoclonidine. I' H l-dih)'d,al_
prenolol. 1''' 11 J-hydroxybenl.ylpindolol, and also I' H J-i,-
oproter<:noIand 1' 1l1-dihydroe,gocryptine (52.84), E•• n
more re .. ntly develOped plletnaffinity prob<:< (tWA) ore
providing .dditional tool. f'" solving the problem •.
MECHANISMS OF ACTION OF EPINEPHRINE
AND NOREPINEPHRINE
tI-Receptor agonists usually activate adenylale cy-
clase. and many of the efff«1S (including do ... n reg-
ulation of Lhe receplor numbers) have been linked
wilh Ihe functions of the cAMP-depcndem protein
kinases, Most Can be mimicked with cAMP and its
analogs and exaggerated with phosphodiesterase
inhibitors ,
Howe<'cr. as di.cussed in Chapter 4. difficulties
arc encountcred when attempts arc made to estab-
lish that cAMP is an obligalory seeond messenger.
Scveral apply to the actions of CAs. For cxample.
myocardial responses to E seem to prt cede elevation
of the levels. and some effeclS of Lhe CA,
cannot be mimicked with the nuc!ootide .• ven when
PDE inh ibitors a rc also used (23. 93) .
Attempts have been made 10 explain,. receptor
responses on the basis of lowering of cAMP levcls Or
of eAMP/cGMP ratios, The oon«pt that they work
in thi. way i•• impli"ic, and it i. not univon:aUy
applicable.
11 is diffieull to definc relationships betwcen a-rC-
eeptor activation and the cyclic nucleotides for slud-
ies conducted in vivo. Choline rgic neuronS can ele-
Vate cAMP or oGM P le<.. is in the nondrenerg ie
neuron, with which Ihey form synapses.
Calcium ions have been implicated in several ways
in mediation of a-adreMrgic responses (23.44). CAs
and receptor-active phannacological agents exert ef-
fecls on plasma membranes Ihat include meLhyl-
alion. and other changes in the pho:spholipids. This
can lead 10 alteralions of membrane fluidity and
permeabi lity and in the funcrions of membrane""s--
sociated ion "pumps'" Some effects of <>-r.ceplor
stimulation can be mimicked by artificial elevation
of cytosol Ca" • and Ih.,. have been li nked with ac-
tiValion of calmodulins and Ca-depc ndem protein ki-
nases (30) , (Sevenl of the interactions between
membrane phospholipid., Ca" . and cyclic nucleo-
tides were considered in Chapters 4. 5. and 7.)
A variely of other mechanisms of action have been
propos<:d. including inHuences exerted on the Na ' l
K ' / ATPases. Much more information will be re-
q uired to formulate definitive hypotheoes. There i,
no reaSOn 10 assume, however, that a unifying COl}-
«pi applicable to all adrenergic functions win
emerge from the new knowledge .
DOPAMINE RECE PTORS
Dopamine rec<:ptors are widely distributed . They
mediate the direct actions of DA on vascular smooth
musde. endocrine glands. and kidney. as well as on
the brain and peripheral nervous syStem. Epinene. a
chemically related tyr<tsine metabolite that is di.'-
cussed later, exerts actions that are dilTocult to dis·
tinguish from those of DA . Apomorphine is a phar-
macological agonist that is highly potent at most
receptor sites. Se.eral other agems used to study DA
functions have more ,elecli.e effects (Fig. 8-5).
On the basis of (a) the kinds of responses invoked.
(b) lhe mechanisms whereby these are achieved. and
(c) the interactions "'ith antagonists and with ago-
oislS other than Ihe ones cited above. allempts ha.e
been madc to divide thcm inlO Ihc lWO groups dc·
scribed below (23,74).
I. D,. D,. or txdlOlory types arc coupled to ade·
nylate cyciascs; Ihe responses have been linked with
aelivation of cAMP-dependenl kinases. Fluophena-
zinc and trifluoperazine are often highly elTective an-
tagonists. Some responses are also blocked by ergot
derivatives such as bromocriptine and !ergotrile.
2. 0 ,. Do. or inhibilory types either lower cAMP
levels or act in other ways that remain to be defined.
A-6,7·DTN (2-amin0-6,7-dihydroxy·I.2.3.4·tetra·
hydronapthalene) mimics the actions at some sites,
and bromocriptine is an agonist at others.
Ahhough thc classification ""rves some u""rut
purposes. it has limitations. Evidently there a re D1I\
a nd 0," subtype (A·19) receptors with o'-crlapping
properties. Each subtype display$ its own character.
istic response pa{(erns when pharmacological agents
arc presented. Some of the receptol'S are presynaptic
(34). and others preju nctional (56). All of the pe-
ripheral ones have properties that distinguish them
from lhe brain types. Certain receptors in the een(ral
nervOuS s}'Stem bind agonists and anUtgon;sts with
low alTonilies. There arc others for which tight bind·
ing can be demonstrated. but (he responses are only
poorly correlated with the alTonities. It is IIOt known
whether several dilTerent molecular types coexist in
the brain. or whether a single kind of receptor can
be reversibly converted to multiple forms (52). Drug
tolerance may require autoreccptors (A. I0).
The three major problems encountered in at·
tempts \0 characterize Ihe rec<:ptor types arc the
IIQnspccific natures of the available ligands. the mul·
tiple consequences of DA receptor aclivation Or an·
tagon;";m, and the interactions between DA and
other regulators.
All of the pharmacological DA agonists and an·
are lipid·soluble substances that can exert
inAuences on the plasma membranes of virtually all
cell typeS. Binding to serotonin rec<:ptors has been
especially troublesome. but there arC also interae--
tions with acetylcholine, histamine. N. Or E rece!>,
IOl'S, or combinations of these. Some agents add ition-
ally affect the metabolism of DA and of other
catecholamines. They can also mooify rcccptor for·
mation and degradation in ways that ca nnOt be pre-
dicted from their other properlies. It has been ,e--
ported, for example, (hat haloperidol increases the
numbers of DA receptors in the rat corpus striatum
a nd decreases them in the pituitary gland (115).
Sovcral recently introduced tools hold promi,e of
rapidly advancing our knowledge in field. it ha,
been reportcd that quinazolooine effectively bloch
the binding of tri(ium.labeled spiperon. to serotonin
receptors (91). that L Y·I 4 1865 binds to just the D,
types ( 130), and that dioxyphenylamine-imizado--
lamine ( DPJ) is specifi c for the D, receptors.
DA invokes changes in i(s target cells that arc
only indirectly linked with cAM P. It can affect thc
composition of membrane the func-
tions of calmodulil1S. and the activities of calcium·
dependent protein kinases. Mooulation of C3"·ae--
tivaled potassium conductance has bc<:n described in
the hippocampus (14).
DA Interactions with Other Ragulato rs
DA binds to both CI and {J adrenergic receptors in
many parts of the body. and it then mimics the ac-
tions "f th06c CAs. When it is taken up by nccvc to<-
minals. DA can be converted to N. It also releases
N from sequestration sites (125). MOl"<Xlver. it inter-
acts with muscarinic rcccptors of sympathetic gan·
glia and it thereby alTects (55).
Noradrcnergic neurons. in turn, contribute to the
regulation of DA rec<:ptor numbers and adenylate
cyclase activity in some parts of the brain (I 23).
DA exerts some histamine--like actions. Certain of
them arc antagonized by histamine receptor block.
ers. whereas others are not. Agcnts regarded as spe-
cific for histamine rcccptors can also indirectly mod-
ify some responses to DA.
DA is a substrate for a variety of enzymes, and
some of the prooucts have biological activities differ·
ent from those of the parent CA. Such metabolism
Can cause serious problems in patient$ receiving
long·term treatment with l·DOPA.
The central elTects are especially diftkult to define
because of the of thc DA neuronal sys-
tems (98). In studies on kittens, it ha$ been demon·
stra ted that DA and cholinergic neurons arc concen·
trated in the same brain regions du ring early
development (61). Later, DA retards acetylcholine
turnover and antagonizes some actions of that neu-
rotransmitter. Nerve growth factor affects both ace-
tycholinesterases and CA secretion in pheochromo--
cytoma <xlis (71). It is suspected of exerting similar
 "
" I
, .. ..
"
" "--/"
'"
N c-c><.
"-
"
"-
,
I
, ...." !.
. "-
,!." " , 'L
I "fi
"'1,,0;,"'" l I •
• c ....

.. ir - \'l.-c-c-
" "
''','·DlN
... _.F ...." "" ..
.
_ _ ""4 ..

"o -.,'- c-,

, '"
i "'''n-''l .... ......
'

- .
.0 "". ...."0-. -
""
I';"'," 441
\ c--.:·c--<: .... """-""'I""
"- I h
0

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.- ""
.J
b
, ;' b .) Po . 0.

'0' L4
influenoes on Iympullctic neurons a nd on the adre-
nal medulla, DA is concentl'llted in the dendrites of
GABA and $ubstanee P neurons.. and it aifC(tS the
rales of relcue of tbo$e transmiuen;, NGf al$O reg-
ulates substance P ru:urons (110). Serotonin indi-
•ecllyoppose$ many actions or
DA_ and some sero-
tonin agoniSI5 alter the resp<lllSC5 10 DA r«eptor
activation.
Opiate re«pton are located on DA neurons. They
an: to mediate enkepllaliner,ic control over
DA release in the brain (34.113). En keph.lin all'O
.egulates acet)'kholine relu.se in sympathetic gan-
glia (7g). and il may modify the effeels or DA at
tllose sites. Actions of DA on the cbemore-
ccptor trigger Z01X of the medulla oblonp\.l that
controls the \IOmitin, relkxes may involve interac-
tions with opioid receptors, (Morphine is a potent
emetic. but it docs not ""crt generaliled DA-like ac-
tiollll.) Adrer.omedullary cells contain and release
cnkephalins. and the peptides play roles in stress an-
algesia (90), DA is . 11'0 koown to affect the
of endorphins and brain VIP. but separale neurons
control adrenal CAl and enkephalins (A-7).
DOPAMINe FUNCTIONS
Influe nce. on I" Vatcul.r S r-le m
DA invokes dClSC_related vasodilation in the .enal.
mesenteric. coronary. and ce.ebral vascular beds..
but it does not innuence blood flow elsc ...'here (e.,.
in skeletal muscle) (S8). DA. o. dobutamine (which
ueflS similar actions). is therefore used in the treat·
ment of suffering cardiogenic. hopo\IOIemie.
or traumatic circulato.y shock.
or
The: vascular functions DA are attributed to ac-
tivation of I special group of 0; re«pton."The)" per·
sist in the presence of agcnl5 that bloc k acetylcho-
line. E. N. and histamine: re«ptOl'S. and "'hen
",ng'ionic blockers such as hexamethonium af<' ad.
Influences on renal blood flow. glomer.
ular filtra tion. and sodium excretion do 1>01 mjuire
interactions with .. adf<'nergic mecha nisms (39).
The actions arC mimicked with A.(,,7_DTN. but
001 with its isomer. A-S.6-0TN. ApomorpItine ;$
said to 1><: a "panial agonist-. butlOmcofits analop
(•. g. N_n-propy lnorapOlTIOf"Phinc) are more
etreeti"".
Sulpiride is. very potent a nUlgonist . Auopho ... -
zine and halOperidol (which strongly oppOSe DA aC-
tions at other sites) a.e very ....a k blockers. In this
system. bromoc:riptlne.lergotri1c. and related agents
arc totally devoid of activity.
- --------
f ig. Dopa ........ ag<:<"Iitl.and
Dop.mlne Regul8tlon o f Pro lactin Sec retio n
DA is. bighly potent inhibitor of prolactin ( PRL)
secretion (79.12 1). It is present in biah concentra-
tions in 1m: pOrtal blood. and it aCtS on both h)"po>-
thalami.: neurons and pituitary gland lactOiropcs .
Afler bindin& to Ihe surfaoc ICOCpton oIlaaOl• • s.
it is internali1.cd and incorpOrated into PRL sec ....
tory gran ules. Many inV6tigatOl'$ belic"" DA is the
pri mary PI F (prolactin inllibilOry factor). but others
suggeSlthat it functions as a PIF releaser. (See Pari
V for additional diseussion.) PRL that travels from
the pituitary ,\.and to tm: h)'lXllha.lamu$ uerU 5OIT1e
negative feedback cont.oI over its own sec.etion. a t
least in pari by affecting DA turllOYCr in the tubero-
infundibular syslem (38)_ (The piluitary honnooe il
not known to affect DA turnove. in other brain
regions.)
PRlsecrction invoh"CS at leUt tWO separable: pro-
cesses.1 "depiction_transforma tion" th.1 Io.... ers th.
rndioimmulIOa5sayablc hormone content of the
gland. and a " release" plOOtS$ that elevates plasma
PRL (91). DA ."idently affects only the first of
lhese (62).
It has been stated that lactot. cop :5 do not contain
a DA-sensiti ve adenylate cyclase (liS). Since VA
aClions on pituitary cells are mimicked with brom<)-
cripline. thef<' are reasons to classify the .eceptors as
0 ;. The pharmacological .gonists include A-6.7-
(which i. ,.. effeclive.' DA). bromocrip.ine.
krgotrile. piribcde1. and A_S.6- DTN. Tho: concept
that DA actions involve IO'<>"tring of cA MP levels is
supported by obscrV3tions made ·... ith V IP. That pep-
lide actiY<lte5 adenyllte cyclase. and it stimulales
PRL secr.tion, OA CO\Interacts the effects of VIP.
but it does not int(rfef<' with prostaglandin f timu-
lation ('04).
p<:rphenazir>e is an ellf<'mcly potent antagonist
is used to maintain hyperproiactinemia and
thcf<'by support the growth of PRl-<1ependcnt
gland tumors in rodents. 11 prob;lbly ad-
ditionall}' acts at othcr ,i tes.
&trogcnsaugment PRl secretion in several ways.
Thcy Io,,'(:r \lIe sensitivities or laClotrope OA rceep-
tOl1O (80). and thcy affect DA turnover in the brain .
lon&..ange effeets include stimulation of eell
proliferation.
Innuenee. o n the Secretion of Othe r
Pituitary Gla nd Hormone.
DA can elevate the plasma &nl"'Ih hor-
mone levell in humans and many other mammals
(94.14S). and il is used to assess pituitary gland
runctions. The actions arc at leasl pilnially allrib-
uted to conversion to N. Of to di.eet interaetionJ witll
alpha adrenergic receptors. (Sec also Chapter 18.)
".
DA ;s 1101 an imp<mam regulator of ACTH re-
lease from the par< distalis. However, in animal,
wilh intermediate IQt;",s, <Onte ACTH is rdeased in
response 10 cerlain forms of Slress (101). and both
/i'..::nrlorphin and DA arc implicated in the stimula-
tion. DA has al:;o b«n observed to depress electrical
activity in the pars intermedia, and to inhibit the re-
lease of ",MSH (42) . The .lfeclsare associated with
GTP-depenrlent inhibition of the adenyl!l. cyclase
(W). p.cndorphin is secreted by both pars distalis
conico\ropcs and pars intermedin rnelanotropes. DA
is reponed 10 depress circulati ng /'I..::ndorphin con-
centrations, and to antagonize the stimulatory ef-
fects of dompcridonc. rnelocloprnmirlc and cerlain
Olher DA receptor amagonists. It may function as a
Ionic inhibilOr for the release of this hormone (1(8).
The secr<:tion of LRH is affected by DA. and
LRH contributes to thc regulation of DA synthesis
in the hypothalamus (1 43). The innuences on the se-
eretion of gonadotropins arC complex (see Part V).
Other Influences on t he Endocrine System
DA and A_6,7_DTN activate parathyroid gland ad·
enylale cydase. and they promote tnc secretion of
parathyroid hormone (5) . In this system. fluophcn·
azine and trifluoperazine are hillhly pOtent antallt>-
nislS, whereas bromocriptine and related agents are
only weak inhibitors.
DA 18-hydroxlase activity in the 7.ona
of the adrenal cortex . It thereby slows
the formation of 18.()H-<:Orticosteronc and the se-
cretion of aldosterone (124).
DA also promotes the secrelion of both glucagon
and insulin.
Influences on the Central Norvoul System
DA is a major regulalor of Ihe utrapyramidal sys-
tem. It is present in high concentrations in Ihe basal
ganglia . where ils roles arc interrelated with some of
its behavioral effocls.
Parkinson's disease is a neurological disorder Ihal
has been attributed to degeneralion of dopaminergie
neurons. lowering of DA concentrations in the cere-
bral ganglia. and disruption of Ihe nonnal halane<:
belwe<:n 3e<:tylcholine stimulalion and DA inhibi·
tion. Its victims suffer muscular rigidity, poslural de-
fecls. involunlary movements that include tremors
and "pill_rolling", and oflen salivation. Muscle c0-
ordination is impaired. and loss of some mOlor func-
tions leads to. among other things, "masking" of the
facial expression. Faligue is common, and many pa.
tients suffer mol"<' severe psychic depression Ihan can
CATECHOlA MINES ANO REGUlATORS
be anributed solely to affliction with a progressive.
debilitating disease.
Although the eoncepl that DA deficiency fully ex·
plain' the etiology may be simplistic. it ;5 supported
by obje<:!iV<' findings. Anticholinergic agents have
relieved the symptoms in some palients. l-DOPA is
now widely used, and it is highly effective in of
Ihe subjocts. often for lime periods.
Autopsy data commonly reveal depigmentalion of
the substantia nigra (a region of the brain involved
in regulation of motor functions which binds DA, its
agonists, and its Similar findings have
been reported for psychiatric patients chronically
treated with phenothiazines (Ill). The drugs are
DA re«ptor antagonists that can invoke a parkin·
sonian syndrome.
Aging rats develop mOlOr disorders anributed to
DA neurOn degeneration. They. too, respond to
treatment with DA agonists (22).
L-DOPA transiently relieves all of the described
problems. The lifting of the psychological deprossion
can . howe'·er. be followed by Ihe appearancc of
'"schiwphrcnia-like" symptoms. Correction of IIIe
motor system impairments can be accompanied by
onSCI of other disorders. such as tics. In lluencos of L-
DOPA on the ehemotrigger ZOne of Ihc medulla o!>-
longata lead to nausea . (l.astric upsets. and some-
times vomiting.
DO PA is metabolized to 30-40 other amines.
many of which arc biologically active . Some of the
products may be the rapeutically desirable . whereas
others are suspected of contributing to the unwanted
·'side-effcclS'". Haloperidol is one of the DA antag·
onists used to lreat nausea and vomiling from other
causes. It is not given to patients wilh Parkinson's
disease because it opposes Ihe beneficial aelions of L·
DOPA.
Apomorphine is a mOre potent emetic. It therofore
cannot be used in place of L-DOPA. (It has. how.
ever. saved the lives of persons who have ingested
noncorrosive poisons. It is incorporaled into poten·
tially dangerous medicalions to protect patients
againsl inadverlant overdosage.)
Whcn given to laboratory animals. apomorphine
invokes stereotyped forms of behavior such as snilf-
ing.lic king. gnawing, and repetitive limb movements
(17,95). Rats housed in groups will also with
each other (134). Amphetamine releases DA, and it
has similar effects Ihat are diminished by prior CA
depletion. DA receptor blockers oppose Ihe behav·
ioral manifestalions.
Apomorphine administration into one side of the
brain causes animals to rotate in the dil"<'etion of the
inject ion site. Destruction of the nigrostriatal path-
ways On One side leads to development of hypersen- Conversion of Tyrosine to
si tivity on the other. Systemic injection of large Dlhydroxyphenylalanlne
dQSCs of DA agonists then promotes rotation towards
This is a major rate-limiting step for the production
the unlesioncd side (1 7).
of all of Ihe CAs. It utilizes molecular oxygen and a
Some of the anoreclic of amphetamines arc
pteridine cofactor. BH. (L-erythro-S.6.7,S-tctrahy-
attributed to DA l'alient, taking ·'anti-psy,
drobioptcrin) combines directly with the tyrosine hy-
chotic·' DA reeepter antagonists f rcquem!y increase
droxylase cn7.ymc, and it donates twO hydrogens. A
their food intake and gain weight. A virally induced
second enzyme, bihydroptcridine reductase. then
form of hyperphagia and obesity in ralS has
catalyzes Ihc lransfcr ofhydrogcns from NADPH to
linked with DA deplet ion (92).
Ihc oxidilCd form of the coraetor (Fig. 8-6).
In rats, the nucleus accumbens (which contributes
to the regulation of mOtOr function,) is said to he a
component of a '·gratification'· syste m. When the
an imals are provided with electrodes that permit
self-stimulation, their behavior can be manipulated Tyrosine is Ihc major precursor. It is oblained from
with apomorphine a nd amphemmines (134) . food and il is delivered via the bloodslream. The cells
aClively trarISport the amino acid. O nly the naturally
occurring 1 form is recognized by the enlymC .
BIOSYNTHESIS OF CATECHOLAMJNES
Some phenylalanine can alio be used. since li,·er. brain.
The formalion of 0,1" N, and E from tyrosine was and other lis.u"," contain 3 phenyl.lon;ne hydroxyt .." .
discussW brieAy in Cl1apter 3 (sec Fig. 3-2). The ell- £ , ccS1i,c quanliti •• of phenylalanine in Ihe blood can.
1.ymes, Ihe cofaclors, and the control si les (76) are however. ,"usc problems. , ince this amino acid compet'"
considered here. with lyrosine f<>r transport into lh. cells. It can al"" com_

Ty"",;oo • 0, ,", NAOP '

NAOPH

TyrO$'" BinyOro-plcri"e
hydroxylase reductase

H H /H
"0 C-C- N
Ii I 'H
000"
3·lOOolyrosi,..

" , ;
C-C-N
CH, H
H ?H'
0-0-"
J"1

- H I \ H
, '"
" 000"

Ftg.8-6. Tyrosine ")'<!<Oxyt .... r6llClion. rO<luc«t 1,,""" 01

P,.. ;<f;r,e cofoct<>r. oom. ;n/oibif«l . .... tori.'" indicole
sit. . to< ad.Mion of H .. cOlw"sion 01 BH, 10 BH •.
1M.. in I _ ' u..... iooI.l "",n,... wilh Ihe \yrooi"" h)dr(D..
ylue. Phuj'lketonllri. (PKU) if a conSCni",! dioorde. in
... hicll phuyl•.!.";",, accumul•• es beQr..., Ih= is _
ellOll,1I ol.1Ie plIcnyl.I..,,,,, hy<l .... yl.se.
Normal.hytOid gland •• elusc 11l'1li11 amounU ol J.k>-
docuyrOloi ne. bu •• h. molecule' I.e !lOOn Icltd upon by a
d.lodinlsc. If ,hi t en.yme is ddC(:li •• , Ihe mo •• bolil.
Cln a«umu llte Ind in •• rfer. w;lh 1M re•• tion. (l. lado-
.ytOlline if. pOtent competi.Of ... ben in vi.ro.)
Thy.oidc<:lom;zed animal. h."" hi,h lytOlli"" hydroxyl.
ase act;.ily. bul;. is 1>01 k........ if .hit it .. llled.o lheir
.."Iow levels of lbe Joiodoryrosi ....
Plasma tyn:.ine leve ls underao circadian nna·
lions that an: affecled not only by the OOII\enl and
timing of the mc.als. but also by .he carbohydrate
intake. the hepatic metabolic rhylhms (41), and the
sec retion of iniulin (which promotes the upla ke of
acids by muscle. liver, and othe r organs)
(ISO).
(... MPT) if. compe.ili..
inhibitor lha. is used in lhe In:lltnt'" of pheoch'''''''''r
tomI. An es'e. of Ibif lytOll;"" .""10& if oned in the lab-
«IIOf)' 10 block CA ;n . he !>noin ....
/o4 elhyl·S-hy<l .... )'tl)'ptopll.ln inbibil! by
eau... hey I'<)mbinc direc tly wi.h .h.
.M OCIllctClt. Iron cbcl.. o;,r, in, •• len: ... i.h the n:aClion be-
cuy""'.
Since only around 2% of blood Iyrosine goes into
the production of CAs, ordinary yariations in plasma
.mino acid conlenl h.ave lillIe (33). E;o.
Ireme malnulrilion can Clu$C problems, especially
.. hen il is imposed ea rly in li fe (49).
COFACTORS
Since Ihe of pl eridine cofactor a'" low
when compared with the enzyme levels. they can be·
come rale·limiling. Guanosine triphosphate cyclo-
hyd ro!a .. catalyzes cofaclor biosynthesis, The activo
ily of lhe adn:oomeduUa ry en1.yme is augm<>nled by
il\$ulin. and also by reserpine (which affecrs CA stor·
age) ( 138). 11 is reduoed by denervalion of Ihe ad",..
nal medulla. (Insulin a nd n:$Crpinc act in vivo ';a
diffe",nl mc<:hanisms '0 increase Slimutalion by lhe
splanchnic """""5.) Diff.n:n\ regulalOf'S con(rui pter·
idine synt hesis in other ccll.ypes, ACTH exerts Ih.
major inftuences in the adrenal cortex (I).
Since bih)'dwpleridine ana1oa' Inhibit the reacti"". it
hIS been luU«.td that the BU, .. duc •..., provides a
_troJ lite 0(4). A dihydrofola .e reduct..., i. II",
needed 10 "",i"!lin cofac:lor le.els. Howe.. r. ""i,her of
is alf«ted by IplanehftM; """'" stimdatioft.
n:lCrpi ..... or the hor""lill« eiled (! )I).
CAMP increases Ihe a ffinily 0( the enzyme for
BII , (I). and il promoles phosphpOrylation
( 141). Scyer;r.l pharmocolO&ical . .enrs thaI affecl
DA synlhesis redistribu.e boain CI M . Some: tarboot·
ymelhylale Ca M . K · depolarization inWlkes Ca'· .
dependent phosphorylal ion of T H at I diffen:nt
locus (A-4).
ENZY ME SY NTHESIS
In the pn:$Cnce of adequa te amounls of sul;;lr3le
and cofactor, lyl'lJSine hydrox)·laK (Ti l ) levels can
bc:comc rale-limiling. The enzyme ha5 been purified
Ind shown 10 have a molecular of 60.000.
Strong, repealed slimulation 0( lhe splanchnic
ncr.u probably provides.he II\lljor stimullll for new
enzym<> syn.hesis. Tne effccu In: believed to be me-
dilled via a specific receplor (which may be cholin·
e rgic) (96). They do not IICem to be cAMP-depen·
dent ( 129). a nd they .", not diminished by high CA
concentrations (144). Protein synlhcsis inhibi.Of'S
block Ihe responses.
Rolea 01 MGF and G tueoeortlc:old a
T he biosynthesis of "'GF (ICe Frgs. 3·22 and JoB)
for
wa5 discussed in Chap'er). The hormone is
for survival and differenliation of ct:lIs derived from
Ihe e mbryonic neural creslS and associa.ed struc·
ture'. Exnienow; NGF inj ecled durin(l "",rly devel.
opmental Siages promoles re.ention of "Um·
ben; of cells Ih.al wwld otherwise die. The influences
are on sc:nwry neurons, preganglionic and
po5lganalioni, sympuhelic system neurons. non·
neuronal of gangli.a. and 00 adrc:nornc-
dullary «lis. Under physiological condi.ions.• he
hormone promoles gencralited le<:elcration of pro-
lein and RNA synlhcsis and .:ell growl h (hal is as-
socialed ",ith indUClion or ornithine decarboxylase.
T hese clTects diminish with advancins mawrily. bUI
Ihoy are 001 totally Iosl . NGF also promol.. differ.
entialion of sympalhetie neurons. It aug ..... nts OUI·
afO'lllh of nons a nd il increases Ihe prodlK:lion of
T H Ind ofdopamine ( O BH). The d0-
pamine dccarbootylasc COIIlcnt also rises, but only in
prop:orlion (0 Ihe gencralited aecumulation of ct:1I
proteins (64).
Cell. respon.iy. 10 NOF ,.·v" both 10... · and hi,b.
amnity .... p.lH'S for tbe hormone, Tbe comple. formed
by the binding 10 iow-affini'y li .es anache. to a memo
bra",," $$OO;:i.ted ··e/fC(:tClt protein" that invok .. conlor·
","Ioonal ch.angcs in .he receptor (119). NOF is .ben
,"ken in.o ,he .. n. by endoc)'iOPt. TIM: i."erl"lltiutioft
may be liftked with COII.-no.ion 0( Jow. 10 hilh-affinily
..plotS, ,he phenomena ... lemporatly tda.ed.
NOF and it> receptor I .. IraMloarted ' 0 the """lear
m.mbra .... Some of the "",I ,cules Ire .hen traMpOTled
.i. micro/ilamcnHlependen, meehlni.m. to .he Iyso-
$Om"'. Thi •• IOp i. lin ked with "down regulalion" of re"
ceplor .. (119).
The inleraelioos wilh Ih. plasma membrane may lead
10 Ihe se""rali<HI of a second me .. cnger lhal modi ..",
bonno"al e]feelS (66) . NGF injecled inlo lhe eyl<>pl.. m
of phea<hro!llO"Ylom. cells do<:s ""Ielie;I the r•• pon ...
oblained by presenling the hormone in Ihe extracellular
fluid.
When admini.tered very early during the course
of development. NGF promotes lransformation of
adrenomedullary cell pre<:urwrs to cells Ihal resem-
ble sympathctic neurons. Axons a"" formed. and the
ele<:trical excitabilily is enhanced. Similar effe<:IS arc
obscrved when pheochromocytoma cells in culture
are exposed to high levels of NG F. When presented
soon afterwa rd. the glucocorlicoid. antagonin Ihe ef-
fects of NGF on axon growth. and they reslore the
chromaffin cell charaCleristics (64).
Afler the adrenal medulla has fully formed, glu·
COC<lrtiooids enhance NGr induction of TH and
DBH. They are not absolUlely required, but in Iheir
prescnce Ihe latent period is shortcncd and more en·
zyme is synthesized (129). DcxamelhaSOlle similarly
stimulates pheochromocyloma cells. The steroids arc
believed 10 act moslly on the genomc 10 accelerale
the production of mRNAs They may addilionally
activate ribonucleoprOlein particles or bring about
siructural modiflcalions of Ihe mRNAs Ihat slabi.
he Ih<:>se mole<:ules or incr<:ase their lranslalional ef·
ficiencies (9).
The synergisms can be demonSlrated in vivo only
after animals have acquired their diurnal glucocor.
liooid rhythms. Cold stress promoleS the release of
both gluCOOOTliooids and CAs. Maximal augmenta·
lion of adrenomedullary TH occurs when the ani.
mals ar<: in Ihe morning. wher<:as peak
changes in superior cervical ganglia enzyme follow
afternoon trealmenl (129).
also enhance Ihe effe<:ts of
splanchnic nerve stimulation. PrClrealmenl of ralS
with a large dose of synt helie steroid "supports" Ihe
inductive effecls of carbaminochQlinc (a cholinomi-
melic) altimes of the day when that agent would not
otherwise affect the enzymes.
The glucocorliooid concentrations r<:quired for in-
duclion exce<:d the ones usually found in the blood
plasma. They are attained in vivo because hormones
synthesi1.cd in the adrenal corlex enter a spec ial por·
lal system that directly 10 the medulla
(35.144). During limes of Slress, adr<:norncdullary
cells can be strongly stimulated when plasma glu"
COC<lrtiooid levels ar<: only 'lightly elevated. In ad-
dition to accelerating steroidogenesis. ACT\i aug·
menl, T H by promoting generation of
cA MP (which acoompanies the steroids to the portal
vessels.)
Some CA·secreling neurons within the brain are
more sensilive to ACTH·glucocorticoid system reg·
ulatOTS than others (145). Adrenaleclomy reduces
T H activity in the median eminence, arcuale. and
dorwmedial nuclei of Ihe hypolhalamus but does not
affe.:1 it in other parts of the hypothalamus.
ACUTE NEGATIVE FEEDBACK CONTROL
High concentrations of fr<:e (cytoplasmic) N inhibit
TH by acting diroctly on the enzyme. Agents that
permit N to enter the neuron cytoplasm but block
the sequestration into secretory granules lo".r TH
activity. Oncs that block neuronal uplake of N from
Ihe environment lend to increase it.
Acute slimulation of the splanchnic nerves brings
about tran,ienl inhibition. possibly via elevalion of
Ihe free N. This is soon followed by more rapid se·
cretion of Ihe N. Chronic splanchnic nerve stimula-
lion elevates the TH aclivity. despite the presence of
high N. DA inhibiton i. receptor-mediated (A4).
ADDITIONAL CONTROL SITES
Chronic nerve stimulation accelerales produclion of
storage vesicle membranes. It the reby prepares the
glands and neurOnS 10 secrete larger quantities of
CA when this is required. Serolonin and other lrans-
mitters in the brain affect the T H by exerting influ·
ences at synap>es Or by SCT"ing as ncuromodulators.
Bi ological Actions 01 DOPA
No dire<:1 actions are known. and very lillIe DOPA
gelS into the bloodslream under normal condilions.
When given systemically. it soon crosses the blood -
brain barrier. and il is rapidly oonverled bolh cen-
lrally and peripherally to DA, which can accamulale
in large amounts in synaptic vesicles and about
displacement of Nand E.
ConversIon 01 DOPA to Dopamine
DOPA decarboxylase (D OC) is also known as l-JI r-
omatie amino acid since it acts on
tryptopban. hislidine . and other amino a,ids with
ring Slru,tures. (Histidine decarboxylase is a differ_
ent enzyme.)
The reaclion requires pyridoxal phosphale as a co-
factor. Only severe B,; deficiency affe<:ls DA produc-
tion. However. the ingestion of vitamin tablelS con_
taining only maderate amounts ca n bla<k the
therapeutic cffects of l-DOPA. Faclors Ihal affect
TH biosynthesis exert similar (but minor)
on DOC.
Inhibitors of DOC include ",methyl-DOPA (AI.
domel). FLA-{iJ, NSD lO IS, carbidopa. and
bcnserazide.
,,,
Aldomel gCls ;nlO Ihc central nervous system.
where it elevates Inc ooncenlrations or both DA and
scrolonin. However. its usc in the treatment of hy·
pertension is auribuled \0 wnversiQn 10 ".methyl.
norepinephrine (an agent that aelS as a "false trans-
mitte," and as an «-adrenergic receptor inhibitor
(70) .) FLA-63 [(bi sj-l ·methy l-4-hornopipera,jnyl
lniocaroonyl-disulfidc], and NSD 1015 ()_hydroxy.
have been used to study DA ac-
cumulation at specific brain sites (38).
Carbidopa and bcnscra>-ide do not croos Ihc blood·
brain barrier in cither dir<:Clion . They can be used as
adjuvants in I.·DOPA therapy, By blocking peri·
pherhal decarboxylation, they increase Ihc quantity
of adminiSlcrw DOPA that enters the brain, and
they simultaneously protect against system ic toxic-
ity. However, in hibition of the decarboxylase also
limits N biosynthesis. Animals given large d=s
have impaired ability to oope with cold environ-
ments. Their urines oonlain high le .. els of OA me·
tabolites formed in Ihe brain . Bcnseruide has also
be. n adm inistered intrae<:rebrally to lower ccntral
but not periphcral OA Icvels.
FATE OF DOPAMINE
OA is en"centTated in the ,ec"'lory gra nul<>< of .. d_
renomed uliary celis and in thc synapt ic vesicies of
neurons (sec Fig. 3·3). Amine that fails to e nter the
sequestration silcs (or leaks OUt of them) is vulner·
able to attac\.: by degradative e nzymes.
Doparninergic neurons discharge the OA, along
with other secretory components, when stimulated.
Some aXOplasmie OA may a lso be "'leased, and OA
is found in adrenal effluents.
However, the granu les and vesicles of celis that
synthesize Nand E contain the enzyme that cata-
the next step in thc pathway. Agents that in-
terfe re with the upta ke of OA into the granules re-
duce the Nand E production and aCe<:lera te DA
loss.
Conversion of DA to Norepinephrine
The reaction is catalyzed by dopamine /1-hydroxyl-
ase (OBH , dopamine oxidase). The factors that en·
hance TH biosynthesis (including NGf, nerve
stim ulation, and glucocorticoids) also increase pro-
duction of OBH.
The oxidase contains copper. Glutathione, cys·
teine, mercaptoethanol, coenzyme A, and other chc·
lators in hibit the acti .. ity (fig. g·7). The cells ,e<:m
to contain an endogenous inhibitor that is chemically
related to but not identical with glutathione (76).
c ... TECHOVIMINES A ND RELATED REGUlATORS
Disulfiram (disulfuram, Creales melabolic
dislurbances in which lhe ingeslioo of •• ry small quan-
lilie' of ethyl .kohol precipitate.lh. onsel of grO<$ly u....
ple... nl .ym plom •. It is laken by alcoholics who can ben-
efil from the u.e of .uch a dele .. enl. Although lhe
hypolensioo and ."sodil.tioo th.1 follow alCOhol intah
are related in part 10 diminished N biO$ynl hesi .. di. ulfi·
ram •• crts oth., clTeets th.t inciud. inhibi lion of hep'lic
alcohot dehyd roge na.e.
Asoorbic acid is an obligatory cofactor (144). It is
reduced to dehydroascorbate, and it a lso plays a role
in stabi lization of the enzyme . Severe deficiency of
thc vitamin impairs CA biosynthesis. ACTH regu ·
lation of the transporl of ascorbic add from the cor·
tex to the medulia and some aspectS of the functions
of the vitamin were discussed in Chap. 7.
The cn.ym. i. ava ilable in pure form . and ant ibodi ",
directed ag.in" it are u",d for immunochemicallocali-
ution of the sites of N (or E) biO$ynlhcsis within lhe cen·
tral nervOlls $)"Stem (69). The anlibodi.s can also be used
to produce . form of " immUlIOSympolheetomy" that i,
Ie ......er. and more readily r...... ibl. than the type ob-
tlinc<! with anti·NGI'.
A conlro ..... ial hypothe.i. attribute. ""me forms of
mental illness 10 lhc D8 H defic iency 'od the <»nS«(u.nl
ele.ation of DA:N le.el, in lhe br.;n (H).
F ATE OF NOREPINEPHRINE
Noradrenergie neurons and somc ad renomed uliary
celis accurTiUlate N in their secretory granules. N i.
released along with OBI 1 a nd other granule com-
pone nts when the e<:lis are stimulated (89,137) .
Sympathetic nerve endings avid ly ta\.:e up N from
synaptic clefts and myoneural junctions, reincorpor·
ate it into vesicles, and can release it when again
stimulated. The sequestration protects the N from
intracellular degradation, and it protects the TH
against negative fe<:dback inhibition .
There a re indication. lbat N i$ ' tored in "pools," some
of which are more readily reeruilable than others. Some
free N may also be released rrom lh. cell. A,oplasmic N
is acted upon by enzymes that arc describe<! lale, in lhis
chapter. Aients Ihat permil neu",,,,, {o lake up the amine
but not incorporalC il inlO the granutes tcnd 10 uttim"ety
deplete nor'pinephrine conten!.
Celis that produe<: epinephrine must release the N
to the cytOplasm, since the enZ)'me that catalyze, the
final step in the biosynthetic path way is located
there.
Conyerslon of Norepinephrine 10 Epnephrlne
Pheny let hanolamine·,y-transferase (PNMT) cata-
lyzes replacement of one of the hydrogen atoms of
 o NH,
HHH I IH
"0 C- N- N- C-C- C- OH

" " "

A. 101t.!>itOfS 01 DOPA dec.,boxylase

"'-C - " "C- OH

HHHH
"' - C- C-
II H
C-C-N-
° H
C-
°
II
C-
HH
N- C- COOH
Ii I
" "
Merc.ploemanol
H
HC - SH
H

"
GIOia'''''''''

"
HS --C--- I
C-
"" COOH
" "
Cysteine

H H H H

HH" W
/C-"C
Hf!
N- C - S- S- C- N

H H H H
Oi $ulilram
IAnt.b<Jsej

flV_ 8·7. Inh;!>itor. 01 """" decorboxy'''. (A) Mel 01

dopominO Ii-hydroxyl". (8).

(he amine moiety with a methyl group derived from
S-adcnosylmclhioninc. The product is E. which is
laken inlO Ihe secretory granules ror storage and
subsequent release.
PNMT . clS on octopamine ""d on other . ubstral<:S
chemically ,elated 10 N. It i. found in highest concentra-
tion, in the adrenal medutl. and in certain parl5 of Ih.
broin (t'p<cially those implicated in olfaclion) (33).
Small amoun" ar. pre$Cnl in lb. he." and in some of
lh. chromaffin tissue •. The product' exert negalive reed·
back conlrQl 01'<" PNMT aCli. ily (144).
GluCOC<lrtiooids are major of the enzyme
(29). ACTH restore the in hypophy-
since it causes the adrena! cor·
to send very large quantities of stcl"Qids to tbe
medullary cells. System ic injection of glucocorti-
coids has SOme stimulatory effect. on adrene rgic
neuronS (possibly because the neurons are high ly
sensitive 10 Ihe steroid . Or have mechanisms for COn-
ccntraling it) . Usually the glucooorticoid concentra-
tions attained in the blood plasma of hypophysecto-
mized animals during steroid treatment arc
inadequate for restoration of the PNMT levels in tbe
adrenal medulla.
In some spe<:ics. Ihe epinephrine-secreting cells of
Ihe adrenal medulla are closer to the blood vessels
Ihan the cells tha t release N (144).
Antibod ies direcled again$l the en7.yme are us<d for 10-
calizalion of the .ile. of E biosynlhesis within lhe brain.
T he E conlcnl of specific rtgion$ par3I1e1$ Ihe .. ain ing r<::-
,,.
?"
I ',/ I ""
'" '" '"00
,",
" "
'j'
" '"M ?"
I
'"'" 64139
'" LY 1340'6
?" "-
"" lV 87 ' 30
"M
action$, and it can b< selecli,ely lowered "'ilh PNMT in-
hibitors Ihal have OQ discernible dree"o" the N .OOOOn-
tration; ($9) (FiB. g.8).
Observation. lhal SKF 7698 rMuttl blood
pressure .. it lowe .... E "ithin lbe medulla have been cited
.. evidence ror .ok. of Ihis amine in 'he cenlral regula.
tioo of cardiovascular function. (12). It may inhibit N
,elease (2SI.
Secret!on 01 the Catecholamlnes
Acetylcholine from the splanchnic nerves provide,
Ihc major slimu lus for the cells of the adrenal me.
dulla. The neurotransmitter promote, dcpolarizali""
of the cell membranes. and Ihi. is associated with
increased uptake of calcium ion. from the s urrourt<!-
ing fluids. Other agents that depolarir.<: (e.g. potas-
sium ions) can also stimulate release. but depolari-
rotion (by whatever means) is !lOt effective when
cells are bathed in calcium_free Auid._ The calcium
iollS have been implicated in ""eml processes. in-
cluding the fusion of granule membranes with the
plasma membranes (41). (See discussion of synexin
in Chapter 3.)
The effects of acetylcholine have been linked with
generation of cyclic nucleotides, activation of protein
kinases. art<! phosphoryl at ions of plasma membrane
components (16) .
The quantities of CAs released are determi ned by
both the numbec5 of fibec5 activa ted and the fre_
quencies of the firings. They Can be lOO-fold greatcr
Ihan the basal amounts following strong stimulation.
As is the case with most cells that engage in exocy-
losis_ total depletion of granules does nO! occur.
CA TECHOLAMINES AND RELAT'EO REGLLO.TORS
, ",
I
OCM'
(I. Y 76:)35)
"M
H H /H
C_C_N
I II "H
0
M
Fig. 8-6. PNMT Onnleit"....
DBH. adenine nucleotides. ions. granule proteins
(chromogranins) and other soluble substances pres-
cnl in secretory granules are discharged along with
the CAs. but insolu ble chromomembrins and cyto-
plasmic enzymes are nOI (I 37). The evacuated gran-
ulc., tu m.... '
of the molc<:ules are destroyed, but $Orne are
recycled.
The cells may be equipped with several kinds of
spox:ialir.<:d receptors and feedback control mecha-
nisms. When histamine, serotonin, angiotensin. glu_
cagon, and other stimulants promote release. loss of
sen.itivity to anyone of them is oot consiSlcmly a.-
sociated with chang,," in responsiveness to
The responsivity Can undergo modifications during
maturation. Thus. for example. fetal celts are di-
rectly stimulated by hypoxia. whereas adult cells are
only indirectly affected .
PG. are believed to C<)nfer protection against over-
stimulation by limiting Ca" uptake . Acet}'lcholine
accelerates PG gencration. and exogenous PG. op-
pose the effect. of both acetylcholine and nerve
stimulation.
There are also adapti"e mechanisms for mhallu"
mem of responses to chronic stimulation that supple-
ment the described inAuences on enl.yme synthesis.
Repeated bouts of fighting promote enlargement of
the adrenal glands of experimental and rc-
 peated "psycho;.wcial stimulation" Iuds to elevation
of tM choline acetyltransrel"lse activi ty ( S1).
Relatlve Quanlltie. 01 N and E Releaeed
1\$ aln:ady noted. tenain kinds of "imuli (e.g. hy-
pOglycemia. hypoxia. and psychic mes.s) promote
prefere ntia l rtlease of E. wllen:as othcrs (sucb as hy.
potension) evokc mostly N secretion . Spe<.:ifiei ty de-
pends 00 the dicnccphalic innervation (11·8). and on
se lective rtiease of CRI! , TRH . SS. and
OIMr pc:ptides(A-l).
OEVELOPMENTALOHANGES
fe tuses of many spe<.:i.. (ine:luding humans) put out
norepinephrine: exclusively. The amine n:leased from
the developing adrena l medull a has been implicated
in the regula tion of blood pressure up to the time
when sympathet ic nerves develop suAic iemly to
ow: r the function. II gr.IduII ine:n:ase in E produc-
tion ao;eompanics ma turation in many of the
mammals.
SPECIES VARIATIONS
The N;E ratios vary widel y. and dilTcrenc:cs in ab-
qu antities reieased may be ew:n gr.ater ( 140).
Two ,enera liza tions 11..·• been made. but Iller. arc
exceptions to both; (a) Animals high on tlte evolu-
tionary Kale tend to put OtIt more ep-inc:phrine; and
(b) Qmi .-ores and all8reuive animals put OUt
N than the more timid herbivora.. Thus. lions se-
lOme SS% of their adrcnomedulla ry CAs as
norepinep/lrinc:. " 'he reas the values for rabbits..
guinea pip. and hams!e ", are in the :N,- I I % range.
Diffen:nees in uperimenta l eondi1ions may account
for $Orne conflicting data in the literature.
The very large amounts or N reieased by chickens
wuld be explained on the basis of the 1\"'1 general_
iution. Some popular rootions o;onceming the per-
$Ona litles or those birds are dilflCult 10 reconcile with
the K<OJId idea. On the ot her hard. lhose who have
worked "'ilh chickens do oot fird them esp:cially
passive. Wha les have the hi,hcsl known N percent-
ages (d ose to 88'1». perhap!l beause of the need for
some to survive in cold wate rs.
INDIVIDUAL VARIATIONS AMONG HUMANS
h has s uggested that persons rc$p<.>nd ing to
st1"CS5 with aggression put O1It relalively mon: N.
whereas those who become a nxiou$ or fearful are E
se<:rclOl"$ (89). The CA o;onccntrations in blood and
urine do DOt $ubsw.ntiate the conc:cpt. but such mea-
sun:mentS teilliule of tht brain leW:ls. In humans..
anxietY'pl"O>'okin g and generally unpleasant stimuli
seem to elicil elevation$ of blood E levels in a ll per·
$Oft/Ility lypes. whereas ones eallin, for physical ef·
fon the N conc:cntrations (26). It Iw also been
l lil ted lbat individual!; ,,'100 se<:rcte bi&hcr E per·
centagc5 when required to perform mernal tasks that
ha.e 00 strong emotional auocia tioru work mOre ef·
ficiently. Stress diseharges mort: DA tha n N Or E
(11· 11).
FOR
CAs Cln be: synthesilCd in different \OJ.YS from II'"
fOIine and phenylala mine. Some of the intermroi_
I tes in the bioc he mical pathway an: "false trans mit.
ters". They an: ta ken up by t he kCretOTy granules.
and they are discharged whe n the cells are lI imu.
Ialed. However. when they bind to ell receptors.
they arc either incffc<:tive or less poIent than the
major e lls. can further depress sympathetic
system funetions by inhibitin, TH .
T'ltam in.
Tyramine is formro by deamination oftYfOIine. It is
consistently found in low concen tra tions in the cau-
da te nucleus. hypothalamus. and othe r pans of the
brain, and in the spinal o;on!. T he heart. kidneys, and
small blood vessels also conta in minute quantities.
It can be: synthesized in the intestine. a nd it is a
o;omponent of chocolate. some e heeses. red wines.
and It is usually rapidly degraded. btlt it can
a«umula. e in individua 1s with mmbolie defects
and in those ta ki.., rnonoIImine oxidase inhibitors.
Although tyramine is ta ken up by sympathelic
nerve endings and incorporated into secretory vesi.
cles, it does not qualify as a false ttlnsmiucr because
it is not disc harged when the neurons arc stim ulated.
and it docs not act on postsynaptic receptors. It is.
howe'Cr. biologically polent. since it displacei N. Its
e ffoxts arc a bolished by agents 1hat deplete C As. and
e.u8lera1ed by oocs that slow N degradation (16,
95 ). Tyramine also serves as a precursor of pheny_
Ieth)'lamine and ocu"",mine (w hich I n: f.l<;I: trans-
mine rs). and it can be: made into dopamine ( Fl!. 3-
9).
Phenyl e th'll e m lne ( PE )
The concen trations of PE in normal b".in arc similar
10 those of enkephalins. Phenylalanine is the major
precur$(ll", and PE accumulation in individuals with
PKU bat been implicated as a cause or menta l n:.
lardation. motor impainnents. and be:1IavWf"a1 dis-
orders (107).
When injec ted into Ini .... " prWul04 with m<>n<>-
ImiM o_idlse PE eticiu ..I"crated Iocx>m<>
 e ... ... ND RE ..... TED REGU ..... TORS

-<
Tyro ...... _._ _ _ _ __ PhenVI.I.";"" _ _ __ •

H H 'H
Pl>coyIethyl.m;ne

TvranW>e

/ O OPAMINE

H H /CH,
"0 C-C-N
H H 'H

HO

Synep/lrine

Fig. O.g. PalllwAy' leading 10 formalion of '"f.f..

Iransminea, '"

tor activity and ' tcre«ypic behavior of tbe kind $CCn
foliowing adminimalion of thc chemically related
amphetaminC$.
T he etrect' are anribuled to direct binding of PE to
DA and to stimulatiOn or DA release,
It is possible that the ,mali amounts of PE generated
serve as neur<)modulators, and that they .et on special.
ized recepto,.. of their OWn.
Oetopamlne
Octopamine is another constituent of normal brain
a nd is additionally found in the hean and in Ihe pi·
neal, adrenal. and salivary glands.
It is a major neurolransmiller in lobsters. crabs,
grasshoppers. and cenain olher animals. No phys-
iological rolcs have been established for venebratcs
(in which it qualifies as a False transmitter).
Retated Amlnes
Oct<>pamine can be methylated to r",m sy...pItTi.... an-
otbe, fatse lran,mille'. A S<C<lnd m<thylalion yidds epi.
nephrirl<:. and. thir<!.
Ep;n;ne i •• rnQr>I)methytated derivative of DA. and it
...,ts DA·like actions. It can be metabolized to E and to
N-met hy lc pineph'i nc .
 CATECHOLA MINE METABO LISM
The effeeu of both acute stimul31ioco or tile sympa-
lhetie nem:s and inua\'(C1!OUS injcclioco of CAs are of
s hort duntion, because the amines In: vt"ry rapidly
from the vidnity of the Tl:CCplOfS. CAs
taken up by nerve terminals can be incorporaled inlo
synaplic vesicles and reeyelOO. MoIeeulCli Ihat enler
the axoplasm but are nOl $Cquestercd in way
(and those Ihal ka l from the vesicles) unde rgo en-
degradation. CAslhal circulate in the blood
ud CAs that a re taken up by other cell types are
actOO on by different enz)·mes.
Upt.k .
CA uplake by neurons on be dis(inaulshed in scv-
eral ways from the relatOO in OIher cell
Iypes.
Uplakt J is Iransport from eXlTaceliulM nuids to
axoplasm. It requires AT P ene rgy •• nd;t is impaired
by metabolic poiS<.>m and inhibilon of Na- / K'-
ATPase (e.g. ouabain). The ralC is 1 1110 atreclOO by
brae changes in utnccllubr 1"a ' .nd K - .
In .... m ....l .. tIM: n<uronat .... mbra ... ")'I'om
e.I;'Uy trampons N (b.1I likes up some E). 8yconuI".
llIe neurons 01" (roes (in E il llIe major Iympalhetic
IrallSmilur) E wilh ,rc.ler .mekn<:y.
Metaraminol (Fia. g·IO) is a "pump" inhibitor
that competcs with tile CM and thereby devates the
peripheral N il i. effeclivt"
when laken orally. is resiStanl to degradation. a nd
canno)l ero5lllbc blood-brain barrkr. il is used in the
trealment of hypotension. Amphetamine, ephedrine,
and axaine.n: among the a,enu lilat do cross the
barrier and ilimulate the centl1l.l nervous system
(16,33) .
The "tricyclic antideprcmlnls" are powerful
pu mp inhibilors Ihat act en the brain, Some{e, g. im_
ipramine). howevcr. are mon: potent for inhibitin,
$Crotonin than 1" uplake. Phenoxybl:nznminc. DCI.
and Olher receptor blockers already described are
weak inhibilors.
is an especially Itroog inhibitor of
DI\ uptake that affccts the extrapyramidal neurons..
Amphetamine and cocaine also inlerfen: with DA
uptake.
...... -
Most of Ihe agen15 exert numerous side..::ffects,
Bennropinc mimics some actions of acetylcholine
and also hu some atropine.like and antihistaminie
propenies. Cocaine is a loca l ancslhetic. Amphet_
amines a nd ccnain OI hen I re mo_mine ""ida..
inhibitors.
Transfers from the axoplasm to the syna ptic Ve$"-
ides also require energy, However. they are driven
by a Ca'- / Mg"_A TPase und the rates arc affected
by ehanlcs in e xt racellular Ca " and Ma" (but not
K · orN. ' ).
CAt taken up by vesidesan: protected against en-
zymatic de,radatioco. Agenls (hal the rcgu.
talon 10 enler Ihe uopbsm bUI block vesicle uptake
bri", a bou t depletion. Reserpine is especially potenl.
since il sains access to the adrenal medulla and
brain and is Iong-aeting. ( It also affects other pro-
ceS$(:s, e.l, seroton in entry into Iranuies.)
Uplokt ] is utili7.cd by 5nl00lll musde. cardiac
SlIlivary glands. ki dneys. and OIher nOn·ncu·
rons. The syslem preferenlially .lfcel5 E.
Uptake 2 inhibitors include prcnylaminc and a va_
riety of naturally occurrin, 5u bstanca s""h as me-
tancpltrinc and oormetnnephrinc. Estradiol, u::stos-
teronc:. and corticosterone can 100a ily bioek the:
tramper' when presented in thai arc
hialler Ihan the oocs usually found in the circulation
but inadequate fer exerting influences on upta ke I.
DOC is quilc e ffcctive. wherea s dielhylstilbestrol
(which interacl5 slTOngly with c.trosen = ptors) is
f. r less potent. Phenoxyben7.amine has ,realer ef·
f«1S on uptake 2 lhan On IIptake I.
CAt ta ken into 100sc ttlls an: npidly degraded by
enzymes. The livt"r also conjupte5 the
CAs and their metaboli u:s with l utrale and glu-
cul"OlUtte. Small quanti ties of N and to oonjupte5 can
be found in Ihe blood, and laraer ones in the
UrIne, Circ ulating DA is 95-99% conj"p ted (A.
I I).
C.I.ehol-o· Melhyllr.n.,.r •••• ( COMT.)
These eytO$Olic al)-wprotdn are abundant
in brain. and kidney. but a re . 1so found in a
wide varkty of OIher structures (includ in, intClline,
Iplcen, skin, blood VCS$CI walls. erythrocytes. adipose
lisne. $.II!ivary glands. piluitary ,lands. and periph-
eral nerves). They inactivate CAs injected inlo Ihe
bloodstream and somc of the molecules rcleased at
synapses (6).
CO MTs catalyze tile transfer 01" methyl groups
from S-adeoos)"lmethionine to E. N. and 01\. "The
prodLIC15 of lhe reactions an: mel.nephrine. 001"-
meta ... pbri"". and l-methoxy-DA. The
enzymes a lso act on deamination melabolites of
lhoic CAs. a nd on catechol esll'Ot!ens 10 form 2_ and
4-rnethoxycslnogens.
 CATECHOLAMINES A ND RE .... TED Rl::GULATOFlS

1 HHH/CH.
C- O-C- C-C - N
"o HC-C-CH
"
o ....-CH,
;/' C-C-N
Ii
H
I
...-H
'Ii
Ii H.../ / I H
C - C- N
H I
....-CH.! - "
..... 11
'Ii
,", , ",

I
C - OCH.
l Cocair>o

r
\" I " "
\
"
I
flC - " "
C-
H
C-
H
"
"CH,

'CH,
IHH/CH,
HC-C -
H H
C-N
H 'H
IHH/CH,
I-fC-C -
H H
C-N
H 'Cli.
ImipramiM
Amilri pt)'lirle

A. A(I(lnts tlIOCI<ing CA I<ans.port across """,onal .... s

"
,

-o - CH ,

\ , ",

"
 COMT inhibitor> include pyrogallol. acetamide. The inhibition somewhat prolongs the actions of
guanethidine:. bretylium. and some tropalone and injected E. but the catCl:holamines are eventually de-
papaverine derivatives. AU have additional effects. graded by ami ne oxidases.
Conisol inhibition may be physiologically imponant.

"
0
ce,
{7 "
0
"
HC-C-N /" {7 " II "
C- N- C-CH,

" '" " ce,"

""
P'/rOgalioi
" Acelamide
,
ce, "" e,
Bretylium

0
O,CH,

/-
"<,
{7
",
Monoam ine
H,c ....O

( MAOs)
"" pap3'Orirle

absent from erythrocytes 11301). There a,.., con tro-

Although the MAOs on the Oilier mitochondrial
membrane. of neuron. have reeei",d the rrtO$t atten·
tion. the quanti ties of such distributed to
other parts of the body exceed those of the ncrv<lUs
system. MAOs have been identified in all glarKIs
studied to date. including both the adrenal concx
and medulla. Salivary glands a"" an e<pecially rich
source. T he enzymes are abundant in liver. kidney,
smooth and cardiac muscle. fibrous connective tis-
sues. bone, and blood platelets (but they seem to be
versies concerning whether all are mitochondrial;
and associations with endoplasmic reticulum have
been suggested. Within the nerYOu' 'ystem, MAO,
arc fQund in glial cells as well as in axOn endings and
dendrites.
MAOs catalyze oxidati,'e dcaminat;ons. The
prod ucts are aldehydes. mOSt of which a,.., subse-
quently further oxidi7..d to acids or reduced to
alcohols , 3,4-dihydroxyphenyl-glycoaldchyde is
formed when MAO. act On either N Or E. It is con-
vened peripherally to 3,4-dihydroxymandclie acid.

"o "
I
C-C-N
H /H
?C-C=O
"
H H .... H ,
o
"
"0
NOREPINEPHR INE 3.' _<j;hy<jro.ypnenyt_ EP INEPHR IN E

I
"0

"0
 CA TECHOLAMINE$ ANO RELATED REGULATORS

"
EP INEPHRINE
____ ..
H,c,O
V
H H
H
C - C-N
-"CH ,
......... H

MC'ancphrine

H,c"
"
COMT 0 C- COOH
3,4.Dihydf<l<ymandelic ocid _ _ _" '' ' ' ' -_ _ ._ "

COMT
NOREPINEPHRINE

Normetancphrine

_____c"O,,",,____-<_
OOPAMINE ..

MAO

H _ H,c,
C-CClCl'" _ • °
"
ac;cl
(HYA)

Fill. 8· " . Formation of m..... Uf;"ary ",.,.bo!;!e8 01

ptoriptler., N. E. and D.o.. (Conjugates .... not tOOwn.)

add is acted upon by sequently undergo oxidative dcamination ( 117) (Fig.

COMT to yield vaniliylmandclic aci d (VMA. 3· g·ll) .
methoxy, 4·hydroxymandelic acid). This is the SQmewhal different pathways predominate in the
major urinary metabolite of both Nand E. It is alSQ central nervoos system (Figs. &'12 and 8·13). Alde-
formed when COMT acts first and the prod ucts sub- hydes formed in reactions catalyzed by MAO. are
 3 .• ·00000000fO<ymandel;" 3.••
oed (OOMA.. DM"') (OOPEG) <6
"

3.•. o;I1Yd'O'TCO;Ok\eh Yde ..

MAO

MeWlep/lrine

;P 3.M('li"oo")'.'-hytlro"l'Q1yc<>aIdeItyde .MAO Norm".n"pl'.-ine

(MfPG)
3-MctflQ,y, "i>yd'o,ym .<"Idel;" MH PG - 3· McthO"l'. HlytlfO<yp/>(myl·
acd (VI.'.AI elhylglyCOllMOPEG)

/
VMA·SuH.",

Fig. 8· 12.
'"
Mojor pathways 10< degradat;oo Of E aoo N in
"""".1 system.

______OOM"',,'______
OOPA • 3.O-Metnyt.DQPA

DOP!MINE ___ "'OMO!''--____'_ 3-0-Melhyl.DOPAM INE

13' Mel hOxytYfamine I

"'0 ""
--,, , , ",<,,-._,",,,,,,.1.:'0",,","_

Oihydro<ypheny1aootic acid
(DOPAC)

HVA'Su!l ate

Fig. 8· 13. Mojo< palhways 10< degradatiOn 0 1 OA in the

"""ir.' Mr.""s I Yltem.

'"
mostly to alcohol., sin"" aldehyde reduc_
ta,e. are mOre active than Ihc dehydrogenascs.
ISOZYMES (33, 95 )
A" predominates in sympathetic nerve end-
ings a nd in Ihc superior cervical ganglia . It is also
present in seroloninergic ncuronS. The preferential
substrates are N and serotonin . Ethyltryptaminc,
CA TECHOlAMINES ANO RELATED REGULATORS
clorgyline, harmine, and harmaline are effeclive in-
hibitors thai elevate both Nand serolonin level,
(Fig. 8·14).
Type B predominates in dopaminergic neuron,. It
aclS mOre effcclivciyon phcnylcthylaminc than does
thc A lype: , but it has liule influence On serotonin.
(Dopamine, tyramine. and tryptamine can. however,
SCrve as substrates ror both of the iso7.ymcs.) Di·
prenyl is an especiall y polent inhibitor.

H H K /OH,
O-C-C -C- N
" ' ' ' ,_ _ C- H
C- N"H
CI H H H H I 'H

'" " """,

,",

,,-Elhy1lryptamine

Harmine
"'" ',";-v"",/'0P
CI-I, 1-1

H"maIi""

I
Depo-e"l'1 Ipron;azid
IMarsllidi
H H 1-1 ,...-H

o-
'"
I C-C-N - N
H H

Phenelzine
'1-1

4-°1-1 H H H H H -

N
I Nialamide

Flg.8-14. Monoami.. o.;cJe.. WIibiIors.

 A different inhibitor, catron
has been usC<! to study pineal gland
en,.ymes. since it affects parenchymal but OOt the
ncuronal
Moot other MAO antagonists affect both A and B
iSO,.ymcs. The antidepressants increase brain levels
of DA. N. E. and serotonin. and their interference
with the usual metabolic pathways leads to the ae-
mulation of false transmillers. They exen other ef-
fects as weU, For example. I110St disrupt Or delay
transmission in the sympathetic ganglia and a com-
mon consequence is orthostatic hypotension. How·
in the presence of tyramine. they can elevate
the blood pressure. The h}'drozine derivatives arc
also hepatotoxic. They prolong or exacerbate the in.
Ouenees of a wide variety of pharmacological and
naturaUy occurring agenu.
ADDITIONAL MECHANISMS FOR
PHARMACOLOGICAL MANIPULATION OF
THE CA SYSTEM
Acetylcholincsterase inhibitors such as physostig-
mine prolong and acetylcholine actions
at ali target sites (neuromuscular junctions of skel-
etal muscle. autonomic ganglia. a nd parasympa-
thetic sy1tem target organs), Inlow concentrations.
atropine blocks mostly the parasympatbetic (mus-
carinic) effects. but in hill her Ones it also acts at the
ganglia . Pilocarpine is an example of a muscarinic
agonist. It affects One component of neural control
Over the adrenal medulla and tends to increase epi-
nephrine secretion . Hexamethonium is a ganglionic
blocker that affects both parasympathetic and sym-
functions and reduees the N release from
the adrenal medulla , Guanethidine and bretylium
interfere with postganglionic transmission in the
sympathetic s}'stem and therefore the release of N
from sympathetic nerve endings. Enkephalins arc
implicated in presynaptic inhibition of the choliner-
gic neurons of sympathetic ganglia. Naloxone. an
opioid receptor antagonis!. overcomes the inhibition
(78).
SER OTONIN
S<:rotonin (5-hydroxytryptamine. 5-HD interacts
with the catecholamine system in many ways. It can
c1icit eA-like responses by displacing N when it i.
ta ken up by noradrenergic nerlle endings and incor·
porated into synaptic vesicles (!O5). and when it
competes with N as a substrate for monoamine
dases . Howe>'er. although it is released in response
to stress. most of its influen""s oppose those of the
sympathetic system. Some serotoninergic neurons
tonically inhibit adrenergic ones. 5_HT modulates
acetylcholine rclease in sympathetic ganglia. and iI
acts directly On smooth muscle and endocrine cells
that are responsive to CA! ,
$erOtoni n-synthesi,,ing neurons within the central
nerliOUs system are concentrated in the raphe and re-
ticular regions of the brain stem, but the axons pro-
ject extensively to other regions. These inelude the
cerebral hemispheres, the cerebellum. and the spinal
cord , Concentrations within parts of the bypothala-
muS are also high (25), and the amine plays impor-
tant roles in the regulation of pitUitary hormone se-
cretion (136). It is implicated in promoting prolactin
release in response to a suckling stimulus (31), and
it affects the secretions of growth bormone. ACTH .
TSH. and gonadotropin•.
Serotonin is a major regulator of circadian
rhythms (48). and many obserllations are wnsistent
with roles in facilitating relaxation and slecp onset .
It coexists with 1'1 in the suprachiasmatic nuclei. and
it mostly <lPPOSCS Ihe actions of N. 5-HT is also the
precursor of melatonin and other indoleamines se-
creted by the pineal gland. The pineal is located
within the brain. but the activities of several of its
Cntymes arc controlled by the postganglionic neu-
rons of Ihe cervical sympathetic ganglia.
Labeled .ntibodie. direcled against tryptophan hy_
(Ihe rale.limiting e"'-yme for synthe,i. )
have been used to the .ite. of .. rOlonin formation
in the brain , The neurons can be deSlroyed with neuro-
t""i,. '" ch a. 5.(,.(Iihydro,ytrypumino (5.6-DHT) and
6.7-DHl'. which are taken up by axOn cndings (Fig. 8-
IS). It is are oxidized 10 metal>--
olite> tha! directly mediate the de.truction (95). Para-
ohloroamphetamino (PCA) is also taken up. The mech_
anism. "'her.by it deplete. serPlonin are only partially
unde"tood. Somt inhibilion of tryptophan hydroxyta,. i.
involved.
Approximately 98% of total 5_HT is found outside
tbe central nervous system. The blood platelets and
gaSlroimcstinal tract account for around 95%. and
serotonin is a component of both central and periph_
eral mast ceUs. Smaller amountS are found in many
endocrine and exocrine glands. induding the thy-
roid. the pancreatic and the salivary glands.
Enterochromaffin cells of the gaStrointestinal tract
make substantial amounts. Serotonin is <H)W known
to be identical with a regulator initially called enter-
amine that is released from the «lis. It stimulates
the contraction of intestinal smooth muscle and in-
creases thc tone.
Blood platelets do not synthesize 5-HT. but they
it up from the cells of the gut and they StOre il.
They release it when small breaks appear in the
blood vessels. and the consequent stimulation of the
smooth muscle of the vaseular system contributes to
hemostasis. 5-HT also has limited platelet-aggrega-
ting polency. The term v(JSOlonin was initially used
for the serotonin released by the platelets.
 CI< TECHOLI<M INES I<ND AELA.TED REGULATORS

H H ..... H
C-C-N
H H 'H

'" "'-V"-,
5.6-OihydIo><y!ryptomine
"
6,7-Dihydro><y!ryp'amine

"ir_HC-C-N
I /H
,...-
, "

o" 0 Nfl>
, .... ?' C-N-C-C-C - O><
H ,1 H H

Bensenuide "
Fig. 8·15. Some agMI. 1....1 inI"",,", wilh _"'onin
•.

Effe<:ts on Ihe vascular system vary with location Biosynthesis

and physiological Acute responses differ from
delayed ones, 'and species differ<:nces haY<: also
enCOuntered. The vessels of the lungs. and those of
the renal and mesenteric beds that are dilated by
DA, are constricted by 5·HT. Vasodilatioo predom·
inates in lhe skin. It is attributed mostly to di rect
interactions with both histamine and serotonin re-
ceptors. but 5·HT also decreases N release and in-
vokes reflues. In common with histamine. it causes
itching sensations.
The most obvious effe<:ts on the hean are me-
diate<! via chemoreceptors and baroreccptors of the
respiratory and cardiovascular s)'Stems. Vagal stirn.
ulation and sympathetic inhibilion can be of suffi-
cient severily to markedly dep"'ss the m}'OCardium.
However, 5·HT also "'leases N locally, and direct
influences on isolated heans are mostly stimulatory.
Effects on peripj,eral glands include inhibition
of insulin. gastrin. and HCI secrelion. Additional
targets arc the parafollicular cells of the thyroid
and the MSH.secreling oneS of the pars imermedia
(42).
The formation of serotonin from tryptophan and the
use of the product to make pineal gland hormones
Were described briefly in Chapter 3 (sec Fig. 3-1).
Since mOSt proteins contain only small amOUnts of
tryptophan. the availability of Ihe substrate Can be-
come rate limiting. This is especially true during cer-
Utin times of the day. because the plasma concentra·
tions of Ihe amino acid undergo marked circadian
variat ions tl1al arc with feeding. hcpatocyte,
glucocorticoid. and insulin rhythms (47).
Since 5-HT has betn implicaled .. . physiological me-
dialor of rclaxal ion .I«p. il hU been recommendod
Ihat iruomniacs lake tryptophan-rich food. and avoid
carbohydratcs_ augmenl inlulin relea.., and
the..,by diverl amino acids from blood to skeletal mu""le
and alh.r li».e,). A problem w;lh Ihe lIO\;on i.lhatlryl'"
tophan·rich food. and the very act of eating provide p<>-
lent <l imuli for lho bota coli, of th. ptnert.lie ;,lel'.
Tryptophan is actively transported into Ihe sere-
tonin.synlhcsizing u:U •. Phenylalanine and tyrosine
compete for the carrier, and high concentrations of
those amino adds interfere with tryptophan uptake.
Thcy can therefore exacerbate the effects of trypu>-
phan deficiency.
Tryptophan defioiency has been observed to lo"'er Ihe
brain 5-HT tevol, of rats and imp,ir their ,bitit), '0 run
maze •. The effects can be reversed by uypt<>phan .dmin-
i'tration (lOS). On 'he "'her hand, although pationlS with
PKU have .ubnormal <:<lncentralion, of and ilS
metaboli'o< in 'heir btood and urine. tryptophan feedinll
uaccrba,e, the symptom,. In the .. individuals. phenyl-
alanine acc umula'ion probably lead, '0 direc, inhibi'ion
or trypt<>phan hydroxyl..c. Phenylalanine r..uietion i,
bencr.ci.l, at loast in part beoau$<: it ""torts ,he en',yme
function •.
Trypto pha n Hydro xylase
This enzyme catalyzes the conversion of tryplophan
to 5_hydroxytryptophn (5-HTP) , The reaclion.
which is sim ilar to the one dC!;cribed for tyrosine hy-
droxylase. utilizes molecular oxygen and requires a
pteridine cofactor. When the substrate levels are ad-
equate, this stcp becomes ratc limiting.
High oxygen tensions accelerate ,erotonin ,ynth •• i. in
vilro, and .nimal. breathing pure nta ke I.rger
amounts than controls, On th. oth.r hand .• nimal. living
at high altitude. do not .. em to exporience serious
difficulti •• ,
normally contain tryptophan hydrox·
ylase lhan thcy nct:d, and they maintain scrotonin
reserves that are large compared with the re\e(1)e
rates. The organism a whole is therehy prOlected
against i"termillent depression of the cireulating
tryptophan concentrations,
Chronic nerve stimulation increases enzyme syn-
thesis. hut dovcnervation only slightly diminishes it
(95) . Neither 3·HT nor 5-HTP seemS to exert neg-
ative feedback control. and no effects of thyroid or
glucocorticoid hormone \evels have been found.
Agents thai retard tryptophan uplakc usually de-
Crease the activity of the enzyme. Lithium. wnieh
accelerates uptake. transiently increases il; but ils
long_range effects are opposite in direction.
concenlrations of phenylalanine dire.:tly in-
hibit the enzyme. Parachlorophcnylalanine (PCPi\).
e.:rtain other phenylalanine analogs. and propylacc-
lamide exert cffe.:ts that can be OVerCOme only by
synthesizing neW en1.yme molecules, These agents
addilionally act on phenylalanine hydroxylase,
whereas 6-fluorotryp\ophan is specific for trypto-
phan hydroxylase,
HTP Dec arb o xylase
5-HTP is immediately converted to serotonin, since
the cells contain large quanlilies of HTP decarbox-
ylase. The enzyme closely rescmbles (and mayevcn
be idenlical with) DOPA decarboxylase. High COn-
centrations of 5-HTP inhibit Ihe decarboxylation of
both substra tes. but agents such as benscrazidc more
obviously impair DOPA metabolism.
Tryptophan can be decarboxyla\ed to tryptamine.
Thai metabolite is formed in excessive quantities
when either tryptophan hydroxlasc or monoamine
oxidase activity is low, Tryptamine can take up
methyl groups from S-adenosylmethione. One prod-
uct of the ruclions is which is
a pOtent hallucinogen. It nas been suggesled thai di_
melhyltryptamine contributes to Ihc symplOnts of
mental illness in some patients (75). but Ihere is no
conclusive proof that its levels in blood or cerebro-
spinal Huid arC ekvated.
Sero tonin St o rage
Studies with labeled 5-HT suggest that serotonin
takcn up by synaptic vesicles of unslimulated neu-
rons can be stored for extended time periods. How-
ever. different kinds of data are consistent wilh IOlal
turnover of body 5-HT cvery 24 hours.
Axonal upta ke of previously released 5_HT is ac-
complished by processes resembling the ones de-
scribed ror CAs. It is similarly depressed by ouabain
and metabolic poisons thai interrere with ATP syn-
thesis. Some differences in responses to "pump" in_
hibitors have been described (Fig. 8-16). Whereas
imipramine is equipotent for transport of Nand 5-
HT, desipramine aCls preferentially on N. Nortrip.
tiline and clomipramine more effectively block se-
rotonin uptake, and fiuoxetine is said to be "spoeific"
for serotonin.
Reserpine and tetrabenazine block 5-HT uptake
into synaptic vesicles, Sine.: amine retained in the
axoplasm is rapidly degraded, these agents slowly
deplete the body of serotonin as well as
catccholamine,.
Metab Oli s m
MAOs catalyze oxidativc dcamination , Most of the
5-hydroxyindole-llcctaldehyde thai is formed is soon
oxidized to 5-OII -indo1c-llcetic acid (5-HIAA). but
small amounts arc reduced in the central nervous
'ystem to 5-0H -tryptophol (Fig. 8-17).
The MAO. of neurons .re mostly of the
A t)'po. Thcy are inhibited by dot"·
gyline. harmaline. and the "broad .poctrum" agents .ueh
as "an)'lcypromine, Since deprenyl preferentially acts on
B typo MAO, it has linle inHuenee on strot""in level.
when it alone i. given. However, when 1\ typo enzyme.
are tota lly inactivated. some effects can be demonstrated.
This i, explained by the prestnec of B 'ype e.,yme in
 C" TfCHOlAMINES "NO RELATED REGULATORS

\ '" h-
I '"h-
"
I
HC -
H H
C-C-N
/CH, "
H H H "CH,

" . Floo. etine

I '"
h-
I '"
h-
"
,", -0I
I "

II H H
C-C-C-N
H H
/CH,

H "H
'"
C. Nonryptyhnc
",
D. Fenllu,,,,,,""

Flg. 8-UI. Some "","';t"". of _01"","", uptake aero ..

-""""I pia""" membtane. (". B. 00(1 C) . Fenfll.ff1Im'"
(OJ inh ib its uplllke into ",,,,,ali/> grenut••.

neuroglial cell •. and tho or 5· HT by noradfcncrgic
axon,.
l:lram $ultatU<$ .alalzy" tormallon 01 "'rOton,n
,ulfale e"e .., The", a", "an'ported oul of Ih. brain neu-
ron •. alont with 5_H IAA. Probenecid non.!'<eifically
'lows the transport of these and othe, acidic maleculei.
""
H,c-C-C\
"" N- S-O
" "/ 0II
H,c - C-C
" " Probene<;id
N·a«tyhransfefa,o. (NAT,) catalY7.c coo.e .. i"" of
.erlon;n to N... cetyl"rQt",,;n. Small quantiti .. of tit<
tabolite art found in the ce rebellum and other parts of
Ihe brain.
As its name ' UU.. ts. bufolenin WI. firsl identified in
amphibian . kin. 11 i. a melhylat<d derivative of
that may be made in vcry .mall amount. by mammalian
b,ains. hs phosphate ."ef. ps;locybin. is a mu.hroom poi·
son. Bolh are POlenl hallucinogen, ,uspocled of inl'Oki",
Iheir effects b)' acti", on ,erot""in re«ptors,
Bolstered by thal lit< uri"". of some p.-
lien .. diagnosed as .... hi'ophrenie·· contain .mall quan'
litie. of bufOienin. whilo their cerebrospinal fluid, have
$uboormal 5-H1AA concent""ions.;t ha. been propooed
Ihal the ill"" .. re.ults from deranged tryptophan "",,,b-
oIism and the con>equent accumulalion of meth),laled $<.
rotonin metabol ites Howev.r, such patienlS often
hav. poor 'ppeliles and lend 10 ",Ie" unbalanced die ...
Tit< """,ibility thai nutrilion.1 'CC<>llnt for
defective tryptophan metaboli.m ,",'; lh",,, ""cessar;ly
eau''"g lh •• ymptoms. ha, nol been ,,...,,ed.
Serotonin thai enters Ihe blood is taken up by Ihc
liver and by pulmonary endothelium. MAOs. alde-
hyde rcduclasc., and aldehyde dehydrogena$<s cal-
aly'-" reaclions of Ih. kinds described for ncuron•.
There art some interesting inlCr.letions wilh <thyl al·
cohol, When large quanlitie, are inge"ed, more trypte-
phol and less 5-H IAA are made. Thi, h., been ",ribuled
to suo."31e competili"" for Ihe dehydfOjlena"" in liver
(but nol in b.. in) (3)) . On the other hand. infusion of
minute amounts of ethyl alcohol into the brdil13 of ralS
invokes . dose-depondenl "craving" for .Ieol\ollha. can
be relieved wilh PC PA (lOS),
Serotonin Metab ollam in t he Plnaal Gland
The pineal gland i. a major ",gula\or of endocrine,
loromolor. and sleep-waking cyele, (see Chaplcr
20), and it may also play roles in hibernalion (142).
AI least some of its functions are medialed by hor_
mones made from tryptophan.
Large quantities of "roIonin arc synlhesized
along metabolic pathways identical with Ihe one de-
.. ribed for serOlonine'gic neuron •. Some 5-HT gocs
to S-I·I IAA. but mOre i. converted to N-acelylscro-
tonin. especially during the hours of darkFICss. Thc
product is Ihen acted upon by hydroxyindole·O-
melhyl-transfera.e to yield melaronin (M LT). The
 //¢;-,_"H
0/ I C-C-N Ii ,..Ii

• H 6 ' H
o
"'-v""" "
o
" Tryptophan
"
S.OH.TrypIOl'Mn
"
IHTP)

_ _ "1_1IiC-C-N
Ii "eli,
It Ii 'eH,

"'-v"""
"
SEROTONIN
"
Bu1<>teni""
(5·1-11)

"
Psilocybin

""
SOf""',.,!,., 0" 1(3 '0 eo

,.,
"
N -Acetyl$!)rotonin

"
C-COOH

"
"C-C-OH
" ""
5·0H·lndoleacebc Acid
"" (5·HlAAl

hormone is released to the blood stream. and it i,
taken up by peripheral organs. Hepa!ic cn"ymcs
convert ML T to 6-OH·ML T. which is excreted inlo
lhe urine either directly or after CQnjuga!ion
sulfate or glucuronide.
Some of thc serotonin is oxidatively dcamina(cd
by MAas. A substantial percentage of thc 5.()H.
indolc-acclaldcnydc lhus formed i, reduced \0 5-
OH-lryploph()l. HIOMT methyla! .. 'Omc of it 10
5-mcthoxY·lr}'ptophoL It also OOnvcrlS S·H IAA to 5·
mcthoxy·indoleacetic acid . ML T. 5-OH-tryptopbol.
and 5-methoxytryplophol afC aU biologically aClive.
Some has also been
identified in pineal gland extracts (122) (Fig. 8-18).
T he pinealocy\ts ha vc Jl-adrenergic receptors. and
they al"<' innervated by postganglionic fibers from thc
superior e<:rvical ganglia_ DestrUClion of the ganglia
or severing of Ihc postganglionic fibers aboli'hes thc
'" AND RELATED REGULATORS

..,d..... A<",
__ "·.«'",
""'" ISHIAA)
IIUI

r --'"OW
,
" "
,/
C C Oli
I, H- H-

5_0H_TAYPTOPHOo.

"'ELATON ' "

",c..O J "H
'O:- .-C-C-OH
, , /" H H

"''''0 _'
GroeOIOO'"

"" p
, / H CH,

"'."'O,""_So"", O-A«','" ..,.,.., •• .

'..,.pI"""",

Fig, 8- 18. FormllliOn Ol mfl18100;0 , 00 rflla"'" l\'IOkICul8 • .

rhythms. It alSQ increases Ihe sensilivity 10 steps Ihal arc blocke<J with protein synthesis inhibi.
nous N (7). tors (1).
Norepinephrine released from the nerve endings In mammals. Ihe pineal gland rhythms are con-
increases the rale of gland uptake of tryplo- trolled by the supraehiasmatic nuclei of the hypo-
phan, the tryptophan activity. and the thalamus. Synchronization with changes in environ-
NAT activity_ The enzyme effects (but nol the up. mental lighting depends upon mClSages that trave l
are evidently acwmpl;she<l in part via activa- from the retina along rctinohypothalamie tracts to
tion of cAMP.dcpendcnl kinases, and Ihey involve the hypothalam ic nuclei (?7). The neuronal path-
ways were described briefly in Chapter 2, and they
arC considered in greater detail in Chapter 20,
Pineal gland functions are modulated by several
hormones, N increases the numbers of rcceptors for
eslTadiol , testosterone, progesterone, and prolactin,
steroids and gonadotropins, in tum, affcct N
turnover in the superior cervical ganglia, and they
act in other ways as ",elL For example, estrogens in-
crease, whereas progesterone decreascs M LT syn-
thesis _ia mechanisms that do not involve interac-
tions with catecholamines (29),
Serotonin Receptors
Serotonin receptors are even mOre difficult to classify
than the ones for dopamine, and it is not yet known
how many types there are, The numerous sites of aC-
tion (hrain neurons. peripheral nerves.. peripheral
ganglia, smooth muscle. and endocrine cells). the
ability of 5·HT to promote release of acetylcholine.
histamine. CAs. and other regulators. the coexis-
tence of substance P in scroloninergic nerve termi-
nals (69), the many different ways that serotonin
target organs can be affccted. and the nonspecific
natu«:s of the antagonists, all contribute to the con-
fusion. The peripheral rc<:eptor antagonists enter the
brain. and they exert numerous influences. However.
the effects on the brain do not resemble the conse-
quences of destruction of the known serotoninergic
neurons. or of administration of pharmacological
that impair 5-HT biosynthesis.
The r«eptors scem to be confined to Ihe cell Sur-
Some of Ihe «:sponses have been linked with
generation of cyclic nuclcotides and with Ihe phos-
phorylation of specifIC neuronal proteins (85). Oth·
ers invol_ing changes in membrane phospholipids.
Cal' entry. and ion conductances may be cAMP-
independent_ It is likely that Slrong slimulation of 5-
HT-secreting neurons is associated with some cyctic
nucleotide «:Iease in the _itinity of neighboring cells.
and that 5-HT can also "nonspecificaUy" affect
membranes of cells that do not have serotonin
receptors.
Anempts bave been made to classify the periph·
eral receptors into ganglionic and postganglionic
types. Morphine is said to block just the ganglionic
effects, but the "classical'" ganglionic blockers such
as hexamethonium do not aff«t the «:sponses.
An alternate suggestion is that the peripheral re-
ceptors Can be divided into "musculotropic" and
"neurotropic" types_ LSD, methysergide, and ROL
(BOL·148, bromo-LSD. 2-bromo-N.N-dimethyl-D·
Iysergide) are among the most effecti_e blockers of
the smooth muscle eff«ts. but they also exert DA.
like actions. Cyprophcpladine strongly antagonizes
5-HT slimulation of smooth muscle, but it is a po-
tent histamine (H,) blocker as welt. Additional
smooth muscle response antagonists includ" <>-adre-
nergic blockers. such as phcnoxyben7.amine. and
chlorpromazine (which affc<:ts DA receptors). Phen·
ylbiguanide and indoleacelamidine are among the
mOSt potent antagonists at the nerve endings. but
they also directly stimu late at those sites (40). Qui·
zapine may be the drug of choice for opposing effects
on Ihe brain (Fig. 8·19).
Spiperone has been used 10 idcntify the brain reo
c<:ptor sites because il bindS wilh very high affinity_
Since it also attaches to OA receptors. it is not uscful
by itself. However. R 43448 is said 10 selectively in·
terfere with spiperone binding to 5·HT receptors,
and information on brain sites can be obtained by
using the two in combination.
Much remains to be learned concerning the na·
tures of the actions of the various receptor binding
agents_ LSD allaehe. more strongly than serotonin
itself to putative hrain 5·HT receptors. and it seems
to function at times as a weak agonist.
HISTAMINE
Histamine is best known for its roles in mediation of
inflammatory and allergic reactions (Chapter 6).
and for its ability to stimulate HCI secretion in th.
stomach. It is released in response to "nonspecific'"
injury Or the presence of certain antige n-antibody
complexes.
This amine is widely distributed throughout the
body (88). It is especially abundant in the lungs . the
intestinal mucosa. and the dermis of the skin. Mast
celts account for much of the contcnt in thc brain
and peripheral tissues . However. there is SOme evi-
dence for the presence of histamine in vascular en·
dothelium and smooth muscle. Circulating hista-
mine is found primarily in the basophilic leukocytes
in most species. but rabbit platelets take up consid·
crable quantities.
In mOSt mammals. the blood vessels display the
mosl obvious responses 10 a syslemie injection. Small
arterioles and capillaries usually dilate. whereas the
venules constrict. The throbbing headaches experi-
enced by humans have been attributed 10 hypoten-
sion and changes in ce«:bral blood Ilow. Delayed of-
fe.:ts on the vaseulalure may result from release of
CAs.
The vessels of the skin dilate. and Hushing is a
usual consequence_ fl inamine also causes itching
sensations (pruritis) and skin (urticaria). In·
tradermal administration leads to the formation of
wheals because of inc«:ased capillary permeability.
hemostasis. leakage of proteins into the perivascular
spaces. and the osmotic drawing or ",ater.
The «:sponses of smooth muscle vary widely witb
". CA TEGHOLAMINE$ AND AEU.TEO REGUl.A TOAS

," , °,
SEROTONIN

"W , "
, Mcthysergide
, ,
C- CH,
H " II H "C-NH,
II

0" / ,
/'
"
,
o-
: I N- C- N -

Pi1e<1)'11>1guar>tOc

BlW\_LSO

°
(SOL)

F-0 -e-e-e- N NJ
j C
"
0
H H
"C;(""'
n

,
b -
"I
,",
H He ,; F

I H H ---"" N
CyptOl>eptadine
II V' I
R 4344S
"
Fig. 8· 111. S,'''''''''•• ot som<I -"'onin ,,,,,.ptor
... 'allQl>;';t. . (Dark_ pariS of LSD 000 I.'81""...,.it<:UeS
ind;C&I. sitM of similarity with ... rolon;.. )

the localion and wilh the species . They are 31'10 af.
rected by physiological $tatU$. a nd by some patho-
logical cond itions . In guinea pigs, sma ll dCtit$ inyoke
imense bronchoconstriction Ihal can lead to death
rrom asphyxia. In humans who suffer from bronchial
asthma, a small dQ:$c Can precipitate an a\tack.
(no"',,".', as discussed in Chapter 3. it is now rec-
ognized Ihal leukotriene. a rc much more polent
stimulants. They are believed to play major roles in
Ihe elkllogy of Ihe clinical disorder.) Slimulalion <or
Ihe smooth muscle of the gaslroinlcslinal lraCI can
cause cramps. V<lmiling. a nd diarrhea.
 The chid and parietal cells of the stomach arc Ihe
most ,esponsi,-. of the exocrine glands. The influ-
ences On both hydrochloric acid and enzyme secre·
lion arc enhanced by acetylcholine. and gastrin is es-
pecially potent for augmenting tile He!. However.
SOme .!focl. Can be demonstrated in Ihe absence of
those regulators. Small doses of histamine can slim-
ulate the salivary. lacrimal. bronchial. pancreatic.
and intestinal glands. and larger OneS increase bile
flow.
Heparin coexists wilh histamine in mast celis.
Bmh regulators alfect bone mineralization. and both
are believed to participate in tissue rcpair. The roles
of histamine in ovulation (se<: Chapter 15) may also
involve interactions with heparin-like mucopoly·
saccharides.
Early in life. almost all of Ihe brain histamine
contained within maSt cells (95). Somewhat latcr,
neuron, acquire small amOUntS (25). Fairly high
concentrations accumulalc in Ihe median eminence.
and Ihese conlribute to regulation of the secretion of
prolactin and other hormones (24). Histamine is also
found in regions involvcd in the control of circadian
rhythms (tl\e suprachiasmatic and supraoptic hypo-
thalamic nuclei. the raphe nuclei. and the pincal
gland). Low conCentrations are present in the mam-
millary bodies and in the ventromedial hypothala mic
nuclei.
Pharmacologic.1 Oan Ix used to determine Ihe
rel'live conlribulions of ma,1 cell and neuron hi'l.mine
in Ihe bra;n, Polymyx;n Band 48{80 rdea .. hi'lamine
from rna .. colis but not from neurons, ",hereas reserpine
seleclively .lfoci. Ih. nerve lerminab. Since ""UTOIlS .yn·
thcsin Ihe amine (whore .. rna .. cell. la kc it up from the
exl,.".llular fluid,). markeT$ for hi,tidine decarboxylase
Can identif), hi".mincrgic neurons, Some IUfn()V<r Slud-
ies ore based on obscrvatioo, Ihat long'lerm .tor.$e ""_
ou" onl}' in Ihe ma,1 cell<.

HC -
I
C
I
" "C_ C
H H
HN ......... ;;::::-N
o
"
"
HN, /- N
'0'"
H
oc,
Imicl.wle acell<;

3·Melnylhislami .. tll __ "

R,bosc
......-N,C y.-i'I
Imod.a,Oie acetic
ac<i-f>I)OSIdc

"1 c- "
c- CCl()M
I"
...... N......... ;;::::-N
"< 0
"
N ·MGtny6mO:l.lc>le
aceli<; ac<i
 ANO R€lATEO REGUlA.TORS

o
I
N' - O-C 0'-,/,,,-,, /,0y ' 0 '-.-,C--o-N.

" " "

O - C-C-C-O
" o, "
"
o

"
C,OItlQIVn sod ... ",
(inM'15 hi'13mi"., ,cle • ..,)

H H . H
HC C-C-C-N-N
I IH I 'H
HN, yN COOH
C

"
H H ..... CH,
HC-C-N
H 'CH,

H H .... CH.
H,c - o _ f "c-" C-O-C-C-N
IHH .... CH,
" "
f'yf"amone
(MeP'f<"n.

"
H H ....CH.
C- C-C-N
IHH .... CH.

"
Chlorpheni'3mine

HHHHHIl
, .... CH, H H H H ....CH,
H,C
I IH HH

Fig. 8·21. f'hII,mocological IhIII onlaQOl1i.&

hillomioeluncl;cn.,
 H H , H
><c
I
C-C - C - N
I H H 'H
S
I 1/
"" "
C -C-C-N'"
H H 'H
fiN, ",'I
,
'C r HC."
"C<
N

c", "
2·Mothy1hiotami"" H H /H 2 (2.Thia,oIy1)-ethy1ami""

I """,
/"'" /C-C-N
H H " H

,
2 (2-PyIidyl)·elhylamine

"
HN, H H H / CH,
C-S-C -C--C- N
Hli'· H H H ' CH,
4' '''01 hylhi.t.m"", Oim.ptit

H H FH
HG C- C- C-N
II II H H ' H

"' ' ,<"

Be,a,,,,,,
H, Raceptor "110";0"

f ig. 8'22. _ hi.tom'"

action •.

Biosynthesis end Metabolism labeled histidine (95) . Ae<=lylhislamine is formed in

Histamine is in a single step from tlK:
amino acid histidine. via a reaclion catalyzed by hi ...
tidine decarboxylase (Fig. 8·20). The quantities of
histidine in the die! can alfet! the amounts formed
in the central nervous system. sine<: there is a relative
abundanC<' of the enzyme under most conditions.
The d=rboxylasc requ ires a
It can be inhibited by hydrazill()-hislidine (whicb is
used as an anti-histaminic), and by a-methylhiiti-
dine (Fig. 8·21).
The major mechanism for inactivation in the
brain i. methylation at the 3 position_ The reaction
is catalyzed by histamine-N-mcthyltransferase
(HNMT). Small amOunts of 3·methy lhistamine arc
excreted into the urine, hut larger ones art:
by MAGs to methylim idalole acet ic acid ,
Peripheral histamine is destroyed mostly by di·
amine oxidase, and this reaction yield'l imidazole
ae<=tic acid. The e nzyme i. present in substantial
quantities in the liver. Although it hu IIQt bocn de-
tected in the brain, imida1.()le. ils riboside, and ri·
bolide ca n he recove red from animals injected wilh
some iovenebrales. but it is 1101 known to be a nor·
mal metabolite in venebratcs.
Receptors
Two types ()f ree<=ptors are recognized. H , receplOts
cofactor. are Iocaled on blood vessels and on the smooth mus-
cle of Ihe bronchi()les and gut. They arc mediators
of vasoconst ricli()n, endothelial cell contraction.
changes in capillary permeabi lity, bronchooonmic-
tion. and incTUtscs in intestinal motilit y_The effects
of H , receptor acti vation by histamine are mimicked
wilh 2-methylhiSlam ine. 2(2·pyridylj.cthylaminc,
and 2(-lhioarolyl}-ethylamine_ Thcy can be blocked
with pyrilami ne and with agents thai interact with
both types of histamine: recept()ts (40,96) (Figs. 8·21
and 8-22).
I I, receptors afflXl gastric secretion and chromaf-
ftn cen funclioru;. Histamine can aCI On them to aC-
celerate the heart , inerease the force of myocardial
contraction. and slow conduction. However, in hu·
mans and SOme othe r species. only e xceedingly large ,
'"
doses have such dfects. Many of thc actions have
been lin ked with cAMP generation. 4-Mcthylhis-
lamine, bet3zo1e, and dimap,;! arc H, r=ptor ag·
onim . Cimclidine and burimanide selectively block
H, type receptors. They have been used with SQme
Success in Ihe treatment of patients with gastric
ulcers .
Both receptor types arC present in the brain. Cen-
trally administered histamine lowers the body tern·
perature, and it invokes arousal, changes in ben.,·,
ior. and activation of cardiovascular reflexes.
REFERENCE
I. Abo.-Doni •. M . M. , and VivorO/i. O. H. Telr._
bio>ple,;n Increa.e< in Adrenal Medulla and C""
Ie>: A factor in the Regulation of Tyro<ine Hy·
dro>),I.... PrtK. Nflil. ANJ.d. Sci. USA 78: 2703_
6,1981.
2. Acheson, A. L. Zigman. M. J .. and Sticker. E.
M. Compe"...tory locToa.., in Ty""irl< Hydrox.
ylase Activi ly in Rat Brain after Intra .. nt rie"lar
[njeetion, of 6·H}'doxydopamine. 107:
537_40,1980.
3. Ahlquist. R. P. Adrenoreecpt<>r Seruili.;ty in Di ..
caS. a, A,sessed th rougb '0 Tcmpera.
lUrC Alteration. f'td. Prrx-. 36: 2S72-4. 1971.
4. Alhquisl. R. P. De.clopmonl of the Conc<:pt of
Alpha and Bet. Ad re notropie Recoplors. Ann.
N. Y. Arad. Sd. 119: 549- 52. 1967.
5. Allie . M. F.• Brown. E. M .• Gardner. D. G .. Spi.,.
gel. A, M" and Aurbach. G. D, Ch.raClcri,,,,.,,,
of the DopomirIC.Responsi .. Adenylate Cydaso
of BovirIC Paratbyroid Cell. and it. Relation,hip
to Paralbyr<>id Hormone Secrelion , £nd{J('rinci.
107: 1776-81. 1980.
6. Axelrod. J . Calcctlo].().Melb)'ltran.ferase and
other ()'Melhyl1r ...fcra •••. Ch.p. 40. pp: 669-
76 of Blaseh ko ot al.. cd ... ,eferenco 19.
1. Axelrod. J , Regulation or tM Re·
CCPIOt in lhe PirICal G land and Red Cell Mem·
brane,. pp. 149-56 of Fuxc. K .. T .• and
l.uft, R.• cd •. R <gul{JIion
Sy.<wtI. Plenum. New York. 1919.
8. Axeil",n. J. Calecholamine Funolion•. Ann
Physio/, 33: 1-30.1911 .
9. B.elge. E. E.• Kapl.n. B. B.. Rei •. D.. and Jot..
T. II, Translation of Tyrosine Hydrox}'I ... from
Poly(A).mR NA in PhCOCbr(ln't<)C)'loma Cell. i.
Enhance<j by Dcxame1hasone. Prrx-. Nail. Arod,
Sci USA 78: 1269-13. 1981.
10. Borka. T .. and Andcrson. p, J .
Ch.pler 10: Pigmen" . Harper &. Row. New
York. 1963.
I I . Ba"m. 0 .. PO"e. D.. J r .. and En'inok. J. Hyper.
glueasoocm ia and ,,·Adrenergic Receptor in
Aoute Hypo. ia, Amer. j, Ph,..;"" ]J7: E404_
E408.1919.
CATECHOL ... MINES ... ND RELATED REGl,Il.ATORS
12. Bearl . P..\1 . Adron.line . The Cryptic Contral
C'lecholamine. in 1: 295 - 7.
1919.
13. Benfey. B. G, Cardiac Adrenoreeeptors at Low
Temperalure: Whal i<IM bperimental hidenoe
for the Adrenoceplor Interconv.",i"" H),polhe'
'is? Fed, Prrx-. 36: 2575-9. 1977.
14, Born.do. L. S .• a nd Prince. D. A. Dopamine Mod·
ulate, a Ca"-Activatod Pot . .. ium Condue .. nco
in Mammalian Hippocampal Pyramidal Cel l•.
Na/u,", 297: 76-9,1982
15, Be""n . J. A, Noropi neph rine and tbe Prcs}'naptic
Control of Adre,",rllic Tran,m ittor Rele.$<. F<d.
PI"Qf',37: 187-90. 19 78.
16, Bhagol. B. D, Mod_ of A,liem 01 AUlonomi<
Drill '. Gr.ccwa)'. New YOI\:.. 1919,
17, Bi .lIChine , J . R .. Shaw, G. M.. Grcc nwald. J. E..
and Dand,lido •• S. M . Clinical Asptets of Do pa-
min<: Agonists a nd Antagoni'ts, Fed. PNX, 37:
2434-9. 1918.
18. Blac\:.. I. R. Regulat"" of AUIOnomic [)evelop-
menl, Ann. N"umul. I: 183-214. 1918,
19. Blas<hlco. H.. Sayors. G .. and Smi l h. A. 0" cds,
01 PhySiology. scc. 7. vol . 6. American
Ph),Siologioal Societ)'. W.shingtoo. D.C.. 1975.
20, Bloom. F, E. Contrasling Princ iples of Synaptic
Phy,iology: i'eptidergic .nd Non'p"ptidcrgk
Neurono, PI'. 187 of K .• IH)kfelt, T .. and
luft. R" od •. ("'lIIral Regula/ion oilM
Spurn, Plcnum. Ne"' York. 1919.
21. Brad,haw. R. A. NervcGroyoth Factor. AM. R,",
Biochern, f 7: 191-216. 1918.
22, Breese. G. R., Mueller, R, A .. Iioilistcr. A.. and
M.ilman. R. I mportancc of Dopaminergic Palh·
ways. nd o,her Neural Sy.tem. to Bchavior and
Act i,," of P.ych01mpic Drugs , Fed. Proc, 37:
2429-33. 1978.
23. Br""' n, E. M.. and Aurbach. G. O. RCCeplOn . nd
s.:cond ),IO<'enge" in Coli Fune1ion and Clinical
Disorde .. , Chap , 8. pp, 247-99 of Freinkd. N..
cd . Canltmporar,. M""bo/;,m. 001. 2. Plcnum.
New York. 198 2.
24. M , Nourotransmi tter< and Hypotha-
I.mic Hormones in the Central Nervous Sy"em.
Frd. PNX. 36: 1960_3. 1977.
25. Brownslein. M , J .. Pal ko.i ... M.• Saaoed",. J. M"
and KiT",r. J. S, Distribulion of H ypolh.l.m ic
Hormones and Ncurotr'"$ mitte r< within l be Di·
cncoph.lon. Chap. I. PI', 1-23 of Martini. l... and
G.l\Qnll. W. F.. cd •. Fron';". in
crin%g}·. vol . 4. Ra"en Pre... New York.
I 976
26. Ca llinSham. B. 1\. C.. cobol.minos in Blood .
Ch.p. 28. pp. 427_45 of Blaschko Cl al .. cd ... ref·
erence 19.
21. Cannon. W , B. &>d;I,. Chang" in Pain, I/unp r,
f'ror and NaKe, Appict"". N.... York. 1929.
28. Cannon. W. D. Th< W;,d"", of/he Body. Nort"".
Ne ..' Yor\:.. 1939,
29. Ca rd inali. I). P. Models in Ncurocndocrinotosy.
 Neurohumoral Pa,hwaY' 10 the Pineal Gland.
T,md, in "",uro.rri. 2: 250--3. 1979.
30. Cheung. W. Y. Play. a Pivotal Role
in Cellular Regulation. Sci,,,,,, 2(J7: 19- 27. 1980.
31. Clemen •. J. A .• Sawyer. B. D..• nd Cerimele. B.
Further Evidence tha, Sew""in i. a Neu.01 .. n.·
milte, Invol •• d in Ih. Conl",1 of Prolaclin Sec,c-
lion . l::ndoaillO/.I(I{)·692-8. 1977.
12. Cohen. P. The Role of P'<>Iein Phosphorylation in
Neura l and Hormonal C""troJ of Cellular ACI;v,
ilY. NlJluU 196: 613_10. 1982.
ll. Cooper. J. R.. Bloom. F. F. .• and Roth. R. H. TIr,
Bi",:}"miclJl Ba.i, of N<"rop},armacaiogy. 0.·
fo.d Uni""rsily P",ss. Ne'" York. 1978.
34 . Costa. E.. Chcney. D. L.. Mao. C. C .• and Mo-
roni. F. Aotion of A nti.""hi>.oph.enic DruSS on
'he Melaboli.m of Aminobulyric Add and Ace·
Iylcholine in Globu •. Pallidu .. Slria,um and N.
Accumbon •. FM. Pro<:. 17: 2408-14.1978.
35. Coupland. R. E. B1O<>d Supply of the Ad",n.1
Gland . Chap. 20. PI'. 283 - 94 of Bla.chko ct .1,.
cd, ..•• ference 19.
36. C"' .... I.. and Sibley. D, R, Reteplor Adapta-
tions to Centrally Acting Drug" Ann, R, •. Ph",.
mll<V>l. Toxico/.ll: 357_91.1981.
37. C.yer. P. E. DiQgMJ/k £nd«rilY)/ogy, ld cd . 0.·
ford Uni"e"i,y 1'..... Ne", YorK. 1979.
D<:mareSl. K. T ... nd Moo",. K. E. Accumulalion
of I.· Dopa in the Medi.n Emine"".: An Inde, of
Tuberoinfundil>ular Dopaminc'llic Ner.e ACl i,·
;1)'. End«rilY)/, 1Q6: 463-8. 1990.
39. OiBona. G. F. Neural Control of Renal Function:
Introouctory Remarks. Fro. Pro<:. 17: 1191. 1918,
40, DoIlgla$. W. W. Hi<tarnine and 5.li)'d'<)J;.ylryp-
larnine (Seroton;n) and Th.i. Anl.goni"s. Chap,
26. PI'· 60'9-46 of Goodm.n. A. G .. Goodman. L.
S .. and Gilman, A .. e<I •. Good",all and Gi/man'.
TM PhQrmaroiogica/ 8Q';' of 6,h
cd. Macmillan. New York. 1980.
41. Dougl.,. W. W. Secr<>llHllOlor Control of Adren.1
Me<lull.ry Sc<",,'ion: Synaptic Membra"" and
Ionic Eve"ts in Stimulus-Secr.tion Coupling.
Chap. 26. PI'. 367-88 <>f BI.><:hko et aI., cd •.. ref·
erence 19.
42. DoIlgla •. W . W .•• nd Ta,.. kevich, p, Aelion p.,.
tcntial. in Gland Cell' of Ihc Rat Pituilary Pa"
Inlcrme<lia: Inhibilion by Dopam;ne. an Inh;bilor
of MStl Sec.etion. J . 285: 171_184.
1918.
43, Ellg ... O. A. Futurc for Ne,". G,OWlh FaClor>.
Trm<i. ill """roui. 1: 316---18. 1979.
44, Exl"". J. H. Mechanism.' In,oIv.d in ... Adrene.·
gic Phenomena: Role of Calcium Ions in ACli"",
of C.lccho]ami"". in Live, and Olher T issues,
Am, J . 138. EJ_I 2. 1980.
45. Felig, P.. and Koivisto. V. Recenl Ad .. nc.s in
Body rud Mctobolism. Chap. 9. PI', 359-84 of
Frei nkel. N.. ed, Com''''J''Xary Mtwooli.m. Vol.
I. Plcnun,. New Yo.k. 1979,
46. Felig. P.. She.win, R. S .. SOnJ,n. V.• Wahren. J ..
H.ndle •. R.• Sacca. L.. Eigle •. M .• Goldbe.g. D..
and Walc<ky. M. Ho.monai InteraClion in 'he
Resulati"" of Blood Glucose. Rt<:. Prog. I/orm.
Rjoh, 1j: 501-29.1979.
47. Fernstrom, J. D. The Innucnco of C;.cadian Vari·
ations in Plasm. Am;"" Add Concontrali"". on
Monoamine Synthe,i.;n 'he Brain. PI', 89-122 of
Krieger. D. T .. ed , t-:ndo<:r'-M Raven
Pr .... New Yo.k. 1979.
48. Fra"tz. A. G. Rhythms in p.olaelin Se<:.c'ion. PI'.
17 of Kriegcr D. T .. cd. I::"d«r/M Rhplhm.r.
Raven P",,,. New Yo.k. 1979.
49. Froodm.n, l. S .• Samu.I,. S .. Fi,h, I.. Schw •• lz.
S. A .. Lange. B., K.". M .. and Morgano. L.
Sparing <>f the Brain in Noona!al Undernutrition:
Amino Acid Transport and Inco,poralion inlo
Brain and Mu.dc. Sci<"'" 2(J7: 902-7, 1980.
50. Fre)" E, A .. Cotc. T, E .. Grewe, C. W .• and Ke·
babi.n. J. W. I'HI Spiropcridol D·2
Dopaminc Receptor Inhibiling Ad.nyl.,e Cy·
da"" AClivily in the lnlermed;ate Lobe of the Ral
PituilalY Gland. t:ndo<rino/. 110: 1897_1904.
1982.
51. Fulle•. R, W . Pha.macology of Brain Epineph.ine
Neuron •. AmI, Rev. PhormMoi. Toxiroi.22: 31 -
1982.
52. Furdg<>ll. R. F, Pha.maco'ogic.' Characleri>.a·
tion of Reooptof1: h. Relation 10 Radioligand·
Bind ing S,udi ••. Fro. Prot. 37: 115_20. 1978.
53. Fu rnes •. J. B.. and Hu.n$lucK. G. Role of C;reu·
la,ing in Ihe Ga'lfQinte$tinal
Tract. Chap. 33. pp. 515- 36 of BI"",hkQ et .1 ..
ed ... reference 19.
54, Fu.e. K.. Andersson. Koo Ufstr1lm. A.. 1I0kfelt.
T.. FcrI.nd. L. Agnali. L E. Per.7. de la Mora.
M .. Sch,,·are>. R.• Encrolh, P.. GUSlafsson. J. A ..
and Sk.ll. p, Neu,..,! ",",mi ller Mechanism, in
Ihe C"""oi of Ihe Stc""ion of Hormones from
Ihe Ante.ior PiIUil.ry. pp, 349-80 of F"xe. K..
I-IOkfel,. T .. and Lufl , R. ed •. (";!"'ral R<gu/aliQl!
of Ih' Hnd«r;rte S,..,,"'. Pienum. N.", York.
1979.
55. Gard ic., R. W .. l'<•• dO$. E. J.. hek$Qn. D. B.•
and Delaunois. A. L. Di<linCI Muscarinic Media-
tion <>f SU'peeled Dopaminc.gic Acti. ity in Sym.
palh.t;c Gang lion •. F,d. Pro<:. 17: 1918.
56. Gncgy. M. E. Relalion<hip of Calmooulin and
Dopamine'llic ACli,ity in Ihe Slfialum. P,d.
Pro<:. 41: 2273-7. 1982
57. Goldbcrs, A. M .. and Welch. B. L. AdaptatiOft <>f
Ill< Adrenal Medulla: SU$tainc<l Inere"'" in Cho-
line ACel)·lIranlfe .... by P<ycbO$OCi.1 Slimula·
lio". Sc;,,," 178: 319-20, 1910.
Goldberg. L L. Kohli. J. D.• KOla Ke. A. N.. and
Volkman. P. H, Characte.istics of lbe Vasc ular
I)op;tminc Reooplor: Compari50n ",ilh Other Re-
cep'Or<, FM. Pr«. 37: 2396-2402.1978.
59. Gold"ein. Moo Saute., A., Hala. F.. Le,.., J. Y..
lI.b •. Y.. Engel. 1.. Fu.c, K.. and H5kfell. T.
Slud ies on I nlcraclions of Epinephrine N.uron.1
S)"tem, wi,h Otller Neu.onal S),>'cm$, PI'. 2{»_
22 <>f Fu.e. K.. Itokfelt. T, and Luft. R .. eds, e",·
IrQI of lh. .S)'sum. Plenum.
New York. 1979.
'"
60. Golt5Chalk,C. W. Ren, l Ne,ves.nd Sodium E."
ereli"", Ann. R.". Plt,..iol. 229_40. 1979.
61 , Gra)'bi.!. A. M .. Pickell,V. M .. Joh T . H .• Rd ••
D_. and C . W .OJr. Di,,,,,, Demonst",_
Ii"" of" Correspondence bet""." lne Dopamine
1,land. and Acclyk!H:>l;nC<I.,.« Patcb •• in the
Dtvtl<>ping$lfiatum. l'rtN. Na,l. Acad. Sc/. USA
78: S871-S, 1981.
62. G,,,,,venor. C. E.• Mena, f., and Whitworth. N.
S, Evidence lhat the Dopamine"ic Prolaclin·!n-
hibiting Factor Mechani sm Regul.t .. Only the
D<plclion-Tran,forma!ion Ph ... and N01 lhe
Relea« Phase of Prolae';n S«:r.tion during
Suckling in Ihc Rat. E"d{)(y'ltO/. 106:
1980.
63. G'y""pa n-WiOOil,ad. O. Uhr.",ucture of ,h.
Chromaffin Cell. Chap. 21. pp. 293-)08 or
IJluchko c, .1.. cd •. , reference 19.
64. Harper. G. P.. and Th",,"c •. H. Target Cell,. Bi·
ologk.1 EfTect .. artd Mechani,m of AClion of
Nerv. Growth faclor and iii Antibodi.s. Ann.
Rn'. Ph",ma,oi. Toxieo/. ll: 205-9. 198L
65. Hesch. R.-D,. !lUsch. M .. Kodding. R,. HolThcn.
(I .• and Me),er. T. Trc .. ment of [)opami ..·Dc·
pendent Shock with Triiodoth)'ronine. Emioc,.
Rsch. Como.. 8: 229-)7. 1981.
66 . Hcumann. R.. Schwab. M .. and Thoenen. H. A
Second M.... ng.r R.quir.d for Ncr"e Growth
Faelor Biologio.1 AClivity" NatuT<: ]92: 8)8-40.
t9SL
67. Himm,.H'g.n. J. Cdlular Thermogc"",i •. Ann.
Nt>, PhYJioi. 38: 31 5-51. 1976.
68. Himms-Hagen. J. Role of th. Adrenal Medulla in
Ad.pt.tion to Cold. Chap. 3S. pp. 637_65 of
Blaschko ct al.. ods .. refercn<c 19.
69. HOkfel!. T .• Johan,$(In. 0 .. ljungdahl. A..
berg. J .. Schul"berg. M .. Fu , •. K .. Gold .. ein.
M.. Stoinbu«h. H .. Verhofstad. A .. and Elde. R.
Neurotransmiu.rs and Neuropeptides: Distribu-
lion Panern. and Cellular Locali"'tion 0$ R..
vealed b)' Immunocytochemistry. pp, 31 - 48 of
Fu,c. K .. H5Hclt. T .. and luft. R.• ed •. C;""a/
Rtgulalion of Ihr EndocriN SpirO.. Plenum.
Ne,. York. 1979.
10. Huff. B. B.. ed. Physicions' Dt.. k 31 ..
cd. MediCal Economios. Oradell. N .L 1977.
7 L I n.strosa. N, C .. R.in .... C. G .. Reichardt. L. F..
and Hall. Z, W. Cellular locali<alion or Ihe Mo-
lecular Form. of Acetylcholir.estcra« in Rat
Pheochromocyloma PCI2 C.II. trealed with
Ner"e GrO"th Faclor. J . NturoJci. I: 1260-7.
1981.
72. I".rsen. l. L. Uptake of Cireulating Cate.:hol·
.m ines. Chap. 43. pp. 713-22 of BI)$Cbko.tll ..
eds .. reference 19,
13. J<>ols. N. Reflex Respiratory Effects of Circulat·
ing Cal""holamine' . Cbap. 31. pp. 481-505 of
Bla«hko ot 01.. cds .. rer.ren"" 19.
74. Kebabian. J, W .. and Cal ... D. B. M.ultiple Re·
for Dopamine . NOlun 177: 93-6. 1979,
CATECHO!.A M tN ES AND RELATED REGUlATORS
75. Ket)'. S. S. The Biological Substrat.s of Abnor-
mal Menial SI.IC•. PmC'. 57: 2267-70. 1978-
76. Kirshn... N. Bios)'nthesi. of tho Catecholami ...,
Chap. 24. pp. 341-55 of BI.«hko ct al .. ed, .. ref·
orencel9.
11. Klein. D. C. Pineal Gland a. a Model of Ncu·
roondo<rinc Conlrol S),,,ems, pp, 303_17 of
Reichlin. S .. Bald ..... r;ni. R. J .. and Martin. J.
B.. Tht •. R..en I're«. Now
Vork.1918.
78 . Kon i,hi. S .. T,uno<>. A .. and Otsuka. M. Enkeph.
alin as • Tr.n.m;ttor f<>r Presynaptic I nhibiti"" in
S)'mathelic Ganglia. Nmun 194: S0-2. 19S1.
79. Krulieh. L Central Neurotransmitters a nd tbe
Sec r.lion of Prolaetin. Gil. 1I1 and TSIL Ann.
R,y. pny'ioJ. 41: 603_15. 1919.
SO, Labrk. F.. Drouin. J .. Lapee. L.. Ferland. l ..
8caulieu. M.. Raymond. V.. and Ma .. icotte. J.
Interactions Between H)'pothlamic and P.riph-
ora l Horm<>nc. at the AnlOrioT Pitui,ary le'oI.
pp. 85-101 of Fuxc. K .. 1I0kfeit. T .. and Luft. R..
cd •. Rtgu/{JIion of Iht I::mioairw SY'ttm.
I'lonum. New York. 1919,
81. Laruloberg. L C:l1echolomines and 'ho S),mp.'
thoadronal S)'Slem. Chap. 8. pp. 117- 231 of In8-
bar. S. H.. cd, Tht YtOF in £><docFino!Ogy /975_
1976. Plenum. Ne'" York. 1916.
82. Landsberg. l. The S),mpathoadrenal S)'!tem.
Chap. 10. pp. 291_344 of Fr.inkel. N .. ed. Tn.
Y"" ;n J-;..a<x,;no/"/I)' /Q77. Plenum. Now V<><\:.
1978.
83. Le Cam. A .. and Froychet. P. Eff.ct of Catechol·
ami ... On Amino Ae id Transport in 1$(Ilaied Ra t
Hepatocyle<. Endo",,·nol. /(/]: 319-85. 1918.
84. lel1<ow;17. R. J. Identiftcation and Regulation of
Alpha' and Receptors,
hoc, 37: 123-9. 1918.
85. Lomoo. J. R .• Novak.Hofer. I .• and Levitan. I. (I.
$cr¢t""in Alters Phosphorylation of Pro-
toin. I n.ide a living Cell . 198: 64-
S. 1982.
86. teoi· Mon,aleini. R.. and C.li<SallQ. P. Th. No"e
Gr""'th Faelor. &imljfk Arne,. 240(61: 68-17.
1979.
87. leoin. B. Presynaptic Lo<a!ion and Axonal
Transport of /I·Adrenoroceptors in Ih. Rat Brain,
l17: 555_7. 1982.
88. l eoy. D. A. Histamin. and Serotonin. Chap. 5.
pp. 141_61 of Wei .. mann. G .. ed. of
Injlammo/imr. Plenum. Ne" York. 1914.
89 . Le"i,. G . P. PhY$iologica l Meehani.m$ CO"trol·
ling Secretory Actioity of Adrenal Medulla .
Chap, 22. pp. 309-19 of Bla«hko'" al.. ed ... ref·
eren« 19.
90. I.o"'i •. J. W .. TordolT. M. G .. Sherman. J . E.. and
I.icl,«kind. J. C. Adrenal Medullary Enkephalin-
Lih P.ptides May M.diate Opioid Str<:$> Anal·
ge!i • . Sdt lU't 1/7: 557_9. 1982.
91. list. S. J .. and S«man. P. RC$(IIUlion of Dopa·
mine )nd Serotonin Receptor Components of
 PHI Spiperone Binding '0 R., B.... in RegiQn •.
P'IX. Nail. Arad. Sri. USA 78: 2620-4.1981.
92 . l)1)n" M j,. Fau't. I. M .• Ilemme •. R. B .• Bu.-
kirk. D, R.. Hi,,,,,h. L arod Zabr i,.i •. J. B. A Vir·
ally induced Ol>esity Syndrome in Mice. &;",a
116: 82-5. 1982.
93, Maggi. A.. U·Prichard. D. c.. and Enna. S. j, fl·
Adrenergic Regula'ion of ",..Adrenergic Recep-
tors in the Central Nervou. Sy".m. &-;tIIU 207:
645-7.1980,
94. Marlin. J. B.. B,.z.au. P.. Tann.nbaum . G, S ..
Willoughby, J. 0 .. Epelbaum. L Terry. l. c..
and Durand. D, Neuroendocr in. Organi ..,io. of
Growlh Hormone Regulalion. pp. 329_53 of
Reichlin. W.• Ba ld.... rini. R. J .. and Marlin. J.
B.. eds. T/o. Hypmnnlamus, Raven Pre ... r--:ew
York. 1978.
9j. McGcer. P. 1... focde •. J. C .. and McGe.r. E. G.
Mol,oula' N. uroMology of Ih. Mammalian
Bmin. Plenum. New York. 1978.
96. Melmon. K. l. The Endocril\Qlotie Funcli"" of
Select.d A"t<>OOids: Catechol.mines. AcelykJ-.o.
line. Seroton in arod Hi<l.mi"". Chap. 10. pp, 5 I S-
88 of William •. R. H .. ed, T.xll>ook oj Endo",;·
IWlogy. 6th <:d . Saunder1. Philadelphia. \981.
97. ),lena. F.. Pacheco. P..• 1Id Grosvcnor. C. E. Ef·
feel of Eleclfic.1 Stimulation of Mamma,y No,,'e
up"" Pituitary .nd Plasma I'T<JI.elin Cooccntra·
lio", in Anestheli?ed Laclali", Ral<. £ndIX,;noI,
106:458-62. 1980.
98. Moore, R, Y.• alld Bloom. r, E. Central Cat.·
cholamin< Neuron An"omy .nd
iology of the Dop.min. Systems, Ann. I(tv. N,,,·
I: 129-69. 1978.
99. Moran. N, C. Adrene,!!ic Receptors. Ch.p. 29.
pp. 447_72 of BI.s<:hko ... 1.. eds .. reference 19.
100. Mo,.n. 1'1 , C. Aims of Ihe Conference. N.Y.
Acad. Sci 1]9: 545-8.1967.
10\. Mo,i arty. G, C. Heterogeneity of ACTl!·Con·
taining Cdl. in lhe Rat Piluitary. with Emphasi.
on the Structure .nd Function of the I nlermed iate
lobe . Ann. N, Y. Ac"d. Sd, 197.- \83_204. 1971.
102, Neil . E. Calecholamine. and the Cardiovascular
SyStem. Ch.p , 30. pp. 41l_89 of Blaschko el al ..
eds .• ",fereocc 19.
103, Nicke,..",. M.. and KutlOS. G. Discussion of Evi·
dence Regarding I ndu<;cd Chonges in Adronoecp'
to,... FNl, P'IX. 36: 2580-3. 1977.
\04. Onali. P.. Seh"'ar". J. P.. and COilta. E. Dopo.
mine,gk Modu lalion of Adenyl.te C}'ci • .., Slim·
ul'lion by V.soaetive Inle>tinal Peplide in Anl.-
rior Pituitary. P'IX. Natl. Acad. Sci. USA 78:
6531 - 4. \981.
105. Pagc. L H. S<N)lonin. Ye>t Book Medical Pobli·
cations. Chicago. 1968,
106. p.l1erOQll. P. H. Environmental Dcterm;.alion of
Autonomic Neurotran,miller Funclion •. Ann.
N.uroJd. I .. \_17. \978.
101. Reynold •. G. P. Phcnyle1h),Jam;ne--A role in
Mental in N,uroul. 1: 265-8.
1979.
108. Robertshaw. D. Catechol.mine. and Control of
Gland" Chap. 36. pp. of Bla,enko
el.t.. od •.. reference 19,
109. Roo;"",. G, A.. Butcher. R. W ... nd Sutherland.
£0, W. Tho Catechol. mines. BiIXhtm, Ac';"",
Horm. 1: 81_\ 11. 1972.
110. Ross. M .. Lofstrandn. S .. Gorin. P. D.. Jonnson .
E. M .. 'rod Schwa"", J. P. U.e of an E'perimen.
tal Autoimmune Model to Define Ne". Growlh
Dependency of Peripheral and Cenl .... \
Substance P.Con t.inins Neurons in 'he Ra .. J,
Nr"roJci. I: I 304-11. 1981,
IIOA, Usc of phololabels to probe Ihe Na.K·ATPa,e
and the ,d.Adrencrgie ReCCplCH'. F.d. PrO<:. n:
2831-41.19n
III, Rutherford. J. D.. Vatner. S. J'.. .nd B'aunwald.
E. Adren.r£ ic Control of M)'oc.rdial Conlraeli!-
it)· in Conciou. Hyperthyroid Dog', Am. J. PhJJ.
iol. 137: H590-H596. 1979,
112. S.Ia?lIr. M .. Sokoloski. T. D .. and Pati!. P. N .
Dilldilijl of Dop.mincrGie Drug, by lJoe Neuro-
mdanin of the Subs"nlia Nigra. S),nlhOlie Mel·
anin ' and Me l.nin G.. nule<. Pmc-. 37:
2403_7,1978.
113. Schwa",. J .. c. Opiate ReeeptOTs on Catechol.·
mine,sic N.u,on .. in B.. in,
1: 137-9. 1979.
114. &ar1. M, L Calccholamines in Relation 10 Ihe
Ele. Chap. 35 . pp. 55J-90 of Blase hkoe t .1. ed •.,
refelence 19,
115. Seem,n. P.. Tcdc<eo. J. L. Lee. T .• Chau.Wong.
M .• Mulier. P .• ... J .. Whilahr. P. M ..
C .. T;ll l« . M. We ;n,.;ch. P .. Friend.
W, c.. and BIOIO'n. G, M, Dop.mine Receplors in
the Cen",1 Nervou. SySlem. FfIl. Prot:. 3J: IJO-
6, 1978.
\ 16. Seino. Y.• Miy.m(}[o. Y.. Moridora. K.• Tami·
nato. T .. ,\ 1'lSu ku ... S.. • nd Imura. H. The Role
of 'he Mech.ni.m in Ih. Hyperga •.
trinemi. or Hyperthyroidi,m. J. Endoainol.
MelQb. 50: 36g_70. 1980.
117. Sharm.n. D. F. The MClObolism of Cireu\.ting
Catechol.minos. Chap. 42. pp. 699-712 of
BI.sch ko cl .1.. ed ... referenoe 19.
118. Sh.,p. B.. ROIl'. R.. L.vin. E.. and Sower1. J. D0-
pamine Regulale, Canine Pla.ma p.Endorphin.
lmmunoreactivit)' Lcvds. EndIXrilWl. 110: 1828-
30. 1982.
119. Shooter. E, .\1 .. Y.n ker, B. A.. I..ndreth. G. E..
.nd SUlter. A. Biosynthe,i. and Mechanism of
Action of Nerve Growlh Faelor. R«, Prog.
/lorm. I(soh, 37: 417 - 39: Di",ussion 439-46.
1981.
120. Silverberg. A. B.• Shah. S. D.. Haymond. M. W ..
• nd Cryer. P. E. Norepinephrine: Hormone and
Neurotran.miller in Man, J. PhYfi(>/ , 134:
E252-E2S6.1978.
\ 21. Silv,"'ini. r .• Liu "i. A.. and Chiodini. P. G. Pro-
laClin olld I'ituilary To"""'. pp. 132- 12 cor Mar·
tini. L.. and Jame •. V. H. T .. ed •. Cllr,..nt Top;'.
in EXp',imenltll Endocrinology. vol. 3. Academic
Pre ... New York. 1918.
122, Smith. L. Larson-Ca"er. D. L.. Loud. C. A ..
'"
l."" •. R. 1\.1 .• Silman. R, E .• Carte,. S . J .. Fran-
0;$. P.• Mullen. P. E.. Hooper. R. J. L.. and Fin·
nie. M. D. A. O-Aoetyl·5-),leth<>.ylryplophol-
Tentali,. Identification in Pineal Glands. Prot.
Brain R..n. 51: 259_68. 1979.
123. Soma., V. R .. Shamoon. H.. and Sherwin. R. S.
ElftCl$ of Physiologic.1 lnfu<ion of Epinephrine
in Normal H uman" Relalioo,hip Bel"'een (be
Meta boiic Res"" ••• ""d ",.Adr.""eg;c Binding,
J. Clin. £ndocriltO/. Me/ab. 50: 294-7,1980.
124. So .." ... J. R.. Berg, G.. Manin. V. S .•• nd M.yes.
D. M. Dopamincrgk Modulation of Aldoste..,ne
Se\':r<;li':m in lhe Rhesu$ Monkey' E. idenoe that
Dopamine Alfect. Ihe laic Pathway of Ald"",.-
ron. Biosynthesi. by Inhibiting ,h. Conversion of
Corlicostorone to 18·Hyd,o'YC<lflic<>Slerone. If".
d",,'inol. 110; 1173_7. 1982.
125. 51"'ke. K. P,,,,),naplic Re«pt<>rS. Ann, R",.
T()xiro/. 21: 1_30. 1981,
126. Sui.. ,. r ..• nd Vetul.ni. J. I'$yohotropic Dru&5
and C)'clic A MP in Ihe Cen"ol No ..,,,,,. Syslem
(With PaJlieuTar R.eference 10 Strialal and Lim·
bic Slructure,j. Chap. 19. PI'. l37-6S of Cramer.
H.. and S<huhz. J.. «lI. Crelic J'." NUc/roJ;J. ..·
oj Anion, Wiley. New York. 1911.
121. Sun. C. L, Thoa. N. iL and Kopin. J. 5, Com.
parison of Ihe ElfeclS of 2-DeO'Yllucose and 1m·
mobilizalion on PI.,ma I.evel. of Catccholamines
and Corlico:<lorone in Awake Rats , EndocfillOl,
/OJ: 306-11.1979.
128. T."in. I . P .. Simon. H.. He,,' •. D.. BI.nc. G.. le
Mool. ),1 .. GlolO'iru;ki. 1-. and Bookaert. J, Non·
Dopami"",sic Fibers ma), Rellu l'le
Sen, iliv. Adenyl... Clola$<: in the Prefronl.1
Cortex .nd Nud.us Accumben •. NalUFt 295:
6%_&.1982.
129, Thoenen. H., .nd Otlen. U. Role, of Adrenocor-
lical Hormone. in the Modulation of Synthesis
.nd Degradation of Invol •• d in Ihe For·
mation of Catccholamiocs, Fr-ont, N'UfO<!ruiocri-
MI. 5: 163-84. 1978 .
13fl. Tipton. K. F. Monoomi"" O.id. ... Chap. 41. 1'1'.
617_97 of Bla,ch, o el aL. cd, .• rderenoe 19.
I 3 I. Tomita. T. Actions of C.techolamine. on S kel.tal
Chap. 34, pp. 537_51 of Blasohko et
132.
cd ... reference 19.
T' UrUla. K.. Freu. E. A .. Grey, •. C. W.. COle. T.
E.. E.hy. R. L. . • rId Kcbabian. J, W. Evidence
Ihat I. Y·141 865 Specif,oally Stimul.le< the [).2
Dopamine Receptor. 291: 463-5, 1981 .
133. Turner. C. I).. and Ba,..... J, T. Gn,,,al
CFinoIQg)". 6th 0<1, Chap. 10. 1'1', 291-323, Phila·
delph i•. 1976.
134. Van R.,..um. J. M, Two Types of Dopamin.
COPlon in ll<ha.ioral R.gulation. F,J. Proc. 37__
24 15-21. 1978.
135. Varano S, S" and Dung• • R. P. Trophio Mecha·
ni,m> in Ihc Peripheral Ner-ou, System.
N<u'Otd. I: 317_61. 1978.
Additional references added in proof will be found on page 893 .
CATECHOLAMmES AND RELATED REGt.U. TORS
136. Verni, os- Danellis, J .• Kellar. K. J.. Kent . D .•
Gonzates. c.. Berger. P. A.. and Barcha •. I . D,
Sorotonin In\'(llv<;ment in Piluitary.Adren.1
FUo<tion. Ann, N. Y. Arad. &i. 297: SI8- 2S.
1977.
131. Vive"". O. H, Mechanism of Secretion of Cate·
eholami"". from Adrenal Medun •. Chap. 27. PI'.
389-426 of Blaschko.t a1.. cd •.• ref.rence t9,
138. Vi ve"". O. H .. Lee. c..I... AbOtt.Donia. M. ,1.1 ..
:-lix,",. J. c.. and Niohol. C. A. Biopterin Cofac·
lor Bios)'nthe<is: Independ.nt R.gulation of GTP
Cyeiohydroluc in Adrena l Medulla .nd
Stlnw 2/3; 349- 50. 1981.
139. Vogt. M. Influen« of Cir"ul";n, Catcohol·
amine. on the Cent,. 1 N.rvous Syst.m. Chop, 39.
pp. 667-8 of Bt...,hko el .1.. ed •.• refor""e 19.
140. Von Euier. U . S . Adrenal Medunary Socetionand
il$ Neu",1 Control . Ch.p. 25. pp. 183-333 of
Martini. 1... and Gaoong. W, F.. ed, .. N.",otn-
docrinl)/ogy. \'(11. 1, Academic Pre$S. Ne,. York,
1967.
141 . Vulliot. P. R.. Lang.n. T. A.. and Weiner. N. Ty.
rosine ..: A Substrate for cyeiio AMp·
Depcndent Proloin Kina ... PrO<', Narl. Acad. Sd.
USA 77: 92-6 . 1980.
142, Wang. I.. C. H . Hibernalion: Endocrinologic As·
poe", Nn. Ph)".;", 41: 287-303.1979.
14J, Wang. W.-K .. Jenq. I.. S .. Chiang. Y.. and Chien.
N. K, Inhibition of Dopamine BiosynthC$ is by G.,..
H",,,,ooc ill Ra1.
296: 354. 1982,
144. Weiner. N. Control of the Bios)'nthesi. of Adrc·
nat Cateoholamine, by the Adrenal M.dulla,
Chap. 25. pp, 357 - 66 of Blaschko.t at., .ds" ref-
.r.rn:e 19.
145 . Wein.r. R. I.. and Ganong. W. r . Role or Br.in
Monoamine. and HiStamine in Rell"lation of An·
terior Pituitary Secretion. Ph)"s;ol. R, o. 58: 9OS-
76. 197$
146. Widdicombe. J, G, Action of Catcohol.minos On
Bronchial Smooth Mu ",le. Chap. 32. pp. 507-13
of Blasch ko et al" ed ... reference 19.
147. William",". J. R EIf.mof Epinephrin. on GI)'·
cOllerlOl),. i, and Contrae1ililY. Cllap,
37. pp, 6()S_36 of BI.schko.t al. .• d, ,, refcreo<e
".
14&. Windhotz. M, . ed. TM M."k Ind.x. 9th Ed .
Merek. Rahway. N.J..
Winkler. H .• a nd Smith. A. I). The Chrom.ffin
Granule and Ihc Storage of Cat.chot. mi ....
Chap. 23. PI' , 321-39 of BI.",h ko et.1.. eds" ref.
erence 19.
150. Wurtm.n. R. J. Nutrients thot Modify Brain
FUo<ti,"" Sdmti/ic A_f. 146: 50-9. 1982,
151. Yoong. J . B, . and Landberg. I.. Catcohol.m in",
"nd the Symp""hOlldrcnal System: T h. Regula-
tion of M.taooli.m. Chap. 8. pp, 24 S-303 of Ing.
bar. S. H.. ed . (."ont'ntfXN"''- t:ndocrillOlogy. "<>I ,
I. Plenum. New York, 1919.
_ _ PART III

Hormones Regulating Water and

Monovalent Ion Metabolism
 9
Aldosterone and the Renin-Angiotensin System
M;ncral(lcortiooid, an:: hormones lhal I"<'gu-
late the nel transfer of monovalent ions from """
fluid oompartmenllo another. In mammals they ael
mOSt obviously on the kidneys 10 pr()mOlC sodium
and water conservation and hydroscn and potassium
ucrction. They thereby play essential roles in the
regulation of extracellular and inU"IIc<:lIular fluid vol-
ume •. systemic blood pressure, and acid-ba5<: bal.
arn:c. InnuencCl on the roIon. the salivary Md Iweal
glands. and elsewhere oomplemcnt those on
the kIdney p,ll,6Q). Receptors have also been Iden-
tified in Ihe duelS of laclaling mammary glands. in
Ihe pituitary (116). and in the brain. Addi1ional lar-
gels may include skeletal mU$Clc. heart. and liver.
Zona glom<:rulolla cctlsoflhe adrenal COfIU make
oldruul'OM. lhe major of Ihe lI'OIIP. Deo.y-
cortieosler()TII: (DOC) and other hormones of lcucT
potencies arc ,ynttle$i1ed in bach tile 7.OI\a fascicu-
lata and zona g!omerulosa. They can assume spc.;ial
imponantt under patbolo&iC1Il cooditions. during
times of acute SIre5$, and when they a.
sterone p=UI"SOfS.
When pRSCnl in high COII«IIIn11ions. pooacster·
one can impair a ldosterone functions by compeli",
with it for '-mone: re«ptOl$. It lICI"Ves as I weak
in aldOliterone def\ciency stales. and il is a lso
oonvefl<:d to in 1M kidney Ind
aoru. (H).
Gh.cocollicoids interlct 10 $OI1l<: CAtCnt with 1.1_
dosteronc reccpton ($). and tlley a!fect $&It Ind
water metabolism in other ways. AldQliteronc CIOn. in
tum. bind to aluCOCOftic:oid re«pton. Some dfo:cts
of very hiah concentrations Ire attributed to stich
me;;:hanisms (49).
In iIOnmamm.li.n .Idoslerone. eoniJO!.
eonkosto...,nc. Ind rol alC<! .. oroid...."llle ph and
.... t .. I»tlnce by aClinl OIl 1",.1 orp'" Ihl l includo lhe
. kiM of amphibian •• lhe urinary bladdors of .. ptiles and
,,,
amploihia .... lhe ph llands or """" hi,.,. .ad reptiles.
,ad'lie ,ill. of certain 0I1bo r"heo (16).
Sodium deprivation. dehydration ....... l.1.oolic aci-
dosis, potassium retention. and hypotension all lead
to augmented mineralocortiooid secretion. Most (but
1101 all) of the stimuli inV<lh-e Ihe Knin .... ngiotensin
sySlem . Aldosterone. in lurn. exerts inhibitory innu·
ences on that system a nd il additionally a!f«:ls the
secretion of antidiuretic hormone.
RtnirlS are protoolytic enzymes produced spc·
cialiw:i cells of the kidneys and al Olher .ites. When
released into the bloodstream, Ihey do:llv. a ngioten'
sin I (a dccapcplitk) from a glyoopl"Q1cin substrate
that is seeTeted by the liver. Angiotensin r nens
$0/11< diKct actions and it also SCfllCS as the precur-
_ of the more potent angio/rtlSilf fI (A·II). I n ad-
dition to p romoting aldOl5tcrone secretion. A-II is a
powerful diprogen and vasoconstrictor. It stimulatts
the sympathetic neTVOOI $}"Mcm. aCtS both dir-ectly
and indir-ectly on the myocardium. affects sodium
appetite. influences kidney runclions in ways.
and contributes to the regulation of s«relion of va-
sopressin, ACTH. prostaglandins. 100
honnolles.
PHYSIOl.OGICAl. FUNCTIONS OF Na ' , K · ,
AND REl.ATED IONS
Dli lrib-ution of SOdium lon,
Na' is by fa r the most abundant of the
cations. acooonling For some 90% of the poositivc
charge. Conocnlrations of meq/litcr arc
maintained in the Mbul k·· interstitial fluids at>d blood
plasma despite marked variations in lhe rales of
dium intake and eXCretion. Sudden changes in
pluma Na' are usually immediately countered by
oompcnsatory transfers of ...aler. SO thaI plasma vol·

ume (rather than concentration) is altered. The kid-
ney conserves water "'hen too :;alt i.< ingeSled,
and it excretes larger than usual amoonu when Ihe
eXlTacellular Na ' COnc<:ntration fans below opti-
mum levels. Animals that are water deprived COm·
pen:;ate by more sodium (13M).
Altbouih Ihey deri .. lheir cMotit ue." from the same
$0\1"""a(ld ha.e Na ' IS the major <cveral .pc.
ciali ..d extracellut .. ""mp.rlmenl$ mainlain ..,mowh.t
different ionic composition •. The group include. the 'yn-
ovial Auid. of the joinu , the aqueous hum<>r of thc cye.
and the .m.n quantiti •• of liquid. found in the bursae.
the e.... ond the perieardial. peritoneal. and pleural
"spaces." Cerebrospinal fluid Na ' coneenWIlion i. only
slightly Iow.r than that of plasma. bUI bone ewacellular
fluid has relalively more K ' ond 1= Na ·.
Bones hold approximately 43% of total body <0-
dium. Moot is extrncc:Uular. and half of it can cx_
change with blood Na. Cartilage and dense fibrous
connective tissue also conside rable quanl ities
of exchangeable Na ' .
Sodium is an essential component of all xnown se-
cretions. including sweat. tears. saliva. bile. and Ihe
gastric, intestinal. and palll'reat1c juices_
In contrast with nlracellular levels.
Na ' concentrations arc low. An average value for
water" is 10 meqjliter. T he high eXlracellu-
lar:intracellular ralios are maintained via re.triction
of Ihe rales of Na ' uptake acrOSS the plasma mem-
b",nes and th rough the operation of "sodium
pumps" that extrude the ions.
Importance 01 Melntalnlng Appropriate
El(tracallutar: Intracellular Concentration
RatloB
The extracellular Na' coIII'en trat iom affect the sen-
.itivities of vascular smooth muscle cells \0 stim uli
thaI promote vasoconwiction, and they act in olhe r
wayS to affect the systemic blood pressuft. Since Ihe
ions do nol readily diffusc across the plasma memo
branes of mOSI eel! types. they also make substantia l
contri but ions 10 Ihe pressure of the
blood plasma and interstitial Aui ds. When prescnt in
adequale .mounts, Ihey proteCI against "wa lcr
logging."
Extracellular Na ' is directly involved in cotrans-
port mechanisms for taking up amino acids and
othe r nutrients against concentralion gradicnt<
(120.201). It supports intestinal absorption of foods
and the establishment of appropriate pHs within the
digestive tract (6 1).
Under normal conditions. the NaHCOj :HHCO,
ratio in blood plasma is around 20:1. The salt and
add work together as a bulfer system to resist
ALDOSTeRONE " NO TH E RENt N·ANGIOTENSIN SYSTE'A
in Ihe H+ concentr.tion when metabolic
wastes are taken up from Ihe tissues and when . 1·
kaline foods enler. Sodi um deprivation lowers the
ralio and invokes a metabolic acidosis thaI can only
parlially be compensa ted for by excreting larger
quantities of CO: in the expired air. The xi dney ad·
juS\!; blood pH by vary ing the urinary Na-
H, PO. :Na, HPO. ratios. by absorbing HCO, along
with Na ' . and by utilizing NH , /Na ' exchanges_
Sodium loading can invoke metabolic alkalosis
under some conditions.
The extracellular Na · concentrations affect the
metabolism of several OIhcr inorganic ions. Thcy
contribute to thc maintenance of both plasma and
intracellular Cal< (166). and they affect the renal
excretion of ealcium and of phosphate. &>-
dium-<lependen t electrochemical gradicnts within
the kidney facilita te renal of excessive K' .
When supranorma l numbers of Na· ions accu·
mulate within the othc r cations are
Wea ke ning of skeletal and myocardial muscle has
been allributed to losses of K ' and Ca", respec·
tively. Intracellular Na ' also d raws
water into the cells.
Cells utilize Na ' /K ' -flTPases to extrude sodium
ions and establish resting potentials that maimain ir-
ritability. Dcpolari7.ations that follow Slimula-
tion involve rapid inward move menu of Na +, while
repolarizations require somewhat slower Na' extru-
sions. The aci vities of Ihe "pu mp" .re regula ted by
the Na - : K ' concent ral ion r.tios.
Na ' deficiency symptom s include wea kn=. las-
situde, nausea. anorexia. and vomiting. Muscle
cramps develop upon exertion. Prolonged deficiency.
and the associa tcd of eXlracd lular fluid
vol ume. c.n impair menial functions and
lead to the onset of coma ( 183).
Sodium Balance
The average mixed diet ta ken by human adults in
urban sellings supplies approximately 3-7 g (130-
300 mcq) of sodium daily. When the kidneys. en-
docrine. nervous. and cardiovascular systems al"<'
functioning normally. and thel"<' is no heavy sweal-
ing, inlakes of lcss than I g arc weillolcratcd. Diets
containing less than 200 mg have been prescribed for
patients suffering from ct: rtain forms of hyperten-
sion. They are designed to depletc body sodium •• nd
they al"<' generally regarded as unpal.table.
Many apparently perfectly healthy persons taxe
12 g or more each day on a regular basis. and the l"<'
arc .eacoast locales in which the values m.y be
higher. In times paSI . heavy salting was Ihe major
method for preservation of fish and meals, and thel"<'
 good ruson 10 believe Ihal members of$(lme com·
mUnilies QJIlSumed even quan tit ies (39).
Foods vary widely in SQ<iium 03ntenl. 0"" hund .. d·
Jr.lm ponions of many rrllill a nd II(;lclablcs <;OII"in I...
Ihan I ms, "''''''''IIh< same ..."hll of
all. ba<;Oll.and oIi_ Can IlIpply 1M.. 1000. 1700.
and 2400 m8. re<pe<:lively tiS).
Moderately aelive healthy adults lose around 23
mg of Na daily Ihrough ill$tR$ible perspiralioll. and
an addi lional 23 rna in the Yisible sweal . Ilta")' work
in hot en";rooments can illCTUSe loss via Ihe lW<at
glanoh fivo- losevenfold. (It is usually then
to ingest NaG tablets to avert dcfi"erw;y Iyn-
dromes.)
A<:a)fd inl to some authOl'S. f«al u<:«"tion 01 s0-
dium does not change: from day to day, even when
there are large >'Jriations in salt intake (80). Others
report lhal adjuslmenlS are made 10 body need$. and
tbill he daily oulpUI can range from 10 10 12S mg
(8S). In nonpregnanl adults, lhe kidney maintaiM
sodium bala occ by Ihe «juivalent of the dif·
ference belwccn inta ke and \o$se$ by OIher r()Ules.
During prokmged fasting, urinary sodium ¢O<\cen·
tralions approach lero.
A positive balance is «=quired 10 support normal
growlh. During and lacta tion. Ihe dietary
requireme nt s ar<: also incr<:ase<i. T he s ha rpen ing of
51lt appelite observed in mosl pregnant iabora tory
onimnl. con be mimicked in .irlin femates bl' ud ·
miniSlering the appropria te hormones. Even larger
quantilies of dietary sodium i rc required in aldosle-
rone deficiency Slales because of loss inlO
Ihe urine. "Salt craving'· is a c haracleristic s)'mp-
tom. Prior 10 diagnosis and inslilulion of r<:piace-
men! the rapy. children have been known to salt
by the handful and 10 add lllge quantities to iee
CrUm and other foods. Unlrealed
anima ls fed ordinary diels rapidly weeumb to de·
hydration and cardiovaKllIa. failure . Rats and some
other mammals un be maintained in JOOd healtb
wilhou l hormones if the drinkin8 water is replaced
by 1'-' NaC\.
When ".-.:" lhe choice. he;lhhy animab of many
species preferenlially drink dilute salillC fluher than
la p water. Herbivores subsist on sah-poor diets. and
remarkable lIones have told of the lenglhs 10
...·hich they will gO to find ··salt licks·' (39).
Optimum Dlet,ry Sodium Inl, ke, lor
Hum,n ,
Humans regularly ingcsling sodium.rich diets
mainlaining good health lend to have largcr extra·
celMar fluid voIu!llCsthan ar<: needed 10 i USlain nor·
mal blood pressun:. It has been CSlimatotl thai the
reserves ca n exceed 2 lite rs. Some observers reaard
Ihis as undesirable. Others p<.lint out tha t imporlant
protection is provided against the otherwise disas·
lrous consequences of hemorrhage. diarrheal d is-
eases, forced hea")' sweating. or periods of unavoid·
able sodium and " a ter deprivat ion (67).
The notiolllhal il is ··he;llthy"· for all humans 10
sharply restriCI sodium intake, and lhe re laled idu
thaI infants should be protecled againsl de"eloping
"salt addiction·· by fcedillg Ihem unsalted mCllI and
vegeubles. have been widely promulgaled in r«Cnt
yc:aT5- Proponents suggest that we have acquired the
habit of uking tOIl much salt because il is too readily
available and boca...., a greal deal of NaCI is un-
knowill8ty ingested wilh plCpared foods.
Some support wmcs fn:.>m statistical SUTVC:)"$ in-
d iCliting higbcr incidences of hypenensioll in $(lei·
eties in wbieh large quanlities of sallS ar<: ingested
(and 0( lower incidenccs ..'here it is customary local
lill ie NaCI). It is aLso known Ihat pa tients wilh cer·
lain forln5 of hypenension sbow improvement when
lhe intake is sharpl y restricled. M oreover. ther<: ar<:
stra ins of highly inbred laboralO<)l animals wilh ge-
netic defects in which hypertension dcyelops only
when the salt inla ke is high.
The desirabilily of severely limi lin& thc salt intake
of the population as a whote ha< been on
It haSlher<:forc been suggCSted
measures be ta ken 10 ident ify sa tl-scn.itivc individ.
uals. so thaI others can continue to cal well ·balanced
d,e\5 The genc rahzed phYSlotoglcal pnnClple
Ihal oplimum leyds of all body constiluentS should
be mainlained seem. 10 apply to sodium . Some ob-
servations illCOll!liotenl with the ·· Everybody shou ld
cat I.,.. salt" idea arc cited.
I. There a re societies in ,..hic h salt is regularly
consumed in la rge quantities. but in which lhe", is
no evidence for a high incidence of hypertension.
Moreover. 00 discerni ble inHuenccs on s)"$lemic
blood pressure CIIn bc demonstra ted ror pn:viously
healthy human subjects voIunlari ly ill8c:stiTil 20--23
g of salt daily for severa l Wttlls.
2. Patients put on severely restricted d iets usua lly
lose weight-in part becausc Ihe foods are U"'"'PPC-
lizin&- but aLso bcca.usc lhey are often el>COU""ed 10
do to. Simple loss of body wl'ighl without red uction
in sodium inlake an be as effCCli"" as sodium de-
plctioll (59) .
1. In rats with dcfo=<:ts diff"",m from lhe
ones described. NaO intake plays no obvious role in
either the establishment or the malnlenance of spon-
taneou sly developing hypcr1cnsion. In ones lha t are
sail sensitive. ;t il often necessary to force quanti' ics
of NaO greatly in excess 0( l hose: taken by normal
animals.
4. J n population. ingesling vcry s mall q uantities of
NaCl, many nondietary reasons can be found ror lhe
low incidences of hypertension.
,,.
S. In urban scttings. hypertensivc:s do no1, as a
group, lend 10 cal mOre salt than their normol.n,j""
connterparts (132). In fact. they often lake less be·
for. they seek out treatmen t. and they generally
have blood and extracellular fluid volume values in
Ihe low-oormal range. The severest of salt restriction
lowers the mC3.n arterial blood pressure in not more
than 30% of patients with "essential" hypertension
(59).
6. There are many indications that when Nael
oonlribu(es 10 blood pressun: problems. it does so
only indirectly in the majority of cases. Simple ex-
pansion of the extracellular Ruid volume (and of the
lotal sodium oontent) does not elevate the systemic
bl<X>d preS'ill"<' of healthy subj«:ts.
Sodium ions afTect Ihe rales of Cal> Iransporl
ac""," cell membranes. Soon after the NaCI intake
is increased. mo,. calcium lost to the urine. Under
normal oonditions. is followed by oompensatory
changes in vitamin D so that a larger
fraction of the dietary calcium is absorbed (26).
Some hypertensive palients are unable to accomplish
such compensation. Caldum deficiency may cause
human hypertension ( 132). and calcium supple·
ments can improve low-renin (A-3).
7. Sodium reWiction and the associated reduction
in ex tracellular fluid volume provide potent stimuli
for generation of A- II. That peptide dirCClly stimu·
lates the smooth musele of the blood vessels. and it
is, in fact, the most potent vasoconstrictor known.
Moreover. A-II activates thc sympathetic nervous
system. and it promotes the secret ion of salt-retain-
ing aldosterone and of antidiuretic
hormonc. Sodium depletion may additionally invoke
secondary hyperte nsion by inhibiting thc ka llikrein-
kinin system. which discussed la ter. There are
forms of human hypertension in which sodium re-
striedon exacerbates the problems and can evcn have
fatal oonscquences.
Potass ium Distribut ion and Balan ce
K + i$ the major intr<l(e/lular cation. It regulates the
activities of enzymes involved in glucose metabolism
and ATP generation, peptide chain assembly on tbe
ribosomes, and DNA biosynthesis (85). It supports
cell growth. differentiation. proliferation. and repair
(104).
Concentralions of ISO meq/liter in "cell water'"
oontrasl wilh Ihose of 3.0-5.0 meq /l iter in the major
exlracellular "nids. Cerebrospinal "uid K ' levels are
slighlly lower than those of blood plasma. In con-
lrast. bone extracellular fluid contains around 25
meq/liter in ad ults and as much as 75-100 mcq/
liter in rapidly growing ju veni les.
AlDOSTERONE AND THE RE NIN-AN(HOTE NSIN SYSTEM
Most secretions have higher K: Na ratios than
blood plasma (but much lower K ' concentrations
than intrace llular fluids). The ra tios in saliva vary
with the secretory rate. but each of the fluids pro-
duced by g .... trointestinal glands has its
tic ionic makeup.
Dietary intake tends to parallel caloric intake. An
"average" human adult eats 2-8 g (50 -200 meq)
daily. Dried apricots are cspc<:ially rich sou rces.
while cantaloupes and beans contain several times as
much K per gram as eggs. checsc. and bread . How-
ever. the variations among foods are small by com-
parison wilh those of sodium_
Growth and tissue repair arc a!SOCiated with pos-
it ive potassiu m balance. whereas catabolic processes
hasten loss_ Heavy sweating. vomiting. and dia rrheal
disease are a mong Ihe conditions that lead 10
depletion.
The kidney is the major regul ator of the K- con·
tent of the bul k eXlracdlular fluids. It rapidly ad-
justs excretion ratC! to changes in intake and use. In
contrast. fecal excetion removes a fairly COnStant
10% of the intake.
Although they tra vel through restricted channels.
K+ ions readily cross plasma membranes in both di-
reelions. They accumulate cells mostly be-
cause they are attracloo to large. negativel y cha rged
proteins and other anions. Thc electri-
cal gradient is opposed by a concentration gradient
that favors oulward diffusion.
K ' exchanges are essential for polari ,.ation. de-
polarization . and r.polarization of excitable cells.
Extracellular K ' ;s a physiological depressant of
the cardiovaseular system, Excessive concentrations
invoke marked vasodilation. They decrease the force
of myocardial contraction, slow oonduction in the
heart. and can cause diastolic arTell!. Pharmacologi_
cal concentrations promote inappropriate secretion
of many hormones. Subnormal leve ls also exert del-
eterious influences on the hcart. They weaken and
can even paralyze skeletal muscle. Thcy additionally
inhibit smooth and bring about inlestinal di-
lalion (145).
Na+I K +·ATPases
These plasma membrane-associated enzymes regu-
late ion exchanges. In many cell types, three Na '
ions are extruded and one to three K ' are ta ken up
for each ATP molecule oonverted to ADP + p;.
Since the is Mg-A TP. the reactions addi-
tionally affect the availa bililies of magnesium and
phosphate ions. Thyroid and catecholamine st imu-
lalion of thermogenesis have been linked with acti-
valion of Ihe "sodium pumps" (122), a nd many of
the effects of mineralocorticoids. glucocorticoids. in· centratio", rise when there is Na ' retention or CI -
sulin. and calciferols involve influences on depletion.
the enzymes. Most of the chloride enters the body as a compo.
Optimum activity re<;juires the appropriate extra- nent of dietary NaCi. and much of it leaves (via
cellular and intracellular Na: K ralios and ion urine, sweat, saliva, and feces) in combination with
concentrations. sodium. When "loop diuretics·' impair CI - transport
Ouabain is one of the pharmacological agents in tbe kidney, they aceelerate urinary excretion of
widely used to inhibit the Na ' jK ' ·ATPaS<'s. It low. sodium and water a, well. However. many cell types
ers the excitability of many cell types by interfering Can independently regulate the movements of the
with the establishment of resting potentials. impairs two kind, of ions A spedfic chloride stimulatory
some transport processes. has deleterious effe<:1S on factor has been described and implicated in adjust-
cell growth. differentiation. and proliferation. and ments to excessive 0- retention. Evidently. it is a
can bring aoout cell swelling consequent to Na ' up- lipid that either originates in the adrenal gland or is
take and osmotic drawing of water. Actions on the dependent upon the adrenal for production (II). Hy-
kidney lead to excessive urinary loss of water. and of pcrchloremic acidosis is a condition in which too
Na · and other ions. much 0 - replaccs the plasma HCOj .
CI - diffuses easily across plasma membranes. T hc
Agent' of tbi. kind (including digitali. and re laled gly-
coside,) have Iiltle effe<:t On norma l hearts wbon given in intracellular concentrations rarely exceed 15 meqj
minute amounts. They are u..d in c.refully controlled liter be<:ause of the electronegativity of the nondif-
dosase. 10 improve cardi.c outpUI in patient .• wi lh my,," fusible anions.
eardial insufficiency. Evidently. they accomplish tbi. by Most of the HCOj of the blood arises from the
permilling th. mu,d. to accumul ... a small e...SS of CO, generated by metabolic reactions. "substantial
Na ' . The ions are 'hen exchanged for extracollu1ar Ca " . fraclion i, reconverted to CO, for release into the
The calcium that ente ... interaca directly with the con- expired air. The quantities that are excreted into the
l .. otil. moch.ni, ms (94). (Additional ,herape",ic bene- urine vary with the sodium intake and the plasma
('I' derive from influence. c.ened on tbe autonomic ncr- HCO l ·
vou'
Harmaline i. another u..,ful tool. It impairs sodium-
dependent tranSpOrt proce\$CS by competing with the Role s of Na+, CI- , K +, and HCO, In
Na' ions f'" enlty (8). Rog ulatlon o f Acld -Basa Bala n c a
o Most cellular enzymes function a\ optimum rates
"0,, ,", / only when the H+ concentration is maintained
within a very narrow range. Intracellular pH is
, \
"0 "0I 0 markedly affected hy changes in the H ' content of
tbe extracellular fluids.
'", The metaoo!ism of nutrients leads to continuous
0 release of acids and acid precursors that must be first
bulfered and then eliminated. In human adulus. re-
o " actions that generate CO, (and thcrefore caroonic
o acid) lead to the daily production of around 26 cq of
H· . The acid is formed spontaneously when (he CO,
" Icvels are high. bUI the reaction is accelerated by
widely distributed caroonic anhydraS<'s (A"(;).
Ouabain carbonic
o 0 anhydraS<'
" " CO, + H,O B,CO) ... H ' + HCO l

An additional 60 meq of sulfuric acid arise from

Chloride and Bic arbonate Ions
Electroneutrality of the extracellular fluids is main·
tained primarily by CI - ions that arc present in con·
centrations of 100. 113. I IS, and 130 mcqjliter in
the blood plasma, ce"'brospinal, bulk interslitial.
and oone fluids. "'spectively. Bicaroonate ions ac-
count for only 26-29 mcq/liter under normal con-
ditions, but they play important roles since the con-
the methionine and cysteine moieties of Ihe 100 g of
protein metabolized. and 20 meq of phosphoric acid
are formed from phosphoproteins. phospholipids.
and nucleic acids. Healthy persons make small
amounts of t1-OH-butyric. uric. and other organic
acids, but tbose with insulin deficiency and conse-
quent impairment of lipid metaoolism produce up to
500 mcq per day.
".
Many mechanisms provide protection against the
buildup oftoxic levels of H ' (183):
I. The lungs continuously remove carbonic acid in
the form of CO) + Hp.
2. Negatively charged proteins combine with H '
10 form poorly ionized acids. This provides protec-
tion against a rapid fall in blood pH.
3. The kidney retains enough Na ' and HCO, \Q
maintain the NaHCO):HHCO, ratio of the blood
plasma, and il excretes rnQ:Sl of the "fixod" acids.
Roles of Erythroc ytes In Maintaining Acl d-
8816 Balance
By carrying "",piratory ga •• s, rcd bl(>:)d cells faoilitate
o,;dalion of some IH"B"nic acid, 10 CO, + H,D. and elim·
ination of th. CO, in the .. pir«! air. The hemoglObin
also "'Ye' os. buffer. sinC(: il' affinity for H ' ;ncre....
wilen oxygen i. gi",," up. The exch,nge, that OC<:Ur as lhe
erythrocytes " .... 1 through lhe systemic capillarics can
be represenled a. follows:
K_Hl>-O , + H ' - IJ-Hb + K' + 0,
hemoglobin from hemoglobin 10 10
leaving lungs li.. ues relurnins 10 plasma ti"u.s
lung'
Al Ihe .. me lime. Ih. erylhrocyle. take up CO,. The
gas is rapidly <:on •• rled to H ' + HCOi . ,inc. red blood
",II. rontain "arronic anhydra.e. Th< lIeO, 1"" '« inlO
thc pla,ma.• nd CI i, laken up. Therefore.lhe celt ' trav_
elling loward, the lungs con lain KCI and H·Hb. In the
pulmonary capillarie,. exchange. occur in lhe opposite
direction. The erythrocytes laXe up Hea" and Ihey
form Ih. CO, Ihal enle .. Ihe expired air.
Bulferlng By Plasma Proteins
NonV<llatile substances cannot be diiJlOlSCd of in the
expired air. Howev<:r, prolcin anions aswciatcd with
plasma Na ' combine with Slrong acids to yield
poorly ionized and nCUlral ..Its:
Na-Proteinatc + HA - H-Protcinatc + NaA
The NaHCO, of the blood pla,ma can also neu-
tralize $Orne of the acid,. Thc immediale effcet is
proteelion again't a fall in the blood pH. Howev<:r.
the NaHCO, i, depleted by such reactions and it
muSt be re,tored.
HA + NaHCO , - HHCO, + NaA
Intracellular Mechani sms f or Adjust ment 01
pH
Cell, contain K-proteinatcs Ihal neutrali7.c some of
the and form potassium salts. Much more acid
can be buffered by calling upon mitochondrial stores
of Ca,(PO.),.
ALDOSTERONE ANO THE RENIN-ANGIOTENSIN SYSTEM
H ' ions that entcr the mitoch<lndria react with
ealcium phosphate to form diffusible eakium and bi·
phosphate enter the cytopla,m:
2H' + Ca )(PO.), = 3 Ca' - + 2 HP01-
Large numbers of hydrogen ions can be buffered
in this way. However, the reactions elevate the cy-
tosol calcium and phosphalc ion cone<:ntrations. The
ct:lls compensate 10 some because Ihe Ca'-
activales pla,ma membrane-a,sociated Ca" IMg" -
A TPascs that extrude calcium. The mitochondrial
,tores are very large when compared with the cytosol
content. but repeatoo recruilment of the reserves
must evenlually be followed by replenishment.
Renal Mechanisms f o r Regulation of ACid-
Baae Balance
To maintain Ihe proper eompooition of the blood
plasma. Ihe kidney must excrete H· ion, in quan-
litie, equivalent to Ihe total amount, inge,ted and
generated. minus the ones neutrali1.cd by alkaline
foods or eliminated as CO, + Hp. It mu,t also con-
serve HCO; and Na · .
BICARBONATE REABSORPTION
The proxImal lubules rceover much of Ihe hltered
bicarbonale, especially when the diel is addic. They
acwmphsh thi, indirectly. sine<: the brush border
does not readily admit the ion,. The major mecha-
ni,m' involve Na +IH ' exehange at the luminal ,ur-
fae<: (9,179), carbonic anhydra ... Ihat ealaly1.c bolh
CO, production in the luminal nuid and HCO, for-
mation in Ihe e<:ll" and activ<: lransport of Na · on
the serosal side that i, "coupled"' to bicarbonate
reabsorption . The "sodium pump"' thaI Iransfcrs
ions to the peritubular capillarie, requires a ouabain-
sen,itive (109) and mitochondrial enzymes
Ihat promotc ATP generation (84).
T he border cells secrete hydrogen ions into
Ihe lumen. These combine with filtered HCOr to
form carbonic acid . The acid i, soon converted to
CO, + H,o. and Ihe gas rapidly diffuse, into the
e<:lIs. One<: inside. the CO, again entcrs into the for-
malion of carbonic acid. but this time the acid ion-
i,£s. T he nel'dy formed H ' is secreted. as the
IICO, is tfansported. along with Na · . to the blood
plasma.
The net effects arc recovery of filtered Na · .
HCO; . and waler, and acidification of the urine.
Since diet, rich in Na · facilitate waler and bicar-
bonatc reabsorption. they mighl be expected to in-
V<lke metabolic alkalosi, as well a, overexpan,ion of
the ECF. Fonunately, although the "tightness of
coupling" ""ries .. i, h the species (2(6). all heaLtlly
kidneys hne some ability to dissociale
1",- a nd HCOj movements (201). so-
dium·rich diels usually conlain subslan lial q ua n·
li lksof Cl - . II is possible 10 reabsorb Na ' in com-
bination wilh CI - , and 10 lhe
nuid (EC F) volume ... it houl cle""I;"1 the blood pH.
On lbe Olher hand. $Odium.odkienl dielS oflen
eau$C meta bolic aeidosis:ali they conlract Ih. EC F.
Proximal tubu le. ut ili/.• carbonic uhydr . .. (CA) 10
Ic<»mpl i, h 80% or the IICO, Srush border
CA also m.in"illS ",n,1 H ' ,radienll. A«lawll",idc
and . d.,ed CA inhibi'Ort "" .. I"'ally block .he rcabootp-
,loa (A_2) .rod I .. ,menl IICO,. NA · . and .....1" UC*
. ion in ",lien" ( 77), U""",VC1'. lhe high IICO; Ic:"els
....'.I.d in lumi .. , Huid. f"cHime blek..:li!fuoioot of Ih.
ion. in more di't.1 pa rts of lhe .. eph,OIIS. NOI all elrects
or th••,ents a,. a"ri b"led 10 earbonie Inhyd,ase
bilion. 1M diurcsis ;,. of sbon duration. and ae.towl,
Imide Iw been ,o.!feet NI ' ud a . but,.,.
b;carbon:n. """"''''''! in !he jeju .... m (I.S).
.0
H,c-C S 0 )I
'nl iri-''><
N N
Normal indiYiduals do 001 ma rkedly expand Ihe
ECF voIurnc "'hcn Ibcy coosurnc $Odium.rn:h dieu.
sinc:e t""'lSiellt of 5lIit and "'lllcr leads 10
IUlrnenlation of the Ii0meI'\Llar fi ltralion rale. Con.
scquently. $lI11$ and waler arc more rapidly
wit h the urino (9). Heah hy subjecI' a lso have do;.
vices Iht protect againSI the development of III<:la-
boIic whcn lhe diet i$ $Odium--deficient.
Small quantit ies of carbonk aeid accumulate. and
these servc as Stimula nts for Na ' and
reabsorplion.
It has beon claimed that diels de fIcient in K ' or
Cl - \Qwer slomerula r filtration rales and then:by fa·
cililale waler and ion H","'evcr. wme slud-
ies designed 10 demooslrale this difficult to in.
le rpn:t. sinc:e tbc regimes usually also conlracl the
EC F i2(6).
There is li miled information on hormonal o;onlrol
over Ihis part of the kid ney. TriiodothytOl'inc has
IKen implicaled as a relublOt of the IITPaK aCliy-
;Iy (49). It is unlikely lhal .ldosterone: din:ctly a f·
(ectsth< bl'\L,h borckr cell$(60. 177), sine.: no high,
affinily reccplOfS for Ihe hormone have been idenli-
ned in Ihe proximal segmenlS of the ne phron. On the
ot her hand. by aCling 1110«' dislally to promote SO>
dium and waler aldOSlerone can indi r«tly
a lf«1 ion moverncnts ( It alw a ffects erythroc)·te CA
[A-4].)
OIa lal Tubull r MeelwllIIll m a fo r Mainta in ing
Plasm. N. -
Althoulh Ihey lra nspon only limi ted quanti ties of
sod ium ;on5. Ihe dislal tubules play major roles in
adj ustment of EC F volume. pH . and elcetrol}' le
A map mechanism for <:ambatling
melabolie acidosis is the of ammonium
ions that can be exchanged for sodium ions.
Distal nephron cells an: ric h in glutamine. glu·
taminase, and I IUla mie dehydroge nase. S kelelal
muscle n:leases glUlamine inlo the bloodstream (97).
bul the kidney cells Qtn generale the amino acid
"'hen lhe supply is ina4equale.
G IUlaminue is a miloc:hondrial rozyrnc t haI cal·
alyzes tile cOllYersion of alutamine 10 .Iutamate +
N H) iFig. 9-1). II qua nl ila li vely less imporlanl
pa lhway Ihat ulilizes keloocids such as pyrUYIIIC can
provide additional N H, (Fia. 9·2).
The N H I difl'U5C!i inlo the tubular Huid, in whieb
il combine$ w;lb H ' to form I mmonium ions. Two
purposes are served: (a) urine acidily 1$ lowered. and
(b) Ihe posili"cly , har.ed N 11: is inlo Ihe
urinc wilh anions, and this frees some Na' for
reabsorplion.
Healthy adult humans engaging in ord inary Ictiy·
itles and taking the ltSual diets ap-
15-50 meq of N H; da il)'. They adjust
Ihe amou nl$ 10 changing nteds by rapi dly a lteri ng
th. aetiy;tie. and b)' ulili zins
sensitive processes for regulating the s},nthcsi5 of lhe
cP1.ymes. There are ronlrovcrsies o;onc;c rninl lhe
conlrol mechanisms (19). H ilh c:onc:enttalioos of
glutamate are 5lIid to redu<=<: glutamiltllsc actiyily.
when:as hi gh concen lrations or slow
Ihe entry of glutamate inlo the mitochond ria.
Change' in NA DH:NAD' ralios resulting from the
second reaction sho... n in Fi.. 9·2 can also a lfcctthe
reaction tates (78). Acid urine h.u a s.rong tcndency
to lrap Ibc am:! 10 form the
N H.i ions (97).
N H; can be u ercled in combinalion wi th phos-
phate and wit h Olher anions. Ellchange of
lhe following kind 100 ronlribule 10 Na '
consoel'Yation.
Na ,HPO. + H- - Na H , PO. + Na '
(lu men) (tu bule) (excreted) (reabsorbed)
ce ll )
INFLUENCES OF PlASMA. K '
CONCENTRATIONS ON ACID- BASE BALANCE
Some K ' can Ix exc!t.ansed for Na '. bUI hype rka.
lemia ICnds 10 promote the dcvelopmr:m of
acidosis in ways (74 ,99). High cooc:enlrn-
lions of K ' depress both N H; excUlion a nd
 ALDOSTERONE AND THE RENIN-ANGIOTENSIN SYSTEM

, "o,
,
C=O
,
C=o

,
H-C-H .. HOH • H-C-H
,
,
H-C - H
,
H-C-H .. NH.

,
H-C-NH.
000_
,
H-C- NI1..
000_

o", o"
,
,
C=O H-C-H
,
,
H-C-H ,
H-C-H .. NAOH + H . .. NH,

,
H-C-H
,
H-C-H .. NH,

,
H-C- NI1..
000_
,
C=O
000_

Glulamate ,,-Ketoglutarate

Fill. \1.1. General ion 01 NH, Irom glulamine .

..,,
C=:O
'",
,
,
C=O
Glutamine
,
H-C-H
,, Iransaminase
•
H-C-H
, ,,
,
H-C-H • • H-C-H
,
,000-
H-C-NH.
,000-
C=O
,
C=O+
000_
,
HC- NH.
000_

G!uwnine
- a-KeIOgiutoran>OIe acid

"",,
,, C=O
,•""
C=O

,
H - C-H
,.,.Amidase
H-C-H
,
,000-
HC- NII> • ,
H-C-H • ,
H-C - H

.-.. ,
C==O
000_

,,·KelOgluta.ramale
,
C=O
000-

"-I(etogIIIta.",,,

Fig. 11-2 . Allomal e I", I""",,hon 01 NH •.


'----... ,,.
, exc,ot"'"
,.,. Hyperkalemia poomote. loss 01 ECF II<.ri<I and d,welopment 01 melaboli< oc_.
low NI-1.O Plod""' .... - --_._ Ie " ,cretiOn
B. " 100<''''0'"' correct"", 01 metabolic itnbal,,,,,,,s
Fig . 9-3.
IlCO j reabsorptioo. As hydrogen ions ac.:umulalc.
they uacerbate (he problems by facilita ting potas-
sium relention (Fig. 9·3A). On the oth.r hand. the
low ammonia levels attc1erale K' excretion . More-
over. both hyperkalemia and acidosis provide polent
slimuli for the se<;rclion of aldosterone. The hormone
acts in several ways to corrC<:l Ihe metabolic defects
(Fig. 9·36).
ADJUSTMENTS TO AATlFICI AlL Y IMPOSED
DISTURBANCES OF ACID-BASE BALANCE
Some appreciation of lhe ability of healthy ".;m.ls to .d-
ju,t lheir acid·bas< balance, to changing noed. can be 00-
tain¢d from ohsef"alions of Ihe ,esponSt. 10 .dminim.·
tion of NH.CI. "nd of Na ' in combinalion with
metabolizable a nion •.
Ammonium ions are toxie 10 Ihe b,ain and heal1.
Th<)$(: produced ... ilhin Ihe nephron. pooe no danger
(.ince Ihey immediatc1Y d iffu$e into the lubular fluid fo,
excretion), but l ny that onler the blood"'.am mu .. b<
,apidly removed.
When N H,C1 is inge ... d. Ihe ammonium ion. are
promplly takon up by the liver and Ihoy are incotpor.t.d
into the relatively innocUOll' ..... t. product. urea .
1Ii,ourine -------1
;"to lOSs • ECF VOlume
1
-
•
MetabOlic
3C001<O
\ Further
K' r.tent"'"
6IOO<l N• .
- _ __ • •_ BIoo<l HeQ,
of on ECF .oIlJIT1OI aM
Since urea i. not ionized. an ",ceSS of nogatively
charged chloride ion. accumulate< in the blood'tream.
The ions are "",n e"cretod into the u ri ne. in combination
with .qui,,,I'nt quantitie< of oalion (mo<tl y No ') . 90th
Ihc ureo and lhe NaCI osmotioo ll), dr.,.. water into lbe
tubular fluid, and one conscqucn« i, copiou' diur«i •.
(For thi , re.."". NI I.CI i. rometim .. gi'en 10 palients
who ,eta;n e.« .. iv. amounts of ..It and ","c,-)
The .ffcct< are transient. Who. the diure.i. invokco
metaoolic acidosi •. tho kidney ... ps up ilS p,oduction ""
ammonium ions . Within 2 to 3 daY'. endog.nou, l"H:
accompani • • CI inlo tho uri ... and .sodium ;OIU are
again .. ab.orbed in I.rgt qu"ntiti.,. Aldo<lerone .tero·
tion is ;ndireClly augmented (183). and thi' furthtr fa-
vol'$ !\Odium .nd ,,"I. r relention.
On Ihe othe, hand. if sodium i. aiven in combination
"ith a melaboliublc ion , uob a$ oilr.1C, • • co'" oation
(Na ' ) i. left 0"'" when Ihe an ion i. o,idized 10 CO , +
Ii, O. Then. more of lht Na - that enter> the glorne,ul'r
filtrate i$ reabsorbed in combination "ilh IiCO; and the
consequ.nce, ore sodium and water rel.ntiOn along with
some metabolic aikalo<i,. Compe ..... to'y adjustments in·
ciud. ,uppr.",ion of NHt ,ynt hesi, and aoeoleroted u,i·
nary ""c",ion Na HCO" Na,IIPO•. a nd othe, sodium
.. It,. The urine becom« alkaline. The a ppc... n« of car·
oonato ion. i. auribUI¢d to the following reaotion thaI
oan ta ke place in the collecting dUCI' (9).
lIeo, + IICO, - 1I0H + cOl- + CO,

FUNCTIONS OF ALDOSTERONE
Effec t, 0 1 " Ido,terone Deficiency: Owert
Symptom'
MMy mammalian species ca n withstand the defI-
ciencies of glucocorticoids and catec holaminCii im·
p05(:d by adre nalectomy. if they an: mainlained in
eomforlable. strCiis-free environments and are given
conlinuous access to water and carbohydrate-rich
pa lal.lble foods. The effecu of mineralocorticoid
d<priva tion then become appartnt.
Within boors after the surgery, the animals bl:gin
to ucrete Ia.ge volumes murine: high ill .sodium bUI
low in potassium. hydrogen, and ammon ium ion con-
lent . This soon leads to lowering of the
fluid volume and the Na HCO): HHCO, ralio of the
blood plasma. Blood pressure falls in pari because of
Ihe reduced plasma volume. but also b«ause K· ac-
cumulates and acu as a m)'OClllrdia l dcpress.ant.
Moreover. the subnormal Na ' diminishes the sensi-
tivity of the vascula. smooth muS(:le to na turaUy oc-
curri", vasoconstrictors such as
The arliCS! overt symptoms are wcakntsS and
let ha ray. Ind these progrcssivcty worsen. Distur-
bances of gamoi mesinal functions arc manifested by
loss of intercst in food. In doas and some other spe-
cies. diarrhea and vomiting often occur. The fall in
s)'$tcmic blood pressure eventually ImpaIrs rena l
functions, and urca a nd other metabolic wasles ac-
cumu llte ;n the blood. In lime. unlreated animals
succu mb 10 a I;Ombina tion of cardiovucular <,:01.
lap$C. acidofi5, renal failure . and hypoglycemia. I....
malUrt ono:s are more vulnerable than adul1$, and
da th;s hastened by unfavorable environmenlal c0n-
ditions or lhe imposilion or SlrtsS.
There are spc<::ies variatiON ;n the order of onset
of sym ploms and in the surviva l limCll. Previously
vigorous .dull rats oflcn cent;nue to cal and drink
lhe usual amounts roc a day Of IW(!. They remain
Ilert and pl\)'$ica tty active. and they have normal
body temperat ures. The ph)'$iolo&ical functions
aradua lty dcl.:line over the: next few days. oot some
untreated animals survive as IonS as 2 wecks. In aN1-
lrlSl, dogs tend 10 lose their appetites wi thi n hours
after the surgery. T hey rapidly become lethargic and
often die within 2 10 J days.
It i. IlOl lX>O>i ble \0 .tudy Ihc elfe.1I of "pure" mi""r.
alooonicoid deficiency by adrcl"IIl«:lomili", an,mali and
admlnll1«i nl /IIlurally OCCtIrrinllh><ocooli<:oid .. since
even "",plleemc:nt" """-I" inleracl w;l h miD<raio<:oni-
cold fC«plon(S). Deum.ll\uooIec Iw bocn used in .......
"'ptrimont> bcca ..... ;t is uid \0 cuM ' IMOtI "pu"," ....
OIICOflic:oid • .,ionJ (18). 8ind,,,, 10 mineralocorticoid ro-
""pton h... ho.... vet. been delnOflllrated (I IS).
Another approa. h is the prutnlalion of "spceilie"
A,NO TfoIE RENIN·... NGIOTENSIN SYSTEU
mineralacorticaid an"lonisu 10 inlacl animals. Triom-
' e tCIIC (filJ. 9-<1) ..... """" ' ''''''Ihl 10 leI in Ihis _yo
Howe<u. it ean exen d f« u in uRtruled. ad •• "" I.., ...
m;>.eel animals.
Spirono/l.cu)ncs are chemically ",llled 10 aido>lcrone.
..d Ihey rorm complexes "j.h mineralocorticoid "'''p-
lOtt. Since !he complexe.I'" IlOl Itan.la<:aled 10 lhe nu-
Clei. 'hese .,c nts do not mimic lhe a.t;<>IIS ollhc hot-
n><>r>e. AId,laelone (SC.9<l20) 10 u,ctu l ror 11I•• i.,inl
lIOme fomu of hyptncll$ion in lIumlM. bul it does more
than I;Ompt' < for .Idosl ....... "'"PIon. It KeeI ..... I.. H '
n etCtion in ",be< ""')"$. , no! i, .11'..10 the bioo)"lllhc!.is of
aldOl' e""'" as "",U as the mcubolism ofoevcral otetoiod
...... " ......... (III). InlCra.,ionJ IndrQICn rtcCplorue·
COUnl fOIl d.. reased libido. impolen<1:. I nd Iynccoo"aslia
In , lid for b",.., ."IOII8< .... nt • ..::I diOlurbar.ces of
11«l ovarian eycl.s in women (40). Som. olhet I,e nl< 11"1111
a", .elaled show Irealet anlim in.raiocorti·
coid pol.nc), and I...., affi nilies for alldrog.n r."plO<$
()6. 40).
SfI(:ondary Consequence. of the
Aldosterone Deficiency
Each of Ihe effects of aldoslerone defieicDCy agg""
yates the problems caused by the others. The kidncy
is alT«led flrsl, and the loss of u lts a nd waler inlO
the urine reduces Ihe volume of Ih e "bul k" inte rsli.
liwl Ouid•. pla.llla <ulullle i. rur
short lime. but he: rnoconecMration develops when
11K: salt , nd fluid resc ..... es.'" d<plelcd. Since mort
Na ' Ihln waler ;s lost. lhe 05motic pr=ure of the
u t"'«llu blr fluids falls. Then. the: cells become
"wa ter·logged- as the hernoconccntration wooscns..
Hyponatremia (low plasma Na ') impairs the
functions of the plasma membra ne ATl'ltscs. Na '
then in the .:.::1Is. and Ihis uacerbates
the hypona l",mia. T hc Na ' ions in Ihe cellsdisplaoo
some K ' ions. and the.e is • furl her fa ll in the
plasma Na: K ralio. Thc amounts of K ' that emer
lhe plasma cannot restore the 05motie pressure. The
hyperblemia docs. however. depress the
myocardium.
Blood pressu.c illitillly begins to fa U becausc of
the mccllanical e ffects of lhe low ci rculating volume.
T he wakened hean heal fun her Io"ers the prc5'
Moreover. the hemoeonot:nlra lion elevates the
blood viscos ity. SO Ihal Ihe pumping action of the
hcan becomes less effective. ll ypotcnsion is further
cucerbated by thc hyponatremia, since Na' 10m in
the plasma arc needed to mIt;nlain l 1«l sensitivity of
the smoot h muscle of lhe vasculature to nalural
vasoconstrictors.
Aldoslerone: also dit«lly alTccll lhe ATPases.
m)'OClllrdill funclions, and vascula r s mooth musclc
tOflC . The hormone can act wil hin a n hour to im-

Fig. 9·4. Some 8Ido. le,.",., "r>1"goniOis.
P'<lV¢ circu lation and el""'trolyle composition if it i.
administered alone to animals thaI have lost some
sails and waler but are 001 yel moribund.
The skeletal muscle weakness of aldosterone defi-
ciency states is allribulcd to intracellular electrolyte
imbalanc.:. abnormal neuronal functions imposed by
the altered plasma romposilion . and failing circula-
lion that impairs both oxygen and nulr;cnt delivery
and waste removal. The muscle wea kness. in (urn.
slows return of blood to the hearl. h also lowers Ihc
OOdy temperature a nd lhu cby depresses the
myocard ium .
Aldosterone deficiency additionally impairs mag-
nesi um melabolism (60.205). The plasma levels of
Mg" risc because less of the ion is SCnt into the
urine and mo,.., is transferred from the muscles to
the blOCld plasma. Hypcrmagnesiumemia depres,cs
neuronal functions, while the los., of muscle ion
wea kens contractions.
The dep,..,ssed lOne and =,..,lOry funetio", of the
gastointestinal tract account for the nausea and an·
orexia. FOCld and water fan off sharply. and
the salts and water lOSt to the urine arc oot ,..,placed.
The metabolic acidosis that began with Na ' and
HCO, loss exacerbates when circulatory impair·
ment permits th. accumulation of acidic metabolite.!
and th. development of hypoxia. The hyperkalemia
a lso depresses ammonium ion production. In tim•.
'/'
,e.
0
'"Spironoiaclone
(AId.,aclontl
" ;;
SC942Q
n
,0
, ,
,,
o --/ '0 , C/1-0 CH,
sc 25152
Ih. blood pre",ure .. '00 low to support gto
merular filtration. and eVen more aci ds are retained
in thc plasma. Additional problems arise because of
the ]XIOf appetite. Carbohydrate deficiency acceler·
atcs the Usc of falty acid fuels, and it depr...es in.
sulin sccretion. As discussed in Chapter 5. ketones
then fonn. In addition to dire<:tly lowering blood pH .
ketones draw water and sodium into the urinc. Fast-
ing also leads to elevation of thc circulaling glucagon
levels (41). and thai hormone further augments the
ketosis.
Concurrent glu cocorticoid dcnciency exaggerates
a ll of the problems, since glucocorticoids ,..,gu la te
ca rbohydrate metabolism. water balance, a nd mus-
ele tOne. Physiological levels stimulate NH ) produc-
tion (98). and this both al kalin izcs the blood and
provides some glucose (lOlA).
Prolongation of Surviva.l Without Hormone
Therapy
Most adrenalectomized animals consume large
quantities of salt if giv:n thc opportunity. Adult
ad renalcctomized ratS Can survive ror months in
strcss-f,..,e environments ir they dri nk 0.9% Or 1% sa-
line inst:ad of tap water. They also scleet the opti-
mum quantities of Nael when thcy are presented
with both water and a mucb stronger salt solution.
",
The underlying are not corrected. but plasma
and EC F volumes and composition are maintained
within oormal rnnges despite the excretion of ex-
c<::cdingly large quantities of sodium-rich u,ine.
Humans with mincralooortiooid deficiencies also
ingest large quantities of sa il. The practice prolongs
su,vival for a time. but only hormone replacement
can COrrecl most of the metabolic defcc!s.
Aldosterone Replacement
When mineralocorticoid therapy is begun afler
adrenalC<:lomy, 00 olh. r special trealment is reo
quired. Aldosterone fully maintains lhe health of ih.
animals. but it is expensive , DOC is often substi-
luted, since i1 mimics most of the aClions.
If treatment is delayed until after some deficiency
symptoms a rC manifested. it is usually necessary 10
additionally provide saline. nutrients. and sometimes
also small doses of glucoconicoids. until electrolyte
balance is re-established. Even these measures will
not Save a moribund animaL In health)' subj ects.
mOSt steroid hormones actions require one or more
hours to develop. Circulatory system impairment
can substantially kngthen the latent period.
Effects 01 Aldosterone Excess
Only some of the of overdosage can be
predicted from the deficiency syndrome. These in-
clude hypokalemic alkalosis and expansion of the
ECF volume. Sodium-rich. pOtasllium_poor diets ex-
acerbate lhc problem.. and carbohydrate-rich food
can augment sodium retention (41,183). Systemic
blood pressure tends to rise, but healthy animals uti-
lize CQmpensatory mechanisms to limit its magni-
tude (19,38) .
Skeletal muscle weakness is a frequent finding. II
is auribUled 10 electrolyte imbalances that differ
from those seen in deficiency states. Paradoxically.
salt appetite and thirst can b<: exaggerated . This
probably results from c..llular dehydration and s tim-
ulation of osmoreceptors.
MINERALOCORTICOID "ESCAPE"
Sodium retention and ECF volume expansion in-
crease progressively for a time. After several days.
however, the animals regain the ability to cxcrcte
more salt and water, even when mineralocorticoid
overdosage is continued. The fluid and electrolyte
balance then stabiti>.e at levels only moderately
higher than those of uninjected. intact controls . The
"eseape" does not extend to all mineralocorticoid ac-
tions. For example, hypokalemia and kaliurcsis per-
sist (14). and sweat glands arc not affected (A-I).
ALDOSTERONE AND THE RENIN-ANGIOTENSIN SYSTEM
Although aldosterone exerts its major actions On
lhe distal portions of the nephron. the secondary in-
creases in sodium and water excretion arc aCCom·
plished by accelerating glomerular filtration and
limiting sodium reabsorption in the proximal COn-
voluted tubules (205). According to observers.
Ihe initiated by the expanded EC f volume
are perpetuated by autorcgulatory mechanisms
within the kidney that do oot depend on hormones
dc!ivered by the s)'Stemic circulation. Olhers believe
that the secrelion of natriuretic hormones is of pri-
mary imponance (16.80). The kallikrein and pros-
taglandin systems may make contributions_ The pro-
posed mechanisms are discuss.d later in this
chapter.
BIOSYNTHESIS AND METABOLISM OF
ALDOSTERONE
It is widely assumed that aldQ';terone biosynthesis
proceeds along the pathways deseribed in Chapter 6
(see fig. 6-6) . According to this concept. a hydro-
genase presem in both the zona glomcrulosa and
7.Ona fasciculala catalyzes the conversion ()f DOC
and corticosterone to IS-OH -DOC and lS-OH-cor-
ticOSlerone, respectively_ Then, a dchydrogenase
present only in {he glomerulosa promotes formation
of an atdehyde group at position !8.
On thc basis of observati<:>ns that (a) DOC and
CQrticostcrone arc more rapidly converted to aldoste-
rone than either of the IS-hydroxylated steroids. (b)
IS.QH-corticosterone can inhibit aldostcrone pro-
duction. and (c) some other en7.yme systems arc
present within the zona glomerulosa . it has been pro-
posed that a different pathway predominates (144)_
Accordi ng to this scheme. tWO CQrtiC<)Sterone meth-
yloxidases (CMO [ and CMO II) are used to form
a steroid-metalloenzyme intermediate that gives rise
to aldosterone (Fig. 9-5). It has additionally heen
proposed that aldosterone functions at some sites as
3 prohormone, i.c .• it is CQnvened to metabolites b<>-
fore it acts on th. target c..lls.
AL.DOSTERONE REGULATION OF SODIUM
TRANSPORT IN THE KIDNEY
Mineralocorticoid Receptors
Studies On rabbits have the existence of
high-affinity ,"CeptOTS in the renal conex and me-
dulla. and !ow... ffinity binding sites in Ihe papillae
(129). The most obvious effects of the hormone arc
uerted on the Collecling (connecting) tubules of the
nephrons. A previously held concept that the hor-
mone acts on the distal convoluted tubules has fallen
into disfavor ( 110,129). hecause of the receptor dis-
 l
tt·DEOXYCORTICOSTERONE
11.HY<ltOXYIa,..
CORTICOSTERONE
CMicosterone Melhy\:).<k!a$e t
INTERMEDIATE ..
ALDOSTERONE
Fi gi. Alt ...... t. coocepts 01 bloo'Iemiclt I>I'th ... ys tor
ot "Idosterone. (The 19.. commonty d;:seussed
patnway i. indicote<i by <IooJble 8ffO'NO.)
tribotion and the observation that neither aldoste-
rone nor spirooolaetoll<' alfects cleetropotential dif·
fer<:nces across Ihc membranes (83). (On the other
hand. Ihere are indicalions lhat aldosterone can ac-
celerate Na ' transport at those sitCl; withoul chang·
ing the IranSlubuiar potential [56].)
The kinds of molecules extraCled from cells pre-
lreale<:! wilh labeled steroids. and studies with pron·
ase. RNases. and other enlymCl;. ar<: consistent with
Ih" belier Ihal Ihe receplo,.,. ar<l prol.i"" with molec-
ular weights of 75.000-100.000 (49).
Four binding proteins that differ from each other
in the relative affinities for the various steroids have
been deseribed. Type I is said to be the "true" al·
dosterone receptor because its binding aflinitie, are.
in decreasing order of magnitude. aldosterone >
DOC > corticosterone> progCl;terone > dexa·
methasone. (Although dexamethasone i, regarded
by some as a "pun::" glucocorticoid. the binding to
the type I protein is substantial. The failure of thai
steroid to display antinatriurelic elTects has been at-
tributed to opposing inAuences r<:sulting from sim ul·
tancous binding to type If proteins .)
Type I] is sa id to be the glucocorticoid receptor.
since its relative alTinities are dexamelhasone > cor-
ticosterone > DOC S aldoslerone :s; cortisol. II
also binds some progesterone. Type III receptors
have S1rangCl;t affinitiCl; for corticosterone (cortico-
sterone > cortisol> DOC > progCl;terone > al-
dosterone > dexamethason<:). Their funct ional sig·
nificance is debated. Similariti.. to corticosterone-
binding globulin have been pointed OUI. but some of
the type ][I receptor is translocatcd in combination
with corticosterone to the nucleus. Type IV has
lower affinitiCl; for all of the stcroids. but it bind,
DOC most strongly (DOC > progesterone> aldo-
sterone > corticosterone> cortisol). and fails toas·
sociatc to any appreciable with dexamctha-
tI).OH·OEOXYCORTICOSTERONE
1 Hfl'dtoxy1'"
, t8-0H·CORTICOSTERONE
sone (56). Interpretations of the physiological
implications of the dilfen::nces in binding must ta ke
into account the high levels of naturally occurring
glucocorticoids in blood plasma (144). the very low
concentrations of aldosterone and OOC. and the n::.
siSlance of dexamethasone to degradation.
Aldosterone Regulation of Sodium Transport
The glom.rular filt,nte underg<>&< eXlen,ive process-
ing before it becomes the tubular fluid of thc distal
nephron. The Na o concent ration is much higher
than thai of thc collecting tubule cell cytoplasm. The
ion, dilfuse pas.sively down the concentration gra·
dient, cross Ihe luminal (mucosal. apical) plasma
membrane. and lravel toward the serosal (basal)
surface of Ihe cell . A "sodi um pump" then actively
transports the Na ' ions to extracellular fluid that
communicates with the pcritubular capillaries (Fig.
9-6).
Aldosterone a«cleratcs Na' transport. Its elTccts
are manifested OnC or mOrc hours a fter the hormone
is presented to the serosal surface. Raising Ihe al ·
dosterone concentration doos not affect thc latent pe-
riod. but il increases the magnit ude of response.
Aldosterone is believed 10 act in three ways; It fa·
cilitatcs pas.sive uptake of Na *; it increases the ae·
tivity of the sodium pump; and it exerts influences
on cell metabolism Ihat augment ATP production.
The processes are inlerrelated. More rapid entry
of Na ' elevates the cytosol Na' concentration. Thi s
increases the sodium pump act ivity and the use of
ATP. Stimulation of thc pump also incrcases ATP
use, and it facilitates pas.sive uptake by augmenting
Ihe concentration gradient . As ATP is converted to
ADP + Pi, the products of the reaction ercate Ihe
conditions for mOre rapid production of ATP. Acti-
vation of metabolic enzymes that provide energy for
,,. ... LDOSTERONE ... NO THE RENIN· ... NGIOTENSIN

SOdium

,,,"sive
, ". , ".
Passage Acti.e

'"'" Ihrough
cell
ultusion

Serosal
MUCO$31
(I"min,( apic,l)
""
, , (ba$lll, cap illal'/l
surface su rface

Fig. 9·6. o;rOCl;o., of $Odium;o., Ir.nspor1 mftUftOO/lod by

....ono.

ATP .ynthesis permits the pump to work elliei·
emly.
SOURCES OF INFORMATION ON
ALDOSTERONE ACTIONS ( 167,187)
The lechnical p.oblem. invol.cd in defining tho siles and
mechani,,,,, of in any OrIC 'peci ... ore formidable.
Mosl of OIIr hypothese. hove boen pieced logether from
bil$ of informal ion acquired from several animallypc •. A
unified picture can Ihen bo drown. bUlthe approoch ob--
.cu[¢' impOrlant speci....,iotio",.
The rabbit kidney bas boen used to Iocali,e hormone
•eceptor .it.... since it i. relatively easy tQ dis.s«t. The
Munich ...1 i. good for micropunclure 5Iudie. because it
ha. nephron. poSilioned dose 10 the ouler .urfae<: of the
kidney, Lar,e mammal. are best fo. projects involving
long'lerm perfusion. and Ihe eoUoeli01U of numelOu$.
c.refully limed sample •.
Some work on the mechanism. of .Idosterone action
have boen condueltd with mammalian kidney prepara·
lion •. The associaled diffieultie. inciude tfte presence of
.. veral differenl ceillypes that are not .a,ily separaled
from each olher and lbe need 10 maintain temperature<
close to those fQund in intact an imal •.
Toad bladder I.an$port. Na ' in • • imil., manner. and
it i. aldoslerone-re'poo,;ve. It offers several .dvam.ge.
over the mamm.lian kidney. It can be studied .1 room
lemperature. and i. hao relatively limple struclure . The
epilhelium comprises a .ingle layer of mucosal cell'thal
i. ,upported by a b.. emenl membrooo. underl)·ing con·
neelive ti"ue. and .mootb mu,cle , Milochondri ... ich
(MR) eells .pan tho width of the epilhelium. aCCounl fo.
15%--20% of Ihe population. and make coniaci witb the
u,inary Huid. Ihe b... menl membrane. and the mOre nu·
merou' gr.nula, (Gl ceil.,
AldoslerOne fCCeptors $Cern 10 bo confined to th. MR
cells. and aldoslerone.induced protei", (described 1.ler)
hove been identified "';Ihin Ihem (161), It has been pro-
pOSCd by some that the MR cell$ are countc.pan. of tbe
"dark cell'" of Ihe rabbil collecling lubule •. However .
<)th ••• have asserted Ihat aldo.lerone action, in mammals
requi,e Ibe coopt.. lion of several cellt)'pe' and have ob-
.... ed thai the in,ulin regulation of N. ' tra"'port in the
MR i. no. paraUeled in the rabbi!.
Me chanism of Aldosterone Stimulation 01
Ns ' Tran6port
The mechanisms whereby "typical" steroid hor•
mones e:tert their actions were di,cu'Ied in Chapter
4. Problems with Ihe concepts. and components of
the hypothesis that are not adequately supported by
evidence were also discussed. and Ihese have recently
been reviewed (83A). Indications that aldosterone
stimulation of Na ' transport is largely 3cwmplished
in the dassical manner (167.187) arc summarized
below (sec fig. 9-7).
I. Tritium-lal1eled hormone crosSes Ihe serosal
plasma membrane. enters the cytoplasm. and forms
comp/exn "'iln high-affinity reup/ors. When aldo-
sterone mrgct cells are presented with labeled ste-
roid. the i,;010pe marker soon accumulates in the cy·
toplasm. Proteins thHt bind aldosterone (and also
other mineralooon iC<lids such as DOC) with high af-
fmity have been identified in aldosterone target cells
but not in cell> unresponsive to the hormone. AI·
though aldosterone enters nontarget cel ls, it docs not
accumulate within them.
2. The hormone-receptor complex undergots a
lime and lemperOlure-aependent '"oClivOIioo" or
transformOlion. after ...hich Ihe coo'plrx Irans/ocates
to Ihe nudt us. The C<lnccntration of radioactive
marker increases in the nudeu s as il de<:reases in the
cytoplasm. Labeled hormone-receptor complexes
have been re<:overed from the cyloplasm. Changes in
the properties of the C<lmpicxes arc seen when Ihe
cells arc incubated at n ' c (but not at O· C).
3. The aClivOIIolt or trall..formation step is be-
{IeVl'd 10 Ix required for binding afthe hornWlU'- re-
uptor complex to the chrommin. The prime candi-
datu for nuclear acceptor molecu/es are nonhistoM
proteins (NlfPs). The binding in some way loads to
the production of mR NAs. 1'lormo"C-recep-
tor complexes do not accumulate in the nucleus if
the cells arc maintained at O' c. and no changes in
RNA synthesis arc then observed. The steroid itself
also fail s 10 ae<:umulate in the nucleus, and the sma ll
I. ALDOSTERONE ent"" eel via seroSa! .....
2. ALDOSTERONE <:ombioes with
4. Actrva!ed compje. tr""SlOCa'e, to nucleus.
bin<ls to ,,,,,,,,is!,,,,,, Pl0\(lin. ot CNomatin
5. New mRNAs 8'" $ynthesize<l
6. mRNA. <Ii""'t formM"" of
Plot"in$
7. AlPs stimtJiate Na . transport
Fig. 11·7 . ··Ct""'a,·· conc&pt for me<:lW>iom 01
'!dO""''''''' s ti"",,"IOon or SOdium (fansport. A.. SIdOSI....,.,.
quantities that do enter do not obviously alTe<:t RNA
synthesis. The aldosterone-receptor cornpcx does
not bind tightly to purified DNA ta ken from target
cells. When an activa ted complex binds to the chro-
matin, evidence for the production of new mRNAs
ineludes mOfe rapi d rates of incorporation of labeled
uridine into mRNA precursors. and the later accu-
mulation in e<:lIsofspeci!lc mRNAs that can be used
to dire<:t protein synthesis in cell-free systems. Inhib-
itors of RNA synthesis block the hormone actions.
4. The IItW mRNAs dir«t Ihe production of a/-
doslero_inducro {A/Psllhat mediate the
auioltS. New proleins have been idontified
in the cytoplasm of target colis exposed to the hor-
mone, and in some cases links have been made with
transporl. Inh ibitors of protein synthesis
block the hormone actions. The latent period is con-
sistent with the need to produce new mRNAs and
proteins.
The AlPs evidently include (a) either "pcr-
meawl" that directly facilitate passive dilTusion of
Nu + across the luminal membanes. Of membrane
components that modulate the functions of preexist-
ing permeasc!; (b) componenls of the "sodium
pump"; and (e) enzymes that facilitate the produc-
tion of ATP.
INFLUENCES OF ALDOSTERONE ON THE
LUMINAL MEMBRANE::;
AlP, have been found wilhin 'he mcmbrant$. Tho dTcoI$
of aldO$t.",,,,, can be mimicked to $Orne e>tenl with am-
photericin B. • polyene antibiot ic obtained from
"''''Fl"t5 ood()Jus. When applied 10 the luminal surface. it
10 fCH"m oomplex -+ A.R
".,
mRNA
/ ' '"'1"'-
mR NA mRNA
\ t I
'" '"
"",,;<10 Ir.. C<tIr: A. aldOst_ _ Ir.. C&fl: R.
NH f>. nonhistCH"ll Plota in.

'"."".Ierate, pa..ive upt.ke of Na '
(187). This lead. se.-
""datil)" to increased us< of energy-providing , u\>$trale<
and more rapid l'O"'port of N. · acrQSS the serosal ,u,-
race. (How",'or. unlike ald"".ro" •. the antibiotic can in_
• "'ase passive N. · transport in (""d bladder rendered in-
sen,itive u> the hormone via substrate deplct;on.)
Arniloride is an atylgu.old. antibiotic .hat binds to the
"o
o o o o
" "
Some lindings are nol e.sily Foiled inlo Ihe aldoslerone
_ mRNA - Al P concept. The ho,mone prom"'''' elon·
galion and "'Iuralion of Ihe fally .dd. of pl.sma mem-
brane phO$pholipid. ud il .cceleral.. incorpo""ion of
labeled acelyl-CoA inlo new fall y add •. II has been pro-
pos«! Ih.1 Ihese changes faCilitate i."",poralion of AlPs
into Ihe membranes (l81). Fally acid synthe,i, inhibit""
block the antinatriuretic actions of aldosterone. arid i.....
hibiton of RNA and of prolein synthesis interfere with
Ihe hon"one·irlduced changcs ,n lipid metaboli .m. On
Ihe other hand. rome of the effects on lipid metaboli,m
are delectable within 30 minutes aftcr ho,mone pres<n-
lation, wh., ... AlPs are not delectable unt,1 1 hoor has
elapsed . AldO$lerone mel.boli, .. implica,ed in the e.rly
aClions ha>. b«n .hown to be formed during the 100.n,
period ( 144). Rapid methylation of apkal membrane:
pho.pholipid •• rId prolein, (A·5) i, one: pOSsibili ,y Ih.1 i.
110101 serio"sly considered . I n load bladder. changes in lhe
aCli>it y of • phO$ pnatase .ffceling m.mbrane <»mpO-
ne.1S and implicated in transpon ha .. b«n observed .
ALDOSTERONE INFLUENCES ON THE
" SODIUM PU Mp ··
Renal Na+/ K' ·AT Pas< oeli> ;l y gradually declines in
rats de priv.d of adren<>C01lical hormones. and it ca. be
slowly restored with m;neral.xQrliCQid •. The obse".tions
AlOOSTERONE AND THE RE NIN-ANGIOTENSIN SYSTEM
mue",.1 membrane and thereby interfere< with passi,-.
uptake of N.' . h block.< lhe aClion. of amphotericin B.
possibly by interfering with the binding of the N.' to;1S
carrier. Aldo:\tcrMC incroa$CS the numberS of .milorid...
binding sites (in a manner ,.",.ptiblo to inlerf.... "".
with ac\in(lmycin D) .• nd pretrCltment with the hormone
prtvents the .miloridc block.
"
o
sugg'" Ih.t the steroid pm"""es biO$ynthesis of pump
pmteins. but most .lIempl. \0 demonstrale Jir«1 effects
h"e yielded negal ive data (187). The res pen ... may de-
pend in pan on interactions wilh glucoconicoid "'''''pIOrs
(49). AldO$temne does. bowe.cr, contribu te to ATP gen-
eration by inducing citrate syntha",. i""'itrk deh)·dro-
genase, malate dehyd rogen . ... and other tn'.ym.. (167).
It also accelorale. production of Ifa""fer and ribosomal
RNAs. bol tllese eifeets are no! detected unlil a/IY No '
transporl b.s bee n affected.
Reguletlon of Sodium Transport In the Colon
T he colon conse rves wa ler. and il ma kes somc con·
tributions 10 the ma intenance or eleclrolyte bala nce.
Sodium iom diffuse passivdy into the mUCO!.aI cells.
and they are actively extruded on the serosal side .
Aldosterone acccleratc$lbe transrers. but the me.:h-
an isms differ from the ones desc ribed ror mamma-
lian kidney a nd load bladder. The stimu lation in-
creases slowly Over a period or several days (208).
whereas maximal cha nges in the renal tubules a re
attained wi lhin 4 hours.
The transport involves both amiloride-scnsitive
and amiloride-resistant components. Some pans or
the lower gut a rc more semitive than others to the
inhibitor, and spcci", differences arc also recognized
(33). Chronic aldosterone overdosage. and long·term
sodium depletion (which oIevatcs the endogenous
levels of the hormone). increase both Na ' j K · ·
ATPase activily and amiloridc sensitivity (208).
Glucocorticoids stimulate Na ' transport in the colon
(and also in Ihe small inlesline). bul Ihey do not
mimic aldosterone aClions on the kidney. Sugges·
lions that the tWO kinds of steroid hormones act on
the gut via common mechanisms (14) are consistent
with observations thaI they similarly affect amilor-
ide·sensitive and amiloride·resistant components of
the transport processcs (33 ). They are not easily rec·
onciled with demonstrations that methylprednisone
(a potent synthetic glucocorticoid) bind.' to nx:cptors
different from the ones that take up
stemnc acetate (a "pure" mineralocorticoid) and
s pironolactone.
Hydrogen Transport
Aldosterone accelerates H ' sc<:retion in both mam-
malian kidney and toad urinary bladder. The major
mechanisms may be augmentation of glutamate de-
hydrogenase levels and stimulation of NH , produe-
tion (although Na'jH' exchanges arC known to
occnr) . They arC blocked by inhibitors of protein. but
not of RNA symhesis (144). Carbonic anhydrase-
dependent bieMbon ate tranoport p","""cd. in the di.·
tal as well as segments of t he nephron. and
inhibilOrs of the enzyme impair the ability of aldo-
sterone to promote urinary acidiflcalion. However.
aldQl;terone seems to play no role in caroonic anhy-
drase induction (I 67).
REGULATION OF K ' EXCRETION
Since hyperkalemia can have dire consequences. il is
not surprising thaI many mechanisms arc used to
averl il. The acute responses 10 potassium loading
aT<: accompli,hed largely via ion redistribution.
These include accelerated uptake or the ion. by liver.
inlestine. mu,cle. and other cell typcs (17) . It has
been demonstrated in humans and other mammal.
that only half of the excess is into the urinc
during the first 4-6 hours when the necessary ad·
jUStmentS of the plasma concentrations are made.
The mtes of K ' transport across plasma mem-
branes are affccted in many parts of the body not
only by the K' concentrations of the cells and
cellular Auids, but a lso by Na ' concent rations. Na · ·
dependent electrochemical gradients, and intracel-
lular and extracellular acidity.
Chronic adaptations include accelerated lQl;s of
K - into the feces. but they depend heavily on renal
mechanisms. some of which are hormone-indepcn.
dent (45). The delivery of K' to the urine is affected
by the pcrmeabilities or the renal cell membranes.
the glomerular filtration rate (which afTects the flow
of fluids through the tubUles). the concentrations of
K'. and some anions in the tubular Huid. and
the aClivities of "potassium pumps" (72.88). K' reg-
ulates a phosphatase lhat aCtS on the Na ' j K --
ATPase complex, and it actl; more slowly to increase
the numbers of potassium pumps (173).
Hormonal rootrols are superimposed Over other
processes. Hyperkalemia stimulates aldosterone rc·
lease. and that steroid is widely regarded as the
major humoral regulator (211). Glucocorticoids
(92). PG •. CAs. insulin (l80). and olher endocrine
secretions play additional roles.
Kidney collecting tubules display remarkable abil-
ities to adjusl their rates of K' transport to body
needs . The activity is accelerated in response to the
ingestion of potassium· rid foods. thc intravenous in·
jeetion of potassium salts. the administration or sev-
eral hormones. when exhausting exercise lead, to the
transfer oftargc number of ion, from skeletal muscle
cells to surrounding Auids. and when renal dis·
orders limit the numbers of funclioning nephrons.
Urinary K' concentrations approach zero in animal.
on poIassium.<Jeficiem diets.
The mechanisms whereby mineralocorticoid. ae·
celerate K' excretion arc only partially understood .
The effects on mammalian kidneys arc enhanced by
high N.' levck but the and bli_
nretic actions can be dissociated . Aldosterone can
ae<:eierate K' excretion when it is administe red to
sodium·replete animals ",'ith good endocrioc balance
in dosages too low to promote Na ' retcntion. The
hormone is also efTective in animals displaying min-
eralocorticoid "escapc". and when the inftuence, on
sodium transport are blocked by actinomycin D. pu·
romyein . and other inhibitors. Under ordinary con-
ditions. no stoichiometric relationships betwcen hor·
mone-stimulated Na' and K' transport can be
demonstrated. and aldosterone fails 10 affect K'
transport in toad bladder. In mammals. males re-
spond to a greater extent than females. probably be--
cause of differenees in steroid metabolism (1 44).
[n addition to .timulating K' tran'port, aldoste-
rone is needed to support SOme of the cfTeets or high
K ' concen trations. The "perm;ss;ve" roles can be
demonstrated in studies of isolated. perfused kid-
neys. and in adrenalectomized animals maintained
on unvarying dosages of mineralocorticoids . They
probably depend in part on the creation of electro-
Chemical gradients that facilitate potassium
excretion.
Mineralocorticoids are reported to increase the
activities of potassium pumps by augmenting base-
lateral membrane surface areas and thereby provid-
ing additional attachment sites for Na'/K'_
AT Pases (88). They elevate the phospholipid COn-

tent of the membranes, and and a proposed function
is insulation of one pump from the oIe<:trical activi-
ties of others.
Hyperkalemia stimulates insulin secl"<'tion, and
studies with somatostatin indicate that at least basal
levels of that hormone arc r"'luil"<'d to support nor-
mal rates of K + transfer acr()SS plasma membranes.
Epinephrine accelerates uptake of the iOlls by skel·
etal and cardiac muscle. Erythrocytes "learn" to
take up mol"<' K+ when the plasma levds Qf the ion
are chronically elevated, but they arc not believed to
play important roles ;n acute responses to potassium
loading.
POlassium loading invokes aldosterone-indcpen-
dent adaptations (45). It promptly affects the activ-
ity of a phosphatase that controls phosphorylation of
a component of thc renal tubule Na ' /K ' ·ATPase,
and it mol"<' slowly increases the numbers of potas·
sium pumps (173). More rapid K ' entry across the
luminal mcmbranes has been observed for colonic
mucosa, and similar effects may be invoked in the
kidney. The ions may be acting on potassium car·
riers or on the operation of an "absorption pump"
( 144). AldClSterone action$ on Ihe colon are similar
in many other ways to the ones established for the
renal mbules.
ALDOSTERONE INFLUENCES ON OTHER
C ELL TYPES
Proteins resembling the mineralocorticoid receptors
have been identified in the small intestine and esoph·
agus, but no functions for them are known (88). AI-
dQSterone is taken up rapidly by skeletal and cardiac
muscle, and it inAuences Na ' and K' transport
across the plasma membranes (50). Curiously, how-
ever, no I"<'ceptors have been identified tbere, and al·
dQSterone is not translocated to the nudei of those:
<xUs. AldQSterone also affects ion transport across
erythrocyte membranes. It cannot act tbere in the
"classical" manner, since those cells lack nuclei.
Salivary and SWeat glands arc generally regarded
all ·'propcr" target organs, sin<x there is evidenec for
the existence of receptors. and the mineralocorti_
coids are known to decrease the Na ' :K ' ratios of
the Measurements of the electrolyte com·
position of saliva al"<' sometimes used in tbe diagnosis
of adrenocortical disorders.
Aldosterone-binding proteins arc present in the
brain, but they have not been extensively studied and
the functions have not been delineated. The likeli-
hood that the proteins are receptors is supported by
of the effects of other s teroids on the binding
(5).
PrOteins with aldosteronc·«:ceptor properties al"<'
AlOOS1EAONE AND THE RENtN-ANGIOTENStN SYSTEM
present in growth hormone-secreting pituitary tumor
cells, and they may also be present in normal so-
matotropcs. Interestingly, however, they have not
been found in the corticotropts, altbough those <xlls
release a peptide that affects a ldosterone biosyn-
thesis (\16). The findings may be related to obser-
vations that patients with disturbances of GH SCc .....
tion oftcn show aldosterone (202).
Much of tbe aldosterone tbat cnters the liver is
converted to other steroids, conjugated, and sent On
to the bile or urine. It not known whether some
effects al"<' directly on hepatocyte., Or
whether some of the metabolite. made in the liver
perform special physiological functions elsewhere.
ALDOSTERONE REC EPTOR NUMBERS
Aldosterone receptor numbe ... increase in untreated
adrenalectom ized animals, and the eff..:ts arc .....
versed by aldosterone administration . Chronic oVer·
dosage diminishes the numbers, and there is rapid
restoration when the hormone i. withdrawn. Accord-
ing to SOme observers, aldosterone is the primary
regulator of the receptors (83). Evidence prescnted
by others for influenee. exerted by A- II and sodium
ions is discussed in the next section. There are con-
dition. under which binding change, and
this provides an explanation for nonparallel changes
in sensitivities and receptor numbers.
The ability of one kind of hormone to bind to .....
ceptors for another can a ssume physiological impor-
tance in some harmone dcficiency Stalcs, and when
tumors release large quantities of biologically aClive
products to the bloodstream .
Glucocorticoids utilize their own receptors to
maintain K ' balance in otherwise untreated adre-
nalectomi7.cd animals. Thcy do this without increas·
ing Na ' (18). (In fact, they can exert an-
tinatriul"<'tic influences under some conditions.)
Low dosages directly modulate Ihe Na' / K ' _
ATPases of thc kidney . They also accelerale K ' ex_
crelion by the gaMrointestinal tract. Unlike aldoste-
rone, they aCt on both the small and large intestine.
1·lighcr concentrations increase glomerular filtra'
tion rates, in part by improving cardiovascular fune-
tions and supporting Ihe actions of catecholamine..
They tend to elevate plasma K ' by accelerating ca-
tabolism and by promoting translocations of K '
from intracellular to extracellular sites. They also
enhance scnsitiyity to potassium loading (88).
Glucocorticoids affect aldostcrone sccrction in
scveral ways. They accelerate production of angi·
Olcnsinogcn, and this leads to the formation of A-II
(a major stimulant of 7.ona glomerulosa cells.) The
inAuenccs they exert on Na ' and K ' metabolism
contribute to the regula tion of renin release, and
this, too, affects A· II production.
Glucocorticoids exert negative feedback control
Over ACTH secretion. This slows production of cor·
ticosterone. which serves as an aldosterone precur·
sor. As discussed later. ACTH additionally acts in
other ways to either increase or decrease aldosterone
release. Moreover. giucocorticoids deprc§s PG syn·
thesis. They can in this way affect the functions of
ADH (an inhibitor of renin release).
WATER TOLERA NCE TESTS
Since glucOCQrticoid deficiency imp.irs the abilit), \0
excrete a " .. tcr load within time periods established
for healthy subjects. water tolerance teslS have bttn
uscd as a diagnostic tool.
Adrenalectomi7.Cd animals given large quantities
of water by stomach tube absorb the nuid vcr)'
slowly. They therefore suffer for a time from me-
chanical pressure on the surrounding structures. "00
from Ihe effects of luminal hypotonicity on the gas·
trointestinal muc=. When the "'aler enters the
bloodstream. it is retained too long, The resulting he·
modilulion and hyponatremia lead to water·logging
of the cells. Some erythrocyles hcmolyze. and the
hemoglobin that is released can clog renal tubules.
More direCI effoxts of hormone deficiency on Ihe kid·
ney impair Ihe ability to appropriately acccierate
waler excrelion .
Adrenaleclomi •.cd animals given glucoconicoids
some hours prior to the lest display normal " .. ICr 101·
crance. Thc hormones exert bcneiicial effe<: ts on the
gastroinleSlinal Iract. on the mechan isms for c.·
changing Ouids betwecn Ihc blood and the imersti·
tial spaces. on the plasma membranes of cells and
the associatcd resistancc to water·logging. On gl.,.
mcrular filtration ralCS. and on renal tubular func·
lion •. They also the waler·«:taining cf·
reen or anlidiuretic hormone. and it has bttn
proposed thaI they decrease ADH release.
Although mineralocorticoid. act most obviously 10
promole walcr and sa lt retcnlion. Ihey can hasten
the excretion of a water 1000d in adrenalectomized
animals, They are les. effoxlive than glucocorticoids
and require more lime to confcr proloxtion, Na · /
K· .ATPases arc the mOSI li kely site. of action.
ALDOSTERONE SECRETION
Hea lt hy human adults secrete 40-200 I'g of aldosle·
rone daily to mainlain plasma level. of 2-10 ng/mL
Cone<:nlration, no higher than 20 ng/ml invoke so--
dium and waler retent ion and kaliuresis , Thc high
potency and rapid clcarane<: are allributed 10 the
very limiled affinilies for plasma proteins. Close 10
36% of circulaling aldosterone is in the free form.
and a n additional 47% associates loosely wlh albu·
min. O nly 17% binds to CRG (214).
In recumbent subjects. the circadian variation' in
hormone secretion tend to parallel those of ACTH .
The levels risc rapidly after the subjects assume an
upright posture (l9).
Sodium depletion markedly augmen ts aldOSlerone
secretion. but il does so indire<:tly. As discussed ea r-
lier in Ihis chapter. plasma Na' concenlralions are
jea lously guarded . a nd hyponatremia only
when Ihe usual regulatory S)'stcms fail. Therofore,
changes in plasma Na · ca nnot provide appropriate
physiological stimuli for the glomcrul= cell s.
(O nly grossly pharmacological variatioru; in extra-
cellular Na' have direct effects.)
The rcnin-angiotensin system is the major regu·
lator of aldoslerone secretion. It is affecled b)' body
sodium content . ECF volume. system ic blood pres·
sure . potassium levels. acid-base balance. renal
blood How. signals received from the central nerv<JUS
system. hormones and other phy>iologieal faclors.
THE JUXTAGLOMERULAR APPARATUS
The juxtaglomerular apparatus (JGA) is a complex
organ situaled wilhin the hilus of the glomerulus. II
eontains e<:1i types derived from both vascular and
tubular componenls of Ihe kidney. and it funclions
in both pereeption and see«:tion (12.117. IIS). A
simplified diagram is shown in fig. 9·8.
The Grenuler Cella
Close 10 its point of entry into Ihe glomerulus. Ihe
affcrent arteriole contains within its medial coa l
(go-anu!3t) cells
Alle 'en!
Me,,,,,
fI g. g-8. [);'"9'a.,.."oli<: repro.....lal"" 0110' ' ' 0 _ ' ' ' '
appa'.'u,.
,.,
groups of specialized cells that replace (and proba-
bly are derived from) lhe usual smooth mUs<:lc. T he
term .. l(1r (JG) is most commonly used
to designate the specialized cells. Other te rms (gran-
ular JG, rny<>cndocrinc. myoepithelial, and epithe-
lioid ) have been applied. however.
J G cells synlhesi7.c and slore renin . T he granulc.s
may contain precun;ors as well as active forms of Ihe
enzyme. Corti cal JG cells contain ITIQre granules
Ihan medullary ones, and there is a direct relation_
ship between gra nularity and renin cantcn!.
Myafibrils are also pres..nt. These are believed to
function as "stretch" receptors that SCnse cha nges in
the diameter of (or the pressure within) Ihe afferent
arteriole (42). Morphologically similar cells ()C<:nr ir-
regularly in mOre proximal portions of the afferent
arte rioles and in the efferent arterioles.
Lacla Cells
Phagocytic components interposed between the en·
dothelium of the glomerulus and the basement mem-
brane are known as mfSangia/ cells. Those that ex-
tend imo the reg ion bounded by the afferent and
efferem arterioles comprise the "extraglomerular
mesangium:' The term /M"i5 (network ) refers to the
numerous inte rtwining cytoplasmic processes that
provide for oontac\ with other oomponents of the
JGA. Other names applied to these ce lls include
agranu/ar. agranu/ar JG. pseudQ-M eisserian. and
GOOI"maghligh (although Goormaghtigh described
the other components of the JGA as Well).
Together with the granular cells, they make up
the "vascular component'" of the JGA. and enler
into the formation of an arteriolar cuff (polar cush.
ion. Po/kissen). Renin has been iden tifted in the lacis
cells, but it has not been established that the enzyme
is there.
The Macula Densa
At the point where it merges with the distal tubule.
the uppermost portion of the thick asce nding limb of
the Henle loop lies againsl thc hilus of Ihe same
nephron. The clcar, columnar epithelial cells of thi,
region differ in appearance from other tubular ceils,
and they are known collectively as the macula densa
(bc<:ause of their closely packed nuclei). They make
oonlaCI with the afferen t and efferent arterioles. and
also with the extra glomerular mesangium. The cell.
are believed to function as sen,itive to
changes in either the composition of the tubular fluid
Or the rales of prescnt3lion of specific ions that ar·
rive from the Henle loops. Na ' and Cl - have re·
ceived the most attention. but other substances con·
AND THE R€NtN· ... NGtDTEN$tN SYSTEM
tained within the tubular fluid . a nd the talal ionic
composition. may be imporlant.
Neural Components
Adrenergic neuronS supply some of the granular
cells and also the smooth muscle of Ihe blood vc ..cl
walls. Catechola mines released from the terminals
affe<:t both renin s.e.:rction and arleriolar tone. There
arc functional connections with several pariS of the
brain (159.17 I ).
RENINS
Renins are highly spc<:ifie peptidase! that act on an·
giotensinogens to release the deeapeptide angioten·
sin t (A·I). They are not known to perform any other
functions(1S S,159) (Fig. 9-9).
Although the enzyme' are made in many parts of
the body. Ihe rapid decline in pla ,m a concentrations
that follows nephre<:tom)' support' the belief Ihat
plasma renins originate primarily in the kidneys.
The molecules evidently undergo processing before
they arc releascd. since the acti"e form that predom·
inates in human plasma is a glycoprotei n with an ap-
parent molecular weight of 48.000. whereas enzymes
purified from kidneys ha"e wci&hts closer to 40.000
(182). Cireulating cn'.yme, arc degraded in the
liver. and patients with hepatic diseases OflC n hve
elevated levels. The plasma half.life in hea lthy hu·
mans has been variously estimated at between 10
and 65 minu les.
Numerou. isozym.. lhat dilfer from each olher in size.
i:KItcctric pOi nu. and cat.tytic activities hay. been iden·
tified from body tissue •. The ooe. of renal origin all seem
to be glyeoprateillS (17t). but tt.ose obtained from rodenl
mandibular gland. can be frcc of carboh)·drate (182).
The apparent molecular ••eights range from 36.000-
63.000. with mool form, dose'tto 40.000 dalton •. It i.
not koown whethcr the product ion of multiple iso>-ymes
has ph)"ioIosical ,igni fieance . It has. 1Io..·..·e'. t>ccn
, how. that p·adr.""rgic .gooi,to profcrontially rele"""
just certain on.. in rat, {t(6). Evidently. tbcsc are mol.
eeules that have been .torcd for a time within the cell'
(t07).
Prorenlns
Proren;ns lack catalytic activity, but they can be
converted in vitro to potent enlymes. In normal
human blood plasma, the prorenin:renin ratio is
around 9.
Studies of amino acid incorporation by isolated
glomeruli, eDNA obtained from rodent salivary
glands. and coli-free translation . all su pporl the be·
 (A1h9-"... . T"'_-.. ' _ _ £..o-<oo )
lief Ihat renin is cleaved from large preeu""rs that
have pre-pro sequenCl'S (1 82A), However, the rela_
tionships between those high-molecula r weight renin
and the circulating pron:nin' a rc not
dear. Prorenin declines somewhat, but it doc. not
disappear from the blood plasma after nephrectomy.
Salt depletion clevates both prorcnin and renin in
healthy subjects. and there is no indication that pro-
renin concentrations fall as renin activity rises,
Morwver. some species (e.g. dogs) do not seem to
have circulating prorenins (182). It has been sug-
gested that prorenin made in the kidney contributes
directly to localir.ed hormonal control. and that mol-
ecules released to the bloodstre..m represenl tmn.<-
port forms of thc
Plasma prorenin is usually not measured directly.
The concenlrations are estima ted from comparisons
of enzyme activities before and after in vitro pro-
cessing. The value' obla ined depend on the tech-
niques used. Average levels for healthy humans are
in general neighborhood of ISO pg prorenin pcr
milliliter.
"Big Renlns "
Big and "big-big'" renin-li ke proteins wilh molecular
weights that can go as high as 140.000 show widely
varying propertie,. Some possess catalytic activity
and may consist of aggregates of sma ller proteins.
Others are believed to be active enzymes associated
with inhibitors that block the catalytic sites
Prorenln Activation
The two procedures commonly used in the labora-
lOry arc "acid activation."' i.e. incubation of Ihe pru-
leins at a pi I of al"Qllnd 3.3. and "cryooct;vat;on:' or
Slorage of the proteins a t lemperalures of - 2' 10 -
4-C.
Botb procedure. deptnd on the pr ... ""e of endogenous
protease. in the preparal;ons. The}' seem to involve one
Or mOre of the following: (a) changes in moleclar config_
uralion that lead to exposure of the c"alytic ,ite.; these
ore not n""essaril)" a.oociatc<! with subst.ntial ch.ng¢$ in
the .i.es and woights: (b) ",parat;""" of the en,.yme from
cndogel'lOll' inhibitors: (c) blocking of the action. of en_
dogenous inhibitors: (d) remov.1 of ,ubot.. te., thot com-
ptte with renin for catalytic ,itcs; and (e) limited proto-
oI)", i. 1hat r.,uh. in the 'emoval of pc ptid .. maSki n!! th.
eatalytic ,itc< bu, has lin lc effect on the molecular
weight.
The acid aC1 ivation permits only partial conversion of
p,,,,enin to renin . It rend ef$ the molecules '""".ptible 10
further cieaV3.$e as soon as the pH i. ra ised.
Factors implicated in physiological activation in-
clude cathepsin> (known to be present in t he Iyso-
SOmes of JG cells). kal1ikrcins (43.52) (lysosomal en-
zymes that affect othe r components of the system
discussed laler). plasmin (89), and Hageman factor
(52). Trypsin is probably not important in vivo. Low
conce ntrations activate prorenin but high ones de-
stroy the .n1.yme. T he roles of sodium ions a rC con-
troversial , The effects of varying the concentrations
in the extracellular nuids of the kidney differ from
those invokcd by cllanging the plasma lewis, Plasma
rcni n levels prom pt ly follo wing tile assumption
of upright post ure. a nd generalized sodium depic tion
exaggeratcs tile responses (175). Hov.'Cvcr. depriva·
tion of suli"lCient magnitude to elevate pla$ma !'Cnin
activity to 12 times the bf.sal values does not o bvi-
ously a li"ect !'enin status within the kidneys of rats
(1 43) ,
Renin Inh ibito r.
Aproliain (Truylol) is • peptide found in kith 00fICC ...
,rations in 10"", spleen. Ind ....11 cen. (..,. Chajlle. 6).
It i. a poIent inhibitor of ,he ","e,ion in wb;ch prchlli-
hein i. eOl1","ed ' 0 kallikrei n (68). and ;, hI. been im·
plica 'ed IS • phy.iol0Il;CiI1 Iuppr<...". or prorcnin
ac\ivltiQrl.
When mlift clea ..... il.... bo'nt'(.'he &llcop<OI.in po<-
tlool oI'M ...iot.""i_en ,ha. ",mai"" i. aloo I pOlen,
inhibilor (Il). A role in ne,a,ive feedbad """,,,,, of 1\.
I produelion hu been $Uucw;<I .
Normal blood plasma contain! stveral lipidlthat may
oct",e IS pb)'$ioloaicII inbibilOt$. One compon<nt '1'I:ot i.
(or reoc:mblCl) pbofpllali<ll'loctrillC .. quir .. 1<1;""ior! by
phosphdipaK A (17).
Pbarmaeolotie.1 .,enn illdude ....., ... t phospholIpidS.
lyoopbo$pholipid. and th.ir I .. toel. peps"'in (I. til·
lyme irolated (rom mic roorpnilmll nd n.med for i, •• f.
(<<:11 on pCPlin aClivity) ( Fill. 9-10). pe pslalin aMIoi-<
(156). peplidCl roll'ed to ,eni" ,.botrale. and pejllide ....
Ilop """... i.i", .,.Ioucine (86..81.llS). R.nin an1ibodko
.'" also eff.ai ....
61"'0"'2""
His-.-"'>o-H;s-leu-leu-Vat-T ty_ Ser--lw--l-eu_ Va1-Tyr-<l--CH,
FI9.9- 10 . Soma r..an
..,.,.; ..... , ..... _ Fio. 9-9. ,
Enzyme, Re leted t o Re n in
h oreni"! nCI on the Io:lme substrates. but they d ilfer
from lhe ",rue'· .coins in ways tha t include
pH optima (159). They promote IcK:alized g(lICra.
tion of angiotensin. The: $itCS in ,,·hie h tlw:y have
been identified ;nc;lude the adrenal ,he sub-
maxillary. pituitary. and pillCa] glands. scwral pam
of the br.;n. the wall l of la rge aner;cs and yeins. the
gastrointesti na l tract and Ihe preg nan t uterus.
TOfIiftS ...... ;nitially fou nd in hilh concentrations in
rodent .. Iivlry JlttndL N"C $ince been icklltificd in
kid ... )... , plcens. '''''01. Ind olher <><P"" <:I ""'''Y mam-
mal. (159). They directly rele.", A_II fl"Qm lhe renin
subst'ato. and they abo calalyze the Ihottenin& or A-I 10
A.I I. Therefor •. tbey I"""ide meChanisms fOl"
01 A·II ,hal <10 not Iho conwrti", cn'l·me de-
scribed later.
A I...... mi.., add peptide identical "'ilk 1M oomponc:n.
of a",iotc ... illOl. n tlu.t i. cleaved by renin il oflen used
10 mUSUro ,.nin . eli. ily. PuudOl"n,;ns re leaso A· I from
,h. peplide. but thoy do ...ot oCt on .",loten,iOOSen.
These: cn>.ymCi aro not belio.. <llo be physiolo$","ny te-
la,ed to the ··true" '.ni .... C.,hep$;n P .• 1)'SQIOOU1.n-
zyme. rnay be Ihe ma;or pselLdoronin found in tts.1>CS.
Speclea Dltlerence,
Human rcnins contain Il1O!'C polar amioo acids than
tile onzymes or atlM:. mammal. t ha I have been stud-
ied thus f. r ( 155). They cleave as ,,'Cn as
(_sol_
Leu·Leu bonds, and can gcnerate A.J from human
reni n substrate. They also act on the substrates from
other .pecics. In cont rast . the other known renin.
cleave only Le u·Leu bonds. and thcy are inelTective
when incubated with human sub$trate (1 g2).
PLASMA RENIN ACTIVITY (PRA )
Usually. plasma renin ac tivity. rather than enzyme
concentration. is measured: When pla<ma is ta ken
from normal human subje<:ts, 100-
gOO ng of angiotensin 1 is gcnerated during a 3-hour
incubation carried OUI undcr standardized condi_
tions. The PRA is higher in the morning than at
night (and a cessation of renin release coinciding
with the onset of REM sleep has ocen obsen·ed
[146]). The mean values aT"<: also higher in individ_
uals ingesting Iow-salt diets.
PRA is obviously relaled 10 faclOfS other Ihan
renin concenlralions. The enzyme :substrale ralios in
blood plasma are in ranges Ihat permit elevation of
the PRA ,,·hen either Ihe sU!>slrate or Ihe enzyme
levcls arc increased. Bolh factors con vary under
physiological cond itions. Exercise evidently leads
mastly to a""derated ren in release. whereas the
higher P RA associated with the luteal phases of
human ovarian cycles. wilh pregnancy (159). and
in SOme women taking oral contraceptives. involves
the production of la!'icr amounts of substrate (g9).
Ano1her parameler. pl.sma renin (PRR) ;,
"mea,u,. of tbe role ofangiotcnsin gener.t;"n when
Qg<'ll(ms renin i, added 10 plasm'. Ek •• I;on of Ih. PRR
in palienlS wilh ehronic renal failure h.. been anribuled
10 deficiency of a lipid pre..,nl in nQrmat blood 'ha' in·
hibi" renin aClivity (t95).
Re n)n Sec retion
Many kinds of ,t imu li affecI the .Iec,.,./ion of reni n
into the blood,tream (21.114.11 7). The mechansms
dilTcr from those alfceting Itxaliud of Ihe
en1.yme within the kidney (42).
BARORECEPTQ R$
The JG (granular) cells within the afferent
of the glomeruli arc believed to tonic.
lory control over renin secretion. They are aCli valed
,,'hen they are sl\'Ctched. Elevation of the sySlemic
blood pressure. expansion of the ECF. and physi()-
logical as well as agents that dilale
the renal arteries, can all accelerate blood fiow 10 tbe
afferent arterioles of Ihc glomeruli, widen Ihe ,·e ..",1
diamelers. and thereby inlensify inhibilion. Pa·
paverine is sometimes used to inhihit renin secrelion.
It is a vasodilator. but it add itionally acts in other
ways.
Renin secretion ca n be increased with afferent ar-
teriole vasoconstrictiors, and with age nts that lower
the systemic blood pressu re sufficie nt ly to impair
renal blood flow. h is also augmented when diet-
ary deficiencies. heavy sweating. hemorrhage . or
othcr conditions lead 10 reduction of the ECF
volume.
Widcly used techn iques for accelerating renin se·
eretion in laboratory animals include clamping of
the abdominal aona above the kidney and clamping
of Ihe renal arteries . It is now recognized that the
effects are achieved by the conseq uent fait in afferent
a rteriolar pressure. A previously held belief Ihatthe
techniques a rc effcc tive because Ihey invoke hypoxia
has ocen discarded . All hough long-tum oxygen dep-
rivalion ultimalely leads to chronic elevation of Ihe
plasma renin 1e,"<:ls. acute hypoxia does not obviously
affect renin secretion when measures arC laken to
maintain adequate pressure within thc alTerent ar·
le rioles (142).
FUNCTIONS OF THE MACULA DENSA
There is universal agreement that the macula densa
( MD) cells play role< in the supppress;on of renin
secr<:lion when the ECF contains large quantities of
NaCI. They perform such funclions cven when the
pressure within alferent arterioles is maintained
"I con"""t ""lue
Cytological studies support the concept that MD
cells ma ke funClional conncct;""s wilh the gl""Jnular
JG componenlS via cytoplasmic projcctions and
plasma membrane speciali'.lllions that permit direCI
eleclrochemical comm unication. MD cells probably
also exert mechanical influences on Ihe JG cells
when they undergo osmolie s","<:lIing Or shri nking.
There are contro"e rsies 0'''' the nature of the sig·
nals perceived by macu la densa ce lls. T he adminis-
tration of large quantite., of saline leads (0 all of Ihe
following: (a) Ihe glomerular filtral ion rate (G FR )
increases; (b) a larger volume of lubular Auid is
made: (c) Ihe Aui d Aows more rapi d ly. and it pre-
senlS Ihe M D cells with Na + ions and Olher filtrale
components at a faster rale: (d) since the brush bor-
der cells reahsorb a smaller fraction of Ihe filtered
solutes. the concentra tions of Na -. CI - , and other
dissolved substances the 10lal osmolality of the tu·
fluid and rise.
It is possible therefore thaI MD cell, are respond-
ing to the raleS of :-1a + presentation, the rat .. of pre-
sentation of other solu tes. and/or the changes in so-
lUie concen trations . The cells may also respond to
changes in turgor or cytosolic composition that result
from loss of water to hyperlonie e nvironmenls or
from the entry of solutes crossing Ihe plasma
membranes .
It is dintcul! \0 determine the importance of each
,..
kind of since every form or
manipulation has secondary consequences. Further
problems of interpretation arise from indications
thal sodium ion concentrations can affcct aetiva/ioil
as well as se<:rclion of renin (42), and from the cf·
fox\! of Ihe various oonditi(ms on inlrarcnal release
of Ihe enzyme. . The Henle loops actively transport
Indications that o.<molality of the tubular fluids is
imponant come from oooervalion, thaI infusions of
hypertonic solutions of glucose. mannitol, urea, and
electrolytes other than Na' or 0 - . Can all depT.",
Ihe renin secretion rale. However. Ihe infusion'S alw
affect tubular fluid flow rales. and they osmotically
draw waler from the cells.
Under physiological C<lndi lions, increases in ECF
volume and Na' concentration, and in tubular flow
rates. are almost invariably ac.:ompanied by accel-
erated mOvementS of ;OIlS. Chronic CI -
loading by infusions of solutions containing cations
such as choline also decreascs renin secretion . Chlo-
ride solutions containing Na'. K' . Or Ca". are sim-
ilarly effective, whereas ones containing those cat·
ions in combinations with other anions arc oo\.
Further indications that CI - can act directly come
from observations that thc increases in plasma renin
Furosemide
(Diural. u..,,)
Diurelics of this kind ... Iso su'pc<:tc<l of exerting di-
T«l influences on Ih. pla,m. membranes of JGA cell ..
and Ihey are said 10 promote renin activation (89) . More-
over, 01lC$ that act more distally can $<Wndarily affcol
lhe How or lubutar ftuid in Ih. MD region.
Chronic potassium loading leads to lowering of
the plasma angiotensin levels (46). while direct KCI
infusion into distal tubules suppresses renin re-
(42). Relalively high con""n trations of K ·
have been used in most of studies (amounts suf-
ficient 10 inv<lke and sc:c·
ondary changes in the cytosolic contcnt of other
ions) . Depolarizalion is generally associated with
ALDOSTERONE AND THE RENIt.LANGIOTENSm SYSTEM
activity that follow the assumption of upright poll-
ture a re greater in human subjects consuming high·
sodium. low-chloride foods than in those ingesting
high·sodium . high-chloride diets (112). (However.
varying the chloride intake has lillie influence in so-
dium-depleted subjects.)
cr .
and they
excrt this effcct on the tubular fluid before it rcaches
the MD cells. The kidneys of most mammals oontain
<;omc nehprons wi th short Henlc loops and other.<
with long ones, and the long ones extract more CI - .
Inverse relationships between the lengths of Ihe
loops and the granuation of the JG cclls have bc<:n
described for mouse nephrons (42)
FUro<Cmidc . nd cthaerynit acid are da"if,ed .. ""loop
diuretics·· lJcc,u"" tbey i""rea ... urine v<ltumc by inhib-
iting CI - ","aelion along Ihe a,ce nding ftenle loops.
The)· h.ve grcalcr off""" On renin « crelion lhan diuret-
ics .cting at olher .ilcs. The observation has been ci lcd
10 ,upport (he notion t h.. Cl i, a majOl" regulator of
renin «erelion. Ho,,·ever, Na ' ow'·ement, through the
loops lend to follow lno.e of Cl . Moreover. lhe diuret;cs
excrt olher .elioo<. They .her reMI blood IIow pallCrn,.
prom<)(e ,.. of renat vessels. and .,:<derate lhe
urinary e"erelion of K ' . Ca' · . • nd Mg' · (1 4 S).
"
O_C _ COOH
"
II •
"H
C-C-C - CH.
o '"
"
Elha<;<)'niC acid
IRCM"I3J<. Ulegil)
elevation of cytosolic Na:K ratios. Oua-
bain (a Na · / K ' ·A TPase inhibitor) also usually cI-
evates the Na: K ralio within the cells. and il. too,
depresses reni n rdease (158).
I n intact animals. polassium loading quite consis-
tently decreases renin seertion. Some of the e!feets
probably result =ndarily from the of
aldosleronc secretion and (he con:;equcnt sodium
and water retention.
High concentrations of O:lracel/u/ar Ca" can de-
press renin secretion (114). an effcct allributed by
some 10 high cytosolic Cal' per sc. and by to
secondary effects on Ca"INa' across Ihe
plasma membranes (158.198). is a concenlra-
 tion range over an inverse rc:lationship be-
tween Ca" levels and rates of rc:nin release be
demonstrated for i,olated. perfused kid ney., (64).
When calcium.free media are perfu,ed. renin re-
lease increases and thc inhibitory effects of high K ' ,
of ouabain. and of angtiotensin II and vasopressin
are blocked. Verapamil, which interferes with Ca l +
uptake by the blunts (but docs not totally abol-
ish) the inhibition by the .arne agents when extra·
cellular Cal . is present (157). All of the preceding
findings lend <upport to the hypothesis that extra'
cellular Ca l. i< a physiological inhibitor.
On the other hand. lhe physiological relevance of
observations made with isolated perfused kidneys
and with ionic concentrations that deviate markedly
from the in vivo values has been questioned (200).
Final evaluation must take inlo account (a) the p0-
tentially damaging effects of calcium·free media on
plasma membranes that can lead to nonSf'Ceific Ic'lk-
age of from the cell. (b) the fact that the
measurements made in the isolated kidney studies
a«' of renin activity (rather than concentrJtion) in
the fluids. (c) the nced for supraphysiological con-
centrations of K ' to demonstra te" consistent Ca l-
inhibition. (d) reports that release of renin by kidney
slices requires extracellular Ca l '. and (e) the nu ·
merous indications that renin release (measured by
the perfusion studies) is different from physiological
.<tcrttion of renin into the bloodstream.
In studIes on rats, It has been found lhat chronic
calcium chloride loading does not affect the PRA ac·
tivity of animals oonsuming diets with the usual
quanlit ies of sodium. athough it can suppress the
renin secretion rCSpOnses to sodium deprivation
(114) . interestingly. equivalent amounts of calcium
given in lhe form of calcium gluconate failed to in-
voke oomparable suppression. Calcium gluconatc is
also less effective than calcium chloride for reducing
lhe rate of renin release, when the salts arc perfused
diroctly into the renal arteries of dogs. There have
been reparls that calcium chloride can sl;muiale
renin secretion from denervaled kidneys of anesthe-
tized doss. Moreover. neither acute nor chronic hy_
pocalcemia has delectable effects on the PRA of hu-
mans. An additional observation dinicuh to reconcile
with the Ca l + inhibition hypothesis is the stimula-
tion of renin release in doss by parathyroid hormone
(a «'gulato' known to inc«,ase cytosolic Ca" in a
wide variety of eel! types including ones within lhc
kidney). Since both calcium loading and parathyroid
hormone signiftcanlly affect potassium metabolism .
some effects of calcium ions on renin secretion in
intact ani mals may be indirectly medialed
(114).
According to al least some observers. epinephrine
sti mulation of renin release requires extracellular
Ca2+ . fi-adrenergie agonists bring about changes
that lead 10 mOre rapid Cal. extrusion from the
cell,. One interpretalion is lhat lhe eXlrusion has the
secondary effeel of lowering the cytQ50lic Cal ' , A
problem with this inlerpr<:talon is that a different ....
quence of events has been established for most ccll
typos lhat engage in exocytosis. Slimulation and
membrane depOlarizalion lead to elevation of the cy-
tosolic Cal<. This. in turn, activate, the ca lcium
pumps. Ca" extrustion follows. Moreover. p·ago--
nists promote cAMP generation. In many cell types,
that nucleotide elevates cytosolic Ca" by releasing
the ions from intracellular sequestration sites.
Therefore, it remains to be determined whether
cell' utili7.e mechanisms for release
of the en,yme that a«' very different from those secn
in most other parts of the body (64). or whether the
indications for Ca h inhibition a«' related to the sf'C'
cial kinds of experimental conditions under ",hich
the effecls have been demonstrated,
The Importance 01 the Renallnnervalion
Although denervated kidneys can make adjustmem,
10 large changes in blood pressure. ECF
"olume. and the ionic composition of Ihe extracellu-
lar fluids, there is little doubt thaI the renal nerves
play important roIcs. Sectioning of the nerveS abol-
Ishes circadian PRi\ rhythms. and it blunlS Or abol -
ishes responses of the rcnin'angiotensin system 10
nonhypotensive hemorrhage . hypoglycemia, hy-
poxia. assumption of upright posture, cervical vagOl-
omy. cervical cooling. intracerebral administration
of angiotensin (27,123), intracerebral administra-
lion of inorganic ions. neurotransmitters. and pharo
macolosica l asents, and adminiSlration of
a wide variety of nonphysiolosical substances, Dc-
nervation also blunts the effects of experimemal ;(}-
terveotions affecting the sinuses. the aortic
and pulmonary baroreceptors. and the arterial
baroreceptors,
When lhc nerves are intact, renin secretion usu-
ally increases following stimulation of specific sitcs
within the medulla oblongata. pons. mesencephalon,
and posterior hypothalamus , It is decreased by stim-
ulation of the ante,ior hypothalamus (21).
Stimulation of the sympathelic nervous system
leads to the diseharge of adrenomedullary hormones.
In addition to direct ly affecting JG cells and renal
vaseular muse Ie. CAs can change the K' concemra·
lions of blood plasma and renal tubular fluids byaf.
fecting transport of the ions across plasma memo
branes. In many spoei.s, they invoke massive release
of erythrocytes from the spleen and lhereby elevate
hemalocrit values. When mCaSu,""s are taken to
".
avoid ele.:lrolyle and ,'olome changes. dosages of
CAs too small to directly aife<:t the JG cells and af-
ferent arterioles accelerate renin secretion. It has
been proposed thai they aCI on extrarenal re<:CplOrs
10 stimulate lhc release: of other mediators, Re-
sponses of this kind 3rC 001 blocked by
lomy or the administration of PG synthesis inhibi·
10rs (103) .
When connections bet ..,•• n the renal nerveS and
Olher P"'(l; of Ihc nervOllS system are severed. elec-
trical stimulation of Ihe cut ends of Ih. nerve, ac-
celerales 1'<'o;n seCN:tion. Three mechanism' have
been suggesled (171):
!. Activation of JG cen /'I-adrenergic receplOrs
and generation of cAMP, (Such clTe<;\S arc mim-
icked with cAMP analogs and thcy can be blocked
with P. but 00\ a, receptor antagonists.)
2. C<>nslricl;on of (hc affcren( ar(erioles. with con-
sequen( lifting of (he wni, inhibitory influcnces oth-
erwise exertcd by the stretch receptors. (",-type ad-
renergic reccptors arc implicatcd hcre: e_idently.
they are ana.wmical\y associatcd with ncrvc tcrmi-
nals different from the ones that go (0 the It-type re-
ceptors [S?].)
3. Depression of the GFR. with consequent slow-
ing of the delivery of ions to thc luminal .urfaces of
MD cells. (This elTeel woold he: w asSume
speCial imporlance when Ihe brush border cells ,e-
roove high ..."cemages of Ihe filtered Na - .J
The receplor Iypes arc nol easily defined (93).
Species varialions are encoumered. Moreover, each
of the pharmacological agents acts at ur.onspecif,c"
sitcs. For erample, some of the elTeels of propranolol
on cell membranes are unrelated 10 It·receptor block.
ing potency.
In humans, dogs. and rats, p, recept<m may he:
directly involved in stimulation of renin se<;retion.
whereas fj, Iypes seem to be more importanl in con-
scious rabbilS and in cal$ (2(0). Somc
central effeCls have been lin ked wilh presynaplic
sites (95) and with a, =eptors.
Serotonin and tryplophan (its precursor) act «n-
trally to eleva le plasma renin activity (142). The ef-
fects may be related 10 roles in the maimenance of
circadian PRA rhYlhms. (Serotonin does 1101 stimu ·
late when it is injecled into renal arteries.)
Not all neumtransminer actiom; can be linked
with Ihe renin-angiOlen,in system. and oot all arc af-
fected by A·I[ receplOr antagonists {SI). Unilaleral
renal is comroonly followed by acceler-
aled water and iiOdium excretion (but decreased
chloride excretion) on the affected side . ·'Dener_a_
lion diuresis and nre allribUled 10 ,,-{Od-
re ncrgic =eptor mediated inAuen«s on Ihe proxi-
mal conV<,lluted lubules.
ANO THE RENIN·ANGIOTENSIN SYSTEM
Effect s of Hormones
Since are released from the adrenal medulla.
certain of their actions arc properly cla..ified as
hormonal.
Angiotensin-II bel ieved to participate in phys-
iological ncgative feedbac k control of renin secre-
tion. Some observers believe that the peplide acts di·
rectly on the JGA (65), since it i. effeclive whcn
presenled directly 10 the kidney. Howe ve r, A-II
stimulates the secrelion of antidiuretic
(ADH). Exogeoous ADH lowers plasma renin and
A-I I ooncentrat;on$ in ;nlacl animals. Homozygous
Bralliebom rats cannol ma ke AOH. and they lack
ncurohypophysial A-II receptors. They have high
renin and A-II levels.
ADH i, a lso implicated as a regulator of angio-
tensin converting The activity;s very high
in the neurohypophysis (but oot at other sites) in
Brallicboro rals (35) .
AD H additionally interacls with A_ II in Olher
W3)"1 . A- II is a potent dirsogen . II can therefore in-
directly expand Ihe ECF volume by stimulating an-
imals to drink. AOH increases wa ler retention. and
il can in this way Ihe d ipsogenic effecIS. The
actions of A- li on both Ihe adrenal cortex and kid-
ney facilitale Na ' relention. whereas ADH some-
limes Invokes m,ld hyponalremla. !'GEs antagonize
ADH actions on Ihe kidney, and angiotensins pro-
mOle PG generalion. Although some investigators
are less convinced than others of the magnitude and
physiological importance of the observations ([00),
AD]·I as well as A_JJ arc released in larger quanti ties
when animals are stressed.
Prostaglandins of Ihe E I)"(lCS. prostacydins, and
thromboxanes_ have been observed 10 increase renin
se<;retion both in vivo and in vim). [n common w;th
CAs. the PG Es promote cAMP generalion in many
cell types. and the nucle<ltide may be a mediator.
However. thc effects can be demonstrated in Ihe
presence of adrcnergic blocking agent •. PGs also af-
feCI urinary excretion of Na' and water. bUI at least
some elTects On renin secrelion do nol depend upon
Ihe sodium balance of the subjects (63 .1 14). Indo-
melhacin a nd eenain other PG synlhesi< inhibitors
depress bolh basal renin secrelion ralc.! and the re-
'Ix>nses 10 >limuli such SQlHum depiction and
heroorrhagc.
Growrh hormone (Gil) is a prorosed slimulant of
renin secretion (105). Observations thaI humans se-
creling too much Gil tend to relain salt nnd .... aler
and to have high systemic blood pressure . and that
exogenous G H reSlores Ihe suboormal ren;n levels in
hypophysectomized miS. are consiSlent with Ihis no-
lion . On the olher hand. physiological roles for GH
f'",u", ,. of "oio =",1""
V..oco",,,k,;"" of ",.,1 .rr".", '''oriol<1
D«",.S«I doli,..,..,. of blood '0 ,II< orr«tnt ."oriole>
S«hum dopl<l;""
COl",".';"" of ,II< . ,"o«lIul.. n... voIu_
Stim.la'ion of the " ... ) "",oe<
S,imuloti"" of ..., ,,,,," of 'ho mod.lI. obloo,at., pon$. midb ..i., POO'"io< hypoth.lomu,
C...d,ol.mi ... octi., "" lI.. d",,,,,ic ""!'Ion
POI'.<. POI •• ",d ,hrornbo"lI<>
Seroton;n .c';n, .. ""lIy
Gluc.go"
Grow,h lY.>tmoo<
",,.,h)'mid "",100II<

fO(",,,,, ''''plicaud I. of "iii. ,«,,11011

I""", ..ed di.motcrS or .ffercn' "tC"""
"'pan'ion of c,,, ... II.I., nuid ""."'"
Hilh ,,,,,,cell.l., K '
/lntioto",in II
/IOU
Somal.,.,.,i.
Hith """",n',,'ions of CI
Hiih <",.cell.l.. N. '
Soma,.,.,",in
",,,,«lIul., c."
(.1", i.,pilcored b)' some in inh itM'ion)
fllc"", l",pI/NlI'" i. ,.him""" "f ,"n'
Pho<p!>oli IY"'I'l\o;»pllolipid,
GI)'C<)pt<I,.in cleaved rrom "'nin ,.1»,,.,,
FaclOl"' io .1."",,0'1 of pi",,,,. ".i. ,.Im' au
G I.""""",;coi<ls
E""",c"'
"""<"<>tI cn •
II
In",lin
s.,-". kid",,), di ..."

have been qucslion.d (171 ). G1-I nol raise lhe
renin levels of inlaCt ralS. and the PRA is not con·
sistently cleyatcd in patients wilh acromegaly, Ad·
ditional proposed hormonal regulators include 5{)-
marosralin (which inhibits GH secretion) (114). and
g/uragon. which promotes cAMP generation in
many ceil types.
REN IN S UBSTRATE S
The circulating renin subslrates "re synthesi1.cd in
and rcleasc:d from hepatocytes. They arc known
under a variety of appellalions. includi ng angiOlen'
and preangiotensins. (Hyperlensinogen.
prehypertcnsin. and preangiolonin arc older names
thai arc now seldom usoo.) All arC species·specific
glycoprotein. lhat vary in glucosamine. s.alie acid.
and hexose conlent (159). Most at"(; <,<,globulins. but
lhose of a few 'pecies migrate with Ihe
lIuman forms with molecular ""'ights of 66,000-
100.000 share physicochemical wilh
57.QOO.dalton glycoproleins obtaincd from hogs.
The renins of most mammals act On subst rates
madc by others. bUI the catalytic potencies arc usu-
ally greatest when the entyme and subslrate come
from lhe same species. Human angiolcnsinogens
have unique N-lcrminal amino acid sequences
(182). and lhey arc effectively cleavoo only by
human reni ns.
Undcr in vilro condilions, trypsin rcleascs tetra·
decapc:ptides from human and other angiotcnsino-
gens. These serve as g<X:>d Substrales for all of the
mammalian enzymes. and also for the pscudore-
nins described earlier (Fig, 9-9). The reaction is not
physiologically relevanl. but the peptide widely
used in renin assays. There are species variations ;n
A-I amino acid sequences. For example. bovine mol.
ecules haye a valine at position 5. Howev.:r. all
mammalian angiotensins are metabolized along
idemical pathways. and all have similar biological
potencies.
".
Reg ulati on of Pl asma Renin Substret e
Co nce ntrations
Since the Ii"", produces the circulating renin sub-
statc. it is !IO! surprising that the level. arc low in
patients with severe hepatic diseases. and in animals
subjected to paniul hcpa1e<:\omy. The conccnlra-
1;{lnS rise aflcr nephrectomy for several rcasons. The
k;d'lq.< Ish up a nd degrade the gi}'coprolcins. and
they ,elea$< renin. It has also ocen thaI a
faClor accumulates in the blood of nephrcc\omil,cd
animals thaI act. on liver slices to accclcrJlc aog;·
olensincgen production (171).
Glucororliroids and esrroge1!s .timulatc the p""
duction of several plasma proleins. and the effecls on
angiatensioogcn can be demonstrated both in viV<)
and in vitro. Stress leads \0 the release of glucocor-
ticoids, and ;1 raises the circulating substra te con-
centmtiolt5. Since nephrectomy is a form of severe
wess. the steroids probably acoount for some of thc
elevations seon in animals subjected to such proce-
du1"<'s (171). The glycoprotein concentrations risc
during p1"<'gnancy and in women taking oral contra·
ceptives. Jn conditions. high PRA is attributcd
to accelerated production of the substrate. The low
angiOtcnsinogen levels of hypophysectomized ani-
mals arc attributed mostly to ACTH and gonadotro-
pin deprivat ion. but GH deficiency. nutritional sta·
tus. and generalized depression of protein synthesis
contribUle.
When presented in high oonecntrations. A-IJ ac·
celerates angiotensioogen production. It has been
proposed that the peptide engages in positive feed·
back control that protects against substrate deple-
tion when renin secretion is augmcn tcd . A· II a lso
promOtes ACTH release. and it can stimulate glu·
cocorticoid secretion directly (at least in cattle).
Moreov<:r. glucocorticoid. play permissive roles that
support A-JI effects On the liver. However. A·(I
stimulation of angiotensinogen production can be
demonstrated when glucocorticoid concentrations do
fIO\ rise above basal levels (16g).
The importance of A- II positive feedback has
been questioned. Salt deprivation accelera tes renin
secretion and it elevates the plasma A·II. but under
those conditions A-II does not correct the substrate
depiction (91).
Insulin nerts numerOuS 1"<'gulatol)' influences on
hepatic protein production. A role in maintaining the
secretion of renin substrate is oonsistent with obser·
vations that the levels are low in patients with inad·
equately controlled diabetes mellitus (148). Gluca·
gon is released under some conditions associated
with stimulation of renin-angiotensin system. but
it d<:l<'s not to have significant effects on thc
substrate levels.
... LDOSTERONE AND THE R£NIN· ... NGIOTENSIN SYSTEM
BIO SYNTH ESIS AND METABOLISM OF THE
ANGIOTEN SIN S
Mosl of the ci rculating A·I is formed directly within
the bloodstream. Allhough the l(}.amino-acid pcp-
tide Can exert some direct actions. it is usually VOl)'
ra pidly converted to A-II (an octapeptide).
Converting Enzymes
Angiotensin converting entymes (ACEs) arc memo
brane-bound. 7.inc<ontaining peptidyl dipeptide hy·
drolases that cleave substrates with free earboxyl
groups. They promote the conversion of A·I to A·II.
of des·asp-A·r to A·111. and of kinins (d=rib.:d
la ter) to biologically inactive peptidcs. Their ability
to degrade the B chain of insulin (95) is of some in·
le1"<'st because of known interactions between insulin
and the bradykinins. Enkcphalin is another of Ihe bi·
ological substrates (53).
At least three different fC)fms of the enzyme arc
fou nd in the lungs (39). One is a glycoprotein ",'ith
a molecular weight of 129.000. II has been estimaled
that 40% of the A-I that cnters the pulmonary cir·
cuit is cleaved to A-II in a single passage.
Converting enzymes at other sitcs have molecubr
weights that range up to 480.000. High activities arc
pre"""t at lite LI u,1t of lite ""nyu-
tubules. and within vascular epithelium. Can·
verting is also found in the blood plasma. the
liver. the heart. the brain. and the uterus.
Several factors (including ADH) afTect the aet iv·
ilies of the en7.ymes. However. the ACE COIlcent·
rations are usually so great (relative to tbose of
substrate) thai the rates of A·J I produclion
do not generally parallcl the changes in activity.
Chloride ions are essen tial. and sodium ions may
contribute.
CONVERTING ENZYM E INHIBITORS
All of the physiological substrates mentionc.:l above
can compete with A·I for the catalytic site of the
ACE . There has been strong interest in the devel·
opment of more potent and highl y specific agents
for the trcatment of patients with "high renin
hypertension."
The first agents found useful as laboratory tools
were obtained from snake Vel10mS (1 28.153). Some
have been synthesi7.ed. and tcprotide (SQ 20881) is
probably the best known oflhe group. Deliberate at ·
tempts to find better agents suitable for administra-
tion to patients have led to the development of cap-
topril (which is effective when taken orall)') and to
some chemically related substances (7).
 I'-;,o-G"'· T,p-P,o-... rg.Pr<>-G .... -lIe· Pro-Pro
SO 2()6Il1
(Te-proM... "BPP-..)
Pharmaoological effects oonsistent with ACE in_
hibition include lessening of peripheral resistance
(with lillie Or no change in cardiac output), and
depression of the plasma A-II and aldosterone levels.
PRA usually rises. Thi. is allribUled to «,flex stim_
ulation of the sympathetic system and lowering of
circulating A-I! . with consequent acceleration of
renin secretion.
Th. amihypertonsive actions im'olve additional
mechanisms (7). Captopril affects I"<'nal blood now
and distribu tion, and it ScemS to blunt pressor re-
sponses to CAs. ADH is a vasoconstrictor_ and its
secretion is inhibitcd. This may be an indirect effect
of A-II depletion. usually develops
hocause of the low aldosterone IC""h. and it oontrib-
utes to the vasodilation . Influences on the kallikrein_
kinin system, and on PG production, vary "'i th the
oondition. under which lhe agent is presented_
Captopril exaggerates th irst and salt appetite.
This has hocn allributed to lhe effects on ADH se-
cretion. However. in rats unable to make ADIl.
ACE inhibitors orten dec«'ase drinkil\i.
Inte resti ngly, captopril can accolerale both the
biosynthesis and release of t he converting en>.ymc at
the very time when it is therapeutically cffeclive
(70). It doc:s not completely block A·J1 produ ction,
si nce toni n. directly cleave the peptide from reni n
substrate.
AMINOPEPTIDASES
These cnzymcs cleave the bond between aspa ragine
and arginine at positions I and 2. They thereby pro-
mote the conversion of A-II to a heptapcptidc. des-
asp-A·H. The product of the «'action is also known
as angiotensin !II (A· ll l). The same enzymes
shorten A·I to a oonapcptide. des-asp-A·l. Convert-
ing enzyme can then catalyze the formation of A-Il l
from Ihe nonapcptide. Removal of the asparagine
renders all of Ihe molecules more suseeptible to a t_
tack by the angiolensinases.
ANGIOTENSINASES
This term is applied to any of the ubiquitous en-
1.ymes (amiooPCPlidases. carboxypeptidases. endo-
peptidases. and dipeptidylaminopeptidases) that cat·
alyze degradation of A·I and its biologically active
prodUcts. High concentrations of sodium ions tend to
H eli,
H H II
o
so 14225
(Gaptc>p<il)
increase the Special ternt$ have been uti.
li7.cd to designate enzymes that act on specific bonds.
(For example. angiotensinase C is a proly1carboxy-
peptidase (154) identified in leu kOC)'tes. kidney. and
elsewhe«,.) All aCt on a wide variety of peptides that
include components of lhe kinin sysle m. and some
angiotensin receptor antagonists_
Angioten sin Receptor Antagon ists
Some A-I I analogs compete with the hormone for
«,coptor sites, and they can therefore be used to treat
patients making excessive amounts of angiotensins.
The best known of the group is saralasin. I t derives
its namc from the replacement orthe first two amino
acid moieties with sarcosine and alanine:
Sar-Ala-Val-Tyr-Val·His·PrO-Ala
Other analogs with diffcrent substitutions (e.g .•
lsar'.ile·-A- II]) have also been tested (1 52 ). The
agenls can lower the blood pressore of ind ividuals
with high "·1 1 levels and c.ln also inhibit aldosterone
secretion under sud oonditions. However. thcy arc
partial "- II agonists as weI! (46) . They can raise the
s)'Stcmic blood pressure by stimulating the sympa·
thetic s)'Stcm. and by acting directly on vaseular
smooth muselc-cven when A·l1 levels are low.
Moroovcr. they have been known to stimulate aldo-
sterone secretion when NaCl ·rich diets inhibit A-II
production .
Sa ralasin a ntagonizes some effects of A·I I I. but a
hcptapeptide. [lle'1·,,·Il!. is more potent.
ANGIOTENSIN REG ULATION OF
ALDOSTERONE SECRETION
Direct stim ulation of >.ona glomerulosa cells by A- II
has been demonstrated in whole anima ls. in isolated
perfused adrenal glands, in tissue slices. a nd in cul-
tured dispersed cells. A· I has simi la r actions. bu t
these are blocked by converting enzyme inhibitors.
A· III is found in 'he adrenat """"'. 'he kidney, ud
blood plasm •. It ha. been reported to be .. potent as A·
t I for stimutation of . terQidogellCsi. in mQ$I .p<:Cics (in.
cluding healthy . •• It-reple te dogs .1Id rats). and it eon
.Iw effectivety inhibit renin secretion. Early .uggcstio",
that A·II mu,t be con""rted to A·1l 1 before it can aet ""
the ad",nal corte, have fIOt been ,uinto"1iated (1.124.
ISS). The heptapeptide i. more .... pidly deg,aded than A·

II by rat adrenal gland, (138). and it i, less
"imulant (If .dren.1 gland, <>f dogs thaI have been
nephrectomized or . ubjecled 10 chronic angioten,in injec-
tion in C<,lmbination with .. It dopletion (1ll). On Ihe
other hand. dose, of A·III that promote aldosterone ""
crelion have negligible influone .. on syslemic blood pre,'
.ure. whereu comparable augmenlation of "e roidogen.
e,i, with A·JI i, associated with marked stimulalion of
vasc"lor ,moolh muscle. Thorefo'e, it i. that A·
III play. 'pecial role, unde, <XIndilion. in which .alt re--
tention butllOt vuocon",iClion i. cequiTO<!. A· 11I i. evi·
dently a more potent stimulant ofCA biosynthe.i,. bUI il
blunts some A-II effccts On the .ympathetic ne'l'¢U' 'Y$-
tern (Ill).
The nonapeplide formed b), removal of the N·ltrminal
asparagine ha. thus far exhibited only ver), "'eak A_Jl_
like act ivity. Ahhough ;t can serve as a precursor of A·
II. doubl ha. been up'e$<cd that il f"nction, .. a phy$-
iological re,ulotor (11)) , Some A-I J!·lik. activity ha,
been ,eponed for an octapeptide obtaincd by removal of
both the N·telmina! Asp and the Alg thaI fGllow> (29).
ft is likely thai differenlial function. of the members of
thi' family of peptide. will be bener appreciated when
more u.e ha, been made of higbly .pe;oific antagonist'
(128). At prosentlim., ilseems reason.blelo believe
lhat A·I I is Ihe major hormo"". and that tbe oth.rs may
p<rform special functions when ' t;m"lotion al
""me . itcs (withoul generalized activation of a/l angio-
ten.in ,eceptors) i. phy.iGlOSically app,opriato,
A-II inleracIS will! other regula lOrs 10 control al-
dosterone secretion , It exem additional influencos on
water and declrolyte balance outside the adrenal
gland (see next section). Zona fasciculata cells do
not respond directy 10 th. P<'ptidc. There are condi-
tions under which they conlribute to aldooterone pro-
duction. since they synthesi7.e cort icosterone (an al_
dosterone precursor).
Effects of A-I! on the Adrenal Co rtex
The rateS of conversion of cholesterol to pregneno-
lone and of corticosterone to aldostero.. are accel -
erated witbin minutes (23). A pathway kading from
DOC to aldosterone may additionally be alTected. at
Icut in rats (2).
StimulatiQrt of protein synthesis can be detected
within half an hour, and a pea k is allstned in 90
minutes. There is evidence for accelerated produc-
tion of one or more proteins alTecting
sid""hain cleavage (159) . All of these effects are
blocked with prolein .ymhesis inhibitors but not
with aCtinomycin D.
INTERACTIONS WITH K' AND Na '
Moderately high concentrations of e xt racellular K'
similarly accelerate conversiQrt of pregnenolone and
ALDOSTERONE ANO THE RENIN-ANGIOTENSIN SYSTEM
cortioosterone to aldosterone. The actions of sub-
muimal dosages of the two rcgulators are additive,
bUI neither can further augment the steroidogenic ef_
fects of maximal amounts of the other (69). Ouabain
lowers intracellular K ' and it dccreases aldosterone
production. These and certain othcr observations are
consistent with the conc.:pt that A- II acts via eleva·
lion of the cytosol K ' (55).
However, very high extracellular K ° decreases
Ihe rate of cort icosterone conversion to aldosterone.
although it acc.:lerates side-chain cleavagc (136) .
Chronic elevation of the extracellular K ' lessens the
affinity of Ihe rec.:ptors for A-I! and it thereby di·
minishes the sensitivity of the zona glomerulosa cells
to low Icvels of the peptide. On Ihe other hand,
chronic hyperkalemia leads to the formation of
larger numbers of A·II receptors. and il thereby en·
hances responses to high doses of A·II (46). Potas·
sium ions additionally increase the effecliveness of
ACTH.
High ooncentrations of extracellular Na o act at
&omc sites late in the steroidogenic patbway to de·
aldosterone release (24). They 31&0 exert long·
range inhibitory influences On the sy nthesis of A·I!
receptors without affecling receptor aftinities (46).
At kast &Orne ofth. changes in sodium balancc exert
A-If independent influences on aldQ<teronc
",;to",';"",.
RELATIONSHIPS TO cAMP
Neither A-II nOr K' stimulation is mediated via
cAM P. In fact. A-I [ increases phosphooicslcrase aC-
tivity (55). These regulators do not block the effects
of ACTII . .. rotonin. and other hormones that aCI
via cAMP. A·I I augments guanylate eyela.. ac tivity
in aorta , heart, and kidney. and cGMP has been im·
plicated in the growth-promoting effects in
COrtex and in actions 0[ the peptide on Ihe kidney
tubules (203). (Some reports that A- II elevates
cAMP have been criticil.cd becau.. Ibe dosages of
the peptides were several orders of magnitude
greater Ihan the physiologiealleveis.)
ROLES OF CALCIUM IONS
Extracellular Ca" is nceded to maintain basallevels
0[ aldosteronc secret ion , Both K' and A·lI acceler-
a te Ca" uptake, Their steroidogenic inAuenecs can
bc mimicked to some e.tent with Ihe calcium iono.
phore A23187 (54). and they are blunted by moth-
oxyverapamil (a calcium channel blocker) (55.62) .
(A·lI has also been shown to exert calcium-<Jepen.
dent influenc.:s on smOOth muscle and liver [73 J,)
However. the maximal effects attainabic wilh
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and that at least $Orne of the innuenc:esof ciCClrolyle
imbalances on secrelion are acoom-
plishW by Iowerins the DA levels. Neilher S<lralnsin
nor direcled againsl ,' -II block Ihe re·
Spol'les 10 f.lIlt deplelion.
MClodopramKk (a DA anlapisl) invokes
prompt elevalions of plasma aldoslerone wilhoul
cha1li;1Ii Ihe $\eroid clearance rales in humans.
monkeys. sheep. and rats (119). 11 tIoesso in dosages
Ihal do not a lfCCI blood pressure. n:nln se<:relion. or
elearol)1e This agent a lso raises 18-0H <;Of.
liooslerono: ooncenlnllion$. bUI IIIcte are /10 associ-
lied changcs in corticosterone. cortisol. DOC. or IS·
OH-oortiooslerone. AItOOugh il p' .... ,IOICS PRL se-
crelion. Ihe innuenttS on do /101
on Ihis. On Ihe <Mller hand. meloclopramide can acl
as a pa"ial DA agonisl in vilro.
Bromocriplinc. a DA anlagonisl. tippOICI Ike ac-
lions of melociopramide bul il does not alter Ihe
basal niles of aldoslerone secrelion. In humans. il
aclS vi, mechanisms indepeooenl of Ihe renin-angio-
tensin syslem 10 bl unl Ihe slimulalory effects of peG-
tural changcs and of diurelics. pc$Sibly by decreas-
ins CA secn:lion (192).
The kidney avidly laKes up endogenous DA and
its r<:ceplor agcmisls a nd and Ihe urinary
DA ConCCn1T1dion< .ooium in.
creascs (30). Innuences of dopamine on renal blood
lkiw were discussed in Chapler 8.
Serotonin
Scrolonin activale! adenyllle cyclase in zona glom-
erulosa (bul not lOna fuciculala) cells ( 147). It ev·
idenlly increases sleroid08cnes i$ via mechanisms dif·
ferenl from lhose au ribuled 10 A· II. Serotonin also
atlS cenlrally 10 affea renin releue ( 142). and il
promotcs se<:relion. Roles in A:gulalion of
the cl1Q.dian PRA rhythms have: proposcd.
Growth Hormone
GH may be more imponanl for I"ooolOlin& growlh
of adrenocoxtical cells aoo for SlruC-
lural inleg:rily lhan for stimullllingllormoo'loc produc-
lion. some limiled onerc-litcs in aldO$lerone
and in renin secrelion Ita... been otIsctved. Piluitary
somalOlr0pc:5 have aldosterone rcccl"ors implicaled
in resulation of GH 5CCf<lion (116) .
Somatottatln
Although it is the major inhibilor of G i l secretion.
$OIl131os131in suppression of aldosterone sccretion
ALOOSTERONE ANO THE RENIN·.t.NQ!()TEN S'N SVSTEM
docs 0101 seem 10 depend on th is action. 7..ona glom-
erulosa cells have $Omat(l$talin receplors. aoo the
peptide decreases Ihe respomc:s 10 A·r r (4).
Me tenkephalln
Enkepha lins aCI cenlrally to inhibll ACT. I n:lea.sc.
They compete wilh A- I u a substrale for convert in,
enzyme. and Ihey may also act directly on lhe:_
slomerulosa. Concenlralions of m<:lenkephalin a$
low as to- 11 M dircclly inhibit aldos",ronc. DOC.
and cortiOOSleloliC from human tumor cells.
and dooe-depcndent rc:spomcs .... ve: been obiained
wilh higher concentrations ( 164).
ANGIOTENSIN INFLUENCES ON THE
CARDIOVASCULAR S YSTEM
The direa effeels of angiotcnsins on vascutar smoolh
muscle arC as imporlanl as lheir inHucnccs 00 lhe
adrenal cortex (159). A. single large do5c of A· II ad-
minislered inlravenously transiently elevales both
sys lolic and diastol ic blood pressures. Conlinuous in-
fusions of Ihe peplide cao sustain the hyperlension
for hours. but lachyphylaxi s develops wilh chrooie
trealmenl.
Although Ihe vasoconstrictor polency of A· II is 40
limes Ihal of an cquimolecular do5c of
rine. i\ is also selective. The mesenteric and cUla·
neous ve:ssels 3rc highly sensilive:. lllosc of Ihe "",I·
monary bed ar<: rc:sistant. and effecls on skek:lal
muscle vary wilh Ihe CA Cerebrnl blood flow
is usually diminished. Coronary vessels diiOlt for
seve:ral reasons thaI include the localized release of
PG s. The renal vessels also dilale when angiotensins
prOmOle PG release in II.. kidney. but effeclS on the
kidney Ire more dfcclively oppascd by sYSlemic
Illan by inlra-renal administration of converting Cit-
zyme inhibitors (21)).
Interactlona w ith Sodium lona
In conU'aSl wilh their inHuenccs on Ike >(IN. ,lomeI"
uba. high exlracellular 1'o.'a ' c;onCCntrations en-
hance A-II "imulalion of vucular ! on(l(lIh mU$(:1c.
The acute responses have: been linked with clfcets (WI
cytosolic Cal<. and on PG met.boIism. C hron ic hy·
pemalremia lends 10 increuc !Ii<: numbers of A.l1
receplors in Ihe blood = I ...al" (altOOugh il\owers
lhem in the adrenal COrtex). Repealed injections of
aldOSlerOIl(! invoke sim ilar mpo<lSCS. whcr<:as salt
depletion brings abou t changes thaI arc oppOSile in
direclion.
AngliOI"nsin II docs no! affect Ihe numbers of ils
Own receptors . However. chronically administered
peptide increases re<:eptor ajJinitieJ in the blood ves-
sels as it lowers them in the adrenal cortex (47).
Effects of A-I and A-Ill
A-I has only weak dTects on most of the blood ves-
sels that respond to A-II. However. there may be
unique A- I receptors in the kid ney. The decapeptide
se lectively decreases blood flow to the inner Corlex
and medulla. whereas_A- II usually decreases flow to
the OUler «Irlex but unpredictable influences on
medullary vessels (10). Doses of A_I II that substan-
tially augment aldosterone secretion are almost de-
void of vasoconstrictor potency.
Effects on Ceplllaries end on the Heart
A- II usually increases capillary permeability. prob-
ably I:>ceause of both PG generation and the elfC<:ts
on thc arterioles.
The heart sc<:ms to have specific receptors. In-
creased contractile force can be demonstrated for
isolated atria and papillary muscles as well as in
vivo. even in the presence of j':I-'Jdrcncrgie reccptor
inhibitors. Chronic increases ventricular
mass via mechanisms dependent on new DNA.
RNA. and protein synthesis. These influences may
he relaled to elevation o( cGMP 1" "..,ls (203). In in_
tact animals. A-][ stimulated re lease of catechol-
amines contributes substantially to the rcsponses.
Usually. cardiac output docs not increase because
reflex bradycardia is invoked .
DIRECT INFUENCES OF ANGIOTENSINS ON
THE KIDNEY
Systemic infusion of moderate amounts of A- II de-
CreaseS sodium excretion (110.114). Studies of the
effects on renal blood pressure and flow (22). and
others involving perfusion of rena l iUbules. are oon-
siSlent with a vaseular action that leads to more ef-
ficient proximal tubu lar reabsorption of the ions
(21). Roles in maintaining sodium balance during
dehydration nave been propo:sed (215). Observations
that very high doses can act on more parts of
the nephron to inVOke natriuresis {I 10) are probably
!lOI physiologically relevant.
AutoregulatIon with In the Kidney
Single nephrons engage in localized hemodynamic
adjustments termed lubuloglomerular i«dba(k. An
increased rate of deli very of urinary fluid to the dis-
talmbule is promptly countered by reduction in the
rates of blood flow and glomerular filtration within
the ",me nephron . 11 is often possible \0 demonstrate
seoondary changes in 1\'a ' lransport. but vascular ef-
fects can be elicited without modifications of reab-
sorption rates. The mechanisms involved in the auto-
regulation may differ from those invoked in response
10 variations in plasma and inteMitial fluid volume
and ion content (210).
Acrording to one concept. rapid presentation of
water and ions to the macula den", region faci litates
MD cell uptake of ions and osmotic swelling. Pres-
sure is thcreby on the neighboring granular
JG cells. and renin is released within the immediate
vicinity . Angiotensin II is then generated. a nd the
peptide oonstriction of the alTerent arteri-
ole of the affceted nephron.
Observations with this scheme include
the presence of both renin substrate and «Inverting
enzyme within the kidney. the vasoconstrictor pe-
tency of A-I I. and the blunting of tubulogtomerular
(eedback following ",It loading. mineralocorticoid
administration. and the administration of ACE in-
hibitors (162). (&tit loading and exogeTlOus aldasH'-
rone both lower kidney renin content.)
A major problem with the hypothesis is that it re-
quires accelerated (localized) renin ",lease when
more water and ions impinge On the MD. This may
be difficult \0 reconcile with the knowledge that ECF
expansion leads to more rapid presentation of the
fluids to the distallUbule. and the inhibition of renin
Stcr-elion (,nto the bloodstream) (21). /\ proposed
solution \0 the dilemma is that high localized con·
centrations of Na - .cr . or some other tubular fluid
component activate (rather than release) renin that
is already present Therefore. sumcient A_II to pro--
mote constriction of the afferent anoriole within the
vicinity car. be produced withou\ affecting en7yme
levels in the systemic blood.
On the other hand. the notion that angiotensin is
the sole (or even major) mediator of wbuloglomer-
ular feedback has been questioned for several rea-
sons (21.210): Undcr conditions other than miner-
alocorticoid administration and ",It deprivation.
tbere are no consistent relationships between t he kid-
ney renin content and the magnitude of the autoreg-
ulatory responses (149). In fact. the feedback is
more efficient for juxtamedullary nephrons (in which
the renin «Intent is low) than for the cortica l ones.
Neither angiotensin-receptOr antagonists nor con-
inhibitors impair the autoregulation.
(Severing of the renal nerves is also without effect.)
A different concept that A- II acts inlrarenally
to maintain vascular tone and the responsiveness to
other stim ul i. Adenosine increases V3.sooonstriction
within the kidney. and it has been proposed a me-
diator ( lSI). Prostaglandins have also been
gested to play imporlam roles. but inhibitors of their
biosynthesis do not block the autoregulation.
,. ALDOSTERO NE AND THE RENIN·... NGIOTENSIN SYSTEM

THE KALLIKREIN-KININ SYSTEM Prostaglandins scem 10 be major regulalOrs of

Kinins arc small peptides that are generated when
catalYlc cleavage of glycoprotein sui:>-
strales. They oppose most of the biological effects of
the angiolcnsins. There is good evidence thaI the kal.
likrein-kinin and renin·angiotensin systems interaci
in complex ways 10 achie"" appropriate va.".
d ila lor / vaSOCOnstr iel or, a nt i hypen ens; ve / hypenc n-
.iye. natriuretic/scxlium_retaining, and diuretic/an-
tidiuretic balances. The two systems share common
enzymcs. and they arc also linked via the PO •. 5<Jrnc
forms of human (135) and experimental ( 108) hy·
pertension have been 3nributed 10 kallikrein system
ddec\s. MincralOCOrliC(lid "escape" is also believed
\Q involve activation of the kinin system (139) . It
should be pointed OUI, however. thaI Ihere i. not uni-
versal agreement on the physiological impOrtance of
the regulators.
Renal Kallikrein, and Prekalllkrelns
Renal kallikrein. arc plasma membra",,·bound
serine proleasc.. They are initially synthesized
wilhin the kidney as
Both prekallikreins and kallikrei n, are present
along the ent ire luminal border of Ihc nephron from
the region of the macula densa to or into the colltet·
ing ducl.'l (31). They are reka.ed into tlle tubular
fluid and they appear in the urine. T he quantitiC!i n·
creted give SQmc indicalion of kinin activity under
ordinary condition •• but faclors affecting activation
of Ihe enzymes and degradation of the kinin. con-
sequently formed can disrupt such relationships.
Since Ihey do nOI enter Ihe circulation. kallikrei ns
have been called (3 1).
prekallihein to kallikrei n conversion. Enzyme aCli-
vation is easily accomplished in vitro if renal lubular
membranes are incubated wilh arachidonate (the
PG I precurSQr). or wilh phospholipase Al (which re-
leases araehidonate from membrane phospholipid.).
Renal tubules alSQ contain kallikrein inhibitors.
Several proteolylic enzymes present in biological
lissues calalyze both prekallikrein and prorenin aC-
livation. Aprolinin inhibition of renin acti vation was
described earlier. The peptide nonspeeifically 'tabi-
lizC$ prckallikre;n. Amiloride (an antibiotic Ihal op-
poses aldOSlerone stimulalion of Na ' trans[101"t) alSQ
interferes with preka llikrein activation (3 1).
Kallikrein SUbstrate
Kininogens are ",-globulins thaI are made in the
liver and released into the bloodstream. The one. af-
fecting renal functions arc filtered by the glomeruli.
They arc found in proximal as well as distal seg-
ments of thc ncphrons. and alSQ in Ihe urine. The
substrale eontains a !3.amino-acid SC<juence that
serves as the precursor of the kinins (Figs. 9_11 and
9·12). Additional kini nogens may be made in the
kidneys.
Klnlna
Renal kallikreins release a decapcptide. Iys-brady-
kin in or Aminopcplidases within the kidney
can Ihen promote conversion of kallidin to brad,-";-
nin (a nonapcptide with similar or identical biologi-
cal activity). The same enzy me shortens the
decapeplide angiolensin I to Ihc nonapcptidc. des-
asp-A-I. and alSQ A-II to A-III . (Fig . 9-13).

KINtNOGEN

t k.l>:.rein
\

KALLIDIN
LV$-SRAOYl(ININ

(.

I
BRADYKININ

Kinin"""

In""t"e
'"
Inacl"e

Fig. 9- 1 1. Formlltoo And degrOdot>on of IUIliidin And

KirW>o .. If _ angio1e-n.in-coowening .....,..."..
Fig. 9·12 lor arTWno . cld •. )
 KININOGEN :
C MC· Te'm .... pcp,jde
N _ N· Te'minal ",,!>,ode

MET·l YS-BRADYl\ININ :
t

L YS·BRAOYKIN IN IKALLIDIN):

BRADYK ININ:

Inoc,;"'e heplape!>'ide
II,om

"'",,' ;_e oo'apepli<\e

(k"'" koli:lin)

In"",;"" oo'apepOi<\e
(ff"'" bra<tykfnin)

Fig. 12. Amino.Cid S6Q-.::M 01 pep'itUI. in Fig_ 9·' '-

r\ differenl presumably of renal ong,n.
deaves met-Iys-bradykinin from the substrate. The
peplide is present in bladder urine. along wilh an en-
zyme known as uropep,in (31) ,
Ki nins are polent generalors of prostaglandins
(133). When administered. they increase Ihe for-
mation of mostly PGI , in thc renal artcrioles. and
mostly PG E, in the collecting ducts. Kinins syml1e-
outside the kidney and deli_cred to the blood-
stream also promote PG generation in blood vessel
walls. and Ihey aClivate PGE 9-ketoreduclase in the
veins. The enzyme catalyzes Ihe oonvcrsion of PGE l
to PGF,.. nnd il has been proposed that ii' activity
i, regulaled by Na ' ooneenlrations (134).
S ti mulation of pre>staglandin gcncmtion is attrib-
uted \0 activation of acid hydrolases and espc.:iaUy
phopholipases of Ihe A Iype (134). Mosi. bul not aiL
of Ihe kinin aClions can be blocked wilh mep.lcrinc

/ _ - -- - Protwlyli:: ""':ymeo - - -_ _,

PRE KALLIKREtN _ _
----- _ _ __ _ ____ - - AptOl;"in - __ _ _ __ _ _ _

KALLIKREIN
.......
" '__ RENIN

ANGIOTENSIN __ ANGIOTENSINOGEN

' \ Converting ANGIO)ENSIN II

enzy"'"

Atnino""P'o;l3se _ _ _ _ _ ...-

ANGIOTENS IN III

Fig . g..13 . En.yrnes oneeting lIO,h tflfI ' .... n-.nvi<>'... oin
0<><1 k.n;k' ...·kl,.;n IHlem,
 AlDOSTERONE AND THE Fi"ENIN ·ANGIOTENSIN SYSTEt.!
""

PREKALllKRE IN KAlliKREIN

KALLIDIN
I
ANGIOTENSIN I

I
SRADYKININ-
I
____ ANGIOTENSiN II
• . PROSTAGlANDINS

I
O! Il'10$1 AClion. of kinins
Antagonism 01 most ""lion of angiolerain II
Fig. g·t4. Pfo.taglandint provid<>
Iri.. the " aIHk' ein·k""" lOCI
,en;n·a og;o,..,.in Oy,t.",o.

(8 phospholipase A inhibitor) and with indometha-
cin and related agents thaI act on the prostaglandin
synthase system . In the of inhibitors of this
ki nd, or when agents affecting the .i n;nases de-
scrib<:d lalcr arc given. the urinary levds of kalli-
krein no longer reflect the funclional SlalUS of lhe
kallikrein synem . When phospholipase. release Ihe
fally acid substrates for PG sy nthesis. calcium ions
SCent to be c=mial mediators. Calcium ionophores
mimic the cffcctsof both A- II and kinins on PG gen-
.",uion PI2).
Some of the interrelationships with the PGs arc
shown in fig. 9·14. In addition to activating pre-
kallikrein and mediating kinin aclions. PGs (indud·
ing PGI : [141]) stim ulate ftnin relcase. The A- II
subsequently generated promotes additional PG pro-
duction. Glucocorticoids inhibit phospholipases in
many cell types. and they also exert numerous influ-
ences on calcium metabolism . Such effects may be
related 10 the glucocorticoid depression of urinary
kallikrein \cvels (I 37).
CH, "C-CH ,
H I H H H /H
N-C - C - C-C - N
HHHH\H
O-CH ,
Mepac";".
Klnlnases
Kininase II is identical with angiotensin converting
enzyme. It cleaves thc C-termi nal dipeptide from
arg·lys·bradykinin. kallidin. and bradykinin. The
products are biologically inactive peptides. The en-
zyme has been localized to the brush border surfaces
of the proxima l tubules (31). [t has high activity
within the kidney (13S).
Since Ihc aflinity for kinins is greater than for A·
II. enzyme inhibilOrs exert their most obvious eifects
on prolongation of the kinin activities within thc kid·
ney. (By contrast . systemically administered con·
vening enl.yme inhibitors usually have greater ef-
fects on A·II.)
Kinina .. I is a different enzyme that deaves the
phenyla laninc.."rginin" bond of th" kinin •. The prod.
uctS arc also biologically inactive. en-
zymes thai allac k the peptides are widely distrib-
Kinins generated by kallikreins outside Ihe
kidney are cleaved to a variety of small peptide •.
Extrarellal Kaltlkreill-Klnin Systems
Renal kallikrein is one of several "'glandular typo""
enzymes that act on the substrates to release kalli·
din. The enzymes have re latively low molecular
weights (24.OOO-W.OOO). and they aCI on low me>-
Iccular weight forms of kininogen •. They are presenl
in many organs, including ehe colon, Ihe exocrine
pancreas. the sweal glands. and Ih. ISalivary glands.
The generated contribute 10 secretory func_
tions. mostly via locali,.. d vasodilaeion .
Blood plasma kallikreins are larger molecules
(with weights of around 100.000), and they act on
bigh molecular weighl ",.globulins secreted by the
liver. They releas. mostly bradykinin. Although
there is the potential for generati ng enormous quan-
tieies of th. nonapeptide. the plasma levels rardy ex·
2.5 ngJm!. This is attributed 10 both the pres·
ence of most plasma kallikrein in proenzyme form
and the bradyki nin half-life of something under 15
seconds (4S). 60-90% of the circulating peptide is
degraded 10 a variety of biologically inactive frag·
ments during a sinsk pas.sagc throuSh the lungs
 There are numerous interactions with the blood-
coagulating Hageman factor can yield
pre kal!ikirc;in acHvltors. and plasmin (formed from
piasmioogen) has similar activity_
The peptides are implicated as mediat<m of in-
flammat ion and of pa in sensations_ When injected
into a nimals. they exert a wide var iety of pharma-
cological actions (48) that seem to be related to
physiological functions.
The kinins arc th e most potent of the physiological
vasodilators. They aCI direcily on arteriolar smooth
muscle. promole the release of both histamine and
PG E,. a nd inhibit norep inephrine disc harge from
sympathelic nerve endings. Cardiac outpul is usually
indireClly increased becausc of both barore<:eptor re-
sponses to the fan in blood pressure and
kinin-Slimulaled T<'lea<e of epincphrine from Ihe
adrenal mcdulla.
By contrast with the cffects on arterioles, the ki-
nins the smooth musclc of ",,,,t vein, and
large arteries. High aClivity of an enl.yme that cat-
alyzcs conversion of PG E1 to PG Flo may acC<)unt for
the in responses (34).
Edema commonly develops. 11 is altributed to
changes in hydrostatic pressure. 10 histamine re-
lease . and to di rect effects of kinins on the permea-
bilit ies of the small venules.
Although exogel1Ous kinins dilate renal vc5.'\Cls. it
is unlikely that circulating peptides have much inllu-
on renal hemodynamics. There are indirect ef_
fcct.1 relaled to the changes in cardiac output and
vasodi la tion outside the kid ney.
Both tissue and spedes "ariations in the responses
of extravascular smOOI h muscle are known. Tracheo-
bronchial constriction ;s most obvious for guinea
pigs. but humans amicted with asthma often show
this . Rats arc: resistant. They more oommonly dis-
play uterine conlraction but duodenal relaxation
(48).
In!luenees of Klnlns on Water and Sodium
Excretion
The kalli krein system is stimulated by
wate r inta ke and by ECF vol ume expansion. The ki_
nins produced then acederalO water excretion, prob-
ably via PG ge neration. Urinary PG
increase under the same conditions. PG E, alone pro-
motes waler diuresis (at least in part it an-
tagonizes A DH). Indomethacin blocks Ihe effect.! of
both the kinin. and the PGE,(139).
Under ordi nary oonditions, kinins tend to incT<'ase
sodium excretion. This is allributed to the vasodila-
tion and the increased blood How to the rc:nal me-
dulla. PG synlhesis inhibitors ,,,,",east the natri-
uresis. (T he inhibitors do nol seriously impair kinin-
mediated vasodilalion, since only around 30% of this
aClivily is PG-dercndcnl.)
Some observers slale Ihat high sodium inla ke has
linle or no influence on the kalli krein system. They
rc:port that expansion of the ECF volume with salt-
f rcc solutions is as effective a stimulant as sali ne ad_
ministration ( 139). Proponents of t his view attribute
the increase, in kinin activity that follow mineralo-
corticoid administration to expansion of the EC F
volume and elevation of Ihe systemic blood pressure.
Othcrs believe thaI mineralocorticoids and posi-
tive sodium balance direClly the
(a) mineralocorticoids aCI on isolaled rcnal cells 10
increase kinin (3 1); (b) palients "'ilh hy-
pe raldosleronism and animals displaying mineralo-
oorticoid "escape" have high urinary concentrations
of kalli krc:ins (50) ; (c) the levels aT<' low in
untreated adrenalectomized animals; and (d) :\0-
dium depletion promotes both aldosterone secretion
and kinin production.
Sodium may exert some mineralocorticoid-inde-
pe ndent effects. For example. it is said to affect the
activity of the enzyme that oonverts PG E, (which in-
fl uences sodium exerction) to f'G F,. (""h ieh lacks
such potcncy) .
Rcnal denervatio n docs I10t affect kinin inn"encc.
on natriuresis. On th. other hand. acetylcholine and
substance P have been implicated in the regulation
(57).
Direct Effects 01 Prostaglandins On Sodium
Although it is established that PGs diT<'etly alTeel
Na ' transport across lOad bladder (110.134). there
are cOnlroYersies OVer possible related functions in
the mammalian kidney. In addition to species vari-
ations. SOme obvious SOurces of confusion ca n be
cited.
I. PGs are made in the kidneys. and they
differ in biological activities as well as in dinribu·
tions along the nephron. PGf1• is a vasoconstrictor .
PG I, is a vasodilator. and PGE, Can ha"e yariable
influenees on the blood Yessels. Vasodilators tend to
increase Na' sodium excretion, whereas vasocon·
strictors a rc often antina triuretic. One segment of
Ihe nephron can respond different ly than another to
Ihe same mole<:ular species. Moreover. it is possible
tha t certain of the f'Gs affcct tubular transporl.
whereas others do not.
2. Some parts of the kidney arc: in 9-keto-
PGE1T<'duclase. an enzyme Ihat ealalyzes conVe r_
sion of PGE, to PGF,., and the affecled
by cle<:trolyte balance.
3. Salt restriction has one effecl on PG
in t he glomerula r region and a Ycry differc:nt one in
tbe renal papilla (34).
4. Responses 10 luminal presentalion of PGs can
be opposile in direction to ones seen after periwbular
admin istration (73A).
".
5. Manipulation of the electrolyte balance affeet.
A-ll production. A·II acts on blood ,,<,=Is, and it is
also said to directly affe<:l Na ' transport. Morea"",.
A- II is a regulator of PG synthesis. and PC. can in_
promote A-ll generalion.
6. Both angiotensins and PC. inleraci wilh Ihe
kallikrein-kinin system.
When PCs arc injected into Ihe renal arteries of
intact animals, large quantities of the hormone arc
delivered \0 the renal corux. The usual response is
nalriuresis, and it is reasonable \0 att ribute Ih is \0
vasodilation. The thaI PGs 3rC natriuretic
derives mostly from such observations. However,
under physiological conditions. Ihis pa rt of Ihe kid-
ney generales very limited quantities of PCs, and it
is rkhly supplied wilh en7.yrncs that degrade endog-
enous hormone. Glomerular and vascular cells
the primary SQIlr<:eS of the PGs (34), and much
POI, than POE,;s made_
Much larger amounts of PGE are synthesized in
the renal medulla. and the function here may wen
be sodium ron5etvation. In rats, salt leads
10 PGE ae<:umulalion. and salt loading 10 depletion
(193,199) . PG synthesis inhibitors impair ad-
a ptations to salt restriction, but they do not seem to
have important innuences in salt·loaded animals
(118). There 3re studies on kidney slices from other
species that are consistent with the ooncept that
PGE, is antinatriuretic. but not all investigators
3gm: that POs perform such functions (73A). At
least some find no effects on either the thick ascend-
ing l'lenle loops or the distal tubu les of rabbit neph·
rons (58).
Kallikrein Influences on Systemic Blood
Pressure
It has been that renal kallikreins play phys-
iological roles in the regulation of systemic bl<XXI
pressure. Urinary kallikrei ns are low in patients with
essential hypertension associated with low aldoste·
rone levels(I27). They are also low in laboratory an·
imals with genetic defects that lead to cievation of
the systemic bl<XXI In Dahl salHensitive
rats, the decrease precedes the onset of hypertension
(31 ).
ANGIOTENSIN INFLUENCES ON THE
NERVOUS SYSTEM AND ADRENAL MEDULLA
Angiotensins are powerful stimulants of the sympa·
theticsystcm (114.159). A- [ and A-II appear to be
equally potent for promoting the release of catechol-
amines from the adrenal medulla and sympathetic
nerve endings. A-II also facilitates neu rolransrni,-
ALDOSTERONE AND THE RENIN·AI<GIOTENSIN SYSTEM
sion, potentiales the effe<:ts of by
slowing its reuptakt, and innuences on protein
metabolism Ihat lead to accelerated production of
the catecholamines.
Although A-II does not readily cross the bl<XXI-
brain barrier. it several effe<:ts on the brain
when it is infused into the sys temic veins. Saralasin
blunts Or blOCKS most of the responses (190). It is
!i kcly that the peptide gains ae<:ess to the neurOnS via
the circurnvcntricular organs.
Brain Renin-AngiotensIn Systems
Although it has been known for mOre than two dee-
ades that A-ll exuts C<:nt ral aClions, definitive evi_
dence for the existence of angiotensin-generating
systems within the brain has only recently been pre·
sented (161).
Minute quantities of A-I [ invoke reprodudble reo
sponses when Ihey are injecled into the cerebral ven-
Iricles, and these Can be blocked with saralasin. The
sa me dosagcs given systemically are ineff..:tive (27).
Since converting is present. A- I mimics the
effects of A_ [1. Its actions are abolished by ACE
A-I and A-II are present in high concentrations at
brain sites believed to contain hormone rtcrplorS.
(A ·1 1I and angiotensin-degrading enzymes have also
been found [711.) The high-affinity binding altllosc
sites is affected by the physiological status in a man·
nCr consistent with roles in the regulation of bl<XXI
pressure and electrolyte balance_ In some spc<;ies, ce-
rebrospinal Auid concentrations of A·[ I exce<:d those
of blood plasma. and the levels are maintained after
nephrectomy.
The angiOieruin<>gens of brain and cerebro&pinal
nuid a re probably not derived from the bl<XXI, since
they are present in high concentrations and possess
properties different from those of plasma renin sub-
strates. The brain a lso contains renin-like en7.ymCS.
The major objections to the concept that brain
its own angiotensins (165.!69.170) seem
to have been reITIQved. II has been suggested. for ex·
ample, that the "renin-li ke" enzymes are actuaily Iy-
SQSQmal cathepsins (169). However. although the Iy-
SQSQmal enzymes can exert such actions, some of the
renin-generating activity is blocked by antirenin a n·
tibodies (161) . [t has a lso been proposed that cen-
traily acting angiotensins are made by ceils of the
blood vessels wails, but generating systems have
been identified for neuroblastoma cells and for cul-
tured neurons from neonatal rat brain •.
Since many effects of central and perip heral A-JI
administration are similar in direction . and inverse
relalionships plasma A-II and t he rates of
 A- I r generation within the brain have been observed
(71), it is likely that regulation of some physiological
functions is accomplished by interactions lxtw..en
the two systems.
When the systemic blood pressure falls, peripher.
ally released A-I I can correct the condition by acting
directly on the arterioics and by increasing catechol-
amine discharge from the adrenal medulla and the
sympathetic ncrve endings. A· I[ within the brain
probably increases systemic blood pre...,ure by pro-
moting catecholamine release in regions affecting
the cardiovascular reflexes. The central effects are
not impaired by adrenalectomy, but they are blocked
with hexamethonium and other agents affecting
gang!i(mic ncurotransmission (27). Some forms of
hypertension are allributed to impaired functions of
central mechan isms invol,'cd in the protecti"e car-
diovascular reflexes. In very young rats, the bloOO·
brain barrier is inwmplete, and it has been proposed
that peripherally generated A_II acts centrally to
maimain the systemic pressure unlilthe sympathetic
systcm has completed its maturation (15).
A·]] regulation of the pituitary gland probably in-
volves both central and peripheral components. In
addition to influences on ADI!. A·ll affects th. re_
lease of ACTH and also of GH. PRL. and LH in
e$\rogen'primed ovariectomiled rats; but it does not
change TSH level s (194). The elfects are blocked
with sa ralasin. Some of the responses are obtained
following both peripherat and centrat administration
of the A_II. and they are amiooted to direct inter_
actions with pituitary gland receptors. However. oth-
ers appear to be mediated via central actions involv_
ing dopaminergie and possibly somatostatin neurons.
Both central and peripherally administered (or se-
creted) A·II Can invoke thirst and the secretion of
ADH. The rolease of ACHI and of cortisol (125)
may be indirect of the stimulation of
ADH. On the other hand . somc ,,<,ntral clfects differ
from the peripheral oneS. for example, natriuresis
can be observed when the renal nerves are intact
(44). and the secretion of aldosterone is supprcsscd
(2g) .
A-II Re gula ti on of Wat er an d Salt Intake
It is appropriate to increase water intake when there
is contraction of the extracellular fluid volume. low_
ering of plasma volume, dcpression of systemic blood
pressure, and elevation of the extracellular fluid s0-
dium content 10 the point where ceUs become dehy.
dratcd. Since the control of water balance is vital, it
is n(lt surprising that the regulatory mechanisms in_
volve multiple, widely distributed receptors, the '<'_
lease of diverse humoral agents. and the ability to
respond differentially to changes in electrolyte con·
centrations and in fluid volumes (6.174) .
A-II is tne most potent dipsogen known. Central
administration of minUie amounts invokes drinking
behavior in well_hydrated animals. (Similar re-
sponses can be elicited by intracerebral injection of
renin substrate. and such effects arc blocked with
ACE inhibitors [1611. While several regions of the
brain. inCluding the organum vasculosum of the lam-
ina terminalis (OVLT), have been implicated (27).
many investigaton; have the importance
of the subfornical organ (SFO) (140). A- II accu·
mulates there after peripheral adnlinistration, and
local presentation of the peptide elicits prompt
changes in the firing activitiC!i of the neurons. Drink·
ing responses to A·II are blocked when the organs
are damaged. The lesions invoke transient adipsi a.
and they permanently impair drinking responses to
cellular dehydration and to intracarotid injections of
hypertonic sa line . Projections to the supraoptic nu·
clei (in which ADH is madel have bet:n demon-
strated(140).
There are conditions under which the central con·
trois over blood pressure Can be separated from th e
ones affecting water balance. and the time courses
for the responses differ in animals subjected to ex-
perimental manipUlations (44). On the other hand.
there are good physiological reasons for coordinating
responses. It has been ,<,ported that peri ventricular
cells located in the anteroventral region of the third
ventricle of the brain (the AY,Y) contain recepton;
for perception of both OOmOtlC and pressor stimuli.
Yery small lesions of this region (which also alfect
the OYL T but n(lt the SFO) lead to abrupt abolition
of drinking responses to dehydration. but they do not
affect eating and other activities and do not totally
block some other aspects of drinking behavior (e.g ..
ones associated with ealing) in rats. The lesions abol-
ish thc sti mulatory effects of A· II and of hypertonic
saline on drinking. a nd they addi tionally impair
ADH secretion, reduce salt intake in response to s0-
dium depletion. and have important influences on
blood pressure. However. baroreceptor_mediated
stimuli for thirst are retaincd (27). There is also ev-
idence for impairment of the release of natriuretic
hormone following NaCI infusion.
Extracellular dehydration provides a major stim·
ulus for elevation of thc plasma A- II. and mueh of
the renin secretion is mediatcd via barorcccptors.
However. ingestion of dry food can also raise the
plasma A·11 in previously well·hydrated animals
(27) . Peripherally generated A·II probably plays
physiological roles in stimulation of drinking. The
levels alla ined when animals are subjected to water
deprivation are in the ranges used to demonstrate ef-
feclS of injected peptide on thc responses (126).
When ra" arc subjected to cold for several days and
are then returned to warm environments. they suffer
dehydration. decreased ability to concentrate urine.

and impressive "thermogenic drinking" that persists
for a long time. Drinking responses of this kind are
blocked with Pr re«ptor antagonists. A·II re<;eptors
and sympathetic system stimulation of thc rcnal an-
giotensin system arc evidently involved in thcrmo-
genic drinki ng. The PRA rises before large increases
in water inlakc become apparent. and r<:.
dulX's the volumes ingested (66) .
Salt appetite control also involves many hormones
and several kinds of receptors. Healthy mammals of
most species prefer dilutc sodium chloride to tap
water. They will ingest large volumes of fluid for
days at a time if solutions containing 0.2%-2.0%
NaCI are substitutw for the usual tap watcr. even
when they have healthy endocrine systems and are
in water and electrolyte balance at the time of the
switc h. However. they show aversions to higher
NaCI concentrations and to fluids containing mQSt
other electrolytes (51).
The taste preferences can be regarded as compo-
nentS of "anticipatory control"' systems. The "extra"
saline is stored as interstitial fluid that can be reo
in the event of hemorrhage or sal t and waler
deprivation. (On the other hand. when animals are
forced to take 5/rong salt solutions. Ihcy soon develop
a diuresis thaI depletes the body of "'aler-l
MQSI animals possess remarkable abilities to
gauge the magnitudes of salt depletion when Ihey
are subjected 10 dietary deprivation. saliva drainage.
blood loss. and other conditions: and they will drink
quantilies of saline Ihat are appropriate for replen·
ishment. Receptors within the moulh. or
esophagus seem to play primary roles in assessment
of the needs, since the consumption best matches the
deprivation when the saline is taken orally (21).
However, baroreccptors of thc arterial Syslem pro-
vide additional informa tion. These may be less effec-
tive sensing devices than ones located in the gaslroin-
teslinal tract and/or hepatic portal vessels, since
animals given intravenous saline infusiorrs following
deprivation often drink more than they need to re-
piaIX' the losses, and more than a nimals given the
Auids intragastrically.
The adrenal glands inf\uenlX' salt intake in scv<:ral
ways. Animals deprived of mineraloe<.>rticoids ingest
more saline than intact controls. The drinking is nut
affected by intragastric or parenteral administration
of NaCI solutions.
Glucocorticoids play roles in the maimenanre of
gustatory receptor functions. Adrenalectomi7.<:d an·
imals can detect the presence of salt in solutions too
dilute to be distinguished from water by intact con-
trols. However. their ability to discriminate betwcen
NaCI and other solutes is impaired when COnCe ntra-
tions above the laste threshold range a re presented.
ALDOSTERONE ... NO THE A£NtN·... NGIOTENStN SYSTEM
The functions of the receptors can be re-
stored wilh glucocorticoids but not with mineralo-
(90).
Adrenocortical insufficiency lcad$ to changes in
the levels of seoeral nonsteroid hormones implicated
in the responses. ACTH se<;retion is augmented. and
that pituilary hormone is kl)(lwn to increase salt ap-
pelite in many species (20). Prolactin is believed to
participate in several ways in the regulation of ciec·
trolyte and water balan... and it too may be inoolved
in modulation of the thirsl and salt appetilc .
Blood angiotensin levels rise soon afler adrenal-
ectomy. and there is good evidence that the peptide
stimulates salt appetite under those conditions (51.
159.174). However. chronic adrenocortical insuffi·
ciency impairs the abilily 10 synthesi'", angiotensin
precursors. Moreover. some changes in Ihe salt ap-
petites of adrenalectomized animalS are not me-
dialed by angiotensins. Intraventrieular injections of
NaCI solutions reduce salt intake in sodium-depleted
sheep. wher<:as intravcntricular presentation of
either A·I! or its receptor antagonists affects water
(but not salt) intake. Some in"estigalors believe Ihat
the effects of A- li on salt intake arc either pharma·
cological or indirect (37) .
Paradoxically. animals overdosed wilh aldoste·
rone. dwxycorticosterone (DOC), and r<:lalOO ste·
roids tend to drink large amonts of saline or 10 select
salted foods. In this case. Ihe response is detrimental.
since it leads to overexpansion of Ihe extracellular
fluid volume and it can enhance the tendencies to de-
velop hypertension. The drive probably arises be-
cause hypernatr<:mia leads to cellular dehydration.
Some of the sensors are located within the brain. le-
sions of the medial anterior hypothalamic regions
and a-adrenergic agonists exacerbate the salt appe-
lite. whereas lesions of the laleral hypotha la mus or
amygdala can suppress it. Interestingly. however.
prior experience with the IlISte of sa lty solutions af·
fects subseq uent responses to brain lC$ioni in ani·
mals overdosed wilh mirn:ralocorticoids. whereas tbe
salt appetite of adrenocortical insufficioncy is an un·
lcarned rl:$PO= (51).
The problems of defining inf\uenlX'S of hormonal
imbalances on salt intake are complicated by Ihe nu_
merous factors that can aifectthirsl, and by tbe ten_
dency for animals to accept saline when Ihey sense
fluid (rather than ele<:trolyle) deficits.
AOH RELEASE
Regulalion of ADH secretion is diseussed in delail
In Chapter 10. Ccntrally administered A·II
promptly elevates plasma ADH, as it promotes
water corrservalion. The actions of ADH on Ibe kid-
ney complement Other angiotensin. mediated mech_
anisms for expansion of the ECF volume. Additional
indications that A- II and ADH interact to maintain
Auid balance come from observations that the SFO
send projections to the supraoptic nuclei (1 40). and
tha t A V)V lesions abolish ADH release in response
to dehydration (27 ). Since A_ II influence< on the
neurohypophysis are diminished by indomethacin.
they may depend on PG generation ( 186).
Enough ADH can be released to augment the hy_
penensive clTcctS of A·[I. (The blood
changes invoked by A·I! are blunted in Bral1[eboro
rat, but the dipsogenicones are not 17 1]). A_I[ reg-
ulation is, howeyer, limited in scope. The peptide is
not an effecti,,,, stimulant when ADH leve[s arc oth-
erwise suppres.sed. e .g.. during over.hydration.
Moreover. blockade of the rcnin_angiotensin system
fails to impair ADH responses to hemorrhage.
A-II GENERATION IN OTHER PARTS OF THE
BODY
Angiotensin receptors have been identiflcd in many
parts of the body. and in most cases it can be dem-
onstrated that this has functional significance.lllood
vessels synthesi>.. substantial quantitics of A·I I. and
the hormone is believed to act locally to fmc
control over the calibers of the arteriolcs. Some A·II
is probably also carried to other targets. but much
more efficient regutation can be accomplished when
each organ is equipped with its own generating
system.
T he salivary glands of male mice make exceed-
ingly large amounts of isorenin. The adrenergic con-
tro[ dilTel"S from that of the kidney. p·type receptors
mediate stimulation. and ", oncs. inhibition (101). It
has been specu la ted that [ocally generated angioten·
sins contributc to the oontrol of salivary flo,," and
composition. Howevt:r. the hormone may perform
different, yet undefined functions. I'emale mice do
not display obvious defects. and the salivary glands
of mo.st other species are not rich in related enzymcs.
No quantitative relationships between tcstO&terone
levels and angiotensin production arc found when
males of different strains are compared (102). and
no influences of salt depiction havc been demon-
strated (159). Removal of the glands has litt le elTect
On the plasma renin activity of mice with intact kid-
neys. but contributions to the PRA havt: been de-
scribed following nephrectomy .
The isorenin-angiotensin system of the uterus is
be liew:d to participate in the regulation of smooth
muscle oontT<lction. and pos.sibly also of blood flow.
Estrogens increase production of both circulating
angiotensinogens and uterine A_I[ receptor!.
whereas progesterone reduces angiotensin binding in
the uteruS. Changes in receptor numbers have been
found to vary with the phase of the estrous cycle in
rats a nd rabbits (176).
Neurohypophysial explants sy nthesize A·I I (189).
It has been suggested that special. Iocali7.ed, inde-
pendent angiOlensin-tenerating systems within the
brain oomribute to ADH control. A-I] receptors
ha,,,, additionally been identi fied in the intestine. and
the peptide has been shown to alTeet transport via
mechanisms that require protein synthesis ([ 21).
REFERENCES
[. Aguilera. G .• Capponi. A .• Bauko l. A.. Fujit •. K .•
Haumge r. R.. and Can. K . J. Metaboli,m and Bi-
ological Aetivitie.of Angiotensin 1t and de. ·A.p'.
AngiOlen$in 11 in Isolated .' dr.n. 1 Glomeru["""
Cells. Endoc'lltO/. /O f : 1279_85.
2. Agui\era;G .. and Ca1l. K. J. Loci of Action of
Rejlu latoT< of Aldosterone Bi osynthesis in t..,.
Iated Gtomerulo$a. Cells. t::ndoc';IIIJ!. I().I: t046_
52. \979.
1. Aguitera, G .. Hyde. C. l.. and Cal1. K. J. Angio-
tensin JJ R.ceplOrs and ?rolactin Relea$<; in Pi·
tui"'y uctotroph •. III: t045- l-O.
t 982.
4. Agui[era. G .. Park. D. S .• and C.I1. K. J. Char_
acteri zat ion of Somatostalin Receplors in the Ral
Adren.t Gtomeru[osa Zon.. Eltdoc,;I!0/. III:
\376_84. 1982.
5. Anderson. N. S.• Il[. and Fanesli[. D. D. Diololl)"
of Mi"e"looo"icoid Rcccp'o". Chap. pro
32)-51 orO· Malley. B. W .• a nd Birnbaumer. L..
.do. /lff'P"N' ond AOIiO" 11. Academic
Pre .... New York. 1978.
6. Ande "son. B. Regul .,ion of Woter lnlake. Ph",_
101. Rn>. 58: 582-603. 1978.
7. Antonaccio. M. J. AngiOlen$in CO..ertinll En·
lyme (ACE) [nhib itor.. Ann. Rt". Pha'moroi.
Tl)xicol. 21: 57_81. tn2.
8. Aronson. P. S .. and BoundS. S. E. Harm.tine In·
hi biti<:>n of N •. Dep<ndent Transport in R.nal Mi_
crovillus Membrane Vesicl.s. A",,,. J. Ph}·siol.
138: F210- F2t7. t980.
9. Arruda. J. A. t., and N. A. ReI.tion-
ship of Renal Sodium and Water Transport to
Hydrogen Ion Secret ion . Ann. Rn". Ph}".;ol. 40:
43_66. \978.
10. Baer. P. G .. and McGiff. J. C. Hormon.\ Syslems
.nd Rena[ Il .modynamics. Ann. Ph}".iol. 42:
589-601.1980.
I t. Baldwi n. G .. Jes.... S. D .• and Wail i",lOn. C. O.
Chloride Transport Stimu[alory Foetor in [l um.n
Uri ne: EtTeet. on Sodium f luxes.nd Preliminary
Characteri,,,,ion. J. Clin. Endocrinel. 49.-
930-6. t9 19.
12. Baraj.s. L. Anatomy of Ihe Ju"agtom¢rutar Ap-
pa"t Ul . Am.,. J. Phyj iol. 137.- F)3l_F343. t 979.
t 3. Barren. J. D.. Enen •. P.. Hid. ka. fl.. and Sam·
bhi. M. P. In Vitro tnhibition of Renin by Human
Des'Angioten,in [ Renin Sul»!r.te. J. Clin. E".
doc';""I. Mtlob. f 8: 96_ t 00. t 979.
'"
14. B.,II, C. P., Binder, H. J .• and HaylloU. J. P.
Role of Glucocortkoidund Aldo>,e",nc in Main-
tenanee of Colonic Tran.porL A_" J. Phy'ioi,
238: FI81-fI86. 1980.
IS. BUler, C. R.o Hor •• th, J. $., and Duggin. G. G.
Effect of Age on Specific AI\3io1en,in II-Bindins
SilO' in Rat Brain. EnJi()(Fino/. 1fJ6: 995_9, 1980.
16. Bentley. p, J. Endo<:ti-
""Ioy_ Cambridge Univer$ily Pre ... New York,
1976.
17. Bi., M. J .• and OtFronzo, R. A. Emarenal Po-
' .... ium H<>mwsta,i •. Amu. j . Physiol. UO:
f2S7-F268,1981.
18. Si., M. J .. Tyler, K.. and Dormnw, R. The Ef·
reclof [)eume,haSOflC QIl Renal Electrolyte E,·
ero,iQ. in the Adrenalcctomi2ed R.t , End"",;"""
//1: 882-8, 1982.
19. Biglieri. E. G. Renin-Angiotensin.Ald""terone.
Chap. 7, pp. 2))-3 of lngba •. S. H.. ed. Com. m-
{XX"'Y End.x,ino/"IY. vol. I, Plenum. New Yo'k.
1979.
20. 81.ine. E. H.. C"",ili, M. D.. Denton. O. A. , Nel·
son. J, F.. and Shul'es. A. A, The Role of ACTH
and Adren.1 Glucoc«ticoids in lilt Sail Appet;le
of Wild Rabbits [01-),<,I<>/aguuunirulu. (L)J . En-
docrinQ/. 97: 793_801. 1975.
21. Blair.Wesl. J. R. Renin.AngiOI.",in S),<lcm and
Sodium Metaboli.m. Chap. 4. pp. 95-143 of Hu·
rau . K.• ed. KldMyand Urinary TTaer Pity.ia/ogy
/I, Universily Park Pres •• Baltimore. 1976.
22. Blanl •. R. C. Segmenlal Renol Vaseul.r Res;,·
1.11«: Single Nephron. Ann. Rtv. Plty.ia/, 41:
573_88, 1980.
23. Braky, L. M .. and William •• G. H. The Elfeclof
AngiOlensin [] and Sarala,in on
OlC)'cortieosle""", Produclion by lsoialed Hum.n
Adrenal Glomerul,," C.II •. J. (.1in, EmJocrinol.
Mtlal>. 49: 600-3. 1919.
24 . Bmley. L M..• nd William s. G. H, The EIf<:<:t of
G•• vil), Sedimentalion on Adrenal Sieroidogene.
$iJ b), Isolated Rat Glom •• ulosa and Fa""iculata
Cells. EndocTInQ/. IQd: SO-5.
25. E. L., S.ilo. I.. Sen, S .. and [Iumpu •• F.
M. In Vilro Steroidogenic P.openi .. of. Ne'"
Hypenension·P.oducing CompOUod Isolated
f,om Normal Human Uri ne , J. Clin. t:nJorTI""'.
51: 176-8. 1980,
26. B,e,lau. N. A.. McGuire. J . L . Zcrwckh. J. E.
and Po., C. y, C. The R<>Ie of Diotary Sodium on
Renal Excretion and Intestina l Absorption of Cal·
cium and on Vil.min D Metaboli,m, J.clin. 1;;'It-
docrillOl. Meral>. j5: ]69_73.1982.
27. Brody. M. J., and John",n, A. K. Role of Iho An·
lero.onlral Third Ventricle Rogion in Fluid and
EI<:<:trol)'lo Bal.""o. Arterial Pressure Regula_
lion. and Hypertcl1$"'n. C hap. 9. pp. 249-92 of
Martini. l.. a nd Ganong. W. F .. cds. Frontl". in
1'01. 6. Ra.on New
York.1980.
28. Brook •. V. L. and Malvin. R. LAn Inlracere·
THE SYSTEM
bral. Phy$iologic.1 Role for Angioten. in: Elfec,"
of Cen"al Blockade. FM, Proc-. 38: 1979.
29, Campbell, W. B- and JacklOll. E, K. Modul.t"'n
of Adrene'gic Transmi .. i,," by Angiolel1$il1$ in
the P<;rfUs<d Ral Mos<nlory. Am.,. J, Phy.;o/.
136: H211_H211. 1919.
30. Caroy. R. M.. . nd Van loon. G. R. Bromoc.ip-
tine Does NOl Inhibit Ihe Aldoslerone RO$pOnS<
to Sodium lXpl<lk>n. J, ENiocrinol,
j$: 162_5. 1982.
31. Carretero, O. A.. and Scicli. A. G. Tho Ren.1
Kallikrein·Kinin Sy$tem. Amy. J. Phy. ia/. 1M:
F247-F255.1980.
32. Casey. M. l. .• nd Mao()Qnald. P. C. format ion
of Oeo.>;ycortiooslcron. from Progesterone in Ex·
",,.adrenal Tis"es: DemonSlralion of Sleroid 21·
Hydrox)'I>s< Activily in lIum.n 11.0.10. J . CIi•.
Endo"'inQ/. Mtlab. jj: 804-6. 1982.
33. Cha,noy. A. N .. Wallach. J .. Ceccarelli. S .. Don·
owin. M.. and Coste"bader. C. L Elfects Qf Spi·
ronolactone and Ami lo'ido on COrtiCOSleroid·ln-
duced Cha nges in COlonic Funct;on. Am.,. J.
Physia/. 141:G300--G305. 1981.
34, Cha umOl·Ri!faud. P.. Oudinel. J.·P .. Sraer, J ..
Lajolto. c.. and Ardaillou. R, Altered PGE, and
PGF,.,- ProdUCli,," by Glomeruli and Papilla of
Sodium.Deplcled and Sodium·Loaded Rat"
A"..". J. Phy.;a/. 24J: F511-F524, 1981 ,
35. C he.inard. C .. and Saavedra. J. M. High Ang io-
lensin-Convorting Enzyme Activity in Ihe Neu·
rohypopby$i. of Bmltleboro Rat. 116:
646-7.1982.
]6. Ciai re, M.. Rafe$l;n-Obli". M. E .. MiChaud. A..
Roth· Moyer, C .. and Corvol. p, Mechanism of
Aclion of • New Ant;aldosloron. Compound.
Pro,enone. EnJ.xrjnQ/, 104: 1194_1 200. 1979.
37. Coghlan. J. P.. Considine. P. J .. Denton. D. A..
Fei. D. T. W.. Leksell. L G .. McKi nley, M. J ..
Muller. A. F.. T.rjan. E .. and Woi,inae,. R, S.
Sodium Appelile in Sheep induced by Cerebral
lnfu.ion of Angiotensin: Comp.:orison wilh $0-
dium Deficien9, Sdma lU: 19$_7. 1981.
38. Corman. B. Carriere. S .. Le Grimelloc. c., and
Cardin.1. J. P"",imal Tubular Respons< 10 Vari·
ations in E.tracellular Sodium Concenlration.
Amcr. J. PhysioL 2]8: F256-F260. 1980.
39, Cushman, D. W.. Cheung. H. S .. Sobo. E. F..
Rubin. 8., and Ondelti, M. A. lXvelopmcn' of
Specific lnhibilors of Angiol .. in I Converting En·
,yme ( Kin inase II). Pm:. 18: 2778-82.
1979.
40. C uller. G. B.. Jr., Pila. J. C .. J r.• Rifka. S. M.,
Menard. R, IL Sauer. M. A.. and Loriaux. D. L.
SC 25152: A Poten, MineralocOrt icoid Anlago-
niSI wilh Reduced Affmily fo, Ihe Sa-Dihydrale..
IOlllorane Ree<:ptor of Human and R.I Pros\a1c.
J. Ciin, t:mJ.xrlnQ/. MtlOb, f7: 111_5. \ 978.
41. Davidson. M. 8. .• nd Erlb.um.A. I. Role of
logene.is in Urinary Sodium Excrelion: Elucida·
tion by Nicot<>nic Acid Administration During
 Fming. J. Clin. Endocrin()/. 49; 818-23.
1979.
42. O.vi<. J . D..• nd F,.edman. R. H. Mecbani<m.
Regulaling Renin Rele""e. Physio!. Rrv. 56: 1-
56.1976.
43. l)erkx. F. H. ,1.1 •• Ton-Tjio"g. H. L.. Man in'l
Veld. A. J .• Schakbmp. M. P. A.• a nd Schale-
kamp. M. A. D. H. AOlioalion of In'<lioe P/a'm.
Renin by Tissue K.lIik,.ins. J. Gin. t:"docr/nol.
Mrtab. 49: 765_9.1979
44. Oi NicolanlOnio. R .. Mendelsohn. F. A. 0 ..
J. S .. Y.. and Do)"le. A. E.
Dissodalion of Dipsogenic and P",,,,,r R.,pons.c.
to Chronio Conlral Angioton.in II in R....
J. PhYJiol. 242: R498- R504. 1982.
45. Doucel. A., and K.l7.. A. I. Renal P01 ... ium Ad-
aplation: Na-K-ATPa .. ACli'ily.ionS lhe Neph-
ron aflcr Chronie Potassium Loading. Amer. J.
Physiol. 218: f)80-F386. 1980.
46. Dougla,. J. G. Errecu of High POI.ssium Diel on
Angioten.in II ReOOPIOrs "nd Angiolen,;n_ ln'
duced Aldootero"" Prod"Clion in Rat Adren.l
Glomorulosa Ccll •. t:ndoainol. 1(}6: 983_90.
1980.
47. Dougla,. J . G .. and Br",,"n. G. P. EfTecls of 1'1(>-
longed low Dosc Infu,;on of Angiolensin II and
Aldoste,,,,,e on Ral Smooth Mo",le and Ad,.nal
AngiOlen'in /I Rcceptof$. t;ndouino!. III: 988-
92. 1982.
48. Dougl ••. W. W. Polypeplides-Angioten.in.
Pla$ma Kinin •. and Olhe ... Chap. 27. pp. 647-67
of et al. . ed, .. rofeTenee H.
49_ Edelman. I. S. R=ptors and ElfeclOrs in 1/.,..-
mone Action on lhe Kidney. Amu. J. nyjiol.
24/' F 333-F339. 1981_
SO. Edelman. I. S .. and Fa""'til. D. O. Mi""r.looo,_
I;coid •. Acrions I/QI"m. I: 321-64. 1970_
SI . Ep'lein. A. N. Neur""ndoerinnlOj;)"of Thirsl and
SaIl Appetilo_ Chap_ 4. 1'1'_ 101-34 of Ganong.
W. F"> and Martini. L. cd •. f"I'O'IU"s in ,v,,,,orrt-
doerinGloV·. vol. 5. Raven Pre ... New York. 19 78_
52 . ErdOs. E. G. Enlyme Inhibitors of lhe Kallik"'in
and Renin System •. /'roc. i$: 2751_2.1979.
53. Erd6s. E_ G_ Inhib;tors of Kinin"", •. Pro<.
38: 2714-7. 1979.
54_ F.kunding. J_ l.. and Call. K_ J_ Cakium- Dc""n-
denl Regulation of Aldosle,,,,,e Production in Ii<>-
'.1«1 Adrco,l Glomcrulooal Cd )" of Ihe
lonophnre A-23187. 110: 2006_10.
1982_
55. hkunding. J. l., Chow. R.. and Call. K. J. The
Role of Calcium in Ihe Stimulalion of Aldosle-
rone Pr<>dUClion by Adrenocorlicolropin, Angi<>-
len<in II. and Pnlassi"m in lsolaled GlomerulO<a
Cells. Endorrino!_ 105: 327-333. 1979.
56. Fan«til. D. D.. and Park. C. S. Sleroid Hormones
and the Kidney. Ann. Phy.• ;ot_ 43: 637-49.
1981.
57_ Fejes-TOlo. G_. S7.on;\$i. G .. 7.ah.j.zk)·, T .. and
Takic •. l. Urinary E,er.tion .fle r
Ren. 1 in the Rat PhYjiol.
/: 219-22. 1918.
58. Fi ne. l. G .. and Tri'na. W. InAuen<:<: of PrQI,la-
glandin. on Sodium Tran.porl <>f loolated Med-
ullary Ne phron Sogment$. Amtr. J. ny<iol. 2J2:
F383_B90.1971.
59. F<>Ikow. B. Physiological A.p«" of Primary Hy-
""rlen.ion. nysiol. 62: 347-504. 1982_
60. Form,", B_ H .. and Mulrow. P. J. Elfect of Cor-
ti"""'le,oid, on Water and Eleotrolyle MCl;Ibo-
lism. Chap_ 13, pp. 119_89 of Blaschko. Ii., S.)··
• ... G.. Ind Smith. D. A.. ed<_ I/andbool o[
Pltysioloy. <CC. 1. 0<>1 . 6. American PhY'inIoj;ical
Society. W.. hinglon, D.C. \975.
61. Fone. J. G .. Machen, T. E.• and K. J_
Mechanism of Ga.tric II' and CI - Transport.
Ann. RN. PIoyjlol. #2: 111-26, 1980.
62. Fn:<ter. R.. lobo. M. V.. H .. ..d Ma-
m,ie. E_ T. Calcium' I" Role in the Mechanism
of Actioo"" Angioten.in /I and Potassium in AI-
dOSle,one Produclion . /:.·f!docrino!. 1Q9: 2\%-
2201.1981.
63. Fr.nco-Saenz. R .. Suzuki. S .. Tan. S. Y.. • nd
Mul""". P_ J_ PrOSlaglandin Stim.lalion of Renin
Rele ... : Indepondene<: of Il_Adrentrgic Receptor
AClivil)" and Possiblc Mechanism of AClioo_ En-
docrino!. 1(}6: 14{l(I-4t. 1980_
64_ Fray. J. C. S. Slimulalion of Renin Rek.", in
Pe,fused Kidney by low Calcium and lIigh M.g_
"esiuIn. Amu. J. ?h)·jiol. 232: FJ77-F382 . 1977.
65. Freeman, R. H. .• nd Davis. J . D. Physiologic.'
Actioo. of AngiOlen.in /I on the Kidney_ F,d.
Proc_ J8: 2276_9.1979.
66. Fregly. M. J. Thermogenic Medialioo
by D<moreccplor ,nd AngiOle""i" II Path"",,)',.
Fed. P,oc. 4/: 2515-19. 1982.
61_ Frie!o. E. 0_ Salt in Hypertension and the Errecls
of Diu,etic .. Ann. Re'. Ph{Jrm{JCOI. Toxicol. 19:
13_23.1979_
68. Frit •. 11 .. Fink. E .• a nd Truschei!. E. Kalli.",in
I nhibit.,... P,oc. 18: 2753-59. 1980_
69. Fujila. K.. Aguilera. G .. and Call. K. J. Tho Role
of Cyclie AM P in AldO$torone Production b)" Iso-
lated Zona GlomtrulO<a Cells. J. BIoi. CMm. 254:
8567_74.1979.
70_ Fyh"luist. F_. HOrllin8, Land G,onhagen-
Riska. C. Induction of Angiotensin l.conoening
Enzyme b)" Captopril in Cullured Hum.n Endo-
Iheli.1 Cell,. J. C/in. End(}(,inol. Mnob. 55: 783_
6.1982 .
71. Ganten. D .• Fuxe. K.. Phillip<. M. I.. Mon". J. F.
10_. a nd Ganten. U. Thc B.-.in l$Crcnin-Ansinten-
'in System: Biochemislry. Locallizalion. and Pos-
sible R<>Ie in Drinking and Blood Pre!o.urc Regu-
lat ion. Chap. 3. pp. 61-9'1 of G.nong. W. r .. and
Manini. L. cd •. in
0<>1. 5. Ravon Press. New Yo'k. 1978.
72. Gar<:;a-Filho. E .. Malnie. G .•• nd Giebisch . G. Ef·
feel$of Change. in Elccuk.1 POlential DitTeren""
on Tubular Pota.,ium Tran'port. Amu. J.
iol. 23$' F235- F246. 1980
7J. G.rri",n. J. C. llnrland. M. K.. Florio. Y. A.. and
T ..·iblc . 0_ A_ The Roleof Calcium Ion .. Mcdia-
lOr of Ih. Elfecls or Anginten,;n II. Calechol·
'"
amin« "nd V.sop, ... in on the Phosphorylation
and Acti.ity of Enlymes in holal<:d Hq'.'OC)"C'.
J. Bioi. Chtrn. 154: 7147-56, 1979.
73A. Gerber, J. G _ Rolt of PrO$tagla ndin. in .he lie_
mOOy.amic and Tubular EffeCI. of Furosemide.
p"",_ 4]- 1707-10. 1983.
74. Gi.bioch. G .• and Stanton, B. Pot ... ium Trans-
pOrI in lhe Nephron. A,.,., Rr.. nyJiol. 41: 241_
56.1979.
75. Gilmon, A. G .. Goodman. L. S .. and Gilman. A..
cds. Goodman and Gilman" Tht Phorrnacolo,;(ol
80#. of Tht"'JVulir>, 6th cd. Macmillan, New
y", k.1900.
76. Gitelman. J. H .• Klapper, D. G .• Alderman. r . R..
and Blythe, W. B. Ala.Gly_ and Val.A,p (Arg' ).
Vasopressin : Bovine Storage F<>rm. of Arginine
Vasopre«in with N.lriuretic Activity. $titl7Ct
207:893-6,198(1.
77. G<>Idbcrg. M, The Renal Ph),.ioI08Y of Diu,etic •.
Chap_ 28. PI'· 1()()3-) I oI'Orl<>ff. J .. and Berlinor.
R. W.• 00 •. HalUil>ook of Physiology, .. c. 8.
Amen .. n Phy.iological Socitty. Wa.hing'on.
D.C.. 1973.
78. GOld.tei •. L. Adaptation of Renal Ammoni. Pro-
duction to Metabolic Acidosi;: A Study in Meta-
bolic ROi"IOlion . PhyJioiolfiil 21; 19_25. 1980,
79, G<>Id"ein. L. Ammonia Production and Excrotion
in the M.mmalian Kid""y. Chap. 9. pp. 283-316
of Thurau. K" ed. KidNY alUi U,ino'}' T,or/
Physlo/0t y II. Universi,y Park Pr .... Balti""' ....
1976.
80, Gonlek. H, C .. p, 22 of Kramer. H. J .. and K'Uck.
F., ed •. NOf';U,..ic IlQrm(J".. Springer_Verl.g.
New York . 1918,
81. GOt,schalk. C. W, Ronal Ner •• , and Si>dium Ex·
cr<:tion. AM. PhysiO/, 4/: 229- 40. 1919.
82. Grantham. J. J .• Ir i,h, J. M.• and Hall. 0, A.
Stud i•• of Isolated Renal Tubule. in Vitro, Ann,
Rt>'. PhYJio/. 40: 249_11. 1978.
83. Gre. in. R. J .. and Sider. R. S. Ald"",.ro ... Re-
ceptor M..,uremenu DUring Change' in Dietary
Sodium. elUio<:,ino/. /08; 109_112. 1982,
83A . Grody. W. W.. Schrade,. W. T .. and O·Malle)'.
B. W. Acti •• tion. Tron,formation. and Subunit
Structure of Steroid Ho,mone Receptors. Enda!.",
J:141-(;3 . 1982.
84. Gullan,.S. R .. Brazy. P. c.. Soltoff. 5 , P.. Dcnni •.
V. W., and M.ndel. L. J. Me,.bolie In hibitors:
Effects on Metabolism and Tran.port in the Pro.-
imal Tubule. Af>lU , J. Physio/, 143.- FI3J-I'I40.
1982.
85. Guthrie. II. A, /nlroduuory Nutrition. Chap, 7,
Mosby. 51. Louis. 1979.
86. Hab<r. E., and Burton, J. Inhibitors of Renin and
their Utility in Phy,i<>logic Studies. f'ro(, 38:
2768-73. 1979.
87, Haberland. G .. and McConn. R, A Ration. l. for
the Therapeutic Action of Aprotinin, Fed. PI'()('.
J8: 276()-7. 1979.
88. Hayslen. J. P.. and Binder. 1-1. J . Mechanism of
ALDOSTERONE AN O THE RENIN·ANGtOTENSIN SYSTEt.!
p", ... ium Adapt.tion. Am ... J. Physjo/. U):
FI01-FlI2.1982
89. Il.dlin. A. M .. Loh. A. Y.. and Osmond. D. Fi·
bri""I),.i •. Renin Act ivity. Protonin in Nor·
mal Women: Effects of herei.e and Oral Contra·
ceptive Medi""tioo. J. Clin. t.·n<!o<:rilloi, Mew!>.
49:663-71. 1979.
9(). Henkin. R. I, The Rol. of Adrenal Corticos'eroids
in Sensory P"""",... Chap. 15. pp. 2O\t-10 of
/landbook of n}'Jio/agy, sec, 7. v<>l. 6. American
Phpiological SO<:iCty, Washing,on. D.C .. 1975.
91. Ilerrm.nn. 11, C .. Morris. B. J .. and Reid. I. A.
Elfec, of Angiot.n,in II and Sodium Ikplction on
Angiotensinogen Production, Am. J. Phy,iO/, 238:
13145_EI49.1980.
92. Ilia!!. N .. Chapman, l. W.. Da.ido •• M. B.. a nd
Shcinkopf. J. A. Adtenal Hormone. and the Reil'
ula1ion af Serum Polaui"m in Pota<sium·l.oade<l
Adton.le.:tomi,ed Dog •. lOS : 21S-
19,1979.
93 . Hi""'ri. N .. Izumi. A... nd I.hirnori. T. Analy.i,
of Mediating Renin Relea'e
Produced by /-"'Protetenol in Con .. ioo, Doll-<.
Am", J. Physio/. 1)8: F387_F393. 1980.
94. Hoffman. B. F.. . nd Bigger. J. T.. Jr. Diiitali'
and Allied Cardi.e Glycoside,. Cnap, 30. pp.
729-60 of G ilm.n el al.. «h .. r.ference 75.
95 . HOllenb<rg. N. K. Pharmacologic.llnlerruplion
of the Renin-Angioten,in System, Ann. R,".
Pha",u>ro/ <II Toxiro/, 19: S59-82. 1919.
96. Horrobin. D. Pro/octi•. • <>1. 6. Eden P...... 51. AI,
bans. Vt .. /918.
<}7, Hughey. R.. Rankin. B. B.. and Cunboy', N. P.
Acute Acidosi. and Ren.1 Arterioveno", Differ_
enc •• of Glu,amine in N<>rm.1 and Adrenalecto-
mized Rat>, A"It'. J, PhYJiai. 238: fI99-F204.
1980.
98 , Hul'er. H, N .. Ilnicki. L. p" Harbott le. J. A.• and
Sebastian. A. Impaired Renal H' Secrelion and
NH, ProduCiion in Min.rol(>lXlrliOOid,D<;ficien'
Glucocortiooid,Replele Dogo. A",,,,. J. f'hyJio/.
]3]: fl 36-1'146, 1977.
99. Hu lter. II. N .. Siiala. J . f ... nd Soba ..;an. A. K'
Deprivation Poten1i., •• 1he Renal Alkalosi"Pm,
ducing Effect of M;neral(>lXlrtiooid . A"",. J.
Phy'i"/' 135.- F298-fJl)9. 1978.
I()(), Husain. M. K .. Mangor. W, M., Roc k, T. W.,
Wei$$, R. J" and Fr.n1z. A. G. V.sop.....in Re--
lea.., Due to Manual R"'traint in the Rat: Role
of Body Compte$$;on and Comp"riSOlt with 01her
Stre"ful Slimuli . EmJQai""l. 1()4.- 641_4. 1979.
101. Iwao. II .. Lin. c.ooS .. and Miche lalki,. A. M. Ef-
fcc, of Adrenergic Aionisl> on Big .nd Small
Ronin. Am ... J. PAy,io/. 138: E41 6-E420.
102. H .. Ho.S.--C., Michelaki•. A, M .. and
Aoki. T. Renin Relea", fram "lou", Submandib-
ular Gland in Vitro. EmJo<:,ino/. III : 758_166.
1982.
103. Jon"",n. M, D.. Fahri. E. R .. Trocn. 8 , R .. and
Barger. A. C. Pla.m. Epinephrineand Control of
 Pla$rna Renin Activit)': Possible E,ua",nal
Mechani,m •. J. 136:
1979.
lOlA. Kamiy •. F.. Kimura. H.• Takeuchi. T .• Kida. K..
and Na kaga""" H. Effect of GIUco<orticoid$ on
Rena l Net Glueo><; RoIea"" In Vivo in Normal
,nd Diabetic Rat •. Am". J. 145; F221_
6. 1983.
104. Kaplan. J. G. Membra"" C.. ion Tran'flOrt and
the Connol of Prnliferation of Mammali.n Cell •.
Ann. Rtv. rhy.iol. 40: 19-41. 1978.
lOS, Kal1.. A. I.. and Lindheimer. M. D. Action' of
Hormones on the Kid""y. Ann. /l.r •. 39:
97-133.1977
106, Kat>. S. A,. and Mal vin. R. l. lsoclcctrie itcte,-
ogeneity of Se<:retcd Renin OitTen after /l.Ad",.
nefgic Stimulation. I::ndlX,inol. III: 814-819.
1982.
107, Kall . S. A.. and Malvin. R. L Socretion of Newly
Synthe,i,ed Renin, I::ndlXrinoi. III: 20 1_7. 1982.
108, Keise,. H. R.. Gell.r. R, G.. Ma,soliu,. H. S .•
and Piuoo. J, J . Urinary Kal likrein in H),pert.n.
• ive Animal M<>dcl •. PriX. 35: 199_202.
1976,
]1)9. Kin".. R. Membrane·Mol« ul., A.pe<:t> of Tu·
bular Tran'port , Chap. 6. pp. 169-210 ofThurau.
K. e<.L Kidnt!yand Urinary Traci PhY' ioiagy, uni·
•• ",ity Pa,k Pr . ... Balt imore. 1976.
110. K"" •. F. G .• and Di 07.· Bu .o. J, A. The Ho,"",nal
Control of Sodium E.cretion. Chap. PP, 173-
98 of McCann. S. M .• ed. PhYJimogy
II. un;ve",;,y P",k Pre ... B.ltimofe. 191'1.
Ill . G. B. Dru, [)esign: [)e"eloping Now Cri-
ter i. , Scirll<t 197: )6-1.1977.
11 2. Kolet, k)". R, J .. Dluhy. R. G .• Cheron. R, G ..• nd
William •. G, H. Diet.,), Chlor ide Modifies Ronin
Rel.ase in Normal H"mans, j , Phrsiol,
241 : FJ61-FJ6), 1981
113. Kono. T .• Ikeda. F. . O>cko. F.• lmur•. It . and
Endo. J. Biological Activity of d... A'I" -Angio.
ten.in I ;n Man. J. Clin. I::ndlXrinoJ. Mtlab. 50:
40-5. 1980.
114. Kotchen. T. A..a nd Gu'hri •. G. P .• J r. hn in·An·
giote ",in-Aldost.'on. and HYl"'rten,ion. End()-
cri". I: 78_'19.1980.
115. Lan. N. c.. Graham. B. G.• Bamer. C..ond Bax·
tef. J.D. Binding of Steroid, to Minemioco,tiooid
Receptor>: Implication. for in Vivo Occupancy by
Glucocorticoid" J . Clin. EndlXrirUJi. Mtlob.
3)2-42.1982.
116. Lan. N. c.. Matulich. D. T .. Morri,. J. A,. and
Baue r. J. D. Mine'alOCOrtiCOid Reeept<>r. Like
Aldosterone-Bindins Prot.in in Cell Culture. En-
docrirlOl. 1()9: 196)_70. 1981.
117. La .. gh.l. 11 .. and Sooley. J. E. The Reni ...An.
gioteMin.Aldosterone Hormonal System and
Regulation of Sodi um. PO!3$$ium and Blood Pr.s-
' ure Homeostasis. Chap. 26. pp. of Or·
loff. J.. and llerli <l<r. R. W.• cd,. lIandbook oj
PhYJiology. s<c. 8. Am.rican Physinlog;c.T Soci·
ety. W.,h ington. D.C.. 1913.
118, LaU,. 11, Ultra' truct ure of the Glomerulu, . nd
Juxtaglomerular Appo""u,. Ch.p. I . pp. 1_29 of
Orloff and Berliner. edL ,ec reference I 17,
119, L.u",. C, G .• B,olt)'. l. M .• Menachcry. A. 1..
and William •. G. H. ),1elo<lopramide Inhibi .. AI·
do$teronc Biosyntb.,i$ in Vitro. f;ndoerinol. 111.-
238-43.1982.
120. Lehninger. A. 1.. Biochrmlstr)-. 2d ed. Worth.
N.,., York.
121. le><n., N. R,. Peach. M. J .• Carcy. R, M,. Poot.
J, A.• and Munday. K, A. Stimulation of Intes-
,in.1 Sodium and Water T ransflO't in vitro by An-
giotensin II and Analog •. HndO"'rino/, 107: 1946_
53.1980.
122, Lin. M. Il.. Tuig. J. G. v .. R""mos. D. R.. Ake ra.
T .• and Leveille. G. A, lIe.t Producton and N.··
K'·ATP.,. En7.ymc Uni\!; in 1.0an .nd Obe$C
(OO/ob) M ice. An,.." J. PhYJiol. 238: 1:193-
1:1 99.1980.
12l. Lokhand,,'.la. M. f" Buck ley. J, P.• and 53ndby_
al•. B. S, Reductionof Pla,m. Renin Activity by
Cenlrally.Admin i'tered Angiotensin II in An.<-
th«i<cd Ca\!;. Clin. & j,.'xf"rim. I:
1978.
124, Lun. S,. Espi n«. E. A.. and H.rt. 0 , S. Ad,en<>-
o.".lio.1 Metaboli$m of Angiotensin in Sheep "'ith
Adrenal Transplants. Am. J. Physim. 235: 1£525-
E5)1.197g.
I H. Mavin. R. L.. Mouw. D.• ond Vander. A, J. An·
gioten,in: Phy<ioiosical Role in Water-Ocpriva-
tion·lnduced Thi" t of R. tS, 197; 171_ 3.
1977.
Illi . Mann. J. f . E .• John,on. A. K .• ond G.nten. D .
Plasma Angioten,in II : Dipsogenic le'el, and
A"tIiot. "'in·Genero'ing Capacity of Renin,
Am". J. pnysiol. 238: R372 - R377. 1980
127, Margoliu,. H. S .. Hor",it'.. D.. Piuoo. J. J,. and
Keiser. H. R. R. lation,hips Among Urinary Kal·
likrein, Mi neralocorticoid, and Human II Yl"'r-
t.n,;ve Di .. a .. , Proc. 35: 203-6.1916.
128. MarShall. G. R. Structur.-Acti,ity Rel>1ion' of
Anllgonisto of tne Renin.Angime"'in Sy.tem.
Fd Pr<><". Jj.- 2494 - 2501. 1976.
129, Mar'.'. D. Aldo><crone Recep'ors in Rabbit
Renal Cort.. and Red Medulla . t.·ndocrinol. 1()6:
61 1-18, 1980.
130. Matsuoka. H .• and Mulrow. P. J. tI·1.ipO'ropin: A
New AldO$terooe-Stimulating Factor. Sci, net
209: 307-8. 1980,
131. R, E. Aldosterone R.spen .. to Long
T.rm Infu,ion of Angio<c",in 11 and Angiotensin
III in Con.cious Dog. Before and Mter Dieta ry
Sodium R'51rietion, Endocrino/. 103: 459--64.
1918.
132. McCarron. D. A.• Morris. C. D.. Henry. 11 . L
and Stanton. J. l. Blood Pre,sure and Nutr ient
Inlake in the United State •. &it "u 214: 1392-8.
1984.
133. McGiff. J. C. Prostaglandin •. Pros,"eyciin' and
Thrombo.. ne<. A"". PhMmaco/,
21:419- 509.1981.
1]4, McGill". J. C .. I«kovit>. II. D.. Terrlgoo. A .. and
Wong. P. Y.· K. Modulation and Medi.tion of the

Renin Kallikrein-K inin by Prostaglan·
din,. Ftd. PrIK. 35: In_80, 1976.
135. McGilf, J. C. and Na'jlelti. A. Kinin<. Renal
Function and Blood Pr=ure Regulation.
P,.x. J5: 172- 4. 1976.
McKenna, T. L Isl.nd. D. P.. Nichol""n, W. E.•
and lidd le. G. W. The Effeet. of P<>tassium ""
and Lale StepS in Aldooterone Iliosyntho,i.
in Cell. of the Zona Glom.ruloa. t"/Id.x,,·noJ. !OJ:
1411_16.1978
I 36A. Mc Kinlcy. M. J .. Denton, D. A.• Nelson. J. F.•
and Wei,ing.r. R. S. Dehydration Induce$ S0-
dium Depletion in Ral>. Rabbits. and Sh.ep.
J. U5: R287_92. 19SJ.
137. McPartland. R. P .. R.pp, J. P., and Suotan;ic. D.
L. Effeel> of Dexamethasone on E.cretion of Uri·
nary Kalli krein and Urinary Protein in Dahl Salt·
Sen,itive .nd Salt-Resistant Ral>. t:trdoc,. Rsch.
Commun. 8: 1981,
138, Mendol""hn. F. A. 0 .. and Kachel. C D. Acti""
of Angiotensin. I. II and 111 on Aldosterone Pro-
ductiOJl by loolated Ral Adren.1 Zona Glomcru·
Iosa Cell<: Importance of Met.bGli,m and C"'"
version of Peptide> in Vitro. t"ndoc';nol. /06:
1980.
139, Mill •• I. H.. Macfarl anc. N. A, A.. Ward. p, E.,
arid Obika. L. F. O. The Renin Kallikrein·Kinin
Syst.m .nd the Regulation of Salt and Water E,-
cr.tion. Ftd. Proc. 35: 181 _88. 1916.
Mi.oIi .. R. R .. Shopiro. R. E., and Hond. P. J.
Subfornical Organ Elferen" to Neural S)'Slent$
for Control of Body Water. Sdr"" Xl5: 1022-25.
1979,
141. MiyaIDOri. I.. Fit,gerald. G, A.. Brown. M . J..
ond Lewi •• P. J. Prootacyc lin Stimulates the
Ronin Angioten.in Aldostero"" Sy<lem in M.n.
J. Cliw. /;,'trdocrill<)l. M.,an. 49: 493_4,1979,
142, Modling ... R S .. Sbonmulltf, J, M..• nd Aro ...
S. P. Stimulation of Aldostcron •. Renin and Cor-
tisol b)' J. t"ndocrinol. Mnah.
48: 1979.
143, M01" imolo. S .. Abe. R .. Fuxuha, •. A.. TanaKo.
K.. and VomamOto. K. Effect <>f Sodium Rc ... iC·
lion on Pla.ma Renin Activity and Renin Gran·
ule. in Rat Kidney, Am.,. J . PhY.lioi. 237: 1'367_
F37 L 1979.
144. Morti •. D. J. The Metaboli,m.nd Mcchani,m of
Action of Ald"'te""", . /;,·trdoc,. Rtv. 1: 234-41.
1981.
145. Mudge. G. Ii. Diuret;c, and Othe, Ag.nts Em·
ployed in the Mobili z..t.tion of Edem. Fluid. Chap.
36. pp, 892_9 15 of Gilm.n <l al .. cd< .. reference
H.
146. Mullen. P. E .• 1ome<. V. It T. Lightm.n. S . L.,
Unsell. C. and Peart. W. S. R.lation,hip Jk.
t"'cen PI •• ma Ronin Acti vity and thc Rapid Eyc
Mo,cment Pha,e of Sleep in Man. J . 0;'1, f'-n·
doc,I,"", Mnah. $0:466_9. 1980,
147. MUll ... J. Suppression of Aldosterone Bios)'n-
the,i. by Treatment of Rats "'ith Adre"""""i,,,,"
ALOO$TEfIONE AND TliE RENtN·ANGIOTE NStN SYSTEM
"opin: Comparison with Glueoe<>rticoid Effocts.
/;'·trdocri",,/103: 2061_68. 1978.
148. Murakami. E .. 1,1j .... d•• K.. and Kokubu. T. Er·
fcc" of In,ulin and Glucagon on Production of
Renin Substrate by the ISOlated Ra. liver. J. Eft--
doc,j,"", 85: 151_3.1980.
149. Murra),. R. D.. and Malvin. R. l. Intm",n.1
Renin and Autoregulation of Renal Pla'ma ...'
and Glom.rular Filt"'ti"" R.tt, Am.." J ,
iol.116: F559_566. 1979.
150. Na'i)e11l, A .. and Colin.-Chourio. J. Inte",etion
of Mineralocorticoid •. Ren,l Prostaglandin. and
the Renal Kallikrein·Kinin S)'stem Fed. Proc.1J:
\89_8.1976.
151. Navar, LG .. PI01h. D. W.. and Bell. P. D, Dist.1
Tubular Feedback Control of Renal Ilemod)'·
namiC$ and Autorcg"lation. Ann. R,..,. PhyJiol.
41: 551_71. 198(1,
152. Needleman. p" Do"glas. J. T .. Jr .• Jak""hik. 8.
A.. Blumberg. A. L. hlhon. P. C. and Mar·
. h.lI. G. P. Angiotens;n Antagonists as Pharma·
cological Tool •. Proc. 35: 2488_93. 1976.
153. Ncedlem,n. P.. and Manhall. G. P. Angioten,in
Antagonist"' Overview and Projection. F.d, Pro,'.
1J: 2486_7 . 1976.
154. Ody • . C E.. M..;nkovie. D. V.. Hammon. K. J ..
Stewart . T. A.• and Erd(ls. E. G. Purificatiol1 and
Properti.s of Prol)'ICarboxYl"'ptida"" (Angioton-
,ina"" C) from Human Kidn.y. J. Hiol. Om,.
2jJ: 5927- 3t, 1978.
Ondelli. M. A .• and Cu,hman. D. W. En')'mC-'of
thc Renin·AngiOlen.in S)'$lOm Their Inhibi-
tor<. Ann. Rt'I'. 8iochm,. 51: 283-308.1982 .
156, Ondeni. M. A" Rubin . 8.. and Cu,hman. D. W.
Desisn of Specir.c I nhib;tors <>f Angioten,i ... Con.
,erting N."., CI ... of Orally Acti"e
AntihyperteMive Agent<. Sdr..u 196: 441--4,
1977.
157, Park. C S .. Han. D. S .. and Fray. J, C S. Cal·
cium in the Control of Renin Secretion: Ca'· In·
ftux as .n Inh ibitory Signal. Am,". J. PhJ"j/oI.
NO: 198 1,
158, Park. C S .. and Malvin. R. L. Calcium in the
Control of R.n;n ReI.as<, A",..,. J, PhyJio/, 13':
F22_Fn.I9I8.
159, P.ach, M. J, Renin·Angiott",in S)'''em: 8i<>-
chemistry and Meeh an;sn" of Action. Ph},Mo/.
R,v. 57: 313_70.1977.
160, Pederson. R. C. Browni •. A. C .. and Ling. N,
Pro-Ad rcnoco";COt ropi nI Endor Phi n· De ri v.d
Peptide" Coo,dinate Action on Adrenal S'eroid·
ogene,i •. Sci,,,,, XJ8: 1044-6, 1980.
161. Phillip<. M, !. N .... Evid.nce for Srain Angiotcn.
'in and for I" Role in Hyperten.ion. Fed, !'roc,
41: 2667-72. 1983.
162. Plo.h . D. W.• • nd N3'ar. G. Intrarenal Effee" of
the Re nin·Angiotcn,i n S)'"em. Fet/, PrQ(:, M:
2280-5.1979.
16J. Pou.,. D, M.. Dunn. P. .\1 .• and McDonald. W.
Evidence Favoring the E,istene. of Two High
 Moleoular Weight Prooursor Forms of Dog Kid-
ney Reni n. Endo"'inol. 105: 348-51. 1979.
164. Rio •. K.. V'rga, I.. Glb. E .. Ki ... R., Vida. S ..
I... da, G .. Di Gteria. K.• Mcd.ihradlZk)·. K,.
Lkhtw.ld. K., and Veaei. P. Mel -Enkeph.lin In-
hibil. Mincraloe<>rticoid Production in Is"l> ttd
Aldo<toronoma Cell •. J. CNn. E/ldoc,illOl.
54: 656-60, 1982.
165, Ram.. y. D. J. , Brown. C .• Re id . I. A. and Keil.
L C. Effect of Tctradocapcptidc Renin Submatc
on Blood Pressure. Plasm. Renin Acti' ity .• nd
Vawpre"in and Adrenocorticotrupin
t:ndoednol. /05: 14(16- 9. 1979,
166, R.. mu,sen, H ... nd Goodman, D. B. P. Relotion·
,hip:l Botwoon Calcium and Cyclic Nudcorides in
Cell A.li.ation, PhYJioi. He", 57: 421-51)9, 1977.
167. Reioh. I. M .. and Se<>tt. W. N. Aldo<terone and
Sodium Balance: Toward, an UnderStanding of
thc B.a,ic Mechani,ms, MI. Sinui J, M.d. 46:
367-77,1979,
168, Reid. I. A- Elfcot of Angioto n,in II and Gluco-
corticoid. on Plasm. Angioton,in Co""emration,
in the Dog. Am". J, 232: E234_E236.
1971.
169. Rtid. I. A- T he Brain R.nin-Angioten,in S),stem:
A Crilical Anal}'.i,. Ftd.I'FOC. 38: 2255-9. 1979,
170. Reid. I. A .. and MolTat. B. Angioton<in II Con·
centration in Cerebrospinal Fluid after Intra,·cn·
trioul.r Injeotion of Angiot.n,ioogon or Rcnin,
£ndoc,;noi. 103: 1494-8. 1978.
17 I . Reid. LA .• o\Iorr i•. B. J.. and Ga nong, W. f. TOe
System. Ann, Rn'. Phr.iol.
40: 377_410.1978.
172. Reinking. L. N. Control of Plasm. Aldosterone in
M.mm.ls. I'hy.iolotiSl lJ: 23_6,1980.
173. Rod,Iguez. H. J .. Hogan. W, C.. llellm.n. R. N ..
and Klahr. S . Mcohani.m of Aotivation of Ren.1
N. ' -K ' -ATPa.. in tOe Rat: ElTcet.ofPota.. ium
Loading. Am". J, I'hpl,JI. 218: F315_F323,
1980.
174. Roll" B. J.. and Roll •. E. T. Tni",. Cambridge
Uni.ersit}' Pr .... Ne ..' York. 1982.
175, Romoff. M. S .. Keu, ch, G., C.mpcs<. V. M .•
Wang. M.-S .. F,i.dl.,. R. M.. Weidmann, P.• and
Ma<>r),. S. G. Effcot of Sodium I ntako on Plasma
Cat.chalomine. in NOl'mal Subject" J. Clin, E"..
dOC,I1!(Ji. Mf/ab. 48: 26-31. 1979.
116, Schirar. A .• Cappooi. A.. and Call. K. J, R.gu-
lation of Uterine II Rcceptor< b), r:,.
tragcn and Prog •• terone. Endoc'illOl. 106: 5- 12.
1980.
177. Schol.r. D. W,. Mi.hina. T .. and Edelman, l. S.
Di,tribution of Aldoste,o"" Re<:eptor< in R.t Kid·
""y Corlic.1 Tubule. Enriched in Proximal and
Distal Segments. Am". J. I'hyslol. nf.- F36O-
Fl6/>. 1979.
178. Schor. N.. Ichikawa. I.. and B,en""r. B. M. Glo-
merular Adaptat ion, to Chronic Dietar)' S.lt Re·
miction or Exee ... A_" J, I'hpiol. 238: F428-
F436.1980.
179. Schwam, G. J. Na · ·Depcndent H ' Em ux from
Pro,imal Tubule: E,idence for R.versiblo
N. '-H' J. I'hYJioi. UI: F380-
F385.1981.
180. Schwartz. G. J.. and Burg. M. B. Mi"" .. locorti·
ooid Effect$on Cation Tran<port by Conical Col·
lceti"3 Tubule. in Vitro, J. I'hYJioi. 235:
F576-FS85, 1978,
181. Scott. W. N .. Reich. 1. M" and Goodman. B. P.
Inhibition of Fall)' Aoid Synthe,i. Pre,ents the
Incorporalion of Aldoste,ooe·lnduced Proteins
into Membran<$. J. BM. eh,m. 254.- 49 S7_9.
1979.
182. Seal),. J. E .. Atla •. S. A.. and J, H. Pro-
renin and Dthcr La'ger Molecu lar Weight Form,
of Em/oc,. I:
182A. Sealy, J. E .. All ... S. A.. and j, H. Pro-
renin in Pla,ma and Kidney. Ftd, I'roc. U ' 2681-
9.1983.
183. S<lkurt, c. E.. cd. I'hpiolo8)·. 4th cd. Little.
Brown. Boston. 1976.
IS4. Selkurt. E. E.. Hoc"l. G. M .. and Weinbe'ge, .
M. H, Is There a PGE·Renin Feedbaok Con,,<>l
Sy<lem in the Canine Kidne),'! R,,,,,I
(Ba.d) I: 189-200, 1978-
Scmple, p, F .. Nicholl •. M. G .. T,ee. M.. and
Fra.. r, R. [de<-Asp'l Angiotcnsin JI in tho Dog;
Blood Levels and Effect. on Aldoste,one. Endo-
103: 1476-82, 1978
186. Share, L intcrrelation,hips Botw«n Vasopr ..,i"
and the Renin·Angioten,in System . F.J. PNX. 38:
2267_71,1979.
187. Sharp. G. W. G .. and leaf. "- Effectl of Aldoste-
rone and I.. Mechanism of Action on Sodium
Tran,porl. Chap. 25. Pl'. 81 5-30 of OrlolT. J.. and
Berli""r. R, W.• ed" lIandl>ook o/ I'h}'si%gy.
""c. 8. Amerioan Phy.iologieal Society. Wa.hing.
ton, D,C .. 1973.
188. Sil'a. P.. Ros •. B.. and Spokes. K. Competition
between Sodium Reabwrption and Gluconeogon.
esi. in Kidney. of Steroid-Treat.d R.... Am ... J.
I'hy.I"'. 238: F2'fO_F295. 1980.
189. Sladek. C. D .. Blair. M. L. and Ram",y. D. J.
further Studi<$on the Role Angiot.""in in the
Osmotic Conlrol of Vasop, . .. in Releas< by the
Organ·Culturcd Rat HY]lOthalamo.N.u",hypo-
phy,ial Syst.m . t·/ldocriMJ. III: 599-607. 1982
19(1. SI.dek, C. D.. and )0)'",. R. J. R<>l. of Angioten.
.in in the Osmotic Control of Vasopressin Role ...
by the Organ·Cultured Rat HY]lOthalamo-Neu_
rohypophy..al Sy't.m, Endoc,jno/. 106: 17J_R.
1980.
191. Sowers, j, R .. Be'g. G .. ."fartin. V, S .. and Mayes.
D. M, Dopaminergio Modulation of Aldootero""
Sccretion in th. Rhelu, Monkey, E'idonce that
Dopa",ine AlTects the Late Pathway of Aldoste·
rO"" Biosynthesi. b)' Inhibiling Ihe Convor:sion of
Corticosterone to 18·Hydro,yoorticostero"". t:".
doc,I""'. 110: 1173_7, 1982.
192. Sowers. j, R.. M.nin. V. L. Stern. N.. Berg.
G, Oopa minergic Control of 18-Hydro')'CO'liros-
t.rone Re<ponse, 10 Posture. Isometric Exercise.
and Diuretic Admini,tration in Normal M.n. J.
C/in. Endoe,IMJ. Mmb. 55: 475_80.1982.

193. Stahl. R. A. K.. Al1allah. A. A-, BI",,", D. L.. and
Lee. J. M, Stimulation of Rabbit Ren.1 PGE,
Biosynthe$is by Dietary Sodium Restriction,
Am.,. J. Pltysio/, ]37: 1979.
194. St<:<:\e, M, K. . MoC. nn. S. M.. . r>d Neg,.".Vilar.
A. Mooulalion by Dopami ne and EstradiOl of tbe
Central Effe<:t.of Angioten, in 11 on Anterior Pi-
tuitary Hormon< Relea", I:.'ndO("r;"o/, III: 722-9.
1982.
195 . R, T .. Kotchen, T. A., Wolch, W. J .,
Curtil , J. J., and Galla, J. H. Different Meeha-
nisms for the In<reased Enzym31ic Acti . ity of
Rcnin in Plasm> of Patients witn Chronic Ren.1
Failure and Patients Re<:<:i.ing Glucocorticoid
Ther.py. J. Clin. EndocriMl. 50: 989_93.
1980,
1%. Tan. S, y ,. and Mu lrow. P. J. L",",' Renin 8,en-
ti.1 Hypertension : railure to DemOlmrate Ex"""
II·Deoxycorticosterone Proouetion. J, Clin, En-
docrinoJ. M e/ab. 790_3, 1979.
197. Tannen. R, L. Ammonia Metabol ism , Amu. J .
Phys;oI, 13$: F265_F277, 1978-
198. Ta.b. M., and &tier. M. Ii., Jr, ReiUlation of
"Na ' Transport by in on
Kidney Epithel i. 1 Cell Une , J, 8101. Ch<m,
11440-4.1979,
199. Tobian. L. Ren.1 Prostaglandin, in Relation to
Sodium Reiulation. Re nal Blood Flow and Hy-
penension. Chap, l. pp. 81_94 ofThum u. K.. ed.
KidMY and llri""ry Trar' Phpiol"tJ, II. linivtT_
.i ty Pa rk Prc". B.ltimore. 1976.
200. Torrel1i, J. Sympathetic Control of Renin Re-
lea ... AM, •. normaW. Toxito/.]1.. 167_92,
1982.
201. Ullrich. K. J, Sugor. Amino Acid and Na ' Co-
transport in the Proximal Tubule, Alln. R ..,
nyJial. __ 181_95, 179.
202. Veldhu;,. J. D.. and Melby. J. C. liolatcd Ald<)-
sterOn¢ [)cfidency in Man : Acquired and Inborn
Errors in the Biosynthesis or Action of Aldoste·
ron'. Endrxr. R",. 2: 495-S17, 1981.
203 . Vesley. 0 , L. Angiotensin II Stimulates Guany.
late Cyclase Activity in Aorta. Heart and Kidney.
Amer. J. Physiol. 241); E391_E393. 1981.
21)4. C. J" and Prin".. M. p, Adren.l Reiula.
tion of ROiional Br.in Angioten.inogcn Content.
EndocriMl. 106' 337-42.19 80.
Additional references added in proof will be on page 893 .
ALDOSTERONE AND THE RENIN·AJoIGIOTENSlt<I SYSTE M
205. Wal .. r. M. Oi • • lent C .. ion" Phy.i""hemic.l
State in Glomerular filtra,e and Urine and Renal
Excreti(HI . Chap. 18. pp. 5S5-86 of Orloff. J .. and
Berliner. R. W.. ed •. lIandbook of Php;oIogy,
$«.8. American Phy'iological Society, Washing-
ton. D.C .. 1973.
206. Warnock. D. G .. and Rector. r. c., Jr, Prolon Se-
eretion by ,he Kidncy. Ann. R",. nyJiIJI. 41:
197-210,1979.
207. WaShburn. D. D.. Kern. D. C .. Orth. D. N.. Ni-
ehol""n, W. E .. Chretien. M .. and Mount. C. D.
Elfect of /:I.Lipo,ropin on Aldoste rone P.-ooU01Lon
in the Isolated Ral Adrenal Cell Preparation .
J. Clin. /:·ndouino/. Mrrah. 54: 613- 18.
I 982 .
208. Will, P. C .. Lebow;tz. J .. and Hopfer. U. Indu<>-
lion of Amik>r ide-Sen<itive Sodium Tran.port in
the Rat Colon by Mineralocorticoid •. Alii"'. J.
Phy,io/. 138: f26 1-F268, 1980.
209. Williams. G. It.. McDonn<II. L. M.. Tai,. S. A.
S., and T.it. J. P. The EIf.. t of Medium Com-
position and in vitro Stimuli on the Conve" io" of
Corticosteron< to Aldosterone in Rat G lnmeru-
losa Ti"ue. End""ri""f. 91: 948_60,1972.
210, W right. F. S. and Briggs. J. p, f<:<:dback Control
of Glome,ular Blood Flow. Pr<;su rc and Filtra·
tion Rate. Phy, ;oI. R.v. 59: 9S8-1006, 1979.
211. Yoong. D. B., and McCu. R. E.. Role of the
Renin-Angiotensin Sy'lom in Pot ... ium Control.
Am"', J, n,·s.oI. 138; R159_ R36J. 1980.
2 12. Zen ..., T. V.. lierman, C. A.. " nd O.-i,. B. B.
EIf""t, of C.lCium a n<.l A23187 On Renal Inner
Medullary Prostailandin E, Synthe.i" Am..r. J ,
Phyj;oI. n8: E371-E376, 1980,
213. Zimmerman. B. G .. Wonll. P. c.. Koonensi,. G,
K.. "nd Kraft. E. J, No Elfcct of lntrarona l
Com,""ing En,yme JnbiJ:)i,ion on Canine Renol
Blood Fklw. Amer. J . PhYJio/, 24J .. H277-H28l.
1982.
21 4. Zipler, R. D.. Meidar. V ., and Hortoo. R. Char-
acter;"ie, of Aldosteron< Binding in Hum.n
J. CUn. End""rinoJ. Mnab. 50: 158- 62.
1980 ,
21S . Zucker, II., Gleason, S , D.. and Schn<ider. E, G.
Renol and Endocrine Re' ponle to Water o.:pri·
>ation in Dog. J, PhYJio/, 242: R296_
R302. 1982.
 10
Vasopressin and Other Regulators of Water and
Electrolyte Metabolism
make major contributions \0 the
of body waler con1cnt . Since they ao-
oomphsh this indirectly, m<!:Slly by promoting s0-
dium conservation, chronic overdosage can invoke
hypcrnatrcmia and cdl dehydration despite expan_
sion of the ECF.
The mammalian hypothalamus synthesizes hor-
moneS that facilitate water reabsorption and reduce
urine volume. The peptides can lower Ihe osmotic
pressure and Na ' concentration of Ihc bl<'XXl . The
beSI known and m<;ISl widely distributed of the reg-
ulators is arginini' vasoprt'ssin (A VP). It derives its
name from its arginine cantom and its ability 10
stimu late vascular smooth muscle, bUI it is also
called omidiww;c hormone (ADH).
DIABETES INSIPIDUS
Diabetes insipidus (DI) develops in animals deprived
of either the hormone Or the ability to respond to it.
DiaMles inereased urine flow. The term in-
sipidus (tasteless) r:fers to the hypotonic, glucose-
free character of the fluid.
The pOlyuria Can be massive. Healthy humans ex·
crete liters of urine daily under ordinary
conditions. Thos: amic t:d with mild ADH defi-
ciency liters. bUI individuals totally
lacking the hormonc have been known to excrete up
to 47 liters (96).
fluid volume depletion invokes se·
vere thirst and polydipsia. Humans totally lac king
ADH may ingest 50 Or more liters of fluid per day.
sinc<: they muSt also replace water lost via the respi·
ratory and gastrointestinal tracts and the skin . AI·
though the aCme eff:cts of the hormone deficiency
do not threaten survival. they seriously impair the
quality of life. Most beverage cups hold 0.2 liters or
less. and the desire to void is invoked by the presence
".
of as li llie as O. 15 liler of urine in the bladder. There-
fore ...verely afflicted subjects cannot steep for ex·
tended periods or cngage in activities far removed
from the required facilities,
Water deprivation can reduce the urine volume.
However, the CQnscquenccs include persistently un·
satisfied thirst, weight loss. and hypernatrcmia. Se-
vere water restriction lead, inevitably to dehydration
and inability to maintain normal blood volume and
body temperature. Although the CQmpensalory
mechanisms described in Chapter 9 provide some
protection, Ihey cannot CQrrcct the problems.
When H,..DI mts are w.tor dep,i ..d. they display
some limited .bility to concentrate urinc. In one study.
the plasma,u,ine osmol.Ii,)· ratio '(JSC from 0.47 to 1.68
within 48 hours. and the urine "0W de<:lined from 90.5 to
8.3 pl/min/ pe, tOO g bod)" "'eigbl. Glomeruta, filtra'ion
rate fell. urea accumulate<! "'ithin the bloOO plasma. and
tess Auid wu delive,ed to the oOlleo,ing duotS of the kid·
ney. How.ver. the animal, !osl ,ubstantial fractions of
thei' body weights .nd tbey su!f.ftd <:Ievation. of the he-
matocriu (SI).
Etio l09 Y of Human 01 (3, 129 )
T he terms h}'pothalamk and D I are applied
to oonditions of absolute Or relative A DH deficiency.
T he disorders are also known as pituitary and vasil-
pres"i"",etUirive Di. neurohypophysial bor·
mone concentrations arc subnormal but the symp-
loms can be alleviated with exogenous A VP and its
analogs.
Genelic defects, head injuries. infe<:tions. surgical
trauma. and pressure by brain tumors can
affect synthesis and/or re leaS(: of A VP. Production
of excessiv.: quantities of "oxytocinascs" and other
e.>.ymes can promote excessively rapid honnont
degradation. $Qme individuals make antibodies di·
'"
reeled against cither Ihe peptide Or its receptors. but
the ability 10 respond 10 high ooncentrations of lbc
pcptides is retained.
Nephrogenic 01 (42) results from inability of lhc
kidneys \0 respond to ADH because (a) the recep-
tors ar. abnQ,mal Or present in \00 few numbers: (b)
hormone-receptor binding is not coupled to e"ents
that should follow; (c) the Henle loops are damaged,
or lhe kidney centa;ns 100 few of the long type (Ihc
loops ar. IIOt lhc direct hormone largets. but Ihey
support lhe water<onscrving actions): (d) ureteral
obstruction exerts back pressur(: On the kidney. and
;1 thereby interferes with ADH aClions; or (e) phar-
macological agents. electrolyte imbalances. and
some bo.monal disorders antagon;,e ADH actions
on the kidney.
Animal modd$ used for lh. study of neph'Oilcnk DI
include a suain of mice wjlh undersi,ed kidne)" and 100
few nephron._ and anolhe< ,'rain with ",=.ioel)' .horl-
e""d Henle loops (161). The ",ion. of ADH on Ihe kid·
ney ar<: believed to be medialed via cA).1P. pe . anlago-
ni'" ADH. since they inlerfere with .Mn),late eycl.,e
aCtivalion .•lfecl r<:nat blood now. and exert aClion. on
Ihe Henle 1001'$ lhal dimini.h A DH elfecl i' .. ne'" (I
Lilhium and lelracyelin. reduce cAM P generation. Lith·
ium addilion.lIy .her, PG metaboli.m (19). in,... ke.
IhiNI.and inh ibits ADH sccr<:lion POI ... ium dcple.
lion depre"., mil<>cbondri.1 generolion of Ihe ATP ,..,.
quire<! to ,upporl aClive tran'pDfl and the maintenance
of ion gr.d i.nl> wilhin the kidne), (42). SuueSlioR'that
h)'po'.lemia antagonizes ADH by promoting PC ge""r·
alion 'r<: I'IOt eon.istent with observations made wilh pe
synt he,i. inhibitors (13).
High con.:en1ralions of caleium ion, in terfere wjlh
, ",
I
O-C-COOH
I
'",
Chlorpropamide is one of the sulfonylureas dis-
cussed in conjunclion wilh Ihe trealment of malu-
rityo()nset diat>ctes mellilus (Chapler 5). It seems \0
slimulale ADH r.lcase and 10 also exert peripheral
aclions Ihat synergi?.e wilh those of Ihe hormone.
Both inhibilion of cyclic nucioolide phosphodiester-
ase and direCI intcraClion wilh ADH receplors have
been proposed (47). This agem is effeclive when
taken orally. bUI;1 lowers Ihe blood glucose wncen-
lralions in some palienl', Tolbutamidc ;s anolher
memt>cr of Ihis pharmawlogical group wilh similar
biological aclivity. (However. glyburide is hypogly·
cemic and diuretic.)
V"SOPRESSIN "NO OTHER REGULATORS
ADH stimulalion of .denylate cycl .... Cbronic... vere
hypercalcemia can lead to the depos ition of ealcium salt.
within lhe Henle loops and distal lubul ...
The lerm '"neurogenic [W' is applied to Ihe rare
U:;e$ in which Ibe primary problem is polydipsia .
(:Qmpulsive walcr drinking can t>c ··psychogenic". or
a wnsequence of impaired meehanisms for regula-
lion of thirs .. "Beer polOmania" is an o.'erdcyeloped
laSle for Ihal i. coupled wilh fa ilure 10 ingest
su fficient food 10 mainlain electrolyle balun..: (44).
High a lcohol inlake exa..:rbales the problem'. since
;1 inhibilS AO H release (5).
T re a tme nt ( 96 , 13 1 )
When the primary problem;, inabilily 10 'ynlhe.i?c
AOH. subSlilUlion Iherapy is obviQUs solUlion.
A VP and lysine vasopr.ss;n (L VP. a chemically and
biologically related hormone made by <;ome mam_
mals) can be la ke n inlranasally_ bUI Ihey mU'1 t>c
adminislere<:l al frequenl inlervals. He sidoxlfeCI S
include elevalion of the s}'1lemic blood pressure and
irrilation of Ihe nasal mucosa. Synlhetic ana·
logs. and especially l-deanlino.8-[)..arginine-A V P
(DDA VP. desmopressin) provide Ihe advanlages of
higher amidiuretic jXllcncy. longer duration of ac-
tion, and minimal effcc.. on smooth mu<cle. Neither
the natural nor synlhelic peplides find much use in
Ihe lreatment of nephrogenic DJ.
Patients who make ADH bul do nOI release it in
suffieienl amounts often respond to agenls such as
clofibrale (Atromid) and carbama7.epinc (Tegrelol).
These drugs are nol effeclive in Df fllIS,
'" \ ,I
I
'"
,
c=o
'",
C",bamazej)On<
EFFECTS OF EXC ESSIVE ADH
The syndrome of inappropriale antidiurelic hormone
(SIADH). in which Ihe levels of A VP arc
for the Slale or hydralion. can develop a' a consc-
quen..: of ..:nlral ncrvQUs system disorders. and in
suffering from lung diseases affecting
chemoTCe<:ptors (pneumonia, tut>crculosis. abscesses.
carcinoma) Or from leukemia or pancrealic Iumol'<
(44). The excessi"e ""aler relention of some palienlS
wilh hepalic cirrhosis may also t>c rclale<:llo elevaled
levels of circulal ing ADH, During pregnanCy . 100
much ADH may t>c released along wilh
 ,

4 /s:;,e -P7" - Ar:__ -NH,

,
Asparagine-NH,
Fig . 10-1. Sl<u<tu,. 01 8'QitW>e
va"",' •• sin.

When large doses of ADH arC '.p"'aledly admin·
istered to experimental animal.. thcre is transient
water retenlion and lhc blood pressure oflcn ri,<!S.
After chronic (realment. thc animals may display
"=3PC" from the effecls that is associa ted with na·
triu resis (106). Large doses of the hormone addiliOl1-
ally stimulate the smooth muS(1c of the gUI and
uterus. and abdominal and vulval pain arc s« n in
patients lakin, replacement therapy. The plasma
gluC<liSC levels may be raised by ADH.
Some re<:ently developed ADH antagonists thaI
have been tested in experimental animals are dis-
cumd later. Agents of thi' kind are IlOt yet available
for dinical use.
CHEMI CAL NATURE OF ADH AND OF
RELATED NEUROHYPOPHYSIAL PEPTIOE S
The structure of arginine vasopres,in is shown in
Fig. 10-1. along with the numbering S)'stcm u'I'd to
identify Ihc ninc amino acid oom]l<lnc nts. (Some au-
thors regard the two cysleine moietics as oomponcms
of a single cystine and therefore refer to the struc-
tures as octapeptides.)
A VI' is the major antidiuretic hormone of mam-
ma Is. The domcstic pig produces Iys; ne vasopressin
(L v r . Fig. 10-2). while some of its relatives (wan-
hogs. hippopotamuses) makc LVI'. A vr.
or both. LVP has also been identif,cd in a slrain of
Peruvian mice. The lysine varianl has biological
properties almOISt identical with those of AVP but its
antidiuretic polency is only tw"thirds as great even
in the animals thai nlake il . The difference probably
has no physiological importam;e. since AOH $Ccre-
tion can be increased severnl fold when more is rc-
quired to mainlain hydration .
Vasopressins have been fouod only in mammal,.
and only Ihese vertebrates produce urea-rich. hyper_
tonic urine in ils presence. In addilion It> effects on
water reaboorpt;on . the peptides affeet other aspect<

",'S67eO
Cyo- TY' ·Phe _Gln_A..,.eys. Pro· Arg- GIy- NH,

Cyo-TV" Phe-Gln-A.,.·cr.· P,"·lYS.GIy.N fl,

0,..- TY' ·lio·GIn- P10' Ar<;l -Gty-NH,

Cy •. TY,·lie.GIn_A"".ey..Pm.leu_Gly_NH>
.
Cy.· Ty' -II;" ·''In_Asn_ 010' Pro- "". (;ly_Nrh

CY'-TY' -Pe- se,.A.,.·Cy.· Pro-II"· GIy-N K,

.
Cy.· Tyr.Iie·s;,,· PM_Cy,_P'o-G"In-Gly _N H,
.
• FIg. 10-2. NOIJ,O/"Iypofltlylill
Valltocin CY'-Ty,. De·GIn·Asn.o,..- Pro-Vat· Gty-NH..

Cys-Ty,.
. . .
.As<>. Asn'Cy,' Pro· Leu· my_Nfl>
poptKSoS, " .. ",is'" incIicate _""'" acid
moieli. . lhl>' ct;fIet (,om tho one. ;n
.<9....... va$Opt"",,in,

ey..
,
Tyr ·1Ie·Gln· A,.,·Cy.·Pro·Leu·Gty·
. NH,
OXVTOCU.
/
, Tyr· k·GIn ·A"'·Cys-OH
Cys· Plo·leu·Gly.Nfb
MELANOSTATIN
PLG (me'a"".,.,". MIF·II
T
pcntapepti<\e
Toc," IM IF-III
of kidney function, systemic blood pressure. !he se-
cretion of some learning and behavior.
and probably also extrarenal water metabolism.
Arginine vasotocin (A VT) watcr a nd
electrolyte balance blood pressure in all 11(",'
mammalian vertebrates. Thc kidneys of reptiles. am·
phibians. and fishes lack the Henle loops needed to
produec hypertonic urinc, but A VT can Mill promotc
conservation of water by affecting renal blood flow,
glomerular filtration. and (in some species) tubular
\ransport (48) . Since AVT h, been identified in
every cia" of vertebrates. including the cyclOSlomes.
it has been speculated that it represents the eYUln·
tionary precursor of all the neurohypophysial nona·
peptides (12). It is antidiuretic in mammals. but il
would be less u'eful for this purjlO5e if secreted inm
the systemic circulalion. since il also strongly con·
tracts uterine muscle.
Thc neurohypophyses of mammalian fetu .... se-
crete considerable quantities of A VT, Laler. A VP
replaces that peptide in thc hypothalamus. (Some
A VT is made in the pineal gland and other circum·
vemricular organs.) According 10 One concept, A VT
plays special roles in regulation of water balance in
lhe fetus (which is regarded as an aquatic animal),
and the "switch" is associated with maturalion.
Some investigators cite the change an eumple of
the now notion that "ontogeny re-
capitulates phylogeny." Hypothalamic A VT has
also been implicated in the regulation of pituitary
functions such as gonadotropin release (I 39).
The three hormones just cite<.! all e<,ntain a basic
amino acid at position 8. With the exception of the
cyclosmmcs. most or all vertebrates secm to produce
at least one additional peptide with a neutral amino
acid at lhe 8 posilion. Mammals make oxytocin
(aT), which has SOme effecl.! On blood pressure and
water balance but functions primarily as a regulalor
VASOPRESSIN AND OTHER Rl:GULA TORS
F ig. 10-3. dew_'iOn
ptodu<:t. of o.ytOCin II\IIt hOY. _
in>plicale<j . . bioIogicol regu!OI"'O .
of contraction of the smoo!h mmcle of the uterus
and myoepithelial edls of lhe mamma'}' gland. aT
ha. al'iQ been identified in the ratfosh. bUI ilS func·
tion. are not known. In birds and SOme other non-
mammalian vertebrales, A VT exertS innucnce, On
the female reproductive tracl that are comparable in
many ways to aT stimulation in the mammaL
Mesotocin (MT) occurs in bird" replile •• amphibian.,
and lungfish.s, II share, 'Om. biologicat prOflCrtit< ",ilh
Ih. mammoti •• Putali •• rolo. in Ih. '.8"lation of
water metabotism are Ciled laoer, lsolocin (IT). iethyQto-
ein and alumilocin (GT) have been identifie<l in ray·
nnncd fishes. and .atitocin and .. pargtocin in the dogfish.
II. peptide of a. yet ,tructure moy be pro-
duced by tb. st urgeon.
There arC indications that lhe nonapeptides func-
tion as pffhorm<mes. Enzymes that catalyze their
cleavage into smaller molecules are present in sev·
eral parIS of the brain (137), and innuences of the
products on behavior and on the release of other hor·
mones ha"e becn demonstrated. It is not certain,
however, that all of the small, biologically active
peptides related to the nonapeptides are derived
from them in vivo. There are aloo controversies con·
cerning their potcncie.. and thc possibility that the
functions as\:ribed to them are. in fact. performed by
other regulators.
O,ylo<in can be cle •• e<l in .;1r0 to yield to<inoie acid
,ing mucture with no ,ido ch.in) and. lripeplide.
(PLG. Fi" 10-3). Since PLG can in·
hibit reka .. of melanoc}'te 'timulaling ho'mone (MSH)
from the piluitary gland il has been called MIF·1 (mel.
aOOC}'lc·inhibiiOry faclor t) (139) .nd md,lIO$lal;n
(\ (9). The co,respoo ding peptide from AVP (pro-Argo
Giy·NI t,) h.., .,imita< bioto,;c.t propen;e$ (62).
h has been by some thaI locinaic acid (which
can be Oblaincd from II. VT.oo MT", well as from OT)
posse'''' melanocyte·stimulating hormone r.te ..;ng ac-
livil)". arkl II>< mokcule h.o, boen <.nod MRf. A ponla" Ihe various segm<:nl$ of the lIenle loops. pres-
poplickd.. i",d f.om i, (fi,. I().l) .... y inbi bil'hc: "",re. enee of subilanlia l numbers of nephrom "" th long
lion. anod i, i< k..... IS M If -II. loops is known 10 be essenlial for prodl,lC\ion of con-
AVT i'""lf. in qlOa1l' i'Ocs" k>w IS 0.001 PI- c;on do- «nlrl,ed urine_ However. as d iseussed laler, it is
ClUse IIIe: pi, uitary &land MS H O:O,II<n' of mia:. if i, is now recognized thaI lIi1Tas,,"c/ I"" featuf'CS of
injec,ed direnly inlO Iiw: 'hlrd .enlrick of lbe brain Ihe rerutl cells. the bel","«:n
(119). and i, <;an b!od 'he inc", ... ,hat OIM ........ follows
<<Il10 .....1 oflM pine.1 gland_ 11 also ""e ...... Ih. incre"",
in bypothalamic PLG conl.nt Iblt rollo,", pine.loc,omy.
PtG. in lu,n. promotes r.leaK or AVT into lb. «rebr<>-
spina l ftuid or •• ". Ii Ii If
A ... u-ted observation is thaI duri", the nilhl (...·h.n
s - c - c -c - T)'f. Phe·G!n·A$<I·eys·PI'QoO·"'9-G!y-NIi.!
seve. al .nl)·.... aClivi,ic$ a.e hiJh). lbe rlU pi ......1.ela.se> I Ii Ii I
AVT bill $IOta AVP. ... pi ......1
&land pcptid .... and ,he MSH alrcctcd by ' bern. are all O(MVP. .. inQ.e.[).Ar$-'\VP:
CIi'lQIIy use!uI .... -.retic .... n ....... pessor octMIy
implicated in "'Iuu-tion of «nlral ftC"""" system fune-
lions Illal show lOCI ob.ioou. n:ialionships 101M of""",nJI
piglllllntalion.

AOH RECEPTOR ANTAGONISTS

T h< $Carch for clTeelive r.ceplor anlagonists has
been frouShl wi,h numerOUS difficullies. M any oflhe
peplide!; Lack specifICity or show agonisl
activi ty, and il has thus br not been pmsiblc to to-
tally 5I:p:ilmu: the anlHtnlid iuretic. anti·pros.5Of. and
oxyllxi ... likc pnlpeni"".
Evidenlly, the ",eeptOl"S thai mediale pressor rc-
IponSCJ(lilTcr from Ihe ones thaI conlrol antidiuresis.
They arc al$Q more readily an lasoni1.cd by availa ble
mel hods. possi bly becau5c Ihere are fewer ' ·<pare'·
1)11 muscle than on kidney
,\n A VP analog """"c;"lIy elTecti...:: for anlagonir.-
the pRUOI' respo' "1 10 lhe hormone (99) and
shoWn to affect blood pressure
dogs to (150) iuhovo'n in MS. 1().4_ The
effects 0( vari0u.5 on diuretic rcsponilCS
ha...:: becn described (140), and the Slruelures of pa-
I<nl. flirly se\e<:livc anlasonisls of the ADH ....
sponse (98) arc also prcsenled in fig. 104. Sludies o (Cli.!,,· [).I ...· PhQ· Val· A..,·Cy.· Pro .A'g. GIy·
on ralS raise the hope Ihat clinica lly clTcelive
will soon be available . ,O_E,
Some substances unrdaled 10 A VP (e.g.. an· o (Ct-I.,).. T)'f -PM -Val-Asn·C,.. P .... Atg. GI)'.1>IIi.!
tibiotic dcmcelo<::yc\inc) can aRI*gonizc 1\ DH effects
on kidney, bUllhe mechani$ms are different_ The
side-clfeclS p..-c\udc Iheir use for treatment at waler
relcnlion. Fisure 104 includes an I.V P analog that
clcvatcs blood prc50Sure (68). o "
o "•• "·•• •
,:l- ;C •
•
PHYSIOLOGICAL MECHANISM S FOR
CONCENTRATING URINE I I
Functional Anatomy 01 the Kidney T
o o"
'Y0 0 ••
•
•
0"
To some utenl, il hall been possible \0 relale eerUtin
of Ihe ",uelural features of lhe kidney to abililY
" " "
10 eomcrve ...... Ier. MO&I mamma ls have Ihree kinds
of ncphrom lhat can be dis\inIUi$hed on the basis of '19. 10-<1. _M .. ·>+"".t ago .If .1I9c1io ..... '1 ....,0
thei, locations wilhin Ihe kidney and 'he kngths of
".
nephron ""smcnts and blood (27,87), but the
distributions of AVP receptors (lOS) are major de-
terminants of the functions.
Grossly. lhe kidney can be di.jdcd inl0 a superf,·
cial rot/u and a mor<: internally located medulla.
The cortex contains Ihe glomeruli. the convoluted
portions of the and distal tubules, the
upper parIS of the straight tubules (wbula recta).
and the cortical origins of Ihe coikcling ducts. Col·
lecting (wone<.:ling) tubules interposed between the
distal convoluted tubules and lhe beginnings of the
coilecting due\s arc more prominent and more
arched in some species Iha n in others. A single renal
artery thaI comes dirC\:11y from the abdominal aOna
cnlers Ihe hilus of Ihe kidney. In the larger animals.
it breaks up into interlobar arteries Ihal cour.;e \()-
warothe periphery. The interlobar arteries give ri",
10 arcuate (arciform) arteries within the cortex. and
Ihese give off inlc rlobular branches. Some of the lat-
ler directly supply the more superfic ial parts of the
kidney. Others provide the afferent arterioles 10 the
glomeruli. Thus. the cortex receives its anerial blood
directly.
The renal medulla is highly developed in all mam·
mals that make strongly hypertonic urincs. It com-
prises OUler and inner and it relX'ivcs its blood
supply from the efferent arteriole> of Ihe glomeruli .
The outer 7.on. is subdivided into ouler and mIWr
Slripes. The forst of these comains the straight part.
(pars recta) of the proximal and distal tubules. The
same nephron segmenls arc known, respectively. as
the thick descending and thick a=nding limbs of
the He nle loops. No direct relation,hips belween the
width of the outer stripe and the ability to wnser\'C
water have been demonstrated. (The region is wide
in ra ts with quite good resistance to water depriva·
tion), bul it is narrow in both Ihe sand ral that lives
in thc desert and the human capable of producing
only moderalely conccnlrated urine 187).) Collect·
ing ducts that originate in the cortex widen as Ihey
paslthrough the outer stripe, and the)" receive fluid
from the collecling tubules of this region.
The inner stripe is universally prescnt. Jt houses
the thick a ..ending and thin descending limbs of Ihc
longcr Henle loops. The inner 7.onc of Ihe mcdulla
forms Ihe renal papilla that protrudes inlO the pcl'is.
The following Ihree types of nephrons have been
described (14):
I. Corlirol or superficial: The glomeruli. t he con·
voluttd ponions of Ihe and distal tubules.
and Ihe wlle<;ting duct.! are in the OUler Ihird of Ihc
The 1·lenle loops. which arc very shorl.
extend only u far (he outer Slripe and they lack
Ihin 3licending segments. The slraight portions of Ihe
proximal (the thick de ..ending Henle loops)
VASOPRESSIN AND OTHER REGut..ATORS
a nd straight portions of distal tubules (thick
ascending portions of the Henle loops) are in the
OUler stripe. A ,cry shOrt. Ihin descending :;egment
of the loop reaches as far as the inner stripe (Fig. II).
5). Each afferent arteriole that from a cor-
lical nephron breaks up imo peritubu-
lar capillaries thai suppl y the proximal. di'lal. and
collecting tubule of Ihe same nephron and commu-
nicate with pcritubular eapill"ries of neighboring
nephron' via a cortical plexus.
2. Juxtamedullary: The glomeru li and convoluted
portions reside within the inner third of lhc renal
cortex. The He nlt loops are long and they have well-
developed, thin ascendi ng. as well as descending.
limbs that pcnetrale deeply imo Ihe inner medulla.
(Some lur n within lhc papilla.) The collecting lu ·
buies join Ihe collecting duct.! tha t descend from
above.
The efferent arte rioles arc large compared with
those of the conical-type nephron •. They give off
small branches that provide a capillary supply 10 the
convoluted tubule •. However, Ihe main portions of
the vessels div ide in the ou ter wipe a nd Ihey become
the de ..ending vasa reCla thai travel in ,·ucular
bundles toward lhe papilla. At various le'·cls. some
vessels leave the bundles to feed capillary networks
of the rcnal medulla. The are especially
dense in the inner stripe. Btood teaving the capillar.
ies COUISCS upward in a ..ending vasa reCla . Some of
the ase<:nding veSliels travel alongsidc the descending
ones in the bundles. bUI others do not.
Some sj>Ccies differences in Ihe organi7.ation of Ihe
vascular bundles have been linked with urine con-
eentralion . In sand rats. mice. and others able 10 pro-
duce highly concentrated urines. thin de>e<:nding
limbs of the shorl loops of the nephrons arc incor·
porated into the bundles. Evidently. urea is trans-
ferred from lhe blood vessels to the cortical nephron
tubules via this rOUle (172) . (Some urea is belie\'Cd
to be Iransferred from vasa recta to corlicaltubules
in olher species as well. although the bundles conlain
only blood vessels.) There is no mingJiIl{l of cortical
and medullary capillary blood .
3. Midrorlical nephroru: These have long. thin as-
cending Henle loops bUI no thin de ..ending
segme nts.
The kidney receives 15%-25% of Ihe cardiac out·
put. and cortica l blood now is around 3-5 ml/min/
g. Although mcdullary flow is only one·lenth as
greal. thc supply i, good when compared with Ihat
of most other organs. Blood How redistribulions
can cause Ihe GFR ro range from 5 to 100
ml/min in humans. but Ihe rowl blood flow seldom
varies by more Ihan 50% under physiological condi·
tions (6).
 Midoorli<;al

A. Q;all'amrnat<: 'epresenlalion 01 neph".ns glQmcruli in $\Jpcrficil>l.

m«ortical. 300 ju,lamedun.t)' reiJion. 011hc kidney JU<lame<lull.t)'

B. ConcenlraliQn lI'_nt c. Osmotic cl\anges in tuoo lar

,"""oundi"9 thin Henle lOOPS fluid passing tfvough the Henle IQO;>

j t
•

D. ""',ernen,. 01 Oons
aOd wa'er conlril><ot"'9
,,'
Fig . 10·5 . Wat ... and el6OtfOly'• • xc!>anveo IOCI"O$S long
H<tnie loops.

'"
Func tio ns 01 the Henle Loo ps
The collecting ducts arC the major siles for adjust-
ment of urinary water excrctian \0 body needs. and
they contain most of the ADH receptors. Their func-
tions require the establishment and maintenance of
a highly hypertonic within the renal
medulla. The Henle loops play major roles in
taining Ihal environment. Some of the COntro.-crsies
over Ihc mechanisms arC attributed 10 marked 'P""
<;ies variations in .\rutlu"" as well as functions
(108,125). but Olhers result from lhc need 10 make
assumptions about Pl"QCc"""s thai haY<' not as yel
been directly m()!litored.
The ability to CQncentrate urine varies widely
among the mammals. Mountain beavers and musk_
rats arc alone end of Ihc spectrum, since Ihcy sel.
dam need 10 oonscrvc water. and they have minimal
resistance to dehydration. They usually excrete hy-
potonic urine. and they cannot achieve concentra·
tions greater than twice those of the blood plasma .
Close to the other end of the continuum. "'"C find
sand rats that seldom encounter drinking water,
They happily consume plants with hypertonic sap.
and they can produce urine 14 times as concenlruted
as blood plasma (125) , Australian mice arc even
more remarkable. They Can safely drink sea water.
since their kidneys produce nuids wilh osmotic prcs-
surcs as high as 9000 mOs/liter (compared with 300
mOs/litcr for blood plasma),
A formerly held oonceptthat the ability to con·
centrate urine varies directly with the relative num·
bers of long Henle loops was based on observations
made in several species. The beavers and muskrats
have only short loops (87A). Humans do not cope
wdt with water deprivation, and only 14%-15% of
the nephrons arc of the juxtamedullary type. lJrine
four times as concentrated as plasma can be made.
but this is accomplished in part by sdcctive shunting
of blood to the medullary regions of the kidney when
the ECF volume is low.
I! was once believed that sand rats have only long
loops. but this misconception has been corn:cu:d
(87A). In fact. these and other rodents with well-
developed abilities to conserve water have mOre short
than long loops (87). Such arrangements ""em to be
necessary. because the maintenance of a strongly hy·
pertonie medullary interstitium evidently depends in
part on cortical nephron transfer of urea and other
solutes from the vasa recta to the long·loopcd neph_
rons (167). Cats and dogs. which are not especially
good concentrators. have only long loops. Howcver.
the fine of SOme resemble those of the
short loops of other species.
OTHER R'EGlJLA.fORS
Fluid Vo lumes Entering and Leav ing the
Henle Loops
Healthy human adults in good endocrine and elec-
trolyte balance produce around 120-125 ml of glo.
mcrular filtrate per minutc (170-180 liters per day),
As the proximal tubules reabsorb gluc()SC, amioo
acids. cieetrolytes. and other esscntial componeRe, of
the filtrate. around 65% of the filtered waler i, ta ken
back. Therefore, thc Henle loops receive more than
60 liters of tubular nuid in a typical day.
As they perform tneir functions. the loops reclaim
an additional 17-27 liters Thu s. 35-40 liters remain
to be processed by the distal portions of the nephron.
Passive Movements 01 Water end Ions
Across the De scending Thin Segments
The uppermost portions of the descending limbs arc
surrounded by interstitial fluid that is isotonic with
both the blood and the fluid within the tubular
lumcn. As they into the deeper portiollS of
the mcdulla . the surfaces of the loop cells
come into contac t with progressively more concen·
trated interstitial fluids (Fig. 10.5B). Since thc
pla,ma membranc, are highly permeable to water.
fluid is osmotically drawn into the hypertonic envi-
ronment. The luminal contents thereby become pro.
gressively more concentrated as thcy approach the
hairpin turn _Some Na + and CI - diffuse into thc de-
scending limb cells and thcn the tubular lumen. and
this further concentrates the luminal fluid , A four·
fold rise in osmolality (from around 300 mOsJlitcr
at the top to 1200 mOs/litcr at the bottom) is usual.
Ac tive Transport of lona
The fine structure of the cells of the ascending limbs
dilTers from that of the desce nding components. The
cells are impermeable to water. They actively ex-
trude chloride ions. and sodium ions follow to main-
ta in clectroneutrality. Ion pumping brings about
progressive dilution of the ascending tubular fluid_
The product finally delivered to the distal convoluted
tubuk is reduced in volume. but it i. actually hyt»
tonic to the blood plasma_
Countercurrent Multlpl1catlon
Highly effective countercurrent multiplication is
achieved by the elose proximity of thc ascending and
descending limbs. the parallel flows in opposite di·
rcctions, and thc active extrusion of chloride ions.
Countcrcurrent exchangcs also occur in the blood
vessel5, The plasma in the uppermOSI parIS of Ihe
vasa reCla is isolonie "'ilh Ihe fluid in the upper parIs
of Ihe dCKending Iknle loop, It is, however, SOme-
what hypertonic wilh respect to in Ihe gen-
eral syslemic cireulation. The change i, acquired
during passage Ihrough the glomerulus , Since mOSI
plasma proteins arc not filtered. Ihey become con-
cenlrated in that blood.
A5 it descends lowards Ihe deeper ",,,,,I medulla,
the blood picks up sailS from the surrounding fluids.
The salts arc not carried awa)". because they arc losl
again as Ihe blood ascends. Special propenics of the
blood ves.. 1walls may additionally contribute 10 salt
conser.alion (8S).
All invesligators evidently agree Ihat (a) Ihe pro-
ccs,ses just described are essential for maintaining a
hypenonic fluid in Ihe renal medulla; (b) urc:t is al>o
concenlraled in the renal medulla. Thi s further CQn·
Iribules 10 Ihe m:,intenancc of Ihe osmolic gradients
(at leasl some of Ihe urca is CQntribuled by Ihe col-
lecting duct cells which lie close 10 Ihe Henle loops);
and (c) other proccs<cs arc probably neoded to ae·
complish and maintain Ihe steep osmolic gradients.
Thcre arc CQntro,·ersi., o,'er the nalures and comri-
bulion' of the olher mechanisms ,
It has been suggested, for example. Ihal Ihe ar·
rangements of blood vessels in the more superfIcial
parIS of the medulla contribute to lrapping of elec-
trolytes in the deep regions. Ihal the upper parIS of
the k>ng de..:ending l1enle loop limb. ,clively <c.
c""te NaCi . and thaI parallel arrangemenls of "short
long loops'" "intermediale long loops". and "long
long loops" eSlablish a cascade Ihat carries saIl
downwards (87A) , Another concept is thaI short·
looped nephrons wnd urea into the long-looped ones.
and thai the urea passively drives NaCI oul of Ihe
lubular nuid (158A) , A third concepl is Ihat Ihe ure·
ters ma ke major conlribUlions 10 urinary concentra-
lion (74A).
ANTIDIURETIC ACTIONS OF VASOPRESSIN
The hypotonic fluid that the aseending limb delivers
10 Ihe distal convoluted lubule undergoes Further di-
lution as aClive transpon processes return relalively
more solute Ihan water to thc bloodstcam. T he urine
that arrives at the collccting dUCIS can have an os.-
molalily as low as 70 mOs/hler. Substantial wmer
reabsorption then occurs in the remainder of the
nephron. Usually, only around 0 .7% of Ihe filtered
waler ends up in Ihe final urine.
The plasma membranes on the serosal surfaces of
the collecting ducts are permeable to water. buI nOl
10 NaCi. Since they are COntinuously exposed to a
hypertonic environment. water is osmotically drawn
from the cells. This creates a gradienlthat facilitatcs
pa.. ive uptake of lubular fluid at Ihe luminal surface
(Fig. 1().6). The quanlity of water Iransferred from
the lumen of Ihc collceling ducl to the interslilium
(and ultintalely 10 the blood plasma) is delermined
primarily by Ihe rale of passage of waler across Ihe
luminal membrane (3).
Although il has other effeCls on the kidney. ADH
aClS mOSt obviously to increase Ihe ....·a/er permeabil-
ity of the luminal (apical) plasma membranes of the
collecting duct cells (83). It is belicved to increase
the numbers of "porcs" or "channels" for passive dif·
fu.ion (4.141). Tight junctions al Ihe luminal Sur-
face block lranseellular (bcl"'ecn-ccll) waler movc·
ments. However (at leasl in amphibian urinary
bladder. which responds simila rly 10 Ihe hormone).
waler that has enlered the cells may Ihen crOSS the
laleral membranes and pass bet",een cells 10 Ihe ser-
osal side (46) , The funclions of apical and wrosal
membranes are inlerrciatcd [45).
ADH arrives via the blood capillaries. and it COm-
bines wilh receptors Ihal are associaled wilh Ihe ser·
osal plasma membrane. II is effc<;live in vilro when
added 10 Ihe balh (bul nol when perfused Ihrough
Ihe collecling ducliumen). The responses can be de-
leeled within minules after presentation of ADH in
concenlrations of 1O- lo M. and Ihey are dose related,
Use of AmphIbian Tilllluell to Study ADH
Aetione
Some of Ihc technical problems involyed in thc study
of mammalian kidneys and SOme of Ihe advantages
afforded by amphibian preparalion5 Were cited in
Chapter 9. The inaccessibility of decp nephrons of
mammalian kidneys is not easily dcall with. and
many studies in mammals ha"c involved CQrlical
(ralher Ihan juxlamedullary) preparations.
Amphibian skins and urinary bladders haye re-
ceplors Ihat interJct with ADH in a manner Ihat
leads 10 acceleration of waler transporl. Since they
also have Olher fealUres Ihal resemble those of lXII-
lecling duct Ihey have boen ",idely used to
Ihc mechanisms of ADH actions.
It should be pointed out. however, that amphibi_
do nol make AVP or L VP. Water transport
conlrolled physiologically by arginine vasotocin and
by other regulators, Some of the ",sponses of the
amphibian preparations 10 A VP differ from those of
mammalian collecting ducts. and applications of Ihe
findings to mammals must be made wilh caulion .
Frogs need to control the rale of waler uplake
Ihe skin. Arginine vawtocin can accelerate
Ihe process and thereby hasten rehydration of ani-
mals that haye returned to waler after a Slay on
land. However. excessive ratc!; of uptake Can wri-
ously disrupl Ihe balance. (Animals kepI in fresh
 V.... SOPRESSIN .... ND OTHER REGUlA. TORS

Tubular

connecling
'"-

, ,
', ..'

," ,
: .i
" i

\, .' ,
...., .,., ..'
., . "'
;, '>-

Fig. 10-6. ColleCting tubul8 _ n t_ ""'''ont.,

""US .r.
arrows show dif6Ction 01 water mew........,1. o.ly 1M CIlifII
ohown.

Water and injected with large d()SCS of ADH become
Water logged. a phenomenon referred to as the
"Brunn effect,"') The urinary bladders cf amphibi·
ans serve as reservoirs for water and electrolytes that
can be used to replenish the blood plasma.
Cytological Changes Associated with
Responses to ADH
Unstimulated cells contain particulate aggregales
enclosed within the ntembranes cf cytcplasmic vac·
uoles or tubules. In antphibian urinary bladder gmn·
ular cells. the structures arc highly organized, and
Ihe aggregates seem !() form ribbon·li ke right·
handed helices that spiral around the tubule> (171).
The crganellts of collecting duct cells differ in ap-
pearance. bU I they are bolieved to function in Ihe
same way (66).
W ithin I minute after the hormone is pr=nted 10
its target cell, the aggregates mOve towa rd the apical
membrane. It has been proposed that the fusion of
the vacuoles or tubules with lhe plasma membrane
increases the surfa,e area and provides the cell with
large numbers of ,hannel. lha( admit water. The
new arrangeme nt persists throughoul the lime pe-
riod during which ADH continues !() aC<:clcratc
waler uptake. Howeyer. there may bo cycles of in·
sertion and relrieval of the organelles. Aftcr hor·
monc withdrawal, (he aggregates return to (he intra·
eytoplasmk location.
Thc lranslocations a re evidently linked with A DH
actions, rather (han with watcr movements per ""
(64 ). They arc seen when artificial manipulation of
the osmOlie pressure of the luminal Auid prevents
water upta ke. lanthanum has lillie effect on the
water uplake ra le in the basal condition. but it a n-
tagoni1-C< ADH stimulation. It interferes with the
accumulation of lhe aggregates wilhin the apical
plasma membrane, possibly by displacing the cal·
cium required for (he fu'ion (19) . (Lanlhanum can.
howcvcr, accelera(e transcellular movementS of
water and ions, possibly by disrupting the tight
junctions.)
In SOme ADH-scnsitive cells, cytoplasmic gran-
ules (which may be unrelated \0 the aggregates juSt
described) move toward the plasma membrane and
are btruded. The cxocytosis leads to increased
thickness of the glycocalyx on the apical side. and il
is associated with apical endocytosis and wilh pino-
cytosis al Ihe serosal side (31). Some observers be-
lieve thai the granules are involved in a second pro-
cess thai facilitates. water uptake.
The serosal surface is exposed to a NaG·rieh hy-
pertonic environment. and sodium ions seem \0 be
essential for the pinocytosis. Pinocytic vesicles eon·
taining uh may be shuttled to the apical membrane
to provide a h)·pcrlooic intracellular microenviron-
ment that facilitates water uptake.
Ro le s of Mic rolu bu le s and Mlc ro fil a ments
The evidence fOf direct participation of these organ-
elles in the responses to ADH is ··circumstantial'·
but impressi'"<: (160). Microtubules mediale intra·
cellular and they may be nceded for
the mo'"<:ments of the vacuoles or tubules. Thc evi·
dencc for cAMP mediation of the ADH actions is
discussed later. In at least some spccies. tubulin!
(Ihe major of the micrOlUbules) are as·
sociated with protein kinases. cA M P is implicated as
a slabili1.er of the asscmbled microtubules.
Colchicine is a plant derivative that binds to tub-
ulins with high affinity and thereby interferes with
microtubule assembly. It has no known effoct on
bao;al ratcs of water uptake. but it blocks Ihe anli-
diuretic action! of AVP and the associated accu·
mulation of the aggregates in the apical membrane.
It loW<'rs microtubule densitiC!l in both "resting·· and
stimulated ""lis. but it doe.s not counteract the ef-
fects of ADH once Ihey have become established.
The findings are consistent with the suggestion that
microtubule! are essential for itri/iatioll but not
maintenance of the a"tidiuresis (77).
- 0
o,,<,
Microfilaments arc implicated in the anchoring of
intracellular components to microtubulesand in reg-
ulation of the properties and functions of plasma
membranes. Cytochalasin B (CB) is One of several
substances derived from molds that disorganize the
microfilaments. It intcrferes with the parlicle-aggre-
gating elfects of ADH and thc innuences on water
transport. Its clfeets can be additive with those of
colchicine when the twO agents are presented early .
However. CB also antagonizes "slab/ished ADH aC-
tiOllS. Therefore . the microfilaments arC probably reo
quired for maintenance as well as initialion of the
water trarupon response (71). They may play roles
in orientation of the aggregates and associated water
channels .
CD and related substances can increase Ihe num_
l.>crs of muliivesicular vacuolC!l within the c)"toplasm.
possibly by interfering with microfilamenHle!",n-
dent migration of pillOC)"tic vesicles. Giant vacuoles
can then form as the hypertonic contents of the ves-
icles osmotically draw water. Aleian blue, which
stimulates pinocytosis. brings about s;milar morpho-
logical changes (31).
Effects o f S e rosal-Side Sodium Chlo rid e
In homozygous Brattleboro rats (which do nOt make
ADH ). the interstitial nuids that bathe the serosal
surfaces of the collecting duct cells contain sub nor·
mal quantities of NaC!, and responses to exogenous
A VP arC impaired. Repeated administration of the
hormone (or its agonists) restores sensitivity as it eI·
evateslhe osmotic pressure and NaCl concentration.
Na · ions have been implicated in augmentation of
A VP binding 10 its roceplon and in the coupling of
the interaction to cAMP generation (134). A post-
cAMP site of action has recently been proposed for
toad urinary bladder (40). Continuously high NaC!
concentrations at the scrosal surfaces can block Ihe
desensitization of target cells that would otherwise
folio",· chronic presentation of A VP. possibly by uf·
focting receptOr configuration.
<
o
<,
<, o
<
CytochJlasm 8

'"
Roles 01 cAMP
Several kinds of evidence support (he belief thai Ihe
aClions of ADH depend on gencraliQn of cAMP. io-
uaedl"'ar translocation of the nucleotide. aelivaliOll
of eAMP4cpcndcnl protein kinase •. and phO$pho-
rylalions of regulatory (15,83). The hor·
IlIOno invokes dose-depcndcn\ dc'-aljon, of adenyl-
ale cyclase and protein kina,e aClivilies. and i1
elevates both intracellular and urinary cAM P levels.
The cyclase system differs in SOme ways from OIlCS
found in Olher herml,me target cells. GTP evidently
has liltle influence on the activily. bUI high serosal
conoxWalions of ATP Can inhibit. ADH aClions can
be mimicked or exaggerated wilh cAMP analogs
and with phosphodiesterase inhibitors. They arc an-
tagonized by mcthohexital (a barbiturJ1C thai inter-
feres wilh cyclase activation). Somatostalin blocks a
variety of cAMf>-dcpcndem hormone actions.
and it anlagoni7.es ADH (20). It is present in am·
phibian urinary bladder and may serve there as a
physiological regulator (46). It antagooi7.cs low dos-
of A VP (and a lso theophylline). but high hor·
mOne concentrations can overcomc its eifects. It may
act by lowering adenylatc cyclase activity. but "post·
cAMP" mechanisms have also bc<:n proposed.
'".
•
HC - C - C
" Interact ions w ith Pro staglandins
"
H,c - C- ClEC- C " ADH promotes Ihc generation of prostaglandins (es-
" I
CH, Mell>o/lc<ifaJ
Cultured pig kidney ""II, that 'hare many properti.,
witb renal medullary ooUs have been ... d to 'tudy the
effeell of LVP (I 34). The hormone ma.imally Slimulate.
adenyl ... cyelase when only limited numbers of the re·
ooptOf1; aft occupied (64), and it also .etivate. type II
cA MP-dcpendent protein kina«. Higb c"""enlfations in_
I'Qke de.en,iti'.. tion <>f the bofmone-dc""ndont eyela..
system . Evidently. this does not require internalization of
the LVP. but il may invol •• cndocytOSi,of the receptors.
The mechanisms whereby the protein kinascs
bring about permeability changes arc not known.
Phosphorylations of membrane components have
been linked with changes in permeability in othcr
cdl typeS. and ADH known to change several al>-
ical membrane properties . Moreo,·cr. membr-Jne
preparations contain components that can servc as
substratcs for both tbc kinases and the phosphatases
thai becn identified in thc (36). On the
olher hand. Ihe prolein kinase! ha,'c also been im-
VA$OPR£S$IN AND ornER REGULATORS
plieated in the functions of microlubulcs and
microfilamcnts.
Roles of C a lCiu m Ions
Some extracellular calcium is needed to achieve
A VP stimulation or waler transport. Calcium iooo-
phorcs mimic Ihc hormone actions, and they en-
hance Ihe eifectiveness of low AVP concentrations
(143). In addition to supporting tne functions of thc
mierotubules and microfilaments and the activation
of adenylate cyclase. the ions may be nCedcd for vac-
uole or tubule fusion to the apical membranes. Very
high Ca" exerts inhibitory influences.
All or the preceding are consistcnt with calmodu-
lin mediation of the cffects of cakium ions. How·
ever. studies "'ith trifluoperazine (which combines
wi1h cakium<almodu lin and thereby impairs its
functions). have yielded data thaI are difficult to in-
terpret. When presented alone to toad bladder. tri·
fluoperazine has no influence On aden}'I-
ate cyclase activity (po'lsibly because basal levels of
en7.yme activity arc maintained without stimulants).
It docs, how..ver, elevate lhe cytosol cAMP and tbe
protein kina", activity. This is .Uribuled to inhibi-
tion of the cAM P'phosphodieslcrasc. The agenl may
additionally exert some calmodulin-independent in·
fluenees on the plasma membrancs that affect water
transport. It can anlagonile CAMP-mediated
antidiuresis.
pecially PGE, and PGE,. but alwsomc PGF,..). The
effects of both th. nalural hormone and syn1hctie
agonislS are dose dependent. (TIley are not linked
with cA MP generalion (65).)
Homozygous Brallieboro rats PUt OUt vcry limited
quanlities of PGs in Ihcir daily urines. quan-
tities are markedly increased when ADH is used to
promolc amidiurcsis (8). The changes persist For a
time afler hormone withdrawal and r<:lUrn of the
urine osmolalities to preinjection levels_
Indomethacin, meclofenamate, aspirin, and other
inhibitors of c}'c\ooxygenase can further depress the
low levels of PG production in Brauleboro rats not
receiving the IIormonc. and they thc
stimulalory eifects of low dosages of A v P. How..ver.
high doses of DDAVP can still invoke some stimu,
lation of PG production .
The rtndings are consistent with the belief that
A I) H induces cyc1ooxygenasc . but thaI it Can also to
somc extent increase PG production by acting on
phospholipases (84) .
 PGE, is a poten! inhibitor of the antidiuretic ac_
lions of A VP in bolh mammalian and amphibian li$-
sues. II has therefo:"<' been suggested that the PCs
participate in physioiugical conlrol of water diurcsis
by exerling negalive feedback inhibit ion .
pc; tlO:>synttlcsis
targer motecute. i, nO' 'imuh'tIC""liy .ccder.tcd. It ....
sume. Ihal all of Ihc sub'lances Iraverse 110< same
palhway"
The nuid. are said 10 r,rsl encounler" hormone-insen-
silive "m<>iecu lar .ieve"· lhal .ereen' QUt large ""tulC'.
They lhen p." lhrough Ihe ADH_respon' ive barrier
(Fig. to-7). When no hormone i. prestnl. waler move-

-----
AOH ..
menU arc imp<de<l by adhe.ion 10 lhe inner ."rface, of
lhe por•• and by h)'drogen bond •. When 1\ VP lhe
Anlidiuresis - - - - lMibit;on pores:' bulk flow i. faei titalcd.
The CQncepls.re difficuli 10 reconcile wilh obscrvalioo.
PGs are believed 10 anlagoni7.e AD!! mostly by that CQkhicine. eytOChalasin B. and SOme .ncslhcl ics 'e-
interfering with hormonal activation of adenylatc ret.rd "'aler lransporl .cross amphibian li"u"".
cyclase. (Cyclic nucleotides can invoke antidiurcsis lha, verapamil and amilot id. selectively .ffecl Na·
in thc presence of thc PGs.) Howc.'cr. prostaglan- movcmonl$,. nd lhal phlorelin and lo nnie acid .ffecl only
urea tran.port (4.t4t).
dins exen several other elfcctson thc kidncys (159).
More widel)' hdd opi nions . rc th.l lhe •• riuul sulU1C!
They inhibit dloride transport across thc thick as- lfaverse parallel bUlscparalo palhw"Y". and Ih.llhc ef-
cending limbs of the Henle loops. and thcy the reby fect. of "011 are linked with incro..", in lhe numbus of
lower the salt concentrations of the interstitial Huids waler channel •.
that bat hc thc serosal mcmbrancs (173). Further re-
ductions in osmolality Can result from depression or
urea reabsorption by the kidney tubules (84).
In at leasl SOme spe¢ies. the pressor elfccls of
ADH seem to makc substantial contributions 10 PG
"80
generation. When DDA VP is given to humans in
""jules '8'
dosages that invoke antidiuresis bUI fail 10 elevate
the blood the PG levels do 001 rise (182).
The responses may be dilferent in rats. DDA VP
hUl; been observed 10 accelerale PG generation in 1_IIOH.sensi"'O
Brattleboro homozygOics. PG production can also be ba"",'
stimulaled in Olher ways. c.g., by acidification of the
I
serosal Huids, Under these condition., rcsponsivc"",ss I
to ADH is blunted, Cyelooxygenase inhibitors coun· I
teract the effeclS of acidification. bUI ADH docs not
(46),
The fael thaI indomethacin can invoke amidi-
uresis in Braltleboro ralS has been ciled as evidence
that PGs exert some inHuenees unrelaled 10 ADH
antagonism, However, high concentrations of Ihe
drug additionally lower phosphodieSlerase activity,
and Ihis complicales the inlerpr<:tations (148),
o
ADH REGULATION OF SOLUTE TRANSPORT
A VP 3e<:<:leratcs Na · transport across amphibian
skin and urinary bladder. The elfeels arc separable
I .. EnIO'!l'"d pore
from Ihose on water uptake (40.141). It has been
proposed that dilferent adenylate eydases a rc acti-
vated. but the same cclltypcs a rc involved in thc r<:-
sponses (64). Apical permeability 10 urca is also in-

_If.,.
Fill . 10_7. Du.1 borr;er hypo!_ •. Top, no AOH: water
creased. Yet another adenylale eydase has been and $mil" ""M"
limit@<! a"""",to
lMou\IIllhe molecular $ ;0. ... but onty
'he ""''''''''''·....,si!l.. I)jJorr;e,.
implicated.
solul•• cannol tflfough 1lle sie ••. W010f
moIeo.JIes . _ . 10 the .... 11. oJlhe portIS of .he
The " Dual Barrier" HypotheSiS sen.;!;" bart..... BOllom. wllh AOH: Walo< and .",IM
SoMe... p;dt)' pa .. belW"" the now poo-e. oj the
Thi, hypothesis was formu lale<llo reconcile Ihe concepl rIOrmone-."" .. I.... barr;e,. large "".,"e • • r. I,m excluded
that ADH increasel pore li7.o1 lhrough which walor and by the moIIlCutar ...... , Wa lo< and _ II """" . _ fto w
Imall ""lute. p. .. wilh observa,ion'lh'l Ihe diffu,ioo of Iflfough enfoo"Qe<l pot •••

'"
Solute Transp ort In Memmall an Co ll ec llng
Du el
When ADH promotes water conservation, only
small cllan,es in N.+ tral\$port an: Ken. Tile elfet"lS
of Il<.>rrrIonc on solute movements may be real
and 1)\11 IlIey an: counteracted by
other mcchanislTl$. they have ti n le overall
inlluence on sodium balance in huhhy a nimals.
Mop. observers find no challtes in utea uplakt
across tile apkal mcmbnnes. Small increases in tile
rates of IIIOY<:mcnl 0( 5OfI\e "mocienncly lipophilic"
substances such as isobul)'11lminc: and a nlip)"rinc
have b«.n attributcG 10 reorpnizlli0n5 of mem-
bnme components a!feel'!!i the phospllolipids ( 147).
ADH Innuene• • on the Henle Loops
In at least some species, AOH acoelcn.u,s chloride:
ion transport across the thick :lelmenls of the 110
ccnding limbs. ADH r«C:plOrs have b«n identifK:d
in the $Crosal membranes (13), AV P in·
vokes a dosc-dcpcndenl ele vation of cAM P (l9), and
the nuclo:otide sc<:m$ \0 med iate the effects (64) .
Marked acceleration of fUfascmide«nsi!ive
NaC l uplake across the thic k segments of medullary
(but nOl cortica l) ase<:nd ing loops has been dcseribed
fur i>ulal<d kid""y lubul"",. The entry
nels in the apical membranes $ellm to be !odium se·
Icctivc. with transl'(11"l linked to Na · / K ' -AT Pase-
powcred Na' cxtrusion via the basola teral mem-
branes. The hormone would be expected 10
promote sodi\Lm COIISCrvlltton. and to the <lI-
molality of the interslitial nuids lhal bathe the ser·
osal surfaces or the rcnallubulcs. I lowever, although
A VP promotes some sodium in rats ....ith
diabetes insipidus. il has lillie e!Ted on sodium bal-
ance in animals thai II<'Crele the Several
CJlplanations have been offered.
When AO H (or OIher factors) the os-
moIalily of lhe interslili.1 Auids. Ihis leads to ae«l·
erau:d baet ftux (pa$$ivc= retu, n leak".) of Naa
aerou the buoialCril surfaces.. High extrlccllula,
Na ' can aJ,o interfere wilh A VP Ictivalion of ade-
nyiale c)'Cla$( in the Henle loops (70).
AVP conccnlrallon$ I S low IS IO ' '' M promote
coIIStriction of the renal blood _ I s (175). o..e
wllSequcocc can be slowing of blood flow through
the reul medulla and decreased of interstitial
Auid sailS 10 the
Influene.e o n Po te . .lum Exc retio n
A nimllis with diabetes insipidus suffer potassium de·
pletion. Although lhe excretion of very large vol·
AND OTH ER RE(l1Jl..A TORS
urnes of watu w<luld be expected to be accompanied
by IIQnspecific "washout"· or ele<:tro!ytcs, the
hypoka lemia thaI develops appears to be rTlOfC di·
rectly related 10 lhe hormone deficiency .
When A VP is over a period or sc:vcral day!,
Ille potas.ium stores are built up, and the,e are
quantitMivc relalionships between the magnillKics of
potassi um retention and lhe effeets (In WIle, conser-
vation. If large d05CS are used. the a nimals eventu-
ally display an reaction lhat inoolve$ lhe
excretion of large quantities of potassium. sodium.
and water. li O'A"C"VCr, even long-term lreall1'lent docs
not Jo,vcr the pot31Sium 1e\"C1$ 10 prei'liection v.:roll1C$
(106).
The mechanisms for regulalion of potassium m.,..
tabolism not fully understood. There are reasons
10 believe that ADH inftueno;c:s are exerted on ...
te,calaled·· cells of the QOIle<;ting dUCL... These cel ls
differ in appearance from Iltosc inVQIvcd in the a...
tid iurelic response. and such cells appaI"Cnlly do 001
display the changes in watcr permeability estab-
lished for the ··chier· ce lls of tlK: ducis.
ADH Infl uence. on Glo m. ,ullir FIII,II Uo n Rllt e
The hormone stimu latcs of Ihe
gial cells of lhe renal glome ruli (27). It in lhis
way alte r Ihc arCa of the filtration surface. The re·
ceptors evidcntly resemble the oncs found in smoolh
m usc le . The responses do IIQt invol ve cA MP or
cG MP (64). and they are not achieved with dosesQf
ODAVP tMt promote ma rked Hor·
monal influcnces cn uril\ary flow rotes and on rcnal
blood ve5SC1s tnat change transcapillary hydraulic
prcssurc differences also affect the filtrllion rale.
Glomerulllr function can be further inftuenccd by
changes in systemic blood pn:ssure. in cxtraellilular
fluid volul1'le and comp<l5ition. and in the ratcs of 5C.
crclion of other hormones.
Nat, lur • • 1s
Natriuresis is a pn.wnincnl fcalUn: of the aforemen-
lioned "escape" =ponsc. AOH may directly c0n-
tribu te ( 158). since pharmaCQlogical dosages inhibit
proximal tubule reabsorption of waler and salts
( 115). invote hemodynamic; ehanscs. and , ffeet
mcsangial cells in ways lhal lead to Ie«!eraltd
GFR. PRA lends 10 decline because of oo.h direcl
and indirect actions of ADiI. An cxpcctod oonse-
quence is decreased aldosterone II<'Crelion. However,
ODAV P. wilh only"'" the pressor potency and no
measurable effects on PRA, also invokes natriuresis
and di uresis if large quanlities a rc repealedly admin.
istered. Moreove r. escape can be demonslrated in
adrenalectomized animals. (Therefore. neither Ihe
pressor nor the aldosterone effects would seem 10 be
essential.)
Many invesligalors allribUle sewndary in·
creases in sodium excretion 10 Ihe «,lease of one or
more hormones" (86). The same «,gu·
lat()f"$ have been in Ihe "escape" thaI fol.
lows chronic overdosage with minentlocorticoids or
the expansion of body salt and water stores by other
meall5. W hen one kidncy is removed, the organ that
rcmains vt:ry ntpidly begill5 to assume the sodium·
excreting functions of two kidneys. and this too may
depend upon uch hormones (69).
The CQnceptlhat a "third factor" (i.e., some thing
other than ADH or aldosterone) plays important
roles in monvalent deetrolyte homeostasis w'" fi rst
introduc<:d several decades ago. Support for it comes
from observations that preparations derived from 00-
dium-loaded expermentai animals (and from pa·
liems with some forms of sodium retention) display
natriuretic or natriferic (sodium transporling) aCliv.
ities when lested in a variely of ways.
The preparation, te"ed indude blood plasma ur in<.
v<l'o." effluent. of several orga n•. tissue extrae". media
i. which kidne}" and other organ. have be<:n incubated.
and purified fraction. derived from these preparation •.
The test obje<:t. include whole animab perfused with
pla.ma from sodium·loo.ded ones. isolated perfused (de·
nervaled) kidneyS. euitured kidney and tu·
bular fragment'. frog skin. and tood urinary bladder. Ef·
fcc" on intestin.1 sodium ,ran'port ha.e been described
for """e of the p"p"",ioo.. Inte ..stingly. salHooded
.nim.l, ,how greater se nSitivity than one, in good wat.r
and electrol)·te halanee prior to receipl of the material •.
de. pile the expectation that Such animol. Wlluld have
high level, of endogotlOUo (Ill).
The elTeets are nOI mimicked by kallikreins. ste·
roid •. angiotensin •. DA . or PG,. Peptides recovered
from atria can in''Oke nalriuresis by alTecting renal
(A·2). or by inhibiting .Idos!crone
production (A_I). Some are for ACE.
Majority opinion favors the notion that natriuretic
hormones arc small peptidcs . perhaps with molecu·
lar weights of 10Cl0 or less (57 . 68). Oxytocin and
related peptides are among the candidates, but they
may function indirectly by promoting the release of
natriuretic factors. Two undecapeptidcs, Ala..(Jly-
AVP a nd Val-A.p-AVP. have been identified in b0-
vine neurohypophysial extracts (54). They exert na·
triuretie effects when presented in oonccntralions of
50 X 10 " M. they lack Ihe pressor activity of
both AD H and some of the proposed as
"true" natriuretic honnones. The possibility that the
undccapcptides serve as ADH precursors has becn
oonsidered. since enzymes that removal of
the first two amino are also presenl in the
Glucagon i$ some 3.5 time. larger. Since it i. se-
creled in response to some forms of manipulalion of
Ihe elcctrolyle and waler balance and Can promole
marked diuresis and natriuresis. it 100 has been im-
plicated (113). A protein with a molecular weight of
45.000 been reported 10 possess bigh potency
(56), but some investigators belie>"C that Ihe larger
contained in extracts arc either hormone
P«'CUTSOrs or regulators associated with other pro-
lein>;. Different observers suggest Ihat natriuretic
hormone is an amine (25). or a sugar deri.ativ<:
(102).
The proposed siles of orisin include the ct:rebral
hemispheres. the hypot halamus or pituilary gland
(93). a nd the kidney (56). At leas! some of the re-
ceptors mediating release are in the brain (106).
Several reaoon. nO'·. been sugge.ted for tne .1",.' prog.
reSS in identifying the hormone •. Thete are indications
that Ihe molecu le, are cbemieally u", .. ble . • !Id that di_
lution by the blood and tissue fluid. of the recipients ac-
celerate. degradation. Heahhy animal. probably posse ..
highly efficient mechanism. for eithe r 'he
hormone, or rde ..ing antagOnist$. It i. ' u,pCeted th.t pi.
tuitary gland. eitber promote natriuretic hormone rclc.",
or ,"erel. substance. that p<rform "pCrmi" ivc" func-
tion •. Structure< that eont.in the moloeules may Jlo"
but no! o}·nthe,i7.c ,hem.
Some allribute Ihe natriuretic clfccls
to inhibtion of proximal tubulM N,,'/ K ' ·A Tl'a ....
(25.57). but have been unable to demonstrate
changes in the activities of Ihose enlymes (169). The
elTeels may be exe rted before IhC filtrate is affcc!ed
by the ATPases. since there are oonsistent increases
in K ' and CI - as well (169). Alternati.cly.
Ihe major could be exerted on Ihe diSlal por-
lions of the nephrons Ihat include the collccting tu-
bules (69).
A difrcrent eoncepl i. thai the hypolha lamu, .'<e-
c«'tes a PG ·releasing faclor (169). However. il ha,
not establiShed Ihat PGs accelerate sodium excretion
(sec Chapter 9).
Choliners;. agonists elevate eGMP concentra-
tions in mammalian kidneys and toad bladder.
Morcover. inlrarenal infusion of acctyleholine is
promptly followed by natriuresis. and the carbachol
brings about inhibilion of Na ' transport in toad
bladder. However. cGM P alone is IIOt effecti.e
(138).
ADH INTERACTIONS WITH
ADRENOCORTICAL HORMONES
Mineralocorticoids indirectly inereasc the clT.ctive·
ness of ADH in several ways. They promote COnser-
valion of sodium (and secondarily of water) and oon·
tribule 10 thc maintenance of systemic blood

pressure. They can in this way increase GFR and the
rate of delivery of Na · and 0 - to Ihe Henle loops.
Reductions in PO gencmtion have been allributed to
inhibitory inA uences on phospholipascs and on renin
release. Aldosterone can also lowcr the activity of
cyclic nucleotide phosphodiestemses.
Toad bladder conlains a steroid· and cAMP·reg-
ulated protein (SCARP) that may provide a direct
site of intemction. Aldosterone promotes dcphos-
pborylaton of phospbo-SCARP. and the effects have
been linked with inAuenccs on sodium traTlSporl.
They are cAMP independent. but can be antago--
ni>.cd by spirooolactones. cAMP also promote. de-
phosphorylation. The are thought 10
either activate a phosphatase or affect
strate binding (65).
On th. other hand. aldosterone promotes potas-
sium excretion. Overdosage can invoke a hypokale-
mia that impairs the functions of ADH.
Hormone Seeretlon
Mechan isms controlling secretion of the two kinds of
hormones arc interrelated in complex ways (177)
(Fig. to-8).
Angiotensin II is regarded a. the major stimulant
for aldosterone secretion. It also acts ecntrally to
promote ADH l"<'lease (9,22). Direct effects can be
demonstrated when the peptide i. incubated with hy·
pothalamic fragments. but mOSt investigators find no
influences on isolated neural lobes (59). Other inAu·
ences may include augmentation of the sensitivities
to osmotic stimuli (157). The e!fectS of A-II are an·
tagonized by saralasin . but not byacetylcholine·re-
ceptOT blockers.
Ftll. to-o. Some interrelot_pl omong AOH. A·II.
ond ad«mocor!ical •.
VASOPRESStN A ND OTHER REGULATORS
AOH aCtS directly on the kidney to inhibit renin
release. It thereby teMs to lower PRA and depress
aldosterone secretion. DDA VP docs not mimic these
actions. One ]XlSsibility is that a spc.:ir,c kind of re·
ccptor is involved in renin regulation (86). Another
is that the hormone accomplishes the functions by
acting On the blood vessels (177).
The effects of ADH on fluid volume
reduce the need for A-II and aldOl'terone. On the
other hand. physiological amounts of the hormone
tend to promote retention of reiati,·ely mol"<' water
than sodium. and they can elevate the plasma potas-
sium concentrations. 80th hyponatrcmia and hyper_
kalemia can facilitate aldosterone secretion. How.
ever, the former also favors renin release. whcl"<'a'
hyperkalemia has an opposing effect.
AVP contributions to regulation of the CRH·
ACTH.adrenocortical system WCre diseussed in
Chapter 7. Although the peptide can increase both
CRIi and glucocorticoid secretion by acting on the
brain and adrenal glaM. respectively. the most im·
jIOrtant inAuences arc exerted on the adenohypoph-
ysis. Electrical stimulation of hyjIOthalamie regions
involved in A VP synthesis leads to elevation of
plasma ACTIi levels in normal (but not in Brattle-
boro homozygous) rats (7). Exogenous AV P raises
blood corticosterone in intact animals and in
ones bearing multiple pituitary transplants that
do not receive hypothalamo-hypophysial blood
(180).
ACTH exerts trophic influences On thc adrenal
oortex. It acutely increases aldosterone sec retion,
promotes the release of some less potent mineralo-
corticoid. from the zona fasciculata, and (at least in
some species) increases progesterone release. The
progesterone interacts to a limited extent with min-
eralocorticoid receptors. It can also be converted to
the mOl"<' potent mineralocorticoid DOC (178).
However. long-range effects include limitation of al-
dosterone secretion.
Brattleboro hom07.ygotes have subnormal gluco-
corticoid and mineralocorticoid concentrations that
can oocorrccted with exogenous A VP (106), aM the
renin levels tend to be high. The animals also have
gluCOCOrtiOOid binding defects that l"<',poM to A VP
(168).
ACTIi acts most obviously to stimulate glucocor-
ticoid secretion. Since glucocorticoid. possess min·
eralOCOrliooid potencies. enhance tht effectiveness of
vasoconstrictors. and inhibit PG formation. they
would be expected to augment the responses to
ADH. However. glucocorticoids also suppress ADB
release (153). and they antagoni,.c A DH actions on
the kidneys of both normal and 01 animals
(148,183).
VASCULAR ACTIONS OF ADH
The term YtJsoprnsin was initially used 10 designate
component of (crude "iXlSterior pitu-
ita ry gland" extract) that elevates systemic blood
pressure . The concentrations used in carly studies
contained 1000 times the quantity of AVP nccded to
invoke antidiuresis. It "'as soon TC<Xlgnizcd that such
pharmacological dosages indiscriminately stimulate
vascular smooth muscle. and that the errccts include
consaktion of the vesscl$ that supply Ihe heart and
brain. It was therefore COIIdudcd that such actions
could not serve physiological purposes.
With refinements of the techniques, subsequent
investigations dcmonstrated that concentrations
within the physiological range have limiled pressor
activity (161) that is st lWive (28). and that ADH-
deficient animals show abnormal vascular responses
to cxogeoous hormone (19 ). Morcover. baroreccp-
tors of thc vascular sy'tem and blood pressure-reg_
ulating hormones contribute to the control of AOH
release. while water-retaining cffects of AOH aug·
mem the scnsitivities of thc blood vessels to sti mu·
lants (100) .
When previously healthy dogs arc subjected 10
limited blood loss. they maintain normal blood pres·
sures. If they are pretreated wilh ADH antagonists.
they cannot do this (although their glucOCQrticoid
and angiotcnsin levels are higher than those of dogs
that arc only bled). doses of A VP elevate the
hlood pressure even in the presence of reserpine and
anesthetics. and following sectioning of the vagus
and sinus nerves ( 150). The findings arc all consis_
tent with the concept that AO H is a physiological
regulator of the blood pressure.
Selecllve Vasoconatrlctlo n
Venuk. are more sensitive than arterioles to AOH
stimulation, and small vessels are generally affocted
to a greater eXlenl than large r ones. VaSQConstric_
tion is easily achieved in the mesenteric, cutaneous.
and skeletal muscle bed., whereas components of the
circuit are resistant.
The overall effect i. restriction of blood How to
certain regions. The arterial blood pressure docs OOt
risc ma rkedly with physiological concentrations.
probably be<:ausc of a combination of limitcd ven·
ous return and the operation of cardiovascular
reflexes.
Animals ,ubjeet<d 10 prolonged. decp an<:$the,i. and to
exten,ive ,urgieal manipUlations of the visceral organs
often display severe hypot¢n<ion with pooling of the blood
in the mesenteric bed. Large doses of vasopr ... in can im·
prove the condition. Pharmacologicat amOUnl$ arc in·
jeCte<! I<>cally into patient> !O control bleedif\3 from
esophageal varices duri ng .urgery.
EFFECTS ON RENAL BLOOD VESSELS
Very small do.es can increase renal blood How. prob-
ably because they facilitate shunting from other
. ite •. Somewhat larger ones "imulate vasoconstric·
tion in both Ihe COnex and medulla (6). By retarding
How rales through the medulla. and by affecting glo-
merular filtration. Ihe larger doses Can contribute to
antidiurcsis.
The quantities found JUSt adequate to promote
water conservation do not usually have much influ·
ence on the renal blood now in normal individuals.
However. thc dosages requircd to correcl diabetes
insipidus in dogs invoke vasoo:.ln'lriction. The find·
ings underlie specu lations Ihal eithe r 0 1 is associ·
ated with development of superscnsitivity to the vas·
cular actions of the hormone (107). OT that DI
animals are deprived of a tonic. physiologi ca l e!Tect
of AVP. A problem "'ith such concepts is that ani-
mals that haw been deprived of AVP for
period, need relatively large amounts of ADH to
promote water conservation. They tend to develop
hypokalemia when they do not receive the hormone.
and this impairs respon.es.
AVP also slimulate. the smooth muscle of the gut
and uteru •. Pharmacological doses restore intestinal
muscle lone in patients subj«ted to prolonged sur-
gical manipulation. AVP release prior to parturition
is believed to contribute to uterine contraelion.
AVI' action< nn liver cell< ore known t<> he
diated via elevation of cytosolic Ca" . and to be in·
dependenl of cAM P generation (49). Similar mech·
anisms may be involved in A VP stimulation of
smooth muscle. «-Adrenergic blocking agents do nol
affcct AVP actions at either si te.
On th e other hand. SOme haY<: been linked
with the rclease of natriuretic hormones. As dis·
cussed in Chapter 9. it has been proposed that Ihe
hormones inhibit Na ' / K' -/l.TPases. and thereby
cause cells to accumulate excessive numbers of s0-
dium ions. Na exchanges Can then second·
arily elevate the calcium ion concentrations within
the cells and facilitate smooth mu.cie comraction
(102). Humoral factors that inhibit Na ' /K'·
ATPases have recently been implicated in the etiol-
ogy of low renin hypertension in both patients and
animals (61 A) .
BIOSYNTHESIS, SECRETION, AND
METABOLISM OF VASOPRESSIN AND
RELATED PEPTIDES
The Mugnocellular Secretory System of the
Hypothalamus ( 3 2)
The suprMplic nuclei (SO N) of mammalian hypo-
thalami arc made up primarily of perikarya of large
(magnocdlular). multipolar n<:urons. In most spc-

cies. the clusters straddle the 1'<l!ltral and lateral sur-
fae<:s of the optic tracts_ Vcry long axon' extending
from the e<:lls travel in bundles (lhe supra<lptico-hy-
pophysial nervc tracls) that descend through the in-
fundibulum, Many of the axOns terminatc within Ihe
vicinily of blood capillaries that supply the neural
lobe of the neurohypophysis, but others end in the
median eminence or on the pars intermedia.
The paraventricular nuclei (PVN) are medial.
dorsal. and cauda l to the SON. They line and may
bulge into the third ventrideofthe brain. In addition
to magnocellular components. they comain consid·
crable numbers of cen bodies of smaller (parvicel·
lular, paTV<)Cellular) neurOnS. The hypothalamo-hy-
pophysial nerve tracts are formed by the joining of
PVN and SON axon bundles ,
The SON are the major sites for biosynthesis of
vasopressin, but some of the hormone is made in the
PV N and in groups of magnoceHular neurons that
reside between the primary cluslers. AVP is also
found in high conccntrations in hypothalamo-hypo-
physial portal blood, It is present in Ihe cerebrospi-
nal fluid. in the vieinit), of the choroid pbus of the
lateral ventriclcs. in pineal glands. and in the supra-
chiasmatic nuclei. $omeof Ihe AVP found in the ex_
trahypothalamic brain undoubtedly ase<:nds from
the pituitary gland. but small amounlS ar<: made
elsewhere and can be detected long afler
hypophysc<:tomy ,
It has been proposed that the SON originate in
the embryo as paircd. well-defined neuron clusters.
but that growth of the optic lTaelS leads to "Orne di ...
persal of the cells (67), Small differences in devel-
opmental pallcrns may aecounl for species varia·
tions in the cell distributions of adults.
M05t of thc oxytocin is synthesized in tlte PVN.
but some is also made in Ihe SON and o1sewhere.
There have been controversies concerning whether a
single neuron can produce both A VI' and OT (181).
Regional differences in the distributions of the two
peptide. (32), observations that most ph)'siological
stimu li affect ju_st one of the hormones. and other
findings ar<: consistent with Ihe existence of separate
cell types (24.89).
Populations of neurons within the magnocellular
nudei lhal differ from eaeb other in electrical prop-
erties have been identified, However, it ha, TIQ\ been
possible 10 relale the hormone COntent to the firing
pallerns (179). Differentiation has been aCCOm-
plished wilh antibodies directed against a protcin
synthcsized along with each of the peptide hor·
mones. Brallieboro rat neurons do OOt make anti·
bodies to AVP·relatcd peptides. but their sympa·
thetic systems. ovaries. and adrenals have AVP-li ke
peptides (A·3) ,
vAsoPRESSIN AN[) OTHER REGULATORS
T he hormollC$ and their associated proteins are
transported down the 1000g axons in secrelory gran·
ules. Thcy arc di-leharged into the sy'temic blood
vessels when the neurons ree<:ive lhe appropriate
Slimuli.
Approximately 10% of magnoccllular neurOnS
synthesi7.c leu-enkepbalin (133). The penta peptide is
present in both SON and PV and it has been iden-
tified along the perimeter of the neural lobe. It may
play roles in regulation of hormone release. Gastrin·
like molecules and dyoorphin have also been found
within the nuclei (146). Cholecystokinin and gluca-
gon·li ke molecules have becn described
(24).
Neurophyslos
Ncurophysins are cysteine-rich protcins wilh molec-
ular weights of around 10.000 Ihat bind covalently
to the neurohypophysial peptides (21.132.1 S2). ac-
cumulate in the secretory granules. and appear in
the blood plasma at the time the hormones arc dis·
charged. They are species specif,e but all have com·
mon features tht include the presence of con_'ider_
able numbers of glycine and proline moielic<.
a 'ingle tyrosine. and no tryptophan. Chemically
identical corCS have two potential binding sites
for the hormones. only one of which may be
utiii1.cd.
Two types seem 10 be universally present in the
normal neurohypophysis: an oxylocin.related prolein
Ibat is also known as eslrogen-slimulaled ncurophy·
sin (ESN). and a vasopressin_related onc thaI has
been called nicolinc-stimulalcd neurophysin (NSN)
because it is r<:leased in humans after cigarette
smoking as well as during stales of water
deprivation.
When investigators first purified the mole.:ules in
different laboratories, they assigned TOman numerals
or capital letters to the proteins. The original no-
mendature is confusing, The A VP·r<:latcd NP of b0-
vine was called Np· ll . It is to the
NP_ II of pigs and rodents. Bovine N P·l and rodenl
Np· II are both associated with oxytocin. A third NP
described in SOme early studies appears to be a deg·
radation produ ct of one of the others. Bralllcboro
ratS make an ESN comparable to the protein of
healthy animals of the same specics. but no NSN.
Neurons located at comparable sites do havc dyoor-
phin. A neurophysin unique to Ihose rats may also
be present (24).
Several kinds of studies indicate thatlhe NPs and
neurohypophysial hormones arc cleaved from com·
mon bigh mole.:ular weight prc<:ursors . dc-
rived from hypothalami have been used in cell.free
systems to synthesize larger p"'pides that C<Jntain the
products. The base sequence of a mRNA from b0-
vine extraCtS that codes for a protein giving risc to
thrce products has been defined (89). One of the
produets is a large peptide that undergoes glyoosy l_
ation. The arrangement of translation products has
bttn identified as follows:
H,N-Signal sequenee_
A VP-A VP neurophysin- Glycopeptidc
The 17.3K product has 19 amino acids in the signal
sequence. n in the NP, and 39 in the glyC<Jpeptide
portion.
The molecules that give rise to oxytocin are
smaller. They evidently are not glycosylated (1 23),
The precu"",,, are beli eved to undergo a prelimi_
nary processing that leads to the formation of more
acidic intermediates known as proprcssophysin (Pro;>-
PP)' and pr(KIxyphysin (f'lxrOP). These have ap-
parent molecular weights in the general neighbor·
hood of IS.{l()(}-.20.ooo. Giycosy1ation of the P,..,.PP
then !iCCms to culminate in the formation of a yet
higher molecular .... eight derivative of approximately
23.000 dalloM. The prohormones are packaged
along with prote<;>lytie en7.ymes ("converting en-
zymes") (24). According to ob$crvers, the pro-
cessing is completed during axonal transport
(60.61 .110.136).
Stimuli that promote AVP release also ",em to ae-
p,,,,,.,,..i,,g. Rat> given 2% .. tine
in pia.., of drinking water release very large quan-
tities of the hormone. and this is as.wciated with at
least transient depiction of neurohypophysial stores
(24).
Many questions regarding the precn""'rs remain
to Ix: answered. Several very large molecules (in.
cluding 80K and 140K types) have bttn found in the
hypothalamus. They contain sequences that bind an·
tibodies directed against ACTH and p..,ndorphin.
and biologically active ACTH Cnn be from
them. It is not known .... heth.r those proteins are yet
larger precursors Or products of posttran'lational
processing. Some of the large molecules may be hor-
mone precursors that have become linked to memo
bmne proteins (123).
The jXlSSibility that pinta! glands make arginine
vasotocin and a related neuroph)'sin is discussed in
Chapter 20. A neurophysin·tike lactoglandin hu
been described for lactating mou", mammary glands
(89) ,
It has been demonstrated in monkeys that the con-
centrations of oxytocin. arginine vasopressin. and
ESN in cerebrospinal Auid undergo circadian
changes that arc unrelated to the variations in the
blood plasma levels. The activities of the neurons in·
volved in the relca", are evident ly controlled by
mechanisms dilTerent from those regulating release
from the neurohypophysis into the systemic capillar-
i.. (122).
Neurophysln Functions
The N Pc. may play roles in protection of the peptide
honnon .. against leakage from the storage granules.
degradation by proteolytic ... and the forma_
tion of intermolecular linkages. Since they
dissocate from the nonapeptides within the blood
plasma. it is unli kely that they contribute to hor.
mOne transport. Although they travel to the hor_
mOne target organ,. suggestions that they arc in_
volved in binding to the receptors have not been
substantiated. Responses to exogenous AVP and OT
do not differ from respon",,, to the hormones given
along with the corresponding NI'li.
Pharmacological C<JnC(:ntrations of NPs can p,..,.
mOte glycogenolysis and lipolysis and exert other
metabolicactionl; (174). It is unlikely that the find·
ings have physiological relevance. Very large quan-
tities must be admini,tered. and the same functions
are handled by smaller amounts of other regulators.
Some special influences on nitrogen metabolism
have been (52). It is not known whether
the binding of NPs to ACTH is related to AVP ,tim-
ulation of CRH-ACTH-glucocortiooid system.
The possibility that re"'ptors and specific fUflCtion.
will be identified not been ruled OUi (24).
AVP Bnd Neurophysln Concentrations
In early st udies. A VP activity was expressed in units.
(I !lU is C<juivalent to 0.4 pg.) The pla'ma AVP lev-
els of adults are usually low during sleep. but tho:se
of the spinal fluid tend to rise during the REM pe.
riods (176). Adrenocortical insufficicncy elevates the
plasma concentrations but the pituitary re-
ServeS. Glucocorticoids normali? both parameters
(154).
Blood concentrations ri,e abruptly in response to
tlte assumption of upright posture or other condi·
tions that suddenly lower the systemic blood pres-
Sure. Basal secretory rates of normal human adults
vary throughout the day. but the plasma levels usu-
ally remain within the range or 0.S-O.8 p8lml (16).
Water deprivation is a potent stimulus. and elien
mild conditions can cievate the concentrations to SO
pgj ml Or more (81).
Since the molecu lar weights of neurophysins are
1000 times those or the peptide hormones. the blood
plasma usually contains a few nanogmms per millil-
iter. The levels arc alTccted by both secretion and
degradation rates, and the", differ for the peptides
and NPs. Hepatic re"'ptoTS with saturable binding
properties are beli..'ed to regulate the degradation
(175).
".
REGULATION OF AVP SECRETION
The Need lor Complex Co ntrol Systems
A VP contributes to physiological regulut ion of
water. sodium. and pootassium metabolism. systemic
blOCld pressure and blood distribution. body temper-
ature. and thc r<:sponses to OOme forms of stress. Sc,·
eral different kinds of r.""ptors are needed \0 sense
changes in body ph)'si(l\ogy and to assess the ade-
quacy of the response •.
There are conditions under which an increased
rate of AOH secretion ameliorates some problems
bUI exacerbates olhers. It then beC<lmcs necessary \0
rely upon "compromises": small impairments of one
function are "accepted" in thc interests of partially
correcting anolher.
The co=quenccs of water dcpri.a\ion can in_
dude contraction of the intcrsliliaillujd and plasma
VQlumes, hypotension. hypernatremia , cellular de_
hydration. and hyperthermia. The deprivation teads
to activation of volume and pressure =Cp!ors. os·
moreceptors. thermorcceptors. possibly also <0-
dium sensors. When mare ADH is released. the ac·
tions On the kidney facilitate water conscrvation. If
even limited quantities of Auid arc ingested. the hy.
povolemia and hypernatremia arc corrected. and
conditions arc more favorable for accomplishing
heat loss . ADH actions on the blood vC$SCtsatso hetp
10 restore the blood prCSSUT<:. At the same time. cu-
taneOus vasoconstriction impairs thermoregulatory
responscs. and potassium retention leads to myocar·
dial depression.
Hemorrhage depletes the body of salts as well as
water. Usually. sufficient nuid is tra""ferred from
extravascular oompartments to the blM plasma 10
partially oomct the fall in blco:xl volume and pres-
sure. but one oonscquence can be dilution of the
blooo:! electrolytes. Pressoreceptors an: then stimu-
lated. but the activities of the osmorcceptOl"S decline.
Some ADH is reteased. and this oomributes to res-
toration of blood volume and pressure. It can simul·
taneeusly worsen the hyponatremia.
When environmental temperatures rise. the
water-conserving effects of ADH facilitate expan-
sion of the plasma volume. They thereby suppon cu·
tancous vasodilation and sweating. Vasoconstriction
of thc subcutaneous vessels at this time is
CQUn terprod uct ive.
bcessive salt intake invokes expansion of the
ECF volume. In some individuals. it ean raise the
systemic blM pressure. Therefore, pressoreceptor
signals for ADH !;Ceretion are inhibited. However.
when carried 10 extremes. lah loading can invoke
hypernatremia and activate the osmorcceptors. If
VASOPAESS IN AND OTHER REGULATORS
more is released. the "olume and pressure
problems
Changes in the electrical activities of individual
hypothalamic neuronS indicate that a single ADH-
secreting cell can be affected by changes in eithcr
osmolality or pressure of the syste mic blood. This
suggests that it receives inputs from mOre than One
kind of receptor (148). Each kind of message may
in,,"olvc its own special neurotransmiller.
Neurotransmitters
The locus cerule"s and pontomedullary reticular for-
mation richly supply the magnocellular nuclei with
noradrcncrgie inneryation. The densest accumula-
tions of terminals are in the ,,<,ntral regions of the
SON that contain cells. CAs are
believed to play major roles in the r<:gulation of hor·
mone release . The targct organs, in turn, contribute
to the establishment of the innervation patterns
(146).
Studies with pharmacological agents su pport the
concept that It·type adrenergic r<:ceptoes mediate
stimulation. wher<:as <>'-type receptors are involved in
inhibit ion (147). The distributions of ncurons affect·
ing the two kinds of receptors may be discretc. De-
struction of A·I cells of thc medulla oblongata leads
to development of vasopressin .... ssociated hyperten_
sion in rabbits (18). There are controversies COrK;Crn·
ing possib le roles for dopamine (and also for seroto-
nin) (162).
The SON oontain large amounts of acetylcholin.
esterase and of choline acetyhra""ferase (94). Direct
application of acetylcholine to hypothalamic prepa-
rations and injections of the neurotransmitter into
the carotid artery can invoke ADH release. Pharo
macological studies indicate a nicotinic (synaptic)
site of action.
The neurons are equipped with uon collaterals
implicated in feedback control. and they
oommunicate with other cell, that release
rlCuromodulators (126). They display regularly re-
curring changes in firing patter"" and sensitivities 10
,timulants (162). GABA depresse, electrical activ-
ity. whereas glutamate Can enhnce it. However,
physiological roles for those sub:stances have not
been established.
Systemically administered ".J[ reaches the neu·
rons via the cir<:umventricular organs. and it stimu-
lates ADH release. Wa(er-<ieprived dogs are far
more sensitive than well·hydrated animal. (124). h
has been proposed that the cells pos-
sess A-II receptors. bnt interactions with catechola·
minergie neurons have not been ruled out. Some in·
vcstigatQrs find direct iQntQphorctic applicatiQn
of A- II increases AOH release. Others report that
injel'tions in\() the subfornical organs stimulate.
whereas dir«:t injox:tiQllS into the SON arc inelfec-
tive(124).
Osmoreceptors and Sodium Sensors
The A OH s«:retory system is exquisitely sensitive tn
small choges in plasma osmolality and soclium enn-
centrat;on. A 1% elcvatinn nf oomotie pressure ab(),'e
the normal range is sufficient tn in,'Oke subs tantial
augmentation of AOH release. and a 2% reduction
can totally shut off hormone .<ccretion. The s)'Stem
also "defends" the Na ' concentration c"en when
this involves elevation of blood pressure and blood
volume to su!"'rnormal levels (63.129.1 47). In COn-
trast. some hypovolemia and hypotension a rc "tol-
erated." Blood pressure and ECF volume Can de-
viate from optimal values by as much as I S% before
thc disturbances nverride the contrnls linked
with the solute effects. On the other hand . hy»>
volemia the responses to osmotic
stimuli (177).
Although many allempts have been made tQ ad-
dress the question (164.165). contrnversies concern_
ing whether there are sodium sensors separate from
the receptors alfeeted by osmolality have not as yet
fully resolved (2).
Under most conditions. high plasma osmolality is
associated with hypernatremia . Wheo substances
other than NaCI are deliberately addcd to thc blood
of previously animals. the conditions created
may be too artificial to permit simple interpl'<'tations
nf the consequences,
Close relationshps between plasma Na + and
plasma AOH levels. and impairment of the abil ity to
respond to watu dcprivation Na ' concentra'
tions are elevated. have been cited as support for the
existence of specific sodium sensors (2) . MorC(lver.
high concentrations of glucose do not directly in-
crease AOH secretion. Howevcr. it has been pointed
out that Na ' can affect OSmOl'<'ceptor.; (since the
ions do oot readily cross the plasma membran",,).
whereas glucose is ta ken up and it draws water intn
the cell'!
Observations that hypertonic &aline and hyper-
tonic sucrose infusions into the carotid arteries pro-
mote AOI-I release. whel'<'as hypertonic urea or glu-
cose do not. have been interpreted by some to
indicate that the hypothalamus contains osmore<:<:p-
tOT$. Supposedly. Ul'<'a is not effective beeausc it
crosses the plasma membranes. In some of the ex-
periments. the useof anesthesia has been avoided be-
causc of indications that the drugs prom(lte AOH
releasc_
EX!",riments of this kind have beon critiCized on
many grounds (2), It has been pointed out that uni-
lateral infus;nns Can inVOke behavioral responses.
and the elfccts on hormone release have been ami1>-
med to streSS.
It is now recogni,cd that SuCrOSe is an irritant that
Can invnke vomiting (129.130). It may therefore
stimulate nociceptors rather than osmnrcccptors
(16). Urea studies are difficult to interpret for sev-
eral reaSOnS. Intravenous injections of hyperosmolar
solminns Can cause SCvere cerebral dehydration.
They Can also damage the blood·brain barrier.
Moreover. when urea penetratcs Ihe cclls. it draws
in water. and the extracellular fluid Na ' rises. To
further complicate mailers. thcre arc indications
tha t brain celts protect themselves against hyper-
tonic environmcnts by generating small molecules
(S).
It C3nnm be assumed that substanccs injected into
the carntid arteries exert their effects on hypotha-
lamic neurons. In fact. most observers believe Ihat
dchydmtion clicits AOH secretion by acting upon
osmoreceptor.; associatcd with circumventricular or-
gans (which arC outside the blood-brain barrier) and
also on receptors outside the brnin. Neurons pro-
tected by the vascular barrier may not be dil'<'ctly
affectcd. Small lesions Ihat destroy just the organum
vasculosum of the lamina terminals (OVL n seri-
ously impair elfects of dehydrat ion on AOH release
in dogs (166).
The roles of the periperal rox:eptors can be studied
by depleting the ECF volume or elevating ils Na '
content. while avoiding central dehydration by in-
jecting water or hypotonic solutions ioto the carotid
arteries. Evidence for the presence of Cl'moreceptors
or sodium sensors in either the liver or the hep:,tic
portal vessels comes frnm observations that inf usio",
of hypertonic not iSOI(lnic) saline into those ve.._
sels invokes AOH S«:l'<'tion. The effects al'<' blocked
by transs«:tion of the hepatic vagal afferent nbers
(29) . Comparable quantities of hy!",rtonic saline in-
jel'ted into systemic veins do not stimulatc ADH se-
cretion. Osmorcceptors may also be present in the
mouth. throat. and stomach. since drinki ng inhibits
ADH release in monke)'S (!56).
Severe potassium depletion dehydrates cells. and
it augme nts the sensitivities to other stimulants.
However. as noted carlier. hypokalemia impairs
renall'<'sponses to the hormone.
Fina! l'<'solution of the problems involved in defin-
ing the ree<: ptors will have to include examination of
apparent s!",cies differences ia responses tn experi-
menta l manipulations. It is reasonable to cxpectthat
sh""p, goots. cats. dogs. and rodents each have their
special forms of adaptation to disturbances in water
and electmlyte homeostasis.
 VASOF'RESSIN AND OTHER REGlJlATORS

Barorecepto r a nd Volume Receptor Contro ls vical vagotomy, but the responses are abolished if
the glossopharyngeal nerves are also severed (14S).
Since ADH can devate systemic blood pres,ure, il is
The cervical vagus carries affeN"m fibers from the
physiologically appropriate for baroreceplors 10 reg-
aortic baroreceptors. When these nerves are severed,
ulate hormone secretion. When other faclOrs are
neither a-adrenergic agonists nor high aorlic pres-
controlled. stretching of the _essel wall$ and cleva-
sures inhibit ADH release.
tian of luminal prcssure inhibit AOH relea,e (104).
The roles of cardiopulmonary receptors with vagal
Di uresis plasma volume expansion. inflalion
afferents are controversial. The failure of sinoaorlic
of balloon, inserted into the left alrium, pumping of
denervation to appreciably affect ADI·I release when
blood into the left atrium. or the damping of certain
the vagus is left intaCI. and the marked increases in
blood vesstls. The antidiuretic responses to hypoten-
hormone secretion that follow subsequent vagotomy,
sion-invoking hemorrhage. contraction of the ECF
have be<:n citcd as evidenC<' for Ihe operation of
by other mea ns. and the placcment of clamps at sites
chronic inhibitory conlrol (161). On Ihe other hand,
thaI cause the blood pressure to fall can all be me-
evidence against participation of pulmonary 'ystem
d iated via baroreceptors. In primates. ADH secre-
receptors comes from studies in which occlusions of
tion is more profoundly affected by blood pressure
pulmonary vessels. or the inse rtion of inflated bal-
than by ECF volume changc, (53).
loons into Ihe right atria. did nol Substantially affecl
The system is extremely difficult to study for
hormone secretion ( 149).
many reasons. Under physiological conditions. baro-
The ability of nicotine to promote ADH release is
receptors engage in tonic conlrol that is both stimu-
amibuled 10 effects exerled on the carotid sinuses.
latory and inhihitory. Axons mediating both kinds of
Hypoxia is said 10 alter ADH rcle""e in the same
responses lravel side by side within the same nerve
way (rather than via activalion of the dcmorecep-
trunks (161), and they are accompanied by fibers
10rs involved in cardio"ascular and respiralory re-
that indirectly affcct ADH release. Differenccs in
sponses). Ethyl alcohol inhibition of AOH release is
sensitivities \0 messages arriving along sinoaortic, as
allributed 10 C<'ntral OCfllOUS system depression. Caf-
compared with atrial receplOrs. have been described
feine slimulation of Ihe brain augments ADH secre·
(100). There are also ,!",cies variations in the se,,"i·
tion. (Its diurelic actions are exerted on thc kidncy.
tivil;"". In IIOmc animaltypc., "'IDOI"CCCP'Or cont",1
and caffeine also stimulates Ihe urinary bladder.)
dominalCS. and in these it has even been suggesled
Ihat their function primarily to adjust
the sensiti vities to changes in osmolality. When C<'r·
INFLUENCES OF VASOPRESSIN AND OF
lain of the receptors are blocked, others can assume
RELATED PEPTIDES ON LEARNING AND
greater imlX'rtanC<'. All of Ihese faclors must be con·
BEHAVIOR
sidered when allemptS are made to dissecL Lhe sys-
Lem by CUlling one Or more neflleS. Vasoprcssin,oxytocin. endorphins,ACTH,andchemi-
Very Slrong stimulation at one site can override cally rdated !",plides are prescnl in several regions
physiological controls a t a nother. Mooerate amounts of Ihe brain and in the cerebrospinal fluid (34,82).
of A-U aCI on hypothalamic neurons to sl imulale All seem to be capable of functionins as neuretrans·
AD H release. High doses can invoke sufficient dc· millers. ncuremodulalors. or both. Minute quan-
va tion of the arterial pressure to inhibit the seerelion lities injected direelly inlo Ihe brain can affect ccre-
(148). Manipulations designed 10 affect JUSt certain bral funclions when there are no changes in Ihe
of Ihe receptors invariably have indi rect influences. concentralions within Ihe systcmic blood.
Thus, for example, if a balloon inserled inlo Ihe left
atrium is inflaled, the pressure in the chamber rises.
Animal ModelS Used for the Study of
baroreceptors respond to the stretch. and ADH se-
Learning and Memory ( 92 )
cretion is inhibited. However.lhe manCuver impairs
ddivery of blood to the ,ystemic arteries. Barorecep- Ral'S ha"" been placed in situations in which thcy
10rs of Ihe carotid sinus and aorta Ihen send signals must "shuttle" from one box to allOl her 1<> avoid rc-
that accelera teADH release. C<'iving electric shocks to Ihe fcct. Brain pcptidcs af-
Carotid sinus baroreceptors evidently play impor- fect the time required to acquire "active avoidancc
lant roles in reflex control of ADH secretion. When \>chavior"', and also the magniludes of concomitant
Ihe blood pressure in their vicinity falls. ADH SCcre- changes in autonomic funclions such as Ihe cardiac
tion increases . .B·ldrenerg ic agonist stimuialion evi- rates. Some invcstigators find Ihal "cxtinclion" (loss
dently depends upon the functions of those receptors. of the responses following removal of thc is
The agents continue to exerl their cffects aflcr Ccr- mort obviously affected by the !"'ptides. Thc regu-
lators been administered before, during, or
after presentation of the external and
have been studied in the presen"" of metabolic in_
hibitors. In SOme specific regions of the brain
ha"" been lesioned.
upassive 3voidanct'·· is tested by requiring animals
to suppress their usual behaviors in order to avoid
pIIinful stimuli. For rats can be trained to
remain within a small enclosure. when they would
otherwise enler a larger. adjoining one.
Since the conditions imposed a rc highly artificial.
allempts have been made to provide the animals
with situations they might encounter outside the lab-
oratory. Adult males have becn confronled wilh ago
gre:l'sive male.' of the same species. or with
receptive females; and hungry animals have been
placed in mnes that contain food.
Some Observatio ns and Inte rpreta ti ons (33,
'"
Hypophysectomy impllirs the ability 10 acquire ae-
livc avoidance responses. Thc ·'Iearning defeeI'· can
be reversed by the administralion of ACTH and of
some of ils fragmenls. One interpretation is that
ACTH faei litalcs involved in short·term
mcmory. The concept is supported by observatioru;
that the peplides can delay exlinclion in intact ani-
m"l. "n<l "1<0 I'm,"c, <levelnl'm"nt nf thr.
amnesia Ihat would otherwise fol low the administrd-
tion of strong eleclric shocks Or exposure to high
CO, C<lnccntrations. There are debates. however,
concerning how much of the effcets au rdated to
changes in "molivation'·. ··generalized arousal", and
the proce= involved in the acquisition. C<lnsolida-
tion. retention. and retrieval of information. The ef-
fects of peplides of this kind are of short duration .
They arc abolished by lesioning the parafascicular
nuclei of the thalamus or Ihe septohippocampal com_
plex (34). but not by ad renalectomy.
Some of the effects of enkephalins on teaming re-
semble the ones described for ACT H. Moreover.
ACTH compeles with opiates for certain of the re-
ceptors. diminishes morphine analgesia. and :;orne·
limes invokes withdrawal sym ploms. On the OIher
hand. the specificities of Ihe interactions a", ques-
lioned . ACTH binds ,,·ith low affinity. and it$ actions
cannot be blocked with naloxone.
Rats ,uhjecled to removal of Ihe ··pOSlerior pitu·
itary gland· · or Ihe injection of anti-A VI> sera can
a(quif"l! active avoida nce ,..,;ponses, but Ihey havc
rapid Brattleboro rats (which lack AVI'
in Iheir ct'rebrospinal Auid as well as hypothalamus
[35]) behave in a similar manner. Vasopressin im-
proves ",tent ion. and the effects are of long duration.
The peptide has also been used with some succcss to
treat human subjecl' suffering from amnesia follow.
ing automobile accidents, and for counteracting ef·
fects of protein synthesi$ inhibitors on memory pro-
cesses in laboratory The actions of Ihe
peplide depend on tlK: exislence of an intact dorsal
adunergic path,,·ay susceptible to damage with 6-
OH-<:Iopamine.
It has been proposed that the de,·elopmem of both
tolerance and addiction to opiates invol""s processes
rdated to long-Iem memory. Vasopressin exagger·
ates both
some actions that arC antagonistic
to lhose of vasap", .. in on both learning
and caleeholamine turnover in the brain. Brallieboro
rats have higher brain oxytocin than controls. and
some of their "learning problems·· could be related
10 this . (However. the Iwo peptides sometimes act in
the same direction. For example, in the presence of
high eStrogen liters. o.)"tocin contrihutes 10 the onset
of umalernal behavior" in rodents and A VP exerts
qualitativdy similar. albeit weaker, effects [120].)
NO!. surprisingly, reactions of animals to one kind
of test differ from those 10 another. For ..ample. en·
kephalins seem to facilitate acquisition of passive
avoidance respolL= bUI they inhihit acquisition of
an active avoidance of foot Shock!; (127). lnterac·
tions wilh peripheral systems can also vary. Thus,
hypophysectomy and corticosterone treatment can
augment avoidance of anack by another animal
while decreasing Ihe avoidance of fOOl shocks (92) .
Evidence that t ile Peptlde& Act Centrally
Th. conceplth"t the peptides act as neurotransmitters or
ncuromodul.torS wi,hin the brnin. wi,hou' dep¢nd.n<;e
0f1 peripheral systems. i. supported by several kinds of
o""'r • ., ,,>M:
1. Dosage. th.t are eff«"i"" when inj •• 'e<! directly into
brnin li .. ue or into the cerebrospinal fluid arc
",ually wi,huu, demonstrable infiuenee if givcn in" •••·
noo.ly. (Some rna)· reach ,uffieient concentroliun, in the
brnin when into th ••• rOlid .rlcries.)
2. Lesion. wilhin specific pam of the brain Can block
the ••;oral'· effect, withOut impairing peripherat
fu!\C,ion •. The hippocampus i. beli.ve<! to be the larget
,ite for AVP influences On tearning and behavior. The'"
.'" PVN proj.ctions to Ihat pari of the bra in. and lesion.
of the hippocampus aboli'h the effect< of 'he peptide. An·
.Iogs of AVP ,ha, hay. diuretic effects. and relat.d pep-
tid.s lhat do not. re.tore lhe ,uboormat binding of corti.
.o<,eron. of Bral1 teboro homolYiotes in hi ppocampal but
not in olh.r bro in regions ( 168).
3. Hormone ·'fragments· · have been prepared that .f·
fect bro,n funClions but not other tarse' OfpnS. For ••.
ampl •. DG_A VP and DG.lVP. the peptid.. derived by
r.mO'o,,1 of Ihc 'ermin.1gtyeinamide from AYP and l VP.
respectively. ha.e .e n,ral .ctions but no i"nuenees on thc
kidn.)·. Similarty. fragments COOlmon 10 ACTli aod
'"
MSH (e.,. ACTIl, 10) affeCI 10.rnin8 but nOl
steroidogenesis,
4. Some of tbe peptide< affect the '"'""".r of cate-
chol.mine> and Olhor tran'milters in lho brain. AgenlS
lhal inlorfere " 'j lh e/fcclS OIl the ncumtr"n'm;tt.'" do not
alfecl "",iphe'al [unclion •.
On ,he (lIh., hand. <ompl<t< <cparal;o" of roles in re8-
ulalion.,r Waler balance from those on learning may rtoI
be ",.list;e. Va..,p'«';" .!fcc" waler balance in lhe
brain a. well as in the periphery. and this contribute
to it$ .en".1 action. (75). Lesion, ,h.l ,ffect fI VP re-
lease in th. brain a lso .ffect cardiovascul.. reHexc1 and
(hirs, (22). Peripheral hormones (e.g. giuC<>Corlicoid.)
play. role in lhe regulatioo of peptide CO"CO"tralion.
wilhin lhe brain. Some of lhe "brain horm"""'" ar. di·
rectly taken up from the blood'tr.am . tho eirc"mven·
lricul.. 'ITuC\UreS Ihat a re "ou15ide Ihe blood·brain bar·
ricr'" Morco'·cr. <"cry one <>f Ihe neuropcj>lido. e.en.
$Orne influcnCC$ On ""ripheral mCI.boli,m <>f waler and
clcclrol)·le •. For exam pic. cnd.".phins ""n"ibule to Ihe
regulalion <>f bolh v.sopreSSin rde.", (94) and electrolYle
Iranspor! in Ihe gut (78). and oX)"lo<in can oppose f\ VP
innuen<:<:$. <>II waler bal.nce and blood pre .. ure . MSll i.
implicalcd ti. resulalor <>f "....er and tlC<:lrolyle melal>-
"H,m (I 15). and ilS aCli"", on pigmcnl <:<;11. in_ol_e """
dium ,ransporl. i)opam ino inhibi .. lhc rele ... of prolac-
lin (0 purporlcd regulator of waler bal."".). e,en.
influencc, on Ihe caroio,·ascula. s)'Slcm. and dep ......
pa", imcrmcdi. sccreli,," of lI..,ndorphin (154).
OTHER ACTIONS OF VASOPRESSIN
Extrarenal Water MetabOlis m
The watcr-wnscrving functions of ADH may be ac·
complished in pari by actiOIl$ exerlcd on thc skin,
salivary glands, biliary trael, and endocrinc pan.
creas. Pharmacological dosages dimin ish
walcr loss in both hcahhy and ancphric humans. and
Ihey counteraCI lhe dehydraling effecls of elhyl al.
cobol (142). Anephric palients secrete quan.
tities of ADH when they accumulale osm<xically aC'
live metabolileS in their blood plasma. They suffer
night sweau; following hemodialysis, po5.Sibly be-
cause lhe pr(l<:wure [(,wetS Ihe AOH levels. As dis-
cussed earlier, the syndrome of inappropriately high
ADH (SIADH) commonly occurs in palients with
tuberculosis. certain other lung diseases. and some
forms of carcinoma. Nighl .weats in these patients
may be relaled 10 Ihe fall in plasma hormonc lcvels
that accompanies bed res!.
Water Metabolism In the Fetus
Waler usually flows pa.. ively across the amnion
from lhe fetus to the mother. In at leaS! some spe-
cies, AVP reduces Ihc flow rate and can reverse its
direction. AVP also affects waler and sodium Irans-
VASOPRESSIN AND OTHER FtEGUlATOA$
porI acro&s felal skin. urinary bladder. and rena11u,
bul.. (121).
Mammalian fetuses secrete AVT. and Ihe peptide
exens influences lhat arc qualitatively similar. It is.
however • less potenl lhat A VP. Larger quanlilies are
released into amniotic fluid in response 10 hemor.
rhage and other forms of Sire... Prolactin is also
present in amniotic fluid, and il is said to augment
lhe effects of AVT. Conisol antagonizes lhe aClions
of both AVT and PRL.
In fetal lambs. surgical Iruuma, hypoxia. hemor·
rhage. and temperature stress can bring aboul up 10
50-fold elevations <)f the A VP levels. bUI the PRL
conccntrali<ms do 001 rise (37). One interprelalion is
that PRL is already present in the quantitie. reo
quired 10 suppon f\ VP function' . Another is that
PRL is not a major regulalor of felal water balance
in all species.
Thc preceding suppon the concept Ihal hypolha.
lamic pcptides regulale felal water balancc. How.
ever, since only high eoncentralions are known t<) af.
feet lhe transporl. it has been proposed Ihat the
hormones ael on rcceptors for a different regulator.
ThermoregulatI on
ADH Can lower melabolie rale and antagonize the
calorigenic effects of CAs (52). The responses ha_c
bc<:n demonstraled in animals with anterior hypo.-
thalamic lesions, and thcy may be relaled 10 inhibi·
tion of lipolysis. Many of thc stimuli for ADH re·
lease invoke thirst. and water intakc facililat ..
cutaneous vasodilation and swealing. In goalS. hy·
pothalamic cooling diminishes drinking. Palicnts
with uncontrolled Dl often Slate lhal ice or very cold
waleT quenches lhirst more effeclively lhan waler
taken at room lemperature (96 ). All ofthc prceeding
suggesl that ADH plays roles in protection against
the development of h}·pcrlhcrmia.
On the other hand. ADH also decreases swcaling,
and il oonstricls skin blood vessels. Moreovcr. pharo
macological doses augmem lipolysis.
Influences on the Endocrine System
The cffectsof exogcnous A VP include slimuiation of
GH and TRH secretion. In many species, S<lmc of
the uons of magnocellular neuro!lS lerminale in Ihe
vieinily of the pars intermedia, and rolcs in the reg·
ulation of MSH secrelion have been proposed.
High concentrations of AVP arc found in the SUo
prachiasmalic nuclei (181) and in hypOlhalamo-hy·
pophysial portal blood. A VP can increase ACTH
and glucoconicoid secretion, and A VP levels rise in
the R1<lrning. These observations raise lhe possibilily
that AVI' contributes to the of gluco-
corticoid rhythms.
Carbohydrate Metabolism
When present in high concentrations. A VI' acts on
the Jiver to accelerate glycogenoly,o;is. The action' are
cAM P-independcnt. and arc believed to be mediated
via elevation of cytosol Cal. (49).
Growth Stimulation
AVI' 3e<:elcrates DNA synth esis and mitosis whcn it
is presented to several kinds of cells cultured without
serum (135). The hormone levels are often elevatcd
in patients with lung and pancreatic tumors. and it
has been proposed that ADH facilitates the growth
of some tumors in vivo. The effects may be li nkcd
with elevation of cytosol Ca' · .
PROLACTIN REGULATION OF WATER AND
ELECTROLYTE EXCRETION
Roles for PRL and related adcnohypoph}'siul hor·
mones in osmoregulation have been established for
nonmamnlalian vertebrate, (10.11). and some estab-
lished functions of PRL on nonrenal strucwres of
mammals suggcst tht influences are cxerted on <alt
and water transport. For example. the complcx ef-
fects on mammary glands (128) evidently involve s0-
dium tran$port (17). and PR L is reported to affect
blood pressure in rats (105) .
Thcre are controversies concerning I"\r-
ticipation in regulation of renal excretion in mam-
malian adults (80) , Lactogenic hormone" havc becn
,<,ported to incroasc renal blood Ilow and GFR in
mammalian heart-lung_kidney preparations and to
promote transient diuresis and natriurcsi' followed
by persistent antidiuresis and <;Odium retention (48),
PK L receptors have been identified in the kidney
(12). and SOme investigators find that the hormone
invokes whon it is given to whole ani-
mals. Inhibition of both water and <;Odium excretion
has been described for rats. and the animals arc said
to show elevations of plasma I'KL when they arc
subjected to waler deprivation. It has also been
stated that human release more PRL when
they are given hypertonic saline. and that hypOtonic
""lutions depress hormone reloase (26).
Other investigators have presented conAicting
data , In one series of experiments. PRJ. kvcls did
not rise in response to several procedures that inVOke
dehydration (103). In another. chronic h)"perprolac-
linemia failed to improve urinary osmolality of rats
with Dl (1) ,
Three nplanations have been advanced to explain
the discrepancies: (a) Prolactin preparations are
often contaminated with AVP. which j, difficult to
rerTlO>'e or inaclivate (1,110); (b) animals obscrvcd
to release PRL in response to dehydration or the in-
jection of hypertonic solutions are actually respond-
ing to S lrl'SS (rather than to of water bal-
ance); and (c) prolaclin aCts primarily to modify the
innuences of olher hormones. and its effects Can only
be demonstratcd under appropriate circumstances.
It can. for example. potentiate the sodium -retaining
innuences of aldosterone (12).
While the presence of PR L in the kid ney has been
cited as evidenee in favor of a role in regulation of
renal functions. il has been pointed OOt that the kid-
ney is a major site for disposal of circulating hor·
mone (8). It is also that PRL is involved in
control of kidney growth and repair (80). r"thcr
than in urine formation. (However. a reootropic f"e-
tor other than PRL is present in pituitary gland ex·
traCtS [114].)
OTHER HORMONES AFFECTING SODIUM
AND WATER EXCRETION
Melanocyte Stimulating Hormones
The pars intermedia is large in camels. llamas. and
other mammals that excrete highl)· concentrated ur·
ines; it is intermcdiate in in rodenlS and other
species that . how good resistance to watcr depri'<l-
110n; and II IS small or totally ab'lcnt In some an,mat.
that easily succumb to dehydration (see fig, 19·3).
It undergoes histologically demonstrable changes
following the administration of hyp.monic NaC!,
but it is not similarly affected by hypertonic KCI or
glucose. Exogenous MSHs arc natriuretic (but n<.>t
kaliuretic) in ratS,
Indications that th. pineal gland affects water and
electrolyte metabolism arc citcd in Chapter 20, and
there are reasons to suggest that it imeraets with tbe
pars intermedia and neurohypophysis to exert fone
controls. Melanocyte inhibitory factors (M IFs) are
small peptides deaved from oxytocin , They arc prob-
ably released from the axon endings of magnocdlu·
lar that terminate in thc vicinity of thc pars
intermedia. It has been reponed that intracarotid in·
jections of M1 Fs promote AVP secretion and also
the release of pineal gland A VT into the cerebrospi-
nal Auid , Pinealeetomi1.cd animals accumulate more
MSH in thoir pituitary glands than intact controls.
AVT injec tions into the third ventricle of the brain
reverse this effect . and they also lower the MSH lev·
els in intact animals (119).
Gtu cagon
Animals in fused with large volumes of saline release
glucagon. and the peptide undoubtedly contributes
,,.
to the diuresis. However. Ihe na·
triuretic fa<;:lors, ;1 promotes the of calcium
and Qf magnesium as well.
A physiQlogical role in control of electrolyte ex_
cretion has not been cstablished for mammals. In
fishes, there are actions antagonized by insulin thai
se<:nt 10 be physiologically important (411.
Calcitonin and Parathyroid Hormone
Exogenous CT is a potent diuretic that can markedly
loW<'. Ihe blood volume, invoke hemoconcentration,
and promote sodium excretion. However. sugges-
tions thai i( is a natriuretic hormone are difficult to
rCC<lnciic with observations thai it accelerates the ex-
cretion of several olher ions. and thai plasma CT
d()CS not rise following salt looding.
Parathyroid hormone inhibits sodium reabsorp--
tion in Ihe proximaitubules. However, it docs n01
C<lnSiSlcmly cause natriuresis. oceause its effects are
C(lunteracted by those of aldosterone (which acts On
the distal portions of the nephron).
Thyroid Hormones
Thyroxine (T.) and triiodothyronine (T,) deficien-
cies are associated with water retcntion and electro-
lyte metabolism defects. Alth(mgh the sodium and
chloride concentrations of the interstitial ftuids are
orten within the normal range. plasma Na- tends to
dC(:line_ Overall potassium balance is negative. but
this has b«n linked with reduction of lean body
mass. Some of the problems arc directly related to
subnormal Na 'J K--ATPase activities. and these
arc e:<acerbated by the low levels of glucocorticoid.
and certain other hormones_
The severely impaired ability to e xcrete a water
load can be explained in several ways. The renal re-
sponses to ADH arc retained . but the plasma levels
of the hormone can be inappropriately dc.'ated. This
is attributed to poor sensitivities of hypothalamic
neurom to inhibitors. Myocard;al weakness and
bradycardia C<)mbine with other hemod)'namic fac-
tors to lower the GFR. and Chronic T , deficieney also
leads to roduction of kidney mass.
The "puff}-" appearance of th e skin (myxedema)
in severe hypothyroidism is rdated to defccts in hy_
aluronic acid and protein metabolism, and the con·
sequent accumulation of mucopolysaccharidcs, pro-
te;ns. and water ;n the subcutaneous spaces.
Capillary permeability defects exacerbate the prob-
lem by permitting leakage of Auid. and proteins into
the perivascular spaces. Poor appeti te and gastroin.
testinal functiom contribute to diminished plasma
protein concentrations. and this probably partially
VASO?RESStN AND OTHER REGULATORS
accounts for the reduction in circulating blood
voiume.
The effects of hormone deficiency Can be COr-
rected with T. or T" but glucocorticoids are only
partially effective_High dosages of thryoid hormones
invoke and dehydration. They elevate met·
abolic rate and body temperature. and they accel-
erate loss of water via the sweat glands and rcspi·
ratory trac\. Since the hormones sharpen the
appetite and stimulate gastrointestinal motility,
moro water is also lost with the The diuresis is
explained in part by the improved renal blood Aow
and GFR. and also the production of larger quan·
tities of urea and other osmotically active metabo-
lites. Normalization of hyaluronic acid metabolism
leads to resorption of the substances that contri bute
to the myxedema.
Gonadal Slaroid s
Es/'ogtn.< tend to promote sodium and water reten·
tion. but the effects arc variable even within a single
species. Increased renin ""cretion and accelerated
prodUction of renin substra te Can elevate the aldo-
sterone levels. but estrogens are effective in animals
displaying mineralocorticoid escape. The retention
can jX)SC problems in susceptible individuals during
pregnancy or following the ingestion of oral
contraceptives.
Estrogens stimulate the secretion of growth hor·
mone and prolactin. They also exert localized inftu-
cnees. the most prominent of which is rapidly devel·
oping retention of water in the uterus. This is
attributed to the release of histamine and
prostaglandins.
Since it is chemically similar to deoxycorticoster-
one. progesterone can interact with mineralocorti-
coid receptors. It is al50 converted in the kidney and
at other sites to tbat steroid (118). When aldosterone
levels are low, progcsterone tends to promote salt
and water retention, When they are high. progester·
one can antagonize aldosterone actions since;t com-
petes for the receptors but has lower flOtcncy. Some
observers haY<' linked '·premenstrual syndrome"
water retention with direct actions of progesterone.
whereas others have suggested that the condition is
related to inadequate progesterone secretion during
the luteal phasc of the ovarian q-c1e. Progestagcn
therapy is effective in limited numbers of patients.
poe.sibly becausc it inhibits PG generation.
Androgens arc anabolic hormon<;.' that promote
conservation of sodium . chloride, potassium. sulfate.
calcium. and phosphate, as well as nitrogen. They
also stimulate the appetite and thereby tne ingestion
of electrolyte-containing foods. Water and salt r.,.
lenlion have b«n dIed undesirable
of androgen therapy for reproductive disor·
ders, but these eannOI be .eparated from Ihe
funclions. (The anabolic aClion. of growth hormone
similarly affect dectrolyte butlhey arc
generally associaled wilh less severe water
relent ion.)
Heparin
Heparin i. a ,ulfated acid mucopolysaccharide .ynlhe.
• i,.cd in many parts of lhc boody. including lhe lunS" h,'or.
heart. 'plccn. and conneeli'e tissues. It has been impli.
Cated in lbe regulation or bone calcificalion. lipid tron ..
port and metaboli,m. most cell function,. and <>Iher pro-
=«. Although pharmacological dose, arc often u",d to
protect against the formation of intra'","ul.. clots. lhc
fael lhat it aCtS latc in the coagulalion c.",.de rai""
question, conce,ni", iii physiological importa""e in con·
lrol of the reaelion sequencc .
Cardiac patients gi"en anlicoogulanl dosages of
heparin a nd relaled glycos.amiooglycans of len in·
crease Iheir waler and salt excrelion 10 a degree Ihat
permi\.S discontinuation of diuretic therapy. Chronic
treatment e"entually affecls the >.ona glomerulosa of
tho adrenal cortex. Usually. this leads to compensa·
lory stimulation of tlte renin.angiotensin·aidosterooc
system. but it can in.uke mineralocorticoid insulli.
cioncy in patients wilh diabete, mellitus and in Olh.
> with I (I 14A).
Suggestion. that acule influences on
metabolism result from direct inhibition of aldosle-
rone secrotion are oot easily reconciled with the fail·
urc 10 observe such effecls when heparin is presenled
10 ad renal glands studied in vi tro (55). MorC<l\'er.
heparin has been shown 10 ae«lerate water and elec·
lrolyle excretion in adrenaleetomilcd ralS (101).
Thymu s Gland Influences on Electrolyte
MetabOlism
ROIS di$play ",..onal 'adation, io water and
ele<:trol)'IC excretion palle rn,. They put 0111 m(lfe sodium.
rmaS$ ium. chlo'idc. and water in February th.n in Jan·
uary. and mote in March th.n in Feb,uar)' . even
lhe urin.ry , alue. ate compated with the dietory inta ke,
(JOI). Chloride e.ctelion ri",s Sharply during thc 'um·
mer monlh •. "od inver><: rel.t ion,hips between urino,y
chloride and u,ina,y phosphate can be demonSlratod
under a variety of condition"
Thymectomy teduces renal e>crclion of sodium. pota.·
.ium. and chlorid. during tim •• when intact animal. h",'e
low and il enhance, the excrelions during lh.
ptak perieds . Thymectom)· al.., imp.i" the .bilil)' to ex·
.tete .. 1t loads. ,ia mechani'm' lhal ar. exaggerated if
the animal. are also adrenalectomiled (74).
The thymo, ,ynthesizes and retea"'. heparin.like mol·
ecule. (30). and il ",gu latesthe heparin co"""nt,ation of
the blOXld pluma (43). Hepar;n injeclion. ··oo,m.I;,o"
Ihe electrolyte ..c"'tion pa11ern, or thymectomized rat.
(10 1), Thymectomy aloo atTeetS calcium m<laboli'm and
the responses to both endogenous .nd ;njecled vit.min 0
($Ce Chap. II), and heparin has be.n implicated in the
,egulation ofoome bone minerali .. tion functions.
These .nd olh.. observation. point to oome rolc or the
thymus in fine control of eleclrolyte metaboli,m, and es·
ptcially in the adjustment$ a»Q<ia\c<j with $Ca$onal
cbanges. Some may be telated to Ihe more rapid synlhe,is
of vitamin 0 during thc .um mcr month•.
COMPARATIVE PHYSIOLOGY OF WATER
AND ELECTROLYTE METABOLISM
Vertebrates ulili7.C a variely of mechanisms 10 cope
wilh environmental factors Ihat aife<:t waler and
ele<:lrolyte (10) . Some of the adapta·
tions are described below. because th ey provide in·
sighls into the and limitations of hormones.
Dssert Mammals (97 , 144,145)
T he of mammali an brain must be
mainlained within a very narrow range. Elevalion..
of more than 1'- 3' above optimum va lue, impair
and e.treme heat ca uses permanent dam-
age, Animals living in deserts must usc special
mechanisms to avoid overheat ing. bocause (a) strong
and warm air Can rapidly devate body tem-
perature. and (b) most mechanisms for cooling the
body use water. which is a SCarce commodity. More·
over. dry en,ironmcnls facilitate evapor:tli'e loss
from thc respira tory tract and the ski n surfaces. e,en
whe n the temperature is in the moderate range.
Small animals arc especially vulnerable to O,er-
hea ling. They ha,e large surface,,·olume ratios Ihal
permit rapid penetration of hea l to Ihe body rore and
faeilita le ,,'ater loss via the skin. They also ha,e mct·
abolic raleS Ihat arc high whcn compared wilh thcir
weights.
Terrestrial rodents have lillie or 00 opportunilY to
drin k. Most cannol ta ke ad'antage of Ihe few .uc·
eulCnl plants in their environment. the
leaves and blossoms are above the ground in places
where Ihe an imals can be spotted by predators.
These animals subsist mOSlly on .eeds Ihat are high
in fat con lent. When metabolil.ed. rats yield more
waler per gram than carbohydr-JICS or proteins, and
there are rew osmolica lly acti"e waSle products.
Foods of this kind also contain 1;l\le undigestible res-
idue. Thcrefore, only minimal quantities of water
lost via Ihe urinary and
There is a limil to the amount of moisture thaI Can
b<: derived. If the food consumption is increased,
more must be supplied and more COl must
be eliminaled. and such processes increase rcspira·
lory loss. Moreover. oxidation of food gener·
'"
ates heal. Obviously, survival 'tralegics mu_,{ be di·
recled at waler const'r.·alion.
The heav)' fur provide, insulation against e"ces-
sive uptake of heal from the environment during
lime. of exposure lO lhe sun, and ab..,r>ee of ,"'eal
gland reduces waler loss.
Special fealures of the respiratQry tract minimil.
Ihc evaporative losses. Air leaving lhe lunp is as
warm as Ihc blood. and it is saturated wilh waler
vapor. As il traverses thc long tOrtuOUS pasagcways.
Ihal lead 10 the nose. SOme cooling is accomplished
because tbe StruCtureS encountered ha,·c a lower
temperature. Since cool air holds less moisture than
warm. some waler condenses on the mucosal Sur-
faces. Progress;". changes take plae.:, and Ihc ex"
pired air thaI finally emerges is substantially re-
duced in both temperature and moisture conlcnt.
Inspired air tra,·erse. lhe same passageways. Sinee
it is very dry at the point of entry. it promotes evap-
oration of the condensed moistul'<'. This accounl' for
Ihe cooling of the airways. The inspired air gradually
picks up moisture as it travel. toward the alveoli of
the
Nasal glands provide additional benefits. Water
that evapOrates from Ihe secrelions cools the nose .
The salts form CruSls thaI are shed from the surfaces
withoU! appreciable quantilies of moisture.
The kidneys arc analomically equipped to make
highly concentraled urine, and they "'spond vigor.
ously to the large amounts of aldosterone and ADH
that a", s«:reled. AldOSlerone also exert, influences
on the gastroi nteslinal traCt and nasal gland, that
contribu te to waler conservation. Some of the ani·
mals Can 10""r their metabolic rates during limes of
the day when they arc inaclive .
Behavioral adapta tions are at least as im!X>rtant
as any of the preced ing. Most desert rodents ,pe nd
the warmest and driest pariS of the day in cool. moist
burrows. A few alternale bouts of activity (during
which the body temperature rises) with longer pc-
riods or res\.
The ability of Ihe dromedary to survive under ad·
verse conditions is even more remar kable. This ani·
mal does not burrow. and it is often exposed to direct
sunlight for extended time periods. Since it is large.
it has a low surface:volume ratio. and it absorbs less
per gram than the small rodents. Heavy fur on
back provides insula tion, and glands
are located OIl und ersurface of the body. where
they are pr(l1eeted against direct exposure to the 'un.
When fully hydrated, Ihe camel mainlains an op-
tim um body temperature. It Can produce several
ti mes as much sweat per meter of body surface per
hour as merino sheep (which arc considered well
adapted to desert environments).
VASOPRESSIN AND OTHER REGt.!LATOR$
The camel does not "waste" water by swealing at
such high rates if it cannot ddn k. Instead. il permits
its body to accumu late heat during the afternoon. It
can tolerale corc as high as 41 · C. be·
cause the blood that supplies Ihe brain no,,", through
strUClures that ha ve been cooled by evaporalion
rrom the l'<'spiratory passagewa)'$.
Since the desert nights arc cool. the accumulated
heat is dissipated without water loss. The tempera-
ture of much of the bod)' Can fall to 34 ' C, but the
brain i, again protecled. It docs not receive blood
Ihat has passed Ihrough the skin. and there is lin1c
cooling of the respiratory passageways at nighl. The
core temperature is low in the morning. and substan-
tial quantities of heat Can be taken up before it rises
above optimum levels.
Camels eal plants that arc high in prOlein contem
but low in cellulose. Their gastrointestinal tracts
contain bacteria that convert urea to ammonia plus
carbon dioxide . and enzymes Ihal facilitale Ihe use
of ammonia for prolein synthesis. T hererore. very lit-
tle urea is len over to draw water into the urine (SO) .
The kidneys efficiently remove sa lts. and under ex-
treme conditions the daily urine volume docs 001 ex-
ceed 1.1 lilers. Its osmolality can be Iwke that of
seawater.
In addition to influences exerted on the kidneys.
hormones contribule 10 the ability to form extremely
dry feces wilh daily volumes of a' little as 1.3
as well as Ihe highly concentrated saliva Ihat ac-
counts for the "breath of Ihe camel".
Unlike most mammals. camel' lolerate substan.
tial ",d uClions in plasma water. This is andbuted in
part to special properties of the membranes of Iheir
e lliptical erylhrocytes (95).
In common with most dosen the ani ·
mals seek shade during the afternoons. The mosl "'-
ma rkable of their adaptations. however. may be
their ability to very rapidly ingest truly remarkable
quantities of water. It is oot unusual for a camel
emerging from a trip on the desert 10 drink 100-135
liters in a few minutes. and SOmC animals ha,'C been
observed to take 200 liters. Waler reservCS equiva-
lent to one-third the body weight can be
lated. Some i. relained in the stomach . and addi·
tional fluids are stored in "water sacs" located at the
sides of Ihe rumen .
Nonpiacental mammals such as Ihe kangaroo find
different solutions to Ihe problems . Although they
possess thermoregulatory systems. they
ma inlain body temperatures lower than those of eu-
therians. Less rood is required 10 sup!X>rt the lower
metabolic rates. less heat is generated. and smalle r
quantities of metabolic wastes arc rormed. Water
loss via Ihe respiratory tract is limited because the
expired air has a relatively low temperature and
moisture oontent . and only limited quamities of CO,
must be removed. Tbid fur protects against exces-
sive uptake of heat from the environment. Some spe-
cies lick scrotal and other limited regions of the body
to achieve heat loss b}' evaporation. Since the ani·
mals can travel rapidly. the}' often manage to fmd
sbade and succulent foods.
Bird s
Birds that long distances do not drink for many
hours. They cannot alford to wcigh down their bod-
ies with ucess water. but the}' must dissi]XItc the
large quantities of heat generated by the Oight muS'
des. They cut down the need for evaporativc Waler
loss b}' maintaining bod}' temperatures 3 ' _ 4 '
higher than those of placental mammals. At most
ambient temperatures. this facilitates transfer of
heat to thc environment.
Most birds pant. Air current. promote rapid evap-
oration of the limited quantities of water th'll arc
used, The blood that supplie. the brain can be ,;cnt
througb the cool regions. and it is unaffected by the
high temperatures that develop in other pan, of the
body (145). The muscular effort involved in panting
is minimzed by synchronization of tbe rate with the
natural oscillation frequency of the respirator}, sys-
tem. (Birds adjust the time periods durin ... which
they engage in such activities to body needs. but they
maintain constant panting rates.) Sin<:e they have
air sacs. the)' can move large volumes of air with-
Out losing mucb carbon dioxide. In thi s respect.
tn ey navc an advantage over mammals that ]XI"!.
Some birds do devdop mild al kalosis. but they
are more tolerant than mammals to small pH
elevations.
Aldosterone and AVT act on the kidneys to limit
water loss. A VT is less potent tban AVP for aug·
menting water reabsorption by the tU-
buies. but it additionally affects electrol),te transport
in other ]XIrts of the nephron and can lower the
GFR. At least in cbickelUi. the overall antidiuretic
effect of A VT ten times that of AVP (12).
Since ureters arc fine tubes. the urine passing
through them must <;<lntain sufficient water to avoid
the formation of precipitates. However. bird ureters
lead into a cloaca in which much of the water is
reabsorbed , Tbelarg. orifice eliminates the "plumb--
ing" problems. The major nitrogenous "'aste is uric
acid. which Can be removed in semisolid form.
Aldosterone promotes water reabsorption in the
gut. In marine forms. it also ac<:clerates nasal gland
concentration of electrolytes. Some species can
therefore drink sea water and remove the excess salts
as powders that blow olf the surfaces of the fea thers.
Angiotcnsin stimulates thirst (112). Birds search for
water when they Oy. Many minimi'.c the dangers of
predation by drinking very rapidly.
Reptiles
Varying degrees of poikilothermy are enoountered.
Low metabolic ratCS slow tbe production of meta-
bolic wastes and keep the body temperatures from
rising excessively. as impermeable skins minimize
evaporation of water from body,uffaces.
Altbougb they depend heavily on succu lent foods.
most desert reptiles drink when tbey can. Many spe_
cies have large urinary bladders that serve as reser-
voirs. T hey uSC salt glands at the base of the tongue.
the orbits of the eyes. or in the nose. to excretc p0.-
tassium and mher electrol),tes,
Unli ke the kidne)'s of birds and mammals. those
of reptiles lack Hcnle loops and they arc incapable
of producing hypertonic urin •. Most species exCrete
a product that is isotonic with th. blood plasma,
Some can vary the relative quantities of uric acid
and urea in accordance with bod}' needs. A major
adaptat ion is the ability to go for long time periods
without excreting urine. Electrolytes can be stored
during times of and excreted when
water be<:omes available.
A VT reduces urine now by lowering the GFR and
accelerating tubular reabsorption. When Water is
abundant, mesotocin antagonistic inOuences.
Aldosterone is not a major of the reptilian
kidney, but it, DOC. and other steroids regulate thc
sal! glands (155). and also the fu!>Ctions of the
doaca and urinary bladder. An osmoregulatory role
for PRL has also been suggestcd (97).
Many reptiles pant. and they ha"e air ""c< that
resemble those of birds (52) . Some talc advantage
of bormonally regulated changes in skin pigmenta_
tion to exchanges of heat with the environ_
ment (see Chapter 20). In many cases, behavioral
adaptations are even more important. The animals
bask in the sun to raise their body temcpratures. and
they seek to avoid overheating.
Crocodiles and aquatic reptiles do not face
the problems of overheating and dehydration . They
do II(It have urinary bladders. but the)' possscss hor-
monally regulated mechanisms for adjusting urine
production when they spend time On land.
Amphibians (1 5 5 )
Amphibians living in fresb water mu.t cope with hy-
potonic environments. They do lillie Or no drinking,
but the highly permeable skin (which perForms ro-
.piratory functions that supplement tilosc of Iungs or
gilts) provides an avenue for uptake of ,,'atCr and s0-
lu tes. The low elcctroly tc content of the blood
plasma (the equivalent of 0.7% Nael for grass frogs

cl)mpared with 0.85% for 3 typical mammal) lesscns
the problems of coping with saIl balance. The urine
is hypotonic and (A l().g alpine newt has
been obser,-ed 10 put out 16 ml of urine pcr day.)
High protein diets. consisling largely of inseclS, sup-
pon the formation of urca and of anlm<)l1ium .alts
that augment solule coneentralions.
When pond-dwelling amphibian. leave their
aqueous environments. the urinary bladdel"$ serve a,
salt and waler reservoil"$. Moisture Can al oo be ab-
sorbed inlo the lower pans of the body fr<m"J wet soil
and from very s hallow puddles. Some animals have
capillary channels thai draw water upward IOward
the mouth (23). Dew, and fog thai condenses on Ihe
skin. provide additional wureeS. Somc speci.s toler-
ate l=cs of up 10 50% of Ihe optimum water COn-
tent. A few have adapted 10 marine environments
and to brackish water.
In anurall'l, A VT aeceleratcs waler and sodium
uptake aCross the 'kin and urinary bbddcr. and it
probably also acts on the gawoimestinal trael. The
skin becomes incrcasingly sensitive to the hormone
as dehydralion progrcsscs. The innuenees On sodium
and water transport are supported by aldostcrone.
corliCQSterone. and related stcroids. In wads. epi-
nephrine contribute., to the controls by increa sing
the pcrmcobility of the . kin and "imut.ling chlo-
ride"""xcreting glands.
A VT also rcduces urine produclion. In addition to
affecting tubular reabsorption. it constrin, the affer_
ent arterioles of the kidney and thereby lowers the
GfR. It probably also contributes to the control of
s)'slemic blood prcssure. T he aClions arc opposed by
mcsotocin. which conslriets the dJerml anerioles
(116).
Prolaclin affects sod ium and water transport
across the toad bladder and contributcs to the main-
tenance of plasma electrolyte contenl. It also plays
some very special roles. Newts spend much of Iheir
lime awa)' from watcr. but they must rcturn 10 it for
reproduction. The PRL Ic,'<:I< rise as the brceding
season approaches. and the hormone influ-
ences on Ihc slin Ihat cause the animals to seck
water (10) . "Water drive" can be invoked in Ihe lab-
oralory by injecting the animals with PRL. The pi-
tuitary hormone also antagoni1.cs
laled metamorphosis. while thyroxine blocks PRL
effects on Ihe skin .
Not surprisingly. the totally aquatic mud puppy
doc.! not usc "'stcr-conserving hormone •.
Fishes
A comprehensive survey of the diverse mechanisms
ulihed by Ihis very large class of vertebrales could
AND OTliER REGULATORS
fill several volumes . Some reprcscntative obscrva-
lioll'l are presented here.
Much of the wster and eleelrolyte exchange lakes
place across which have surfaces many limes
grcater Ihan Ihose of Ihe skin. Steroid hormones af-
fect moslly chloride-secreting cells. bUI they also
Slimulate electrolyte transpon across gastrointes-
tinal epithelia.
Paralactin is an adenohypophysial hormone r.,.
lated to the PRLs of other vertebrates. It controls
bolh struCtures and funclions of Ihe mucous cells of
Ihe skin and il can aCI on ionic pumps. Euryhaline
species rcquirc Ihe hormone when Ihey gl) from sail
10 fresh water. The adaplations arc linked with
changes in piluilary gland and skin morphology. An-
imals thaI are hypophyscelomi1cd rapidly succumb
10 sodium loss when placed in fresh water. They can
be prolecled b)' pretreatment with eilher fish pitu-
ilary gland extracts Or mammalian proiactins.
PRL 3ffcels cyclic nucleolide generation and
Na ' / K ' -ATPase activities in gills. rectal glands.
and kidocys (71). and ;1 may in Ihis way conlribute
to osmorcgulalion. The effects on the A TPascs are
opposed by Ihose of thyroxine (which protects some
euryhaline fishes against the effects of transfer from
fresh II) seawaler).
Fi.h A VT and other f'Cplide' >hQwn in
fig. 10-2. Freshwater species have no known necd 10
COnServe w3ler. and in Ihese A VT seems to prommc
diuresis. There arc SOme in which neurohypophysial
pcplides augment branchial blood ftow and elCClro-
Iyte exchanges aCrOSS Ihc gills. The hormones also
play roles in the rcgulalion of blood pressure.
Marine fishes seawater. and they exCrelc
electrolytes via the gills. Some maintain blood plas-
mas wilh very high solute contcnlS by accumulating
urca or trimethylaminc The hagfish (a cycl<:>-
Slome) scems to be unique among the vertebr-Jle. in
thai il lends \"lOt 10 osmorcgulale in a comparable
manner . lIS adaplations resemble lhose of marine
inverlebrates.
THE UROPHYSIS (90)
The urophys is is found al the caudal end of the
spinal cord of somc of Ihe bony fi shes. Its morphol-
ogy rcsembles that of the neuroh)·pophys is. and it
seems 10 perform .imilar fUnelions. It secrctes uro-
ten,ins Ihat affecl blood prcssure and waler b.1Iance.
along wilh urophysins Ihat a1'<: neurophy' in-like pro-
te iM. Fully developed organs arc prc<;cnt only in te-
lcosl.l. but related sccretl)ry structure., have been de-
scribed for cartilaginous fishes.
Uroten'in I Slimulates smOOlh muscle in fish. and
il promotes the excretion of calcium and magne-
sium. II is chemically related 10 CRH. and it is also
a potent stimulant for ACTH release. It can bind 10
mammalian receptors.l(}wer the blood pressure. and
selectively dilate mesenteric blood vessels (91) . The
following amino acid sequence has been
H· Am·Asp-Asp- Pro- Pro- II.-Scr- lie· Asp-Leu-Th r·
Phe-His·Lcu·Len·Arg·Asn-Met-lle-Glu·Met·Ala_
A rg-Ile-G In· A.n-G In· A rg-G Iu-G In-A Ia·G Iy- Leu-
Asn·Arg-Lys-Tyr- Leu_Asp-Glu· Val-N H,
Urotensin I I is biologically mOre like oxytocin in
that it slimulale. all kinds of smOC)th muscle. How.
ever. il is a dodecapeptide that is chemically relalcd
to somatostalin. It antagonizes the influente,
of low osmotic pressure on the pituitary gland that
!ead to PRL release. possibly by hlocking
thannels involved in the secretory proccSl; (58). It
has also been implicated in the regulation of sodium
metabolism. Three forms have been described (A-4j.
THE CORPUSCLES OF S TANN IUS (11 7A)
These are vascularized StruCture, found near Ihe
kidneys of many of the bony fIShes. They haye cal-
ciferol reCeplOr1;. and they arc belie"ed 10 regulale
calcium metabolism in marine forms exposed 10 high
concentratiO/!! of the mineral. No analogous organ,
have been identified in other vertebrale<.
An enzyme that resemble< rcnin has also been
identified. Since angiotensins contribute 10 thc reg-
ulation of blood prcssulX' and funclions in
fishes. the corpuscles may perform OIhcr functions
( 112), An earlier concept Ihal they seeretc udreTl()-
steroids ha' becn di",ardcd.
REFERENCES
I. Adler. R, A.. Dolphin. S,. Szcfier. M.. and Sok<>l.
H. W. The Eff""" of Circulating Prolactin in
Ra .. "'ith H.r<:ditary Hypothalamic Diabetes In·
,ipidu, (BTOuleboro Strain ), End(X,;noI. IOj:
1001_6.1979.
2. And ....... n. B. R.gulation of Water Intake.
iol Rno. 58' 582-603. 1978.
3. Andreoli. T. E.. Gran'ham. J. J,. and Rector. F.
C . Jr. Disru.balK"t. in Bod)' Fluid O.mololil),.
Ame.ican Phy.iolosical Society. Bethe1d •. Md,.
1977.
4, Andr""li. T. E,. and Schafer. J . A. Some Consid·
eration, of the Role or Antidiuretic Horm""e in
Water Hom"""t.,i, . R",. Prog. I/OFm. 33:
387-431. 1077,
S, Arieff. A. I. . Gui1-(ldo. R.• and L"",rowil7.. V. C
Pathophysiology of H)'pe.,..mol.r S'a'.'. Ch.p.
,
II. pp. 227-50 of Andr""l; Ct.1.. .• referen""
6. Au kland. K. Renal Blood Flow. Chap. 2. pp, 25-
79 of Thurau. K.• ed .. KidMY and Uri"",y nau
Ph,..iology II. Univ."ity Park Pre>4. Baltimore.
In6,
7. Baenschi. A, J .• VaUet. P.• Bauman. J. B.. and
Gi..,d. J. Neur.l lobe of Pituitar)' Modulate.
Corticotr<>pin Release in the Rat. EIf(/O(",ino/.
/()6: 878-82.1980.
Bauer. A. G, C. Wilson. S, H. P... nd Lambert'.
S. W. J. The Kidney is ,he Main Sil. 01" Prolactin
Elimination in Patients ",i,h Li,'Cf Discase. J.
C/in, EIf(/(X,illOl. Mnah. j/: 70_3. \980.
9, Bealer. S, L. Phillips. M. L. John",". A, K, . and
Schmid. P. G , Anleroventr.1 Third Ventricle Le-
.i"". Reduce Antidiuretic Responses to Angioten·
sin II. Am". J. Ph,.<lo/, 2J6: E610-E6IS. 1979.
10, Ben,ley. P. S. Com""ra,iw f.·ndo,,;-
noiDgy. Cambridge Uni,e"i,y Pr .... New York.
1976,
1 I. Ben,l.y. p, J . Emioc,iMS and Osmougu/alion.
Springer-Verlag. New Y<>rX. 1971.
12. Bentley. P. J. Eyolu,ion of Neu""'ypophy.ial
Peptide Functions. pp. 9S_1 06 of P.!ti and Epple.
cd ... reference 117.
11. Berl. T .. A;..,nbrey. G. 1\ .• and Li na•• S. I.. R.nal
Con<xntrating Ocfcot in tbe Hypokalemio Rat i,
Prostaglandin Independent. An,." J. Ph,.slo/.
lJII: F37_F41. 1980.
14. Berry. C. A, Hetcrogeneity of Tubular Transport
in the Nephron . /Inn, R,". Physlol. 44:
1982.
IS , IIi •. \I, J,. Dewitt. S.. and r<>rr ..,. J . N .• Jr. Dis-
sociati"" Bet"'""n Urine and Renal Pap-
illar)' C)'clie AMP Conten, Followin, Vuopre<--
.in and DDAYP. Am.,. J. Ph)".iol. 1]7:
rns. \979.
16. lIie. P. Osmoreceptor>. Yawp",,,in. and Control
or Rena l Wa,er Excretion. I'hy.• ;o/. R<"" W: 961 -
1048.
17. Bisbee. CA .. Mach.n. T. E .. and Bern. H . A,
Mou.e M.mmary Ep ithelial Cell. on Floating
Collagen Gels: Transepith.li.1 Ion T",nspor1 and
Effects of Pr<>lactin. Proc. Nat/. Arod. Sci, USA
76' 536_40.1979.
18. Ble"ing. W . W .. S"ed. A. y,. and R.i •. D, J . [)e.
muction of Nor.drenr,ie Neurons in Rabbit
B",in"ent Elevate. Pla.m" Va""pr ... in. Causing
Hypertension, Sd,lICt 117: 661_2. 1982,
19, Bourget. J .• Chevalier. J .. and Gobin. R. Ultra·
,tructural Studies 00 the Moode of Aot io" of An_
tidiuretic Ilorntoo.: The I nhibitoty Effect of Lan·
'h.num. AI/n. NY. Aead. Sci. J71: 1l1_42. 1981.
20, IIr.uthor. N,. l.evine. B. S,. Coburn, J. W .• and
Kleeman. C R, I nteraction of Scm"",,"'in with
PTH and A VP: Renal Effects, Am. " J, Phy.r;oI,
237' E42R_E431. 1979.
21. Bre,lo"'. E. Chentistry and Biology 01" the Neu-
r<>phy.in •. Ann. R,". BjO("hem. 43: 151_74.1979.
22. Brody. M. J .• and Johnson. A. K, Itole of the An-
leroyentr.1 Third Ventriclo Regi"" in Fluid and
EIcCtr<>lyle Balance. Arterial Pressure Regula-
'ion. and Hyperten. ion. Chap, 9. pp. 249_92 of
.\ ia"ini. 1... and Ganong. W. r .• cds. Fro",itr. In
v<>1. 6. Raven PreIS. New
York. 1980.
.00
23. Bm",'n. S. C. and Brown. P. C. Wate, Balance in
lhe California Newt. TO'kha larosO. J.
PkpiQ/. 238: RII3_RI 18. 1980.
24. Ilrov.'n"cin. M. J .. Russell. J. T •• rId Gainer, H.
Biosynthe.is of POII,.,j", Pi,uitar), Hormones,
frolll;". ,v.urtNndoainrn. 7: 31-75.1982 .
25. Ruehle,", v, M.. Jr. Column Chromatography of
Pl •• rna l".lrif.ric Activity. pp. IJ 1_9 of Kramer.
H. J .• and KrOck. cd •. • •• fcreno< 86.
26. Buckman. M. T. and Pea ke. G . T. Osm<>la r Con-
trol of Prol.ctin Sc<:rtlion in Man. Seimct 181:
755_7.1913.
27. Bulger. R. E..• 00 Dobyan. D. C. Recent Ad_
vance, in Renal Morphology. Ann, Roo. PhYJiO/,
44: 147_79, 1982.
28. Chan. D. K. O. Comparative Ph),siology of III<
V,$Om<),or EffcolS <>f Ne urohypoph),sial Peptide>
in tho Verleb,ales. Arne', ZOO!. /7: 751-6 1. 1971.
29. Chwalbi n, k.· Moncla , J. Role of Hepatic Port.l
Osmoreceplioo in Ihe Comrol of AD H Rele.",.
Am ... J. Phpi"'. lJ6: E603_E609. 1979 .
30. Cla,k. S. 1... Jr. Incorporalion of Sulfale by Ihe
M"".., Thlmuo: 11$ Relation to Stcrction b)'
Medullary Epilhelial C.II. and 10 T hymic Lym·
phopoie.is. J. Exp. Md /18: 921_49. 1%8.
31. D.,i •. W. 1... Jon ••. R. G .. Hagler. I!. K .. Good·
man. D. B, p .. and Knight. J. P. Intraoellula,
Wate, T ransporl in Ihe AC lion of AD I1, Ann,
N ,Y. Acad, S ri. 371: I I 8_29. 198 I.
n. Odendini. R .. ,nd Zimmerm.n. E. A. The M,S'
noeeHula, Neurosecretory S),>lcm of the M.m·
m.li.n Hypothal.mus, pp. I 11_S2 of Reichlin.
S .. Balde .... rini. R, J .• nd Manin. J . B .. cd" Thr
Hypolha/omu" Ra,'en Press, Ne'" York. 1918.
n, DeWied. D, Pituita,y Ncuropeptide, and 8th••·
ier. pp. 291_314 of Fux • . K .. Hl\kell. T .. and
Lufl. R.. cd •. emlrol 0/ Endrx;,i""
S;"Um. Pio nu m, New York. 1919.
34. D.. and VCNtceg. D. H. G, NeurohylX'"
phy,o.1 Prineipl« and Memory. Ftd. Pr<x. 38:
2348-S4 . 1919.
)5, Dos,crom. J .. Grtid.nu •. TJ. 0, yW .. and Dc·
D. V.wp.... in in Cerebrospina l Fluid and
PI.,ma of Man. Dog .nd Rat. A",..,. J. Phy.iol.
]31: E463-7. 1978.
36, Do"$>.. T. P .• S.OO •. H .. and Hocht<r. O. Cyclic
AMP·Dependent Reversible Phosphorylation of
Renal Medulla'y Pla.ma Membrane Prolcin. E"..
do"I""'. 91: 157- 63, 1972.
37. Drum mond. W. H.. Rudolph. A. M.. Kei l. I.. e..
Gluckm an. P. D.. MacDonald. A. M.. . nd Hey·
m.nn. A rginine vaso!'",... in and ProI.et in a ftc r
Hemorrhage in Ihe Fetal Lamb. J. Phy.iol.
]38: E214-E219. 1980.
38, Dunn. M. J .. Greely. H. P .. Vallin.lI .. Kinler. L
B.. a nd Bccuwk... R .. 111. Rcn.1 Excrttion of
Prostaslaooin. E, .nd F,a in Diabetes Insipidu.
R.... Am". J. Phy.i"'. US: E62J_E621. 1978.
39 , Edw.rd •. R. M.. Jackson. B. A .. aoo Dou... T. P.
Pr(l1cin Kinas- Acti,ity in 1001..«1 TubuloS of
VASOPRESSIN " ND OTHER REGLlLAT0n5
Rat Ren.1 Medulla. J. Phy.i"'. 238: F269_
F278. 1980.
40. ESilena. P .. and Reinaeh, p, Vasopressin Resis·
ta nce Inducod by low Sodium and High Manni·
tol in Toad Bladder. Endoc,itlOl. III: 1001_9.
1982.
41. Epple. A.. Brin n. J. E.. aoo Young. J . B. E""lu·
tion of PanCT<atic 1.lel Funclion , Pl'. 269- 321 of
Pani and Epple. ... rdcre""e 117.
4 2. Ep'tein. F. H . Di't " rb.""es in Renal Concen"al·
ing Abilil)'. Chap, I 2. pp, H 1-65 of And,ooli et
aI., eds .. refe'cnce 3.
43 . Fachel, J.. Vallo nl . K.. and Stark. E. The EffecI
of ThymeCtomy. Ad .. nal«I""'y and C<>rlkcid
Treatmenl on the Se,"m Heparin le, d of tho
Rat. PhJ'JloJ. Arod. Sd. l/ulW. Suppl. T 26:
64_5.196S.
44 . Fano,,;1. D. D. H)'posrnol31 Syndromes. Ch.p.
,
13. Pl'. 261_84 01" Andrcoli ct . 1.. ed ..... ference
45 . Fi nn. A. I. Chongi ng Cooc<p1S of Tran""pilheli. 1
Sodi"m Tran.port. Ph}'.ioJ. Rn;. 56: 453-64.
1976.
46. Forrest. J. N .. J r .. and Goodman. D. D. P. pH.
Depo ndent P,ostagland in E, Prod uclion and Sa-
ntal"'lalin : Modulators of the Actio n of V.so-
pressin in the Toad Urinar), Bladder. AM, N. Y.
A cad, Sd. 371: 180_92. 1981.
47, Forre.t. J. N .• J r... 00 Singer. I. Drug-Induced
lnterf«<nco with Ae,ion of Aotidiuretic Hor_
mone. en.p. 15. pp. 309- 40 of Andreoli Ct al.,
ods .• roferenco 3.
48. Forster. R. P. Com para I;'. Venebrate Physiology
and Renal Concepto. Ch.p, 8. Pl'. 161-84 of Or·
loff. J .. and Berliner. R. W .. eds, Handbook 01
Physiology. sec , 8. American Physiological Sod.
el)'. Wa.h ingloo, D.C .. 1913.
49. G arri",". J. C .. Borland •. K .. FIo,ior. V. A.. and
Twiblc. D. i\. The Role of Calcium Ion as. Me-
diator of tho Effect. of Angiolen.in II. Catechol.
amine. aoo Vasop ..ssin on the Phosphorylation
and AClivity of En,ymc. in Isolated He",t""),I",
J. BloJ. Chnn. 254:7147_S6. 1979.
50. Gauthier.Pi ltcrs. H.. and Do". A. I. Th. ('tlm.l.
Uni'.rsity of Chic.go Pres<. Chicago. 1981.
51. Gell ai. M.• Edwa,d •. B. R.. aoo Valtin. H. Uri.
nary Concentraling Ability During Dehydrat ion
in Ihe Absenee of V.sop.... in , Am ... J. Phy.ioJ.
237. FI(I()..F I04. 1979.
52. Georgc. J. C. Cant para Ii". Phj'jiology of Meta·
bolic Res""n"" to Neurohypeph)'>ial Hormones
in VeT(Cbrat... Am.r. ZOO/, 17: 187_808.1977.
53. Gilmert. J. P.. Zuder. I. H.. Ellington. M. J ..
Richard •• M. A .. and Share. L Fai lu,e of Acute
I ntra y.seular Volume bpansioo to AII.r Pla.ma
VasoprO$$in in th. Nonhuman Primate, MtKtJ""
Itlsrirularis, t:nd<x' intJl. 106: 979-82 , 1980.
54. Gilciman. H. J .. Klapper, D. G.Aldorman. F. R. ,
and BI )'the W. fI. Ala-GI)". and Val·Asp [Ars'l.
Vaso]>l"c<$in: Bovine Storage Forms of A,ginine
 Vasopressin ",ith Natriuretic Acti.it y. SdMU
;07: 893-6. 1980.
55. Glli1.. E.. and Sugar. K. Elfect of Hep",in and l Ie-
pari[IQids On the Synthc<i< .,.. Aldo.teronc and
Corticosterone b)' the Rat Adrenal Gland . t:nd<>-
crin&. 74: 159_64. 1964.
56. Godon. J, P. Renal Or igin of a N.lri urcl ic Ma-
ter ial: Some Chemical Pf(>p< rt iC1. pp. 88_99 of
Kramer and KrUck. ed, .• fe ference 86.
57. Gonid. IL C. Mechani.m .,.. Action of Natri·
.
u"'tic Hormon<: Inhibit'" of N.·K·ATPa",. pp.
108_19 of Kramer and Kruck. ed •. . referc""e
58. Grau. E. G .. Ni'hioka . R, S ,.• nd Bern. H. A, H-
feet.of Somatostatin .nd Urote nsin l i on Til"pia
Pituit.r)" Pr<>l.ctin Rele.", .nd lnteracti(>1'l' be·
t"'oon Somatostatin. Osmotic Prc .. ur•. Ca " .
.nd Ade"",ine )'Y-Monopho:!ph. te in Prolactin
Relea", in Vitro, t:ndoCFinoi. I/f): 9 10- 1S. 1982.
59, Gregs. C. M.. and Malvin. R. L l""ali'.tion of
Cc"'ral Sitc<of Act ion of Angiote",in li on ADH
Rele.", in Vitro. J. Php;ol. 1)4: FIJS-
FI40.1978 ,
60. Gruber. K. A.. and Morri•. M. Di",ct Detection
of the Vasopressin l'rce urSOr. /:·ndoe,. R5Ch. Com·
7: 45-59.1980.
61. Guidice. L c.. and Chai ken. I. M. Immunologi.
cal and Chem ical Identification of a Neurophy·
'in_Containing Protein Coded by Me""nger
RNA from Bovine Hypotha lamus. Pro<, Nail,
Acad, Sri. USA 76: 1800-4. 1979.
&11\, t t.,ddy. r . J .•• nd P.m"."i. M. n, of a
Humoral Sodium-Pota"ium Pump in
Low·Ren in Hypcnen<ion. Pro<. 4l: 2671-
80.1 980.
62, lI . dl")'. N. E-. "nd Hrub)'. V, J. Neurohypophy·
. ial Peptide, and the Regulation of Melanophore
St imulating 1·lormo"" (MS H) Steretion. A",..,.
Zoo/.!7:809-21.1977.
6). lI ammer. M .. LadcfOgcd. J, . and Olga"rd. K. Re·
lation.hip iktwcen Pla.m. Osmolality and
Plasma VasopreSSin in Iluman SubjeclO. A",..,. J.
PhyJ;{)/, 1)8: E111- ElI1. 1980.
64, Handler. J . S .. and Orloff. J. Antidiuretic Hor·
mone , Ann, PhYJioi. 41: 61 1-24. 1981.
6S, Handler. J, S .• St",wler. G, J ..• nd OdQIf. J. Role
of Protein Synthesis .nd Phosphoprotein Metab-
oli.m in Cellular Respon", to Vasopl'CS$in. Chap.
4. PI', 85-95 of Artdrcoli et al.. ed •. • reference) ,
66. Harm.llei. M. c.. Kach.dorian. W. A __ Vahin.
H .• ,nd DiScala. V. A. Antidiuretic Hormone-In·
duced In tramembraTlOll' Alteratio", in Mamma·
li.n Collecting Duct'. A",..,. J. PhY5Io/, 235:
F440_F443.1978.
67. Haymaker. W .• Anderson. E.• and Nauta. W . J.
II,. ed •. Ifypmha!amuj. Thom ••• Springfield .
HI . 1969
68. H.y• . R. M. Agents Affceting the Renal Con"'r·
vation of Water. Chap, 37. pp. 916-28 of Good·
man and Gilman's Pha,maro/aglcal Sa';J oj
Tht"'{MmicJ, New York. 1980.
69, Ha),. lell. J, P. Functioo.1 Adaptalion to Reduc-
tion in Renal M.... Phy';{)/' Rrv. 59: 137-64.
1979,
7f). lIerbe rt. S . C __ Culpepper. R. M .. and AndrcOli .
T. E, NoCl Tran'port in Mou", Medullary Thick
Ascending Limbs. Il l. Modulation of the ADH Ef·
feet by Peritubular Osmolality. Am". J. f'A}'sj{)/.
UI.· F443_F451. 1981.
71. 1I0nn. K. V,. and Ch,.in. W. Mechanism of Ae-
tion of Some Polypeptide HormQlIC. in an E,olu _
tionary Serie. of Vertebrates. rp. I ))-66 of Pang
72.
73.
and Epple. ed.,. reference 117.
Il orrOOin. D. F. Prolactin •• a Regulator of Fluid
.nd Electrolytc Met.boli,m in Mamm.I •. f"ed.
1'ro<". J9: 2567-70.
Imbe".Tehoul. M .. Ch.hardes. D.. Mont.gut .
M .• Clique. A,. and M<>rcl. F. Varopr=in·Depen-
dent Adenylate Cyclase Acti.ities in the Rat Kid·
ne)" Medulla: Evidence for Two Sep.rate of
Action, Endoe,;noi. 101: 1254 - 61. 1978.
H. laanu •. S, D,. and Martin. C. R. An &tra·Adr.,.
n.l R«pon.. to Sod ium loading Revealed by
Thymectomy. of (0111"..'. Endoe,;n&. 10:
147-54.1968.
74A. Jamison. R. l. The Ronal Conce ntrating Mcch·
ani,m: Micropuncture Studics of the Renal Me·
dulla. Pro<, 42: 2392-7. 198).
1S, Jenkin,. J. S ,_ Mather. H. M, _ a nd A"g. V. V._
sopre" in in Hum. n Cerebrospinal Fluid. J. Clin.
/:·ndoe';nol. M: 364-7. 198f).
76, John""'. M. D .• Kinter. l. B.• and Bceu"'kes. R ..
Ill. Effect' of AVP .nd DDAVP on PI.. ma
Renin I\c,i.i,y and electrolyte ( . eretioo in Con·
scioos Dogs. Am". J. I'hYJio/. 216: F66-F70.
1979.
77. K.chad",ian. W, A.. Ell i' . S. J.. and Muller. J.
Possi ble Roles for .\lic,,,,ubu les and Microfila-
menl> in ADII Action on Toad Urinar), Bladder.
,lm,T. J. Ph}"j;o/. 136: FI4- F20. 1979.
78. Kachur. J. F .. .\1 illef. R. J .. and Field. M, Control
of Guinea Pig Inte' tinal Electrolyte Excretion by
• Ii Opiate Receptor. f'ro<, Nml. At;(Jd. Sci. USA
77: 2/5)_6. 1980,
79. Karmazyn. M .• Manku. M. S,. and Horrobin. D.
F, Ch.nges of V. ",u l. r Reacti.ity l nducod by
low Vasoprc.s.in Concentra tions: Inte ... cti"".
",ith Cortisol and lithium and I'ouible In volve·
ment of PrO<Iaglandins. /:'ndoe,jn& , 102: 1230--6.
1978.
80. Kat'. A. l.. and lindheimef. M. D. Action, of
HotnlOnes on the Kidnoy. Ann, Re •. Physjol. )9:
97_134.1977.
81. Katl_ F. H,. Smith. J . A.. lock. J . P... nd Loelfel.
0, E. Pl •• ma Vosopre .. in Variation "nd Renin
Activity in Norm.1 Hum.n,. If):
1919.
g2. Kendall. J .. and OrwQlI. E. Anlerior Pituitary
Hormone< in the Brain and Other E'trapituitary
Sites. Chap. 2. pp. ))-6S of Marlini . L..and Gan'
ong. W. F .• cd •. F,,,,,rj,,, in
vol. 6. Ra.e n Pre ... Ne'" York. 1980.
8). Kinn¢. R.. and Seh"·"'t'. 1. l. Asymmetric Di ..
tributi(>1'l of Renal Epi thelial Cell Membrane
,.,
FUrI<l;on in the Action of Antidiuretie Hormone
a nd Parath)'roid Hormone. Chap. 2. PI'. 37-55 of
Andreoli 01 al .. eds" reference).
84. Kinlor. L. B.• Dunn. M. J.. Beck. T, R.o
llceuwk ••. R.o III. .nd Ha$$id, A. The I n,.... _
lions of Prost.glandins .0<1 Vasopressin in the
Kidney. N.Y. Acad. Sci. 371: 163-18. 19S1.
gS. Kramer. H. J. Antinatriforic.oo Na,riumic Ac-
ti";li •• in Hum"n PI.,m. F<>Ilowing Acute a nd
Chronic Sah lMdi",. PI'. 24-)) of Kramer and
KrUck. eds .. reference 86.
86_ Kramer. H. J .. and KrUck, F.• ed •.
I/or""",,'. Springer.Verlag. New York. 1978.
87. K,il, W. Structural Organi7"lion of the Ren.1
Medulla: COm par. I;>. and Funclional AspeclS.
J. Pltysiol. 24/: R3-RI6. 1981.
87A. Kri., W. Structural Organiu,ion of ,he Renal
Medulla!,)' Coonlerl\ow 5)"tem. Proc. 41:
2379_85.1983.
88. Kriz. W .• Bar"'1I. J. M.. and Poter. S. The Ren.1
Vueul.ture; Anatomical·Fu""tional Aspecl • .
Chap. I. pp. 1-21 01 Thurau. K..ed. KidMyand
Urinary Tracr PhY'iology II. University I'lIrl:.
P"'''. Bailimo,..,. 1976.
89. Umd. H .. Schult,. G.. &hmale. 11 .• and Richter.
D. Nucleotide Sequence of Cloned cON A Encod·
ing IIovine Arginine Va.opr",'in.Neurophysin II
Precursor. Na/u,e ]95: 299-303. 1982.
90, Lederi • . K. Chcmical P,,)penie< and the Ph)'.i<>-
losieal and Pharmacological Action, of Urophy-
si.1 Peptide •. AmtT. ZooJ. 17.- 823- 32. 1977,
91, Lederi,. K.. leiter. 1\.. McM .. ter. 0 .. and
Moore. G, Complete Amino Acid Sequence of
Urotensin 1, a Hypolen,ive.nd Corticotropin.Re·
ic"ing Ncu.opeptide from C.tOSIOmus. SdtrlCt
218: 162- 4. 1982,
92, l.eshncr. A. L An In/roduclI'Qn 10 B,hayioral En--
d""';lIOlogy. Dxford University Pr=. New Vork.
1978.
93. Lichardu,. B,. and Ponce. J. Acute HypOphysec·
tomy_A Model for the Study of Hormon.1
Mechanism' of Nat.iurcsis. pp, 6-15 of Kramer
and KrUck. ed". reference 86.
94, Lightm.n. S. L.. and Farsling. M, L. Evidencefor
Endogenous Dpioid Conlrol of Vasopressin Re-
lease in Man . J. CI'n. 50:
569-71. 19&0.
95. Liv,... 1\.. and Kuiper, P. J. C. Unique Proptrti",
of the Camel Erythrocyte Membm,... B/<Kh;II1,
Bioph,.l . .'lela. 318: 41_9. 1973.
96. Mamy. R, H. Oiabel'" Insipidu" Chap. 14. pp.
285-307 of Andrwli <t .1 .. <;<Is.. rtference 3.
97. Maloiy. G. M .. ed. Coml"',alfw PJry.'%gy of
Animals. Academic Pre». New Vorl.
1972.
98. Manning. M,. Klis. W. 1\., Olm • . A.. &to. j,. and
Saw),e,. W . H. Design of More Potenl and Selec-
ti.e Antagoni<t$ of the Antidiurelic RespOnse< to
Arginine.V.sopre .. in Devo;d of Anlidiu",!ic
Agoni,m . J. Mdidn , Chern. 2': 414_19. 1982.
'}9, Mannini. M .• and Sawyer. W. H. Antag<>nim of
AND OTHER FlEGUV,TORS
Vasopressor and Anlidiuretic Re<pon.e, to Argi-
nine Vasopres,in , Ann, Inl. M,d. 96.- 520_2. 1982.
100. Maoning. R. 0 .. Jr.. Guyton. A. c.. Coleman. T,
c.. and McCaa. R, E, 11)'perte",ion in Dogs Our·
ing Antidiurelic Hormone and HypOtonic Saline
[nfu,ion. Am..r. J, Ph;-..-o/. 236.- H314_IU22.
1979.
101. Ma'tin. C. R. Thymu, Gland and Hepa,in Influ·
ence. On Renal Electrol)". bere'ion in Male
Hooded Rats. Gen. & CM'",," f.·M<K';rllJl. 1$.-
3)9_5 1.1970.
102. M.... J, L. Natriurelic HOlmone Linl:.ed to H)'.
pertell$ion, 21}: IUS-7. 1981.
103. M.ltheij. J. A. M. Evidence Against a Rote for
Prolacti n in Osmore8ulat ion in lhe Rat: Watcr
B.I.nco Studies. End"",. RIch. 1_9.
1977.
104. Menninger. R. p, Re.""n"" of Supraoptic Neu·
rosecrctory CellS to Change< in Left Atrial Di<-
tensi"". J. Phys'ol. 236: R261-R267.
1979.
105. Mills. O. E.. Buckm.o. M. T.. and Pe.ke. G. T.
Ncon.t.1 Troatmcnt with Anli "'mm 10 ProIac,in
u,..'.rs Blood Pressure in Ral', Sc'.. nn 217: 162-
4. 1982
106, Mohring. J .. Kohrs. G,. Mohring. B.• Pctri. M..
Hom,y, E.• and Ha.ck. D. Effect. of Prolonged
V'wp .."in Treatment in Bmut.boro R.I, wilh
DiabetUln,ipidu •. •. J. fl06-
fttt. t9n,
1M. Monos. E.. Cox. R. H.• a nd Pcl • ....,n. L, H. Dircct
Effect of Phy.iologic.1 [)OSC, of Argin;,.. Vaso-
pressin <>II thc Arterial W.II in Vivo. An .. , . J.
Ph,.Jlo/, 234: H 16 7-H I 72. 1978,
108. Morel. F. Sile< of Hormone Ac'ion in tbe M.m.
malian Nephron. Alii", J. Phy.'o/. 140: FI S9-
FI64 1981.
109. Mou,",. D. R .• V.nde,. A. J.• Bourgoignie. J, J..
Kut$Chin,ki. S . S" and Malbi ... N. P. No"prc<-
SOl Mechani,ms in CNS-I nduced Nalriu ... i•.
Am ... J. Php;ol. 137: FI 57_t· I66. 1919,
110. Nicola,. P.• Camicr. M.. Lauber. M.. M..... M.-
J. D .. Mohring. J.. and Cohen. P. Immunologic.1
lden!ifoe.tion of High Molecular Weighl Forms
Common to Bovine Ncurophysin .nd v.soprc<-
sin. Pror. ,va/I. Arad. Sci, USA 77: 2S81-91.
1980.
Il l. Nicoll. C. S. Ontogeny and Evolution of Prot.c-
FUIIC,ion<. Frd.P."". 39: 2S63_6. 1980.
112. N ishimura. H. Evolution of the Renin·Angiot.n·
sin S)'stCm, pp. 313_404 of Pang and Epple. cds ..
reference 117.
113. Ni1Cl. A. The H"moral Control of SalillC Nair;·
ul.,is. pp. 57-65 of Kramer & KrUck. cd•.• ref·
eronc.86.
114, Nomu ... K.. PUCII . D.. Nichol",n. W, E .. and
Liddle. G. W. Partial Purir.cation and Char-4cle,·
i,,ation of. RenotropiC Fraction from Dvine Pi·
luil" ies. p,()(". ,vat!. Acad. Sci. USA 79: 6615_9.
1982
114A. O·Kelly. R,. Magee. F.. and McKenna. T. J ..
 Rooti •• lieparin Therapy Inhibits Aldosterone
Production. J. Clln. EndlXTinoi. 56: 108-
12.1983.
115. Oria.. R.. and McCann. S. ),I , Natriuretic F.ffocl
of MSII in the Water·Loaded Rat. Pro<: SIX.
Exp. Bioi. Md. 1)1: 46g...74. 19iO
116. Pang. P. K. T. Osmoregulatory Functionsof Neu-
roh),poph)'$i.1 li ormont' in FiSh", and Amphibi.
•••. Am",. Zool.17:739- 49. 1977.
Iii. ?.g. P. K. T __ and Epple. A.. eds. Eo;oJulkm of
V,,/.brale t:ndlXriM Sysums. To,"s Tech. Press.
Lubboch. 1980.
IliA, Pang. P. K, T .• Kenny. A. D.. and Oguro.e. Evo-
lution of Endocrine Cont rol of Calcium Regul •.
tion. PI'. 323- 56 of Pang arid Epple. eds .• ref.,·
cncel17.
118, Pavel. S. Pre .. nce of Relali"ely High Concentr •.
tion' of Arginine V.sotocin in the Cerebrospinal
fluid of Ne,.'born< a.d Infan ... J. Ciin, EndlXri·
nol. Mnab. 5(J: 271-3.1980.
119, PaveL S .. Goldstein. R .. Gheorghiu. C .. and Call>.
M. Pineal Va5Olocin: into Cot Cerebro-
spinal Fluid by Melanocyte-Slimulating Hor·
"IOn. Rek ...· lnhibiting F#clor, Srimu 197:
I 79- 80. 1971.
120. Ptd.r .. n. C. "- . and Prange. A. I .. Ir. Induction
of ,\ lolernal Behayior in Vi,gin Rats after [ntra·
eercbro"enl'icular Admini'tration of Oxytocin.
Pro<:, I\'all, Aead, Sri, USA 76:666[_5. 1979.
121. Perk •. A. M. Developmental .rId
AspecU of the Neurohypophy.i •. Am". Zwl. 17:
833_49. [977.
122. Perlow, M. J .. Reppert, S. M.. Artman. H. A..
Fi'her. D. A.. &if. S. M.. and Robinson. A. G.
Oxytocin. Vasopressin. and Estroge • .stimulated
Ncuroph},in: Dad)' Pancrn. of Conc<:ntra!ion in
Cerebrospinal Fluid. 216: 1416- [8. 1982.
123. Pickering. B. T. Prohormone. for V.sopre .. in.
]95.- 280. 1982.
124. Ramsay. D. J. ElTee .. of Circulating Angioten.in
II on the Blain. ;.-
263-85. 1982.
[25. Rector. F. e.. Jr. Renal ConcentT.t ing Meeh.·
nisms. Chap. 8. PI'. '19_96 of Arldreol; et .1 ..
ed, .. reference 3,
[26. Renaud . L. P.. Q. J .. ond Blume. H. W,
Neuroph)"ioIogy of Hypolhalamic Peptide Ii;.
Neur"" •. PI', I [9-36 of Fu.e. K.. HOkfelt. T .. and
Luft . R .. ed,. C<nlral Endoui",
Sy,uno. Plenum. New York. 1919.
In. Rigter. H.. Jensen. R. A.. Martinet. J. L Jr.,
Messing. R, B.. Vasquez. B. J .. Liang. K, e. • • nd
McGaugh. J, L En!;epha[in and Fear·Motivat«l
Roh.yior. Pro<:, Nail, Acad. Sci. USA 77: 3129-
32.1980.
128. Rillema. I. A. Mech.ni.m of Prol.ctin Action.
Prill:, 19: 2593_8. 1980.
129. Robertson. G. L Tlte Regulation of Vasopressin
function in Health ond Disease, R«. P'ag.
Horno. R.ch. 31: 333-74. 1911.
130. Robcrt5On. G, 1.., Alhar. S .. and Shclton. R. L.
o.mot;c Con!rol of Vasop ..... in Funclion. Chap.
6, PI'. 126_48 of Andreoli claL, cd •. , r<felcnu 1.
131. Robinson. r\. G. ODAVP in the Treatment of
Central Diabetes In.ipidu,. N ..... Eng. j, M,d.
]94:507-[1. [976.
132. Robinson, A. G, Nenroph)',i .., an Aid to Under·
.tanding the Structure and Func!ion of the Neu·
mh}'l"'phy.i •. Chap. 2. PI', 35_59 of Ganong. W.
F" and Martini.L .. cd •. Fronli.,s in I\'t urt><'ndf>-
erina/at)', vol, 5, Ra-on Pre ... New York. 1978.
Ill. Rossi ... J .. Pittman. Q .. B[oom. F" and Guille-
min, R. Distribution of Opioid Peptides in the Pi·
tuitary: A New HYl"'thalamie-PaTS NolV¢S;l En·
kephali.<rgic Pathway. 1',,1, P'IX. 39: 2555_60.
1980,
134, Roy. C ... nd Ausiello. D. A, Regulation of Vaso-
p ..... in Binding to Inlact Cells, Ann. N.Y. Aead.
Sd. J'1}: 92_104. [981.
I 35 , Ro,cngurt. E.. I",gg. A.. and Pettkan. P. Vaso-
pn:s,in Slimu[ation of Mou .. 3T3 Cell Gro"lh.
Pror, Na/I. Arod. Sci. USA 76: [284-1. [919,
[36 . Russell, J. T .. Srownstein. M, J .. and Gainer. H.
Trypoin Liberate. an Arginine V•• op ..... in·Like
?':ptid. . .d Ne urophy$in from" Mr 20.000 Pu·
tatiye Common Preeu"",. Pro<:. Nail. Acad. Sri.
USA 76: 6()a6_90. 1979.
[37 , Saffran. M. HYl"'lhalamic Control of the Seere·
tion of MeI.nocyte·Stimu [aling Hormone (MSH)
and Adrenocortiro1ropin (ACTU). Chap. [I. PI'.
225-35 of I'orter. J . C .. cd. lfypor/t{Jlamic P'pfid<
/10,-1110"" ami PilUi/ar}' Plenum.
New York. [977.
138. Sah ib. M. K.. Sch ... am. I. II.. arid lbndler. I. S.
Inh ibition of Toad Urinary Bladder Sodium
Tran'pott b)' Carbamylcholine: P""ible Role of
Cye[ic GM p, Am". j . PIt,.'ior lJ5: F586_f59 [<
1978,
139. S .... yer. W. H. EVo[ulion of ActiYe Neurohy(XI-
ph)"i.1 Principle. Amoni\ the Vertebrat.., Anon.
Zool. 17: 727-37, 1977.
140. Sa,.')"er. W. H.. Pang. P. K. T .. Sctc./" McEnroe.
M .. L.mme'. B.. and Manning. M. Va"'pre"in
Analogs that Antagonile Antidiurelic R.. pon ...
by R.t, to Antidiuretic !lormone. 21].-
49_51. 1981.
[4[, Schafer. J. A.. and Andreo[i, T. E. AClion of An·
tidiuretic Hormone on Water and Nonelectrolyte
Tran,port Pr"""",," in M.mmalian Collecling
Tubuie •. Chap. 3. pp. 57-83 of Andreoli et aI.,
cds .. rderc""e 3.
14]. Schlein. E. M .. Spooner. G. R .. Day. e., Picker·
ing. M.• and Cade. R. E,tr"ena[ Water Loss ond
Ant idiuretic Hormone. J. Appl. Physioi. 31 : 569-
72. [971.
143. Schlondolff. 0 .. Kachador;an. A .. Ley;n. D. N ..
and Levine. S. D. E"ide""e for Calmod ulin De·
pende.uofWa!er Pel",eabilily in Toad Urinaty
Bladder. Ann. N.Y. Arod. Sci. 371: [94-203.
1981.
14 4. Schmidl·Nie lsen. K. Animal Phy'ioiogy: Adap-
falion and f;n"ironm<nl. 2d ed. Cambridge Uni·
veroity Pre". New York. 19 79 .
145. Schmidt.Nielsen. K. 11_ Animals Wo,-k, Cam·
bridge Univ.ro'ty Pre", New Vork. 1972.
146. ScI>¢k: T, J.. "nd Sladek. J. R.. Jr. Supraoptic Nu·
."
cieUI of the Brattleboro Rat Has "n Altered Af·
r.",,1 Noradrenc.gic Inpul. 2/4: 347_9,
1981.
147. Schrier, R. W.. Borl. T .• and Anderson. R. J . Os-
moti. and NonosmOlic Control of Vosoprc<sin
R.I< • ..,. Am ... J. Phy.;<>i. 236: Fnl-D12.
1979.
148. Schrier, R. W .• Be.I. T .• Andorson. R. J .. and
McDonald, K. M . NOt\O$mol.r Contro! of Renal
Water E•• retion. Chap. 7, pp. 149-178 of An-
dreoli 01 .1.. cd, .. reference J.
149. S<hull,. H. D., Fat.r. D. c., Sundel. W. D .• Gecr.
P. G .•• 0<1 GC>Ctz. K. L. Refl •••• Elicited b)' Ac ute
Stretch of Atrial,", Pulmonary Rc...,ptors in Coo·
«iou. Dogs. Am". J. Physiol. lU: HIOM_
HI076,I982
150. Sch",'.rt". J .. and Reid. L A. Effect of Vaoopr ••.
,in ElI",,<.d. on Blood Pr ... ur. Regulat"'" Du,-
ing Hemorrhage in Con<eiol!. Dog>. £nt1ocrincl.
/09: 1778-80,1981.
151. Scott, W, N.. and Goodman. D. B. P.. cds_ /lor-
"'0'111/ of TTam"",' of lOllS
and Ann, N,Y. Acad. Sci., ><>1 . 372. New
York. 1981.
152. Seif. S. M., and Robin",n, A. G. Local iutionand
Rde .. e of NcuToph},.in •. Ann. Rtv. Physio/, 40:
34S_J6.1978.
153. Scif. S. M.• Robinson. A. G .. Zimmerman. E, A..
and Wilkins. J. Plasma Ncurophy, in and VaS<).
p.. in 'he Rat: RO'l"'n,e to Adron.loclOmy
and Steroid R¢placemenl. £miOCl"in()l. 10J: 1009-
15.1978,
154. Sharp B., Ross. R .. L.. in. E., and Sowe,.. J. I)Q.
pamine Regula, •• Canine Pla.ma /I· Endorphin-
Immunore.ctivity U:>cl •. /:.·mioc,in()l. 110: 1828-
30. 1982.
ISS. Soo.m.h,. V, H., and Nagy. K. A. Osmo",gu·
I.,i"" ,n Amphibian •• nd R.ptil.,. Ann. N....
Phys;o/. 39: 449_71, 197.
156. Simoonet, G .. Rodriguez. F.. Fumon. F., Cu,·
nichow. P., and Vincent, J. D. Va",pre$$in Re·
Ie... and [)rin king Induc.d by Inlracraniallnjec-
ti"" of Angioten.in II ,n Mon'ey. Amer, J.
Phys;o/, 237: R20-R25. 1979.
I n, Sladek. C. 0 .. and Jo)"nt. R. J. R<>Ie of Angioten·
• in in Ih. Osmolic C""lrol of V.sop .... in R.I ....
by Ihe Organ-Cul1urcd Rot lIypothalamo-Neu.
n)hypophy",al S}'Slem , Hmioc';n()f. 106: 173 - 8.
1980.
158. Smi1h, M. J .• Jr .. Cowl.y. A. W .. J, .. Guyton. A.
C .. 000 Manning. R. D., Jr. and Chronic
Effecl' of Vasopr.,...;" on Blood P.... ur • . Eleclro-
ly1 •• and Fluid Volume$, Am". J. ])7:
F232-F240.1979.
IS8A. Stephe""",. J . L The Renal C""""nlr.ling
Mechan i. m: Fund.menl.1 Th,o'e1ical Concepts.
Ftd. Proe, 41: 2386_91. 1983.
159. Stoke>. J. B. Inlegnlled AC1i"", or Renal Med,
ullary Proslaglandin. in Ihe Con1rol of Wale, E. -
c""ion . Am" . J, PhYJiO/. 240: F471-F4S0. 1981.
Y"'SOPRESSIN "'NO OTHER REGULATORS
160. Ta)"lor. A. Role o>f Microtubule, and Microfila·
men" in Ihe Action of V.,.,pre"in. Chap. S. Pl'.
97_124 of And,,,,,li.1 a1.. ed •.• reference 3.
161. Thame$. M. D.. and Schmid. P. G. Cardiopul_
mon.ry R.cep1ors wilh Vagal A/ferenl' Tonic.lly
Inhibi1 AOH Rei .... in the Dog. Am", J . Phys-
;0/. lJ7: 11299- 11304. 1979.
162. Tho'n. N . A.. RUII<' 1. J. T., C ..
and Treiman. M. AC1iva1ion or Rel.a. . . nd
of Rei""", or Neurohypophyseal
Hormone. , Pl'. 49-60 of F.xe. K.. HOkf.l1. T .•
000 Luft. R .• ed •. Ct nlrol Rrgul(}li"" oflh, £n-
doe,iM Sy.<um. Plenum. N.w York, 1979.
163, Thra,her, T. N . O<moroccptor Mediation or
Thirst .nd Va"""e"in Sccre1ion in 1he Dog. fnJ,
Pf"()(, 41: 2528-32. 1982.
164. Thrashe" T . N.. Brown. C. J .• K.il. L. c.. and
Ramsay. D. J . Thirst .nd V.sopr.$$in R.lease in
Ihe Dog: An O<moreceplOr or Sodium Receptor
Meehani,m? Am... J. Plty"oi. 238: Rl33_R339,
1980.
165, Thr .. her. T. N .. Jonc •. R. G., K"il. L. C.. Brown.
e. J .. and R.Ul •• Y. D. J, Drinking and V. "'p,es·
'in Re lea,e during Ventricular Infu.ion$ of Hy_
f'Cnonie Solutions, Am". J. Phy.<io/, 2]8: R340-
R345.1980.
166. Thra,her. T, N .. K.il. L. C. and Ramsay. D. J.
Lesions of 1he Organum Va.culOISum of 'he l am-
ina Terminali. (DV LT) AUenu.le Osmo1ically-
TOOuccd ilrin kinJ: .nd V.<oprc"in Scc<Otion in
lhe Dog. t:""oe,;no/, 110: 1837_9, 1982.
167, Val1in H. Gene1ic Model, for HypolhalamiC and
Ncphn)gcnic Diabe1es In.ipidu. , Chop. 9. pp,
191-215 of Andr<Oli e1 al.. cd •.. reference 3.
168 Veldh ui•. H. D., and Dc KI<>oI. E. R, Vasop, ... in,
Relo1e<! Pep1ide$ I nerea .. Ih. Hippocampal Cor-
ticost.ron. R.ceptor Capaci1y of Diabe1e. [n.i·
pid", (B,anleboro) Rats, 110: 153-7,
1982.
169. Vi.kopc,. R. J .. Wold, H.• Cz.c7.k.., J . W.• and
Ullmann, T. D. Th. Effcet of Nalriu<o1ic Male-
ri.1 1",1"ed rr<>m Ur ine or EC F-Exp.OOed Sub-
jeci. on (Na + K) ATPa.e of Ra1 Ki dney. PI',
102_3 of Kram.r and KrOck. eds.. <ofcrence 86.
170, Vo,he ... H., YOThe ... U. F.. and Solomon. S .
Con1amin'1ion of Prolac1in Pr.paralion. by An-
tidiuretic HOTmon •• OO O'yt<>oin , AmN. J. PhyJ-
io/, 2]j: FlI8- FJ24. 1978.
171, Wade. J. B.• Ste1son. 0, L.. an Lewi •. S, A. ADH
AC1ion: Evid.nce for" Membrane Shunle Mech-
ani.m. Ann. N. y, Acad. Sci. 371: 106_16. 1981,
172. Walk.r. l. A .. and V.ilin. H. Biological [mpor-
,ance of Nephron HC1.rog.neily, Ann, R .... Ph}"J-
10/, 203 - 19. 1982.
173. Wal ker. L. A" WhQf1on. A. R" Smi,el. M ..
France. R .. and Fr6lich. J, C. An1idiur.1k Hor-
mone Increascs R.nal Prostaglondin Synlhe,is in
Vivo. Am ... J , Phys;o/. 235: FlSO-FI85. 1978.
174. Walt"'. R .• ed. CarriN' of Ptp,idt
lIomwnu. Ann. N.Y , Acad. Sci. vol. 248. 1975.
IH, Waher. R.. Smilh. C. W.. Mehla. P. K.. Booni.r-
ern. S .• A"uda. J . A. L., and Ku",.man. N. A.
Conformalional Consideralions of Vaoopres,in as
a Gu ide 10 Dcvclopmem of Biolo,i"ol Probe. and
Therapeulic Agenls, Chap. l. pp. 1- 36 of An·
dreoli el al.. ed, .. referene<o 3.
116. Weil.man. R. E,. a nd Fisher. D. A. Arginine Va·
oopm.sin Melaboli,m in Dogs, I. Evidence for .
Re.:Opl<>r_Modialed Me.:h.nism, Am.,. j, PhY' _
ioi. ]Jj: ES91-E591. 1978,
117. Weil,man. R. E .. Rovic>. y. A.. Oddi •• T. H.. and
Fisher. D, A. Effccl of Osm<>laHly on Ar,inine
Va<opreo,in and Renin aft .. Homor·
,hase , Am.,. J. Ph),sioi 238: E62-E68, 1980.
178. Win kel. C. A., and MacOonald. P. C. Dcoxycor·
,iooslorone (DOC) Biosynthesis in Human Kid·
nC}' Tissue; The PoIOntial for Ihe Formation of a
Potenl Mineraioconicoid al it. Site of Action.
Ab'tract 61S. p. 228 . End",,!. Soc. Mtg. Wa,h·
ington. D.C.. 19SO.
A· I, K.. Mu lrow. P. J .• Fran<»Sac"". R..
Snajd.., R.• and Rapp, J . Inhibition of Ald,..l<>-
rooe Production by an Atrial Extr.ct . Sd'fI« lU:
992_4.1 984.
A·2 . At[as. S. A .. Kld .. n. 1[, D.. C. margo. M. J .. Jan·
u"",,wie>. A .. So.ly. J. 10 .. Laragh, J . H.. Schilling,
J . W.. L.wick i. J. A.. Johnson. L. K.• • nd Maack.
T . Purir ,"lion. Sc<jucneing. and S)"nlhc<i. of No.·
Iriuretic and Vasoactive Ral Alria[ Peptide. Nil-
",,,,309:111_9.198 4.
179. Yam .shit •. H .. K,""umi. K.• and Brook$. C
MoC. Rhythmic Panern. of Discharge in Hypo-
lhalamic Neurosecretory Neurons of Cats and
Oog<. Proc. Nm/, Acad. Sci, USA 76: 6684- 8.
1919.
ISO. V.,uda. N.. Geer. M . A.. and Panton. p, Studies
on the Silt or Act;on of Inducing
AdrenocorticOtropin Scerel ion. End""i""', 10J:
906- 11.1978,
181. Zimmerman. E. A. Loca[i,.ation of Hypolhal.mic
Horm""", by Immu nocyto<;h. mica i Tc<;hniqu ...
Fronl. .. nd()(,"FinoJ. 4: 25-62.1976.
182. Zipser. R. 0 .. Little. T. E .. Wil$On. W.. and Du ke.
R. Dual Elfects of Antidiuretic Hormone on Uri.
nory Prootagl.ndin E, Excretion in M.n. j, Clin,
t.'ndlXn'noJ. Mtfob. j3: 522_6. 1981.
[83. Zusm.n. R. M.. H. R., and Hand ler. J, S,
Elfec, of Adrena[ Steroid, on V""'1'reOSin-Slim.
u[ated PGE Synthe.i. and Water F[ow. Am..r. J.
Physiol. 134: F5 12_F540. 1918.
A·3 . lIonncr. T , I.. and Brown.tein. ,\1, J. V.oopre"in.
T issue·Spo:c if,c Ocfce" and the Brallitboro Ral .
Na/un J/O: 11. 1984.
A·4. Ich ikawa. T.• Loderi •. K.. and Kob.}'.shi. H . Pri·
m.r)" Slruclures of Multiple Form. of Urot.n.in
in the Uroph)'.i, of the Corp. Cyrpinus carpio.
Gen. ("o""par. t"ndlXrim::,illQl. 55: 133- 41. 1984,
_ __ PART IV _ __

Hormonal Regulation of Calcium and

Phosphate Metabolism
 11
Functions of Calcium, Phosphorus, and Calciferols
It is Yirtually impossible 10 overstate the iml'Ortancc
of calcium and phosphorus in the initiation, ma;n-
lenance, regulation. and coor<:lination of physiologi-
cal functions (202,215). The mineral, interact in
many ways, bul.sch is additionally involved in pro-
ce"., that arc only indirectly affected by lhe other.
Calciferols control the intestinal absorption of cal·
cium a nd phosphorus. They cooperate with para thy-
roid hQrrnonc. ,aleilon;n. and other regulators 10
the Ca" and H J>Ql- concentralion< of
both intracellular and extracellular fluids. and lhey
ma ke major contribu tions to bone growth and
remodeling .
FUNCTIONS OF CALCIUM
maimain vcry low o),looollc ea}. concentra-
lions when they arc "at rcst." They aCCQmplish this
by limiting the nile of uplake from the environn'ent.
by pumping ou t and by seq uestering the
calcium in tem""rarily inacli"" (but recruitable)
form in mitodondria and other organelles (35.40)_
Most physiological stimulants rapidly elevate the
cytosol Ca'+. Th ey can do this by acce lerating up.
take of the ions from the cxtracellular fluids. or by
recruiting the calcium. It is often !"'>Si_
ble to mimic their act ions by artificially raising the
concentrations (203). Many cell ty(lC< transiently
lose the abil ity to res""nd when they a re bathed in
calci um-deficicnt media.
Calcium ions ",gulate the activit ies of en7.yme<
that control intermediate metabolism (93) and thc
bi%ymhesis of proteins. and ONAs (212).
They affect cell growth . differentiation. and prolif-
eration (190), the secretion of hormones.
millers. and exocrine gland products (52.233), the
metabol ic processing of parathyroid hormone, calci-
ferols, and other regulators. and the generation of
prostaglandins and steroid hormones.
Since thcy link cell excitation with the events that
follow, calcium ions have been called " universal cou-
plers" (204)_ They arc indispensa ble for the commo-
tion of skeletal, smooth, and cardiac muscle
(77.192.206) and for the motility of nonmusele cclls.
Influences on microtubular a nd micromament sys-
temS (65) contribute to endocytosis. the
mo""mem. of chromosome. during cell divi.ion, the
dispersion of chromatophore<, the establ ishment of
cell contours. the outgrowth of neurites,
Irans""rt, and Ihe actions of A OH and other hor-
mones (93).
Calci um-<lependent functions include the secre-
lion of cn7ym es and ions l"C<luired for the digestion
of food: the intestinal absorption of "itamins, phos-
phate. and other nutrients (105): thermogenesis (7)
and thermoregulation (72); photoreceptor activalion
in the eye (277): fertili,,a tion (129) and the cortical
reaclion that follows: and oo<:yte maturation (134).
The transport of Cal. acl"QS.' intracellular mem-
branes involves movements of other ions. some of
which contribute to the maintenance of ccll pH and
water content, Certain of the transport processes re-
qui re AT P energy, others affect ilS generation, and
ye t dilfcrem kind. of interaclions been de-
scribed for bone.
Cylosolic Cal> affe<;ts several propert ies of the
plasma membranes_ It regulates Ihe actiyitic.' of
"calcium pumps", modifies the phosphol ipid con-
tent. and influence< cell-to--cell communication
(159).
The tXI,ocellulo' calcium ion concentration con-
trols the eXlcrnal:internal concentration sradienl<.
a nd thereby the rates of (a) ca lcium uptake from the
e nvironment: (b) calcium eje<;lion from the cell; and
'"
(c) catransport and amiporl processes utilized in the
acquisit ion of nutrients. Extracellular Ca" modifies
membrane structure and surface charge. and (her<:-
forc cell excitability and the ac\j,jlies of several
membrane-bound {I 59). It is a major de-
terminant of cell adhesion. aggregation and agglu-
tination. OOnlaC\ inhibition of proliferation, and
phagocytosis_ It inllucllC<:S the lensile wenglh. de-
formability. and repair of membranes. and thereby
(among other things) leukocyte diapedesis and the
ability of erythrocytes to sn ..... ;vc by nar·
row capillaries. Extracellular Cal< is also essential
for blood coagulation and the activation of
complement.
Even the ability of some \0 bring about cell
death depends on the uptake of excessi .. , numbers of
calcium ions (217). Defective regulation of transport
has been as a cause of undisciplined pro-
of tumor (16).
A suddcn. marked risc in the blood Ca lo in·
voke arrest of the hearl. Small er. more grad·
ual elevations impair and brain func·
tions , Chronic hypercalcemia (high blood calcium)
leads to the deposition of minerals in soft tissues.
Thc of hypocale<:mia arc equally
grave. since neuromuscular is exagger-
atOO . Tre .......... pmgre<.< 10 convul<ion<. and dM lh con
resnh from spasm of respiratory tract muscles. (Stt
discussilm of tetany in Chapter 12.)
SPECIFICITY OF RESPONSES TO CHANGES
IN CALCIUM ION CONCENTRATIONS
In contrast with cytosolic Cal . concentrations of
10- ' -10 - 7 M. the plasma le\'<'ls exceed 10- 1 M.
When a specific hormone or neurotransmiuer
"opens the caleium gates" of the plasma membrane.
the intcrnal concentrations can rapidly risc to or
cVen above 10- ' M. Some stimulants ra ise the cy-
tosol Ca" by recruiting the ions from intracellular
seq uestration sites or by utilizing both mechanisms.
Certain regulators lowe, cytosolic Ca" by block-
ing the entry channels and promoting transfer oftne
ions to organelles. It is also possible 10 activate the
plasma membrane pumps. but the high con·
centration gradients limit the effectiveness of
processes. A singlc regulator can raise the cytosolic
Ca l, in one cell type and lower it in a nother.
The endocrine panero.. contain, .. v... 1diff.rent kind.
of cell •. and it can be .sed to iilu"'''te SOme of the pro·
e.dinS oI>$<:",.tion$. Who. the blood ,Iucose concent ...·
tion. ri,e. the ,uiar bind, to receptors no the beta coli,.
The r•• ultins change, in tho plasma m.mbrane prope"
tie, permit more rapid uptake of e.lc ium ion,. and in,ulin
CALCIUM , PIIOSPHORUS AND TNE CAlCtFEROLS
is releas.d. Glucose also .cl5 no alpha cell receptors. b.t
in thi' ca .. it lowers the cytosol C.". and gl.o.gon ..·
crdian i. inhibit.d (28). Pancr.atie i.lots .dditionally
comain F ce\l,th" SCCrete pa""'eatie pOlypeptido (PPl.
All of th. «lIlype' recei"e cbolinergic innervatino. and
acetylcholine acts on them to cle,... t. the c)'toool Ca".
The neurotransmiu.r can therefore . und.r the 'ight dr·
cumSlances. promOte the secretion of in.ulin. Slucagon.
and PP. When th. glucose: concentration. are close: to of>"
,imum Ie,el,. but the "'raceilular Ca" i.low. tho "" •.
rottansmilt., invok •• just PP rei ..... Tho alpha and beta
c.lls re,pond when extracellular Ca" i, higher. and thoi,
abilities to do so are modifocd by )'et anothe, pancreatie
islet h(>fmono. somatostatin (lS8).
SOME PHYSIOLOGICAL ROLES OF
PHOSPHORUS
As a n essential component at ATP. ADP. creatine
phosphate, NAD. FAD. coenzyme A. pyridoxal
phosphate. thiamine pyrophosphate. glucos0>6-phOlS-
phate, glyceraldehyde-J·phosphate. and large num·
bers of related molecule', phosphorus is directly in·
volved in processes that provide cells with energy in
usable form. Phosphate also participates in the reg·
ulation of the associated metabolic reactions .• ince it
is an indispensable part of p. of cGM P and re-
lated cyclic nucleotides. of GTP and Olher adenylate
cyclase modulators. and of all RNAs. D NA •. and
phospbolipi&.
A. discussed in Chapter 4. eydic nucleotides ae-
tivale protein kinases that catsl)"'e of phos-
phate groups from high..,ncrgy nucleotide. such as
ATP to enzymes and other regulatory molecules.
They thereby exert profound innuenees over cell me-
tabolism. Cyclic nuclcotid .. ind.pendcnt protein ki-
nases utili7-c similar meChanisms.
The kidney eXCT<:les much of the excess Na· and
K' in thc form of phosphate 51111$ , It can vary the
Na: HPO :NaH,po. ratios of the urine in accor-
dance with body needs. and it can substitute NH;
for Na ' when this becomes appropriate.
SOME CALCIUM-PHOSPHATE
INTERACTIONS
Calcium ion, are modulators of enzymes affecting
thc phosphorylation! of protei ns. phospholipids, and
OIher molecules. The lisl includes adeny late cyclases,
guanylate cyclases, phosphodiesterases. and
nucleotide·independent protein kinasc<. Many of the
inRuences exerted On glycogonolysis. lipolysi,. glu_
coneogenesis. and other facets of intermediate me--
tabolism. as well as On protein . RNA. and DNA syn-
thesis. aT<: linked wilh roles in regulation of the
cyclic nuel.olides , Calcium ions also interact with
 Mg", which is involved in facets of phos-
phate metabolism.
Cakiunl pumps and Na'/K '-ATPases contain
CQIllponents whooc activities arc regulated by phos-
phorylation-dephosphorylation reactions. In many
cell types, the Na' and K - concentrations affect the
rateS of Ca" transport. High cytosolk Ca '" facili-
tates HPOl - uptake, and both intracellular and ex-
tracellular phosphate regulate calcium transport.
Calcium and phosphate are s<:questered together
in mitochondria as Ca,(PO,b In bone. dentin, and
enamel. the matrix that confers rigidity
is comprised largel y of crystals containing large
quantilies of calcium and phosphate. In blood
plasma. some of the Ca" binds to HP01- to form
poorly ionil.ed CaH PO,. Therefore. high plasma
phosphate levels reduce the rraetion of IOtal calcium
that is present in the form of free calcium ion. Since
only the free ion is biologically active. phosphate lev,
els can profoundly alfect runctions controlled by
Ca'" .
Hypocalcemia is the primary stimulant for the re-
lease of parathyroid hormone. PTH facilita tes the
transfer of both Ca" and HPO! - from other sites
to the blood plasma. The direct consequences are el-
evation of the plasma content of both iollS. However,
PTH is a potent phospha turetic. As phosphatc is
transfcrred from the blood to the urine, the pla!ima
phosphate concentrations fall, and the fraction of
pla,ma calcium pre,ent in ionic form i""rca",'.
Therefore. the nct elfe.:ts of PTH on the blood are
(a) elevation of total caleium; (b) elevation of the
calcium:phosphale ratio; (c) elevation of the cal-
cium ion:total calcium ratio; and (d) depression of
tOial phosphate.
Vitamin D must be converted 10 a hormone. 1.25-
dihydrox),vitamin D. before it can intes-
tinal absorption of calcium and phosphorus. Major
regulators of the rate-limiting for the con-
version include PTH. calcium ions, and phosphate
levels.
The multifaceted roles of calcium about
its ability to combine with protoplasmic constituents
that include proleins. lipids. and carbohydrates
(255). Since it is divalent . Ca" Can enter inlO the
formation of "phosphate bridges". It binds to anions
such as citratc 10 yield poorly diffusiblc
and it regulates the metabolism of some
of those ions. Ca" additionally neutralizes negative
charges and forms chelates.
CALCIUM-BINDING PROTEINS
There are controversies concern ing whcther the
major innuenccs exerted on membrane, that alfect
structure. electrical properties. permeability, and en-
zyme activities depend primarily On interactions
with phospholipids (103.213) Or wilh proteins (135).
At least some metabolic and transport functions re-
quire interactions with calcium-binding protein,.
The most important of those mole.:ules may well be
the calmodulins (132.163), but roles for synexin in
CMlCytosis, for troponin in muscle comraction. and
for intestinal calcium-binding proteins in absorption
of dietary calcium are described elsewhere.
CALMODULINS (CaMs )
These proteins .iere discussed in Chapter 4, and only
some observations are cited here (56.1 32.272). Older
designations include cakium-<iependent regulator
(CDR). calcium regulator protein (CRP), and cal-
cimedin. The molecules are chemically similar to
troponin C of skeletal muscle. and they arc related
in some ways to the intestinal calcium-binding pro-
teins (243). (1Io"'ever. their synthesis ;s not con-
trolled by calciferols [441.)
CaMs are present in inactive forms in "resting'"
cells. When the cy tosol Ca" rises. they combine
with the ions. undergo configurational cha nges. and
thcn serve as intermediates for many of the intracel·
lular actions of Ca" (190). CaMs arC directly in-
volved in (a) regulations of the activities of adcnylate
cyclases, cyclic nucleotide phosphodiesterases. phos-
phorylase kinas<:s. myosin ligh t-<:hain kinases. and
other (b) initiation of DNA biosynthesis;
(e) ncurotran. mil1cr biosynthc.i,; (d) phospholipid
turnover; (e) active transport of Ca" across mcm-
branes; and (f) depolymerization of microtubules.
Specific proteins that modulate CaM functions have
been identified (l31).
CALCIUM ROLES IN CELL MOTILITY
Calcium ions play indispensable roles in thc contrac-
tions of skeletal. smooth. and cardiac muscle (4). In
some kinds of nonmusde celis. the ions acti vate
aetin-containing myofilament systems. In others.
Ca" affects protoplasmic viscosity. cytolasmic
stream ing, and Ihe ability to send OUt pseudopods.
Skeletel Muscle
The thick (myosin) r.lamcnt' have p.ojection. th aI COn
bindlO ,pecific actin . ita. and acti •• table ATP.se.
When the musele i, al ... t .• ttopooin_t.opomy<:<>in CQtJI.
pie. physically btocks Ihc . ctin ,itc •.
Stimulation invokes depolarization and relea« of oat-
cium ion, from lhc $.l'wpla,mic reticulum. According to
widely held hypotheses. tropenin undergoes a conforma_
tion.1 ch'llAc when il bind. calcium. Thi' affects the
tropomyosin in a manntr that cutminates in u"m .. king
of Ihc .. tin-binding . ites. Cross-brid,a form between Ihe
thick and thin filament •. Contraclion i••c<:Qmpli.he<I
when ATP energy i, u><:d 10 brillA about bending or .hort-
'"
ening nf the: cross-bridge •. so tha, lh. Ihin filaments are
moved acr¢SS lh. I hid ones. Ther. ar< direct relation_
ships bel"'ceo lb. '!uantilie. of Ca" relc.. od and the tcn·
'ions lbat ean be generated in 'he muscle r,bers. Duting
the rela",ioo pha •• , ATP energy i. used 10 pump cal·
cium ions back into t he »rooplasmic reticutum (88).
Calcium ion, . lso cont ribute ind irectly to ATP gener-
ation by aClivating the glycogen phosphorylue b kina ..
i •• <>I.ed in oonvcrsion or muscle glycogen to glucose-
ph(l$phate. Calmodulin is Me of the subunits of Ihe
enzyme.
hcrni .. ly high Ca" imped .. the No '
and K ' roov,menlO involved in ",,11 dcpolaril.lOlion$ and
,.pola,i",,';on._ HypOCalcemia con markedly .ugment
nc"mmuK.lar •• citabilily.
Cardiac Muscle
Cardiac musck also has a sarcopl •• mic retkulum from
which calcium ion. are dis.charged following depot.ri",,_
I;on. and Ihe ion •• re .imil.,ly inVQlved in Ihe eonlfae-
lion., H",,'e>'er. Ca" i•• dd ilionally laken up fmm lhe
envimnmenl. AT P energy i. uled duri ng con' ''¢lion. and
it i, .Iso needed for bol h pumping Ca' · back into III< ,.,_
cop l.. m;. miculum and lhe <>pcration of pluma mem_
brane pumps lhat eXlrude the ioos. Since cardiac mu,cie
use, moslly fatly acid fuci .. lhere i. leu dopenderICC on
Ca" for ATP gonoration lhan i. III< e.se for •• el01.1
musck.
Hyper<.lcemia the Ca" uptake f",m the
environmenl. It Ihereby .. o, the for« of
tion. and il impai" relnalion, Extremely high concen_
tration. can .y'lolic .. .. , High eXlfaedtular
N.· "eaken. myoca rdial contractile fo.-«. evidenlly by
di'placing ellcium, (O n Iho othor hand. therap"Ulic doo-
age. of diaitoli. are believo<llo impro,'e oOlllractilo foree
by ;nh;bitins the No '/ K - -ATPa"" The ;"If.«lI ular ac-
cumulal ion of No - acti.ate. Na ' /Ca" ",change< lhat
may involve milochondrl... woll a. pl.,m. membranes
{SOl. and cylosolie Ca" i. ",eo"da,ily dovated,)
Pota .. ium ion. ",.dily <ross Ihe pla.ma membra no •.
HYP" rbJemi. lowe" resting potential...10"" oonduc-
lion. woaken. myocardial con\taclile force. and
cardiae d ilalalion. It. effool. are exaccrb .. ed by
hypocakemia.
Smooth Muscle
Smooth m"$Ole l.ck5 highly doveloped. c.ldum ..loring
saccopl.,mie rotieula and orderly arransement< of thick
and Ihin filament<. When Stimulated. il 10k.. up Ca"
from t he o"raeollular Huid •. and form. Co-CaM com_
plex"" This lead. to aet ivalion of my.,.;n lighl..:h.in ki-
n..... pho\.phorylation. of specific .it.. on the myo<in
nlOiceul ... m}'osin binding 10 .etin. and .<Iivaticn of
ATPa"I. In SOme cell lyPO>. Ca·CaM stimul.lel pla.ma
membrane pumps thaI extrude C. '· . It may fU!!<:lion in
thi, ''''l to bring aboul smooth musclo relaxalion , Hy_
percalcemia can invoke ,mooth mUIcle .pa<m_
CALCIUM. PHOSPHORl.l S ANO THE CALCIFEAOLS
CALCIUM AND PHOSPHATE INFLUENCES
ON MICROTUBULES
Tho func tions o f and Aagella. the movements of
chrom()SOmo:s d u ring milosis, axonal transport. Ihe
secretion of al least some hormones. and some olher
intracellular Iranslocations a re all dependenl on mi-
erolllbules. Assembly and disas", m bly of the organ-
. nes arc associated with phosplJOrylatiort
and the hydrolysis of GTP. Ca-CaM promotes de-
polymerization (65,251).
CELL-TO·CELL COMMUNICATION
Closure of intercellular channels uliH'.cd for Irans-
j UrlCtional has 1:>«:n l inked wilh elevalion
of c)'I()S01 Ca", It has been proposed Ihal Ihe
changes invoked in'IQlve in pore size."
misalign m.n l. of the aperture;s of neighboring cells.
or both (150), Although nonjunctional portions of
the membrane usually undergo dcpolari'.lltion, Ihe
process docs nOl seem to be .ilher ncccosary or suf-
ficient. Calcium is also inV{)lved in l he scaling off of
membrane ehaMels belwecn healthy and damaged
cells.
CALCIUM TRANSPORT ACROSS
MEMBRANES, MECHANISMS
The mechanisms are complex. and Ihey vary from
one cell Iype to anolher ( 162,203). High cXlrnccllu -
lar:imracellular coneenlral ion gradicnl$ and the
electronegalivity of Ihe cell interiors facilitale pa<--
siv. uptake. Al lea" three differem processes CQn_
tribute to inward "calcium lca k" (\97). H ormones
and neu rolran.miucrs can affce l Ihe emry Channels.
A calci u m -specific palhway functions indepen-
dently of changes in membrane polarilY and involves
COlransporl of Na ·. A $Ocond channel is -indc-
pende nl but becomes more imponanl when acelyl-
choli ne 0' o ther .. gulators bring aboul dcpolaril"-
lion. In SOmO cell types. such Ca" entry invokes
aCliva l ion of a polal.Sium pump involved in K ' ex-
\tusion. This Can provide proleclion againsl exces-
sive prolongalion of tbe depolarization. (T he p«:<--
ence of high cylosolic Ca'" at t be time o f Stimula l ion
can, howeve r, have secondary consequences on K·
movemenls [78J and on the activilies of Na ' / K ' -
ATPases.)
Enlty requires specific ca rriers. Evidently, it is
limiled by Iheir availabilily. a nd by special proper·
tics of the plasma membranes.
Many regulalOtS elic;1 mpid changes in plasma
membrane phosplJOlipids. a nd Ihc consequences irl-
clude .horations of membrane Huidilies, lJsually.
there is an associaled acceleration of Ca" uptake.
 The COIl"<Opt that hydrolysis of phOSphatidylinositol
(P I) results in rapid opening of the calcium channel, ha.
been sefiously considered by many inve$ligatofi, but;t i,
now challenged (III) , It has been pointed OUt th.t (a)
the phospholip.... implicated are in the cytosol rather
than in th. pla,m. membrane: (b) cycle. or ph"'ph.,i.
d),linosi,o! breakdown and rcs)'n,h.,is are cumbe,.,.,mc,
and thcy are "SSOcialed ",ilh Ihe uso or large quanti tics of
ATP energy: (e) en>;ymc' ",quire<! for thc re,ynthe,i. are
on the endopl •• mic relic.lum. and Iherefore the mecha_
nism. must ;m'olv" "'me exchange problem>;.nd (d) in
..,me edt types. phospholip.uo activation can be second-
ary to Ca" entry. h i, ,I.., known that membrane phos_
pholipid cyde, differ from One cell 'ypc to another (even
when 'hey inv<>lve 'he same kind. of molee"I«). The ..
. re re. __ to beli... that the cone<:p1S w;1I eventually be
modified, ($ce Chapter 4 and A-2).
When cytOSQlic Cal . excessively (or when
the cell is returning to its "resling" state). il beoomes
necessary to rapidly dispose of some of Ihe ions. In-
tracellular sequestration is Ihe first line of defen<e.
The processes are promptly initiated and tbey can
deal with subStantial numbcrs or ions, However. Ihey
cannot alone maintain low cytosolic Cal ' over
lended time periods (218). Plasma membrane
"pumps" Ihal ulilize ATP energy to the ions
are present in mOSt (and possibly all) ceillypes.
The pumps ha_e been most intensively studied in
mammalian erythrocyles (257), They contain one or
more proleins Ihal undergo calcium-medialed phes-
pborylations, The rcaClions precede Ca"
and they are associated wilh Ihe oonversion af ATP
to ADP. Magnesium ions are necded to bring "bout
phClSphorylation (although somc phos-
phate transfer can occur in their absence). Mg" has
additionally been implica led in promoling COn_cr_
sion or Ihe phosphorylaled protein 10 a more activc
form Ihat is direclly invol_ed in the transporl. De-
phosphorylalion af the activaled protein also r.,.
quires ATP energy. The extrusion of Ca" may be
linked with either Ihe aetivalion Slcp or Ihc sub,.,.
quenl dephosphorylation (218).
Calmodulins aClivate the erylhrocyle pumps.
Membrane phospholipids playas )'et undefined roles
Ihal may include orienlation of Ihe proteins. (The
pump docs not operale when these molecules are
rcmo,·ed.)
Mg" ICa'" -A T Pases are distincl from Na +I K ' _
ATPascs. but the two interacl. Sodium pumps con-
tain phosphoproteins, and both high eXlcrnal Na '
and high eytosolie K+ facilitate Ca" extrusion. In
some cell types. Ca" ejeclion is linked with Na '
entry. Since steep concentration gradienlS fadlitale
rapid uptake or Na +. a carrier with amni ties for both
Cal< and Na+ can pas.,ive\y draw Na ' into Ihe cell
and return to the membrane with Ca " , However,
such a sYSlem can function only when Na' I K' -
ATPases maintain low cytosolic Na +, Caldum an-
liporl i. Iherefore indirectly driven by energy r.,.
leased from ATP.
Mitochondrial Uptake and Relea se
In nonmuscle cells, the mitochondria can ta ke up the
equivalent of 500 timcs as much calcium as is pres-
ent in the cylosoL There arc separate cantrols for up-
lake and release. and the differ from
lhose invol_ed in endoplasmic reticulum (27) and
plasma membrane sequeslralion. Some invesligators
belicve Ihal Ihe mitochondria play major roles in
regulation of eylosol Ca" , II has been pointed out.
however, thai Ihe Ca'" concenlrations within Ihc
affeel the aClivilies of several en7.ymes, and
the mitochondria must therefore adjuSlthdr uptakes
to internal n""ds, It is also recognized Ihal Ihe very
high external Ca" concenlrations widely used for in
vilro studics Can irreversibly damage the organelles
(49). and thereby provide data thai are not physio-
logically relevant.
The uplake is electrophoretic (49) a nd carricr-
mediated (83). A glycoprolein with a molecular
weight of around 30.000 has been identified in both
inner and Outer membranes bUI not in the matrix. It
may be inv<llved in initial binding of the Ca'·. (An-
tibodies direcled against it impair encrgy·li nked
Ca" uplake without affoeting Olher mitochondrial
functions,) A different prolein with a molecular
weight of arou nd 3000 (ealciphorin) may then act in
series with the glycoprotein to deliver the ions to the
matrix .
Calcium enlry inlo the mitochondria is a.'>SOCiated
with aceelcrd ted electron transport and H' ejection,
The energy lransfers arc di,·crled from ATP synth ·
sis. and they Can be ha rnessed 10 promote Ca" up-
take. Agents Ihat interfere with electron lransporl
block the uplake. bUI oligomycin (which inhibilS
ADP phosphorylalion) doc, 1101. Extramilochondrial
ATP may also be used.
Usually. Ihere is simultaneous enlry or phosphate
ions inlo the milochondria. The procc!oS i, not essen-
lial for calcium uptake. bUI much more calcium can
bc internalized when this occurs.
MitOChondrial sequeslration involves the forma-
tion of an inaclive (but recrUitable) oomp1cx and the
release of H ' ions,
3Cal + + 2HPOj-". Ca,(PO.h + 2H '
Precipilation permits Ihe accumulation of large
quantili« of ions withaul corresponding cievation of
Ihe free ion ooncenlralions within Ihe matrix. The
milochondria! Slores of amorphous calcium
phosphale. Subslances wilh in Ihc mitochondria pre.
venl the rormalion of hydroxyapalite crystals. l'hos-
phocilrale 10 be the mosl important of them.
Magncsium ions arc believed 10 bc physiological in·
." CALCIUM. PHOSPHOIIUS AN I) THE CALCIFEIIOLS

hibitor.; of ion uptake that oontribute 10 Ihe main-
tenance of homeostasis.
MQSI of the hydrogen ions liberated by the precip-
itation reaction enter the cytosol. ThC1"<'forc, the se-
questration lowers cytosolic pH.
Release of calcium from Ihe mitochondria is a
separate affe<:led by agents that do nOI aher
the uplake. In many cdl types, ;\ depends upon
Na '/Ca" exchanges. e12 and C14 fally acids can
act via Na' -independent me<:hanisms to aCCI'lcralC
Ihe release . They may do this by binding and di-
rectly transporting Ihe calcium. The physiological
significance of the observations has no1 been defined.
Steroids. insulin. and glucagon are among the hor-
mones reponed \0 regulale mitochondrial transport
Qf C3". cA MP can promote release under some
oondi\ions, but not enough is as yet known concern·
ing ils phy>io\ogical roles in this oonneclioo _
Some Agents Used to Study Calcium
Exchanges
Ca/dum iOllOpho;es ,uch "' 1\23181 elo.ate the cytosol
Ca" by e.tracellul., ions a<ross the pla,m.
membran .., They the,eby mimic thc aClions of many
h<>1mortes. Howev,,, > high concemt.tion. of these agcnts
can also aecelerate t"ns]XI" acrOlS orp.ncllc m.m-
broR< •. Som. .!feel protein ,yn,hui,
other proctsSe$_
EDTA (.thyl .... diami ... t.t"'ac.t.te) i, • chelator
that bind, divalent "nd lfi.alent cation,. It is added to
e.u.cellul.. Huid, 10 impede C." uptake. but it.lso af-
feelS Mg'- tran']XIrt_ The sodium .. 11 (N.,-EDT". di-
wdium edetlte) Cln invoke hypocalemic lot."y when it
i,.dminister.d intrave""".ly_ t.·GTA (ethylencglycol bi.
N.N -Ielraatetate) m<>re specifically bind. c.lcium.
At'qU(}l";n HUO'05C" in Ihe presence ofCa". There are
wndilion, under which il can be used to estimate the f,tC
cllcium ion wntent of cen. Or o,ganelle,. bu t Ihe tech_
nical difficulti ....social.d wilh mic,..,.injectiono limit its
.".TtlrOOOIOxin interferes with N. ' uptake across
plasma membrane •. and therefore with Ca'-/Na' co-
transport . Vrrapamil block, sodium-independont. mem-
brane de]XIlarization·lin ked calcium uptake.
VaUtl<Jm}"ein r.eilitate. K' entry Ind slows Ca" up-
take when the Huid. bathing the cells are rich in K ', It
accelerate. K ' extru,ion and incre ..... CI" entry in th.
pre,ence of high extracellular No' _ is.n
uncoupler of o.idoti.e ph<>spboryJalioo thai cln block
Ca" /i l ' .nti]XI". Rurhmium ted and lan/han,,", im_
pli, the binding ¢f c.lcium to it< mitochondrial carrier.
bUlthey do not .ffect electron Iran.pon. RUlhenium red
is an e.pec;atly ullool . • ince it selectively blocks CI"
enlry bUI n<)t egress, Sulfbydryl "g.nI •• uclt •• N..,thyl-
malcimide (NEM) •• idently affect ",,\cium tran.port in_
directly by ... rting inHucnces "" phosphate ion
movemcnl$ ,
Vanadau (penta.ale nt .anadium) inhibits both basal
and CaM·>Iimulated caldunl pump .cti.ili.s , It mlY
al$O be a physiological regulator of No ' / K' e..hange
(256). Zine iom c,"rl .imilor innuc"",.
Cells handle Sr" and Co" in .imilar w'y$. and radio-
active form. of both etement> can be "oed a, ma,kef$_
Some Mg" is n«:dod to SUp]XIrt calcium metabolism. but
high ooncentratm can interfe,e ... ith C." uplake (83)_

Calcium mium _,ate (versenat,,)

(di,c>dium$On o! EDTA .roe' Ca tlinding)

If cmN CH ,
:!':IHHH I HN
H,cO-< } --C- C - C - C -N- C - ' OCH,
I HHH HH
'-"='-'>H,- C- CH
,
'", V..-apomil
 CALCI UM INTAKE, DISTRIBUTION, AND
TURN OVER
Dl,ttlb utlon
MOfe Ihan of the toul calcium of Ihc human
adult body is found in the matri<:es of hard Hssues.
Depending on the age. and of lhe individual.
this can smountlO lOOO-1 400g. Most of it is in the
bones. but dentin and enamel haV<l high mineral CQn.
ccntrations.
Cbc to 90% of the remain<kr is intracellular.
Some is bou.nd to plasma mcmbnne components.
cytoplumie and other Ofganie rnoIc:cules
(""",lIy protein Of lipid). Much more is contained
with in and especially 11M: larcoplumic re-
ticula of the' muscles and the mitochondria.
Th is leaves only 1.0-1.5 (or 0. 1% of total OOdy
calcium) to be distributed 10 ull of thc ex tracellular
lIuid s. Blood plasma concentrations are rigid ly main·
tained wilhin narrow limits that do not go mueh
below 9 .4 Of mud above 10.6 ma/ dl (4.6-5.2 mcq/
liler) under normal conditions.
Approximately 46.5% of plu .... glcium is avail·
able as the t»oIogically active fre<: ion. Another 6.5'i(,
fOfms diffusible but poorly ionizw complues with
inorganic phospha le. citrate. bicarbonate. and Oth. r
sntall components of the blood. Plasma proteins. cs-
pecially elbumin, bind Ihc rest in roondilTusible form
(200). Large variations in phosphate. citrate, Q' pro-
tein oonccntrations can alTecl the fraction of cakium
present as Cal<.
Turnoyer
Studies wilh "Ca support Ihc belief tha t all of the
utracellular nuid calcium is renewed 40-50 times a
day, that the calcium comentS of heart and liver are
exchanged every 4 hours. and that 5keletal muscle
replacement ta kes 8-12 hOllI"$.
Calcium turoover in bone varies with physiologi-
cal statuS and wilh season and time of da y. Although
only a small fraction of total bode mineral is ,vail·
able for rapid exchange with the bulk
fluid, the absolute qua ntity is very lIrse when c0m-
pared wit h the mineral ronl.nt or the fluid. It lias
b«n estimated tilat some 600-700 ml or bone cal-
cium is resorbed a nd replaced dai ly, and that 20% of
the bone sa lts turns Over in a yea r (105). The rates
of exchange are su bjec t to regulation by hormones
and ot her faclors..
Inlake e nd ExcreUon
NUlril ionist5 in the Unitw SillIes advise human
Idull! 10 ingest 600- [000 mg of calcium daily. and
to increue amounts during pregnucy Of lacta-
tion. the inla kes are much lower in many
other countncs in whKh calciu m-dcficiclloC)' disor-
ders Ire l1(li widespread.
Calcium from the food mingles wilh some 600 mg
secreted by the gastroinlestinal alands. Therefore.
an individual ingesling goo m8 Iccumulates 1400
mg wjlhin Ihe intestinal lumen ovcr the COUI'iC of a
day. Typically. 700 mg passes OIIt wilh the feces.
This is a mixture of food · and secretion-dcrived min-
eraI. Thc remainder is ab$orbed into the blood·
S1ream. II Ihcn with and to some extcnl re-
places the <;aieium already pn:$Cnt in 5totage sites
thaI ineludc bone. ulracell ular and intracellular
fluids, and Ofpnelles such as mitO::hondria and sar·
coplasmic reticula. Only traces or calcium appear in
Ihe 5wUt. arid balance is maintained by sending 100
mg into thc urine. Some net retention is re_
quired to su pport skelctal growth and repair. and to
replenish SIOres that ha vc berome depleted durin8 an
illness.
Intcstinalabsorption rales Irc controlled by hor·
mones, and especially caieiferob. Healthy hu·
mans ingestinl 1000 mgjday lost the C<{uiva1ent of
9()'i(, of the intake 10 the f«es. When the diel sup-
plies only 400 mg. fecal loss represents 75% or the
inta ke. Fecal values fall to the equivalent or on ly
35'i(, when the food provides 150 mg. In each case.
ca lcium bala nce is maintained if 100 mg is se nt into
Ihc urmc. Yel smaller intakes Ire associa tcd with re-
duct ions in urinary caleium. However. 8rossly defi·
cient diets lead incvilabl y to depletion.
Pb)"lates. o..alatcs. and some olher vegetable com-
ponenl$ bind calcium and lhereby intcrrcrc with at.-
IQrption 01 the mineral. Diets that a n:: highlyalh·
line or uCCS5ively rich in phosphates also retard
calcium absorption . but some phosphate and sOOium
arc newed. Lactate and $everal other small organic
anions enhance calci um Ordinary varia·
tioni in the quantit it cs of $uch $ubstances do not
markedly impair alta inmcnt or calcium balance.
RENAL EXCRETION OF CALCIUM
Calcium that associates with small. di ffusible anions
such.t citrate, bica rbonale, and phosphate. and free
Ca l ' , can rapidly enle r the 810merular filt ra!e. Usu·
a lly, SOme 10.000 mg is filtered daily. 99(10-9950 mg
of which is reabsorbed . The cells of the proximal
convoluted lubules reclaim 55%, the He nle loops a n
additiona l 2O'Ir-30%. a nd the di$lal convolutw tu·
buies 10%-15'" of the filtered load. Final adjust_
ments 01 the uritUllY calciu m are made in lhe w -
lectina lubules. in which the uptake va ries from 2%
to 8'1... Pa rathyroid bormonc. <;aldferols. and other
re8ulatOl"$ .ITeet mostly d islaltubular portions of the
...
ntphrons. but $011lC oonlrols are exerted more
proximally.
Na " and C." reabsorption rllel paralld each
other in the prollimal $eament (98), A similar rt=la·
tionship often pertains in the Henle loops. but thore
an:: conditions under ""hieh Il'I<M:mcnlS of t he tWl)
kinds of ions an be diuoci.Jled. Dislal tubular rub-
sorption usually p.ocecds ataillSt a _ntn.lion
gradient in a Na ' .illdepc:lldent manner.
PHOS PHATE DI STRI BUTION AND
METABOLISM
On a weight basis. 1110: ,ollh hum"n body <,:()IIuins
half as much phosphor\lS U ealcium (500- 1OOg).
Around 85% is wilhin the skcleloo and ha lf llle rOo
minder is in skeletal mUKIe. Ihe maSKS of
ti$lIes a.e 8:nel1l.lIy Il'(:aler in ma les lhan in
females, 100al body aml.n! averages 8% morc in
males.
A typical mi1cd diet supplies 900 mg. A quantity
c.. uivalcnt 10 7()%"'90% of lhe intake i1 Iosl via lite
feces. Urinary cxcrctloo varies widely in accordance
with needs and accounts for 10%-30% of intake on
a long-range basis.
_ Although renal phosphate is indireclly
linked wilh lhc of ca lciunl. >Odium. aod
OIher ion5, the tubule is the major site for
I'<'absorption . Some 40% of the filtered load is re-
claimed by the tirsl convolutions (It leut in dogs),
Reabsorption there is not strongly Na'.<Jependent,
but the 2O'l.-10% taken bact in the remaining por·
tiORS of the oonvolu ted tubule t ... along
with Na'. Some phosphate $Cern! to be sn;!rtlfd by
the distal nephron. Parathyroid honnofIe is a major
of phosphate excretion. but ulci fe rolsand
othe, hormones significant inH..ena:s.
Plasma al'<' more variable than those of ul·
cium. Huma n adults 2.S-<4.S mg/dl. ,,'hile
growing children nuintain Yalues doser to 6.0 mgt
dl. Then: arc obvious species differences. and c0n-
centrations in CJ.CUfof IOmg/ dl .re considered """.
ma l for some StOlins of ralS.
Approximately 70% of plasma phorphorus is c0-
valently linked to proIeins and lipids. Smaller
amounu are lIOfoCV>'alcntly bound 10 such molecule:.
ot arc com)'lO!M:nu of diffu.i blc complexes. The am-
centrations of IlPOI· and of II ,PO; have been es-
timated II aoo 0. 11 mM. respectively.... hile
pol· lcvcl$ may IlOt exceed 8 X 10·' m M . Py..,
phosphate (P. P) attain. 50--80 mM concentrations
in adult bone matrix. and there are small
in cells and tilo!;ue Ouids.
CALCIUM. PHOSPHORUS AND THE
INORGANI C AND ORGANI C CO NS IT UENTS
OF BON E
Bone is a complex. metabolically aCl ive tilo!;lIC that
undergoes oontinuous changes in oompOSilion (20 I).
It is affected by nUlritional stat\L5, mechanical fac-
tors, numerous bIood-borne and Ioxal regulalOfS, and
by aging. The struelure Yaries with location and with
chall&es in bod>" chemistry. The vast millCTll ro-
$C!'VC$ make major contributions to calcium and
phosphonos homeostasis, but many other body o;:om.
ponenu participate.
Bone Mlne,,1
65'10-70% of the dry "'eight of adult, compact bone
consists of orpnic salu that been depo!'ited
inlo an otganic matrix. TIle ratio of Ca to P in ne ... ly
forming bone is close to I . It rapidly rises to 1.3 and
eventually attains a value of 2.0 in old. stable bone.
The first association of tile calcium and phosphate
evidently leads to tM fotmation of arnorpllolLs
brushite. CaHPO.· 2H:O (174). This is follo"'ed by
convel")ion 10 a morphous calcium phOOlph31c and
then to octacalcium phosphale. Ca,H,( PO,),' SII:O.
Furlher maturation =\Llts in 1M production of crys-
lalline h)'droxyapatitc. which has va,iously been rep-
•.
or Ca,,,,(H,Oh,·(PO,).'(OIl),. Some calcium car·
bonate (CaCO,), along witb small amounlS of mag·
nesium. potassi um, sodium. citralc. chloride. Huo-
ride. and bicarbonate. a re also present in ol der bone
mineral.
It has been estima ted by IIOrI'M: thai 10lt-4O% of
the mineral;s in amotphou.s fotm, Only around 1%
of the total is readil>" solubilized for e xchange ... ith
the blood plasma (113). The Labile portion CIIidcnlly
comes from both newly forming bone and (rom older
tissue that is de.5troycd during remodeling. Sponay
bone eonUlin5 less mineral by than compact
bone. but iu disproportioflately large su rface sug·
gests that it plays greater roles in <:alcium and p/loI-
pilate homeostasis.
Most or our information on the crystalline struc-
ture comes from X·ray diffraction and electron mi·
croscopy Studies. Some cu rrent controversies ari$C
f.om alternate interpretations of tile: same data.
whereas others arc rdated 10 differena:s in sample
sel«tion.
Orga nic Matrix
30%-33% of the dry weigbt of tbe bone (')()$ of lhe
organic comem) is col/agtn. TM most abundant of
the noncollagenoo. prote in, (NCP) i. os/weald". a
vitamin K-dependcnt compOnent whose formation in
bone cells is alfected by calciferols (173). The cells
also make OSloonectin (a phosphoprolein), and Ihey
at least 10 pla.ma proteins thaI include
albumin and immunoglobulins (165). Some gly<:<:&
aminoglycans. lipids. and small diffusible organic
anions are also present. The lerm ground subs/allCt'
dcsignales oompOnenlS that arc not incorpOraled into
the oollagcn phase.
The rdative contribution. of organic vs. inorganic com·
ponen .. to strUCIU,..,. ten,ile Strength. and rigidity Can be
demon.lrated .. tectivdy removing one of them, A
long bone soaked in acid or in EDTA ooIutio" I..... min·
ral' and rig idity but ,etain. its eOnt""N and len,ile
'lrenglh. (It can Ihen be twisled i"toa knol_) [fbigh tern·
peraturo, arc used 10 burn <>If Ihe organic mallcr. Ihe
mineral ro,idue is reduccd to a brittle rna<$._ (With care·
fut handli ng. Ihe COntout'S ore pre....ed. but burned bone
,hatters if louched even Iighlly.)
Co llagen s
30% of lotal body protein is of Ihi, kind_ Skin. len_
don . dentin. carti lage. blood vessel wans. and the
various basemcnt membranes comain substantial
amounts. The proteins perform "Orne nonstructural
functions. For example. they affect cell adhesion and
platelet aggregalion (36).
Although all varielies , halO common fea ture,.
sc'Cral Iypes Ihat differ from each other in amino
-G Iy-X -Y -G Iy-Pr<:>- Y-G Iy-X -H yd rox yprtrG Iy-Pr<:>- H yd rOx yp""
",-Chain coils ha'C three amino acids per turn.
The high contcnt of glycinc. proline. and hydroxy-
proline (around 330. 100. and 100 moieties, respe¢"
livcly) pre"cnts formation o f thc 3.6 amino acid
turns thaI charactcrir.e most other linear protcins ,
The glycinc-rich <egments arc separated from
each Olher by ones containing polar amino acid,_ Ly-
.ine and hydroxyproline are present in bolh regions.
Small quantitie, of other amino acids arc also found.
but completed molecules lack deteelable amounlS of
cYSleine, cystine. and tryptophan.
TROPOCOLLAGEN
Threc lY chains wind aboul each other 10 form a rod-
s haped superhelix 2800---3000 A long with a diame-
ler of 136-16 A. The resulting tropocollagcn i. sa id
to be rigid by some and semirigid by others ( 100).
T ypc [ collagcn of bone has mostly twO a I( [) chains
and one of Ihe ",2 kind. A form with three al( l )
chains has also been identified. In at least SOme col-
lagen" Ihe"," arc ",I. a2 and "') chains that dilfer
acid makeup na_e been identified (63) . Same lissue.
contain mixtures or undergo developmental changes
in which one type is roplaced by another. Bone con.
tain, type I. A closely related prolein is found in den-
tin. tendon, 'kin, blood vesse l walls, and gastrointes-
tinal Iracl. but the ntolecules in osseous tissue may
undergo special post-translational modifications thaI
affect minerali7.alion. Type II predominates in car-
tilage. Iype ][I is present in skin. blood vessel •. and
gUI, while type IV may be confined to basement
membranes (36),
STRUCTURE: (l CHAINS
The", chains are lincar proteins with molecular
weights of around 95.000 conlaining approximately
1050 amino acid moietie'. Each has a long helical
=tion in which every Ihird compOnent is glycine.
Short. straighl telopcplide, near both amino and
carboxy lerminal' direCt conformalional changes
tlC<'ded for subSe<]uent formation of fibrils (96):
T eIopeptide COOH
Nonpolar segments within the helix approxi-
mately 15 residues long ha'C the following se-
quences. in which X and Y are usually hydroxypr<:>-
line Or alanine (184).
sl ightly from each Olher in amino acid makeup
(201), (eartil'lge collagens contain three more basic
",1 [11] components.)
MICRQFlBRILS AND FIBERS
Tropocollagens joi n end to end in long strand. that
associale with others to form cylindrical microftla_
menl. (microfthril.) with varying lengths and 44_11.
diameters , Each """m. to compri.. five imerwined
Tclopeptides fill the approximately 4(i().i\.
gapll betwcen Ihe helical pOrtions (Fig. II-I).
The gaps are staggered in adjacent tropocollagen
strands. The spacing is said 10 be essential for sub.
sequent minerali7.alion, hut similar arrangements
can be found in noncalcifying tissu e•.
Microfibri l. polymerize to form highly ordered fi-
brils (fibers) 150- 1500 A in diameter wilh repeating
units 640 A long (Fig. II-IC). Advantage is taken
of Ihe ahility of polar group,; within the gaps to bind
chromium, SO that a banded appearance becomes ev-
ident in electron micrographs (Fig. 11-2).
". CALCIUM, PHOSPHORUS AND THE CALCIF£ROlS

= )
'"001"-''-'-'- ,,'
-.".-
S. MiOfolibril lor FormoHon •

.iol....·",
--'
. ..... .
,

C. Fibril Formoli""

.... Oz • It-C .... NH. - R'CHO + N":

,<0
• •
+ CHOC""" -",-C><- CHzI'
•
R,'CHO+ ""'Y'I'. :;:ORCH.tKI<o'¥- .... O
,
Fill. 11 · 1.Formatioe oj COllagen • . (Rep<inted with
pOormihiOn I,om RasmoSM/I. '.1..."""" ZOO.)

BIo synthesis of Collagen (82, 168 )
TRANSLATION AND PRELIMINARY
PROCESSING
Each Chain is synthesized on ils own ri-
bosomal component of a pOlycislron complex. It has
been suggested Ihat Ihe cells oon\ain Iwice as much
mRNA for the production of 0:1(1) as fQr ,,2. How_
ever, there are indications thai only a single gene
oopy exists for nch and Ihat regulatory mechanisms
aSSure the formation of Iwice as much of lhe 0:1(1)
type. The hereditary oondition osteogenesis imper.
fecta Iype I is associated wi th Ihe production of
equal arnoonts of Pro« I (I) and Pro «2(1). Here. the
ra te of collagen synthesis is limiled by the amounts
of the Pro 0:1(1). and the clinically demonstrable de-
fe<:ts include bone fragililY. The palients may not
H,N-Signal sequence-Amino lerminal pcptide--aChain-Carboxy te rminal peplide-COOH
have a gene Ihal normally coordinates Ihe synthesis
of the IWO types of pro 0: chains (22). Substantial
amounts of the 0:2 Iype chains are degraded. possibly bonds of procollagen, and they also have some tryp-
because they lack a conformational deteminant re-
quired for extrusion from the cell.
The initial 1500-amioo.acid gene products have
signal sequences that arc cleaved when the nascent
chains are into the cisternae of the endo-
plasmic reticulum. An amino terminal peptide is rc;.
moved duri ng intracdlular po6Hransiationai pro-
cessing, while a carboxy terminal peptide is retained
until after the protein is extruded from the cell. The
pre--p"'"'" chain that would be obtained if the
component persisted until completion of the molculc
w()IJld have the following sequence.
He prQ" chain (which lacks the signal sequence)
is an intermediate oontaining some 1200 amiJl() acid
moieties.
Since pro-chains associate very early, it is
likely thallhe NH,lerminal peptides play roles in
recognition. The Cterminal components contain Ihe
cysleine groups thai form the interchain disulfide
tophan. Those amino acids are not found in the final
products.
Fig. 11·2 . Edge oj . 'ts<I<p1ion ""nol &1'-<1;" by
I. mell. , bono . A, ' ''"' uPPw Iolt I. a porIion 01 an 0",00101 ...
"""'A"""" • ",,,,,,,,,-, ("""<Ii ,""" """ ... """n' ."... "",
.... ,0cuIum, SUblaCer>1 !<> . '. ,''' COI'agen 111><,. oj lwo
HYDROXYLATION
During Ihc normal course of evenlS. each of Ihe
chains is hydroxylaled al specific silC.l prior to for-
mation of the superhC\ix. (All of the hydroxyproline
and hydroxylysinc arises in this way; no hydroxy-
laled amino acids are incorporaled into the init ial
gene product .)
II was formerly b<lie>cd 'hI' Ih. hydroxyl. led amino
acid, are unique 10 oollagen, Howe.er. lbe gi)'eoprOlein.
of bone grou nd substance and of el.Slin hIt.e ""me
hydr<>llylysine,
Hydroxylalions normally proc=d wbile the chains
are still auached 10 Ihe ribosome;s. and Ihey are rap-
idly followed by glycosylalions. Th. processed chains
then wi nd about each other 10 form Ihe prorol/(1gen
that is ex truded. (When hydroxylalions cannol
occur. pro a chai ns form proux;ol/(1gen helices.)
Peplidyl proli ne and peplidyllysinc hydroxylascs
a rC mixed-function oxidases associated with thc en·
doplasmic reticulu m. The reactions they calalyze re-
quire molecular oxygen. ferrous ions, coPl"'r. and air
corbate. as well as an energy SOurCe deri""d from the
oonversion of a-kctoglutarate to succinate, Th. spc-
u.......... liz"'" ••• ood It t'" low .. t\gtIt il t'" dense
minorati,"", boNt. (Alt .. R. R. Coope< at 01.. J. -..t >d
.Jo;n, &Jro 48A ' " .. ) ( """"" . "" I'AW,,"," •
,el ..""".32)
cialized requi rements may be related to mechanism,
for Ih. regulation of collagen biosynthesis.
II ha, becn proposed Ihat Ihe ascorbate activates
thc hydroxylases. It i, also believed to accelerale col-
lagen biosynthesis by facilitat ing assembly of poly-
ribosomes directing the translalion (231). and it can
additionally affCCl laclale production. Cells cultured
in ascorbic acid-deficient media rel.ase <>-chain
fragments and proteins thai are rapidly
degraded. The skeletal dcfe.:ts. impaired wound
healing, and other oollagcn-del"'ndent disorders
linked with vita min C defiieney have been a tt ribuled
10 impaired hydroxylalion.
Coppe r is required for induction of Ihe Iysyl hy·
droxylase. The bone fragility of ooPl"'r-deficient an·
imals is associated with impaired cross-linking. High
concentrations of thc mineral retard collagen de-
struction. probably beca use they activate an endo-
peroxidase that catalYl.e5 the oonversion of PeE to
PGF",. Patients with rheumatoid arthritis and ac·
celeraled bone resorption have elevated copper levels
(271). This may be related to compensatory mech·
anisms for limiting the bone dcstruction.
Roles for calciferols in t hc regulation are sug-
gested by the presence of poorly hydroxylatcd 00\'
'"
lagen in the matrices of rachitic bones. The effects
of the hormones are discussed later in the chapter,
High lactate levels facilitate hydl"QxylaliollS, and
hormones acting on bone aTC known to affeci lactatc
production.
Some forms of osteogenesis imperfects have been
linhd with derangements in enzyme functions. but
translational defects Ihal bring about replacement of
a port ion of the type [ collagen by the Iype 111 col·
lagen have been described (21).
The hydroxylation, are believed 10 involve for-
malion of intermc<iiate peroxyglutaratcs (184) (Fig .
11 -3). Lysine hydroxylase' -Gly·X-Lys-
Gly· moiet ies of the hdix and also lysine residues
present a1 specific silcs within the tclopeptidcs. Only
around 20% of the lysine moielies become hydroxy·
laled in bono. whereas the values are dose, \0 60%
for cartilage , Both hydroxylated and nonhydroxy-
lated Iysyl groups cn ter into the formation of crOS&-
bridges.
Prolyl hydroxylases attach specifically \0 -Gly-X-
Pr<rGly- moieti ... The OH groups arc found mostly
at thc 4 ]X)Silion but very small omounts of 3-OH-
proline have been detected in bone (and larger ones
in collagens of other tissue types). The percentages
of proline groups affected similar for the various
kinds of collagen-around 45% for bone and caTli-
lage (types I and II) and 55% for type III.
GL YCOSYLA TION
Certain of the hydroxyl)'s)'1 residu es Ihal do nOI
cnter into thc formation of cross-bridges are ;003
glycosylated. The major product in adult mamma_
lian bone is a galactosyl-h)'droxylysyl ITHlici\y (fig.
11-4). In the skin. a sccond reaction leads to the for_
mation of substantial quantities of gluoosyl-galac\o-
syl-Iysyl moieties. Some collagens also COIltain man·
nose. amino sugars. and other carbohydrate
components.
II has been suggcsted that glyoosylation i. an im-
portant determinant of the st ru cture of the finis hed
collagen, a nd that it affeclS the sizes and locations of
the spaces into which mineral c2 n be deposited , Sug-
ars may also bind phosphopc:ptidcs that have been
implicated in the calcification process ... The Slruc-
lUre of dentin differs from tbat of bone. and the dis-
tribution of dihydroxylysino-norleucine also differs
in the two tissue types (136).
CROSS-LINKAGES
Lysine oxidase catalY7.es the conversion of lysine and
of hydroxylysine to allysine and hydroxyallysi ne. re-
spectively (Fig. 11-5). An allysine of the tclopcptide
CALCIUM, PHOSPHORUS AND THE CALC tFEROLS
.;an tben combine with a hydroxylysine of the helix
to form a hydroxyl,'sino-norleudne bridge. The lat-
ter may also be deriyed from interaction of a (cio-
peptide hydroxyallysine with a lysine from the
A is rormed by
eombina(ion of a (elopeptide hydrQxyallysine with a
hydroxylysine of the
Intramolecular bonds (between components of the
same chain) onen involye aldol condensations that
link allysines and hydroxyallysines.
Disulfide linkages are formed between cysteine
ITHlieties of carboxy-terminal telopeptides of neigh-
boring chain<.
PROCOLLAGEN
Amino-terminal segments arc probably cleaved after
(he hydroxylation. Slyeosylation, and cross-linkage
reactions have been completed. The resuiting prod-
uct is a triple helix consisting of Ihr.., pro ('< chains
entwined aboul each other (with the carboxy-ter-
minal telopc ptides st ill anaehed, see FiS_ II-Ii\).
Extrusion of procollasen into the extracellular space
evidently involyes functions of thc GaiSi apparatus
and of microtubules, Colchicine (which impaiT'S mi_
crotubule function) blocks the secretion. Sinee tuni_
cam),ein ("0 inhibitor of glycosylation) also inter-
feres with release. it has becn proposed Ihat the
carbobydrate groups are involved in the s<x:rctory
processes. Howeyer. as has been noted. unhydroxy_
lated chains can be extruded. Tunicamycin may
therefore interfere by causing hydroxylated residues
to anach fITmly \0 the glycosylase enzyme,.
CONVERSION OF PROCOLLAGEN TO
TROPOCOLLAGEN
This process involves limited, controlled proteolysis
that resulis in shortening of each of the pro '" chains
to subunits of around 1050 amino acids each (lhc '"
chains) and removal of the sulfur- and tryptophan·
containing carbox),-terminal peptides , In addi tion.
deayage of rcsidual components of the am ino-ter-
minal peptides seemS \0 "unmask" the sites involved
in JIOlymerization of tropocollagen 10 form the mi·
crofibrils. It has been suggested that the process is
delayed unti l after ext rusion of thc protein, 10 pr<>-
tcct against intracellular forma tion of collagen
(201) ,
COMPLETION OF COLLAGEN BIOSYNTHESIS
The polymerization appears to be accomplished
spon taneously (i.e. without thc need for enzymes).
The microfibrils formed then associate to make mi·
 o
",
0-0

"'",,
"0"

"'",
0- 0
g
o
\"
,
"0"
,
itCH
00,
0 -0
S
Succinate
"
o
' -OH -P ro.tyl

Fig . 11 ·a. PtopQM<j ' NC!;on Hq<J..-.oe lot ptOiyl

hyd ro xyl,'ion.

",
"""
0,
ly.yl hydroxyla..

.. . Kclogiuuuato _
ASCOt""'&
Suc6na,c ' CO. -
"'",,
HO- Cii
HCII
,
"'",
C, ",0
'N / H C,

"
Hy",o,ylysyi

GIOCO$yI-
UDP-GILlCOse _____ UDP _ galaclosyl.
h ""'''''ytysyl

G.'actopy,anosyl-hydro'ylysyl

Fill. 11-4. HY<!toxylalion and o l lyo.l

resi<l""s oj •.
 CALCIUM, PHOSPHORUS AND THE CAtCIFEROLS

""
O= C- C- C- R

·0, HH,
-............ Ii Ii
"" O= C-C- C- A
,o
6
"Ly"oo
OH.
"
HYIl",'yaltysine
15<, -OH-... NH,·odipie "" ., seml,lklel'lyde)
A. O.<lal"e d.am .... ''''''

""
H1N- C-C -A ____
H Ii
R - C- C = N- C - C - R
H H

" o' H H 0
AIIy.One
(telopcpti6ej
Hyd<oxyly$>rIC
(heh)
" .,te,me<jiale "
H H H H H
I-'"
Ly.'"" R-C-C-N - C - C - R
(","jx) (lelopeptQc )
H H H b
"
""
R-C-C=
, O "
H,N- C - R
H Ii H H H
- - - -••_ R-C-C - N- C- C-R
o b o' I I II'
0
"
Hydro'yallys"e " "
Hydro,yIy<"""y<lrO'Y<>orleocine "
(telopept'del 1r.,J1.)

8 . In'crehain cross-linkage

""
A-C-C = O • O= C - C - R "" --'"'"""'----
• R-C - C= C - R

" o 6=0
,\I1y . ...
"
Hydro'yallysine "
AI<IoI """""",,,hon t>ri<!ge

Fill. 11·5. FOtmatk>n of CfI.in cro ..

crofibcrs (collagen fibers). Finally. a "maturation"
process, which may involve a combination of hydro-
gcn bonding. dehydration. and the formation of new
cov.lent linkages, scrves to stabilize the fibers.
MINERALIZATION OF COLLAGEN
According to the epitaxy concept, min...alimtion is
a passive process in which calcium arK! phosphate
pre.:ipitate at "nucleation sites" provided by the
gaps within Ihe collagen complexes. The initial bind·
ing of minerals to specific amino acid siles leads to
the deposition of amorphous aggregations. Soon af·
te rward. tiny crystals form and then grow (ll.
This nalion has oot been completely abandoned,
but it is incompatible with indications thaI bone ceil,
play active roles in mineralimtion.
In many species, considerable time elapses be·
 tween collagen formation and calcification. The in·
terval averages 8-10 days for human adults. but it
is not uniform at all sites. It is shorter during periods
of rapid skeletal growth. (NO! surprisingly. rodent'
attaining adult Si70t in three months fail to show the
delays characteri stic of humans requiring two dec-
ades.) According to the epitaxy concept, the lime is
needed for the collagen to ··mature." However, a
more li kely explanation is Ihat osteoblasts rnodulate
to osteocytes, or that osteocytes allain appropriale
phases of their rnetabolic cydes during the intcrvab.
HistochentiCal and electron micrograph data
consistent with accumulation of calcium at sites of
new bone formation via pl"QCesses that are indcpcn-
dent of ntechanisms for phosphate deposition (II.
and with the formation of a continuous mineral
phase that involves Ihe insertion of inorganic salts
into the "'lumina"' of the collagen as well as
into the gaps betw«:n the helices.
Membrane-bound vesides have been identified in
all kinds of calcifying tissues-not only bone. but
also cartilage. dentin. deer antler, and structures
such as arteriole u'alls and skin that can undergo
metastatic calcification (10). The vesicles contain al-
kaline phosphatase!. ATPases, and other ent-ymes.
The surface membranes resemble the plasma mem-
branes of bone and carlilage cells. The vesicles are
small (around 1000 A in diameler) and Ihcy differ
in other ways from lysosomCiS and mitochondria
(5.196). Several kinds of observations support the
belief thaI these structures direclly contribute t{l mi-
nerali'.ation (5, I0): (a) The vesides appt"ar in Ihe di-
rect vicinity of tissue that is about to cakify: (b) Ihe
first idenlifiable apatite crystals form within or in
cl{ISC appOSition t{l the surfaces of the vesicles: (c)
the ve,icles contain substantial quantities of lipid,
that include cholesterol, glycolipid" sphingomyelin,
and also phosphatidylserine (a substance known to
have a high affinity for calcium, especially in the
presence (If phosphate) (276). Therefore, they have
pmperties consistent with a m\c in mineral accu-
mulation; and (d) the activities of Ihc phosphatases
have been directly linked with mineralization in two
ways (81). They destroy known inhibitors of miner-
alization that include ATP, "D P, pllo5phoglycerate.
and pyrophosphate (269). and Ihe)' provide high.lo-
calized concentralions of orthophosphale (which not
only serves as a hydroxyapatite component but also
has stirnulatory effects on calcium deposition)
(167.249). Phoophatase activilY is present at the
OUler surfaces. and ;1 increases bofore the onset of
mineralization (10). At least One of the bone pho&-
may be regulated by ascorbic acid (11).
Four hYJXItheses for the ongins of the vesicles
have been considered (196).
I. The most widely held hypothesis is that Ihe
structures bud olf from osteoblaSl.s. The vesiclCiS con-
tain actin and myosin, and microfilaments are im-
plicated in the maintenance of structure and JXI5'Iibly
also in migration (172). The vesides may undergo
maturational processes after detachment from Ihc
oslcoblasts.
2. Fully formed vesides are made within Ihe cells
and they are then byexotytosis.
3. Cells givin8 rise to the vesicles die. and the
structures are the remnants.
4. Cells extrude macromolecular cornJXIncnts Ihat
undergo assembly within the matrix .
11 has been suggested Ihat bone and cartilage a ils
do nol themsel"es undergo calcification when they
participate in malrix mineralization. because the
vesides Ihey form inilially contain only minute
quantities of the inorganic substancCiS. There are his-
tological findings compatible wilh the COnCepl that
chondrocytcs accumulate calcium and phosphate
within mitochondria. and that the minerals are
subsequently transferred to extracellular vesicles
(9.41 ).
ATP docs nOl provide energy for the active trans-
port of the calcium (214). In fact, ATP and pyre--
phosphate block crystallization. Deoxycholate. an
inhibitor of vesicle ATPase activity, and beryllium,
an alkaline phosphalase inhibitor, both interfere
with matrix mineralization (10). The ATPase is be-
lieved to function as a nonspecific triphosphatase
whose major role is ATP removal. The enzyme may
additionally indireClly promote the aocumulation of
NADH and phosphoenolpyru.alc. It is known Ihat
the concentration! of those substances rise when
minerals. (On the Olher
hand, matrix formation separates the cens from the
capillaries. and the re!iuhing hypoxia may account
for the higher NADH and PEP levels.)
The lipids bind calcium. and they may in this way
contribute 10 mincrali7.ation. The "esides of healthy
animals bind sudan hlaek, a reaction attributed to
the presencc of phosphatid}"lserine linked to calcium.
The cartilage of vilamin D-dcficient animals COn-
tains vesicles tbat do not stain. pmbably because the
calcium content of the tissue is very low. The reac-
lions can bo restored by administering Ihe .ilamin.
Staining is also reversibly losl when bone formation
is irnpaired by ascorbic acid deficiency (124). The
lipids probably do more than accumulate calcium
(275). They adhere tenaciously 10 newly formed
rnineral, and their ability 10 accumulate calcium is
enhanced by orthophosphate.
11 has been proposed that the vCiSicles also either
produce a ··mineral_forrning agent'" or remove an in_
hibitor. A substance with such activity has been iso-
lated from healing rachitic cartilage (I 21). Morpho-
genetic functions have additionally been suggested
(230).
The role of vitamin K in the biooynthesis of ",{<3r-
, -,

•
5

... .." .•
•
, ,•
•
,•
.'
• • •

. '" • .,
' ..' • •
, •
•
., ",. •
• •
•
,
• •
"
•
• •
•
.., ,0 ,., ••
- ,
," • •

••
 l l .e. A. Cm...... t.... at the .."'" 01 the d",phy'is
oJlIHI n.d;"'. 1... .,..,.y-ol<l ral. e l.o1<"" m."ogo-oph. (I)
Periosltum. (2) prlm. ry swngy bono. (3) oinII" layer 01
OO1O<>b1a.,slorming endo$teum. (') ""t"""yt .... (5)
.on""'. <>1 t>Miosteal oprout. (6) o.pillar"'". (1)
primo,y _ marro'" 0.111 . X 600. 8. P...."'"leum. diaphysis
oj ,adlus. e "''''_ ' 01.,... simlla, 10 'octa"llle" A, lWO'
day-ol<l,.t, &l6Ctron lI'Iicfog<oph. (1) "ucr.; 01 fibrObiaots,
(2) ooIlaQOf>OUs fiber., (3) _ oj OSleoprogeollor 0011.,
(0) _ <>1 0$1001II . .,•. (5) oot.oi<l. (6) _ a'l,ed
.,- ------------------------------------
box)' glUlamic acid (Cia) and of pMein, conlaining
\hi' $ubstance was discu"cd in Chapter I. Bone Cia
protein (HG P. osteoca1cin) accounl, for some 15% of
Try-Lcu·Asp-H i.·Trp-l.eu·Gly·Ala· Hyp-Ala-Pr<}-Tyr- Pro-Asp-
Pr<}- Leu·G la· Pro- L 'fl- Arg·G Ia· Va I-C ys·G la- Lc U·As n· Pr<}-Asp-C ys· Asp-
(;lu-Lcu·Ala·A'p-His- lle·Gl y·Phe-G ln-Glu·Ala_T)'r·Arg_Arg_Phe·
Tyr-Gly_Pr<}- Val
The prolcin is made by bUI il does !lOt
appear until afler is well under "'ay.
The Gl a chains bind directly 10 h)'droxyapatile. and
Ihc prOlein can retard cryslal accu l11u la lion, liow_
ever. the funclions arc not kllOwn. Roles in bolh r""
modeling and regulation of the PTH-calcitonin sys-
tem have been proposed. The high levels found in
palienls wilh several kinds of bone disease tend to
dedine with effCClivc treatment (66).
BONE CELLS
Although lhey account for only a minUle fraction of
the weight. bone cells arc essenlial for the maint""
nance of structural imegrit y and f of the tis·
SUe (75.197). AtioaSI four distinct type.< are recog·
nizcd, each with ils own characteristic
morphological a nd biochemical fealures (1 52).
Cells o f the Periosteu m a nd Endosteu m
The periosteum is a oont;nuoos membrane that 00.·
all bon""forming (Fig. 11-6). It is richly
bonfI matrix "';_01. pa'tly ,erne_eel durl"ll
pr0i>l,atln pro<en). (7) 0$1"",bI.ot in the proee .. 01 bU>o
compielery our,<><>r'Ide<I by minerali,"" bonfI mal,lx , (8)
OOl"""yt& in bone locuno, X S&OO. (RI>od in. ,of",,,,,,,,, 20.)
C. DiagrorM>O'" ",pre",o"1;"'" 01 . Met"", 01 bono, TPIe
dropilOll ,__ ..'u "'bulk"' exlra".Uula, nuid: _ dots, boo.
e xl'ocellula, ftu;d, Sileo <>1 c.k:iklll;"'" . ,. SItOwn by IIHI
da,konoid ' ... ;.,... •. e. 0$1_,,; 0 .. , O$leoeyte, Arr"",.
Incl;cot. propMod '"""y of bulk ECF barw""" ,he celt. or><!
, ......... of luOds f,om OSleobl.Sls to the bulk ECF.
the noncollagenou, prolein content of bone. The b0-
vine form has 49 amillO acid, with the fo11ol>o'ing se-
quence (195).
vasculari1.cd and innerYated. and it contains fibro-
blasts that make collagenoos and clast ic A
oonlinuoos ring of cell. silnated between the fibro-
blaSIS and the tissue separate. the "bulk"
extracellular nuid from the nuid comparlmem
within th. bone. Most of Ih. cells are of the "ostc<>-
progenitor" lype. Thcy are thc of oswo-
blasts and Ihe only "'true" bone cells capable of cn-
gaging in mil()sis and the renewal of populalions.
Acoording to SOme the cell ring includes
"'surface osteocytcs" or "resting ostooblasts" Ihat
pump minerals from bone to Ihe bulk ECF. Olhers
allributc the funclion to ost e(lprogcnitor cells.
The bone nuid is derived from the blood plasma,
but il differs from it in electrolyte composition. It
cireulalcs around the oslcoblasts and osteocytcs
(Fig. 11-6C). Its makeup is described later in this
chapter and ils role in maintenance of calcium h<}-
moostasi, is discussed in Cha pter 12.
Em/rummr line. the marrow cavities and the
larger of the Haversian canals (through ""hich bone
cells dcrive nourishment), It contains the om'(xias/s
involvcd in bone resorption a nd remodeling.
."
O, teobla, t,
The oslcobla&lS are lhe txJnf-/orming cells thaI $yn-
lhc:si ,.c and ext rude ooIlagen and manufaclurc lhe
glycQproteins and othe r matrix oomponenls. They lie
bet .... een 1he OSloopr<l8cni\OI' celli and the OS\eocyles.
In actively IfOwing liswe. lhey are cuboidal and
have a ,,·ell.dcvcJoped rough clldoplasmic reticulum
.... i1h numel'l)ll$ ribosomes, buophilic: cytoplasm rich
in RNA and a1blille phosphaw¢. and &1)'WItn
granules. The nuclei arc prominent and _tain
Ihn::c Of more nucleoli. The GoI&i vesidcs an: large.
bUllhcre are only limited nu mbt:n 01 mitochondria.
The membnncs show pinocylic.nd
vesicles. Since Oltcobla$U KOO prorc$$('$ to ne;,.
bori ng cells of lhe umc type and 10 ,1>1: undo.:rlyi"l
oste<.>cyles,thcy may be components of &ianl syncy-
tia. Conditions lhal inle. 'ere with coIlaten symhesis
(e.g. vitamin C def,dcrlCY) can lead II) di$Ol'sani,,a.
lion of the endoplasmic r.["ular structures (15).
T he 1erm "pre<)l;leobluf' is 50mClimes used \0 des-
ignate cens that have: not yel fully developed th.i,
potentia l, whereas tile Icrm
" resting QlttQblast" hu been applied to celis of this
type tha t have become fla ttened and less activ<:o
OsteocytOl
Whe n surrounded by coll agenous matri 1. the Qlte<)-
blam are transformed in to OiSteocytes. The conver·
sion is referred 10 as modulatiOtl (ratller I han differ-
en tiation). sinc;c one Iype of high ly specia lized ceil is
changed inlO anot her.
The endopla.mie reticulum 01 lhe cell bcwmes
disorganized and lhe cytoplasm more .:krISe, IS lit-
crnl e Xlensions 10 neiahboring 0:(: 11, show up moR
dislinctly. Numerous milocholldr;' with well-<lcv<:l·
oped cristae and many clcctron-dcnso:: gnn ulc:l rich
in calcium pltOiSphate appear •• lons with l}'SOSQmcs
that contain acid hydrolUCI but not collqenases.
Fully mature osteocytcs becom.: trapped Wl hin
small Qlvilics (lacunae) surTOtmded by matri1.
Small qua ntities of bone EC F <:imllate around the
cells and lhe p.. );t$SC$ by whiCh Ihey communicate
wilh neishbori", celli. Hormones and ions can i...
voke rapid so that the ocllilimo.st fill the
laCliMc at ocnain times and lj)PQr shrunken It
other1.
The interval thai ela pses between roIlagcn mltri1
formation and mineraliulion has been rdated 10 Ihc
need for mod ulation of ostcoblasts to OiSleocylC5.
There a rc also indications Ihal OiSlcoc:ylcs go Ihrough
recurring cyclcs thaI begin with accumu lation of cal·
cium in the cytoplas m. The minera l ;1 neXI tra ns-
lerred to the nucleus. after ",hich a "ju xtanuclear
C"LCtUM. PHOSPtlORUS AND THI! CALC IFEROLS
appa ralus·' invokes a swi tch from mi neral accumu·
lal ion to mineral secretion (I). S inee ca lcium 'P-
pe.ll.r1 in Ihe ma trix earlier than phosphate, a nd since
collagen has phosphokinase lctivi ty. it is li kely thaI
mineralization involves much more than .impk P«'"
cipitalion into prepa red siles.
Osteocylcs are by far lhe most numcl'()U.S of the
cells of malure bone. Together ... ilh the OiSltQblasu.
Ihcy acc:ount for 95% of the populalion. It is widely
believed thaI the OStcocytcs play major roles in cal-
cium homeostasis..
O s leoclas ls
These are Ihc largest and least numcrousoflhe bone
cells. MOSt eonta;n lour 10 five nucle;. but !lOme
as many as 300 and are visible 10 lhe naked eye.
Mononuclear precursors <:an luse 10 form mul·
tilobed cells. Fragments connectcd to the main por.
tion by na rrow cytoplasmic strands can also pinch
off 10 form smallcr units.
Nume rous tiny cytoplasmic processes eXlcnded
toward sites 01 a ctive bone resorplion give the cells
their charactcristic " ruffled:' '·brus h,'" or "Strialed"
borders. At such times. the mitochond ria become
ladcn "'ith d ectron-densc, amorphous calcium 1'1105-
phatc "'hile Ihc lysosome. can be 10 be filled
",ilh proteolyllc cnzymes. T he Gotg ' a re ... etl-<levct·
oped. but no endoplasmic ret icu lum;s vis ible.
Relationships among Ihe Cell Typa.
l! is eslablished Ihat osteoblast. develop from OiSlto-
progen ilor a nd that rise 10 0iS-
leocytes. "There are con tfOV'Crsics. eonccr ....
iog Ihe origins of OiStoodaslS lnd the relationships
between lloose cells a nd the OiSlcOOlasU; ( Fi&- 11_7 ).
Normal boo: undergoes conlinoous remodelina in
",·hieh 'dOIption is coupled to aceret;o". Accordin,
to One concept. oucoc:)"Ics first panially
the ma trix and thereby render the ti$sue more vul-
nerable 10osteOClastie au ack. An OppOSing vie"'JlOint
is thaI endosteal osteoclasts initiale the re$OrpIion.
One hypolllcsis s ta tes Ihat OiSleoclasu lorm di·
rect ly from osleoprogenitOl" eells.and Ihat they later
moduLale to OiSteoblasts (201). Anot he r i, lhat_
oslcoprogcnilors are prcoslcoblaslS. ",lIerU$ OIhcrf
are pt'CQ$lcoclasts (75). A belief mote widely held
lhan dIller of the prcced ina is that blood.nd lissue
mono<:ytes serve as Ihe major OiSteoclast prec ursor
"" lis.
When o'S "" , issue is c.posed bricfty to Ui t;llcd thy.
midine. llIe .. di.,.ctivily be, ins 10 build up in OII«IClult
wilhin \ 2 hours .nd reach .. ma. im um lev.ls 01 Ioou ...
 ,
Osteoclasts , Ostoobl"l$
Mast cell.
liss.,.. aM
/
SIKfOIJO(Iing
tIIQo(I
o.le<>l>I.", do no1 have delOctabk 'mQ\In" until after J6
hours, and the radioacli.ily within them poal:< .1 120
hours. Tho findi.", arc oQn<istent with the $C4ucn<c: 0$-
le<>pfogcnilOf - ""<",,Ia.t - 001.001." (201). Ho"'t"'r.
the", Ire 1,,"'0 ah.fnale interpretations: (a) some "'''M-
progtnitor cell$ rapidly develop intO ",,<,«Iam. whilo
others '//7I>-/Y mature into osteoblast,. and (b) ""tc""lam
.Iready pre<en1 whon the thymidine i. pJC$tnlod take up
the label from ostooprogon;lOr ceUs. The possibi lity ,h.l
ct.lain of the ""tobla.l. modula'e 10 ha. a l",
b«n consid.red (198),
Other Ce ll Types Found In 80ne
Small numbers of mast cells migrate in from (he Sur-
rounding Since they contain hCp;lrio and
other regulators implicated in bone resorption, they
may play physiological roles. Sinusoidal epithelial
cells have also been suspected of releasing biol<>gi.
cally active m<>iecules that affect bone formation and
resorption.
BONE EXTRACELLULAR FLUID
Allhough il is ultimately derived from the bloo:l
plasma, bone ECF maintains a unique composition
Ihat may be essential for bone formation and r<:mod·
cling as well a$ for bone participation in overall mi ....
.ral homeostasis.
The K+ concentration varies wilh Ihc melabolic
activities and wilh honnonal Status. However. it can
be held al constant levels when dietary deprivalion
is of sufficient severity 10 lower Ihe plasma coneen·
Fig. 1 1·1. PropoMd
.mong trw. various ty,," of _ o.tl'.
lrations. For mature bone. 25 mM is average, but
values in excess of 100 mM ar<: found during times
of rapid skdemlgrowlh. (By contraSI. blood pbsm.
K' is doser to 4 m M.)
Ph""pitatc co"ox"tral;ons arc usually ,;",;10' ill
the IWO compartmenls, wherea' the calcium conoxn·
!ration in bone ECF is only around half that of the
blood. It tends to rise when the phoophatc c<mcentra·
tion increases_ Bone ECI' contains relalively mOt"<'
0- but less Mg" and Na ' than the blood plasma.
pi I seems 10 Ix only 0.1 unit lowcr (173), but thi,
may have physiological significance.
The exchange rtl(:chanisms not fully under-
stood. [t ba' Ixen proposed that the "bulk" ECF en-
ters the bonc moslly via extracdlular pathways,
whereas surface cells scerete Huids across their
plasma membranes.
BONE " GROUND SUBSTANCE"
Noncollagenous molecules make up around 1% of
the organic malter of bone. The ostcocalcin previ.
ously cited is the major prOlein in Ihis group. The
mixture also contains glycoproteins that arc taken
from the bloo:l and concentraled, glycosaminogly.
cans (the most abundant of which is chondroitin-4-
sulfate), and small quantities of phosphatid}'lserine
and of phosphatidylinosilol. Moot of the components
bind calcium. One suggestiOll is that such molecules
concentrale calcium for thc purpose of "presenting"
it 10 bone surfaces. On Ihe oth.r hand. il has bc<:n
observed Ihat the levels arc higher in oollagens Ihat
."
dQ not calcify than in bone. They fall in cartilage just
prior 1<.> the onset of calcification. Moreover. hor-
mones thaI accelerate bone resorption bring 300m
depolymerization of the glyoosaminoglycans. Such
findings are consistent with roles in inhibition of
mineralization.
1\ is likely Ihal each component will hn"" 10 be
studied individually 10 determine the relationships 10
hone functions.
CALCIFEROLS
Vitamin OJ (cholecalciferol) is a scoostcroid that Can
be 101ally synthesized from endogenou s prt<:u,sors or
obtained as such from the die! (68), The pathway
shown in Fig. 3·28 has been presented by several au-
thors. but it is now f<l«lgni7-OO that vitamin 0 and
ils mClabolilics are prescnt in solution as pairs of
equilibrating conformational forms (181 AJ. Vitamin
0, (ergocakifcrol) is produced arlinciall y from a
plam or fungal derivative. ergosterol (Fig. 3-30).
The term "itamin f) , has obsolete. since sub-
stances formerly so designated are now to
consist of mixtures of steroid radiation products.
Although SOme of the fishes Can make the vitamin
without benefit of sunlight. mammals require a
source of ultraviolet radiation. The photolytic reac·
tions were first studied in vitro (26.117). and they
were subsequently shown to procecd within the epi·
dermis (119.220).
Biosynthesis
Since it as the direct precursor of vitamin OJ
(OJ), 7...:1ehydrocholesterol (7-DC) is also called
provitamin D. It can be obtained directly from some
foods. or synthesized from acetyl-CoA. 11owcver.
much of it is formed from cholesterol. A cholesterol.
is abundant in the small intestine_
u,sser amounts arc present in the skin, but skin ac-
cumulates large quantities of the provitamin. The
conjugated double bonds are essential, since they
pennit the molecules to absorb radiation.
Ultraviolet radiation of suitable wavelengths
(295-300 nm) promotes conversion of substantial
quantities of 7_DC to previtamin 0 (prcchokcalci·
ferol). The lauer then undergoes a spontaneous.
heat...:lcpendcnt isomcri7.ation to D,. Natural sun·
light provides radiation of somewhat longer "'ave·
lengths as well. and it Can promote reversible i50m-
ui7.ation of the previtamin 10 or 10
tachyslerol (156) (Fig. 11·8).
CollCtUM, PHOSPHORUS AHD THE CA LCtFEROLS
Dietar!f Sources
Humans who live mostly indoors or in regions that
do oot rec<:ive adequate 501ar radiation require ex·
ogeoous vitamin. Since marine teleosls StOre large
quantities in their livers, the oils derived from those
orgalli arc among the best sources. (A single gram
of oil e'traCled from tuna or mackerel can supply
more than 1000 times the daily human require-
ment .) Bird embryos developing within arc
shielded from the sun. and they obta in the vitamin
from egg yolks, ",hich comain moderate amounts_
Nursing infants get the vitamin from milk . and dairy
produclScomain SOmC vitamin D. However. it is now
the custom to supplement Ihe milk taken by children
",ilh artificially derived D,.
Humans. rats. and mClSI other ulilizc 0 ,
a s well as DJ • and the mOre rapid degradation of Ihc
hormones derived from 0 , may le'!en the chances of
developing toxicities. Chickens a nd ""mc of the mon-
keys cannot the SUb'litution. probabl)' because
they rapidly degrade mOISt of the 0 , and much
of the remainder imo the bile (6?).
Vitamin Absorption and Trans port
When large doses 01 0 , or OJ arc adminIstered,
60%-90% enters the lacteals, becomes incorporated
inlO lipoprotein complexes of chylomicrons. and en-
ters the lymphatic vcs.scls (15.68) . The absorption
requires other lipid, in the intestinal lumen nnd bile
salts. It i. impaired when there is biliary oostruclion.
hepatic diseasc that alTeet, bile formation. or intes·
tinal dysfunction of the kind associated with celiac
discase Or sprut. Re<:cm studics with smallcr doses
indicate that substantial fractions enter the hepatic
portal bloooJ {and that _Iuch absorption is unalTected
by biliary obstruction (228). 2S-Hydrox),vitamin D
is more efficiently absorbed than the vitamin itself.
Small quantities of thc vitamin and the 2S..()H de-
rivative circulate in association with tran,calciferin.
an cr globulin. Yet smaller oneS combine with fatty
acids. but the sites of esterification arc not known.
Vitamin 0 half.life in the blood pla,ma is 19-25
hours ( I IO.lll).
DJ made in the skin travels along with the same
protciru;. and much of it enters the liver. When the
caleiferols are inj ected intravenously. the plasma
concentrations rise transiently. but much of the
.oid is taken up by skeletal muscles, bones. adipose
tissue. and other lipid. rich sites. Stored vitamin is
only slowly released into the bloodstream. and it tan
be found in the tissues long after the administration.
 /

I
'-
7· Dc hydroc!'<>leSlerOi

,
,
> •
<
"-
h d
'0 Y

I /

> 'A

Fig . 1 '-8. by irra<;liation of 7·

deeydtoclloleotOfOI ,

Transport Proteins humans ho," an add;!;"",,1 prOlein [h", bind,

wjth high affinity (0 only lho vila min •. Chicken, and
Speci., differe""", are ' "",m. MOSt mammal' h"c " .i· <orne ,,'hc r birds 'f...
id to have ooe protei n l ha. bind<
,.min D binding protein (DBP) lh.l wit h (he" iU'1 D, and a different One 1hat al<ooi .. ol ,,·ith bolh lho
globulin fraclion and bind, "'ilh high affinity to D,. D,. vi tamin and ito mClaboli,i.,.. Avian DDP. include (J glo\>.
25-01I-<.kifcrols, and ¢lho, mOI.bolites lh.l indudo 24, ulin, 3"d albumin-like moleculcl, Elcph"nlS and kille'
25·di.() H and 25. 26-d i-01I calciferolS (142. 182). In hu- ,,'hal.. arc among lhe m.mmall believcd to also u(ili7.<
m.n,. protein, identifIed "'llh im mu oological techniques albumin-like proleins (142). The DDPs of bony fi.hc, ife
• .,j the name "group-ipc<;ifi o protein'" (Gc pro- of lhe ,,_globulin type .... herea, tho« of cart ilaginou,
lein) .. om 10 be chemically idemical ,,';!h lhc ORPs . fi,h.,. and of am phibians are lipoproteins (182).
Thoy may <c"'. Olher fU",,1ions. A<_ding l<} <orne ob- TI>< concentration< in human blll<>Cl plasma ar<: in 11><

'"
ronge of 250-SOO ",/ml. They Ire eleV'I(d durin, preg_
,",..,y.nd follow;., the in,.,Lion 01 oral CQIItrluplivCl
(60). Ho pol;" production il ;nft •• ...::.d by Other steroid.,
and by ph.. macolo,i •• II,<nLl ,"", affcct prole;. melab-
oIism. Si"". lbe bindi., >ila I rc IlOl mot. lllan 2'l>-1 0%
oc<"pi«! by III 01 11K cII.i fef<)!$. i. has becft q>CCulaLed
,hal lilt pr«.illS perform lunclions un•• lllt<! to .itamin
D mCllboIism. N.;,IM:, .;''''';. 0 delici.ocrlX"' ,h. pr ....
cr><:e 01 e>.ce»ivc 1.",,1s of II>< cakil.roI•• rrea.,hc ..on-
cefI, ra,ioM oIlhe pl'Ol ci", (J.8),
The transport play roles in regulation of
the rales of transfer 01 cakifl'rols 10 IBrlei or",ns
and degradation si les (31). In birds. the)' abo «Nt-
tribule \0 tile ability \0 ,he: villm;. in
egg yolk. and in ma rn rnal$ll1cy may si mi)arl}' fac il-
itale tra MlI" oI lhl' v;lImin 10 mil k.
Metabolle DI.po.al
The liver avidly takes up 0 , from the bloodstream.
and;\ thereby pla)1 roles in rcaubl ion of [be plasma
concen1 ra lioos. (65%- 85% of II moderate dose of la-
beled vitamin can be delected in Iha t organ
afler injection into the bloodSI!l'am .) According 10
some observers, only the vilamin is taken up ( liS).
bUI others state Ih a t Ihe liver a lso <Xlncenlmtes me-
tabolites (137 ,220).
Mosl of the vitamin is eon vcrted to de-
rivative th at i$ subsequently used 10 make molecules
of high bi<)lQgica l polency. The palhways are de ·
$Cribed later. Small amounts are me taboliled in
OIhe. ways.
The li ver conjugate.! D, with glucuronic aeid and
sends the product into the bile. Some of tl!< conju-
gale is eliminaled wil h the fe<;e5, but an enterolle-
patic ci rc ulation pc rmilllbe body to redaim a frae-
tion of il (1J7). Sulfate conjugate.! appear in both
the bile and urine. and some D,su lfate can be found
in Ihe milk oI laClati ng u imlt\s. The i$ abo a
sile for ,idc-chain clava&< 01 Ql1ei fcrol metabolite.!.
Some of the deriva tives rNly have biolockal func-
tions. but Others a re d egndation products (220 ).
Vltaml" D Toaieity
Although the yitamin il5t"lf i$ said to be devoid of
bioIosical Ictiyity ( 181), long-term overdosage can
invole This OC<:urs be<:ausc I he usual mtth-
anisml; for li milill& lhe ra lCI 01 <;(Inversion to hor-
IIl(lfIq a re impai red a nd be<:ause ve ry high OJIIttn·
lrations of 2S-hydroxyllled ca lci ferol! can exert
pharmacolotliCII I actions. The 2S.() H· D may ae-
CQUnl fO\" lo. icity Iha t O<:CUrI in Pilliont! unable: to
synthC!!ilC 1.25·0 (122). Metabolic degradation
C,,-LC tUM , PHOSPHORuS "-HO THE C"-LCtfEROLS
ClInl"Klt keep pace with chronic ingestion of ve ry la rge
quant ities. Radioactively labeled 0 , has been de-
I«ted six months afler injeelion \If a single la rge
6c6c in u""ri"",ntal a nima l5. ar.d adipose tissue
concenlralions comparable 1\1 lhose of cod liver oil
have been found in a patienl IWI> )'eaJS a fter ccsu-
tion of ca lciferol therapy ( 236).
On Ihe other hand. toxicilY rarely OC<:uJS under
more natural amdillons. e.g. in li feguards and fa rm-
C"JS receiving intense and prolonged CJCpasure to sun-
light. ( Excessi,.. solar radia tion can. however. have
other delelcrious cffccts..) Protective facton include
lhe following. (a) The q uantities of pre-O, formed in
the .Jr.in a!l' limiled by the a vaila bility of the 7-OC
precurwrs. (b) f'rc.D, to D, <;(Inversion plo<:«ds
dowly. Somc prcvila min can be S1orc<l ( 119). and
unall a mou ntS are isomcri7.ed 10 Other steroids. (e)
Ahhougb Ihere are debates oonccming Ihc magni·
tudes of the effects. it is cccTtain that suntanning re-
duces uhravioici rar penetration into the skin. (d)
Blood and lissue rcservcsof D, that are built up dur-
ing the summer months are dcpleled during the win·
ter. (11 has been estimated that hea lthy human
ad ult. require 10 Or 400 IU of 0 , da il y. a nd Ihat
the blcod concccnt rations can vary between 80 a nd 450
;og [105]). (c) The first slep in metabolic act ivation
of the vitamin )'ields a product of low potency that
can be stored in substa ntial '1ua ntitie •. The ratC at
which il i. formed declines as the stores build up. In
higher an ima l,. every cdl type except the eryth ro-
cyle <cems to be capable of binding some of the me·
tabolile, and both normal bone slructure and min-
e",1 homeostasis Can be ma inlainci as the pla!mIt
concentrations of tbe metabolite vary over a 6-1().
fold range . Lifeguards do not seem 10 suffer ill of·
fe<;lS when lhe concenlrations rise to SO IliJml d uro
ina the summer months. whik adults Ii"''''
in winter do not develop dcfociency symptoms if the
illdoors
concentrations a re ItS low as 8-10 na/ml. (f) The:
rate of OOIlvc",ion of lhe intermed iale 10 lhe bioIog.
ically potent produCl$ is rigidly reguilled by lhe sec-
ondary e ffects of the mctabolitf:1;. (Toxiciy develops
rapidl)' if large: doses of the acti"" hormone are in-
jected). (g) The ratc!! or calc iferol dclll'dalion and
excretion accelera te .. hen Ihe raises the
blood concentrations, and (b) ch ronically ele-
vated hormone levels invoke limiled tarsel 0(:11
resistan<.:e.
The: consequences of e x"""urc 10 >OIar radiation
$how some interesting species variations. Heavily
furred anima ls and 0"'" Ihal buTTQW during the day-
liSht hours do not readily develop dcfic icn<.:ie$, de-
spite faCtlhal some continue t\l grow throughout
m<l'lt of aduhhood. 11 is \\"ell known that rats given
rachitogenic diets acquire ""vere deficiencies only
when they are maintained in darkne)S.
TOXICITY SYMPTOMS
Since vitamin 0 mctabolities accelerate inteslinal
absorption of ca ldum and of phosphorus. and since
high levels can also markedly increase thc ratcs of
transfer of the minerals from bone to blood.
is associated with the development of hypercalcemia
and hyperphosphatemia,
Some of the problems that r",ult from hypercal-
cemia have been Ciled. Im pairment of neuromuscu-
lar and cerebral functions accounts for the serum-
tions of weakne)S. lassitude. and fatiguc. and for
headache. irritabilily. shorl a((enlion and loss
of memory_ ( In eXlreme cases. individuals experi-
enCe hallucinations and delusions. and thcy may dis-
play aberrant behavior.) Excessi"e stimulalion of Ihe
smoolh muscle of Ihe gasiroinleslinal tract invokes
nausea, aoorexia. and sometimes vomiting. along
with either diarrhea or C<lnstipation, The effects on
cardiac muscle result in elevalion of the systolic
blood pre)Sure. Interference with actions of antidi_
uretic hormone leads to polyuria. nocturia . dehydra_
tion, and elevation of Ihe body lemperaturc.
Most of Ihe preceding effects can be rapidly re-
''<'rscd by appropriate treatment. However, the
chronic ekvation of plasrna calcium and phosphate
concentrations also prorrKlles deposilion of calcium
sahs in sofllissucs (melaslalic calcificalion). and the
damage inflicted is permanent. The kidneys arc the
SileS m(lSl commonly affected. The calcium salts
usually appear firsl in Ihe ascending Henle loops. As
nephrocalcinosis progresses. other parIS of Ihe organ
are involved and sovere necrosis can follow. Accu·
mulalions of calcium deposits in the walls of the ar-
terioles result ;n sliffening of Ihe vessels and there-
fore loss of abilily 10 contraCI and dilatc in response
10 changing needs. When the aorla is affected. il IJe.
comes inciaslic. Since il cann(lt "gi.'e" during sys-
101e, the internal pressure rises excossively , Eventu-
ally, the walls becomed thinned and aneurysms
devdop, In exlremc cases. Ihey ruplure. Calcium
salts are also dejXISited into the myocardium and
into the smooth musde of the gastroi ntostinaltracl.
When hypervitaminosis D C<lntinuos for prolongcd
periods, the saits sometimes accumulate in the skin,
Ibe lungs, and the brain.
The influences on bone are variable, and they de-
pend to SOme extent On the calcium intake. In addi·
lion 10 the demineralizing effecls of toxic levels of
1.25-<1i.oH-0). the depression of paralhyroid hor-
mOne secretion impairs renewal of bone cell popu-
lations. The hyperphosphatemia invokes aboormal
mi neralization and in some cases osleopetrosis.
ACCIDENTAL P01SONING
Poisoning in humans usually results from faulty
judgments concerning the requirements for exoge-
nous vi tamin O. It has occurred in adults unaw'arc
of thc dangers of regularly ingesting high potency
pills supplying 50-200 times the required dosagc_
Parents familiar with lower·potency fish oil. have in_
advertently poisoned Iheir infants by fccding spoon·
fuls of concentrate. designed for adminislralion by
the drop. Overdosages of the vitamin and ils syn-
thetic analogs have been prescribed for patients with
parathyroid hormone deficicnc)' when plasma cal-
cium levds did not riso as promptly as cxpeclcd fol-
lowing ingestion of smallcr amounts. There was a
Hrne when patients wilh certain forms of arthrili.
were given grossly pharmacological dosages. Fonu.
nately, this practicc has been discontinued.
The leaves of So/l1t1"'" gIJ'Cophyll"", (malacoxy-
Ion), of Cis/,um diwtl(l"'. and of Trisleum j/(lvis-
emS contain biologically potenl glycoside,; I)f 1,25-0,
and of Ia-OH-O, (which can be rapidly 2S·hydrox-
ylatcd) (68). The roles of the steroids in Ihe plants
are not known, Cattle gra,,ing on them have devel-
oped hypervitami!lO'lis D (110.258), in some ca<es
with fatal consequences. The plant products fond
some use in the treatment of human disease. but il
is nc=ry to exert caution in judging the dosages.
Vltarnln D DeficIency
Children deprived of both adequate cxposu", to sun-
light and dietary vitamin 0 supplemcnts develop
rickelS. The)' canOOI absorb enough calcium and
phosphorus to support normal bone rnincrali'.ation .
Since skeletal structures lack the usual rigidity and
resistance to pre.sure, C<lmmon findings arc bowing
of the legs and malformalions of the Ihoracic cage
and pelvis_
Congenital rickets is a more severe form of the
disorder Iha t arises in children born to vitamin D-
defIcient mOlhers. When vitamin deprivation comin-
UC$ throughout infancy, additional features can in-
clude widening of the cranial sutures, posterior nat-
tening of thc skull, bulging of the costochondral
junctions, and enlargement of the wrists. Dental
eruption is delayed and the tccth are defective. Usu-
ally, therc is skeletal muscle "'<'akness as well (15).
Osteomalacia is the adult counterpart. Whcn the
vitamin deficiency is imposed after the growth pe-
riod, bone deformities are less common and less ob-
vious, However, the victims suffer bonc pain, in-
creased lendencies to develop fractures. and musele
weakness.
Parathyroid hormone sec"'tion is usually aug-
mented. It provides some prote<:tion against the de-

velopment of hypocalcemia, but it exacerbates the
bone problems.
CONVERSION OF C. TO 2S·0H·C.
Most of the cholecalciferol 25-hydroxylase is found
in the liver. Animals subjected 10 ligalion of Ihe he-
palic arteries Qr to hepatectomy do not convert sig·
nificant quantities of 0 , to 2S.QH-D,. Low levels of
enzyme activity have !xcn found in the kidney, small
intestine, and ds<:whc""
The reactions utili,.e molecular oxygcn and they
requi", NAOPH. Although most aUlhors state that
the enzyme is associated with the endoplasmic "'lic·
ulum (220), others have identified activity in mite>-
ehondrial fractions. The hepatic cn'.yme can accept
alternate substrates that include 0,. I",·OH_O,. and
SOme vitamin analogs.
Regulation of 2S·Hydroxyla8a Activity
It is generally agrecd that physiological factors
some controb over the activity of the enzyme (liS).
However, there arc CQnlroversics concerning the
mechanisms involved and Ihe efTeClivcncs.. of the
regulation (89).
THE CONCEPT OF NEGATtVE F EEDBACK
INHIBITION
II has been suggested that high con""ntrations of 2S-
OH·O) within the liver exorl direct product inhibi·
tion over activity of the enzyme. and that such con·
Irol provides substantial protection against vitamin
D toxicilY.
The rollowing observations support the CQncep"
(a) Healthy subjects tolerate long-term ingcslion of
four to five times the daily dose of the vitamin
needed to support physiological (b) vita·
min !)..deficient individual. form 2S.QH· O, mOre
rapidly than ones in good nutritional balance when
a mooeratOHized dose of the vitamin is adminis-
tered; (c) when the dosages are va ried over a 25-fold
range. an wen·nourished subjects "how similar aCult
ineremenls in plasma 25-011·0,; and (d ) when ani·
mals are pretreated with D" livers subsequcntly ex·
cised and stud ied in vitro only slowly convert added
vitamin 0 to 25.QH-O,.
It has been stated that only the hepatic levels of
25.QH·O, are involved in the controls . No efTeclSof
varying plasma 2S.QH-D J on the enzyme activity
have been found.
If the oontrols do operme as suggested. Ihey pro-
vide prote<:tion only under certain conditions.
Chronic vitamin overdosage leads to the accumula-
tion of quantities of 2S.QH · D" po:ssibly
CALCIUM. PHOSPHORUS AND THE CALCtFEROLS
because the vitamin Serves as a substrate for "non-
specific" enzymes that include hepatic cholesterol_
25-hydroxylase.
PROBLEMS WITH THE CONCEPT
Under in vivo CQnditions. the liver may never aCCu-
mulate sufficient 2S.QH·O, to exert negative foed·
back CQnlrOr. Usually. the metabolite is promptly re-
leased into the bloodstream (89). Morcover. in vivo
regulation may involve substrate rather than prod-
uct. It was found in one study that mts pretreated
with vitamin 0 had low rates of 25·hydroxylation
when the livers were excised and studied in vitro. In
CQntrast. those given 2S.QH-D, failed to show the
depression. In another study, a I S·fold of the
2S-hydroxylalcd metabolite only slightly aflccted
the activity of the en'.y me in chickens (89).
According to some observers. vitamin 0 is usually
in short supply. and Ihe 2S·hydroxylase enr.yme
functions at a high but constanl rate as substrate
concentralions are varied o,.. r a limited range. If too
much 0 , is p",sented to the liver. either the vitamin
itself or a protein related to it exerts supprcs.'ive in_
fluences (po:ssibly by slTecting af-
finities). The influences of substrate concentrations
on en?yme activity are much more obvious when the
livers arc taken from [).deficient Ihan rrom vitamin
replete animals (89.117).
The failure to achieve acute. stecp elevations of
the plasma 25.QH ·O, following administration of
large doses of the vitamin to ",pletc subjec1s could
be related to the binding of 0 ) to proteins that would
otherwise facilitate transport of the 2S-hydroxylated
metabolite from the liver to the bloodst",am.
Extrahepatic tissues probably CQntributc to regu'
lation of the plasma 2S.QH. D,. When a mooerate
amount of D) is taken orally, the vitamin i$ delivered
\0 the liver at a controlled rate. The plasma 2S.QH·
0 ) levci, rise transiently. but many dilTcrent cell
types then ta ke up the metabolite and <tore it . If the
vitamin is injected into a vein. the rise in plasma 25-
OH·O) is delayed bUi sustained. This is altributed
to rapid uptake of the vitamin by extrahepatic cells
and subsequent slow release of it to the liver.
The plasma halr·life of 25·0H-D, is I S-30 days
under normal conditions (89). The presence of polar
groups at both ends of the molecule is believed to
aeCQunt for mOre rapid bindins to cell proteill$ than
is the cas<: for the vitamin,
Seasonal Variations In Plasma 2S-oH-O,
The plasma C<lnc<:mrations for individuals liv ing in
temperate zones arC highest during the summer and
 autumn and loweSt during winter and
spring. In humans. the high and low ranges are 25-
50 ng/ ml and 9-16 ng/ml, respectively (60,166,
IS 7.261). The seasonal variations have been dirc<:tly
oorrelated with the number of hours of daylight
(239). However, because of local differences in pat-
terns of exposure to sunlight and in use of food sup-
plements. si x·fold variations have been enoountered
in studies comparing subjects in one geographical 10-
calc with those in another (235). There are also
striking differencc5 among individuals within each
group. Evidently. levels of more than 80 ng/ ml dur-
ing the summer and of less than 6 nglml in th. win-
ter do not in'·oke abnormal symptoms. Values re-
corded for populations in which the incidences of
rickets and ootoomalacia are high ate closer to 3-4
ng/ml. Adults chronically overdosed Can have mOre
than 1000 ng/ml.
It has been s tated that the seaSQllal variations
have lillie innuenee on physiological functions. since
2S-QIi·D) has low biological potency and the re-
serves built up at onc time are Ulilized 3t another.
On the Olher hand. the changes may be dirc<:tly
linked ,,·ith certain drcumannual rhythms. Some
species undergo reproductive system involution dur-
ing thc winter. and others produce smaller litters
with lower birth wcights and slower growth. Rats
maintaincd in temperature-<:Qntrolled laboratorie.
but exposed to natural photoperiod changes cxCrete
smaller percentages or dietary sodium. potassium.
and chloride during the winter months (161). as they
retain less calcium. The excretion pallcrns can be
markedly altered by administering vitamin D. and
the responses differ in summer compared with win-
ter (13) .
Seasonal variations in calciferol functions that
favor mOre rapid bone growth during th. spri ng and
summer could be advantageous to animals that de-
pend (directly or indirectly) on plants for food. Veg-
etation becomes more plentiful in mOSt locales dur-
ing the warmer The climate permits
existence outside protected burrows for longer time
periods. and less cnergy is expended for maintaining
body temperature.
Although 25-QII.D, binds with high affinity to
cellubr proteins and Can thereby be ooncentrated in
many tissuos. it evidently docs oot form oompll:.1lcs
that are translocated 10 the nuclei of calciferol hor-
mOne target cells.
METABOLISM OF 25-oH-V1TAMIN D.
The kidneys contain a 25·01 1..::holecalciferol I".hy_
droxylase that catalyzes the conversion of 2S-QH_D,
to 1.25-dihydroxy vitamin D, (1.25-0). The reaction
is controlled by parathyroid hormone, hy phosphate
and calcium level s. and by several other regulators.
S ince the product (also known as calcitriol) is a
highly potent hormone that acts on intestine, bone.
kidney, and other targets. it has been widely and in.
tensively studied. A growing body of new evidence
raises the possibility that other potent physiological
regulators arc derived from 2S-QH·D) (lSI A. A·I).
1,2S· D is effective in picornolar concentratiom.
$ome of its actions involve hinding to a cytosolic re·
ceptor. translOCation of the hormone-reccptor oom-
plex to the and subsequent acceleration of
RNA synthesis. In oommon with glucocorticoids,
mineralocorticoids, androgens, and 1,2S·
D is more polar than its biologically less active pre-
cursors. The increased polarity augmcnts the affini-
ties and specificiticsof binding to the rc<:eptors (89).
The calciferol may additionally have special prop-
erties not shared with other steroid hormones be·
cause ftexibility is oonferred on the molecules by
opening of the Bring (178,182).
Only minute of 1.25-D are made hy
well_fed individuals. The plasma levels are then in
the range of 20--4S pgfml (X_ to those of 25-
OH · D,). They can several fold ,,·hen the diet is
calcium-d.r,cient but contains adequate vitamin D.
The hormone binds 10 plasma proteins. and those
proteins are believed to play roles in regulation of thc
rates of 1.2S·D uptake by the target cells (31). Since
the half-life in the blood plasma is only around 5-14
hours. it is likely that small quantities are madc
either continuousty or at short. resutarty rc<:urring
intervals.
The proximal convoluted tubules of the kidney
contain most of the enzyme (118). but SOme is pres-
ent in the glomeruli of at least certain species (191).
All of the known symptoms of vitamin D deficiency
develop in subjects Ihat havc been nephrectomized
or have renal damage that involves cells making the
cnzyme. even when large amounts of D or 2S-OH-D
are gi,·en. The deficiency cffocts can be oorrected
with exogcnous 1,2S-D. Some la·hydroxylase is
present in placenta and in embryonic bone. The
quantities in adult bone arc too low to support min·
eral
The hormone is directly secreted into the bile. and
much of it is lost via the fcces. Although recovery
via the enterohepatic circulation is limitcd. it has
been susgested that enough returns \0 excrt some
negative feedback control over the 2S·hydroxylase
(ISA). Small quantities of 1.2S-0 also appear in the
uTlne.
In calcium· and vitamin D-repletc subjects. much
larger amounts of 2S.QH-D arc acted on by 24·hy-
dro. ylascs that promote the formation of 24R.25-di·
hydroxy vitamin 0 (19 1). The plasma levels of that
metabolite are typically 100 times those of the 1.25-
O. They vary with vitamin D intake and they show
seasonal changes in individuals exposed to more nat_
". CALCIUM, PHOSPHORUS AND THE" CALCIFEROl S

ural sunlight during tlle summer months. Both 1,25_
D and 24.25-0 can Ix converted in the kidney 10
1,24,25-tribydroxyv;lamin D. The laueT has some
biological activity of the kinds shown by 1.25-0. but
it is less polent. 24·H ydroxylascs OUlSide Ihc kidney
may perform spc<:ial functions_ The inlC!)\inal cn-
1,ymc seems \0 provide limited protection against ov-
cractivityof 1.25-D by catalyzing its conversion \0
the 1.24,25 metabolite. Some observers believe Ihal
24.25-dh)'droxyvilamin D plays special rolC!i in skel-
etal structure growth. and a 24-hydroxylase has
been identified in cartilage.
The liver is a major site for disposal of 25-OH-D
as well as 1.25-0. Substantial quantities arc directly
senl into the bile for excretion via the gastroiotes-
tinallracl. Only small amounts are rcwvered by lbe
enterohepatic circuit (94). Calciferols arc also con-
jugated in the liver. or converte<! to other metabolites
that may be degradation products.
Some 25-OH·D is made into vi-
tamin D in the kidney. The derivative possesses bi-
ological activity. but its functions have not been de-
fined. It was formerly believed that the 25.26
derivative is an interntediate in the pathway for for-

25.26·di·OH·O,

25·0H-D,

,/
, » /

! ,);
-----
"
•
'"
, 000<
\ .24.25·tn·OH -O,
, '" 25-0H·O, ·26.23·ladone

I
c'
• .
'"
Fill_ I 109 M"'aboiic de<iva,;vH 01 , '!em;" D., " oter''''.
mdica!. s" ""lures Shown in F;g_ 3-3 t_
malion of a major vilamin m<.:lIboiile. 23.()H-0,.
26,2J-.bclont (67). bul il is now known Ihal Ihe lao-
10IlC is formc:d much more I'lIpidly from 2l.25-dihy-
dl'Olly vilamin 0 (248). Allhou&h 11(1 .ctions of lhe
IaclOfIC as yel been do:scribed. tM possibilily
Ihal il performs some special funclions has not been
ruled out.
Calcilroic acid is a watcr-wluble deriva tive of vi·
0 pl'<'5Cm in both liver and intCSline (220). It
is the main biliary cxcl'<'lion product derived from
1.2300. On Ihe OIher hand. it may also be Ihe poi-
lulalei! metabolile that ronlribules to regliialion or
inlC$till/l l absorption of calo;ium. Yet anolMr melab-
oIite. eholccalcioieacid. arises in 1M kidncy (Fig. I I·
9). Many addilioNl m<.:taboliles ha...: rttCnlly been
idcntined (18IA). These inch.&: 24-o:to-2WH·D,
and (l30A).
RENAL 25-OH-O, 1a-HYOROX'tLA$E
TlIc rate of formalion of 1.23oD from 25'()H· O, in
well·nourished human adults is wimatcd al 0.3-
1.0-1<8 per day. It can vary widely in re$JIOnsc to di-
etary manipulations .nd .bo undcr palhological
o;ond'tionJ.
Thc 2WH-D, la-hydl'Ollylase stTOngly resembles
enzymes of Ihe adl'<'nal corte1 involved in the bio-
S)'nlhesis of glucocorticoids and mincmlocoliooids It
is a mixed function Ihal r<:qllir<:s mole<:ular
O);ygcn. Mg", an protein s;m-
ilar 10 .drC!IOCOflical I reductase: Ihal is
probably a flavoprotein. and B CYlochrome P-4.50.
The S)'$lem binds inhibilOf'$ discussed in Chapter 6
Illat incl ude aminoglulethimide and metyrapone
(I 5).
R. gul.llon by Calcium
It is possible 10 ada pt 10 diets that differ widely in
calcium conlcnl by making compensalory adjust·
ments of the la-hydroxylase activity. Usually. the
o;irculatinl 1.2300 vary invef$Cly with tile cal-
o;ium supply. Hllmans slIbj«te4 10 condilions in
which lile plasma Ca" is Io..-.:I'<:d by )<J,-5'1.
been I'<'JIOn e4 10 illCfUSC Ihe hormone up 10
(3). Animals mainllline4 on D-deficient diets
or wbj«te4 to r<:nal injury become hypocaJ«:mi<.:
when they are g;ven ordinary food. If they r<:ceiV<'
constanl dosagcs of 1.23oD. Iheir blood
calcium levels vary directly with the mineral content
of the food.
The role in calcium fOIISCrvlI'1on has been
liko"e<!'o Ibe role or in lOdium COIIK ...... ';o"
(19): (.) JuSl as lnimlls deprived or ,lie mi"" ....1ocnoti-
coid can 011"";"" wben pven ""'Y I..... qllanti,ia oJ di_
ctary sodium, p.,,,iously bealtby ora can .urvive for a
time without ealdkrols if tbey.re .i •• " food e>lremely
11 _10 . In
' . . ..", 01 ,.,. 01 1.25-di-OH-D, prOduCtion. - . _ ....
ot t I _ I ..... _. 0.0-.... ot 1tIIIi_.
rich in calcium.nd mode .... l. in phofpl>orul conI.'" (ll
(""....,.cr. ,n both O«!inll')' di<t •• ..., likely 10 i_vote
m;neral!»la..,. problem.): (b) >Om. timited adjustm.n"
in miner.1 metaboi i,m can be made w;lhouI Ih. hor·
mone.: and (c) wh.n Ibe hormone i. provided.
I","" <14P>< ber.... " adju.'''''''' 1,.;"""", """"al i,..,!.
bola led perfuscd kidneys taken from calcium-dc-
animals produce lalge quanlities of
1.25_0 (210). and high lo-hydtolCylase activily can
be: demonstrated for kidneys studied in vitro.
When such olll ""Ilons ""'''' initia lly made. tltere
wer<: SUIIC!itions lhal the rontrots involved simplc.
direct interactions (sec Fig. 11-10). 11 has sin« be-
come obvious Ihal this is not the ease.
Sma ll quanti lies of Ca" ar<: cSSe nl ial fer epera·
tion of the enzyme. If mitochondria al'<' uwrdy de-
picted of the ions (e.g. by te calcium-dc-
plclcd media containing ehelatins 1gents). there if a
limited range over ...-hkh small inen:ments in l
- e.
roncc:nlrations elkit .ugmenlation of lhe
Ia-hydroxyasc: activity (Ftg. II-II). Parathyroidcc-
lomized uimalf show sever<:ly blunted re$ponSCl; 10
dietary calcium deprivat icn. and their kidneys hmve
low la·hydroxylase
On the other hand. animals totally deprived of
PTH do make limi/til adjustment! te their diets
(1$3) that ineludc some increases in 1,2.5-0 levels
wilen tile food is calcium poor. It is JXlUibic thaI
PTH deficiency inY<lkes mechanisms thaI
do not IInder normal condilions. Some direct
stimulatory effects of hypocalccmi. on tile la-hy-
droxylase have been docribed in parathyroidcclo-
mi7.cd humans (134).
."
Cai<:ium· Secret"'" 01
oef.,ient • • more par.thyroi<;l
, 2S·QH·D,
,
hormone
,,
,,,
j ,,,
,,,
, .2S-(I;.()H· Q,
calCium
I rate 01
,,,
,
,,
from s,,,"11 "'""Ii"",,I
,,,
) ,
No<mocalcem<a
Infl uences 0' l norgarde Ph osph ate
Co ncentratlons
AhlKlugh quantitative differences reb led 10 age "nd
sex have boen demonstrated for tenain species
(IOI), severe restriction of dietary phosphorus ulti·
lJ;et aty P _ __ ._ Hypophospllalomia _ _
,",ric'K>n
In inIaC! animal. (including humans), blood cal-
cium levels usually riS". This has been allribUled to
,he inAuenC<'sexerlcd by Ihe 1.25·0 on intestinal aD-
sorpt ion of Ihe calcium (102). However. low phos·
phate levels Can act in other ways. Thcy lead to more
effect ive concentration of both endogenous and CA·
ogcllQus 1.25-D by intestinal cells. and therefore to
sharpening of the sensitivity to the hormone (60).
Thcy also facili tate calcium absorption when the
1,25-0 leves do IlQt risco Moreove r. since thcy impair
bone mineralization, more calcium is made availablc
to the extracellular fluids (Fig 11·12).
The possibility that PTI-! acts via changes in ex_
tracellular phosphale to increase la.hydroxylase ac-
tivity has been considered for two reasons: The hor-
ITKIne inhibits renal tubular reabsortion of phosphate
and it thereby lowers blood phosphate levels. It also
sccms to bring about localized depression of pb06-
phalc conC<'ntration. in the vicinity of kidney ccll.
thaI have thc en7.yme (153).
On the OIher hand, hypophosphatemic influences
CALC IUM , PHOSPHORUS AND TH E CAlCIFERO!.S
Bone, Kklney, ere.
f ig. 1 1· 1 1 .
"""'i,'ion of
Par.thytOid _
oJ C.' · on l,2S-(I;·
OH·D, production .
malely inVQkcs hypopllQSphatcmia and secondary el·
evation of the circulating 1.25·0. Since the 1,25·0
promotes intcslinal absorption of phosphate as well
as of calcium. it is easy to visualize a negalive fced·
bacK relationship similar to (he one for cal.
cium in fig. 11·10.
locreaoe<l
c.. absorption
<._ """
,,,.hydoxylase
\ "",ivi!)' \.
" .... '''''' .... o<l.
_
-------------- - - - - P absorplOO<'l
on 1,25-D levels arc dearly IlQt depe ndent on stim-
ulation of PTH secretion. The change. in calciferol
b·els in the blood and the secondary clevation of
plasma Ca" can be invoked by phosphate depletion
in parathyroidectomized a nimals. (Hypercalcemia
inhibit' PTH scerelion, and PTH levels arc gener-
ally subnormal in hypopllospha lemic stales.) It is
also worth IlQting thaI high PTH wou ld be un-
desirable when the food is phosphate [l'OOr, Since
the oormonc tends 10 further deplete body
pho<phate
The concept of direct negative feedback control of
la-hydroxylase by extracellular phosphate is incon-
sistent with numerou s observations. In studies in
which other factors were maintained at constant lev-
els. no inverse relationships between plasma
HPO;- and plasma 1.25-D leyels were found. More·
over. ,'cO)· high concentralions of illQrganic pb06-
phate do nol depress U5·D synthesis (229). They
may fail to do so for secondary rcasons. High phos-
phate levels in Ihc blood lend to lower plasma Cal .

,,,' bone
,,-
--- ,
"
" - - ,
.. 0"",,- at II.,..",
--
oIl .2M) syrn/"IrItit
- - - - - _____
Fig. 11· 12. Poaiblo inlu . ·
_ . . . . , 111" I.........
_IKIM:In.
becau.sc (a) they intestinal absorption of cal.
dum: ( b) ;hey facilitate ptWipitation of ca lcium
in bone: (c) they flei.iwte mitochondrial S1e-
qu(:Stration of calcium: (d) by P!"()ll1()l5ina the for·
mation of un·ioniud calcium·phosphate
they lower the fraction of 10tai circula ting calcium
that is present rts free calcium ion: and (c) they seem
to I _n the Knsitivity of intC$1inal mUCC!5a1 cells to
1,25- D. lbe resultin, hypocal«mia can thcn over.
ride any in hibitory ctfe<:1$ of phosphate on thc la-
hydroxylase.
Direct stud ies 01" the dfects or Va!)'ina ex traccl.
lular phosphate on cll7.)me sy$tcms in vitro 8r<: dif.
fieull to conduct because of the presence or
o..bind.
irlJ! proteins that inhibit t he activi ty The
e nzyme canPlOl runction when thc extracellular
Auids <;QfIta in no phosphate. probably because ptJos..
pilate atf«ts thc flow of protons and elecu'oos and
the mitochondrial uptake or calcium. Thcr<: is II.
ran,e over whi.:h small incremenlS in phosphate
inVOke dose· rela ted augmema tion of In-hyd roxy-
lase activi ty. ' IOVo·cver. lhe effe<:u of the additioru
depend hea vily On the availa bil ity of both Cal '
and H -.
It was noted that a nima" give n unva!)',n, dosages
of exogenous 1.25·0 lose the ir ability to adjust to
changes in dietary calcium. Thcy retain thei r ability
to adapt to cl\allga in the phosphate contcnt of the
rood.
"anSI&< 01 ea""",, all(l phospll.ate " ' ,
r _____ __ ___ _
--
01 pI>osphIr .. Cllj:1 " "", ""
"""'1>' .. ;' ._ .r. 0..:........
EFFECTS OF METABOLIC ACIDOSIS
lo,,"Cring of the plasma pi .. leads to aUlmentation
or the pla$l1la calcium that i.
as Ca1+. In ra t.. acidosis im pairs conversion of 25-
OH·O, to 1.25_0. and it a l$Q seems to invoke some
target organ to 1.25· 0 (1 43). It may ad.
ditionally 1.25-0 clearance ( II) . A l-
though related ctfecu in humalJ!i have been ques-
tiorled (1)1). child!"Cn ,"ith renal tuhlar acidosis
develop rickets a nd show growth retardation that ;s
effecti vely tr<:ated by alkalinization ( Ill).
Parathy.old Ho.moll, A'gu latlon olth,
A,nal l ..-Hydrollylaa,
There secms to be uni"rsal agreement that PTH is
the major regulalor (60.39). Pluma 1.25-0 is ele-
vated by hype. porath)·roidism even when ther<: is
concurrent hypercalcemia . The 1.25· 0 falls arter
para thyroidectomy despite the hypocalcem ia. AI.
though parathyroidectomized ( PX) an imals can
s(pmc,"hat accelerate 1.2j·[) synthesis .... hen they ar<:
fcd calcium.poor diets. they cannel mailltain 1IOf".
mocalcemia. in pan because of tbe deprt"$SCd 1,25-
o level s.
I'isbes and do not p< 'I ,. I'lrathyl"Oid
,lands.. ar>d I",")·.", .. id '0 IKk l .... h)'TO'ylue acti.ily
(89) (ol'hough lhe)' sy"'hcf.i", ClrlciferOll). Neil"", ,.;.

'"
tam;n D <lOr its 25_h}'d'{lxylatcd deri>a!;' .... ms to ole·
,.,.th. plasma Ca " in the .. animals (186)_
RELATIONSHIPS TO CAMP
At least some of the effects of PTH are rne<;liated via
cAMP. The hormone activates adenylate cydase in
par(l; {If the kidney, and both the nucleotide and its
analogs accelerate 1,25·D production in Ibe absence
of PTH. More<lvcr. cydic nucleotide phosphodiester-
ase inhibitors synergi7.e wilh low levol. of PTH. It
has been proposed that a cAMP-dcpcndem protein
kinase calalY7'<=s phosphorylation of the cytochrome
1'-450 (89). [nnucnees on the mitochondria may be
similar to those described fOT ACTH and LH On the
adrenal cortex and gonads. respectively (89). In both
cases, there seems to be a need for formalion of a
labile protein whose synthesis is dire<:led by a slable
mRNA. (However. unlike observations made for tho
pituitary hormones. acute effects of cAMP are not
blocked by cycloheximide. and some acceleralion of
1.25-D synthesis can be oblained without the
prolein.)
cAMP is to ..erl numerous influences on
Iranscriplion and tranSlalion (209). The possibility
Ihat il indu= the renal enzyme is consislent wilh
Ihe of high plasma 1,25·D in Ihe pres-
enCC of hyperparathyroidism and hypercalcemia.
and with the 14-48 hours animals with parathryoid
glands require to fully adapl 10 calcium·poor diets ,
A renal 24-hydroxylase competes wilh Ihe la-hy-
droxylase for the 25-OH·D substrale. cAMP may
decrease Ihc activity of Ihe 24-hydroxylase, since
PTH is known to do Ihis.
PTH can also exert indirect effects. High levels
invoke metabolic acidosis (199), since Ihey inhibil
hydrogen exc retion as well as sodium and bicarbon-
ate reabsorption. PTH also the cytosol Ca"
in many cell types. and it can in that way alfect pr<>-
tein synthesis.
The effects of PTH and of parathyroidectomy on
I",·hydroxylase and on 24·hydroxylase are easily
demonmated in young rats. Oldcr ones retain the
24-hydroxylase responses. but they become refrae-
tory to those on the I·hydroxylase even when cAMP
generatiQII is accomplished (12).
CalCitonIn Regulaton of 1<>-Hydroxylase
Activity
Although calcitonin (C11 activates some renal ade-
nylale cyclases, there al'<' controversies concerning
possible roles in regulation of the hydroxylase. Ex-
ogenous hormone can correct hypen:alcemia, but
reasonable amounts do not invoke hypocalcemia in
healthy animals. CT is released following the admin·
CALCIUM, PHOSPHORUS AND THE CAlCIFEROlS
iwation of a large dose of OJ (87). and it provides
limited prolection against thc development of vita_
min D le)xicity (20.87). It is also secretcd when cal·
cium-depeleled animals ingest calcium-rich food.
Under physiological conditions. the blood levels risc
shortly before meals. and its major function at thai
time seems te) be postprandial conservation of the
mineral (244). CT also alfects appetite. phoophate
metabolism. and the functions of certain bone cells,
Some observers believe that it simultaneously accel.
erates production of 1.25-D and protects against the
bone-resorbing elfects of thc stcroid during the
natal period (221).
large doses can elevate plasma 1.25-0 in intact.
but not in PK animals (151). The effeels of pre-
.. nting CT to kidney pl'<'parations are inconsistent.
Effects of 1,25-0 on Ita own Biosynthesis
High levels of extracellular 1,25·D depress I",·hy.
droxylase activity bolh in vivo and in vitro. The en·
1.ymc activity is greater in animals that are D defi-
cient and hypocalcemic than in OTICS with similar
calcium levels that are oot deficient in the vitamin.
Thc kidney possesses high-affinity receptors for 1.25·
D. and translocation of the hormone·receptor com-
plex to the nucleus is foHowed by accelerated syn·
thesis of some mRNi\s. Influences on thc la-hy-
droxylase activity can be blocked with transcription
inhibitors (3).
All of the preceding observations suggest that
I ,25-D panicipates in negative fcedback control over
its own synthesis in a manner reminiscent of gluco-
corticoid inhibition of steroidogenesis in the adrenal
cortex , On thc other hand. the relationships an:
probably much more complex. 1.25·D induces renal
25-0H-D,·24·hydroxylase (an enr.yme diseui\sed
later that can divert substrate away from the I«-hy.
droxylase). Some observers find that 24.25-di-OH-
DJ inhibits PTH secrelion. but the effects of both
this metabolite and 1.25·D on Ihe parathryoid gland
are controversial (1 8 IAI·
A rapidly growing body of evidence suggests that
1,25-D plays a more gelU'ra/iud role in Ihe regula·
tion of mitochoodrial uptake of Cal<. It could in this
way alfect both the renal enzymes and the parathy.
roid gland. Mitochondria within the kidneys of D-
deficient animals al'<' elongated and heavy when
compared with those of controls. and they have im·
paired ability to both accumulate and release cal·
cium iollS. (89). 1.25·0 lowers la-hydroxylase activo
ity only in Ihe pl'<'sence of adequate Ca". [t can
restore the appearance and functions of the mito-
chondria via mechanisms susceptible to block by in·
hibitors of RNA transcription.
Insulin Influences on 1a -HydrolCylss8
Activity
Insulin dcf,ciency is associated with hypertrophy of
the intestinal mucosa. impaired calcium absorption.
and suboormallcvcls of 1.25-D in both the blood and
thc intestine. despite unaltered hormollC clearance
ratCs. Parathyroid hormone secretion is augmented.
but it fails to correct the low al'livity .
Experimental animals maintain plasma calcium and
phosphate concentrations when fed. but they tend to
become hypocalcemic if fasted .
Children with juvenile onset type diabetes mellitus
suffer 05tcopcnia but not ostcomalacia (223). Losses
of calcium and phosphate into the urine ha" e been
directly corrdated with the magnitude of glycosuria .
Exogenous 1.25-D can improve calcium absorption.
but neither vitamin D nor 25-OH·0 is effcctive
(234).
Insutin alone cOrreCts the cakium absorption rate.
the intcstinal mucosa morphology. and the abilit)" to
synthesize and conc.:ntrate 1.25-D. !t promotcs
renal conservation of calcium and it can accelerate
calcium transport across intestinal sacs studied in
vitro. It also increases calcium uptake by several
kinds of cells (40). In childrcn with diabetcs melli-
tus. it maintains the blood calcium and phosphate
concentrations. However. although it support<
growth and the altainment of normal 'talUre. it fails
to cono<t the <»teoj>C"ia. Phy.;.,togicat lcvelo a re ev_
idently needed for health)' bone formation. but phar_
macologkal accelerate resorption .
In birds. nonhypogly"mic dosages of in,u tin
'he pt:um3 Ca" (t85). The etl"tcts are blunted bu, not
aboli.hed by pa'alhyroidtc'OITly. A ditl"ercn' pep' ide
made in bird pancreatic i,I<I' is believed to ""ntribute 10
c.lcium
Chronic vitamin 0 deftciency impairs insulin (but
not glucagon) secretion. The defect cannot be COr-
rected with calc iu m-rich fluids (180). but it may be
rdated to chronic failure to maintain adequate cy-
10$0/ Ca , • • with consequent impairment of stimulus-
secretion coupling, Observations made on a slrain of
diabetic mice are consistent with thc concept. Glu-
cose stimulates beta cell uptake of Ca " in a !lOlmal
manner, but this is not followed by insulin lelcase
and th. associated calcium egress (225). Prcgnant
diabotic women display stimulus-secrction
coupling defects. It is nol known whether their fail_
ure to acquire the high PTH levels characleristic of
normal pregnancy is a!lOther manifestation of lhe
same problem. since the parathryoid glands arc
probably affectcd by their subnormal plasma mag-
nesium levell; (64),
In animals with nonnal beta cells. acule elevation
of the extracellular Ca lo slimulates insu lin secre-
tion. but persistcnt hypercalcemia depr= it (208).
Pancreatic polypeptide release not show such
calcium concentration dependence (1 I 3).
Glucocortlcolds
GluCQCQrticoid level. arc typically elevated in insu-
lin-<loficiency stales. The steroids oppose most of the
anabolic actions of insulin. and they have been im-
plicated as mediators of the mineral metabolism
defc.:\S,
Glucocorticoids acutely dcvate plasma Ca' -.
probably because they stimulate PTH secretion and
thereby accelerate production of \.25-0 (30). They
inhibit collagen synthesis. and this makcs more cal-
cium available for transport to the extracellular
lIuids. Glucocorticoid, also depress calcitonin s«:rt:-
tion (149).
Delayed. sustained deprcssion of the calcium Icv-
ds evidently involves multiple mechanisms.
I. According 10 some ob'-Crvers. the adrcfIQCQrtical
hormones compete with 1.25-0 for the same recep-
tors (245). The notion is eonsistcnt wilh thc estab-
lished use of glucocorticoids for trt:atment of vitamin
o poisoning and wilh the prOlcction afforded by
l.25-0 against glucocorticoid-invoked o:ncoporosis.
Others have failcd to find such competition (II 5),
Moreover. 1.25-D can only partially correct the bone
problems of patients receiving pharmacological
doses of glucocorticoids ( 147).
2. Glucocorticoids are reported to dc.:rease 1.25-
o rec.:ptor numbers in the intcst;nes of mice
(whereas adrenaleC!omy increases the numbers). On
the OIhe r hand, although the adrenal hormones
..
lower calcium levels in rats. they seem to actu ally
increase the receptor numbers (11 5).
3. Glucocordicoids may antagonize the cffects of
1.25-0 on both bone and kidney via mechanisms un-
related to changes in rec.:ptor numbers (?9.1 79) or
1.25-D binding. Interfercnce with production of cal-
cium·binding prOleins and al kalinc phosphatase has
been suggested (80).
4. By accelerating the conversion of 1.25-0 to
more polar metabolites. glucocorticoids may facili-
tate both inactivation and excrction 01" the calcife rols
(I 87).
5. Although they interfere with bone matrix syn-
thesis. glucocorticoids can provide some protection
againn bone resorption by stabilizing Iy-
SOSOme5 and thereby retard ing thc release of proteo-
lytic enzymes and other hydrolases.
6. Influences on pTOtein synthes is in the
liver include SOme effecls on production of calciferol
transporters.
7. Gl ucocorticoid! imeract with several other reg-
ulators. and they have been implicatcd as mediators
of estrogen influenccs on the renewal of bone cell
populations. They may thereby affect calcium me-
tabol ism indi rectly (79).
..,
Pro lactin
Egg-laying birds must markedly accelerate their cal-
cium abSQrption rales as they prepare \0 make min-
erai_rich shells and yolks. When injected into chicks.
PRL accelerate. calcium and phosphate absorption.
and it invokes hype=lccmia and hypercaiciuria. [n
D-replele animals, ;1 probably aciS p,im3rily on the
I".hydroxylase. PRL derived from lUrkeys increases
the enzyme activity wilhin 1 hour afler it is pre--
sented 10 chick kidney slices. Mammalian PRL is
also effective. but it mU!l\ be used in higher omeen-
lrations (29). PRL can also. however. elevate the
plasma Ca" of vilamin-deficient chicks (89).
PRL affects calcium melalK.>lism differently in
rals. During the early stages of lactation. circulating
PRL is high. calcium absorption is accelerated. and
plasma 1.25.]) can be elevated as much as four-fold.
Bromocriptine (an inhibitor of PRL se<:retion) re-
turns the 1.25-D to prelactational levels. but it does
not affect the calciferol concentrations in age-
matched nonlactating controls. However. PRL does
not seem to directly augment I<t'-hydroxlasc activity
(155). It accelerates calcium abi>Qrption in [).defi-
cient rats (108). Pregnant and lactating females that
arC [).deficient utiliu calciferol.independent nlech-
anisms to mobili1-c bone calcium (169), and PRL
may contribute to this. It is poosible thaI PRL inter-
acts with calciferols to increase the calcium content
of milk under normal condilions, sin"" there is recent
evidencc for thc presence of 1.25·0 ...:cptors in
mammary tissuc (181 A).
T hc likelihood that PRL supports metabolic ad-
justments to lactation in humans has been ques-
tioned (108). [t is worth noting in thi5 connccti<Jn,
that a 25(1.g ral may be called upon 10 feoo up 10 19
pups Ihat increase from 4 to 40 g each over a three-
week period. By contrast. a [3Q..pound woman
who docs 001 offer other food to her infanl sup-
ports a weight gain of some 6-8 pounds over six
months.
Eslrogen levels undergo substantial changes dur·
ing the course of ovarian cyeles. The steroids arc po.
lent stimulants for PRl release. and cor..spond·
ing changes in plasma PRL have described.
The,"" are no known associated 1,25·0 rhylhms
( 19).
PRllevels can be lowered wilh calcitonin (125)
and clevated with PTH (126). Dopamine is a phys-
iologica[ inhibitor of PRL secretion and il can an-
tagonize the effects of PTH. The relevance of such
observations is not clear. since patients with hyper-
prolaetinemia usua lly have oormal PTH arK! 1,25-D
concentl"lltions, whereas oncs with hyperparathy.
roidism tend to havc normal PRL (2).
CALC tUM, PHOSPHORUS AND THE CAl CtFEROl S
Growth Ho rm one
Although growth hormone (GH) and I>RL share
COmmOn chemical and bio[ogical propcnies. GH
does nol affect the I-hydroxylase activity of prepa·
rations of chick kidney sensitive to PRL. GH can.
however. enhance 1.25·D production if it is injecled
into birds. The possibi[ily that it acts via somato.
medins or other intermediates has been considered
(102).
Hypophysectomy depresses the plasma 1.25-D
kvels in ralS, and il impairs responses to phosphate
deprivation. Unlike intact controls given similar
food, piluitary-<leprivcd rats aClually show further
depression of Ih. 1.25-0 coneentralions and Ihey fail
to elevate their plasma Ca". (Hypophy5e<:tomized
animals can, howe""r. increase 1.2S·0 production in
response to either calcium deprivation Or PTH
administration.)
GH can normalize 1.25- D levels in hypophysce'
u)mized animals eating ordinary food (1SS). How·
ever, it probably does not contribute to adjustments
of imaci animals to phosphatc deprivation. Thc GH
[evels are not elevatoo when Ihe diet i5 dcflcient in
that mineral. When children of short stature 5how
growth relponses 10 GH. changes in cal·
cium and phospbate metabolism can be demon·
stratoo. but there is 110 corresponding elevation of
I.25-D [evels (97) . Chronic Gil deficiency in hu·
mans is not consistently associated with low 1.25·0
(137). Some aeromegalics ha"" high calcifcrollevcls
but others do IIOt.
GH more effectively restores 1.25·D levels in hy-
pophysectomized animals when the parathyroid
glands are present. bUI it is nOI totally devoid of such
polency in their absence. G H al so nt>rma[izcs Ihe aT>"
pearanccs of paralhyroid glands that haY<: under·
gone postnypophyseclomy atrophy . On the other
hand, the anabolic effects of GH in subjects previ·
ous[y deficient in that hormone are not associated
with elevation of the plasma J>TH (95).
It has been projX)Sed that Ihe pituitary gland se·
crete. parathyroid gland regulators unrelaled to G H
Or PRL (85 .139). GH may inleract ,,·ith such stirn·
u[ants. [t is also possible Ihal impure GH prepara-
lions contain such contaminants.
Somatostati n
SS is a recognized inhibitor of GH secretion, and at
least pharmacological concentrations insulin
release. The peptide has been shown to directly ar·
feet bone cell differentiation via mechanisms susee!>"
tible to anlagon;sm by eilher GH or insulin (265).
Gonadal Sleroids
Dil"<'cl inRuen""s of eslrogens on I a-hydroxylase ac-
livity in mammals al"<' unlikely. As noled prcviously.
no cyclical varialions in plasma 1.25-D accompany
menslrual cyeles in women (19).
Plasm. l.H-D are much hiEher in l.yinE hen.
than in I"<'productivtly inactive fern. Ie •. and tbey '1"<' very
low in <a<lr.ted . dull>of either sex, Est radiol alo"" par-
tially .estor« the <:(Incentmlion, in ..."ales, Neitb«
PlXllle51erone nor t«lOSterone alone is effective. buttbosc
>! ••oids augment til< stimulatory innuenec. of the estro-
gen (246) , On tbe other b.nd. the "croid, do IIOt elevate
l.2S- D in vitamin_' .pl... animal. fed calcium_rich diets.
nor do they .ffect I-hydroxylase activity when te. ted in
vitro (17). E.trogen. promote formation of medullary
bone;n boIb m.le, and remale, (SI). and they do <0 in
• itamin-def,eient a. ,",'ell as in ... ell·nourished .n;m.ls,
Tbe incl"<'.sed I-hydroxylase activ ity probably re.ult,
from upta ke of large quantities of calcium by such bone.
[n fem.["". estrogens ,1<0 incre.se e.lcium use by tbe
'hell gland •.
Mammals do not posse", .hell g[ands_ and III< forma-
tion of a .imi[.r form of .""ngy bone in ,<>dent' ch.oni_
".11)' ovcrd= d with ca[ciferol. is mt)Stly of pharmacolo-
,ical interest . On the otll<r hand. tbe OOse"ed estroge.
inn"en«. on endoste.1 cell proliferation and on coo •• r-
•ion of OSlcoprogcn itO< cell. to osteoblast. may be .cle-
v.nt. since cell. lining endosteal .u,faces of ad ult bum.n
trabecular bone . how .imila. chara.teristics {13 8) .
Malerna[ estrogen and progestogen le.ds rise
... ben fela[ growlh require. large quanlilies of cal-
ciu m. and plasma [.25-0 is usually high during
pregnancy (108). Ho"'ever, calciferols may not be
major regulators of mineral homeostasis al .uch
limes (13J).
are both di rect and indirecl indications that
gonadal steroids a re involved in the formation and
main lenance of bone . During adolescencc. lh. hor-
mones a re implicated in calcification of lhe epiphy-
ses, T hey alfect muscle strenglh and growlh. and
these indirectly regulale bone mass and remodeling.
Normal aging i. associated wi lh gradual loss of bone
mass. with increased susceptibili ly to fracturc. and
wilh depressed rales of bone healing. Short-lerm ad-
minimation of eSlrogen. and androgens can delay
the mineral loss and hasten heali ng. [I has also been
observed that estradiol and teStosterone inhibil cal-
cium release from felal bones mai ntained in c ulture
(198). T he transient nalU re of the beneFtcial effects
of estrogens in patients wilh postmenopausal Qliteo-
porosi, may result from ste roid inhibition of the pro-
liferalion of Qliteoprogcnitor cell' (sec Chapler 12),
In young, c)'cling fe male rats. the rate of new bone
,ynthesis fa lls periodically during the phases of ovar-
ian activity associated with high plasma estrogen
(266).
Indi rect inAuenccs On calciferol met abolism are
also suggested. The slcroids affect Ihe activilies of
mitochondrial enzymes and they may contribute 10
Ihc control of calcium uplake by the organelles. Es-
trogens also bind 10 Ihe proximal tubule siles wilhin
Ihc kidney Ihat regulalc [.25-D syn thesis (240),
Conversion of 25 -0 H-D 10 24,2S-Dlhydroxy
Vitamin D
[n animals tha t I"<'ceive adequate amounts of cal·
cium. phosphorus. and vilamin D. n"IOSl of the 25·
OH-D is converted to 24.25-dihydroxy Vilamin D
(24.25-D). Renal 24-hydroxylase activity Can be in-
creased by high eXlracd lu lar concentra tions of cal·
eium a nd phosphate. PT H also slimulates. but it is
nol absolulely required .
Since hypophyseClom ized a nimals ma ke re latively
large amoun lS of 24.25-D. and Ihis is correclCd by
GH adminislralion. it has been suggested thai G H
retard. induclion of Ihe 24-hydroxy lase . The hor-
mone may. however. aCI indirectly.
Kidneys tahn from animals deprived of calcium .
vitamin D. or both have low 24- and high la-hy-
droxylase aClivilies. Normalization is read ily lccom-
plishcd with appropriale replacemenl thcrapy (21 0) .
is reported to enhance accumulation of
2S.()H -D, and of ilS 24-hydroxylated derivative in
blood and lissues. but 10 decl"<'ase inleStinal and
renal 1.25-D. (263). T,. T. and TSH very rapidly
acce[erale 24,25·D prod"Clion by isola tcd. perfused
ral bdney' (130A). 24-H ydroxylases arc present in
intestine. cartilage. and elsewhere.
CALCIFEROL METABOLISM IN FETUSES
AND NEONATES
The placenta cOnlains 3 I·hydroxylase Ih3t provides
ncph reetomi1.cd pregnant females with 1.25-D whe n
vitamin D is administered (247.264) . Its activ ity
seems 10 be regu[atcd by faclors al ready ciled. but
placen la[ [aclogen may contribute ([ 37.221 ),
The enzyme i. ncedcd primarily to aSSu re Ihat Ihc
mother absorbs sufficient calcium and phosphorus to
support fetal growlh. Neither the fCla[ inte.line nor
the fetal kidneyscems to respond 10 [.25-0 ([76)_
( [n rats. receptors for the hormone first appear clQlie
to the time of wea ning [70] .)
[n fact. concept uses may require proteclion
again't aceumulalion of [.25-D. Choleealcifero[ rap-
idly crosses the placenta. and <Orne 2S.QH-D enters.
but onl), minule quanlilies of 1.2S-D Ca n be detected
in fetal blood when thc mother is give n a moderale
dose of labelcd hormone. Moreover. mOSI of Ihe
1.25-D Iha l is taken up is soon inactivaled by esle r-
ificalion . [f pregnanl ralS are given very large doses
..,
of 1.25-0. the consequences indude mluced line,
size and impaired growth of Ihe surviving f.IUses.
The failure of feluses to conV<Ort vitamin 0 to
I ,25-D is explained in several ways. I mmatnre livers
have very lilli. of the cholecalciferol-25-hydroxyla",
enzyme. Placental "pumps" maintain high levels of
calcium in retal blood, and this may account for Ihe
very low levols of PTH. Fetal bl<XXI is also high in
phosphate and in calci\()!lin. Ail of lhe prC<'eding
would be eXpeI'led 10 limit la-hydroxylase aClivi\y
(219). Some 24.25-0 accumulates in the fetal skel-
elan, but the conccnlralioru; arc low when
with \hO$C of juveniles.
5<'xm arter birth, loss of the ioHn.nces of the cal-
cium pumps leads to a decline in plasma Ca". PTH
secretion Ihen increases. The liver also gradually ac-
quires more 25-hydroxylase activity. The matura-
tional changes would be expected to elevate 1.25·D.
but some observers believe that other regulators con·
tribute. at least in human infants (221).
NUr$ing infants of mOSt species are kept OIlt of di-
rect sunlight. They receive mostly sulfocanjugates of
0) in Ihe milk . Hydrolysis by intesti",,1 enzymes is
evidently efficient. since the sulfocanjugatcs do no!
accumulate in the pups. The bones acquire
tial amounts of 24.25-di.QH·D . Plasma concenlra·
tions of that metabolite are high up 10 day 14 in ra ts
(when milk is Ihe only food). They fall through day
25 as increasing quantities of solid food are taken,
whereas Ihe 1,25_D levels rise (106).
Calciferol. may play special roles in nUl"$ing in-
fants. During Ihe first 18 days after birth. the intes-
tines of rat pups are insensiti"" to 1,25·D. The hor_
mone is evidently not n""ded for stimulation of
calcium uptake because absorption i. accomplished
at fir$t largely by pinocytosis, and the calcium con·
centration of milk is high. When the mother receives
adequate vitamin D. the infants undergo gradual
maturation of the intcstinal mucosa that is rcHceted
in ability to take up large quantities of dietary cal·
dum after weaning. Pups fed by vitamin4eficient
mothers do nOl develop in this way (107). After
weaning, they become hypocalcemic, develop severe
rickets, and are unable to respond to PTH . In con-
trast. pups fed by vitamin-replete mothel"$ can with_
stand vitamin D deficiency after weaning without
becaming hypocalcemic Or losing responsiven .... to
PTH. This occurs despite total disappearance of
1.25oD from the blood and severely impaired bone
development (144).
A problem with interpretation of the obscrvatiOll$ jUlt
cited i. that the vitamin D4.fieient diet given to the
weanling' was devoid of lllu""",,. Sinee """t C(lml1'l(:r·
.ially prepared rachitogeniC diel> (:<;Intoin ,Iu""",,. passi-
CALCtUM. PHOSPHORUS AND THE CALCIFEAOL$
ble effects of sugar C<>/ltent on mineral melabolism should
be .I$<;$$ed ( t 44).
There are also indicalion' that vitamin {).deficient
mothers of at least some 'train. cannot produce ad-
equate quantities of milk. evon when the infant' re-
ceive etlOUgh calcium to maintain normal plasma
Ca" . The pups then stop growing after the first
week (43).
CLINICAL USE OF EXOGENOUS
CALCIFEROLS
In otherwise healthy patients. calciferol defidendes
are most easily corrected by oral administration of
either DJ or 0,. Patients with intestinal disorders
thaI impair the absorption of fat-wlublc molc<;ules
usuall y respond to injection. of the vitamins.
1,25-D has recently become availab!e for individ_
uals with hepatic disorders that lower 25·hydroxyl.
ase activity, and with renal diseases that interfere
with canversion of 25-OH·D, to 1,25-D. It is now
being used almost routinely in hemodialysis patients
to oorrect hYfKlCaiccmia and the secretion of exces·
sive amounts of PTH. Some beneficial effects in
WOmen with postmenopausal ostooporosis bave been
described .
la·hydroxylase was more widely used in the paSt
for trealment of palients with good liver function
(and therefore adequate 25·hydroxylase activity).
There have been claims that it is superior to 1.25oD
for some purposes (25).
PTH would seem 10 be the agent of choice for
treatment of postsurgical, idiopalhic, or congenital
hypoparathyroidism. Howe""r, the hormone is ex·
pensive. difficult to obtain, and unsuitable for oral
administration. Moreover, refractoriness often de·
velops when from olher species are re-
peatedly injected.
Dihydrotachysterol (OHT) is an artificial steroid
that can maintain normocalcemia in such patients,
and in ones with pseudohypoparathyroidism. II is
mOre effective than the natural vitamin for mobili.
zation of bone calcium (112). (It i. nol useful for the
Ireatmem of rickets.)
DHT can be regarded as a reduction prodUCI of
D" and it has been referred to as DHT,. However.
the position of Ihe OH group on carbon 3 aecaunts
for its abilily to interact with the 1.25-D receptor.
The corresponding reduction product of D, (DHT, )
has been given \0 experimental animals.
The tachysterols undergo 25ohydl"Oltylation in the
liver. They do not require l-h)'droxylalion to aCI on
nephrtaomized animals, and they are
when taken orally .

, traled by blood vessels and lymph capillaries (lac-
" I
) each is equipped with some 2000 hair-li ke microvilli
I "brush border"· appearancc (Fig. 11_14). Fine. non·
, been applied to the extracellular bordcr. but thc sur-
, , 0"
Oi hyd'OIi1<01>Y'ton"
(DHT,I
Since the calciferols numerous it
could be advantagoous to develop agents that are se-
lective. for example. ones that accelerate intcstinal
absorption of calcium and phosphorus without pre>-
moting excessive mobilization of bone minerals_This
may nOI be accomplished until after the controver·
sies concerning the differences in activities of natu-
rally occurring molecules have been resolved, As will
be discussed. there arc some unanswered questions
ooncerni ng the specific roles for 24.25-di-OH-D and
other metaoolities.
CALC IFEROL REGULATION OF CALC IUM
AND PHOSPHORUS ABSORPTION
Within the small intestine, cakium and phosphorus
derived from food mingle with minerals secreted by
the glands of the digestive system. Calciferols can
increase the rates at which calcium and phospho",'
are takc n upand Ihe percentages of those suootanCC&
absorbed. They affect the formation, structures, and
properties of the cells Ihat border Ihe lumen (179).
Calcium traverses several morphologically defined
struClures as it journeys from the intestinal lumen to
the bloodstream, and calciferols are known 10 act at
mUltiple sites (69). The horITH)nes also play roles in
regulalion of gastrointeslinaltract motility (24), but
no inAuenCC& on glandular secretion have becn de-
scribcd(179).
The Absorptive Surface 01 the Intestine
Shelf-li ke folds (plicae circulares) and villi increase
the area of the inlestine thai is exposed to the lu-
minal contents, The villi af<' finger_li ke projcclions
cove",d by epithelium thai reSI on a basement mem-
bra ne . Each cantains a canntttive lissue core pene-
teals). and some smooth muscle ( Fig. II-D), The
vi ll i are longer and mOre numerous in Ihe duodenum
than in the jejunum. They assumc a club-like shape
in Ih. ileum (207).
Two kinds of epilhelial cells have idcmified.
The OneS directly involved in absorption arc most nu_
merous in the duodenum. They arc columnar. and
Ihat project into Ihe lumen and account for thc
branching filaments course through thc microvilli to
Icrminale at the apical (luminal) in a trilam-
inar plasma membrane. The term " fu7.zy coat"· has
face layer is also known as the glyoocalYI< because
of Ihe presence of glyoosaminoglycans Al kalinc
phosphatases and other enzymes have been locali7.ed
10 th is region. The opposite ends of the filaments
penetrate into the cells where they terminale in
"rootlets'· that are embe<Jdcd in a terminal ",·cb of
fibrils. Scattered. mucus-secrcting goblet cells arc
also present at Ihe duodenal surface. They are ITH)re
numerous in the lower porlions of Ihe lract that in-
clude the jejunum.
The presence of tight junctions between Ihe epi-
thelial cells is consistent with the belief that most (if
not all) mineral translocalion is trsnsceUular. Move-
ments of calcium and phosphorus arc accomplished
by separale processes(IIO). but both arc affected by
the luminal Ca: P ralios. the blood minerals. and thc
calciferols.
Calcium Absorption: Slles Bnd Mechani sms
In hcalthy. well-nourished animals. calcium absorp-
tion proceeds at a maximum rate in the duodenum.
However. this segment of (he intestine is short (20
em for the human adult). and il aCCOUntS for jusl a
small fraction of (he total calcium uptake. (The
human jejunum is around 275 em long and the ileum
closer 10 425 cm.)
In calcium- and vitamin D-rcplele rats. the lrans-
port rate in the duodenum is five times greater than
in the ilcum. When labeled calcium is presented in
solution. 7%. 17%, and 63% of the absorption occurs
in the duodenum, jejunum. and ileum. respectively.
while colon and stomach account for 8% and 2%
(261). Calcium presented as a component of solid
food is preferentially taken up by the ileum. with up
to 89% absorption from that region.
Young rats fed calcium-rleficient diets respond to
vitamin 0 administration by rapidly accelerating
duodenal uptake, and the bulk of the mineral is ab-
sorbed there. Gradually. Ihe transport rates in lower
ponions of the tract increase (60).
 •••
.. .
."
'
·"
...1 .

, I
I
, '
.'
.,
, • ,
,
"

, .
,•

. -," .,.
.
", ,
,
., - ,
.. ,
,

..
"
,
,
. ..,
.. ...
, I

..,. . . ,.
.
'
 Fig. 1 '· 14 . A . Surf."" ep<thelUn Of rat "" • .,inal villus,
<Iuodenum . elec,'"" mictOll'ai>/'l. ( 1) Intestmai """...,. (2)
r>I.>O je; of aboorpti .... cells, (3) ba .... 1par! .,. muc.,.,. cell.
••. (5) (6) m;T«I>o<\c!,j• • ( 1)
in""""Uul. r Spa"". (8) bIoo<I capi llar;e. in .. _ . proptl. ,
(9) ,>,mpM'Oc oapillary, (10) mIIny c e lIO in "'" conno;;,;ve
' i$SW c.nnot ". _ tifit<lo, thi . magnitocotion. X '830. B.
Enl"""",,on, oj or•• _10, 10 rect.<lQle ... A. ,ot dLlOdenun\,
eloetron mOc'09faph. ( t) u.n.n. (2) m;';'Q'I;a!i, (3)
toOlI., .... 'ar",; .....1wOb. mitoclloOOtia , (5) 11'" ""1,,,
endopIasm;c 'e1icu1L11'11, (e) 1" "'81 borde<$, (7)

, secondary X 6000. (RI>odin. ",,"'...,., 207)

Fig. 11- 13. Int""liM, villu, from r.l <luoden<Im. tip region, (9) po.'C.pill'f"/ . _. (10) ,ymp/lalie c;>pill." y
Io<9ludO"1aluctior> tr.ough I'" mi<lclle 01 "'" ""'., eleelron (la o,,,,,,) . (11) SI\"'IoOlh ( 12) the cor. ot the
mi<:rograph. ( 1 ) Inl&$linall...,.,n, (2) nude; oj absorpti.... ,.ll ul ('omma ptopt"ia) ;s made up of IOOS& """"""ti.e
cell. in 1M ""tace OI>'fleIOlm. (3) b. ...II. - ' , (.) ,; _ "';1h • ot 81SO<ted cel l ( 13 )
rTIUOO\J. (goDIet) ""II', ( 5 ) " ''''",,lIular .pace . (6) rwelol lytnpIwx:yt.... e n tlwough the ..... r• .,. opit"-I;um. ( , . l
01 aDoorpli". cells, oppa,,,,,,ly Doeing s hed into thO inl ••lin. 1 """"",ine cell (argy,OphiI """l . X 660. (Rlw>din, .......c.
I....,..,. (7) ClOSS o"".;or, oj _ _ Ole , (8) bIoocI CllpiliariftS. ron
...
Ca ldum firs! comes inlO contact with the glycQ-
Here, negatively charged su lfate groups and
other ions iniliale the uptake. The neU step seems 10
be transfer of the mineral to calcium-binding com-
ponents of the plasma membrane. The low-affinity
.iles a'" believed to be phosphate g!'()llp:! of mem-
brane pbQspholipids. whereas the high-affinity oncs
arc proteins. The uptake rale, can vary with changes
in phospholipid ma ke up and with ins"'li,m of cer_
lain prole ins into the brush horder membran ... D if_
ferent kind, of proteins are implicated in transfer of
the ions 10 the cell interior.
The eiecln)negalivity and low free Ca" CQntcnt of
lh. cytosol are bel ieved 10 faci litate calion entry. 0.-
gancll.. and intracellular membra nes have been im-
plicated in protection of the cell against ucessive cI·
cvations of the Ca " concentrations (46) and in
facilitation of transcellular mOvements of the ion •.
Extrusion a t the serosal side is an active. energy_
requiring process. It may depend primarily on oper-
ation of a ouabain-insensitive Ca ' (Mg' · -ATPase .
Some extracellular Na ' is needed to anain maxi-
mum extrusion rates (119). but exc=ively bigh wn-
eentrations impair rather than facilitate Na ' (Ca' -
excbange.
VItamIn D-Ind .. p .. nd .. nl Calcium Uptak ..
Animals fe<! calcium_rich food build up high intra-
luminal Ca" concentrations. T he ions move down
tbe ir concentration gradients, enter the cells. and
exit at the serosal s urfaces. A nonsalUrable transport
process that is calciferol_independent has been iden_
tified. It is unaffected by age or previous calci um in_
take (46). It may assume specia l importance in nurs-
ing infants that have not yet developed sensitivity to
1,2S-0, and in vitamin D-deficient animals given
diets with high Ca: P ratios. However. it cannot sup-
port ca lcium homeostasis in vitamin D-deficient an-
imals fed ordinary food.
Calciferol Hormones Allecting Transport
[t is believe<! that vi tamin 0 must be converted to
1,25·0 before it Ca n stimulate calcium uptake. The
vitamin itself is inactive when stud ied in vitro, and it
fails to accelerate ca lcium absorption when it is
given to nephrectomized animals. In intact animals,
many hours elapse from the time of vitamin 0 ad-
minist ration to t he onset of the first detectable re-
sponse. The latent pe riod is substantially shortened
when 1,25-0 is used , Intermediate values arc found
with 25-0H-O.
Very low concentrations of 1,25-0 elicit maximal
increases in calcium transport across inverted intcs-
CALCtUM. PHOSPHORUS AND THE CALCtFEROLS
tinal sacs studied in vit ro_ but only massive amounts
2S-OH-D have demonstrable effects.
When large doses are given to an imals, 24.25-0
accelerates calcium absorption. It probably must
undergo I-hydroxylation_ since it is ineffcctive in no-
phrectomiz,:d anima ls. 1.24. 2S-Trihydroxyvitamin
D is appro:<imately one-third as potent as 1.25-0.
and it is rapidly degraded .
An intestinal 24-h)'droxytase catalyzes convcrsion
of 1.2S-0 to 1,24,2S-trihyd roxy vitamin O. The en-
'yme may confer SOme protection against
outsidc of as well as within the gut. It has been ob-
served that a single la rge dose of 1.2S-0 is equally
potent for stimulation of bone resorption when given
orally or parenterally. However. chronic overdosage
has greater effects if the pa renteral routc is used
(179).
Plasma concentra tions of
o risc and fall in parallel with those of 2S-OH- D.
The twO metabolites are said to exert similar actions
on intestine and bone, but the functions of the 26-
hydroxy derivative are nOt known.
It has becn widely assumed that 1.25-D is de-
graded Or prepared for excKtion by enzymes of the
target tissues. There has been ,"cent speculation
that SOme of the steroids derived from it subserve
specialized functions (181 ).
1,25-0 Actions on the Intestine
A rapidly growing body of evidence supports the be-
lief that 1.25-D acts in several different ways to ac-
celera te absorption of calcium (181.252). Responses
to administration of the hormone are multiphasic.
They a rc affected by the agcs of the test subje<:ts and
by past nutritional and endocrine history (45). Some
are bloc ked by inhibitors of R N A synthesis, and oth-
ens by inhibitors of protein but not RNA synthesis.
Vet different ones involve ehanges in membrane
lipids.
INDUCTION OF SPECIFIC mRNAs AND
PROTEINS
1.2.5- D crosses the plasma membranes and enters
the cytoplasm. Receptors that bind with high affinity
and specificity have been identified in the brush bor-
der cells (70.193.227.262). Contrary to earlier re-
pons that the receptors have molecular .... cights of
47.000-70,000 and sedimentation constants of
around 3.7. it is now believed that unoccupied rccep-
tors have weights of 90.000-100.000 (ISlA). Some
authors state that the hormone-receptor complex
unde rgoes an "activation" step before it translocates
\0 the nucleus, but others attribute the delay in nu-
clear binding to slow association of tho steroid and
protein molecu les. Maximum binding of the complex
10 the chromalin is achieved wilhin 2-4 hours at
37' C. Tho complex can be rcleased from the nucleus
by DNases. but not by RNases Or prOlcolytic
enzymes.
Accelo raled incorporation of labeled uridine Or Or-
otic aeid into mRNA precursors can be demon·
strated soon afterward. and the effect peab within
3-4 hours after Iht initial presentation of the hor-
mone 10 the target cell. Laler. the rate of incorpo-
ration of labeled leucine into proteins increases.
mRNAs that code for Ihe proteins have been re-
covered from e<:lIs and used to direct synthesis in
cell·free systems (53). Severnl vilamin D..;Jepcndent
proteins have been isolate<:! and shown 10 affect cal-
cium uptake.
Actinomycin D and <MIma nitin block several of
the actions of 1.25·D. This is taken as evidence that
the bormone acts via induction of new mRNAs.
(However. when given to animals. aClioomycin 0
can also interfere with the conversion of vilamin 0
to 1,25-D.)
Although high concentrations of 25-01-1-0 can af.
feci calcium transport in vitro. it is believed Ihat this
melabolite docs not form hormone-rcceptor com·
plexes Ihal lranslocate to the nucleu •.
CALCIUM·BINDING PROTEI NS (CaBPs)
Cells contain a variety of cytosolic
proteins that bind tightly to calcium. They also take
up some Sr" and Bah . but they Ilave little affinity
for Mg " and other biologically important cations
(260).
Certain members of the group are called vitamin
I).dependem CaBPs. because they are presenl only
in cells that possess U5·0 receplors. and they are
induced by Ibe hormone. Ther. are severnl reasons
for linking the Ones in the intesline with calcium ab-
sorption. The prolein conccntralions fall to unde-
tectable levels in D-deficient animals. and they ar.
restored by vilamin administration. Although some
effects of 1.25·0 have short latent periods. it has
been observed that the major. sustained stimulation
of calcium uplake is preceded by Ihe appearance of
the mRNAs thaI direcl the synthesis of the proteins
(142). There are dosage ranges over which 1·25·D
and CaBP levels. and also CaBP cooe<:ntrnlions and
calcium transport rates. rise in parallel (47).
On the other hand. it has become apparent Ihat
Ihe following simple sequence fails 10 the ac·
tions of tile calciferols (259).
DJ - 1.25-D - mRNA for CaBP -
CaBP production - Increased calcium uptake
Some slim ulation of calcium transport precedes
the appeamne<: of the CaBPs. and SOme Can be ac-
complished in the presence of inhibilOrs of prolein
and of RNA synthesis. The dedine of tile lranspon
response many hours after injection of a si ngle dose
of 1.25·0 is more rapid than the loss of CaBP. and
the effects of other regulators (e.g. glucocorticoids)
on calcium uptake are oot well correlated with
changes in CaBP levels. Moreover. there are agMe-
pendent differences in the magnitudes of calcium
transport acceleration associated with a
increment of CaBP (13). Induction of the proleins
may require some prior elevation of tile cytosol Ca"
for reasons OIller than generalized influences of tile
ions on protein synthesis. In parathyroidectomized
animals, 1.25-D is effective only when the diet is rich
in calcium (250).
CaBPs do not appear to influence the permeability
of the luminal membrane to calcium. Once the cal·
dum enters. the cell requires protection against ex·
cessive elevation of the cylQWI ion conlent (44).
Some observers believe that the proteins act primar-
ily as "buffers" thai bind tile ions a nd later deliver
Ihem to the serosal surfaces. Others suggest that
component. of Ibe Golgi and endoplasmic reticular
membranes perform such functions (sinC<' binding
Ihere is affected by vitamin D). They link the pro.
tein. with the function. of the Cal+_ATPase at the
serosal side (46).
Tile faclOrs affecling the produclion of a CaBP
wilh a molecular weight of9000 that bind. 200 nmol
Ca per mg were studied in several groups of rats
(46). Animals maintained On high-calcium diets
supplemented with viTamin D accumulated SOmo 2S
nmol of CaBP per gram of intestinal muCOSa . When
given a single dose of 1.25-0. their CaRP levels
began to rise within half an hour. and they doubled
in an hour. ne high levels persisted for the next 24
hours. Since Ihe described changes in CuBP could be
blocked with cycloheximide but not wilh actinomy.
cin D. it Illal the hormone acted al the level
of translation. One possibility i. thai newly formed
labile protein activatcd a mRNA coding
for the CaBP. Anolher is thatille new protein cat-
con,-ersion of a pre-CaBP to CaBP.
Rals on low-calcium diets su pplemented with vi-
lamin D accumulated 50 nmol of CaBP per gram .
Presumably. they already had high 1.25·0 levels,
si ncc low-<:alcium diets are associated wilh high I<r-
activity. When additional 1.25-D was
adminislered CaBP rose substantially. but only afler
7 hours. Peak values were attained at 9-10 hours.
and they then declined rapidly. In these: animals. the
changes in CaRP could be blocked wilh actinomycin
O. The high initial levels of CuB P, the long latent
period, and the effects of actinomycin O. are all con·
siSlent with Ihe suggcslion thai all of the mRNA
...
coding for Ca BP was in active form before the 1.2S-
D supplement waS given. and thl CaRP levclscould
not risc (0 yet higher levels unlil Ihe hormone pro-
moted thc synthesis of new mRNA. The rapid re-
lurn of thc CaBP 10 pre-inje<:li(m values
further thai thc cells possess mechanisms for pro-
tecting themselves against ae<:umulatiQn of excessive
quantities of the calcium binding protein.
Rats maintained on diets deficient in both calcium
and vitamin D did not have deleCtable leveb of
CaBP until ancr they were given Ih. 1,25·D. 8 hours
aflcr Ihc hormone was injected, the CaBP levels
began \0 rise. hours were required to attain
pea k kvels. and the effects wCre sustained. When
oompa",d with the low..:alcium. vilamin D supple-
menled animals. the members of this group required
longer latent period. and they achieved lower final
CaRP concentrations. Therefore. in addition to lack·
ing stores of aetivatablc mRNA. they seemed to suf·
fer other kinds of defects that impaired responses to
the hormone.
Changes in rateS of c.1lcium uptake aCr05S intes-
tinal saCS prepared from the rats showed some time-
course relationships to the synthe.is of the CaSP.
The mOSt prompt responses were found for the vita-
min D- and calcium·replcte group. and the most de-
for Ih e vit.min D-ddicient group.
Interestingly. however. whereas 1.25-D is the cal-
ciferol obviously required to maintain normal rates
of mineral absorption. other naturally occurring
molecules can induce the CaBPs when presented to
em bryonic chick duodenum in culture. 1. 25-D Wa5
found to be effcctive in 10_'1 M concentration •• but
vitamin D and 25..()H -D can promote the formation
of the protein in concentrations of 10 • M and 10- 1•
M . respectively. The levels are lower than the ones
found in the circulation. 24,25-0 15 less potent than
25·D. 1.24.25-D fully imitates 1,25· D's influences
on CaB P production, but it is a less effective stimu·
lant of calcium uptake (62).
OTHER CALCIFEROL-INDUCED PROTEINS
It is IIOt yet known how many kinds of proteins are
induced by 1.25_D. A brush border protein with a
molecular weight of around 18500 that binds 350
nmol Ca/mg has been implicated in the initial as·
socia tions of the ions with the plasma mcmhrane
(46). A much larger protein with a molecular weight
of 200.000 and 20.45(}.daiton subunits that avidly
bind calcium has been given the name IMCal (in-
testinal membrane calcium-binding protein) (216).
Its propenies and location ma ke it sui tablc for par-
ticipation in transport of the calcium aCrOSS the
CALCIUM, PHOSPHORUS AND THE CALCtfEROLS
membrane and latcr delivery of the ions to the cell
interior.
Calciferols increase the brush border actin content
(1 20). and it has been ob:$erved that cytochalasin in-
terferes with both actin assembly and calcium up-
take (l28). The binding of calmodulin to the memo
branes and the phosphorylation of proteins are also
reduced. However. the effects are not associated
with subl;tantial changes in morphological features
that can be detected in electron micrographs (120).
Other cell constituents affected are components of
the Goigi membranes (which bind more calcium in
vitamin-replete than in deficient cells). Entymcs in-
creaJled by 1.25·D indude Cal> I Mg' · ·A TPase and
alka li ne phospha tase .
The hormone is ta ken up and bound by cells
withi n the intestinal crypts. It is likely that some of
the actions with long latent periods are related to in-
fiuences that can Ix: exerted only on immature cells
that later migrate up"'ards (130). I.25·D is addi-
tionally implicated in acceleration of cell prolifera-
tion. elongation of the microvilli. and augmentation
of the absorptive surface.
INFLUENCES O N BRUSH BORDER
MEMBRANES THAT DO NOT INVOLVE
ACTIONS ON TH E NUCU:US
The membranes of vitamin· replete animals have
higher permcabilities to calcium than those of vita-
min-defic ient animals (250). It has been demon-
strated that changes in phospholipid content
can affect calcium uptake without exerting simulta·
neous influences on other functions such as gluco:sc
transport (84). The influences exerted by I ,25·D af_
fect membrane nuidity. They include aCCeleration of
phosphatidylcholinc synthesis and of phosphat idyl-
cholinc acylation-dcaeylation cycles (205). The
phosphatidy\ :eholine ratios and the quantities of un·
saturated rally acids contained within the phospha·
tidylcholinc are incr<:ased. The effects .w em to be
specific. No changes in cholesterol content or in
phosphatid)'linositol have been found.
The inAuencC!i on membrane phospholipids Can
procce<J in the presence of inhibitors of protein i)·n·
They are easily linked wilh acceleration of
calcium uptake. and it has been proposed that they
serve to convert latent calcium channels to active
ones. Animals suffe ring essential fatty acid deficien-
cies do not show increased passive uptake of calcium
in response to 1,25-D.
The addition of methyl esters of cis-vacccnie acid
can enhance calcium uptake across membranes
taken from [).deficient animals in a manner com·
parable to 1.2>-0. whereas tile: addi tion of esters of
Ir<l/IJ·ya«eni<: acid leads to reduction in mcmbr.lroc
fluidily Ind slowing of the tn.nsporl in mcmbnnes
from yitami'H'epkte Inimals (lOS). Filipin is a p0-
lyene a nt ibiotic that inten.CI$ with plasma mem-
llfane lipids and elicits changes in transpoft charac·
teristics reminiscent of the (HIC$ obtained .... ith
caleircrols (181).
It hal becn pointed oul. howcyer, Ihat on
upta ke of calcium aCross brush border membrane
vesides studied in vitro mUSI be intcrpreled .... ilh
Qlution. since intra«llular f«tors may be: major de-
tcnninants of the in vivo rates. In $Iudic:s wilh <:<)1"'
tito!, il was observed that marked 6c:pression of in
vivo calcium uptake could be: eliciled wilhout chang-
inlthe rates of uptake across vesidcs deri ved from
the anima ls (224).
The mox:hanisms whereby hiah <XH\Centrations of
2S-OH-D affect calcium Iranspon arc not known. 11
has b«n reported by ...,me thai the metabolile pref-
erentially binds 10 the nuclea. envelope. T he binding
to mitoc:hondrilll membranes could al..., facilitate
nlcium cnlry and IlIe:reby play roles in regulation of
cyI010I Ca" 01 in the lransfer of calcium 10 tile ser·
osal border.
Pho.ph oru. Absorptio n
Cale ,rerols 'ncrease the nile of phosphorus absorp-
lion. and they can do Ihis even in IIIe: absence of cal-
cium (60,7 1). While the mnimal lransport rate is
said to be: in the jejunum. pbosphate is taken up O"ol'r
tile lenglh of tile small imestillC. As was noted. Ille
proc ." is OOIIlroIled by facton {)Iller than 1.2>-
UCC.
Rclali\<Cly little is known of the mechanilJl'l:i
(1 46). It has been poinledoul thaI Ihcy diffe r insev.
eral respee ls from th(ll;e affC;:Iing calcium upla).:c.
For one thing. phosphale goes againt! Ihe eleClrical
gradient as it enlers the bonier membrane. A
specifie carrier has been (110).
The slimulation lias b«n linked wilh induclion of
both Ca BP 111011 alkaline phoJpNlll$II: (90). II re-
quires luminal Na ·. and it Kern' to in vol"" Na -·P;
ootranspon (114)
,h.,
The pos.ibi li,y calcifcro!$ OIhu Ihan 1.25·D con·
"ibule 10 Ihe regulalion i •• uUcsled by "udie. of "IS
with. ,ene,ie def"'" ,h. , iml"in phooph.te ai>sorplioo
Ind ,h. ",by invoke. hYP"Phoophalcmia e. cn ,,·h<n
pI:;I.ma 1.2$-D Ie"els.", in lhe _mal "nl'. II ,... ob-
..,,,,,d lhal Ihh<>ulh lho(: ...d boroes of U.c "'''
responded '0 eJI",enous 1.25·0. only I...oH·O nbsl ....
, ilily impanel ,Ile .... of diet:ory (2S). On
, he {)Iher haod. I...oH·D con main'.'n hiBh pluma
l.n.D in "'" ,.;,h Knll .,.'oodYSltOl'hy (92).
CaBPs IN OTHER TISSUES
In "itami. (}.deficient chieks. proteins that bind a ....
tibodies directed againsl inteslinal Ca BP ha"" been
found in numerous organs tlult include ).:idney. a:re-
bral cona. hypolhalamul. adrenal. thy·
rOO. and paralhyroid glands. lC$lis, and bone. Fol·
lowing administration of calciferols. the prolcin at...,
appears in Ihe seru m. while Ih. eoncen lralions in lhe
inlcStine increase more than at ot her sites. IncreasC$
followin, hormone treatment have a lso been round
for kidney. pancreas. bone. adrenal. and oomc other
, iS$\lei (57).
The findings are conWslcnt wilh a growing belief
Ihal calciferol! act on 01 ,II kinds of cells. La-
be:le!! 1.2>-0 has bc<:n obsc"",d 10 bind wilh high
affini ty to the nuclei of epidcrmis. renal epilhelium .
lactating mammary gland. pituilary gla nd cells. and
p<lNllhryoid gland cells. as well a5 al some olher ,ilcS
(241 ). It has also been repof1cd Ihat vilamin D ilself
acts directly on Ihe epidermis 10 alfeet the synthesis
of calcium.binding protei'" (18g). Tile roles in most
of the are as yel uJ>dcfined. It is kno.... n lilal
the stimulate production of numerous
proteins Other than Ca BP outsidc the: intestine (58).
CALCIFEROL ACTIONS ON BONE AND
CARTILAGE
Contin uous remodeling of bone 1....0
object ives: (3) Bone ctll popUlations are renewed.
Ihe S;:teS and shpes of skelelal struCtures an:
adapted to prevailing needl. and appropriate repairs
are made: and (b) controlled uptake and release of
mincrab. especially in nc ...·ly rormed bone. make
major conlribulions 10 tile mainlenance of CJClracel·
lular calcium and phosphalC oonc.:ntr.llioos. When
nutritiO<\ is adequate. Ihe!wo functions complemenl
each other. When calcium is in 'hort supply. homeo-
StB lie lake p'ecedence. even when \be ske!·
is ad"ersely affected (198 ).
AGE·RELA TED CHANGES
In well·fed infants and juveniles. 11(:10" bone fOlma-
lion procttds more rapidly than resorption. and Ihis
leads to nel accumulalion of skelelal lissuc. Thc re-
sorption is essent ial for allainmenl of normal bone
con lours. mainlenance of the marrow pro-
.ision of channels for passage of ne rves and blood
vesse ls, and release of caleium to thc ext racellular
Ruids. Ph)'SioIogical concentrations of 1.25·0 are =-
sent;al for normal growth bul pllumaoological ones
impair m.JlrU production (116).
Young go through a pha$c during .. hich
bone mass and mi...,ral contCnl teoo to $Iab,li..,. and

remodeling seems to be imporlant primarily for the
mineral exchange and the healing of fraclures , How-
ever. there are conditions under which marked I()-
calizcd or generali1.ed changes in bone mass can
occur. Ind ividuals who leave desk jobs to enler oc-
cupations that req uire standing and walking acquire
heavier leg bones. and racket-wielding armS of avid
lennis players have Ihicker bones than their counler-
parts. whercas bones confined to casts during the
healing of fractures undergo transient atrophy. Bcd-
ridden patients. and astronauts deprived of the usual
gravitalional forces, can lose very substantial quan-
tilies of bone minerals to the urine.
Normal aging is associaled wilh more rapid re-
sorption than new bone formation (164), and also
wilh changes in the physical properties of Ihe cry:;.
tals that can lessen tensile strength (54). Osteoid as
"'ell as mineral content declines. Although some im_
pairmenl of calciferol metabolism can occur (39),
excessive bone loss in palienlS on ordinary diets usu-
ally leads to Ihe dC\'elopmem of osteoporosis rather
than osteomalacia.
It has b«" "a,ed Ihat he.hhy postmenopaused women
lose bone al con,tan, rat .... 0<1 th.t those with initially
•malt bono ma .. are the ones most lil:oly to suITer debil_
it.ting osteopOr<t<is and tendencies to devetop fraolures
lato in life (6). However accelerated booe loss followiflil
",coopaUK or ovariectomy h•• bocn tinked with declinin&
estrogen level •. Some observers believe that estrogen d.-.
licicncy e,aUcralos the $<;nsitivity to parathyroid hor-
mone (59). bUI others qu .. tion this (148). A, discussed
in rart V, adipose ti ..."o converi. othor sieroid. to estro-
gen,. and .Iender women have been reported to lose bone
rna... and minel'lll, al more rapid I'lIle, than individual.
with larger "(}rC$ of ,ubcutaneous fat (9t). EX08<"0.'
estrogen< can alleast tran,iently slow the Io<scs. and they
may under ",me "'mdilion, accompti,h reversal of Ihe
negali" balance (59.9t). There are claims that calciferot
, upplcmenu are beneficial. Howe"r . • ltbongh 1,25_D in-
cre.",s c.lcium absorption. it also tend. to bring abou t
porallel increases in bon" resorplion rIIte. and urinary
c.lcium excretion.
MINERAL DISTRIBUTiON
Minerals during bone degradalion emer
lxxIy pools that are replenished from dietary sources
and by renal losses. The pools provide tho
ions that circulate and the ones taken up by newly
formi ng bone and other lxxIy tissues. [n rapidly
growing chicks and puppies, some 60%-64% of the
plasma calcium is of direct dietary origin whcreas
30%-34% previously resided in bone (133).
The mineral content of the extracellu lar fluids
profoundly affects bone physiology. Calcium deft_
CAlCtU Ioi . PHOSPHORUS AND THE CALCIFEROLS
ciency seems to preferentially intpair production of
cartilaginous and bony matrix (at least the
early stages), whereas pholiphate deficiency m(H"e di·
rectly retards mineralization. Rats generally havc
higher plasma phosphale Icvel, than most other spe·
tics. They do not us ually develop rickets when de-
prived of calciferols but provided with diets contain-
ing ordinary Ca:P ratios , They acquire the disorder
if the Ca :P ratio is high. Calcium-<leprived ratS arc
hypocalcemic and they tend 10 develop osleoporosis.
Dogs and several other animal types studied in the
laboratory do develop rickets when calciferol d.-.
privod. even if the diel contains substantial quan-
tities of phosphorus (68). It should be pointed OUt.
however. Ihat both genetic factors and microenviron-
ments contribute 10 species variations in response to
mineral levels. Moreover. hypocalcemia exerts indi_
rect inHuences, since il provides the stimulu, for
PTH secretiOl\.
Calciferol Accumulation In Bone
When a single dose of labeled OJ is given \0 rachitic
rats. much of the radioactivity can SOOn be found in
the skeleton. Some is still present after 48 hours .
Initially. the vitamin itself is taken up. and as
much as 21% of the dose enters the bonos. OJ is then
.scnl \0 the liver for 25-hydroxylation, and bone con-
centralions 0[" 25-O H-D build up OvU a 6-S-hour
period, Two proleins Ihat specifically bind thai m.-.
tabolile have been idenlifiod (2l). Afler some time,
mOre than 50% of bone calciferol content is in this
form, while 0, accounts for an additional 35%. Skd-
etal tissue posseses some 24-hydroxylase activity,
and it also takes up 24.2S.QH-O from Ihe blood.
There is little la-hydroxylaK activity. and only min_
ute amounts of I-hydro.ylated cakiferols are found
in the Skeleton.
The findings suggest that 25.QH-O and metabo-
lites made front it in osseous tissue perform special
functions. On the other hand, bone SC<:ntS to contain
specific high_affinity rece ptor.s for 1.25_D but not for
either 25.QH-O or 24.25.QH -D. Therefore, only Ihe
la-hydroxylated metabolite would be expected to
engage in processes requiring the binding of hor-
mone-receptor complexes to the nuclei ( 160). (The
findings do 1101 rul e Out inHuenees exened in other
ways, e.g, on membranes or on Ihe binding of 1,25-
D to its receptor.)
" Anabolic " Ac tions of Calclferols
Abnormal findings in rickets and osteomalacia !n_
clude low mineral:osteoid ratio. low alka line phos-
phatase activity, impaircd lysyl oxidase function.,
and morphologically demonstrable lesions. Calcifer·
ols can all of the problems (except in rare
individuals unable to respond to the hormones).
Calciferols are also said to promote bone miner·
al;'-"tion indepl'ndenlly of their ability to oorrcct
blood <:alcium and phosphorus leve\s(34). and to fa·
cilitiale bone maturation (76).
" Catabolic" Effects
1,25·0 acts;n vilro to rcduce both ostooid and min·
eral oomponent. of bone. Its ability to increase the
numbers of multinucleatc osteoclasts has lik·
encd to the influences exerted by PTH (238), but re·
cent findings indicate that it acts dire<:tly On Icub·
cylic receptors to promote oonversion of mono-
cyles to large. phagocytic cells (195A). 1.25·0 also
augments the acid phosphtase activity of the
cell' (237). Such findin8" have been inlerpreted 10
mean Ihat the hormone accelerate, bone resorption
In VIVO.
However. studies on calcium IUrrl()ller in chicks
suggest that neither vitamin 0 deficiency nor calci·
ferol replaCemenl affe<:ts boll(: resorption rotes
(133). It has also poinled out that osteoclasts
cannOI directly destroy mature. calcified bone rna·
trix. One component of the hypl'realcemic action
may be stimulation of production by osteoblast. of
mineral-solubilizing factors (232) . Therc are several
findings consistent with 1.25·0 inhibition of new
bone fOrmalion. and this could increase the 4uan·
tities of minerals available for release to the
cellular fluids. Newly formed brushite is used to re-
plc nish blood calcium, and l.25·D may slow its
oonversion to lcss acccssible bone mineral.
PHYSIOLOGICAL VALUE OF CATABOLIC
ACTIO NS
1,25·0 inAuences on resorption or inhibilion of
new matrix synthe,is are said 10 against pro-
duction of excessive quantities of osteoid (157). They
may also assure provision of ade4uate oon·
cent rations in the direct vicinity of new matrix
does form.
A different concept is thai 1.25-0 i. primarily all-
abolic when Ihe mineral supplies are adequate, and
thai the catabolic actions are invoked only when
there is a need to elevate Ihe blood calcium levels.
The notion is supported by observations that only os-
leoblasts are stimulated when the supplies are good,
whereas osleoclasts as well are affected in mineral
deficiency slales (39). Catabolism may require
higher 1.25·0 ooneenlrations thaI are achieved only
in hypocalcemic stales.
Speciel Functlone of Certain Calclfarol
Metabolltee
There are conditions under which exogenous 25·
OH·O improves bone mineroli'.alion, elevatcs serum
phosphate and al kaline and is senerally
beneficial 10 patients with osteomalacia. whereas
neither 1.25·0 nor 24,25-0 brings about similar im·
provement (33). Since sugge'lions that 25-0H·0 is
anabolic while the l· hydroxylated derivative is not,
have not been supported by oomparisons of aClions
of the in vitro (237). other explanations
have been offered. For one thing. 25"() H·0 aCI. on
the kidney to increase renal conservation of phos-
phate (33). and elevation of the extracellular pllos-
phate alone should have beneficial effeels. For
another, exogenous 25..()H·0 may aSSure the main·
tenance of optimum levels of 1.25·0 in the blood.
The metabolite is efficiently absorbed (228).
and it <:an bring about su,tained. moderate elevation
of circulaling 1,25·0 (140). (By contrast. 1.25·0 is
rapidly degraded. When taken orally. it is likely to
provoke transient rises to toxic levels followed by
depression 10 suboptimum ooncentrations.)
Most in vitro obse rvalions are consistent with ac-
tions of 25..()H·0 similar in direction to those of
1,25·D (237), or with lillie or no acti vity when mod·
erale concentralions arc used (42). 25..()H·O may
therefor. serve the function of protecting bone cens
agai"", exce.. ive effecto of Ihe powe,ful hormone by
interfering wilh binding to the receptor.
IMPORTANCE OF 24·HY OROXYLATION
Bone oonlains substantial quantities of 24.25..() H·D.
and there have been suggestions that il plays SOme
special role in bone ph%iology (71,157 .177) wbicb
may be relaled to promoting mineralization (39).
When laying hens arc given either 25'()H·D or
24,25·0 as their sole source of calciferol. fertility is
maintained and Ihe embryos go through normal de·
velopment and hatching. If just 1.25·0 is given in-
stead, large numbers of embryos are los\. The sug·
g.,;t;on that 24,25·0 is specifically needed (and that
25..()H·0 i. effecti ve because it is converted 10 thaI
metabolite) has been questioned. Calclferols fluori·
naled at the 24 position cannot undergo 24-hydrox·
ylation bUI they can substitute in vivo for 24,25..()H·
o in chicks (8) and also in rats (170). In most in
vitro studios, 24,25..()H· O either aCls weakly 3$ a
1,25·0 agonist or fails 10 display biological aetivilY.
It may aceelenlte ONA synthesis (A·I).
Altbough 1,25·0 receptors in bone show some
cbaracleriSI;cs resembling those described for tbe
small intestine, differences have also been described.
1,24,25·D i, an ext remely wea k agonist in the gu t,

and dihydrotachysterol (which promotes calcium ab-
sorption) has no known effects (237).
It is evident from the preceding ob.ervations that
much remains to be learned calciferol
regulation of bone physiology.
CALCIFEROL REGULATI ON OF
PARATHYROID HORMONE SECRETION
PTII secretion is usually augmented by calciferol de-
ficiency. This is attributed at least in part to the hy_
pocalcemia that results from impaired intestinal ab-
sorption and bone metabolism, and possibly also
from 1= of calciferol regulation of renal functions.
PTH then provides SOme protection against devel_
opment of severe hypocal«mia. However. the effects
of that hormone are blunted in {).deficient animal,.
PTH secretion also increases when renal disorders
depress or abolish Ia-hydroxylase activity.
Some actions of PTH are exened on bone cells re-
sponsive 10 1.25·D. but the two Itormones act on dif-
ferent receptors (273). PTH can bone re·
sorption. but it also exerts some influences on cell
proliferation that are I10t mimicked with 1.25-D.
The most common bone disorder of hyperparathy·
roidism is osteitis fibrosa cystica. a condition in
which .ome of the bone matrix i. replaced by fibrous
connective tissue. It is likely. howe''Cr. that PTH
makes sub.tantial contributions to the bone patltol·
ogy associated with calciferol deficiency. The sever·
ity of the 05tC<lporosis that follows immobili7.ation in
rats is diminished by parathyroidectomy (127).
1.25-D indirectly suppresses PTH secretion. since
it elevates the Ca1+. Direct effecls of the cal-
ciferol on parathyroid gland cdls arc complex. Spe·
cific, high-affinily re«ptors for 1.25-D have been
identified in the glands. and hormone·receptor com-
plexes translocate to the nuclei (123). I! has bttn
proposed that minute amounts of the calciferol are
required to maintain !Klrmal cell functions (74,183).
and concentrations of 10 II M can increase PTH se-
crelion. According to some observers. concentrations
of 10 ,. M directly inhibit. and ones of 10- 1 M 3re
even mOre effective (55) . Others have I10t observed
acute inhibition (99). but some long·range in"uenees
on PTH relcase or on the sensitivity to calcium ion
inhibition have I10t been ruled out (183).
The preceding findings can be easily fitted into a
concept for homeostatic adjustments. When the
1.25·D levels arc vcry low. PTH is ncedcd to supple-
ment thc infiuences of the calciferol on life-suslain·
ing maintenance of the plasma Ca l - . When 1.25·D
levels rise, normocal«mia can be achievcd in the
presence of low PTH. Perhaps some direct inhibitory
inHuences of 1.25-D on PTH secrelion can more ef.
CALC tUM. PHOSPHORUS THE CAl C!FEROlS
fcctively control the activilY of the parathyroid cells
than just the changes in Ihc plasma calcium.
However, although paralhyroid cells do nOt COn·
lain specific. high-affinilY receptors for cenain other
calciferol melabolites. there arC good rCaSOnS for be·
lieving Ihat somcthing other than 1.25-D serves as
the major regulator (171).
In hyperealcemic states. 1.25-D levds arc usually
well below Ihe concentration range associated with-
inhibition. AI such times. the C<lncentrations of 25-
OH-O. 24.2S-OH·D. and 25 .26-D may be adequate
for regulation of PTH secretion by bovine parathy·
roid cells. It has also been reported that although
1.25·D only partially reduces thc si7.c of parathyroid
glands of kidney-damaged rats (92). combinations of
1.25 and 24.25 metabolites totally suppress the hy-
perplasia. Similar influences of 24.25-OH·D on cn-
larged parathyroid glands of ca1cifcrol-<leprived
chicks have been described. A synthetic analog, lcr-
2<k1ihydroxy vitamin D is reporled to be highly ef-
fective for controlling the hyperparathyroidism of
rats with immobili7.ation ostC<lporosis, and it has
becn suggested that this agenl is safer Ihan 1.25-D
in such conditions (127). 2S,26-Dihydroxyvilamin D
(137) and 2S.oH . D are also effeetivedepre>S:lnts of
PTH secrelion. and Ihey can accomplish this wilhout
elevating the blood Ca l - (171 I.
I! will be nccessary to explain controversial find·
ings regarding the effects of 1.25,0 and 24.25,D on
parathyroid function (39) before definitivc conclu-
sions concerning the control mechanism$ can be
drawn.
CALC IFEROL AC TI ONS ON THE KIDNEY
Specific, high-affinity receptors for 1.25-0 are pres-
ent in the kidney. and Ihey bear close
10 the proteins found in the intcstine. The Itormone
excrts scveral influences unrelated to its roles in the
regulation of la-hydroxylase activity (241). These
are difficuh to definc because (a) the effects of the
hormonc on induction of CaBP and othcr
are nOI the same 31 (211). (b) specicsdiffcr-
enCeS in renal responses to 1.2S·D have been ob-
served (14S), (c) there arc numerous interactions
with other regulators that control elcctrolyte excre·
lion. (d) the eXira-renal effects of 1.25·1) contribute
10 the roles of the hormone in the regulation of elcc·
lrolyte excrelion. and (e) 25·0H·D binds to the hor,
monc receplON. The affinily is lower. but the con-
centrations of that metabolite arc of sumeient
magnitude 10 affect Ihe biological functions (61) .
Calciferols may faeili1ate renal conservation of
calcium and phosphorus. especially during times of
skeletal growth and repair and when the dietary sup'
 ply of lhe minerals is limited. HO,",'tver ..... hen 1.2S-
o deVltes Ihe plasma Ca'*. it a u,ments calciuria.
MOiIt 01 the actions of PTIi on lhe kidncy have
' -n linked .... it h cAM P ,cnc: ralion (86.214). Calc;'
ferols anl.lgOnize the effects. but lhey do flO! consis-
tently .ffect t he plK.>lp!>odieste rasc activity. 2S-OH·
o has been re ported 10 Oppo$C the plK.>lphalurie ac·
lions of glucagon (which a . c a lso thoughl 10 be
cAMP.med iated) (194 ). On the olher ha nd. a l·
t housh CT is yel another hormone Ihat promotes
cA M P generation, o;a k:iferol in leractions can vary
.... ith tIM: upcrirncntal QOIlditions.
All hormones cxcning major innuellCC$ on cal·
cium mctJ.boIism aff«t the renal ncretion of $0-
di um Ind c hloride. Palients .... ith hypcrparathy ..... d.
ism often develop h)'perehlorcmil: acidoois ( 199).
Acidoois can Ihen exacerbale the problems of PTH
excess by 3e<:cle.aling . ena l loss of ca lc ium (60). It
also impairs conver.ion of 25-O H·0 10 1.25·D
(14]).
Cakifcrol deficienc), also leads 10 the development
of hypcrchlorcmic acidosis (60). Although uagscr·
Ited PTH activity may be CMlCtIlOUS DJ
can lu,menl chloride excretion in pal'llth)'roidecto-
mized animals (13). ThyroidecUlOll)' removes the
soorec 0( <.:al<;itonin. aoo il bl untS thc effecls of lhe
calciferol.
CALCIFEHOL ACTIONS ON SK ELETAL
MUSCLE AND OTHER TISSUES
M uscle ,",ukncss is a common fiooing in villm in /)
deficiency states. C hanges in ele<:tf"Olll)"08l'l1ms Ind
Iocali«d disorganizalion of m)"Ofibrils have been de-
scribed. Tbc: lroponin C <:Ollleni of lhe is sub-
roormal. and t he milothondria show reduecd calcium
<;onlent (39), Improvcment can be achieved with
ei lher 25·01-1·0 or 1.25· D. cven whcn Ihe dosages
are insu fficie nt for olevaCion of cireu laling calcium
and phospha te oonc<= ntrationl, T hey are u.sociatcd
wit h 50mC lowering of SCrum al ka line phosphatasc
(60). The wea kness probably <;OIllribules 10 lhe d i·
reet effects of IlOi IIIOuC deficiency on lhe bOhe!S.
Tbc:re is gl'O\Oins awarcnc:§$ lbat calcifcrols are
widely involved in phYSioiocical pr<lC'wes IMt arc
linked ...ith movements of calcium ions. Recent fi oo.
i!liS Ihe hormones in bo!IC marrow d iffcr.
cnt iation (268) and in acq uisil ion of normal phago:>-
cylic and in Aa mmatory reaction! (23 ). Vita min D
Ilso $Cems to be a modulator of skin c)'rosi nasc rc-
spon$C$lo ullraviolcc radia tion (189).
REFERENCES
I. I\aron. J . E. Ili<'oio&ical .... pte •• 0( 11K: Relalion-
Ihip Belw""n Vil.min D .DOl Bone. 6. Pr.
2<l1-6S of l.awson, ed .. ref.r.nce 14 1.
2. ... d. m•. N. D.. G •• 'h .... ,I •• T. L.. G ray. R. W.•
H...,n. T. C. and Leman". J .• Jr. TlIe Inlo""l;1·
. ioMhips ''''''''1 Proiaelin. 1.2S-Dihyd fUlyvi·
Ilm;n D. Ind P:oralhynlid Hormone in ll umanJ.
J. eli... £NlrxrflfDi. oNI: 62\1.-30. 1979.
1. Adam ... N. 0 .. Gray. R. W.. IIId l emonll. J .• J •.
The El'fo<lS <>f O ral CaCO, Lo.4in. and Diel• •)'
Cllci um Dr:privalion on Pla.ma I.2S-Dihyd."xy.
vii. min D Concentrations in HOllthy I\dull<. J.
Clln. EndoerillOl. #8: 1008- 16, 1919.
• . Adeblein, R. S .. Rc.ula l'Ofl and Kioclies of Ihe
I\ctin-Myosin-ATP Inlcraction. Ann. R.....
921-S6. 1980.
S. Ali. S. Y. Analysi. 0( "hln. Vesicles and Thcir
kole in l hoe CalcifiCltion of I:piph)'IC11 ClnilllC.
Frd. " -. Jj: 1J5-42. 1971>
6. Aloia. J. R.• R..... P.• VI ..... ni. A.. Zan.i. 1..lnd
COh n. S . H. Rate of Bone l Cllt in Postmcoopau.. 1
and o.,e<>POfO\;c Women. J. Ph},Ji"'. 141.-
E82_ E86.1982,
7. I\I-Shaik haly. M. I I. M .• Ned ...... r<l. J.• and
Can""" . D. Sodiu m· l nduc.d Calcium Rclcl"
from MitOChondri, in Br .... n I\dip(lOC n ......
Proc. Nail. AaJ. Sd. USA 16: llSG-l. 1919.
• . Ame<:nuddin. S .. Sunde. 1.1 .. Dr:luea. H. F.• Ike..
u ..... N .• and Kobayashi. Y. 24-11)'dC'O>.)'bllon or
2S-U)'dtOJ:yvi'amin D,: I. i, Rtqui, <c! for I:mbr)··
OO'IOe Development in Chicko? &k1lCr 217: 4S1_2.
1982.
9, H. C. Mal ri. C.leific.,ion.
IN. PTO<. Jj: IOS_ S. '916.
10, I\nde""", H e. ond S.j<:l.r•. S W . Calci fica.
lion of Rac hitic: Clrtila,. 10 Study Mal ri. V.. i.
cle hnc.1on Frd. Proe. Jj: 148 -Sl. 1916.
II. "'nderson. T. R.. and Tovcrud. S. U. f irm 0(
Fe'· a .... A_rbi<; ... cid Ofl "cid Phosp/tawcs
from Ral Bone. CIl/rit Tlnw Iftl. ) 4: 54_9. 1982.
12. "'mbltt••• H. J .• W"""'u ...... 1. 0'1 •• 7..<:....".. T.
V....... o..i ... 8 . O. 1:11""".. of Para.
thy. oid H... mone On lh. R.... I I.2S·o; hydrol Y-
vil.min D, and 24.2S. Dihyd ro.y.ilamin D, P*
d uc,ion or You n8 aod I\dull R.".
III : 1339-44. 1982.
ll. Armb.echl. H. J .. 2<:=r. T. V.. and n •• i•. 8. B.
Eff"". of Vilamin 0 M.'obo/iles <)fl ' nlest; ... 1
Clkium l\bsiM']>tion ud Cllcium.Bindi", P*
lein in You.,,« and Adult Rill. £NlrxriMI. 106:
14. G. D.• «I. of PA"WlOV. OCC.
7. vol. 1. American Ph)'lOiololkal Sociely. Wa<h.
i""OO'I. D,C.. 1911>
IS, I\ urbach. G. D.• Marx . S . J .. and Spie,.e]. A. "1 .
Para lhyroid Hormone, Clteilonin. and Ihe Caki·
rerols , Ch. p. 19. pp. 921-1031 of Wi lliam •. R, H.
cd. TUlbook of l:."rn/oer/IlOlOV·, Saurliler$. 198 1.
16. Bal k. S. 0 .. Polimeni. P. I.. \loon. 8. 5 .. I.e-
Stour,_. D. N .• and Mitchell. R. S. Prolifera·
tion 0( ROllS Sam>ma Vir",·l nrec,cd. bIOI..,. 0(
Nor"",1 Chick ... Fi.robb ... i. I Medium 0( Re..
d uc«l Calcium and Ma,,,",um Concenl.. llon.
PTO<. NaIl. MaJ. Sri. USA 16: 3913_16. 1919.
17. !:lor. A .. l nd Hu ... dl'. S . The Inleraclion Be, ween
Diell.y Calciu m and Gon.da il lotlnon .. in TIleir
.., Elfeol00 PI.,m. Caldum. Bone. 2HI}'dro,¥ci'Io-
l<calciferol·I.Hydroxyl.... and Duodenal Cot·
cium-Binding Protein, Mea.ured by • Radioim-
mo"",,=y in Chic); •. /()f: 1455- 60,
1979.
18. Ila ... n. D . T .• Lee, S. W.o and A_;oli. L. v. Ac·
Guired Allerat;on. in Vit.min 0 M... boli,m in
Acule Acidotic Slate. Co/elj. Int. 34: 165_
8, 1982.
18A. a. ... n. D. T .• and Milne. M. 1.25 Dihydroxyvi.
tamin D· I ndu«d I nhibilion of 'H·H Hydro.yyi-
tamin 0 P",dUClion by lh. Rachitic Rat Li'er In
Vitro. CO/elj Ti.. Int. 35: 46 1_4. 1983.
19. Baran. D. T .• Whyte, M. P .• Haussler. M. R.•
De/tOol. L. J. $Ia'op;>],ky. E.• and Avi<>li. t. V.
Elfocl of the Me.SIr .. t Cycle on Cllcium-Reg.-
I.ting Hormon .. in the No.mal Young Woman.
J. C/in, Endoc-r;l/IJl. Mmh. 50: 377-9, 1980.
20. Barlcl. J.,P. Inhibition by Calcitonin of Hyper_
calcemia Inducci by 1.25·Dihydroxyellolccalci.
feffll. J. Endl><rintJl. 8j; 63_7. 19S0.
21. Barl>< •• J . J .. aod Law",n. D. E. M. Biochemi"ry
of Bone in Relalion to the Function of Vitamin D.
Chap. 7. pp. 267-302 of Lawson. ed .. reference
141.
22. Barsh. G. S .. David, K. E .. and Byers. P. H. Type
I O!.teogcnesis Impcrfcc,a , A NonfulICliontll AI·
lele for Prool(l) Chain. of Type I Pro<oIlagen.
f'Nx. Nail. Acad. Sri. USA 79: 3838_42. 1982.
2). BarShovi,. Z .. Noff, 0 .. Ed.'''oin. S.. Moy. ',
M. $hibolet. S .• and Goldman. R. 1.25-Dihy-
droxyvitamin D, and the Resula';,,' of M.cro-
phage Fune!ion. (",,1<4 nw" Inl. JJ: 673 - 6.
1981.
24 . Barton. J. C .. Con.-..d. M. E .. Harrison, L.. ".d
Nu by. $. Eff"",. of Vi .. min D on Absorplion
and Relention of Lead. Am.,. J. P/rYJiol 138:
GI24_GI30.1980.
25. Be.mer. W. G.. Wil"'n. M. c.. and DeLuca. H.
Succe.. ful Trea!ment of Gcnc,ically Hypopboo-
phatemiC Mice by Ia-IIy<1ro.yvilamin D, but
N<II I.2S·Dihydro.y_i'amin D, . End(JCrino/. 106:
1949_55. 1980.
26. Bell. P. A. The Chemistry of !he Vilamin$ D.
Ch.p. 1. pp. I-SO of La"""n ed .• rderence 141.
27. Bellomo. G .. Jewell, S. A.. Thor. II .. and Orren_
iu •. S. Regulation of Inlr'cellular Calcium Com·
partmtntaliza,ion: Sludies wilh lsolaled Hepa!o.
cy'., and I·Bulyl lIydropero.ide. PrOt. Narl.
Acad. Sri. USA 79.- 6842_6. 1982.
28. Ber"ren. P. 0 .. O!.teMOn. C. G .• Pews.on. B..
.nd Hd lm.n. II. E_idcncc for Divergent Glucose
Effoct. on Calcium Metaboli<m in P'''''r'.lic fj.
<>-Con •. l::ndO(,intJl. 10j: 1463-8. 1979.
29. Bikle, D. D.. Spencer. E. M.. Burke. W. H .. and
RO$t. C. R. ProlaCtin bUI Not O"""lh Hormone
Stimulale. 1.25·Dihydroxy.i!amin 0 , ProduCtion
by Chick Renal P.-.;paration. in Vi,ro. EM()(,i·
111)/.107:81-4,1980.
30. BI ,bo>. J .. and Care. A. D. Natu.-.; of the CO,!;,
CALCIUM. PHOSPHORUS AND THE CAlCIFEROLS
coid Response. (",,/eif. Tis.'Ut 1m. 14: 217-18,
1982.
31. Blauslcin. M. P".nd Nel""n. M. T. Sodium·Cal·
cium Exchange' The Role in ,h. Regula!ion of
Cell Calcium . Ch.p. 6. pp. 217-36 of Ca rafoli,
cd .. reference 48.
32. Bloom, W ... nd fawccu, D. W. A Tarbook of
Hi.<rQlogy. I fuh «I. Saunders. Philadelphia. 1975.
33. Oordier. P" Ra,mu"",n. H.. Mori., P.. Miravc,.
L Gueri •• L.nd R),ekawer!, A. Vitamin D Me_
taboli!e. and 00110 Mino .. ",-",ion in Man. J.
Clm. Endac,il1l)/. Mt/"b. 46: 284_92.1978.
34. Oori •. A .. Hur le)'. J. F.. Trmal. T.. Mallon, J. P ..
and Matus>e •.-lui, D. S. Evidence for the Promo-
lion of Bone Minorali,-,,'ion b), 1.25-D ihydro.)".
cholce.lciferol in Ihe Rat Unrel.ted 10 Ihe Cor-
reClion of Dcfieie""ies In CalC ium and
Phosphor.,. J. NUl'. 108: 1899-1906, 1978.
3S . Borlo. A. II. Regulalion of the Mitochondrial
Con trol of Cellula, Calcium Hom..,.ta,i. and
Calcium Transpor! by Phosphat<, Paralhyroid
Hormone, Calcilonin. Vilamin D aod Cyclic
A.\\ P pp. 217_28 of Talmage. R. V.. Owen. M..
and Parsons. J . A" ed •. Calcium R'p/aringlfor-
monn. EI«:vier, New Vork. 1976.
36. Born.tein. P... nd S.ge. H. Structurally Diotinct
Con.gen T)"[>cs. Ann. N, •. Bioc/r,m. 49: 957_
1003.1980.
)7. Bouillon. R., and Va. Baclen. fl. T,-,,"'port of Vi·
0: Sisnifieonce of Fr<c ond To,.l Coneen'
Iralions of the Vitamin D M,,!.boli,e •. ("a/eif.
Ti.SUt Int. JJ: 4S 1-3. 1981.
38. Bouillon. R .. Vandoren. G .. V.n lI.elen, H.. and
DeMoor. P. of Effcel of Ih. Vitamin D Sla·
tu' on the Co""entr:ation of ,he Vit.min [).Bind·
;ng Prolein in \he Rat Serum. EndO(,intJl. 107:
16Q-.-3.1980.
)9. 8raUlb3!. N .• Lee. D.1l. N .. and Kleeman. C. R..
The Divalent Ion. Calcium. Phosphor.,. and
Magne.ium and Vit.min D. C,,"p. 12. pp. 441_
526 of Fr.inke l. N., ed. C""I.mporo'y M t laOO-
ii<m. _01. 2 Plenum. New YOfk. 1982.
40. Brau'igan. D. L.. Kerrick. W. G. L.. and Fiocher.
E. fl. In.ulin.nd Gluc0se--6-Phosph ... Slimul.·
'ion of C." Up,.ke by Skinned Mu""le Fib<rs.
PrOt. Nal/. ANd. &i. USA 77: 936- 9. 1980.
41. IIrighton. C. T ... nd Hunt. R. M. Hi<lochemieal
I.ocalizalion of C.kium in Growlh PI ... Mito.
.hondria and Malri. vesicl... F,d. PM/;. 35: 143_
7,1976.
42. Bringhursl. F. R.• and Potts, J. T .. Jr .. Eff""t. of
VilOmin D Metabolile.and Analog< on Bone Col·
lagen Synlhe.i, in Vitro. ("aleij. Tinu. Int. J4.-
103-10,1982.
43. Bromm.ge. R .•• nd Neuman. W. F. Grow'h Fail·
Ur< in Vil.min [)'Dcficion' Rat Pup'. (",,/cif. Ti.-
"" Int. JJ: 277_80. 1981.
44. Bronner, F. Vi .. min D and Memb.-..ne Slructun:
and Funcl ion. FM. Pnx-. 41 :60.1 982 .
4S. Bronner. F. I.te.tinal Calcium Absorption and
 Tran.poll. Ch.p. 7. pp. 237_62 of Carofoli. ed"
roferonee
46. Bronn.r. .• Lipton. J" Pan'u. D" Buckley. M"
Singh. R".nd Miller. A. Molecular and Tran;.
poll Effco" of 1.25-dihydroxyvitamin DJ in Rat
Duodenum . Ftd, Proc-. 4 1: 6 t -5, 1982.
47, l!run •. M. E. H" Bru" •. D. E" and Aviolk L V.
Vitamin D-Depcndent C.lcium,Binding Pt",.in
of Rat Inte"ine: Chang.. Durin$ Postnatal De·
velopment and Sen$iti.ily 10
Iccaleifero!. EndorriMi. 1M: 934-8. 1979.
48. Carafoli. E.. cd. MrrnhNJM T"''''porl 01 Cal-
dum, Academic Pre ... New Y"' k. 1982.
49. Carafoli. E. The Tran.""rt of Calcium Across the
Inner Membrane of Mi1ochondri • . Chap. ). pp.
109-39 of C.rafoli. cd .. refcrence 48.
50. C'r.lroli. E.. and Crompton. M" The Regula1ion
of Inlracellubr Calcium by Mitochondria, Ann.
N.Y. Acad, Sci, J07: 1918.
SI. Castillo. L. Tanak •. y " Winel.nd. M. J" Jow-
.. y. J. 0" .nd DeLuc •. H, F. ProdUClion of 1,25·
Oihydro.),.i.. min OJ .nd Formation of Medul-
lar)' Bone in Ihe Lay ing Hen . End""'riMi. 104;
1598_11101. 1979.
52. Ceco".IIi. 8.. Hurlbul . W. 1" .• DeCamilli. 1"" and
Mcldol•• i. J. The Effect or Extracellular Calcium
on the Org.ni,.. tion of the Pla.m.·
lemma in T""O Secretory System •. An". NY,
Acad, Sci. 307· 6S3-5. 1978,
53. Ch.rle,. M. A" Mafti.1. J" ZoIoc k. 0" M",ri.·
sey. R ... nd BaXler. J, D. Re8ul.t i<m or Calcium ·
Binding Protdn Messenger RNA by I,U·Dihy.
drox)'choloc.lc ikr(>l . Calif r;"ut In!. JJ: 15-18 .
1981.
54, Chal1erji. S .. W.II. J. C .. ond Jeffery. J. W . Age-
Rel.t.d Chang•• in the Orienlalion and Panicle
5i'e of the Mi ner.1 Ph.se in Human Femoral
Cortical Bone. Cakif ]j'"Ut 1m. 3J: 561_74.
198 '-
55, Cherlo",. B. S .. Baker. G. R., Henry. H. L .and
Norm.n. A. W. Effects of Vitamin 0 Metabolile.
on Bovine Parathyroid HOIJno-ne Role ... in Vitro.
Amu. J. Phyjiol. 218: El84- E388. 1980.
56 , Cheung. W. Y. Calmodulin Pl.y< a Pivotal Role
in C.llula, Regulation. Sdtn" ]()7: 19-27. 1980.
57, Christa' os. S .. Friedl.nder. E. J .. Frandsen. B.
R.. and Norman. A. W. Sludies on the Mode of
AC1;on of Caleiforol. XIII. Development and Ap-
plication of a Radioimmunoa ... y for Vitamin D-
Dependent Chick In .. stin.1 Calcium.Binding
Protein and Ti .. ue Di.lribulion. End"",rillO/, 104:
1495_IS03.1979,
S8. Chri.lakos. S .. and Norman. A. W. Vilamin D-
Dependent Calcium Binding Protein and ilS Ro·
lalion to 1.25·Dihydro. yvilamin 0 Recoptor l.Q.
c.liution and Concentration. PP 371-8 or Ca .. -
foli. referenO<' 48-
S9. Chriotian.en. C .. Maze ... R. B.. Tran."",,I. I. . and
Jan.en, G. F. hctor< in Ro.pon .. to Treatment
of Ea,ly Postmeoopau .. 1 Bone Lou. Cakif Ti,_
'Ut In!. J3; 575_81. 198 I.
60. Coburn. J . W .. Kuro"w •. K.. and Kleem. n. C.
R. Divalent Ion Metaboli.m. Chap. II. pp. 401-
110 of Freinkel. N .. cd . Conumporary Mtlaho-
riM'. vol, L Plenum, Ne'" Yor'. 1919.
61, Colston. K. W .• a nd Feld m.n. O. oemo",,,.,;"n
or • 1.2S-Dihydroxycholccalcir.rol Cylopl.smic
Receptor·Like Binder in Moo", Kidney. J.
MtMh. 49: 798_800.1979.
62, Corr.dino. R. A. St ruet"re.Aelivity Relation·
.hips .,.. Vitamin D Metabolite. and An.logs in
the Induction of Calcium-Binding Protein in
Organ-Cultured Embl},{mic Duodenum .
pp. l85_92 of Siegel.t 81... d•. rererence 226.
63. CroUCh. E.. Sage. H .. and Bornstein. P. StTUetural
Ba.;, for Apparent Heterogeneity of Collagen. in
Ilum.n Basement Membranes: Type IV P,oool-
lagen Contai", Two Distinct Cha;n •. P1'()(, Norf.
Acad, Sri. USA 77: 74S- 9. 1980.
64. C,uik,han' , D. 1"" Pitkin, R. H" Reynold •. W,
A.. Willi .m •. G, A... nd H.rgis. G. K. Altered
Maternal C.lcium HonlCOiU.;, in Di.helie PteK-
nane),. J. Cfin. t'ndorriMi. Mtlah. SO; 264- 7.
19S0.
65. Dedm.n. J. R .. Brinkley. B. R.. and Me.ns. A. R.
Regulation of Micronlamcn" and Microtubule,
b)' Calcium and Cyclic A\1P, pp. 131-14 of
Greengard .nd Robison •• d... referonce 104.
M. Deftos. L J .. Panhemore. J, G .. and PriO<'. P. A.
Cha nge' in PI •• m. Bone GLA Pr<>tein Ou,;ng
Tr.atment of Bone Di ...... Cold! T;.. 34:
121 _4.1982.
67. DeLuca ..... F. Recent Ad •• ""e, in the Metal><>-
li.m of Vitamin 0, Ann, ReY. Phy'iol. 4J: 199_
209.1981.
6S, DeLuea. H, F.. ed. Tht FQI-Solubl, V;1O",i,...
Plenum 1"..... New Yotk. 1978.
69, Deluc •. fl, F. Vitamin 0 and Calcium TraM-
poll. pp. 356-75 of Scarpa .nd Carafoli. ed,., rer·
erencellS.
70. DeLuca. H .. hancheschi, R. T., Halloran. B. 1".,
.00 \1 .... ro. E, R. M<>I.cular Events Involved in
1.25-<lihydroxyvilamin D, Stimulation of Inles·
tin.1 Calcium Tran,port, F,d, Pror. 4 1: 66-71.
1982.
11. DeLuc., H. F.. and Schnoc., H. K, Metaboli.m
and AClion< of Vitamin D. Ann. Rn-. BiorMm. 45:
631-66.1916.
72. Denbow. D. M .. and Edens. F, W. Effects of In-
travenlricular Injection. of Sodium and Calcium
OIl Body Temperature in the Chiclen. Am". J,
PhY.lio/, 119: R62-R6S. 1980.
73. Desroche •. D.. and Martin. C. R. &.,.,nal. Vi-
tamin D and Thymus Innuenee$ On Ren.l Elec-
trolyle E. eretion Panern •. f'tJ, Pror. J9: 661
(abslr.).1980,
74. Dietel. M.. Dorn, G .. Montz. R.. and Altenlhr. E.
Innuenccof Vitamin D,. 1,25·Dihydro.yvit.min
0 , .• 00 l4.2S-Dihydroxyvitamin DJ on P.raIhy-
r(lid H",mone Sec",tion. Ado!lOSine Y. S'-M ono-
phosphate Relea ... and Ultr •• lructure of Para-
thyroid Glands in Organ Culture. t.'ndorriMi.
/OJ: 231-45.1919.
7S Dot)'. S. G .. Robinson. R, A .. and SchofI.ld. B.
."
Morphology of Bon. and Siaining
Charaoter istic. of Bone Cen,. Cbap_ 2. pp. 3-23
of "urbach. cd .. ",(erence 14.
76. Dupoi •. Y .. Dig".d. A .. and Gaudin-Ihr<ling. F.
Effecl of Vitamin D (kf,oicocy On lJrin3rY E,ore-
'ion of Conneclive Tissue Deri •• ,ive. (Hydro'Y'
prolin" a nd G lyC<lSamiooglycan.) in Rat •. calif
Tj,jut/m. 33: 177- 80.1981.
77. Eb..hi. S .• M ibwa. T .• Hir.i•• ,'.1 .. and t"ooo.
mura, Y. The Regulatory Rolo of CalCium in
MU$Ole. pp. 1_61 of Scarp" a nd C arofoli. ed.,.
referencellj,
78. R .• aod Ewald. D. Residual Calcium 100.
Depr= Activalion of Calcium-Dependent
,c"L 116: 730--2. 1982.
79. £"'01, Y _, Sil\>crmann, M .• Lewin$Qn. D ., S"ydcl.
N .. Tnistcr. Z .• and Hard!. A. Elevated Concen-
tration. of Synthetic Fluorinated GluCOCOrliCQid
Analogo Tr3nsienl1y Incre ... the Int racellu la,
Exchang.abie CalCium in Cultured Ik>nc Cell •.
Calrlj. Ti.. Int, 258-64, 1982.
80. Fehor. J. J .• and W ....'m.n. R. H . Int."in.1
Caieium·Binding Protein and Calcium Abso,p-
tion in COrti<ol·Trea ted Chic." Effects of Vit.·
min DJ and 1.25·Dih),d'ox),vilamin 0 , £mJoc,-j·
,wi, 547_51. 1979.
81 . Feli ., R" and Flei,ch, II. Role of Mal,i . Vosiok.
in Calcif,cation. Ftd. Proc. )j: 169- 71. 1976.
82. Fc"le'. J. H" .nd F."l er. L. I. Bios),nth«i, of
Procolbgen, . Ann. R"". 1 29_62,
83. Fi,k.m. G .. and Lohninger. A. L. The Meeh.·
ni,m, and Regulat ion of Miloxhondrial Ca"
Tronsporl. Ftd. Proc. 39: 2433- 6. 1980,
84. Fontaine. 0 .. M.numOlO. T .• Goodman. D. B. P..
and Rasmu, .. n. H. Lipooomic Control of C. ' ·
Transport' Rel'lion,hip 10 Meehani.m of AClion
of 1.25·Dih}'drox)'.iumin D, . Proc. NOli. Arod.
Srl. USA 78: 1151 - 4. 1981.
85. FooI. ine . 0 .. Pavlo.ilch. H... nd Hal"'n. S. 25·
H),drox),cholcc.iciferol Metaboli.m in Hypoph)'.
scclOmi'ed R.... t·nJ"..rinol. 102: 1822-6. 1978.
86. F<>rle. L. R .. Nidol$. G. A.. and Anont. C. S.
Renal Aden),l.te Cyda"" and Ihe Inte,rel"i",,·
ship Between P"d, ,,hyroid Hor"","e and Vit.min
D in the Regulation of Urinary Phosphate and
Ade"",i .. Cyclic 3'.5'.MollOphospnatc Exe ....
tion. J. Oi/). 1"'7"1.57: 559-68. 1976.
87. Frankel. S .. and Yas"m.ra. S. Chan8es in Ihe
Th)'roidal Content of Th)'rocalciloni n Produced
by Vil.min Din Ral1, t:ndocrillfJl. 88: 267_70.
1970.
Fr.. nlini·Arm.trong. C. S"uc,ure of Sarco-
plasmic Re,ic.lum. Frd. Proc. )9: 2403-9.1980.
89. Fr'""r. D. R. Reg"lalion of the ."1et31>oIi,m "f Vi·
tamin D, nysioJ, R"". 6/): 551-61 1. 1980.
90. Fre"nO. T S. Inle.tinal Phosphate and the Vita·
min IH)ep<ndcn <Calci um· Binding Protoi n•. pp,
407_8 of Siege l c"1.. ed ... referenee 226,
9). Frumar. A. M .. Meldrum. D. R.. Gcol •. F.. Sha·
monki. I. M .. T,uaryn. I. V.. Dcftos. I.. J .. and
CALCIUM , PHOSPHORUS AND THE CALC1FEIIOlS
Judd, H, L. Rel'lion.hip of F.'ti", Urinary Cal·
eium to Cireul'li", Emoge n and Body Weigh, in
Postmenopausal Women. J, El1docrinol.
Mnab, W: 1980.
92. Fuxu,him •. M .. Niki. R.. Ohkawa, fL, Shimi,.u.
T .. Mal.unaso. I., N.kono. H .. Ta\:'.ga ki. Y .• Ni-
shii, Y .• Ohno. K. •• nd Suda, T. Comparative
Therap<.lk Effeet' of Vitamin 0 , and its Dcriv·
.,ive> On Ex""rimen,.1 Renal o.teodY"rophy.
t"ndocrj,lOl. 107: 328-33.1980,
93. G."i",n. J . C. Borl.nd. M, K .• Florio. V, A.. and
T"' ible. D. A. The Role of C.lcium Ion ••• Me·
di"or of the Effect. of Angiotensin II , Catechol·
amine,. and V.<op..... in on Ihe pno.phorylation
and Acti.ity of En,.ymc; in Isolated Htp"""ytcs.
J, Hiol, Chr",. 1979.
94, Ga,con-Barre. M. Biliary Exeretioo of [JHJ.25·
H),dro.yvilamin 0 , in the Vilam;n D·IXpleted
ROI. A",,,,. J . Phyliol. U}: 1982.
95 . Gcll>ard. H. A.. Stern. P. H .. and U·Priehard. D .
C. 1,2S·Dih)·drox)'.il.min DJ Nude .. Receptors
in Ihe Piluita ry. 1247_9, 1980.
96. Gelman. R, A .. Popp"e. 0 . c.. and Piel. K, A.
Colla8en Fibril Formation in Vitro. J . Bioi. Chr",.
254: 11741-5. 1979.
97. Gc"ner, J . M .. Horsl. R.I... Broo.du$. A. E., Ru·
mo"", •. H.. and Genel. M. Parat hyroid Function
.nd Vitamin 0 Motaboli,m during Human
Gro"'th Hormone Replacement. J. Clin, t 'nt/Q('r/·
"'" M , ,,,h. IQ· 1979
98. GoldOorg. M .. Agu,. Z. S .. and Goldfarb. S.
Renal Handli"i of Calcium and Phosphate.
Chap, 7. pp. 2 11 -56 of Thu,a". K .. ed. Kid",y
and Urinary '["raN PhyJiology I/. University Park
Press. Baltimore. 1976,
<)-9, Golden. P.. A.• Martin, K .. Bellorin·
FOOl . E.. R.. Klahr. S .• and $Iatopolk.y.
E, Lack of a DirccI EffccI of 1.25.Dihydroxycho.
kcaie ife roion Parathyroid Hormone Secretion by
Norm.1 Bovine Parath)'roid Gland •. t'nJocrinoi.
107:602_7.1980.
100. Granl. M. E .. and Jackson. D. S. Thc Biosyn·
thc;i, of Procollagen. pp. 77_113 of C.mpOoIi. P.
1'.'.• and Aldridge, W, N .. cd •. Essay.. In BI<xhtm-
i.try. vol, 12. Ac.demie Pr.... Ntw York. 1976.
10 I. Gra)'. R, W. Effect. of Age .nd Sex on the Reg·
ulation of Pla.ma 1,25(OH),.Vilamin D by pno.-
pho,u, in the R"I. CQkij. Int. 3): 471_84.
1981.
102, Gray. R. W. Conlrol of Pla,ma US-{OHl,·Vi.
tamin D Concentr.lion. by C.lcium .nd ph<JS-
piloru, in the Ral ' Effect' of HypophY"Clomy.
Cakif. Ti;su, Int. 33: 485_8,1981 .
103. Green. D. 10.. Fry. M.. and Blond in. G. A. ph<JS-
pholipid,", the Molecu lar Inmumen " of I"" and
Solule Transport in Biologic.1 Membra .... Proc.
Nail. Acad. &/, USA 77: 257_61. 1980.
104. Gree"i.rd. P.. and Robison. A.. cd •. AdWlnn. in
(.)'dir ,'01 . 11. R.ven Pr=.
New Y<>rk. 1979.
 lOS . Vuthrie. H. A, inlTl;ducIOI"Y NUITili(H! 4th cd.
Mosby. St . Loois. 1979.
106. H,llo"n. B. P.. B.nh<il. E. N .. arK! DeLuca. H,
F. Vitamin D Metabolism During Pregnancy and
Lactati"" in the Rat. Pmc. Ntlii. Acad. Sci USA
76: SS49-Sl. 1979.
107. Halloran. B. P.. and De Luca . It. f. Calcium
Tran'f'Ort in Smalll",."ine Durinll Ear ly Devcl·
opment: Role of Vi,amin D. Am". J.
219: G473-G479.1980,
108. llallo.. n. B, P.. and DeLuca. H. F. Calei um
Tran,po.-t in Small Inlestine Durinll Pregnancy
arK! Lactation. Am". J. nyslol. ZJ9: E64_E68.
1980,
109. Ha'per. J. F.• Cheung. W. Y .. W.lIace. R. W .•
H",ng. It. L.. Levine. S. N .• and Steiner. A. L.
Loc.h,ation of C. lmodulin in Ral Tiuucs. Prot:.
Na,l. Aead, Sci, USA 77: 366- 70.1980,
110. Hauukr . .\1. R .. and McCain. T. A. Ba'ic and
Clinical Concepl< Related 10 Vitamin D Metal>--
h,m and Action, Eng. J. M.d. 197: 974_83.
1041-j.().1971.
III, llawth<>r ... J . N. I. Poo.ph.tidyli1'lOSitol Now
O"t of the Colcium G.tc? 295: 281 - 2.
1982.
112, llaynes. R. c.. Jr .• and Murnd. F, Agenl< Affecl-
ing CalcifIcation: Calcium. p.ra,hyr<>id Hor·
mo ... Cal cilOnin. Vilam in D and Olher Com·
pound,. Ch.p. 65. pp. I of Vilman. A. v"
Goodman. L S" .nd Gilm'n. A.. cds, Goodman
uml Gilman', ne n",,,,aMlngiral &lsi>
" {>t lllie•. Macmill.n. York. 1980.
113. Herm.n<en. K,.• nd Sehwa",__ T. W. The Inftu·
.nce of Calcium on the 8a ... 1 and Acelylcholine'
Stimubted Seeret;on of Pancreatio Polypeptide.
f.·ndlXf'inol. 1M: 1469_74. 1979
I 14. H ildmann. B,. Stordli . C., Dani'i. v.. and
H. Regulation of No ' .p, Cotr.n,porl by 1.25-
Dihydro»'"i .. min D, in Rabbi, Duoden.1 nru,h·
Border Membra ... Am". J . Ph,..iol. 141: G533-
(;539.1982.
11S. H;rsl. M .. and Feldm,n. D. GluCOCO)/I;coid Rcg-
ul.tion of 1.2S (OH),Yitamin D, R<ocp'o", Di·
"ergen' Elfec" on Mou", and Rat Inlest;nc. En·
drxrint>l.III. 1400_2. 1982.
116. HocI-.. J . M .. Kr.am. B. E,. and Rai". L. G. A"·
toadiographic Sludy of EIf<:<:, of US· Dih)'.
droxyvilamin D, on Bone Maltix Synlhcsis In Vi-
I.min D Replete R.... Ca/eif. 71.. Inl. 34.-
347-Sl. 1982.
117, Holick. M, F..• nd Clarl-.. M. G. The Pholobioge'
..si, and Metabolism of Vitamin D. Ftd. PrO(:.
37.2567_74.1978 .
118. Ii oliel-., M. F.. and DeLuca. H. F. Met.boli.m of
Vitamin D, Chap. 2. pp. 51_91 of L.w$Ol]. ed __
refercnce 14 1,
119. Holick. M. f .. MacLaughlin. J. A.. 0 ..1-.. ),1. B.,
Holick. S . A.. 1'<>11S. J . T .. Jr .. Andcrson. R. R .•
HI"nl-.. l. 11 .. Parri.h, J. A.. and Eli ••• P. Photo)-
')'nthe!i' of Pre"i"min D, in Human Skin and
Ph)'siologic Consequences. lIO: 203-5.
1980.
120. Howe. C. L.. Keller. T. C. S .. Ill . MC>i:I$Clcer. M.
S ..• nd Was.uman. R. H. An.I)'si. of Cytoskcl-
ctal Proteins and Ca '· .o.pendent R'8ulaliQn of
SlrUCIUr. in InlO'linol B.ush Borders from Rach·
itic Chicks. Pmc. N",I. Acad, Sci. USA 79: 1134_
8. 1982.
121 . Iloweli. L>. S,. Pil •. J, c.. "nd AI.. rez.J. Possible
Role of E,tr.ccliular Matrix Ve.icles in Caleir,·
cation of Healing Rachitic Fed. Pro<.
35. 1976.
122. Hug he •. M. R.. Baylin\: , D. J.. Vonncrman. W.
A.. Toverud. S , U .. Ramp. W, K., and Hau"ler,
M. R. Innutnceof DietA'y Vit.min O, on 'he Cir·
culating Coo<entral;on of its Aclive Metabolile in
the Chic \: .nd R"t. Emirxrl""'- I()(): 799_806.
1977.
lB. Hugh ... 1>1. R.. and Haussler. M. R. 1.2S_Dihy_
dro,),vitamin D, Receplors in Parathyroid
Gland •. J. Bi"l. 153: 1065_73. 1978.
124. I.ving. J. T. Inler",lalions of M. l.i. Lipids. Ve.·
iele, and C.lcifieation . Fd. PrO(:, 35.- 109_11.
1976
125. I... ac. R.. Merceron. R,. Cailiens. G.. Raymond.
J. · 1' ..• nd Ardailiou . R. Elfcct$ of Calei.onin on
Sa",1 and Thyr01rOpin·Rclca.ing-H ormone·
Stimul.lOd Prol •• tin Secretion in M.n. J. C/in.
I:;ndocr;no/, Melob, 50: lOll-IS. 1980,
126. r... ac. R,. Me",e,.,.. R, E.. Caillen •• G .. Ra)"
mond. J . · P. and Ard.ill"". R. Effect of Pam,hy.
roid Hormono on Pla,ma Prolactin in Man . J.
Clin. Endrxrino/, 47: 18_21. 1978.
127. I,",,'a. Y.. Makita. T .. lIioo. S.. lIashimo'o. Y..
Kushida . K.. looue. T... nd Ori mo. 11. Immobih·
'-"lion Osteopo,osis and Vitamin D: Eff<:<:1
of Active Vitam in AMlog. on 'he Developmenl (>/
Immooili""'tion o.leo>por",i, in Rato. Calif. Tis-
.• ur In!. 33: 623_30.1981.
128, J.nde. S, S,. arK! l.i,kova. Kiar. M, Effecl' of C)'-
loch"I ..;n Band Dihydrocyt<;>chal•• in B On Cal·
ciun, Tran'pon by Inlcslinal Absorptive Celis.
Calclf. Tissur 1m. 33: 143-S I. 1981.
119, Jone •• H. P.• I.cn,. R. W .. Palevi". 8. A,. and
Cormie •. M. J. C.lmodulin '--<>cali,,",!ion in Mam·
malian Spormalo,,,,,. Pro<, Nal/, Acad. Sci. USA
71: 2772_6.1980.
130. Jon«. P. G ..• nd lIau"ler. M. R. Scin'illation
Au"..radiographic L<>eali'-"lion <>f 1.2S-Dih)·-
dro,yvilamin D, in Chid Inte,,;ne. Endrxrino/.
104.' 3IJ_21.1979.
130A. Kano. K, arK! Jone •. G, Direct in "I"" Eff<:<:1 of
Thy roid Hormones on 25· Hydro,)·vi la min D,
MClaboli, m in lh e Perfu,ed R. l Kidney. Ende-
crintol. 114; 330_6. 1984.
iJl. Klct. C. B.. C.ouch. T. 11, .• nd K.in k., M. H.
C.lcinc"rin: A C.lcium - and Calmodulin-Bind·
ing Protein (>/ the Nervou. SY"cm . Prot:. N ar/.
Acad. USA 76: 19,9,
In Klee. C. R. CrouCh . T. IL. and Richm.n. P. G.
Caln,od"lin. Ann, IIty, 49:
1980
1l3. Klein. I.. Di"'cl Measuremcnl of Bonc Resorplion
and C"lei"m Con"'r""ion during Vitamin D Dc-
."
ficicncyor HYP"r>;!aminosi. D . Prrx. No'/. /trod.
Sci. USA 77: I 818-22. \980.
134. K<>S'ello .... 1\. 8.. and Morrill, G. A. Calcium Dc-
pendenco of S teroid •• d Gu,n ine l',S'-Mono-
phosphate InductiQn of Germina] Vc<icJe Brea k_
down in RaIUJ. OocY'os, £trdlXrioo/. 106.-
1012_19,1980.
IlS. KI'fl,ingc r, R. 1I. The Informalional Role of Cal·
cium in the Cy!oooi. pp. 1-26 of Gr«ngard, Po.
and Robi<on. G. A.. ed •. Ad"""as in
RtJt<lffh. vol. II. R... n Press, New Y<)rk, 1979.
136. Kuboki. Y .• Mechanic. G. L. Compa,ali'e
Molecular DiSlribU1ion of CrQ$$·Linh In Don.
and D.;ntin CoIl.gen Structure- Function Rola·
(ion,hips. Calci! Ti«u< In. 34: 306_8, 1982.
I J7. Kum3r. R. The Metabolism of 1.25- Dihydroxy-
,il.min D J • £ltdlXr;". R,y. I: 258_67, 1980.
138. Ku.uhar •. S .. and Schroer. H. Cytology .nd Au_
toradiography of "-'lrOgen. lnd uced Oiffertntia-
l ion nf Avinn End""te.1 Cell" Cokif.
34: 352-8.1982.
Tis,,,. Int.
139. Latm.n . N. Pituitary Stimu lation nf Parathyroid
Hormone E'idence for • Parathyroid
S,imulating Hor"",,,,,, J. Exp, ZOO!. 212: 313- 22.
1980.
140. l.a"'<»'in. S .• Zer,"'ekh. J. E.• G I.... K ... nd Pak.
C y , C. A bili,y of 2S·Hydroxy,i\3m in 0 , T he r·
apy to Augment Serum 1.25. and 24.25-Dihy_
droxY'i1amin D in i'oot m<lH)pausal o.'",",por",i •.
J. CUn, M"4b , SO: 593-6. 1980.
141. LaW>Or!. D. E, M .. ed, Vitamin 0, Academic
PreiS, New Y<>rk. 1918.
14 2, Law'-<)n. D . 1:.. M. Biochemical Resp<>nses of t he
Intestine t<> Vitamin D. Chap. 5. pp. 167-200 of
Law.oo. cd .. rde",nte 141.
143. Lee. S. W .. Russell. J.. and A'ioli. L V. 2S·ity·
drQ.ycholtcalcifcroi '0 1,2S.D ih yd,,,,,ycholecal.
cife,o]: Conversion Impaired by Sysl.mic Meta-
bolic Acid""i •. Sd."". 195: 994..(;. 1917.
144 , Lo'ter. G, E .. Vaode, Wiel. C. J .. G ray. T. K .. and
Talm.g<. R . V. 0 O< ficieney in Rat<
with Normal Scrum C.lci u m
p_, Nml. A C<ld. &i, USA 79: 4791-4. 1982.
145. I.e" inc. B- S .. BraUlbar. N .. and Coburn. J. W.
Vitamin D Affeel lhe Ren.1 Handling of
Calcium .nd Ph""phoru,? Min., ol & £I«trolyte
M.tob. 6.- 295_302. 1978.
146. Liang. C. T. . Barne$.. J .. Che ng. L. Balakir. R ..
and Sackt<>r. R. EffeetsQf 1.2S-(O H),D, Admin_
iStered;n ViV<;l <>n Phosphate Upt.ke by Isolated
Chkk Rena) Cell. , AIn". J. Physiol. 142: C3 12_
018.1982 .
141. Li ndg",n. J. U .. Merchanl. C. R.. and DeLuca.
H. F. Effec! of 1.2S.Dihydll)xyvi"m in 0 , (l!I Os-
t<opcnia Induced by Prednisolone in Adull Ru •.
Calei/. Int. 34: 253-57 . 1982.
148. Lindgren. U.. a nd DeLuca. H. Role of Par. lh y·
roid Hormone and D J in
lhe De'elopment <>f Osleopcnia in Oophorect<>m_
i,-ed RatS. Cold! 34: $10-14. 1982.
CALCIUM. PHOSPHORUS AND THE CAlCIFEROlS
149. LoCascio. V.. Ad.mi . S .. A,wH. L. V.. C<>mina·
cini. L Galva nin;. G .. Genna ri. C. Imbimbo. B.•
and Scuro. L. A. Suppressi.e Effect of Chronic
G luCQCorlicoid Trea,menl on Cire.l.ling Calci·
looin in Man, Calc-i! Tissur Int, 34: 309-10.
1982.
150. I.o<won'lein. W. R.. and R=. Il C.lcium in
(JUrIC,ional) In'ercdlul. r Cont mun ication and.
Thought (l!I iI' Boh ..;or in Jntracellula r Com·
munica,ion. Ann, N .Y. A cad. Sci. 307: 285-307.
1978.
151. L<>renc. R.• Tanaka. Y .. O<L"<a. H. F.. and
J OIl"'. G. LocI-. of Elfec, of Calcil0nin On 'he
ula,ion of Vitamin 0 MClaboli,m in lhe R.I. E...
d(x-,;lt(J/. 100' 468- n. 1977.
I Luben. R, A .• Wong. G . L.. and Cohn. D. V. Bio-
chemical Ch.raCleriUtion wilh Pa .. lhonnon<:
and Calcilonin nf Isola led Bone Ce ll.: Provi,ion.1
Identification of O<'<oblas,. and Osleod.s,s. E".
doc,,·1tOI. 99: 526--34.1976.
ISJ. Lund. B.. S0r.ns.cn. O . II.. L.nd. B.. Bi,h<>p. N.
E ... nd Norman . A. W. Stimu lation of 1.25· Di·
hydro. yvitamin 0 Prod uc,ion by Paralhyroid
II<>rmonc and Ilypocalcemia in Man. J. Clin. E".
doc';1tOI. Mnob. 50.- 480- 84. 1980.
)54. Lund. B.. Soren.en . O . H .. Lund. R.. Bishop. J.
E .. and Norman. A. W. Vilamin D Me!.bolism in
Hypop.1ralhyroidism . J, CUn, Eftdoc,;no!.
51: 606_10.1980.
ISS. ... I .. Col"oo. K. W .. S7-"lko . M .•• nd
Sr. nos. E. A Su"ey of the lIotmonal F.eto"
lhat C<>nt rol C.lcium MClOboli$m. rp, 345_54 of
Scarpa and Carafoli. ed,. ",ference 215.
156. M.cL.ughl;n. J. A. . Ande""n. R. R.• and Holick.
M. F. Spectral Characlcr of Sunlight Modula le,
Phmosynlhe,i. <>f Pre, i, .m;n·D, its Phmoiso-
me" in H uman Skin. 216: 1001 - 3. 1982.
J n. Malluche. H. H .. Henry. H.. Mey.,&bellel-. . W.•
Sherman. D.. M... ry. S , G .• and Norman. A. W.
Effect. and Inlcraction. of 24.2S R(OI-l),0, and
US (01-1),0, on Bone. 4""". J. Phy,io!. 1M:
E494_E49S. 1980.
158. Mandari..,. L.. lI<>h. M .• Blanchard . W .• Pallon.
G.. and a.rich. J, Stimulation of I".ulin Role.",
in lhe Absen<e of Ex lracellular C. lcium by lio-
bU lylmethyban'hinc and Inhibilion of Som.to-
'talin. Hlldoai""l. 1(}6: 430-3. 1980.
159. ManeI)'. J, F. Eff.Cl. of Co Ion; on Cdl Mem·
branes. Fnl. P_. 15: 1804- 10. 1966.
160. Manol'gas, S. C ... nd O<ftos. L. J. Comp.1rison
of 1.25· . 25· .• nd 24.2H l ydroxyl'led Vitamin
D, Binding in Fe,al Ral Cal .. riae .nd Osleogenk
Sarcoma Cell, Cold! Ti.,u, I w. 3J: 655-6 1.
1981.
161. Mart in. C. R. GI. nd and Heparin In flu·
ences on Renal Electrolyto Excre,ion in Male
Hooded Ra ... Gm & Campa', £ndo.:';1tOI. 15.-
339-51. 1910,
162. Ma rlono&i. A. N. Calcium Pumps. Introd uction
10 Symposium . Fnl. h oc. 39: 2401-2.1 980,
16), Ma". J, L Calmcxlulin: A Prolein for All Sea·
$On • . 108: 274-6. 1980.
164, Ma". J . L. O>lroporo:;is: New lklp for Thinning
Il¢nc<. Sci,,,,,, 107: 628_30. 1980.
Mbuyi. J .• ),1 .. J.. Blo<mmcn. F.•• nd
Sleven •. E. PI .. ma Proleins in Human Corlieal
Bone: En'ichmcnl of "" HS·GlyCOprolCin. n,
Acid.Gl),coprol.in. and IgE. Cakif. Ti"u, 1m.
34: 229-31. 1982.
166. McLaughlin. M.. Fiorn.y. A.• Lc.ler. E.. Ragsa,
H . P. R .. Brown, D. J.. .nd Will,. M . R. Sea",,,,,1
Varialion, in Se,um
in H.allh)' PeOple. wnct, I: 536_8. 1974,
161. McParllin. J .. Sk,.b.no'. P .. and Powell. D,
Early EifcClO of Paralh y'oid Ho,mone on Rot
Cal,'ar;,n Bone Al kalin. Phoophala",.
Il0l,103: 1573-8. 197&.
168. Miller. E. J.. and Malub,. V, J, Bi",ynlh.. isof
CoUasen: The Biochemi,,', View . PrlX'. 3J:
1191-1204.1974 ,
169. Mille r. S. C .. Hallo,.n. B. P.. DeLue • . It. "nd
Jee. W. S. S. Ro le of Vilam in 0 in Mawnal Skd·
elal Change. During Pregnancy and Laclalion: A
Hi.lOO\(lrphomeuic Sludy. Calci/ 34:
245_52. 1982.
170. Millor. S, C. B. P .. DeLuc •. II, F.. Va·
mad •. S .. Takayama. H .. and Jee. W. S. S. Slud·
i•• on II>< Role of 24·Hydroxyla1ion of Vi I. min 0
in the Minerali,.lion of C.,tiioge and Bon. of Vi·
lamin Rats, CGki! 1m. 33:
1981.
111. Mira.ct. L. GuCri •. J .• Redel. J .. No,m.n. 1\.,
and Rydewaerl. A. Aelion of Vitamin D MOlal>-
<>Iitc, on PTH Secretion in Man. ('a/ri/ Tissue
1m. 31: 191_4, 1981.
172. Muhlrad. A.. Bab. I. 1\.. Deul""h. D.. and Sela. J.
Occurrence of AClin· Like Prolein in Extracellul.r
Ve,id .. ('"ki/ Ti&$ur Inl. 34: 376-81. 1982.
173. Neuman. M. W. Blood: &no EGuHibrium. Cakif.
Ti.. 34: 1 11_20. 1982.
174, Ncuman. W. F.. Neuman . M . W.. Diamond. A.
G .. .\Ien.nle"u . J.. and Gibbon.. W. S.
Blood :&11< Di.. I. Studio, of the Sol·
ubility Characte,i'tics of Bru,hile, Apalil. Mi.·
lUf<. and Tl><i, Stabilization by Noncollage ""u,
Protei"" of llone. Caleif. Inl, 14: 149_51.
1982,
Its. Nichol •. G .. Jr" and W.... rman . R, H" ed •.
lula, for C"ldu", T'''I!.if'' and /10-
mfflS""i•. Academic Pre", Now Yo,k. 1971.
176. Noff. D.. and Ed.!>l.in. S. Vilamin D and it' Hy·
droxylate<l Mot"bolilO' in lhe Ral. HortnOM
R$ch. 9: 292-300.1918.
177. NolT. D" Simkin. A" and Edelstein. S, Err.ClOf
Cholec.lcifc,oI De,ivative; On th< Mochanical
Properlie. of Chick Bones. Calrif. Inl. 34,'
501_5.19S2
178, Norman. A. W . Biochemical Properl i., of II>< In·
le"inal ReceplO' Sy"om fo, lhe Sleroid Hor·
mone 1.25-Dihyd,oxyvilamin D. Ar-
Ii"", lIorm. 1978.
179. No,man. A. W, Calcium and Phosphorus Aboor»'
tion , Chap. 1. pp. 93_1 J2 of La"son. e<I .. refer·
enco 14 1.
180. Norman. A. W" Frankel. B. J.. HeidtA. M" and
Grodsky. G. M. Vitamin D [)cf1cioncy Inhibits
Pancrealie Sec,.lion of In."lin. Scirl!('t 109: 823-
5. 1980.
181. Norman. A. W.. Putkoy. J . A ... nd Nomo,.. L
InteSlinal Cal cium Transport ; Pleiotropic Effects
Medi.led b)' Vitamin D. Frd, Pmc. 41: 78-83.
\982.
ISlA, Norman. A. W.. Roth. J.. and O,ci. L The Vi·
l.min f) Endoc,in. Sy'tem: Stcroid MOlaboli,m.
H",mone ReceptOr<. and Biological Re<p<>It'"
(Calcium Binding Prolein.). EndlX,i", R,". J:
331_66. 1982.
182. Norman. A. W .. and Wcck'ler. W. R. Vil.min f)
RcceplOr< and Biol<>tic Re<pon"" . Chap, 18. pp.
H)_II ofO ·M alloy. B, W.. and Birnboume'. L..
cd., R=p'OI" and 110m"'", Action II. Academio
P,e",. "ow York. 1978.
183. Oldham. S. B.. Smi'h. R.. Hartenbo""". D. L.
Henry. H, 1... No.rman, A. W .. and Coburn. J. W.
The ACUle EIf«I. o>f
forol on Serum immunoreactive Paralh),roid Ho,·
mone< in l hc L>og. f;'ndlX';IOOI. 104: 248--S4. 1919.
Orten. H. 11.. and Nouh".,. O. W. lIurn"n Hilr
91h ed. Mosby. S1 . Loui •. 19H.
Polmio'i. G . M. A.. J.. and Hinlon. A.
Hyporcalcemic Effecl of I n.ulin in 1h< Chid. f;'n-
dlX'rinol.l04' 1778_84. 1979.
Pans. P. K. T .. Kenn),. I\. D.. and C. E"",
IUlion of Endoc,ine Control of C.lcium Regula·
lion, pp. 323-56 of Pang. P. K. T.. and Epple. A ..
ed •. f;"'QIUlion of EndlX'/'" Sy'lem•.
Texas Tech Pre ... Lubboc k. 1980.
187. l'or<on •• J. I\. Funclional Interactions Ocl"",cn
Vilamin ]) Melaboli,m and Othe' C.lcium.Reg.
ulating Hormone •. Chap. 10. pp, 387- 41S or
La"'son. cd .. ,do'cnco 141.
188. P..lovilCh . J. H .. Llottari. D.. Didierjean. L..
Saurol. J. H .. and Salsan. S. Vila mi n D.[)cpen.
denl Calcium Binding Protein in Rat Epidermis,
pp, 4 17_19 of Siegcl 01 al.. cd • ., ,-deTo".,e 226,
189, Pa.k>vilCh. J, It. Ri>'. M. and Bal>an. S. Vila·
min D NU lfilion l ne, •• ",. Skin Tyrosin.", R.·
.t>OO'" 1o Exposuro to Radi.1ion. Mol.
<f C.II. I;ndlXriflOl. 25: 1982.
190. Perri,. A. D.. Whilficld. J. F... nd TOIg, P. K.
Rolc of Caloium in 'he Con l rol of Growlh and
Cell Di.;,ion. NalUn 1I9: 527-9, 1968.
191. E. W.. Gbazaria n. J. G .. and Garand"
J, C. Mi,.d·Func1ion Oxida.e; of 25-- H),d,o.y·
"boIcealife",1 in 1",I.ted Chick Kidney Glomer·
uli: Evidence f'" Nuclea, Localizalion, Calei!
Ti1SU, Inl. 3J: 19-25. 1981.
192. Ph,"g. J. M.. and Wei ... I. W. Maintenance of
Calcium I-Iome"'la,i •. Chap. 6. pp, 157-68 or
Aurb.ch. cd .. ,.fe,ence 14.
193. Pike. J, W.. and Hausslc r. M. Pu rification of
Chic ke n In'•• tinal Receplo, for 1.2S·Dihydroxy.
.ilamin D. PlYX'. Nad. Acad. Sci. USA 76: S485-
9.1979.
.,
194. P"""'!Ur, M. M.. and Wald. II . Evidence!o' In-
tuforonc. of H (OH) Vitam in I), with Phospba.
turic Ac,ion of Glue.,,,n. AIIIY, J. UQ:
1'269- 1'275,1981.
195. Pric •. P. A. The Vitamin K-Dependent Pr<>\cin of
Bone. Pl'. 449_60 of Siegel cl al .. eds" rererence
226.
195A. Prow.dini. D. M.. T$(Iuka •. C. D.. Oeft05, L. J .•
and MarlO'", ••. S. C. 1.25_Dihyd""yvitamin D,
Receptors in Human Leukocytes. 121:
1181_3,198).
196. Rabioov;teh, A. L. and 'Anderson. C. Biogene,i.
of Malrix Ve,icl .. in Canilag. Growth Plales.
Ftd. PftK. JJ: II 2-16, 1976.
197. Racker. E. Flues of Ca" and Concept<.
/'roc. J9: 2422-6.1980.
198. Raj,,_. L G. Mechanisms of Bone Rt$Orption.
Chap. 4. pp. 117-36 of Au,bach, N .. refer."".
"
19'). Rai ... L. G .. Mundy. G. R" Dietrkh,J. W .•• nd
C •• ali •• E. M. Hormonal Regulation of Mine",1
Metaboli ' m. Chap. 6, pp. 199-240 of McCann. S.
M.. cd. End"",irw Physiu!ogy II. University Park
P", ... Bahimo",. t977.
200. Rasmussen. It. Parathyroid Bormone. Calcitonin
and 'he Calciferol,. Chap. I L pp. 660-773 of
Williams. R. 11 .. ed. o[ End""'in%ty.
5th ed. Saunders. Philadelphia. 1974.
20 I. Rasmussen. H.. and Bor<li.r. P. nt
and e,l/ufa, Basis if M, 'abolic BOM Diu,u, .
William, &. Wilkin •. Bahimore. 1974.
202. R•• mu,.en, J .. and Goodman . D. B. P. Relation·
ships Between Calcium and Cyclic Nucleotide< in
Cdl Activation . Physio/. R,y. 57.' 421-509, 1977.
203. Rasmussen. H.. Goodman. D. P .. Friedmann. N ..
Allen, J. E.. and Kurohwa. K. Ionic ContrOl of
Calcium MetaboUsm, Chap. 10. pp, 225-64 of
Aurbach. cd .• ",fefence 14,
204. Rasmussen. H.. and Gu'tin. M. C. Some A'pe<:t'
of HOfnl(lnal Contro)! of Cellular Calcium Motab-
oli,m , pp. 391-400 of Scarpa and Carafoli. cds ..
referenee2lS ,
205. Ra,mussen. R, Matsumoto. T .. Fontaine. 0 .. and
Goodman. D. B. P. RolcofChanBes in Membrane
Lipid Structure in the ActiO/! of t.25-dih)'d.o.y·
.itam in D,. Ftd, PrIX. 41: 72-7.1982 .
206. Reeve •. J. P .. and Sut ko. J. l. Sodium-Caldum
ExchanBe ACti.ity Generale< • Current in Car·
diac Membrane Vesicle" S<-;t"", 108: 1461-4.
1980.
207. Rhodin. J, A. G, 111110/0/0'. Oxfo>rd Univ.rsity
Preu. New York. 1974.
208. ROjdmark. S .. Ishida, T .. Bloom. G.. Chou. M . C.
V.. and Field. J, B. EIf..,t of Int"'portal Calcium
Infu.ion "" In.ulin .o<I Glucagon S.."'tioo and
He»lltic Glucose Output in Anc,thcti,.d Dog'.
t:ndIX,illOl. /04: 814_21, 1979.
209. Rosenf.ld . M. G .. and Barrieux. A. Regulation of
Protein .. i, Polypeptide Ilornl(lne. and
C)'elic AMP, pp. 20S- 64 of Greensa,d. P. G .. and
C ,llCIUM, PHOS PHORU S ,lND THE'
Robison. G. A.. cd •. Adva"",' in Rt-
ua,ch. vol, /I, Raven Pr .... New York . 1979.
210. Rosenthal. A. M .. Jon ... G., Kooh, S. W., and
Fraser. D. 2S·Hydroxyvitamin 0 , Metaboli'm by
Isolated Perfused Rat Am",. J. Physiol.
2J9: EI2-E20. 1980.
21 t. Roth. L Brown. D.• Norman. A. W .. and Orci. L.
Localization of the Vit.min [)'Dopendcnt Cal-
eium.Binding Protein in Mammalian Kidncy.
All"", J. PhYJiol. 143: F243_F2S2. 1982,
212. Rubin. A. B .. T.ra,aki. M .. and San"i. H, Major
Intracellular Cations and Growth Control: Cor,
respondence Among Magnesium Content. Protein
Synth.,is. and the On.. t of DNA Synthesis in
IIAL.Bjc3Tl Cell" Pro<:. Nal/, Arod, Sri, USA
76: 3917-21. 1979.
211 . Rubin. R. P.. and L.aychocl:.. S, G, Prostaglandin\
and Calcium·Membrane Interactions in Sccte_
lOry Glands. Ann. N, Y. Acad. Sd 307: 377-89.
214.
1978.
Sadjera.S. W .. Franklin. S .. and Fo"una. R. Ma·
Iri. ve,icle$ of Bo.ine F.tal Cartilage: Metabolic
Potenti.l and $olubili13tion with DotergenlS.
I-"d. PrIX 3': 154_5.
215. Scarp., A.. and C.rafoli. E. Tran'port
and Cell Function. Ann. N. V, Acad, ScI. vol.
307.1978,
216. SChachter. D,. and Ko,,'.rski. S. Isolation of the
Protein IMe.1, a Vit.min D.Dopendent Mem-
bmne Component of the Int.,lin.1 Transport
Mechani,m. Ft d. PI"O{". 41: 84_7 .1982.
21 7. Sch.nne. F. A. X.. Kane. A. B., Young. E. E.. and
Farber. J. L. Calcium Dop<ndenee of To. ie C.II
Doath: A Final Common Pathway. 2Q6:
700-2.1979.
218, Sch.",nann. H. J. The Plasma Membron. Cal·
cium Pump of Erythrocytes .nd Other Animal
Cells. Chap. 2. pp. 41- 108 of Carafoli, cd .. ref·
ercnce 48.
219 , Sohedew;e. H. K" and Fi'her. D. A. Perinatal
Mine",1 HomC<>S13.i •. Ch.p. 19. pp, of
Tulchin,ky. D" and Ryan. K. J.• cds.
F"al ErrJIX,'-lIOloty. Saundets. Philadelphi•.
1980,
220. Schnoos. H. K.. and DoL"ca. H. F. Reoen' Pr"ll-
t,:s, in Vitamin D Metaboli,m and the Ch<mimy
of Vitamin D Metabolites. Ftd, PrIX. 39: 2723- 9.
1980.
221. Seine. V .. Ishida. M.. Yamaoka. K .• Ishii. T ..
Hi.j ima. T" lkoharo. C .. Tanaka. Y., Matsuda.
S __ Shi""",uji. T .. Vab"uchi. H.• MOfimmo. S ..
and Oni.hi, T. Serum Calcium Regulating I!or--
mOnes in the Pc,inatal Pe,iod. Cahf. Inr.
H: 131-5. 1982.
222. Shapiro. I. M .• Golub. E. E.• Kakuta. S., H.,.I·
g.o..,.1.. H"vcry. 1.. Chanco. B" and Fra.c •. P.
Initiation of Endochond,al Calcification is Re-
lated to Change, in the Redo. Slate of H)'.
pcnmphic Chondrocyte •. Seimu 217: 950---2.
1981.
223. Shore. R. M.• Chosnoy. R. W .. Maze ... R. 8..
RO$<. P. G .. and B.rgm.n. G. J. Oste<>peni. in Ju-
"onilo Di.bet ••. CaM! 1m. 33: 455-7 .
1981.
224. Shull,. T . 0 .. Bollm.n. S .• and Kum.,. R. \)e.
eroa>cd Intestinal Cokium Absorption In Vivo
and Normal Bru.h Bord.. Mcmbrane Vesicle
ellcium Uptake in Cortisol·Trea1ed Chicken"
Evidence for Di.soeiation of Cakium Absorption
from B.u,h Border Ve,kle Uptake. Proo:. Nor/.
Acad. Sri. USA 79: 1982.
225. Siegel. E. G .. Wolhemi. C B.. Sh.rp. G. W. G .•
He.berll. L.. and Reoold. A. E. Role of C.'· in
Impair<;d In.ulin Relta<<: from 1.lct. of Diabetic
(C57BL/ K.J-db/db) Mice. Am". J. PhyliO/.
119: 1:132_8.1980.
226. Siegel. F. L.. Carafoli. E.• Kret$inger. R. H,.
M.clcnnan. D. H, . • nd Wasserman. R, H ..
cds. Caie;"",-B;nding PrOle;",: SlrUC!Uff and
Funcr;o". Flscvier North· Holland, Ne'" York.
19&0.
227. Simpson, R. U .. and DeLuca. It. F. PurifIcation
of Chickcn Intcstin.l Rceeptor for I",H·Dihy'
dro'yv,tamin D, 10 App.rent Homogeneity. Proc.
Nail. Acad. Sci, USA 79: 16-20. 1982.
228 . Sitrin. M. I).. Pliad. K. L, Bolt. M. J, G.. and
Rosenberg, I. H. Compari",n of Vitamin D and
2$·Hydrox),vitamin 0 Absorption in the Rat.
Am". J. Ph,'Jjo/ , 242: G326----G332. 1982.
229, Siu. G. M .• and Draper. H . H. In.I"<' ... d US·
Dih),droxyvit.min OJ S)'nthe.i, in Rats Fed A
Diet. (,,,lei! Inl. 33:
667-72. 1981.
230. Slavlin. Ii. c.. Croi ..... nt. R, D.• SrinSa$. P.. Ma-
tos'an. P.. Wil",n. P" Mino. W.• and Guenther.
H. Matri, V.. icle !1cteroseneity: Possible Mor_
phogenctie Fun¢tion, for Matrix Ve"eks, F. d.
Proo:. Jj: 127-34. 1976.
231. Sodd. J.• Feng. J.. Yen. E. H. K.• and Meloher,
A. H. Effect of A>¢Orb,c Acid on Protei n S)'nthe-
.i•• nd Collagen 1t)'dro.yla1ion in Continuou,
Flo ... Organ Cultu"", of Adult Mou", Poriodontal
Tissue., Calrij Inl. 3#: 408_15. 1982.
232. Somorm.n. M. J.•• nd Ncum.n, W. F Relalive
Elfcctiven ... of Vitamin D Metobolites in In·
creasing Bone Mine,.1 Solubility. CIJkij
Int. jJ: 159-65. 1981.
2H. J, R.. Walker. S .• Solla". E .. and Herzog,
J. InhibitiGn of Anterior PiluilOry Hormone Ro-
k ... by Infu,ion of Calcium Chloride in the Rat.
t:ml""r'nol. 106: ISOIl_14. 1980.
23 4, Speno.r. E. 1'01 •• Khalil. M.. and Tobi.""n,O. Ex·
perimcntal Diabete. in thc Rat Causes.n Insulin·
Re.e"ibk Deere... in R.nal 25·Hydr<>x),vitomin
D,·la·Hydroxylase Activity. End""""",. 107:
300-S.1980.
n5. Stanbury. S. W .. and M'",.r. I::. 8. Clinical A.·
pccl10f Vitamin D Metaboli.m in Man, Ch.p. 9.
pp. 343-86 of cd .. refercnco 141.
236. Stanbury. S, W..• nd Mawer. E, S. PhY'ioIogic.l
MpcclSof Vitamin 0 Metaboli'm in Mon. Ch.p.
8, pp. 303-41 of La"",,", cd .. refercnce 141 .
237. Stern. P. I·!. A M¢oolog on A""lop, In Vitr<> Ef.
f",,!> of Vitamin D M<tabolite. and Consideration
<)/ tbe Mi""r.)i'.otio. Que"ion. CQlciJ- Ti.. 1m.
33: 1_4. 1981.
238. Storn, P. fl .• Orr. M. F.. and Brull. E, 10nophor.
A23187 Promotes Osteoclast Formation in Bone
Organ Culture. Ca/eif. TiJJUt /"" J4: 31_6. 1982,
239. Stryd. R. p.. Gilbertson, T. J" and SIlInden. M .
N. A Seasona! V.riation Study of 2S·Hydro.y-
vitamin D, Serum Level, in Normal Huma",. J.
Clin. t:"docrinol. Mtlab. 48: 771-S. 1979,
240. Slumpf. W. E .• Sac. M __ Na,baitz. R.• Reid. F,
A.• Deluea. H. F.. . nd Tan.ka. Y. Collul.r .nd
Subcellular loc.li,.otion of 1.25-(OH),.Vitamin
D, in Ra! Kidne)', Campa,;",n with L«ali:<a1ion
of Paralhyr";d Hormone and 8".dlol. P,oc.
N",/. Aead. Sci. USA 77: 1 149_53. 1980.
241. Stumpf. W. E.. Sac. M .. Reid. F. A., Tan.ka. Y .•
and DeLuca. H, F, Tarllct Cell. for I.2S-Dihy-
d",x),vitamin 0 , in Int"'tin.1 Tract. St<)mach.
Kidney. Skin. Pituitary and Parathyroid .
XJ6. 1188_90. 1979.
242. Sud •. T .. Horiuchi. N .. Sasaki. S .. E,,,wa . I. . • nd
IllSuro. O. I mporta ..e of I nlramitocltondrial Cal·
eium for lS·Hydroxyeholecakife",l·l·Hydrox)'I-
.sc Activit)' in Chick Kidney Mitochondria. pp.
411_1 4 of Talmage. R. V.. Owen. M., and Par·
"'"'. J. A .• cd •. Calcium- Regulaling /(ormONS.
EI,ev ier. New York. 1976.
243, S>cbcn),i. D. M. E.. Obendorf. S. K.• and MotTat.
K. StruClUrc of Vi,.min I)·Dependent Calcium·
Sindini Pr<>1ein f'on' Bovine Intest ine.
194: 327_32.1982.
244. Talmage. R. V.. Grubb, S, A .. Norima!su. Ii ..
and V"ndcrWicl. C. J, Evidcnce for an Imponant
Role for Calcitonin. Proo:. N oli. Acad. Sci. 77:
609_13. \980.
245. Tam. C. S .. Wilson. I). R.. Hitchm.n. A. Land
Harrison. J . E. Protec!ive EtTect of Vitamin 0, on
Bone AppositiOn from ,he Inhibitory Action of
H)'drocorlisone in Rat •. Calci/- Ti<SUt 1m, 3J:
167_72. 1981.
146. Tanaka . Y.• C ..lillo. L.. Winoland. M. J ... nd
DeLuca, H. F. Synergistic EIf.. t of Proll.. terone.
Testostorone. and El".di<>! in the Stimulation of
Chick Rcnal 25.l-Iydroxyvitamin D,.la·Hydrox,
),1.",. t:nd""rinolID3: 21)3S-9. 1978.
247. Ta naka. Y.. Halloran. B.. Sehnocs. H.. and
DeLuca. H. F. In Vit", Proouetionof 1.25.Dihy_
dro,),vitamin D., by R.t Placental Ti"u •. Pro<.
Nar/. Aead. Sci. USA 76: 5033_5. 1979.
248, Y.. DeLuc •. H. F.. 5<hflOC" .• Ike-
k.w •. "I .. and Eguchi. T. 23.lS-Dihydroxyvi·
lamin 0 ,: A Natura l Precursor in the Biosyn.
the.is of 2S-llydroxyvilamin D, ·26.23·lactono.
Proo:. Nail. Aead.Sci. USA 78. 4805_8. 1981.
249. Tenenbaum. H. C. and Heerscho. J. N. M, Dif·
kr.ntiation of Ostooblast. and Formation of Bone
in Vitro. Co/cij 1m. J4: 76-9. 1982.
2)0. Thoma ... t. M.. Cui,iniet--GleilCs. P.• and M."
!hie•. 1-1. Relativo Importance of Parathyroid
Gland, and Dic," ry Cokium in the Regulation of

Inte.tin.1 CaBP Synthe.i. in Rot •. pp. 421_2 of
Siegel ct aI., ed,,, rde",n.e 226.
251. Tin,"'hdf. S. N .. and Grisham, L M . In Vitro
Assembly of Cytoplasmic Microtubule. , Ann.
Bloch"" . 49: 565-91. 1980.
252. Toffolon, E. p.. P.chet. M. M .. and 1... lbacher.
K . Demon",a tion of the Rapid Aotion of PUT.
Cr)'st.lline 1,,· H)'dr,",y Vitamin D, and 1".25·
Dih)"dro.y Vilamin D, on I nl"linal Calcium Up-
lake. Pro<:. Nail. Arod. Sri. USA 71: 229-30,
1975.
253. TrochseL U.• Ei'man. J. A .. Fischer, J. A.. Bon·
jour, J , P.• and Fleiseh, H. Calcium.Dependenl,
Par.thyroid Hormone-Independonl Regulation of
1.25·Dih),droxyvitamin D . Am", J. Plrysioi.
10119_10124,1980,
H4. Tur""r. R. T .. Bott.millet. B. L. Howard, G. A..
and B.)'link. D. J, In Vii,.., Metaboli. m of 25.H)"_
droxyv itomin D, by Isolated Kid ..y Cel" Pro<:.
Na,l. Acad. Sci. USA 77: 1537_40. 1980,
H5. Urry. D. W. Basic AspeClS ofColcium Chemistry
and Interactions: On the M • ...,ng.r Role of Cal-
cium, pp, J_27 of Sca,pa and C.rafoii. ed . .. ",f·
orenee 215.
256. Vincon.i, F. F" aed A,hleman, B. T. C.lmodulin
Stimulated Calc ium ATPase: Inhibition b)' Zinc
and Vanad.te. pp. 173-9 of Siegel et.1.. ed ... r.f·
crence 226.
2n. Vineen,;, F. F" and La,""n. F. L The Plasma
.\femb,"ne C .. teium Pump: Reg"I"i"" by a Sot·
uble Co" Binding Protein. Prot. J9:
JL 1980.
258. W.= rmon. R. Ii. Phy.iological Reg"lali.", of
Caleium Metaboli.m: The Consequcnee< of E. _
CO" Inl.k. of 1,25.Dihydroxycholocaldferol from
Natural $ource;. Ann. NY. Acad. Sci. J07: 442-
4,1918,
259. W • ...,rm. n, R, H. Vitamin D-Indueed Caldum·
Birlding Protein._An Ovcr>icw pp. of
Scarpa and Ca .. foli, eds .. rcfc",nee 215.
260, Wa"",rman, R, H.. Fullmer. C. S .. and Taylor. A.
:>l . The Vitamin D·Dependent Prot.in •. Chap. 4,
pp. 133-66 of La"""n, ed .. refere"". 141.
261. Wa"",rman, R. It .. and Taylor, A. N. Gastroin-
lestinal AbsorpliOn of Calcium and Phosphoru •.
Chap. 5, pp. 137- 55 of Aurbach. cd .. reference
"
262, Weck,ler, W. R .. Mason, R. S .. and Norman. A.
W. Specific Cy,osol ReceplOrs for 1.25-0ihy.
drm)'vitamin D, in Human Intestine, J. C/ln. t'n-
dlwi""l. 71 5-1 7, 1979.
263. Wei,man. Y .. Eisenbtr,. Z .. Lube l.ki, R" Spirer,
Z .• Ed.lstein. S .. and Har.II, A. Decre.sed 1.25-
Dih)"droxycholecaloifttol and Increased 25-Hy-
drox)' arid 24,2S·Dihydroxyebolecaloiferol in Tis-
A·I. lIenr)'. H. L.. and Norm.n. A. W. Vitamin D:
Metabolism .rId oiological Actions, Ann.
493_520,1984.
C ALCtUM, PHOSPHORUS AND THE CAL CIFE RDLS
'Uc' of R.tS Treatcd .... ith Thyroxine, CiJlclj Tis-
1m. 31,"445-7,1981.
264. Wei.m.n, Y .• Vargas. A.. Dueken, G" Reiter. E"
and Root. A. W. Synthesis of 1,25· Dihydro,)'Vi·
t.min D in the Nephreeh)mi>ed Pregnant Rat,
Hndoc,;'",I. 101," 1992-6. 1978.
265. Wei", R, E.. R.ddi, A. H.. and Nimn i, M. E. S0-
matostatin Can I..,,;ally Inhibit Proiif.r"ion .nd
DilTerentiat ion of Cartilage and Bone Precursor
Cold! Int. 33: 425-30.1981.
266, Whilson, S. W" Dawson, L. R.. and Jee, W. S. S.
A Tc"acyclirIC Study of Cyclic I.ongitudin, l
Hone in the F.male Rat Httdoc,illlJl. 101:
2006_10,1978.
267, Whyle, M. P.• Haddad. J, G .. Jr .. Walters. D D..
and Stamp, T. C. B. Vit.min D Bioavailability:
s.,rum 25·!lyd,oxyvitamin D l.e>oI. in Man after
Oral. Subcutaneous, Inltamu,cular and Inlta"e'
noo. Vit. min D Admini. tration. J. Clin. Emioc,i_
""/. Mnab, 906-1 I. 1979.
268. Wientroub, $ .. Hagen. M. p" and Reddi, A. H.
Reduction of Hematopoietic Stem Call< .nd
Adaptive Iner •• ,e in Cell Cycle Rale in Rickel<,
A"",. 3. Physioi. U3: Cl03-C306. 1982.
269. William. G.. and Salli., J. D. Structural Factors
Influencing lhe Ability of CompOUnd. to Inhibit
Hydro'Y.pllt;te Formation. /n/. ]4:
169-77. 1982.
170. William,. R. J . P. A G.neral Inl,oduclion!O lhe
Spce;.1 p,." ".,,,;« of the 10<1 . .<I The;,
Deploymcn! in Biology. pp. 3-1J of Siegol et 01..
cd ... reference 226,
211. Wil"",. T .. Kat<. J. M .. and Gray. D, H. Inhibi·
tion of Aetiv. BorIC Resorpl ion by COPP<'r. Cal<i!
Tissu, lnt. 13: 35_39,1981.
2n. Wol ff. D. J .. and Brostrom. C. O. Properties and
Funeli"", of Calcium-Dependent Regulator ?ro-
lein. pp. 27-88 of Gr<:<ng.n:t .nd Robison. ed."
referenee 104.
273. Wong, G. L. Luben, R. A.. and Cohn. D. V, 1.25-
Dihydrox}'cholecalciferol .nd Par.tho"none: Ef-
fccts on Isolated Oste""la ..·Uke arid Osteobl.lt·
Cell •. S""tN 197: 663-5. 1917.
274. Wrenn, R. W.. a nd Biddulph. D. M. Correlation
Bctween C)'clic AMP t..: .... I•• nd Calcium Efflu,
in Isolated Renal Cortical Tubulo<. J. (.f·e/Ie
Nuc!. Ruh . .I: 239_50,1979.
275. Wuthicr, R. E.
P,o<:, Jj.117- 21. 1976.
of Malti. Ve,icles.
276. Yaar i. "- M..• nd Shapiro, J. M. Effect of Phos-
phat. on Phosph.tidyl.erine·Mcdiated Calcium
Tran.port . Calc,! Inl, J4: 4J - H. 1982,
277. Yoshil:ami, S" and Hngin •. W, A. C.leium in Ex·
citation of Venebrale Rod •• nd CO"" •. Ann. N. y,
307.- 545-60.1978.
A·2. Somly'" A. P. Ccllul., Site of Caleium [(egula.
tion. Na"'" 3()9: S 16_7. 1984.
 12
Parathyroid Hormone, Calcitonin, and Other Regulators of
Calcium and Phosphorus Metabolism
Parathyroid hormone (PTH, parathromonc, para-
thy.in) is best known for ils roles in maintaining
plasma calcium and phosphate wncentrations. It di-
rectly regulates bone cell functions. calciferol melal,).
olism, electrolyte excretion. and scYeral olher phys.-
iological processes.
PARATHYROID HORMONE DEFICIENCY
In,"lI y deprived nf PTH .. ,,,,,,,rnh In hyf>C>-
calccmie teta ny. Th. first signs are euggerated
neuromuscular responses 10 stimulation. Soon
afterward. tremors and muscle 'pasms become spon-
laooous. and Ih. inadvertent slamming of a door can
precipitate con vulsi ons. Ultimately, spasm of th.
muscle, of Ihc larynx or diaphragm lead, 10
stra ngu lation.
Heightened neuromuscular excitability is easily
demonstrated in patients secreting subnormal quan-
tities of PTH. Percussion of the facial nerves invokes
oontractions of the associated muscles. and applica-
tion of a tourniquet that impairs oxygen delivery to
the a rms elicits carpopedal spasms. Hyperventilation
reduces the fraction of total blood calcium that is
present in the form of free (biologically active) ion.
and the oonsequences include tremors of the fingers.
tongue, and regions aTOllnd the lips.
In chronic hypoparathyroidism. overactivity of
muscles of the gastrointestinallraet often blunts the
appet ite. In severe cases. vomiting a nd diarrhea in-
voke dehydration and loss of the abili ty to regulate
body temperature. while biliary oolic results from
spasm of the sphincter museles. Contracti011$ of the
Jaw museles impede speech, and drying of the
skin increases the susceptibility to infection. Hair
and fingernail growth are defective, and chil_
..,
dren additionally suffer delayed dentition. Long-
range deleterious inAuenee, On the skeleton are
des ibc:d later.
The blood-brain barrier provides some protection
against rapid depression of cc rebrospinal "uid Ca"
during the early stages of hypocalcemia (67). How_
ever, permeability is ultimately affected . and this
probably acooun\s for the rise in intracranial pres-
,u re, the changes in clectrocnccphalcsram pallerns.
and the paresthesias that include prickling and tin-
eli ne ",,".. ,inn< in •• nd lip re-
gions. Patients with long-standing PTH deficiency
oflen experience irritability and psychic depression.
EFFECTS OF PTH ADMINISTRATION
When a moderate·sized dose is administered to
parathyroidcctomizw animals, some of the earliest
effects are exerted on the kidney. Phosphaturia. na-
and bicarbonate ilOOn lead to the
development of hypophosphatemia and mild meta-
bolic Since the fraction of blood calcium
present in ionic form increases. of tetany
can Ix alleviated Ixfore elevation of total blood ca l-
cium ii achieved.
Restoration of norrnocalcem ia requires more time.
PTII facilitates transfers of minerals from bonc and
other tinues to the extracellular fluids. It promotes
renal coll$Crvation of calcium. and its influences on
calciferol metabol ism lead to more rapid absorption
of dietary calcium.
True hypercalcemia devdops if large doses a rC re-
peatedly injected . The toxic effects inClude excessive
stimulation of the myocardium and interfere nce
with relaxation. In extreme cru;cs, the end·result is
systolic arrest. (In previously healthy a nimals, the
heart is easily arrested by intravenous injection of
calcium sa lts.)
...
CHRONIC HYPERPARATHYR01DISM
During the early stages. hypertension develops be·
cause of the increased cardiac output and the con-
striction of systemic blood v=ls. (Coronary and
cenain othe r blood vessels. do, howe>cr. dilate in re-
sponse 10 the hormone [41J.) The effe<:!s of hyper-
calcemia on the gastrointestinal tract Can cause an-
orexia and oonstipation. High calcium levels also
imerfere with the actions of antidiuretic hormone
(79), and impairoo waler conservation can exacer-
bate Ihc natriuresis. and bicarbonate
loss . Thirst. dehydration. and fever are common
findings.
Hypercalcemia probably aeCQants for some of the
disturbances in mental functions, but PTH may ad_
ditionally directly facilitate brain cell upta ke of cal_
cium ions. Some relief has been obtained with dO&-
ages of calciferols that dep«,ss PTH levels without
lowering the plasma calci um ion CQIICCntratiom
(66).
The manifcstatioll$ include headache, weakness,
las'litude, and memory loss. Severely affected indio
viduals ca n beCQmc delirious. experience hallucina·
tions, and paranoid behavior. The encephal-
ogram pattcrll$ a rc abnormal . and the erroncous
diagnosis ()f "psychosis" has been applied. However,
CQrrcction of Ihe hormonal imb.lance us ually
promptly alleviates the sym plOms.
Chronic hypercalcemia leads eventually to the de·
position of calcium salts in soft tissues. The problem
is exacerbated when 1,25-dihydroxyvilamin D (1.25-
D) levels a re also elevated, since Ihe calciferol lends
to inc«'ase Ihc plasma phosphate as well as calcium
concentralions. The kidney is a common si te for met-
astat ic calcifIcation . The res ult ing nephrocalcinosis
is irreversible. and impairmenl of renal functions in-
vokes hypertension via me<::hanisms 001 dire<::tly re-
lated to the calcium levels. W hen calcium salts are
deposiled into blood vessel walls. arterioles bcwme
stiffened and unable to engage in the dilations and
constriClions needed 10 effectively redistribute the
flow. Sliffening of Ihe a()rta is even more dangerous.
since the walls Can no longer "give" in respOnse t()
pressure. The s}'l'lolic pressure is elevaled, whereas
Ihc diaslolic p«'Ssure may be lowered. The myocar.
dium and Ihe smOOlh muscle of Ihc gastroinlestinal
traCI arc additional si tes for metastalic calcificalion.
INDIVIDUAL DIFFERENCES IN RESPONSES
TO CHANGES IN BLOOD CALCIUM
Unde r normal condili()n •. plasma calcium levels for
adult humans arc in the range of 9.5-10.5 mg/d!.
Some individuals ex!",rience severe symploms when
PTH , CALCITONIN AND OTHER REGULATORS
concentrations fall 10 8.0 Or rise above 12.0. Olh·
ers tolerate wider fluclualions. possibly be<:ausc the
calcium ion content varies less tban Ihe tOlal cal·
cium. The liming of samples may be imp::.rtanl.
since diurnal varialions in plasma calcium have been
described (144).
THE PARATHYROID GLANDS
Most adult humans have lWO pairs of parathyroid
glands embeddcd wi thin Ihe jXlSterior s urfaces of Ihe
thyroid capsule. The 10lal weights arc a round 120
mg for males and 140 for females (7) . Addit ional
bits of tissue Ihal can undergo hY!"'rtrophy when Ihe
main strUClUres are removed arc commonly fOJnd
associated wilh the Ihymus gland or situated along
esophageal and Irachea l surfalXs. Mammals show
marked species variations in numbers and locations
of Ihc gland$ (171),
Guinea piS$ all<) usually a.quiro lWO pairs .,r gland •.
wheroas raU and mice typically develop a . ingle pair
weighing around 2 mg embedde<l along the late ral . ur·
faces of Ihe thyroid, Cow •. goat •. and sheep often have
on. pair >"""i.ttd with, a nd another «pa ratcd from. the
thyroid glands. In pigs. the pamh)'roids can be located
wilhin tht thymus Or attached to Ihe common ClITOIid
.rlery.
Embryologicat stud ies pro.iM elue$ 10 Ihe ...;at;o", in
numbe rs and arrange menU. The parathyroid cell. origi ·
nate in the pharyngeal pOuches. and IhOile slruClure. also
contain Ihe forerunners of the th)'mus gland. aortic bod·
ie$. and uhimobranehial tissue (39), The major comp<>-
n<nts of Ihe thyroid glands originate in neighboring . Iruo-
ture., bUI some Ihyroid cells may . 11<) be present within
Ihe pouches (102). Evidentl}'. the paue rR$ <>f mi&"'liQn
10 the r,nal ,it., are tI()( rigidly controlled , Recenl demo
on.tration that .blation of neu .. 1 crest cell, Ca n impair
dcvelopment.,r Ihe thymus and Ihyroid gland. (l6A).
alOllg with the .,tab lished origin of <;Ilei-
lonin-sccroting cell •. r.ise the pouibilily that ""me .ari·
al ion. occur prior to pharyngeal pouch differentiation.
It has been '"U'51ed that the widespread oceurrCnce
.,r "accessory tissue'· confers a .utvi.. 1advantage . since
the main glands . re located a l ,i t.. susctpl iblc 10 injury.
Such lissue complicates the problems of su r,ical
correction of hyperparathyroidism in patientS and of
studying lIormone deficiency in the laboratory ,
Paralhyroid glands seem to be unive ..... lIy pre«nl in
terrestrial .ertebrates ( 11 1), It i. widely believed Ihal
bony fishes do not pos.sc... ueh endocrin< tissue. It has
been .taled that eartil.gino•• fish •• coold ha.e no usc for
PTH si nce Ihey do nOt pO$SC<s Irue bone. Howe.er.o>·
seou, tissue has recenlly been foond in them (78), and
SOme ohsor.e" describe parathYn)id.li ke "ruetures in
cl •• mobranch. (111 ).
All parathyroid glands contain cells" thaI
synthesi?.e and release PTH . They are generally a r-
ranged in cords (Fig. 2-2). and they seem to undergo
cycles of and ··rcst'· that are out of phase
with th e activit ies of neighboring cells. The darker
ones have morphological characteristics consislent
wilh direct participat ion in the secrelion, numerous
gra nules. well..:leveloped endoplasmic reticulum and
Golgi vesicles. and low glycoge n COnten!. The light
<;<:lIs. which are sometimes said to be "resting." arc
rich in glycogen. They contain few granules . a nd the
Golgi regions are less prominent than in the dark
Oxyphil cell. idenlified in many species may be
Chief cells that undergone degcnerati(m. They
do 00\ appear in humans until after puberty.
PARATHYROID HORMONES
PTHs are single·<:hained peptides cOnlaining 84
amino acid moieties (71). Small variations in com-
position are encoun tered among individuals as well
as among species. and a single subjeci ca n have two
dilferent types (73) . However. PTH taken from one
kind of mammal is biologically potent when it i. ad.
ministered to another. The amioo acids al positions
15-30 seem to be involved in binding to receptors.
but molecules containing jU5t Ihe first 29 moieties
arc fully active. The amino acid. at positions 1-3
seem to be required for receptor activation (74).
Fragments consisling of amino acids 3-34 a rc potcnt
PTH inhibitors (l IS).
PRE·PROPAAATHYRO ID HORMONE
IP Amino ••
Amino aeon
·a1. ·30
0<
_.
Fig. 12-1. Me1abolic ptoce •• ing of pt""P'Of>lrathyroid
1>0<_. IP. '";1;.to< poop1;de; SS. signal_a; PS. pro
Blo8ynthe8is
In common wit h other proteins destined for export.
PTHs originale as components of larger precursors
(72). When mRNAs coding for them are extracted
from bovine glands and are used to direct protein
in cell-free systems. a pre·pro-paralhyroid
hormone containing an initiator peptide. a "signal"'
(leader) sequence. a nd a pr<KOmponent can be re-
covered 12-1 and 12·2).
The emire 1)5 amino acid is never
formed in (he para thyroid co1b. A methionyl pepti-
dase removes the in itiator peptide when the naSCent
chain contains 20-30 am ino a cid moieties. Thc sig-
na! s.eq uence facilitates (Tampon of the growing
chain (0 the cistcrna of (he rough endoplasmic retic-
ulum. An enzyme associated with the membrane
catalyzes rupture of the glycy\·lysyl bond between
the signal and prosequencesjust before or soon after
the translation is completed. The signal componen t
probably undergoes rapid degradation. since it can·
oot be found in the parathyroid gland.
The 9O-amioo acid Pro-PTH remaining after re·
moval of thc signal sequence is transloeatC<:i to the
Golgi region for further processing. and it ean be de·
tected there around 15 minutes after initiation of the
peptide chain assem bly. The prohormone exertS
SOme PTH·like actions. but it has very low potency.
A trypsin·like "prohormone-convcrting en7.}·me'·
catalyzes conversion of Pro-PTH 10 the 84 amino
PARATHYROID HORMONE
more
, .
s." -A1a·Lyo·Asp· Met_" al-ly.-val-Me')
( J
leu- f>he·Cy.·!Ie· ...... -Leu- Met· Val·1Ie
I
l y'-Se" Val-Ly.·lys-Arg
V81.s.r.GIiJ.!Ie.GIn@Met.HD
\23 •• 61Sg
•. GIy.Leu.
" ,. " ,. '3 12 11 10
Glu ·Arg. Vol..(3lo-T rp-le u 'Ar9.L)'S. LY• . LeU)
,g 20 " 2> OJ . . 2. '" 27 ,.
, __ - - - -- ---- PIle·A",,· Hi._ VaI •.o...p.GIn
r, :I< '" 32 31 >0
' -- -- - --- --- - ----- - ---- GIn·COOH
• ae« vary willi I!Je opeciM .
acid PTH . At least some of the product is inc()rp<)-
rated inw granules for storage and subsequent secre-
tkln . 1t i. "(II \::nown whethc< a ny Pro.PTH is ta\::en
into Ille or whether some PTH (and p0s-
sibly Pro-PTH) exils (he plasma membranes.
No prohormone is belie_cd 10 be se<:relcd by cxocy-
tosis (71).
Microlubules probably play roles in Pro-PTH pro-
cessing and transport (7). When c()lchicine or vin-
blastine is presented directly 10 parathyroid cells.
some changes in microstructure occur and the rate
of removal of the pro--sequence is depressed . (How-
ever, the cells retain the ability to increase hormone
se.:retion in response to hypocalcemia [30].)
Up to 70% of newly synthesized hormone is re-
leased to the cytoplasm. where it becomes vulnerable
to attack by proteolytic enLYmes (1 26). The bond at
position 33-34 is the most frequently affected (71).
bill cleavages OCCur at many sites. The resulting pel>-
tides can then undergo funher degradation.
Parathyroid gland, contain a cathepsin B that
cleaves PTH \>(,twcen amino acids 36 a nd 37, and a
cathepsin D that separates moieties 34 and 35
(BA). When blood calcium levels are high. the
major secretory products are carboxy-termina l frag-
ments that include 34-84 and 37-84 peptides. The
molecules do not possess PTH potency, but the p0s-
sibil ity that they perform regu latory roles has been
COI!sidered (126). Something like one-half the car·
boxy·terminal fragments formed end up in the ve-
I>OUS effluent.
P lli. CA.LCITON IN ANO OTIiER REGUlATORS
Pro ""'l""nce
Fig. 12-2.
" signal peptid. ·.. "I)I"Q" peptide. and
'1\1 PTIi 10< !he malo< Io<m of !he bovine
po'atn1'<>!d hormone. Tho c ir<:led IminO
Amino-terminal fragments are also produced
within the parathyroid cell •. Those possessing al
lea.t the fin! 29 am ino CJfcrt action,
(Synthetic peptides consisting of amino adds 1_34
are widely used to study the functions of the har-
mone. In m(lSt studies their dfe<:ts are indistinguish-
able from the ones obtained with equimolecular
quantities of PTH I-S4.)
The amino-terminal fragments formed within the
glands evidently undergo rapid intracellular degra·
dation . They cannot be found in apprt\:iablc
amounts in the efflucnts Or in culture media.
In addition to inhibiting PTH release. high ron·
Centr31ions of calcium ions accelerate hormone deg·
radation. Calcium-activatcd protuses have bec n
identified (7 1).
PTH thai enters the circulation is tahn up by
many cel l types. The liver cleaves th: hormone, and
hepatic enzymes a lso attack oxidized (inactivated)
peptides. Both li ver and kidney are known to release
C-terminal and N_terminal fragments 10 Ih. blood·
stream. Sone cells d egrade only acti ve hormont", p0s-
s ibly because the cleavage is in some way related to
the hormont" actions (58). However, rupture of pel>-
tide bonds does not seem to be essential for hormonal
actions. The slow and incomplete deSradation of
PTH in osseous tissue may be related to tight bind-
ing to the re<:eptors.
N-terminal fragments that entcr the bloodstream
disappear rapidly. They arc both filtcred by the glo-
meruli and acted upon by renal tubular epithelium
enzymes. Cterminal oomponents have longer half-
lives . They are jusl filtered. and plasma proteins
seem 10 relard Ihe degradation (126). Under normal
oonditions. liule Or no intact PTH appears in Ihc
urine.
Blood plasma contains of PTH and its
products. Since the older immunoassays rccogni7.ed
inactive fragments. the hormone levds were overes-
timated . Antisera thai detect just Ihc active oompo-
nents have recently been developed (III). Conccn·
trnticns seem to be not much greater than 1O- 1l M.
The half·lifc for PTH is "ery shon (1.2-2.g minutes
for the dog (165]).
Parathyroid Secretory Proleln
Parathyroid secretory protcin (PSI', secretory pro·
lein I. SP-I) is a glycoprotcin wilh a molecular
weighl of around 150.000 (125) oonlaining 70,000
dalton subunits (33). It cl()SCly resembles the chrom o
ogranin A Ihal is released along wilh calecholamines
from Ihe adrenal medulla (35). Calcium ions and
other rogulalors exerl parallel innuenccs on PSP and
PTH release, bUllhe molar ratios oflhe proleins can
vary. All AI'UO cells may make PSP (A·2).
The functions of PSP aro nOt known (15). Rol ""
in intraedlular lransport of PTH have been pro-
posed. bUI there have been suggestions Ihal psp is a
<Wlgi veside wmponcnl who .. cXlnt,ion from para-
Ihyroid cells is ooincidental to PTII release .
Hormones Related to PTH
The pituitary glands of SOme fish"" and amphibian.,
and (XlSSi bly also some mammals. comain an as yel
inwmplelely characterized "hypercakemic faclor"
(hyperealcin). Possible evolutionary links belween
such molecules and Ihe peplides produccd by vertc·
bralc paralhyroid glands have been proposed (34).
REGULATION OF PTH SECRETION
Parathyroid glands seem to continuously engage in
the partial degradation. and release of
PTH . By comparison wilh other peptide·secreling
organs, Ihey store vcr)' little active product.
(Healthy individual'S have enough insulin to satisfy
requirements for several whereas PTH re·
serves could not support nceds for more than 6-7
hours.)
Biological regulalors probably never totally ShUI
off the secroticn. The high plasma PTH or newborn
calves and of palienlS wilh parathyroid adenomas is
allribUlcd to the prosencc of large numbers of cells
engaging in basal level activity (91). Cal. changes
do nol rapidly afTect mRNA levels (A4).
RoIs8 01 CalCium Ions
Calcium ion concentrations of the extracdlular
fluids are the major regula tors. Hype rcalcemia rap-
idly lowers the rates of PTH and PSP release (20.
I 25) . whercas hypocalcemia stimulates.
The mechanisms of action are II i. widely
.<lumcd Ihal irICrtases in eXl racellul.. Ca" wneenlra·
lions lead 10 corre.ponding elev.lions of eylosolic C."
According to One pOinl of view. lhe cen. have "cateium
recepIO"'" that mcdiatethe rcs""ns"", (A·7).
Allhough hyperealcomia invoke< dose-dependent
depression of Ihe plasma memb,"nc pOlenlial. it is un-
li kely Ihal hyperpotari,"'tion $Iimulole<. Supraph)'>iot.
ogica] tcyel. of K' depolari,e Ihe membra .... bUI Ihcy
PTH <eOrelion. Moreover. Ih. crfcc1S of high K •
and low Ca l' arc addilive (45).
AB t 87 facititale. calcium entry inlO many •.
II inhibits PTH secretion when Ihe cells aro bathed in
fluid. wnl.ining Ca". bUI it doc. not h.". Ihi, .ffect
when the calcium i. omilled. Taken IOsether. Ihe Endings
'U(!.gO'1 In.t A23187 inhibilion depends On elevation of
lhe cytosol Ca l -. Ho,,·over. thc ionophore opposes Ihe
.timulatory elfecl' of D adrenergic agoni.t< a nd of IIOme
Other agenl •. e"en ",hen tho olt racellular Co'" i, low
(60). M=vor. it accelerate. Ca" emux bUI h.. lillle
effcct on calcium uplako (20). Since Ant a7 is k"""" 10
influonce Ihe introcelluta, di$llihUlion or catcium. it i.
tikety Ihat it aeli in Ihi. way 10 .harpen the sen.ili"ity 10
ch.nges in extracellular ion wncontrot ians.
A. di:;cus.sed later. cAMP and it. analog. slimulalc
PTII se<:retion. In m.ny colt Iype •. high cylo<olic Ca"
te.d. 10 Ihe formation of ealcium",almooulin. and the
consequcnce. indude both inhibition 01 adcnyt3tc cyclase
and activ. tion of cyclic nucleotide poo.phodiestorase •.
Paralhyroid gland coli. conta;n both calntooutin and Id·
enylate cyclase thaI art exqui,iloly sensilive to
calcium inhibition (140). Hyperealcomia and A21tS7
lower Ihc cAMP levels. They can .tso clici, change, in
phosphodic",era", activit)·. A major oWcct of high C)'lo-
IIOlic Ca" in Ihese celts m.y be interrerence wilh Ihe
binding of cAMP '0 protein ki nase •.
Studio< of celt. laken from palienli wilh para lhyroid
,land lumors provide e"idenco Ihal al le.'1 SOme effoolS
of calcium are unrelated 10 cilher cAMP gencralion or
activ'liOll of protein kina,e' (t9). Ca" <lim"lales PG
,)·nt he.i. and phospholipid lurnover (1\.1) in normal coli.
a, ",·ell. The ch.nge. in PTH se<:re,ion . re q"anlitalively
much more imp",ssi"c than Ihc effect. on cA MP kvel.
(lOl). and hypereatcomi. can inhibil hormonc release
when cAMP concentrations are high.
It i. universally agreed that hypercalcemia leads
10 accelerated degradation of PTH within Ihc para·
Ihyroid cell, (117). Although some observers believe
Ihal Ca" depresses Ihe synth""is or postlransla·
lional processing of Pre-Pro-PTH (123), others do
nol (33A). Prolonged hyperealcemia ultimately im-
pairs DNA synthcsis and it thereby reduces Ihe
numbers of cells lhat engage in hormone production.
(Chronic hypocalcemia Icads to parathyroid gland
hyperplasia.)

Role of cAMP
Epinephrine. dopamine, isoproterenol . and other
agents that activate adenylate cyclase bring about
dos.,.rdated increases in PTH secretion that parallel
the e1evatioos of cAM? (21,140). Prostaglandin E,
and secretin have similar effects (71). Phosphodies-
terase inhibitors such as theophylline and MIX re-
tard cAM? degradation, and these. too, enhance
hormone relcase.
Norepinephrine and a-a,drenergic agonists depress
both cAMP levels and PTH release . i'OF2a inhibi-
tion has been altribUled 10 both lowering of adenyl-
ale cyclase aetivily and aClivation of phosphodi"l;ler-
ases. Ho",'ever, this regulator problably exerts
addilional influences, since it is effective in the pres,
ence of both cAMP and high Cal . (6O,6t).
Two endogenous substrates for the cAMP.{!epen_
denl protein kinase,>; have identified, and their
phosphorylalions have been linked with cAMP gen-
eralion. However, no influences of calcium ions on
either the associated prolein kinase activity or on
protein phosphatase activity have been found (103 ).
There are indications Ihat cAMP promot"l; rdease
of only previously synthesized PTII. whereas hypo-
calcemia affects both stored and freshly syn\hesizoo
hormone (3M).
Ma gnesium lon8
Some Mg" is nccdw to maintain parathyroid cell
functions and the sensitivty to Ca" inhibilion . In
addition to their roles in adenylale cyclase activa -
lion, the ions are believed 10 perform special func-
tions and to ac t at sites distinct from the ones af-
fected by Cal> (125). Humans seve rely depleted of
magnesium tend to dcvelop hypoparathyroidism.
In at least some spc<:ies. high concentrations of
Mgl> are inhibilory. Some observers do 001 believe
that the findings arC relevant to physiological con-
trol . the concen trations used in the studies were
twice as great as Ihose found under normal condi-
tions. Others point out that much lower concentra-
tions influence thc release of both PTH and PSP
when the Ca '" is moderately elevated.
Monovale nt Callons
Parathyroid utilize Na ' jCa'" exchange me<:h-
anisms to removc numbers of calcium
ions (\72). Low Na ' . and Na ' j K '
-ATPase inhibitors. impair of the system.
They permit intracellular of Ca" , and
depress PTH release. K ' may stimulate byactivat-
ing the pump.
PTfi, CALCtTONtN AND OTHER REGULATORS
Other Factors Affecting PTH Secretion
I nfluences of calciferols and of some other regulators
were disclLSSoo in Chap. II. High concentrations of
phQ!Ophale in the euracellular fluids can accelerate
PTH secretion in several ways: (a) They lowcr
plasma calcium by facilitating bone mineral;Ulian:
(b) they can lower plasma Ca" by affecting calci-
ferol metabolism and thereby the intestinal absorp-
tion of minerals; and (c) they a.sso<:iale with caldum
ions in the blood and thereby reduce the fraction
that is present in the form of free Cal<. Mineralo-
corticoids also lower Ihe ionized oomponent when
they elevate blood pH.
There arc conditions under which CT lowers the
plasma Ca>+ and therefore indirectly augments
PTH secretion. However. CT additionally stimulates
even when the plasma Ca" is high. It may do so by
interfering with calcium uptake.
Gastrointestinal hormones Ihat promote ealci-
tooin release can also ac t directly on parathyroid
gland to accelerate both cAM P generation and
PTH secretion. Secretin is highly effeclive (195) .
Glucagon acts in some species but not in others. In-
Auenccs of cholecystokinin are difficult to assess.
since the preparations are often contaminated with
secretin .
GluCC<lrtiC<lid. affect calcium metaboli,m in many
ways. and they can augmenl PTH secrelion when
they lower the blood Ca '·. There is some evidence
for calcium-independent C<lntro! of the paralhyroid
cells (71).
Stimulatory innuences of prolactin on secrc-
tion and of PTH on prolactin release have been dc-
scribed in patients (161). However. although prolac-
tin levels are high during normal human pregnancy,
some recent studies have failed to confirm earlier
suggestions that plasma PTH is at that lime
(63.187).
Growth hormone increases PTH secretion. and it
may exe rt both direct and indirect innuences. find-
ings with somatostatin have been inconsistent.
Neuroendoc rine Control
The parathyroid glands arc innervated. Separate r.,.
ccptors for a- and ,8--adrenergic agonists have been
identified. and these may be distinct from the Ones
affected by dopamine (140). Although at least somc
of the effects of cate<:holamine agonists and antago-
nists can be dissociated from innuences exerted on
Ca" concentrations (120). the physiological signifi-
cance of the innervation has not been defined. Since
CT and PTH exert opposing effe<:tson bone. and the
neurotransmitters can stimulate the soc retion of
both of the hormones. it has been suggeste<:! that
CAs cannot be important regulators. On the other
hand, some kidney functions secm to require coor-
dinate<:! actions of PTH and CT.
Most duirnal secretory rhythms are regulated by
neuroendocrine systems. Diurnal variations in PTH
levels that include nocturnal peaks have been de-
scribed for some species (55), but no obvious pat-
terns were detected in a recent study of normal and
hyperparathyroid human subjects ( 165).
PARATHYROID HORMONE ACTIONS ON THE
KIDNEY
When moderate dosages of PTH are in.ic<;ted into
parathyroidectomi1.ed animals. the responses include
increased uri nary excrction of sodium, phosphate,
bicarbonate, and amino acids, along with decreas<XI
eKretion of calcium and hydrogen . Pharmacological
amounts also lower glomerular filtration rates. These
effects can be dernonstrated for isolated. perfused
kidneys, as well as when PTH is injected into one
renal artery and ureteral cannulas are used to coilect
specimens from treated and control sides.
Observations that patients with hyperparathyroid-
ism develop hyperehloremie acidosis (I 54), and that
parathyroidectomy can increase chloride excretion
(41). suggest roles in chloride ronservation. The ef-
fects probably contribute to PTH lunctions. and to
the toxic elTects of overdosage. Acidosis per sc aug-
rnents the responses of bone to PTH. and it Can in-
terfere with renal reabsorption of cakium (114) .
Renal Excretion of Phosphate
The kidneys play major roles in regulation 01 blood
phosphate concentrations. They rapidly adjust ex-
cretion rates to changes in diet. romposition of the
blood plasma. and hormonal status (32. 46) .
rn healthy, well-fed animals. 70%-80% of filtered
phosphate is reabsorbed in the proximal coovolute<:!
tubule$. Virtually all of the remainder ends up in the
urine. Under special conditions (e.g. PTH depriva-
tion or phosphate IClading). the Henle loops may ab-
sorb an additional 5% of the filtered load.
When only phosphate-free food is given, almost all
of the filtered phosphate is reabsorbed. Renal ad-
justments reach maxirna within one day alter the
diet is first presented, and they persist when the an-
ions are administere<:! parenterally. It has therefore
been suggested that the gastrointestinal tract pro-
vides some signal to the kidney (32).
PT H receptors have been identified in the proxi-
mal tubules (I). Although the hormone ordinarily
inhibits phosphate reabsorption when it is present in
sufficient quantities, PTH cannot oppose the conser-
vation associate<:! with dietary deprivation.
Animals fed excessive quant ities of phospha te Can
lower proximal tubular reabsorption to half the fil-
tered load. Renal adaptations may add itionally in-
volve some tubular secret ion of the ions.
Phosphate and sodium transport are linked in sev-
eral ways. In isolated systems. tw() sodium ions are
usually transported for each one of phosphate. Oua-
bain and other Na · jK · -AT Pasc inhibitors impair
phosphate reabsorption. It is believed that sodium
ions are needed to establish electrical gradients that
facilitate movements of phosphate. and it has also
been proposc<i that brush border membranes contain
components that interact with both Na · and
HPOl- .
interre lationships bet"-een thc ions arc . however,
complex. Proximal tubules reabsorb many times
more Na· than phospha te. When they are presented
witb high roncentrations of either glurosc or amino
acids. the tubules accelerate sodium reabsorption
but they take up less phosphate.
Phosphate reabsorption is augmented by acidifi-
cation of the filtrate and by increases in CO, ronten\.
It was at one time believed that hydrogen ions ac-
celerate the uptake by promoting conversion of
IIPO!- to H H po., but it is now known that the di-
valent anion is preferentially transpaned.
PTH Regulation of Phosphate Excration
Parathyroidectomized animals excrete subnormal
quantities of phosphate, and they soon develop hy-
perphosphaternia. PTII can correct the problems
within minutes.
When plasma inorganic phosphate concentration
falls, the fraction of total calcium prestnt as free ion
Therefore, symptoms of tetany can be alle-
viated. Only later does PT H increase tbe absolute
concentrations of calcium in the blood.
Considerations 01 this kind underlie the concepts
tbat PTH acts tonically on the kidney to maintain
phospbate excretion rat",. and that hormone-stimu-
lated phosphaturia secondarily facilitates solubili-
7.ation of bone mineral.
It has rcccntly been demonstrated, however, that
concentrations of PTH just adequate for promoting
transfer of minerals from bone to blood do not elicit
changes in renal excretion (28). 11 is also hown that
the major, sustained influences On blood calc ium are
linked with the biosynthesis of new mRNAs and
proteins.
Thercfore. it now appears that phosphaturic ef-
leets assume importance only under special circum-
stances. PT H corrects the effects of long-term PTH
deprivation. It normalizes the plasma phosphate lev-
els when adjustments 10 calcium deprivation include
strong stimulation of the parathyroid glands and the
transfer of substantia! quantities of minerals from

bone to blood. The phosphaturic cffects are also use-
ful when large quantities of 1.25-0 are made and
these promote intcstinal absorption of cllOugh phos-
phate to affect the plasma levels.
In hypercalcemic states. the dangers of metastatic
calcification are diminished by lowering the phos-
phate conl:<'ntf3.tions. Since hypcrvitarnillQSis D
lcads to simultancous clevalion of bolh calcium a nd
phosphate lovcis, il more onen invokes sc,·ere mela-
static calcification. However. chronic hyperparath)"-
even tually brings about the pathological
changes.
When bone i, cxpooed in vitro 10 fluid, ""nl.ining low
calcium, ph()$phatc ··solubility product .... it rele.",.
",me of iii mineral. Acc<>rd ing 10 an early hypothesis.
PTH .eU in thi, way to elevate the pla,ma calcium.
However. although hypopilo>phatemia retard. borIC min·
er.lization. we "",w know th.t lhe sol"bilit)· product i.
nc,·cr lowered s"!liciently to promote calcium rele",' in
vivo.
PTH Regulation of Ca lcium Excretion
Although a substantial fraction of the dielary cal.
cium is eliminated via lhe feces, the kidney is re-
sponsible for the major adjustments of to
body needs. Calcium Ihat is nol bound to plasrna
macromolecules is fillered by the glomeruli . Some
11.000 mg is handled in this way each day by
healthy. well·fed human adults (65). 50%-55% of
the filtered load is reabsorbed by the 1:<'11, of the
proximal tubule . and mOISt of the remainder is (aken
up more distally. Usually. on ly around 100 mg ap-
pears in Ihe final urine in each 24-hour period (177).
Calcium rca bsorplion sites have been identified
for the Henle loops. the distal convoluted tubules.
and the medu llary collecting duClS (12). The loops
can account for uptake of as much as 30% of the
filtcred load (65). and they may be major regulatory
sites.
Parathyroidectomy is soon followed by acccler-
ated of calcium into the urine. evCn when the
plasma Ca' · is s ubnonnal. The acute cffects are
more marked in oldcr than in young animals (g9).
Some observers believe that PTH influences On the
kidney that lead to calcium conservation make
major contribut ions to mineral homeostasis (131 ).
PTH increases calcium reabsorption by acting on
the Ihick ascending loops of the renal cortex (lg)
and possibly also on the distal convoluted lubules (in
which re<:eptors havc been idenlified). No effects
have been found for Ihe medullary ascending loops
(12). In Ihe proximal convoluted tubules. PTH ac-
celerates calcium loss.
The calcium-oonserving aclions probably assurne
PTH. CALCITONtN ANO OTHER REGULATORS
special importanee when inadequate diets or calei-
ferol limit th e ability to maintain nor·
mocalccmia . They are easily masked by other ac-
lions of the hormone. When PT H accelerates
transfer of calcium from bone to blood, the rise in
plasma Ca l - and consequent augmentation of gl<r
merular filtrate Ca l - invoke hypercalciuria.
Calcium and <odium io"" move together in the
proximal portion. of lhe nephron. and Na ' / K ' _AT_
Pase inhibitors affect both. More distally, the trans-
ports can be dissociated (65).
Influences o n Acld-Baso Balance
PTH incrcases bicarbonate loss into the urine (119)
and decreases hydrogen The effectSCan be
accompanied by some loweri ng of carbonic anhy-
drase activity. and inhibitors such .. aceta1.OIamide
mimic the hormone actions (94). However. no direct
cffecls of PTH on the enl.yrne have been found
(154). In (he distal portions of the nephron. alkal-
ini1.alion of Ihc tubular fluid facilitates calcium con·
servalion (7). Whon sunicient bicarbonate is lost to
result in lowered blood pH. aldosterone secretion aC-
celerates (10).
PARATHYROID HORMONE ACTIONS ON
BONE
Parathyroid hormone resulates the functions of all
known bone cell types (159). Although the hyper·
calcemic actions arC often linked with stimulation of
resorption. it is importanl to point oUlthat low level.
of PTH are essential for rnaintaining healthy bone
structu re and normal remodeling. Young animals
chronically deprived of the hormone grow at slower
rates than controls and thcy suffer , kele(al defects.
Some osteoclast functions rersis1 ;n the defIciency
states (166), but osteoblast activities are impaired.
Influences on Osteoprogenltor Celie
PTH exerts mostly anabolic effects when it is present
in the usual amounts. It accelerates cell proliferalion
and thereby eontributcs to renewal of the popula·
tiol\$. There is more rapid incorporation of labeled
thymidine into DNA. uridine inlo RNA. and amino
acids into proteins. The effects are exerted directly
on cells, bUI the vasodi lator aClions may make some
contribution.
Osteoprogc nitor cells differenl;ate into bone-form·
ing osteoblasts. They probably do no1 require hor-
monal support to do this. High PTH concentrations
retaro the maturation. and the long·range conse-
quences include lessening of mineral upta ke.
Chronic. severe hyperparat hyroidism also leads to
 proliferation of fibroblastS and the rep lace-
ment of normal bone witn fibrou s ronnective tissue
(wteiti' fibl"Q:$a cystica).
Inlluences on Osteoblssts
PTH limits growth of the cells and the synthesis of
bone It lowers alkaline phosphatase. proline
hydroxylase. and isocitric dehydrogenase activities
(196). and it retards formation of the mRNAs that
direct oollagen synthesis (31).
Chronic overdosage reduces osteoblast :osteoclast
ratios. probably by decreasing t ne modulation of os·
teoprogenitor cells to osteoblam and accelerating
tne modulation of Q<teoblasts to osteocytes as well as
increasing the numbers of multinucleate osteoclasts.
The oonecpt tbat PTH facilitates conversion of os--
teporogenitor cdl, to osteoclasts is not widely ac·
cepted. PTH may auract prcastroclasts to absorp-
tion sites (1 27). but it probably docs this indirectly.
Acrording 10 a recently presented hypothesis
(166). VrH diso rgani,es a proteclive laye r of ostro-
blasts lhat separales bone surfaces from bone extm·
cellular fluid (possibly by promoting reduction in cell
size ). This permits osteoclasts to gain acceSS to the
underlying tissue.
Influences on Osteocytes
The osteocyt .. are tnc """,t nurnerou< and probably
tne most versatile of the bone cell<. They reside in
lacunae, and they are bathed in bone extracellular
fluid. The matrix su rrounding young osteocytes is
relatively low in collagen content. and there are in·
dications th t some (If the mineral is in the form of
readily re<:ruitablc brushite. Soon after PTH is pre-
sented. the spaces octween the cells a nd thc walls of
the lacunae enlarge. These and olher findings are
consistent with thc idea that the early phases of
PT II.invoked hypercalcemia arc linkcd with con'..,-
sion of ·'osteogenic osteocyte," to ··ostcolytic oste(\-
cytes." The hormonc accelerates glywlysis and it
lowers isocitric dehydrogenase activity. The result-
ing accumulation of lactate and citrate contributes
to transport of calcium from bone to blood plasma
(108). Chronically elevated PTH levels ultimalely
kill osteocytcs.
Techniques have been dcvised for separating
PTH-sensit;ve osteoblasts from PTH and calcitonin-
sensitive ostcoclasts (19 7). It is likely that many of
thc effe<:ts describ«! for osteoblast! are alw appli-
cable to osteogenic QSteocytes.
Influences on Osteoclasts
Although the early hype!'Calcemic aClions may result
from actions on the OSteocytes. thc delayed. sus-
tained effects require osteoclast aClivation. In addi·
tion 10 playing some role in attraction of osteoclast
prccursors and existing osteoclasts to bone !'Csorption
sitcs, PTH facilitates fusion of mononuclear cclls
into multinucleate Oncs (54) . and it augments phag-
ocytic activity that is associatcd with changes in the
cell surfaces. The osteoclasts arc then said to present
··r uffled borders·· to resorplion sites.
Actions On Iysosomes leading to release of p·glu-
curonidasc. giucosaminidase, acid phosphatases.
cathepsins. and olher matrix-<legrading enzymes
OCCur early (52). and these can be blocked with
memhrane·stabili7.ing agents. Sustained clTects that
involve funher dcgradation of bone and thc appear·
ance of hydroxyproline and other products in the
urine arc linked with induclion of new proteins
( 150). Synthesis of hyaluronatc is accelerated (196).
Inhibitors of RNA and protein synthesis di minish
thc sustained hypercalcemic elTecls.
PTH may also in som e way prolong Ihe li,·es of
the osteoclasts. However. thc hypothesis that OSteo-
clasts found at remodeling siles evcntually modulatc
to ost""blasts via processes \hat can be relarded by
PTH (I 59) is not widely accepted (152).
MECHANISMS OF ACTION OF
PARATHYROID HOROMONE
There is substantial support for the concept that
most Or all of thc actions of PTH are lin ked with
elevation of the cytosol Ca" (196). When the hor-
mone is presented in vitro to bonc and ki dney prep-
ara tions. there is a prompt incrcase in the rate of
Ca" uptake. This is attributed to changes in plasma
membrane permeability. When PTH is injected inlo
animals, an early fall in blood calcium ooneentration
precedes Ihe sustai ned rise (24).
Most of the actions Can be blOCked by bathing the
cclis in calcium-free Auid s, by exposing them to ve-
rapamil (49), and with membrane-!ltabihing agents
that presumably interfere with dcpolarizatiolWl5S0-
cia ted calcium upta ke (50). Most a re mimicked with
ionophores and other agents that artificially elevate
the e)"tosol Ca" (51).
Higb c)"tosol Ca" aClivatcs several bone and kid·
ney cnlymes . O ne consequence is stimulation of
··calcium pumps·· Ihat transfer n'inerals from bone
to blood. Aceelerated calcium egress has been demo
onstrated in vitro. A23187 also increases calcium re-
lease from the ce lls if the fluids rontain calcium.
PTH exerts some inAuenccs On nucleic acid me-
tabolism that arc not obtained with the ionophore.
O ne interpretation is that the hormone additionally
acts in other ways. Another is that A23187 influ-
e ncoson calciu m mOvements aCross both plasma a nd
organelle membranes cannot oc rontrolled by the
cells and the toxic effe.:ts of the agent limil i1S ability
to mimic PTH (43).

Calcium release depends at least in part on Na ' i
Ca" exchange and on the presence of a steep eon·
gradiem that facilitates rapid Na ' entry.
II is impaired by R1000valent ionophores that elevate
eytosol Na ' (98). by ouabain (which docs not block
PTH stimulation of adenyl ale cyclase 176]). and by
bathing cells in sodium..:lefieient fluids.
Although the initial effects of the hormone are e.-
ened on the plasma membranes. influences on or-
ganelles may funher elevate the cytosol Ca". PTH
enters proximal convoluted tubule cells of the kid-
ney, and it localizes in the mitochondria (132).
When presented to isolated mitochondria. it affeets
both respiration and calcium egress.
Roles of cAMP
PT. l activates adcnylate cyclase in all of its known
target cells. It can do this when it is presented to the
kidney in concentrations as low as 10- " M (82). In
intact animals. ;t elicits dose..:lcpcndcnt increases in
urinary cAMP. Protein kinases are activatcd. and
conain proteins undergo phosphorylations (8).
cAMP. it! analogs. and agents thai promote cAMP
generation mimic many of the PTH actions. Phos-
phodiesterase inhibitors augmcnt them.
The nucleotide activales several enlymes. inelud·
ing those in\'(llved in renal gluconeogenesis (I).
When it binds to ser(>lll) surfaces of renal epithe·
lium. protein kinases on thc luminal side arc affected
and the changes have b«n linked with roles in reg-
ulalion of permeability cbaracteristies (I 24).
In at least S<lme celltypcs, cAMP f.cilitates trans·
fer of calcium from the mitochondria to the cytosol
(17). Such actions may amplify the effe<:ts exerted
On the plasma membranes that lead to elevation of
the cytosolic Ca" . Cakium ionophores also raise the
cAMP levels.
While the pr«eding findings are consistent with
roles for cAMP in mediation of PTH actions. and
with positive feedback mechanisms involving Ca"
and the nucleotide. it has also been observed that
PTH can accomplish many of its missions when a
rise in cellular cAMP is prevented.
Interactions with Prostagtand lns
PTH promotes generation of pr<.>Staglaooins. POEs
mimic many PTH aCliom;, including oncs leading to
accelerated bone resorption. They augment the cf-
feelS of low concentrations of PTH on the adenylate
cyclase of renal tubules. Although they seem to be
acting on the same enzyme. PTH and PGs utilize
different receptors (14). The effects of POs on
PTH, CALCITONI N A.NO OTHER REGULATORS
cAMP generation are augmemed by high cylosolic
Ca l + (141). In human subjects, calcium infusions
have been observed to augment both cAMP gener·
ation and phosphaturic responses to PTH in
hypoparathyroid but not hyperparathyroid states
(15).
Mechanical stress is a physiologically important
stimulus for bone growth. The stress promotes the
release of POs (lSI), and the effecls are supported
by PTH. "fh<, anabolic responses probably depend on
the coupling of bone-resorbing actions to new bone
formation .
Ph osphstUrlc Actions 01 PTH
This seems to involve multiple mechanisms (I).
High cytosolic Cal< reduces the permeability of lu·
minal surfaces of proximal tubular cells to Na".
and this secondarily slows phosphate reabsorption.
PTH eXertS some influences on the tight junctions
betwe<:n the cells that lead to accelerated backnuxes
of reabsorbed ion. Aecderaled Na ' / H ' exdange
alS<l seems to take place.
A peptide consisting of amino acids 3-34 of PTH
amagoni7.cs several actions of the hormone. includ-
ing the ability to acti""tc adenylate cyclase. Obser-
vations that it fails to impair Ihe phosphaturic re-
sporules raise the possibility tbat cA MP does not
se ..." as an obligatory mediator for this function
(1Ig).
Interac tio ns with Calc lferols
PTH indirectly facililates intestinal absorption of
calcium and phosphorus, ,ince it activates the en-
'-yme needed to make l,25·0. The calciferol evi·
dcndy supports PTH actions in ,everal ways. It can
inerease cellular as well as plasma calcium and phos-
phate content, and it may be needed to keep SOme of
the bone calcium in readily reeruitable form. Calci-
ferols also contribute to the ability of PTH to elevate
intracellular cAMP. 24.25·Dihydro.yvitamin D is
reported to raise both basal and PTH·stimubted
cAMP levcls in the kidney. possibly via inhibition of
cyclic nucleotide phosphodiesterases (113). 1.25·D
can act alone on PTH-sensitive cells 10 accelerate
bone resorption.
Severe, chronic vilamin D deficiency blocb the
hypercalcemic actions of PTH and it blunts the
phosphaturic ones_ This is explained in part of the
basis of depletion of intracellular mineral stores.
However, when Ihe deficiency impairs intestinal ab-
sorption of calcium, the resulting hypocalcemia
stimulate. the secretion of PTH. The high levels of
PTH may also be related to lifting the inhibitory in-
nuences normally exerted on parathyroid gland cdl$
by 24,ZS-dihydroxyvitamin O. Some Io$.s of sensitiv-
ity to PTH is then allributcd to "down regulation"'
of hormone receptor numbers because of chronically
elevatcd plasma levels (92). PTH .ensilivit y returns
slowly when the vitamin 0 dcfitiency is corrected .
Some of the delay probably invol""s gradual resto-
ration of receptor numbers.
OTHER ACTIONS OF PARATHYROID
HORMONE
In addition to regulating the functions of all born:
cell types. att<:lerating production of 1.25·0. affect-
ing urinary excretion of ions. dilating some blood
vessels. and contributing to control of mineral me-
tabolism within the e<:nlral nervou s system. PTH is
implicated in other processes (95) .
When PTH is given to animal, previously de-
prived of the hormone. the quantities of phosphate
excreted into the urine far exceed tlte amounts lost
from the blood plasma . Evidently. PTH accelerates
(and parathyroidectomy diminishes) the rates of
phosphate relcase from liver. skeletal muscles. lungs.
and erythrocytes. The innuene<:s do not exceed to all
cell types. They cannot be demonstrated. for exam·
pie. for spleen or intestine (121).
PTH promote. regeneration of the livcr followin8
partial hepatectomy (ISO). The effects have been
linked with inAuenees exerted on nucleic acid metal>-
olism. (However, ahhough the hormone affects
RNA methylation in bone it docs not seem to do this
in liver [159).)
The ability of PTH to promote calcium uptake
may account for the stimulatory elfects on prolifer-
ation of thymocytes (146) and precur-
sors (95). on secretion of gastrin and gastric acid
(37). and on the release of gonado\Topins (36). PTH
also increases calcium uptake by the .kin. and it af-
fects the electrolyte composition of milk (180) . It
can accelerate migration of phagocytic leukocytes
(93). and it rna)' play special regulatory roles in the
bmin (66).
CALCITONlNS
Calcitonins are species·speeific peptides that con-
tribute in special ways to the regulation of minc .. 1
metabolism . They are made by fishes (including ones
with cartilaginous skeletons and acellular bone). as
well as by amphibians> reptiles. birds. and mammals.
but they are probably not present in eyclostomes.
Since fishes and urodcle amphibians are not
known 10 possess parathyroid glands (135). and an-
urans do not acquire them before entry into meta-
morphosis (40). tho calcitonins are said 10 be "more
ancient" regulators than PTH.
Cheml etry
All of the molecules contain 32 amino acid moieties
and include a C·termillal pro!inamide. The cysteines
at poo:;itions I and 7 are linked by a disulfido bridge.
The various form, differ from oach other in both
chemical compositions and isoelcctrie points (148).
At least some species make more than one CT.
and two or more varieties can be present in the sa me
animal. The distributions among ,ertebmtc groups
support the notion that an ancestral gene underwent
duplication early during the course of evolution. It is
known, for examp!e> that ungulates make hormone.
very different from the OntS found in either humans
or ftshes.
The amino acid sequence for human CT is com-
pared with the most prevalent of the salmon hor-
mones (SCT·!) in Fig. 12-3. Sixteen of the mClictics
are identical. Human CT shares 19 identities with
SCT-Ill. but only 14 with the poreine regulator and
13 with ovine CT.
The hormone extracted from one animal group is
biologically acti"e when administered to another. [n
fact. fish calcitonins often elicit responses of greater
magnitude and longer duration than the mammalian
molecules. The higher potellCies are attributed
m(lStly to tightcr binding to the receptors. but SOme
of the peptides are also highly resistant to degrada-
tion by hepatic enzymes. E.idently. there has been
greater "'e.olutionary conser.ation·· of receptor
structure than of the mRNAs that direct the
biosynthesis.
Mammals produce many nlOTC hormone
cules than fishes. and the lower potencies may con-
tribute to attainment of finer control over the func_
tions. On the hand. some
that CT i, a mOre important hormone in the non·
mammalian vertebrates.
Bioeynthesle of Ca lcitonin and Re lated
Peptlde8
A mRNA coding for the formation of a calcitonin
precursor was first obtained from rats. and it was
used to directlhc $ynthesis of a IJ6-amino acid pre-
pro-caicitonin. The prediction that additional biolog-
ically active peptides could be deaved from the same
primary transcript (88) was SOOn realized. Tho
17.500 dalton human CT procursor was shown to re-
loase a C·tcrminal peptide to the bloodSlream in
equimolecular quantities with CT. The newly dis-
covered peptide lowers plasma calcium levels when

j----j
H,N.Cys.GIy-Asn-Leu-s", -Tn,.Cys.Met _Le u_Gly_ Thr·TYJ
12"'6".'0"'2
GIn.P'O. Ph<>-lhr· His· Pile· Ly.·Asn·P!le· .... p.-GIn. Til<
2< 2J 22 2. :10 19 IS 11
[
Thr ·Ala·" .Oly. V8f.GIy.Ala·P",. CON Ii.>
25 2& 27 2' 30 " !Ii
, ,
I
H,N-Cys-@Asn- Leu- St,,-Thr - Cy.-@-lcu-Gt,'
I
1 2 .! e
given alone. a nd ;1 markedly enhances the effe<;\s of
CT. H<>wcvcr. it doc> not affect the pla. rna >Od ium .
polassium. Or phosphate ooncemralions. On the
H-Asp-Mct-Scr·Ser-Asp-Leu-Glu-
Arg·Asp-His-Arg·P,o-His·Val-Ser·Met·Pro-Gln·Asn·Ala-Asn.QH
The peplide is also known as kmacaidl!. II has b«n
identified in the C <xlls of normal thyroid glands.
and in medullary carcinomas (2A). as well as in
blood plasma.
Recent in"'<'Sligations have revealed that the RNA
lranscribed from the calcitonin gene is processed in
a differenl way in neural tissue:' 11 gives risc to a
mRNA that directs the symhosis of a 16.000 dalton
prOlein which shares identical N-terminal amino
acid sequences with pro-ca!citonin. A 37·arnino acid
carnponem cleaved from ils carboxy·tcrminal re·
gional has been given the uarm calcitonin gene
lalM (CGRP). The neuropcplidc has a
unique distribution within the brain. and it has also
been found in the adrenal medulla. The proposed
funclions include contributions to Ihe regulation of
systemic blood pressure. ingestive behavior. and
some endocrine functions (170A).
II is possible that pro.<:alcilonins are secreted in
some species_ A protein that filS the description has
been idenlified in the trout (167).
PTH. CALCITONIN AND OTHER AEGlJl.ATORS
,8 '" ,. "
A. Hunan cak;ilor'lin
Fig. 12·3. Amino .oK! _ ... ..,.s,O<
""man arid I"" salmOn
6. Salmon calci,."...., 1 ce lcilon;n I.
basi. of its amill<) acid oom(Xl<ition. the peptide was
ini,ially called PDN-ll. It 0.... the following .Irue-
ture (I lOA)
Ce llula r O rigi n s o f Ille Calello n ln s
CT-secreling cells are belie",<,d to arise in the embry·
onic neural creslS (139). In .ubmam malian verte-
brates. they migrale to the mosl posterior (flflh pair)
of the branchial pouchos (39) (fig. 12-4). There,
they associate with thyroid gland and thymus gland
prccursors. In air-breathing forms. they also mingle
with cells that will later be incorporated into che-
moreceplOrs and parathyroid glands,
The portions of the pouchcs containing the largest
numbers of CT cells became organi7.ed into discrete
ultimobranchial bodies (UBs. ultimobranchial
glands). Th= are rich in cholinosterase, and they
are innervated in al least some The UB,
often aS.ume morphological similar
10 Ihose of Ihyroid gland,. For example. they may
contain follicle, and colloid,
Mosl of the CT cells of marsupial and placental
mammalian embr)'os migrate to the fourth pair of
branchial pouehes and associate with the developing
 Derivatives of Branchlol Pouches

Elasmobranchs :0000e
Ultlmobronchlol
Thymus

Amphibians
UITImobrorchial
Parathyroids Aortic
ThyrT'IUs

Birds
,_ ,.,
vu(Q I
Ultimobronchial
,,_ , .
Parathyroids .....,r IC
Fig. 12·4. Diag<ammalic
_____ th ads 'o-pt"&s... ,.tior> 01 I"" em",yc>nic
and gtor>dula, <!er;YOI;ve. ot ,"-
l><arlCltiat pOUC"-.;n va,.,.,"
(gi!)
Mammols
"as..... (Cow. O. H.
Endoc,ine con,roI of calc.....,
Ultimabronchia! J. Endocrir>Qi. 43: 131-
61,1ge9.)

thyroid gland •. In humans and some Olher Other Sites of Synthesis

they become lh. "parafollicu lar", "inlcrfollicular".
Or "C' cells scallored along the peripheries of lhe
Ibyroid follicles.
Differenc.. in Ihe .it.... hapes. and l()Cation, of the
«lis have boen described. CT «Ils can occur in clu'ters
(e.,. in ral') or .ingly (in mice). Some at< incorpor.ted
inlO foUid., that produ« the iodinated thyroid hor·
mone •• and others form follicles of their own within th.
thyroid gland'. The cell, aro concentrated in the .;cinity
orth. parathyroid ,land, in some anim.1 type. but II{)t in
others.
When it was first established thallhyroid glands
conlain CT cells. the hormone waS named thyrneal.
eitonin (TCT). The term calcitonin (CT) is !lOW pre-
ferred, since it can be: applied to peptide made al
other siles.
The term C cell rdeTS 10 the hormone oontcnt.
while light, a'gyrophil, and granula, d..ignate Ihe
ways in which calcilonin-secreting cells differ in ap-
pc.ranee and staining propenies from components
of the thyroid gland that synthesile thyroxine and
Iriiodothyronine.
Neural crest contributions to and
adrenal gland differentialion may pania!!y explain
CT cell distribu(ion.
THYMUS GLANDS
Calcitonin celts often migrate to Ihe Ihymus gland.
This is OOmmOn in humans. in which bolh
celt Iypc. and caiciionins have been identified
(59). The Ihymusesof at least some species also con-
lain peplide, of dilferent chemical makeups and me>-
lecular weights contribule to calcium homeosta-
sis (109.122). There are conditions in which
thymectomy the effects of ncising (hy-
roid CT celts.
PITUITARY GLAND AND BRAIN
CT-like immunoreactivity has been demonstrated
For pituitary gland and mmor ,,<,lls that make
ACTHs and MSHs (29,44). and it is known lhat
ACTH -like peplidcs are made by some Ihyroid
".
gland tumors (69). There has been specu lat ion On
Ihe possibility that CT a nd ACTH arise from a com·
mOn pre.:ursor. However. it is mort: widely believed
thaI the molecules dcte<:\cd in pi tuitary glands, and
also in the hypothalamus, are either different pe ...
tides Ihal cross-react wilh CT-antiscra or CT thai
has been taken up from blood plasma by circumv.n-
tricular organs (170M· Differences belwC<'" pitu-
iUlry and thyroid CTs can be detected wilh some an·
tibodies (38), and glands lack CT mRNAs
(87), MOfeQver. ACTH and CT rdease arc .vi·
dondy independently C<lntrollcd (101), and both pi-
tuitary gland and hypothalamic CT content are low·
ered by thyroidectomy. (It has also been rC(Xlrtcd
Ihal somatostatin and CT coexist within [hc same
thyroid gland cells. and that the two hormones 3re
often released together (13) . No biosymhetic links
have be<ln established.)
Observations thaI circumvcntricular <Jt&ans ]Xl5-
sess hi&h-affinily binding sites f<Jr CT. and that
normal quantities <Jf CT are laken up by Bmulebor<J
ralS, SUpporl SUsgeSli<Jns Ihal CT plays roles in Ihe
cenlral re&U lali<Jo <Jf clCX:lrolyle balance and in Ihe
release <Jf some piluilary gland h<Jrm<Jnes (57). Brain
CT <Jr relaled peplides may also oonlribUle \<J appe-
lite ronlroL Ek>lh inlracerebral injecli<Jns of the hor·
rn<Ine (57) and chani!C!i in the brain Cal . INa' ra·
ti<.lS can reduce food intake withOut invoking iUness,
and tho brains of SOme strains of genetically obese
rats have be<:n reported 10 show impaired CT
binding.
ADRENAL GLAND
A CT·like substance has been identified in pig adre-
nal &lands (90). Thc finding may be relaled 10 (a)
Ihe known influences of adrenaleClomy on blood cal·
dum levels, and (b) the recogni'.cd effects of ste--
roids. PTH and CT on mineral homeQ5tasis
(2.85.157).
Plasms C o ncentrat ion s
M<.lSt measurements are made with immunoassays.
because oommonly used bioassays cannot dctectlcss
than the equivalent of 0.5-5 ng of porcine CT (128) .
It is not certain Ihat all of Ihe peplide measured is
biolo&ically potenl .
At leasl some hormone seems to be oontinuously
present in normal human adults (3) . Values "my
widely among healthy individuals of thc same spe·
ciesand at different times of the day wilhin the same
subject. Mean ooncentrations of 20 pg/ml (range 5-
100) are typkal, although values of up to 450 pg/ ml
have bttn reported (128). CT cells '\Qte up Ihe pep-
PTH. CALCITONIN AND OTHER REGULATORS
tide when they are secreting limited amounts. Strong
stimulation can then rapidly clevate the plasma oon-
cenlrations to 7000 pg/ml. The levels arc consis-
lently high in patients with hypercalcemia or med·
ullary car(:illOma of the lh}Toid gland.
Very high basal levels in laboratory ra lS have been
attributed to Ihe continuation of skelelal growth dur-
ing adulthood. It should be pointed OUI, however.
Ihat the animals are routinely maintained in un·
s haded cages in brighlly Iii rooms. and Ihey arc fed
vitamin Ikupplemented, cakium·rich diets. Under
more nalural conditions, rats spend mOSt of their
time in darkness or dim light. and they then manage
to symhcsi2c adequate amounts of Ihe vitamin.
There i, such a high incidence of CT--<:en hyperpla·
sia in laboralory animals pcrmined to approach Ihe
ends of their lifHpans (3) that tumors are easily col·
leCled for the study of CT functions ( I 70). It is likely
that chronically elcvaled calciferol and calcium con·
centrations overstimulale the gla nds (56).
The high CT levels in gra7,ing a nimals lIa"e becn
altribuled 10 Ihe ronsumption of calcium.rich diels.
However. selective breeding for milK production has
providcd us with populati(Kls showing special min.
eral requirements. The calcium concentration of
cow·s milk is rIVe limes that of Ihe blood plasma. and
a laclaling animal can lose 50 i! of calcium pcr day.
Cows rekasc very large quantities of CT around Ihe
time of parturition (25), and many become severely
hypocalcemic at thai time. Bulls fed cakium·rich
diets commonly develop CT cell nC<)plasms and os-
leopetrosis (99) ,
Although half·lives in Ihc blood plasma are mea·
sured in minute•. CT. can elic il responses of long
duration. The hormone is avidly taken up by larget
tissues. It binds tightly to receptors. but it;s also rap.
idly degraded.
Influences of Ple$ ma ea"
Acule elevation of plasma Cal- invoKcs prompt re·
lease of preformed CT. This is associated wilh cen
degranulat ion and depleti(Kl of Olher in_
cluding acetylcholinesterase (27). Rats repeatedly
overdosed wilh vitamin D show seVere depl etion of
thyroid gland CT oonlenl (56). The release i$ not af·
fected by prolein synthesis inhibitors.
Chronic hypercalcemia prolongs the degranula·
tion. The ability to make CT improves. but there is
little horrn<lnc storage. lnerea= in cell silcs. nu·
elear:cytoplasmic ratios. and mitotic raleS have been
described for dogs (\39). Patients wilh parathyroid
adenomas usually have CT<ell hyperplasia (149)
and persistently high cireulatin& CT. Simila r re-
sponses to hyperv itami nosis D have been observed.
 When calcium salts are ingested in quantities too
small to elevate thc blood Cal<. influences
on gastrointestinal glands can stimulate CT
secret ion.
Hypocalcemia suppresses CT release. but thc cells
continue to make and store hormone. A subseq uent
hypercalcemic stimulus can Ihen elicit rekase of
vcry large a mount' of the reserves.
Paralhyroidectomiud .... , $ go thrO<lgh. phase during
which they ,ulfer hypocalcemia.nd ,(0", up CT. FOT un-
'nown ",ason,. <J'IO$t ",establish normocalcemia within
Ihree months. (The adaplat;on cannot be .,plain<:d on
Ihe basi, of hype rtrophy of paralhyroid ",mnanlS.) As
the circulating Ca" ri .... gradually inc",asing quanlitie>
of CT arc rc!ca$e<llo lhc bl<)Odm.am. Thi> is all ributed
10 both lifting of thc hypocalcemic inhibition .0<1 leakage
of CT from ··o>.rloaded·· coli,. Par.thyroidectomi,ed.n-
imals aflificially protect¢<! against th. hypoc.lcomia do
not .hQw comparable change. in CT cell .Iru"u"" and
funclion. (142).
Influences of Plasma Phosphate
Plasma inorganic phosphate concenlrations do nol
seem to d;,n:r/y alfect CT secretion. High concen-
Iration, do, howe>er, lower the fraction of blood cal·
cium that is present as free ion. PTH stimulation of
CT c<:lIs probably involves hypophosphatcmic as
well as hypercalcemic actions of that hormone.
Effects of CT on Plasma CalCium and
Phosphate Concentrations
Moderate dosages of CT eorrcet hypercalcemia.
However, although aCUte lowering of the Ca" to
subnormal levels can be demonstrated (168). peNis-
tent hypocalcemia is usually not invoked in intact
animals. By contra". the ,arne amounts of exoge-
nous CT ca n bring about sustained
phospnarem;Q (84). The observations arc consistent
with the belief that CT decreases the rates of cal-
cium and phosphate release from bone. but that it
additionally accelerates phosphate uplake by othcr
kinds of cells (121).
Antisera directed against CT can raisc the plasma
Ca" and impair homeostatic adjustments to injec-
tions of hypercalcemic agents. There arc C<lnditions
under which thyroide<:tomy has similar effeelS
(169).
Physiological Relevance ojlhe Preceding
Observations
It was for a time bc lievcdthat plasma Cal. is main-
tained within a very narrow range because small el-
evation, stim ulate CT release. wherea, ,ma ll depres-
sions call forth PTH . Since the underlying
observa tions were obta ined from animals exposed to
unusual conditions. the concept has been questioned.
Some of the controversies C<lncerning CT functions
are cited.
I. Since nonmammalian venebratcs have discrete.
highly organized. usually innervated uhimobran-
chial glands. whereas mammals have just scallered
CT cells within the thyroids. il has been argued that
the mammal;an c<:lls are nothing mOre than "cvolu-
tionary carry"Overs" thaI wCr. never lost because
they have no harmful effects.
This view is not easily reconciled with the follow-
iog. (a ) CT-se.:rcting cells are universally found in
all mammalian spee;es stud ied to date. (b) On a
body weight basis. mammals have more lotal CT
than other vertebrates. and they release larger quan-
lilies when stimulated. (c) The CT levels are af-
fected by other factors. e.g. Ihey arc higher in older
than ;n younger animals. and higher in females than
in ma les. and they arc also higher in animal' secret-
ing large amounts of PTH or ingesting Substantial
quantities of vitamin O. (d) Elfecls of both CT in-
jection and hormone deprivati01l Can be demon-
strated. (e) Mammals pOSscss elaborate mechanisms
for regulating CT releasc and for mai ntnining diur-
nal plasma concentralion rhythms.
2. A need for CT is apparent in marine fishes liv-
ing in calcium-rich environments. and in birds that
must et\l.age in massive rales of calcium turno,"er
when they produce eggs and eggshells. It has been
stated that mammals do not have comparable needs
for hormones Ihat low." the blood calcium, since
bone avidly takes up the mineral and PTH defi-
ciency soon invokes hypocalcemia.
Such notions fail to explain the presence of well-
developed ultimobranchial bodies in freshwater
fishes and in male and juvenile birds , Thcy cannot
be reconcilcd with the production of more CT hor-
mone per gram body weight in mammals than in
fishes. MOl"QCver. as will be discussed later. there are
condition, under which CT-deprivcd animals de-
velop hypercalcemia.
). T he need for CT in humans has been ques-
tioned because many patients rcmain normocal-
cemie following thyroidectomy. On the other hand.
SOme become intermittently hypercalcemic, and re-
pealed bouts can lead to nephrocalcinosis (85). An-
imals chronically deprived of CT have been known
to develop cataracts (138). Usually. there is compen-
satory dcpression of the PTH levels. and this impairs
bone remodeling. In some individuals, thymus
gla nds may supply limiled amounts of CT (59).
4. Patients with parathyroid adenonlas develop
hypercalcemia despite Ihe presence of CT cells. This
is partially explained on thc basis of inability of CT
to override the effects of persistently elevated PTH
and some down regulation of CT re<:eptor numbers.

On the other hand, CT levels a re characteristically
elevated, and they can be espe.;ially high in
(137). It is likely that the elfoxts of PTH would
be exacerbated if the CT were oot present.
5. Patients with CT«creting medullary carcino-
mas do not often soifer hypocalcemia. They do. how-
ever, se<: rete large quantities of PTH, and many sec-
ondarily a<:qu ire parathyroid gland adenomas (149).
Moroover, even whcn they maintain normoca1cemia.
they may sulfcr bone disorders and other problems
relatcd to hypeT$eCretion of PTH (158). As has been
noted. cows releasing large amounts of CT a round
the time of parturition become hypocalcemic (25).
It seems reasonable to conclude that CT performs
physiological functions in mammals, but the idea hat
it directly interacts with PTH on a tonic basis is
simplistie.
GASTROINTESTINAL: CALCITONIN
INTERRELATIONSHIPS
The sight, smell, laSle. and even thought of food can
initiate a "cephalic" or "anticipatory" phase of gas-
tric secretion. When food enters the stomach, disten·
sion of the wall$, vagal impulses. and certain dietary
oomponenlS, slimulate the release of gaslrin from
the C. cell •. Gastrin acU on the parietal cells to in-
crease HCI production, and it performs Olher func>-
tions in the digestive tract (see Part I). AI least some
of its eff""u are mediated by histamine. and hista-
mine alone invokes HCI secretion. Pentagastrin
(PG) is a sy nthetic peptide that interacts with gas-
trin reCeptOTS.
In humans, pigs, and other "gastrin-sensitive"
species, gastrin is a potent stimulator of CT release.
II is effective even when the plasma Cal > concentra-
tion is in the low-normal range. and it can sensiti'.e
the CT cells to a hypercale<:mic The
of pentagastrin are dose related, and they are addi-
tive with those Qf hypercalcemia (37). The quantities
of gastrin required to activate lhe CT cells are in a
range consistent with roles in regula-
tion of the CT cells. and there is an associated faU
in plasma Ca1 +.
Cholec)'Stokinin-pancre<lzymin (CC K·PZ) isa dif-
ferent peptide released during digestion. It shares
chemical and biological properties with gastrin. and
its ability to promote CT release may involve inter-
actions with gastrin ree<:ptors. Glucagon or a hor-
mOne closely related to it (enteroglueagon) is also se-
creted during digestion, especially when the meal is
ricb in protein and poor in carbohydratc. At least in
humans, glucagon promotes cr release (136).
Ingestion of quantities of calcium-rich food too
PTH. C"'lQTON IN "'NO OTHER REGUL"'TORS
small to diroxtly raise the blood Ca" also leads to
cr secretion, The are attributed to stimula-
tion of gastroinlestinal traCI glands. including Qnes
thai secrete gastrin.
Meal-related CT secretion has severa!
quenees. At leaSt part of the fall in plasma Ca 1+ is
attributed to the hormone. CT may also be a regu-
latOr of digestive system glands. It inhibits basal Se_
cretion of HCl in humans. and it antagonizes the ef_
fects of pentagastrin, histamine, and calcium (128).
Under at least some conditions. it also retards intes-
tinal absorption of calcium in vitamin-replete but
nol in calciferol-<lepleted tau. Many observers be-
lieve that it is an appetite depressant.
Secretin is released by the S cells of the duodenum
and jejunum whcn acidic chymc leaves the stomac h.
It opposes many actions of gastrin. including ones
exened on thc parietal of the stomach. When
given alone. secretin does not have deu:ctable influ_
ene<:s on CT secrelion. but it opposes gastrin stimu_
lalion. S""retin can ind'r«I/y accelerate CT release,
it promotes PTH secretion . PTH stimulates
both the gastrin and the CT cells. The eff",ts of se-
e«'lin on the parathryoid glands are opposed by cal_
citonin (Fig. 12-5).
In "gastrin-insensitive" species. such as rau, gas-
trin is a pOOr stimulant of HCI secretion. Althou£h
moderate dosagcs of the hormone enhance CT re-
lease in su ckling infants and lactating mothers (37).
only very largc doses have such effoxt! in adult COn_
trols (168). On the other hand, both gastrin and his-
tamine lower the plasma (a/dum, even in thyroid-
e<:tomizcd animls. Metiamidc (a histaminc receptor
antagonist) blocks the actions of both gastrin and
histamine.
Gastre<:tomy abolishes the hypocalcemia invoked
by gastrin and hislamine. whereas removal of sub-
Slantial segments of Ihe intestine is wilhout effeci. It
has therefore been suggested Ihat some other regu-
lator is «'leased by the stomach. However, pentagas-
trin promotes CT «,lease in gastre<:tom;1.ed rats
(96).
It seems. therefore. that factors associated with
both food intake and HCI production contribute to a
"paradoxical" fall in plasma Ca" at times when the
mincra! is being absorbed from the intestine, and
that something other than CT is involved in the over·
all responses.
Diurn al Caleium and CT Rhythm s
The pallerns have been studied most intensively in
raiS. They are said to occur in other but not
all investigators find Ihem in humans (165).
 PARATHYROID
HORMONE
,, ,
, Olge$tion
,,,
,,,
,
Stoma<h
faCI""
...I
,,
,,
,,
, ,, GASTRIN
t
, FOO<! cale"..",
Fill. 12·5. Guttin.
pa ,alnyroO:j 1>0<,...,.... In' .... Olion •. - . St;mu1.Ik>n .•.- . _,
InI1;M.""
When food .I,,·ars available. the rat ta\.:es
largest meal soon afler Ille onset of darkness. The
calcium rhythms can be exaggeraled by oITering
food on ly al this lime.
Plasma calcium concentrations begin 10 ran 2-4
hours before the usual lime of feed ing. The trend
continues for an additional 2-4 hours. whether or
not food is provided. The calcium then rises gradu·
ally over a 12·l1Our period. The morning peak is 0.6-
0.7 mgfd! higher lhan lhe evening low point when
lhe diet contains ordinary amounts of calcium and
phosphorus (144). Plasma inorganic phosphate con·
centrations show parallel changes.
Pla.ma CT rises around Ihc lime Ihal Ihc calcium
Olnc.:nlralion begins 10 fall. and il probably ac·
OlUnl. for much of Ihe calcium change (169). If an-
tisera directed againsl CT a", given, the magnitude
of hypercalcemia elcited i. directly ",Ialed 10 Ihe
prevailing CT Olncen lration. If thyroideclomy is
performed JUSt bofore Ihe usual feeding time, Ihe
calcium in the blood rises sharply (169). The same
surgery bas effecl if it is done at other timcs.
Howcver, although eilhcr Ihyroidectomy or parathy.
roidectomy can alter the liming of the diurnal
rhythm and the magnilude of Olncentration chnge,
neither of the procedures IOlally abolishes Ihe pal.
lerns {1 45 ).
.,..-'------,
'-,
"\
I,
,I
,/
/
Hel an<!
If thyroidectomized animals arc faMed for many
hours and are then fed a calcium· rich meal. Ihey de·
velop marked poslprandial hype rcalcemia and hy-
pe=lciuria. By Olmrast. intact animal. (and thy·
roidectomized ones pretreated wilh en
exhibit
much smaller elevations of the plasma calcium. and
Inc), retain more of the absorbed mineral.
Proposed Functions of the CT Rhythms
CT may act in the following ways to ,uppon cflitien!
utili7.l11ion of dielary calcium (178).
I. The rise in plasma CT Ihat p",ccdes food intake
and Olntinue. for 50me time afterward decreases the
rates at which minerals a", transferred from bone to
blood plasma.
2. Th.",fore. plasma calcium is maintained at low
bel. as food is absorbed from the intestinc.
3. Plasma calcium Olncentralion is the major de-
terminant of thc calcium Olnlent of Ihe glomerular
filtrate ( 193). When CT averts hypercalcemia. it
pT<lteCIS against excessive loss of calcium into the
filtrate.
4. The low plasma calcium permits PTH to be se-
creled at optimal rates. CT docs not antogonize Ih.
influcnces of PTH on renal conservation of calcium.

E. cessive kan,ler (II
,,-
calcium Irom tlOnfr
1
Oeplel"'" 01
boM calcium
Fig. EWflCts Of
melaboi;om.
Therefore, muclt of the filtered calcium IS
reabsorbed.
S. PTH increases the activity of 25·hydroxyvi_
tamin D la·hydroxylase. 1.25·Dihydroxyvitamin D
is then made al an optimum rate. The calciferol pro;>-
motes intestinal absorption (If dielary calcium.
6. CT facililales transfer of phasphale from blood
to bone and other tissues. The tissue phosphale in-
Creases cdlular calcium uplake .
7. Since mineral reServes arc built up during meal
absorplion, the body does not suffer mineral deple-
tion during times of fasling.
The consequences of calcitonin deficiency are
shown in Fig. 12-6.
The described concepts are consistent "'ith many
experimental findings. It has been observed. for ex-
ample. that (a) bones of CT4eprived animals fed
calcium·rich food conlain less recruitable mineral
than bones from healthy controls (1'11). and (b)
whereas the urinary calcium of intact animals is re-
lated to the quantity of mineral consumed on Ihe
previous day. Ihe urinary calcium of thyroidccto;>-
mized animals is determined by the quamity con·
sumed on the day of measurement (182).
It hs been further suggested thai when CT low-
e"i Ihe plasma calcium before the time of food in-
take. there are favorable effecls on the neuromus-
cular system Ihat facililatc food searching.
gathering. and ingestion (182). CT may play addi-
tional roles in appetite regulation (57). possibly by
Ihe calcium content of Ihe cerebrospinal
fluid. Animals injected intraccrebrally with small
amounts of CT food in ta kc al the usual limc.
PTH . CALCITONIN AND OTHER REGlA.ATOAS
Decreased intestinal
absorp'''''' 01 calc.....,
an<! phosphorus
calCit ....... "",,,,"ivalion on Cf.1cium
However. they lend to take smaHer meal •. Some
forms of genetic obesity arc attributed 10 subnormal
numhers of CT in the brain.
" Milk Factors" Affecting Calcitonin
Sacr.. Uon
Suckling infants probably especially conlpel.
ling needs to conserve minerals. The CT levels rise
mOre steeply hefore f""ding Ihan is the ease for older
animals, and hormone sensitivity is high. The neural
crest origin of CT cells (I 3'1). the presenee of .s·ad·
renergic re<:eptors. and the inhibitory innuences of
p-rcceptor antagonists ( I 20) are all consistent with
neuroendocrine mediation of the "antieipalory" ele_
vation of CT.
Pups that are permitted to feed show a se<XIndary
elevation of the CT. whereas ones denied the oppor·
tunity to suckle do not. It has heen sug-
gested that mil k contains secretagogues (62) .
Ral milk i. rich in lipids, and Ihese may contrib-
ute 10 the CT elevation. Exogenous triglycerides in-
voke rapid and sustained CT sccretion without alTec·
tig the blood calcium le,cls. They probably act via
release of gastrointestinal hormones. Some innu-
ences of lactose and of other milk components have
also been described.
Soon after weaning. young ralS have very low cir-
culating CT levels (143). The change in diet may
account for this to some extent. Howe>'cr. juveniles
are especially sensitive to CT. and they probably re-
quire only small amounts. secretion of
growth hormone is believed to contribute to the ad-
aptations. G H enhances the target organ sen·
sitivityjI28)_
CT Secretion during Pregnancy and
lactati on
Circulating CT rises during pregnancy. This is be-
lieved to provide the motber with some prmection
against bone demineraliw,tion. as largc
quantit ies of calcium and phosphate al'<' transferC<'d
to the fetuSC$. The osseous ti$Sue mineral content i$
suboormal in pregnant ewes and gOOtS deprived of
CT (II).
Further elevation of the CT occurs during lacta·
tion. The change is csl"'cially marked in 'I"'cies in
which the infants make heavy demands for minerals_
A rat mother Can be uJlOn to release tbe equiv-
alem of five timcs hcr plasma CQI1tent of calcium into
the milk in a single day (189). Even when fed a cal·
ci um-rich diet. her plasma calcium cone<:ntrntion is
10% lower than that of a female of the
same age. Smaller in CT and me-
tabolism ha,-e been described for lactating WOmen.
CT lowers prolactin in lactating animals (133). and
it may in this way provide SOme protec tion again"
bone loss.
CT Function s during Fetal Llle
C can be found in the thyroid glands of human
fetuses as early as II ....-eeks (before
the thyroid gland follicles have formed). Although
the fetus is (by postnatal standards).
the cells undergo rapid differentiation and they pro.
due<: measurable amounts of CT by the 14t h week.
T he CT levelselimb steadily thereafter unt il close to
the time of birth. Premature infants have higher
blood levels of the hormone than full·term infanu.
The involved in promoting the cell matura·
tion arc not known. but hypothalamic regulation is
unlikely (104)_
CT may perform special functions during devel·
opmental stages in which bone formation proceeds
mueh more rapidly than bone I'<'sorption. It is p0s-
sible that normal fetal gro..... th requires the mainte-
of low plasma calcium levels.
As term PT]; is secreted in larger
amounts, and the blood levels rise (147.
163). The changes may re/loxt the need for more
tensivc bone C<'modeling at this time_
CT Changes with Advancing Age
Progressive declines in both basal levels of plasma
CT and the CT responses to a chal-
lenge have been described for women and also for
coW'S. However. the ability to reestablish normocal-
cemia following infusion of salls is retained
(174).
Some observers report higher CT levels in men
than in women (3). Others find 00 differences under
basal and they attribute tbe mol'<' pro-
nounced I'<'sponses to stimuli for CT release in men
to storage of larger quantities of reserves (136).
There are probably some important species differ.
since adult female rats evidently have higher
CT and more vigorous resJlOI\$CS to slim-
ulation than adult males (143).
Attempts havc been made to link declining CT se-
with a high inddence of osteoporosis in aging
..... omen. Ho ..... ever. the most rapid age-related reduc-
tions occur during the third decade.
Influences of Somatostatin (SS) on
Calcitonin Secretion
The presence of SS in some CT-secreting cells (13.
120). and the esmblished inAuences of SS in some
othcr I'<'gions, raise the poossibility that Ihe peptide
participates in paracrine eontrol of hormone seCre-
tion. !t has been observed that large doses of SS in-
hibit CT release in rats even in the presence of hy·
percalcemia. and thaI SS antagonizes the
stimulatory influences of caleinm. PTH. and food in·
take (37).
!t has been proposed that SS in neg·
ative control in some Food intake
and Olher stimulams of CT secretion elevate the
plasma SS (70). and SS infusions lower the plasma
CT ( 106) . Some regulation may addilionally be
complished indirectly. SS inhibits the se<:retion
of gastrin. IIlucagon. secretin. and PTII. Morcover.
food deprivation is reported to augment SS se<:retion
(183). Sine<: both CT and arc implicated
as appetite depressants. SS inhibition of Ihe se<:re·
tion could encourage eating.
Problems with Ihc concepts inelude caldum-de.
pressing influences of SS that ..... ould be to
secondarily augment CT sCl:rctiQn. and the failul'<' of
SOme investigators to find substantial of
SS on in humans and somc other
mammals (120).
Influences of Prostaglandlna
PG E1 infusions invoke hypercalcemia in intact ani-
mals. probably be<:ausc of actions exerted on bont
(184). Some cells may be responsivc to both PTIl
and PGs. and others just to PGs (112). It is imer-
esting to oote. howeyer. that whereas PGs ca n acti·
vate o.steoclasts and aceelerate bone resportion in
par(Jlh)"oideelomiud animals. they do OOt invoke
..,
hypercalcemia (190) . The observations support the
thai calcium mobilization is a pr<IUSS dis-
linct from bone resorption, a nd that PT H inA ue nces
on (he blood calcium 1"'eis involve actions exerted
on O$lwcytc • .
Since only massive dosages invoke hypcrcalcemia.
il is unl ikely that PGs are physiological regulators of
CT :\Ccretion (27). On the other hand, since SQme
tumors release vcry large qua ntities, and the blood
levels can be elevated in conditions associated with
antibody activation of complement (156). PGs arc
implicated in pathQlogical Pl"QCcsses (80) .
Effects of Dietary Phosphate
CT facilita tes the transport of phosphate from blood
plasma 10 cells. Animals fed diets excessively rich in-
ph"'phalc usua lly manage to ma intain oormopho&-
phalemia. but their hypocalcemic responses to CT
are euggerated. Phosphate deprivation the re-
verse effect ( 1?9).
CT Functi ons In Hibern at ing Mammals
CT may con tribute to the ability to mainta in min-
erai homeostasis during times of prolonged fasting.
"C-cell Gyele," involving degranulation during the
wi nter months. regranulation during the spring. and
en la rgement of the granules during the summer.
have been described for some sP<X'ies (139).
Thyroc alcito nin Rel ease Fact or
Cont iguous endocrine structures ean engage in phys-
iologica lly relevant interactions. For example. glu-
cocorticoids affect the biosyn thesis of epinephrine.
glucagon st imulates insulin release . a nd testoste ron<:
made by one ovarian cclltype is converted 10 estro-
gen in another.
Since parathyroidectomy impairs the ability to re-
establish normocalcemia following the injection of
large doses of PTH . it has been proposed that nor·
mal parathyroid cells secrete a "'thyrocalci toni n reo
lease factor" (64). The concept has aesthetic appea l.
but it has not received support (85).
CALCITONIN ACTIONS ON BONE
CT opposes the bone-resorbi ng effeclsof PTH, pm;-
taglandins. vitamin A, ealciferols. cA MP analogs.
calciu m ionophores. a nd other agents (128). II also
less impressively inhibits spontaneous resorption (7).
Allhough CT aifects the renal excretion of several
ions. and it is also said to retard intcslinal absorption
PTH. CALCITONIN AND DJ1jER REGUlATORS
of calcium (153). Ihe changes in bone do not depend
on those largets .
At least SOme of the e ffects are exerted on cells
identified on the basis of morphological appearance
or enzyme activities as osleoclaSlS. Hormone recep-
tors have been ident ified, and within minutes after
CT presemation the cells retract their microvilli
from resorption surfaces. T he cells then appea r
smaller and more widely spaced . After some hours.
fewer osteoclasts can be counted. and the ones that
persist have nuclei. CT may also reta rd the fu·
sion of monocytic prec ursors into new giant cell s
(54) .
The rapidity with which early responses are man·
ifested. and the failure of either RNA or protein syn-
thesis inhibitors to affect those changes. are oonsis-
tent wit h actions on the plasma membranes. These
probably include mechanisms leading to depression
of the cytosol C a". It was noted that bone·resorbing
agents p romote calci um uptake. The secondary ron-
seq ue nces include accelerated calcium emux and
cha nges in the activities of Iyso&omai en7.ymCS in·
volved in bone degradation. CT rapidly in·
hibi ts calc ium and it later retards calcium re-
lease. The influences on bone resorption are
evidently closely lin ked with the intcrference with
calc iu m upta ke (17 5). Calcium stores prior to pre-
senta tion of the CT may not be major de terminants
of the responses. since the hormone is effcctive in
parathyroidectomized animals and in ones made cal-
ciferol deficient.
W he n CT is injected in travenously in to intact an·
imals. plasma calcium begins to fall within IS min-
utes. a nd a effcct is achieved in around
one hour.
Bone ce lls are said to display "escape"" phenom-
ena. since the eifects of CT on resorption are tran-
sient . T he persistence of large numbers of receptors
indicates thai down regulation cannot fu lly explain
the cha nges. It has becn proposed that differentia·
tion and recruitme m lead to the aceumulation of
large numbers of CT·insensitive osteoclasIS. The 00-
tion is supJXlrted by observations that irradiation of
bone cells prior to exposure to CT averts Ihe escape.
The trea tment does not blunt PTH st imulation of
bone resorption. but it can block PTH fac ilitation of
the differentiation of CT·insensiti ve osteoc laSIS (97).
DNA synthesis inhibitors do not mimic the efTeclSof
radiation.
Allcmpts have been made to reconcile CT st imu-
lation of adenylate cyclase with PTH a ntagonism
(since PTH increases cA M P levels in t he same kinds
of cells). The nucleotide is not a likely med ia tor of
CT actions. and the following suggestions have been
made: (a) There are subJXlpulations of osteoclasts.
Only some of the cells increase their bone-resorbing
activity when the cAMP IC"els rise; (b) each hor-
mone increases cAMP concentrations in its own sub-
cellular compartment. and the locus determines the
cell response; (c) small increases in cAMP levels in
response to PTH lead to ac",,1cmted bone resorption.
Larger ones resulting from CT stimulation inhibit
the responses; (d) both of the hormones elevate
cAMP. However. each its speciali7.ed inHu-
ences on cytosol chemistry that determine the con-
sC{juences of the rise (6,68); and (c) PTH directly
activates adenylate cyclase and it utili7es cAMP as
a mediator. When CT brings about different
chan8es in the cells, cAMP generation occun
secondarily.
fourth idea is consistent with some nndings.
In addition to retarding calcium inAux. CT promotes
phosphate entry. High cytosolic HPol facilitates
mitochondrial uptake of calcium in the presen"" of
cAMP. whereas low cytosolic HPOl faVQrs mito-
chondrial release of minerals (17,160) . PTH pro-
motes phosphate The bluming of PTH ae-
tions in vitamin 0 deficiency states may result from
depletion of intracellular stores of cakium phos-
phate. CT continues to inhibit bo"" rc.wrption in cal-
eiferol-dcprived tissues (40,84).
Although direct inAuenc.. of CT on other bone
cel! types have not demonstrated, it is
that the hOfmone affects multiple targets in osseous
tissues. The magnitudes of change in calcium and
phosphate melabolism seem to be too great to be ex_
plained totally on the basis of osteoclasl inhibilion.
Osleocytes present very large surfaces to bone ex-
tracellular Ruid, and thes.:. eeUs are also believed to
possess "cakium pumps" Ihal bone min_
erals to extracellular Ruids. When CT is adminis-
tered, the cells enlarge to fill Ihe lacunae and their
cytoplasmic:nudcar ratios rise . Bo"" Auid cakium
and phosphate concentrations Can increase within 15
( 179). Therefore. CT may affeci OSteocytCS,
either directly or by modifying the microenviron-
ment. Observations that CT ean increase alkaline
phosphatase activity arc oonsistcnt with inAuences
on osteoblasts or OSteocytes that engage in matrix
formation. CT may oppose PTH inhibition of such
cells, as effects on cakium uptake blunt PTH fa-
dlitation of osteoprogenitor ""II proliferation and dif-
ferentiation . It is li kely that CT interacts with PTH
and other regulators to maintain oormal bone StrUC-
ture and functions (84).
According to some observers. the primary influ-
ences of CT are exerted OIl potassium ion transport.
As in Chapter II, bone Auid has very high
K' concentrations that va ry with the metabolie
functions (rather than with plasma K ' ). CT rapidly
affects sodium, hydrogen and citmle, as well as p0-
tassium levels. and its inAuen"". on calcium and
phosphate may be secondary consequences (129). It
is also possible that CT regulates chloride metabo-
lism. Bone nuid is rich in 0 - . and CT. PTH. and
all affect chloride excretion (47). More-
over, gastric 1-10 is a regulator of CT secretion.
CT has been given to patients with osteoporosis in
the hope that benent would be derived from the in-
hibitory effeclS on bone resorption. No long-range ef-
fects have been achieved, probably because of the es-
cape phenomenon and some interference with
normal renewal of bone cell POpUlalions.
Paget's disease (osteitis deformans) is a disordef
involving overactivity of both bone_forming and
bone-resorbing cells. phcl$phalase activity
and hydroxyproline excretion are both high. and de-
formities Can result from replacement of normalti ..
sue with bone of different structure. Severe cases are
associated with bone pain. Sodium etidronate may
provide better therap)·than cr (A-i).
The actions of CT and PTH on bone are com-
pared in Table 12_1.
CALCITONIN ACTIONS ON THE KIDNEY
Specific, high·affmity CT reCeptors have been iden-
tified in mammalian kidneys. The hormone aCtivales
adenylatc cyclases in certain parts of the nephrons ,
and amounts too small to affect plasma calcium or
phosphate dilate renal blood vessels (4). At lea"1
pharmacclogieal dosages or potent preparalions in-
crease renal excretion of sodium, potassium, sulfate.
chloride , and water. Piseine hormones may also de-
crease magnesium seerction in rats (2.124).
Species diiTcrences in locali711tions of the CT -sen-
si tive adenylate cyclases, in binding affinities. in
amounts of cAMP generated (68), in responses to
both cAMP and CT. and in interactions with PTH
(128). all ccmplieate Ihe problems of determining
the physiological importance of calcitonin actions on
the kidneys . Nanomolar concentrations of CT ele-
vate cGMP in human renal cortical cells. Higher
ones are needed to achieve delayed activation of ad-
enylate cyclase (A-3).
In most species. PTH and CT affect adenylate cy-
clascs in different segments of the How_
ever, in rat cortical aseending loops effects of the
two regulators are nonadditive and the actions may
be exerted on the same enzymes (124).
Parathyroidectomy increases the numbers of CT re-
ceptors, at least in rats (I).
Dogs may be less responsive Ihan most olher
mammals to CT. Natriuresis is of such magnitude in
ralS that CT ha5 been proposed 10 function as a na-
triuretic hormone. Increased Na ' is also
easily demonstrated for humans. sheep, and rabbits.
but it is an inconsistent finding in dogs. Phosphaturic
effects are seen in bolh parathyroidectomized and
 P1'H. C"LC!TONIN "NO REGULA. TOIlS

Err.... O(PTH EIr.."ofCT

T.... I.. of ""I<;i • ., I""" boo< ECF ro """"Ie"'ted R.'onl<d

bkrod pi""'"
of by 'oone otHl <>rh« In hibited Stim.la"d
«II.
Prolileration of .",_,ni'"" ""II. "ced,rated Ddo"d
Mod.l .. ion of pm • ....,. «II. '0 0<1. )'0<1 """,,! ... ,ed
.,.,«>1>1.",
Lif,.p"" 01 .,.,eobl.." Shortened L .... 'h.n<d
CoI l.!<n . y.,.." i, " ""<001.." Dop"""d Stim.I."d
Modulation of ""«>1>1..,, 10 ""_)10' ".""kfOted Dolo),<d

o.",oly'" ,"' i,i'y of "" co<y'" Stim.l ..od Inhibited

"«.m"laiion or lactooe. <i" ... , OM 10<,,»«1
h)'drug<. or """""y'"
o.''''''')'t< . i•• Rod.c<d.l.eunar .pa«
"I..,ed
I.or". mul,i,.d,,, •.
micro,illi ",.oded
O,e .. 11 r... or """" "'''''1'''''" 1""",>0<1
on C)"""," c," Inc=>O<I
C.leilorot d<pe""""". M"" .rrw. dimi.i,hed
c.lcilerol "" r,e"'''''1
Enl"i<d. ",cu .. r .poc<
,m,1I
Sm.n. f'OI".ded. mi<rQVil li
... '""c,,d
n.:: ..."ed
Err..,,, pc"i<l in pm<n« of
cakif.rot d.l"i."",

intact rats and sheep and also in human subjecls Ihal
are healthy, hypoparthyroid. or afflicted with Pagel's
disease (128). Phosphaturia in dogs is abolished by
pa ra th yroideetom y.
Adrenalectomy reverses the nalTiurosis. bUI il
does nol impair kidney responses to some pharma-
cological agenls that augment sodium elcretion (I).
By contrast. PTH-invoked natriuresis is counter·
acted by mineralocorticoids.
Species differences in calciuric responses
(177,193) may be related to Ihe segment of the kid·
ney most affected by cr. Hypercalciuria has treen
described for humans and shecp but not for ralS.
ADDITIONAL EFFECTS OF CT IN MAMMALS
Exogenous cr exert.! selective influenc<:s on water
and electrolyte transport in the various segmenls of
the intestine. Water. sodium. polassium, and chlo.
ride excretion are increased in Ihe jejunum, whereas
bicarbonate is relained. In the ileum. water. sodium.
potassium, and chloride excretion are also increased,
but bicarbonate excretion is increased as well, Cal·
cium absorption is. however. inhibited. The high in·
cidence of diarrhea in patients with medullary Car·
cinomas of the thyroid gland may be related 10 such
effccts. CT can also inhibit contraclion of the gall
bladder and depress functions of the exocrine pan·
CreaS (128).
cr opposes PTH al many siles. It depresses Ihe
mitogenic influenes on thymocyles and some Olhor
kinds "r cells (116), and il interferes with PTH·i".
voxed dilation of hepatic blood vessels.
CALCITONIN FUNCTIONS IN BIRO S
Chick embryos begin to transfer large quantities of
eggshell calcium to Ihe blood plasma around the
IOlh to 11th day, and they ac.:umulatc bone mineral
soon afterward (9). The ullimobranchial bodies
undergo rapid growth around the same time. Pbsma
cr first reaches delectable levels (equivalent to
1000 mU/liter by rat bioassay) on day 17 (186).
The concentrations risc steadily to 2700 mUlliter by
the 20th day (when the birds arc Slill brealhing
through the shell). CT may aCI at this stage to reg-
ulate the plasma concentralions and support rapid
bone growth .
Shortly before the time of hatching. CT levels
elimb steep ly. and they roach 11.000 mU/liter by
the "pipping'" Slagc. The rapid release has been al-
tribuled to development of hypoxia and respiratory
acidosis that lead secondarily to discharge of cate-
cholamincs (9). Whcn tbe chicks breathe air. the CT
concentrations fall precipitously. No hormonc is de-
tectable in the plasma after the first day post-
hatching.
The dramatic changes in the conc<:ntrations sug-
gest that CT plays somc role in supporting adjust-
to life oulside the shell.
When chicks arc fcd calcium-rich diets. the ulti-
mobranchial bodies undergo hypertrophy and the
plasma CT levels risco UltimobranchialeClomized
chicks grow and mature, but they ingC$1 1= food
than intact controls. When Ihey atlain adulthood,
Ihe females also lay eggs that are small and thin-
shelled (39). Normal mature females gi"en the usual
kinds of food have larger glands and higher plasma
CT than mature males.
evidently utili1.e insulin to maintain their
calcium concentrations. Nonhypoglyccmic dosages
exen effects. and thcy can raisc the
plasma calcium even in thc prescnce of vitamin 0
deficiency (134).
CALCITONIN FUNCTIONS IN AMPHIBIANS
The "Iypical"' anuran begins life in a pond. spends
moot of its adulthood in or near watcr of low calcium
content. and cntcrs the water for brecding. It utilizes
paravenebrai time .ac< to store calcium. and it ro>-
cruits the mineral as needed.
Ultimobranchialcctomy impairs the buildup of
Ihe calcium reserves. bone mineralization and the
abilily to heal fractures. Calcium_rich diets in"oke
uitimobranchial gland hypenrophy . These observa·
tions al"<' consistent with roles for CT in calcium con-
servation and control of plasma of thc mineral.
!-Iowever. repeated injection of CT el<'l'l1leJ the
plalima calcium. The hormone may also contribule
to regulation of reproductive system function,. Pro-
lactin invokes the "water drive" during the brc<:ding
Season. It can additionally raise the plasma calcium
and promote uhimobrancbial gland hypertrophy
(39).
Some urodclcs lack parathyroid glands. and in
cenain others paralhyroide.:tomy has no dfeets on
the blood calcium levels. Prolactin invokes hypercal-
cemia in a few species (135) .
CALCITONIN FUNCTIONS IN FISHES
Although piseine calcilonins arc highly potent
agents for correcting hypercalcemia in mammals.
Ihcy do not lower the plasma ca";ium in salmon.
trout. killifish, and some other species. (They do,
howcver. have influences On thc skelcton.) When
some of the marine teleost> are placed in calcium_
free water. CTs proteet against the devc:l<>pment of
fatal hypocalcemia.
Human PTH ' - )4 can accelerate Cal . egress
across the gills and thereby lower blood levels. Es-
trogens elevate the plasma calcum (and the steroids
can do this in birds and SOme amphibians as well).
Pitu itary factors also raise the plasma calcium. The
active components include ACTH and prolactin in
a t least some spe¢ies (US). Corpuscles of Stannius
in teleost. and holosteans secrete a PTH·like peptide
(A·5) . Relationships to hypocalcin (135) or tcleo-
cakin (a glycopeptide) arc unclcar.
The following observations suggest that CT inter-
acts with Olher endocrine glands 10 protect against
hypercalccmia in cels: (a) W hen the animals arc
maintained in fresh waler. CT can lower Ihe plasma
calcium; (b) when th. fish are trallSferred 10 salt
walOr, the ultimobranehial glands enlarge and the
plasma CT levds rise; {c) the glands also enlarge if
the corpuseles of Stannius are excised; and (d) In
One study. sham operated controls had plasma cal-
cium concentrations of 13.6 mg/dl. Th.levels in an-
imals subjected 10 ultimobranchialectomy. stann icc-
IOmy. and combined ultimobranchialectomy·
slannicctomy averaged 15.7. 18.9. and 30.4 mg/dl.
rcspeeti"cly (39).
In mammals, calcitonin.. usually lo.... er the plasma
phosphate. They may also do so in catfish (85). In
eels. they are reported to elevate the levels.
Utile is known of calcium regulation in elasmo-
branehs. The meehanisms differ from those of le-
leoots. sinc<: thc skelelon is mostly cartilaginous. Es-
trogen is not hypercalccmie in these fishes (135).
CT levels risc with advancing age in some of the
teleosts. The changes may be related to hypercal·
cemic effects of gonadal hormones. Especially high
hormone concentrations have been found in salmon
around the time of ,pawning. They may provide
transient protection against excessively rapid bone
resorption when vcry large amounts of glucoconi-
coids arc released.
Several indications that CT secretion is undcr
neuroendocrine control hve been cited. and it was
also noted thaI CT levels rise in mammals Ihal hi·
bernate. It is interesting to note in this connection
that the uhimobranchial glands of cave fish
undergo hype rtrophy if the animals are kept in dark-
ness for extended time periods.
ADRENOCORTICAL HORMONE REGULATION
OF CALCIUM HOMEOSTASIS
Adrenalectomy leads to the development of hyper-
calcemia in cats. dogs. rabbits, and rats. Similar cf-
fecu havc becn described for patients wilh Addison's
disease and for those undergoing subtotal adrenal.
e.:tomy (90.157). G\ucoeortiooid deprivation blunts
.,
Or abolishes Ihc hypocalcemia Iha! olher"-;se follows
parathyroidectomy. It can also relieve tetany (85).
since both 10lal calcium and Cal ' levels arc in-
creased (157).
The natriuretic and some other rcsponS"s to CT
are losl in adrcnalectorni7.ed animal. (2). However,
pharmacological diuretics are stili drec!;v •. Since
neilher glucocorticoid. nor mineralocorticoid. fully
«'Store the sensitivity to CT. other regulator.; may be
involved. A IIQnsteroidal PTH amagonist has been
reCQvered from pig adrenal glands (90).
In intact glucocorticoid injccti<>ns
lower plasma calcium and phosphate levels. They
mitigate calciferol toxicity symptoms. but they can-
nol corrC<'1 Ihe hypercalcemia of hyperparathyroid·
ism (157).
The $(croids increase the calcium conlcnt of the
gl()rnerular filtrate (193), and th ey inhibit tubular
reabsorption (I 57). However. gluCQCQrticoid, also
deereas<: intestinal absorption of the mineral.
Some authors State that C<lrtisone docs not affect
CT influences on blood calcium (85). Others report
blunting of the responses and attribute this to steroid
influences exerted On bone (188). Since repeated
doses of synthetic gluCQCQrtiC<lids decrease CT secre-
tion (107). thcy would be expc<:ted to minimizc the
calcium-<lepressing effects. The inhibition is not of
sufficient magnitude to overcome the renal and in·
testinal respons<:s.
Although cortisone also lowcrs blood phosphate,
CT can .till increas<: urinary excretion of phosphate
(8S).
Influences on Bone
The pharmacological actions arc beller known than
thc physiological ones. Repeated administration of
high doses of glucocorticoid. lead. to the develop-
ment of oste<Jporosis. Thi. has been obs<:rved in ex·
perimental animalS and in patients taking thc ste-
roid. for anti-inflammatory and other properties.
Several mechanisrm; are involved. The most im·
portant may be inhibition of ostcoprogenitor cell pro-
liferation and therdore interference with the re-
ru:wal of bone cell populations. Glucocorticoid.
antagonize the effects of epidermal growth factor
and other regulators on DNA synthesis and mitosis
(22.23). They diminish production of somatomedins.
and they oppose the efTects of both SM. and insulin
on protein synthesis. The hypocalcemic actions lead
to s<:condary augmentation of PTH s<:erction. and
the steroids can exacerbate the bone-resorbing influ·
ences of high PTH levels.
The early effects of presenting moderate amountS
of glucocorticoids to cultures of fetal calvariae con-
PTH . CALClTONtN AND OTHER REGULATORS
trast sharply with preceding observations. Col.
lagen synthc.sis accelerate>< within 3 hours. and tbe
persists for 2 days (22.23). There are
smaller increases in the production of noncollagcn·
ous but no effects on DNA Or RNA have
been found.
Physiological l.vels of glucocorticoid. arc belicved
to maintain the functions of preexisting ostcobla.ts
and to support the anabolic actions of insulin and 5<)-
matomedins (153) and also of a bonc-<lerived growth
can be recovered from bone cui·
ture media The steroids may additionally an·
tagonize i it influences of epidermal
growth factor on collagen synthesis (23).
Low levels of PTH arc needed to support osteo-
genesis. Glucocorticoids:IC<:m \0 play roles in main·
taining the responsiveness to PTR possibly by low.
ering cyclic nucleotide phoophodic.steras<: acti'ity
(130). Higher concentrations of PTH facilitate bone
resorption. Moderate amount5 of glucocorticoid. arc
believed to oppose the resorbing influences of both
PTH and of 1.25·0. Since the steroids lower the
plasma citrate levels (lSI), they probably cxert
some of their on ostcocyte,. In ad·
dition, they can delay onset of CT "escape."
Prostagiandilllj are potent stim"lant5 of bone re-
sorption. increas<: collagenase activity (MO) and
retard collagen .ynthe.is. Glucocorticoids depress
PC in many cell types. It i, that
anabolic actions are re lated to thi., since
the of glucocorticoids Can be demonstrated in
presence of inhibitors of PO (48). On
the other hand. glucocorticoids arc useful agents
under pathological conditions in which excessivo
amounts of POE, are made . PCs arc relcas<:d in
large quantities in inflammatory disorders and by
some kinds of cells. In addition to acting di·
rectly. the molecule. releas<:d by monocytes promote
generation of osteoclast.activating factor (OAF)
(199) . The lymphokine is a highly potent bonc·re-
sorbing agent.
INFLUENCES OF GONADAL STEROIDS
H is easier to dtseribe the ovorall efTects of gonadal
.t.roids on minoral metabolism and bone than it is
to define the mechanisms of action. The hormones
act at several sites. and most of the influences are
indirect. There are species differences in the re-
sponses. and some confusion roles of go-
nadal steroids in humans has resulted from the use
of inappropriate animal moods (173).
Unde r physiological conditions. estrogen. testos-
terone, and adrenal androgens promote closure of
the epiphyses of the long bones of most mammalian
 SpeClCS (16.81). Juveniles secreting excessivc
amounts suITer premature termination of bone elon-
gation, Androgcm stimulate the appet ite. promote
growth and of skeletal musde. and
exert othcr anabolic a<:1ions. They also modulate re-
sponses to CT (176). Boys secreting too much te!;-
tosterone arc usually taller than other y<lungstcrs of
the same age. but they never altain full adult stat·
ure. Estrogen, can retard growth of bone and carti-
lage. and girls producing too much estrogen often suf·
fer severe stunting (gl). Problem. also ari'e when
immature adolescents take oral contraceptive,. Hy_
pogonadal conditions early in life can extend the
growing period and invoke mild forms of gigantism,
Gonadal steroids are sometimes gh'en to elderly
pat ienl S to hasten the healing of fraclUres. They
haY<' also been used 10 terminate growth in juveniles
secreting exe<:ssive amounlS of growth hormone,
Sine<: bone cells are not believed to contain estro.
gen receptors (153), al least some of the gro,,·th.in.
hibiting actions have been attributed to inhibition of
somatomedin generation. The steroids also exert in·
Auenee. On calciferol and calcium metabolism and
On responses to glucocorticoid •.
interactions wilh glucocorticoid, may be espc_
daUy important in rats. In young adult female:;.
there arc cyclical changes in bone growth rates. wilh
the 101'1 points occurring at times when plasma estro.
gens peak. Estrogens stimulate glucocorticoid secre-
tion. and the glucocortiCOid concentrations are high
during those phases of the estrous c)·cle., Adrenal.
ectomy abolishes the cyclic decline in bone forma·
tion rate (194).
Physiological rol", of estrogens in adu lt women
are difficult to assess, Normal aging i. associated
with gradual reduction of bone mass. and Ihe rate of
loss is said to acederate foUowing menopause and
after ovariectomy, The term pos/menopiJu$al OJ/fQ--
p<>rosi., is applied when bone 10:ss is of sufficient mag_
nitude to markedly increase susceptibility to frac-
lure. It has been reported that 25% of white women
suffer One Or mOre fractures by the age of 65 (II 5).
Wrists, pelvic bones. and vertehrae are the most
commonly affected. Decl ining estrogen levels aT< im-
plicated, and Ihere have been numerous studies SUjr
porting the concept that estrogen therapy slow. bone
loss. In SOme cases. estrogens alone Or in combina·
tion with other agents have been found to partially
re verse Ihe condition. Usually, however, the benefits
a re transient (42.115).
Several explanations for the beneficial effeCis of
estrogens have been offered. but there arc problems
with most of them. The coneept that estrogens im-
prove the absorption of dietary calcium is based on
observations that the hormone diminishes fecal
losses. Howe,'cr. it has been demonstrated that es-
trogens reduce intestinal stat/ion of calcium (16).
and this may explain the lowering of fecal calcium
content, The intestinal absorption may, in fael, be
roouced . Suggestions that promote renal
conservation of calcium ha "e not been supported by
studi", involving infusiom of the steroids iOIO renal
arteries (53). Inhibitory influences on intestinal at>-
sorption, with consequent lowering of plasma cal.
cium may account for some decrease in urinary cal-
cium . Observations that 1.25-D levels can rise with
estrogen therapy u nderlie the notion that the steroid
renal 25·hydroxyvitamin D I",·hydroxyl-
ase activity. Here. the effect may be better explained
on th. basi, of slower degradation of the 1.25·D
(lOS). Observations that parathyroidectomy does
not prevent the bone loss that follows ovariectomy
and that parathyroid extracts do not increase the os·
teopen ia (105) arc difficult to reconcile with Ihe idea
that estrogens diminish sensitivity 10 PHI. Morc-
over, no influences of estrogens gi ven in dosages
ranging from 2.5 I'g to 5,0 mg on PTH-mediated
cAMP accumulation wero found in one studyon rats
(113).
Only grossly pharmacological concentrations of
estrogens have been shown to affcct thc metabolic
activities of bone studied in culture (26). Some ro-
versa! of ovariectomy·invoked depression of bone re-
sorption and new formation rateS has been dc>cribed
for rats (42). but there are &Cveral reasons for ques-
tioning the relevance to bo'ne problems of aging
wOmen. lonuenees of estTOgens on bone cell differ-
entiation in birds (100) arc prohahly even more dis-
tantly related.
Additiona! problems complicate interpretations of
the relationships between estrogens and bone func·
tions. The ag!>-3ssocialed reduction in bone mass Can
be demonstrated in the fourth decade. when most
women are still menstruating. !n WOmen who even·
tually develop osteoporosis. the interval between the
beginning of mcnopaU$l: and the on&ct of skeletal
system symptoms is much longer for individuals in
whom there is early ce.sation of the ovarian cycles
Ihan in those in whom this occur! laler. Some
women continue to make substantiai quantities of es-
trogens long after they have stopped ovulating, Sev-
eral non hormonal factors Ihat predispose to devel·
opment of the osteopoT05is have been identified (7).
but others are un known.
Studies of the rates of bone resorption must take
into account the probability that women who see k
treatment for osteopoT05i s may have already gone
through a period of rapid reduction in bone mass.
The very fact that less bone is ava ilable could ac·
count for failure to find greater reabsorption:new
bone formation ratios than in healthy age-matched
controls.
Osteoporosis progresses intermillently. Periods in
which there is rapid bone loss alternate with ones of
...
relative stability. Patients are most likely 10 seek out
IrcalmcnllQward Ihe end of an "active" pha>;e. They
may therefore show "improvement" during the en-
suing WI:<'U, whether or IIO! treatment is given.
Some indi viduals even respond well to placdXl/l
(164). Initiation of a oourse of treatment Can gen-
craIe nol only optimism, but also motivation for in-
creasing activity. In sedentary individuals, the very
act of going regularly 10 a phJSician can affect the
lifestyle. Use and strengthening of Skeletal muscles
facilitiates accumulation of new bone ( I 51), and the
effects may be enhanced if the appetite is improved.
11 is probably also ne<:essary to determine the 0p-
timum amounts of calcium and vitamin D that
should be offered 31 lhe time of institution of hor-
mone treatment. Small increments in vitamin Din·
take would be eXpC<:ted to improve calcium asorp-
tion, whereas larger ones can accelerate bone
resorption. Moderate incrcases in calcium intake can
provide minerals for new bone formation. Larger
ones depress 1.25-0 formation. Both the vitamin and
the calcium can alfect the rates of PTH secretion.
OTHER FACTORS AFFECTING BONE
In addition to promoting generation of somatome-
dins (86). growlh hormone exerts trophic influences
on the gastrointestinal tracl. and il alfects Ihe seCre-
tion of digeslive system hormones and related regu·
lators (198). It increases the and it mayac-
celerale tbe formation of 1,25-D ( 110).
When administered to normal subjects. G H can
elevate the plasma calcium level. and invoke hyper·
calcinria. The elfects On urinary excretion are antag·
onized by estrogens (16). I ncreased sensitivity to tbe
hypocalcemic elfccts of calcitonin (84) mayaccoont
for reestablishment of norm(lC3leemia when GH is
administered for long time periods.
Early in life, GH is an important stimulant for
proliferation and dilferentiation of chondroprogcni·
tor and OSteoprogenitor cells. It also promotes bio-
synthesis of oollagen and other bone oompon.nts.
and it increases mineralization and vascularil.ation
(162). In mature animals. it stimulates both bone
formation and bone resorption.
The effect! of excesses are probably linked mo5t
closely with $Omatomcdin production. In juveniles,
the oonsequences are elongation of the long bones
(gigantism), since GH does not promote closure of
the epiphyses. In adult!. the symptoms of acromeg·
aly include thickening of the bones of the jaws. el·
bows, knees. fingers. and toes .
Physiological levels of thyroid hormones are es-
sential for normal skeletal growth and maturation
and for secretion of GH. Pharmaoological doses tend
PTH. CALCITONtN AND OTHER REGUlATORS
10 accelerate bone resorption and hydroxyproline ex·
cretion. Plasma calcium concentrations are usually
elevated . and this probably accounts for the
caleiuria (! 93) . I nnucnces on gastrointestinal motil·
ity can affect calcium absorption from the small in·
testine (77).
hormone does not seem to af·
feet the biosynthesis of calcitonins, but there are in·
dications thaI iodine accumulation by thyroid cells
in some way facilitates cr secretion (84).
Epidermal growth factor is believed to be a phys-
iological regulator that promotes proliferation of os-
tooprogenitor cells but inhibits oollagen synthesis
and stimulates bone resorption (155).
Vitamin A supports bone remodeling. In defi·
ciency states. the passageways for nerves and blood
vessels do not enlarge sufficiently. Infants deprived
of the vitamin have detective loolh formation_Toxic
doses increase bone resorption, probably via labili·
7.alion of lysosomal membranes and release of pro-
leolytic The cffects are opposed by cr.
oontribute to bone remodeling (A-6.
A·8. 1\·9). Nonhormonal factors affect Ca' · and
For example, metabolic acidosis lcads to
negative caleium balano;. This can occur in para·
thyroidectomiled animals, but it is exacerbaled by
PTH (114).
REFERENCES
l. Agus. Z. S.. Wasserstein. A.. and Goldfarb, S_
f>TH. Calcitonin. Nudeotideu nd the Kid·
ney. Ann. Rr _. Physioi. 0 : 583- 9S. 1981.
2. Aldred. J . Po. KleS2.y",ki. R. R., Stubbs. R. K..
and Bastian. J. W. R"'Iuirement of the Ad .. n.1
for Cert.in Urine !':I«!rolyte Elfects of Salmon
Ca lcit"" in in Rats. Proc. Soc. Exp_ Biol_ Md
07: 114_51. 1971 .
2A . Ali·Rachedi, A .. Vamdell. l. M., Facer. P.. Hill·
yard. C. J .. Craii. R. K.. Macintyre. I.• and
Polak. J . M_ Immunoeyto<hemical Loc31i-ation of
Katacllcin. a Calcium_Loweri"3 Hormone
Cleave<! from the Hum.n Calcitonin Precursors.
j. Clin. f;-NlocrllYJl. Mnab. 57: 681)-2.1983.
3. Arnaud. C. 0_ Calcium HOmOOSt3,i l; Regul.tory
Elements and their Integration. Prrx. 37:
2557-60,1978.
4. Aukl.nd, K. Renal Blood Flow. Chap. 2. pp. 23 -
79 01' Thurau, K, cd . Kid""y and Urinary Troct
fl. University Park P..... Baltimor •.
1976.
S_ Aurbach G. 0., vol ed. HaNibook
Sec. 7. vol. 7. Am.rkan Physiological Society.
Washington. D.C .. 1916.
6. Aurbach. G. D.. and Cha ... L R. Cyclic Nuelca-
tidC$ .nd Biochemical Action, of Parathyroid
 Hormone and Calcitonin. Chap. IS. pp. 3S3_81 of
Aurbaoh. ed .. rcference 5.
7. Aurbach. G. D .• Marx. S. J .• and Spicgcl. A. M.
Parathyroid Hormon •. Calcitonin, and the C,loi·
ferol •. Chap. I<J. pp. <J22-1031 of Williams. R.
H .. ed. TUlbook 0/ £nd«,,"""'OV. 6.h cd. Saun·
Philadelphia. 1981.
8. Ausiella. D. A.. R"",nblau. M.• and Dayer, J. M.
Parathyroid Hormone Mooulate. Protein Kin ...
in Giant CeU Tumors of Human Bone Amtr. J.
Pity';o/' 239: EI44_EI49. 1980.
9. B.imbridgc. K. G .• nd Taylor. T. G. RoleofCal·
dlonin in Calcium Homeostasi. in the Chick Em·
bryo. J. Endoai""'. 85: 171_85. 1980.
10. Barhn. A.. Marilus. R.. Winkelsberg. G .. Ve.hu·
run. D .• and Blum. 1. Primary Hyperparathyroid·
i.m, Possible CIU .. of Primary Hyperaldostero-
ni,m In a 60-Year-Old Womu . J. (.1;n.
End"",;""". Mtrob. 51: 144_7. 1980.
II. Barlol, J. P .. and Garel. J. M. Physiological Role
of Calcilonin in Pregnanl GoalS and Ewes. pp.
I 19-21 of T.lmage e. 01.. cds. reference 181.
12. Bengele.lI. II.. Ale .. nder. E. A.. and lechene.
C. P. Calcium and Magn.sium Transporl Along
the Inner MeduUary Collecting DUCI of the Rat.
14=,. J. PhytiQI. 239: F24_F29. 1980.
13. lkrelowilz. M .. Cibeliu •. M .. Szabo. M .. Froh·
man. A .. EJI'lein. S.. and Bell. N. II. SomalO)-
Slatin·Lixe Immunoroaolivity in a T .... n.planl.blc
Medullary Carcinoma of Rat Tttyroid, Parlial
Chromatograph ic and Bi<)logio.1 Characteri ... ·
lion. End"",;I10/. 107: 1418-24. 1980.
14. Biddulph. D. M.. Currie. M . G .. and Wrenn. R.
w. Effecl. and Inleraction. of Paralhyroid Hor-
mone and Prostaglandins on Ade_inc ]',5".
Monopilosphale Concemratio.. in Isolated Renal
Tubule •. t:nd"",''''''. I(H: 1164_11. 1979.
IS. Bikle. D. D.. Ind Herman. R. H. Colcium Poten-
tiales lhe Cyclic Nueleotide and Phosphaturic
Re.ponse 10 Paralhyroid H<>rmonc Infu.ion. J.
Clin. t·nd"",i""l. 56: 11 _17. 1983.
16. Birge. S. J .• and Avioli L. V. The Effecl of Oral
Conl,aceplives on Calcium AMcrption . pp. 48S_
92 of Salhaniok 01 al.. eds .• rcfor<nt(: 173.
1M. Ilo<kman. D. E.and Kirby. M. L. Dependence of
Th)'mus Development on Derivatives of the
Neural Crest . Sdenu 213: 498-l-OO. 1984.
17. Sorlc. 1\. B. Regulation of the Mitochondrial
Conlrol of Cellular Caldum Homeost.,i. and
Calcium Transporl by Phosph.te. Parathyroid
Hormone. Calcitonin. Vilamin D and cyclic
AMP. pp. 217_28 of Talmage ct 01.. cd •. refer·
e """ I 8 1.
18. Bourdeau. J. E .. and 8urS. M. B. EIf..1 of PTH
on Calcium Transpon Across the Conical Thick
Ascend ing limb of Henle', Loop. J. Phys_
iol. 239: FI 21-FI26. l<JSO.
19. Brown. E. M. ReI.lion.hip of 3'Y·AdeOOline
Monophosphote Aocumulation to Parathyroid
H<>rmone Rele •• e in Dispe .... d Cell' from Palh-
<.>IOSio.1 Hum,n Paralhyroid Tissue. J. Clin. Ell-
d«'inol. Mrlab. 52: 961-8. 1981.
20. Bro"n. E. 1.1 .• G.rdn«. D. G.. and Aurbach. G .
D. EIf«ts of the Cllcium lonopbore A2318 7 on
Di.pe .... d Bovine Paralhyroid Cell,. t ·nd"",;"",.
106: 133-8. 1980.
21. Brown. E. M .• Gardner, G., Windeck. R. A., and
Aurbach. G. D. Rel . tion.hip of Intracellular
3'S_Adenosine Monophosphue Accumulation 10
Parathyroid Hormone Relea .. from Di.pe .... d
So.inc Parothyroid Cell •. End"",;"",. /OJ: 2323_
41. I<J7S.
22. C.nali" E.. Peck. W. A.. and Rai ... L. G. Stim-
ulation of DNA .nd Collagen Synlhesi s by Au·
tologou. Growth Flct<>r in Cullured Felal Rat
Cal.aria. Sd.nu 210: 1021-3, 1980.
2). Canalis, E .. and Rai ... L. G. Effect of Epidermal
Growth Faelor On Bone Formalion in Vitro. E,..
d"",IIIOi. I(U: 862-9.1979.
24. Coniggia. A.• and Gennari. C. Early Effect. of
Calcitonin in Man, Comparison wilh Early Ef-
fect. of Parathyroid Hormone. pp. 154-6 of Tal·
mage et al .. ed •. reference 18\.
25. Capen. C. C. o.nd Youlli. D. M. Thyrocalcitonio;
Evide""e f<>r Release in • Spontaneous HypOCal·
cemic Disorder. 157: 20S-6. 1967.
26. Caputo. C. B.• Meadow. D.• and Rai ... L. G.
Failure of ESlrogen. and Androgens 10 Inhibil
Bone Resorption in EruJ"",;"",.
98: 1065-S. 1<J76.
27. Care. A. D .• Bat... R. F. L.. Swaminalhan. R.,
Sea ..... C G.. Peakrock. M.. Mawer. E. B.. Tay·
lor, C. M .. DeLuca. II. F.. Tomlinson. S .. and
O·Riordan. J. L. H. The Control of r.ralhyroid
HormQne .nd Calcitonin Secretion and Iheir In·
leraclion with Olher Endocri ... System •. pp. 10 I-
10 of T .lmage el aJ.. ed •.• reference 181.
28. Carney. S .. and Thompson. L. Effecl of Differing
CortCenlralions of Paralhyroid Ilormone on Ral
Renal Electrolyte E,eretio • . J. PhYJi()/.
UJ:FS I4_FSI7.1982.
2<J. Catherwood , 8. D.• and Dcr"",. L. J. Presence by
R.dioimmunoa .... y of a Calcitonin·Like SuI>-
stance in Porcine Pituitary Gland •. Ender""",.
106: 1886-91. 1980.
30. Chan.rd. J .• Blacl;, R.. Pu\:.erson. M .• Lewis. J ..
Klahr. S.• and SlalOpoisky. E. The Eff«IS of Col·
chioine and Vinbla.tine on Paralhyroid H<>rmone
Secrelion in lhc Ral. End",,'i""'. 10/: 1792-
1800. 1917.
3\. Clark. I. AIt.ration. In Bon<: tRNA Methyl·
Transferases Induced by Pa .... lhyroid Ilormone.
Calcitonin. ACTH .nd Dibulyryl Cyclic AMP.
pp. \95_203 of Talmage el al.. cds .. refere.ce
I 81.
32. Coburn. J. W.• Kurokawa. K.. and Kleeman. C.
R. Di.alenl Ion Metabolism. Chap. I I. pp. 401-
60 of Freinkel. N .. cd. C()JfUm[>OFo'y M . laoo.
Ii$m. Plenum. New York. 1978.
33. Cohn. D. V.• Morrissey. J. J .• Shof'IOll. R. E .. and
Chu. L. l. H. Coseorelion of Secretory Protei"..1
and Paralh<>rmone by Dispersed Bovine Par.thy·
roid Cell •. t"nd",,';no/. 110: 625_30. 1982.
33A. Cohn. D. and Elling. J. Biosynlhe.i •• Processing.

and Seorction of P:arathormone and =r.tory
P""ein-J. Rec, Prot. Hom •. Rsclt. 39: 181-203,
1983.
H. Cohn. D. Y.. Smordo. F. 1.., Jr., and Morri$$ty, J.
1. Evidence fer Internaillemolegy in B<wine Pre-
propaCllhyroid Hormone. Prot:. Narl. Acad. Sci.
USA 76: 1469-71. 1979.
35. Cohn. D. Y., Zangerle. R., Fischer·Colbrie, R..
Chu. L. l.. Ellini. J. J.. Hamill"". J . W.. and
Winkler. H. Similarity of Secretor)' PrOtein I
from Parolhyroid Gland to Chrornogranin A from
Adrenal Medulla. Proc. Nctl. AC/Jd. Sci. UStf 79:
6056_9.1982.
36. Conn. P. M .. D. C., a nd Sandhu, F. S.
Alteration of the InlraCeliular Calcium Lt"el
Stimul.te" Gonadotropin Release frQm Cuitured
Rot Anlerior Pituilary Cell •. Elldoc,iltOi. /OJ:
1122_7.1979.
37 . Cooper. C. W .. Bolm.n. R. M .. III .. linehan. M ..
a nd Wells. S. A .. Jr. Interrolation,hips Between
Calcium. Calcemic Hormones. and G .. trointes·
tinal Hormones. RH:, Prog. iformo", Rsch. 34:
2S9-78. 1978,
38. Cooper,. W .. Peng. T. -C .. Obic . J. F" and Gor-
nero S. C. Ca!eitonin-Lik. ImmulIQre.etivily in
Rat and Human Pituiu ry Gland" Hislochemical
In Vilro and In Vivo Studie •. HndocriltOi. 107;
98-107, 1980.
39. Copp. D. H. Comparali.e EndocrillQlogy of C. I·
0;10n;n. Chap. 19. pp. of "u,bo<h. od ..
reference 5.
40. Copp. D. H. Endocrine Regulalion of Calcium
Metabolism. Ann, Rty, Physlo/, 32: 61 - 86. 1970,
41. Crass. M. r.. [ I I, an<! P:ang. P. K. T. P:aralhyroid
Hormone: A Coron.ry "'lory Vasodil.tor. Sei.
enO< 207: t087_9. 1980.
42. Cru .... R. L.. and Hong. K. C. Th. Elfect of
LAng Term Administration .". Bone
Metabolism in lhe Femal. Rat. HnJocriltOi. 104:
1188-93.1979.
43 . DeBartolo, T. F., Peli. I.. E .. C .. and
Hahn. T. J. Comparison of Paralhyroid Hormone
and Calcium lonophore A23187 Elfccts on Bon.
Resorption and Nucleic Acid SynthO$is in CuI·
lured Fetal Rat Bone. Ca/cij. TiUUt In,. 495_
SOO.1982.
44. Deft",. I.. J .. BUllon. D.. Cath.rwood. B. D..
Bone, H. G., Parlhemore, J. G .• Guillem;n. R..
Walkins. W. B .. and MOOIe. R, Y. DemonstrOlion
by lmmul>Qpero>.idase HislochemiStry of Calci·
tonin in the Anterior I.obc of the Rat Pituitary. J.
C/in. t:ndoc,ino/. Mt lCh. 47: 457_60.1978.
45. Dempster. D. W .. TOOkr. P. H.. 011 ... P.. Ilorn,
W .. and Fischer. J. A. P01(l$$ium Stimulates
P:a .. thyroid Hormone Release from Peri/used
Paralhyroid Cells. Endocrino/, III: 191-S. 1982.
46. Denni .. V. W. Slead. W. W.. and M)' .... J. I..
Renal Handling of PhoiIph ... and Caleium. Ann.
Rn-. Phy';o/. 41: 257-71. 1979,
PTH. C"'LCITQN I'-I ... NO OTHER REGUlo'.TORS
47. Del"",he,. D. Thymus Gland. Vitamin D and
Seasonal Inftueno.. 00 Ele<:trolyle Metabolism.
Ph.D The.is. ttun!er Coll.ge CUNY. 1981.
48. Dietrich. J . W .. C.nalis. E. M.. Main • . I), M ..
and Raj".. I.. G. Effects of Glucocorticoid, on
F..al Rat Bone Q,lIagen Synthesis in VilrO. En-
doc'lnoI. 104: 715-21. 1979.
49. Dietrich. J . W., .nd Duffield. R Elfecl$ of lhe
Calcium Antagonisl Verapamil "" In Vitro Syn,
of Skeletal Coilagen and Nonoollagcn Pr0-
tein, Endoc';ItOi. 1M: 1168-72. 1979.
50. Diwieh, l. W., Mundy. G. R.. and Rai". I.. G.
Inhibition of Bon. in Ti .. ue Cultu.e
by Mcmbranc-Slabili7.ing DruglO. I::ndoc';nol.
104: 1644-8, 1979.
51. DietriCh. J. W., and Paddock. D. N. In VilrO Ef·
fec!s of lonophare Alll87 on Skeletal Collagen
and Noncollagon Protein Synth.. il. Endoc,iltOi.
104: 493-9.1979.
52. Eilon. G .. and Rai ... I.. G. Compa.iwn of the Ef·
focts of Stimulators and Inhibitors of Resorption
on Ih. Release of Lysosomal Enzym .. and Radic-
acti.e Calcium from Fel.1 Bone in Organ Cul-
ture, EnJocdnol. J(}J: 1969_7S. 1978.
53. Eisenberg. E. EIf«ts of ESI"'ll.n .". Calcium Mo·
tabolism in Man. pp. S03_17 of Salhanick et al..
eds .• re ference 173.
54. Feldman. R. S., Krieger, N . S .. and T.,hjian. A.
H.. Jr. Effects of Parathyroid Ilorman • • nd C.I·
<i'onin on 0 .,...,1. .. Fo,mat;on in Vi,ro. b'ndo
(dnol. 107: 1137-43. 1980.
55. Fiocher. J . A.. Blum. J. W .. I!Qrn. W.. Dam-
bacher. M. A ... nd Dempster. D. W. Regulation
of Paralhyroid HOlfnone in Vitro and in
Vi".". Ca/dj. Tissut Inl. H : 313-16. 1982.
56. Fr.n kel. S .. and Ya,umura, S . Intralhyro;dal
Thyme.leilonin Level, in Neonatal and Adult
Rat<. EndocriltOi. 87: 602-5. 1970.
57 . Freed. W, J .. P.rlow. M, J ... nd Wyatt. R, J. C.I·
citonin, Inhibitory ElfeCI On Eating in Rat<. &/.
elf« 206: 850-2. 1979.
58 , Freitag, J . J" Martin, K. J ., Coor.dC$, M. 8.. and
Slatopolsky. E. Metabolism of Paralhyroid Hor·
mone by Fetal Rat Calv.ri •. /:'ndocrino/. 104:
SItJ-16.1979.
59. Galanle. 1... Gudmund""n. T . V.. M.nh ...... E.
W., Tse. A., Willi.ms. E. 0 .. W<XIdhouse. N. J .
Y.. and Macintyre. I. Thymic and Parathyroid
Origin of Calcitonin in Man. u,If«' 1: S37, 1968.
60. G.rdner. D. G .• Brown. E, M .. Altie. M. F.. and
Aurbach. G. D. f'roslaglan<lin·M.dialcl Slimu·
lalion of Aden",ine )'.5'·MoIIQPhoilphat. Aecu·
mulation and Parathyroid Hormone Rcleuc in
Disperse<! Human Parathyroid Cell •. J. C/in, 1:'<>-
d(J(,ino/. Mtloh. 51: 21)-5,1980.
61. Gardner. D. G .. Brown. E. M .. Windeck. R.. and
Aurbach, G. D. Prostoglandin F,. Inhibit' 3',S'
Adenosine Mooophoilphate Accumulation and
Parathyroid Hormone Release frQm .... d
 I;Iovine Cells. t.'IUi{J('rIMl. I(H: 1_7.
1979.
62. Gatel. J .• M., arKI Bresnatd. P.. Milk Faotors C""·
trolling the PI .. ma Calcitonin Level in the Ne,,""
born R.t. t.'ndoaiMl. /(H; 1617_23. 1979,
63. Gillene. M. F., Insosna. K. L.. Lewis. A. M ... 00
Baran. D. T. InHuence of on Immu,
noreaotive Paratb)'roid Hormone Levd •. Calcif.
Ti"ut In!. J4: 9_1 2. 1982.
64. Gines. R. F.. and I,.in. G. L. Thyroid and Pa,a-
thyroid Rol« in Hypercalcemia: hidence for a
Thyrocalcitonin-R.leasing factor. Sdtllu /48.-
1737-9,1965.
65. Goldberg. M .. Agus. Z, S .. and Goldfarb. S.
Renal Handling of Cakium and Phosph ....
Chap. 1. pp. 211_56 of Thurau. K.. ed, KidNy
and U,i"",y Traci Phy,iology II. University Park
Pro ... Baltimore. 1976.
6{;, Goldstein. D. A.. Feinstein, E. I.. Chui. L. A..
Pwal>hir.man. R ... nd Massry. S. G. The Rei.·
ti"".hip betwoon the Abnormaliti", in Electroen·
cephalogram lind Blood I.e.el, "f Par.thyroid
Hormone in Di.I)'si. Patients. J. CIi• . t.·ndoc,i/tOl,
M' lab. 5/.iJ0-4. 1980.
67. Gold .. ein. D. A .. Romoff, M .. Bogin. E .. and
Ma.sry, S. G. Relationship Ix',,'ccn 'he Concc"..
\r.tion. of Calcium and Phoiphoru, in Blood and
Cerebrospinal Fluid , J. Clm. EnJocdnoi, Me/ab.
49: 58-62. 1979.
68. Goltzman, D. ExaminatiOl\ of Int<r$peoies Diff.,.
ctIC'" in Renal and Skeletal Receptot Binding.rK1
Adenylale Cyclase Stimulation with Human Cal·
oitonin. EndouiMl, 10il: \980.
69. Gohzman. D.. Huang. S,·N .. Brownc. C .. arKI
Solomon. S. Adrenocortieo>lropin and Calcitonin
in Medullary Thyroid C.",inoma: Frequcncy of
OccurretICe and Localization in the Samo Cell
Type b)' Immunocytochemistry. J. CIi•. Em/ocr!·
MI. Me/db, 49: 364- 9.1979 ,
10. GU7.m.n. S., Lonovi",. J., ChayviaUe. J.·A .•
Hejtmancik. K, E,. Rayf"td. P. L. and Thomp.
.<On. J . C. Effec," of Gastrin on Citeulating Lev.ls
ofSoma,,,,min. Pancreario .• nd Va·
soactive Intestinal Peptide in Dogs. £ndoc,IIKli,
107: 231-6, 1980.
71. Habene" J. F. Regulation of Pa,athyroid Ho,-
mone $core,ion and Bi",yntho$is. Ann. Rn'. PhyJ_
101. 43: 211-223.1981.
72. Habencr, J. F.. and Kronenberg, H. M. Parathy.
roid Hormone Bi",ynthesis: Structure and Func-
tion (If Biosynthetio P,ecurwn, Proc. 17:
2561-6. 1978.
73. H.bener. J. f .. and Pom. J. T., Jt. Chemistry.
Bi",ynthesis. $ccreti"" and Metabolism of Para·
thyroid Chap, 13. pp. 313-42 "f Au,·
b.ch. ed .. teference 5.
14. H.bener. J. F., and P"uo, J. T. Jr. Clcavag",A.·
sociated Enhancement of an Antigonic Site in the
Biologioally Acti •• NHrTe,minal Re8ion, <>f
Parathyroid Hotmone. £ndocrllKli, 105: 115-19.
1979.
15. H.bener, J, F.. and POllS. J. T" Jr. Sulxollular
Di Stributions of Pa'ath),roid Hotm"ne, Hormonal
Procurw ... and Patathyroid Secretory Protein.
t.·ndoc,iMl. 104. 265_74. 1979,
76, Hahn. T. J .. DeBartolo. T. F.. and Hal"ead. L.
R. Ouabain Effects Qn Ho,monally-SrimulatOO
Bone R...,rption and C)'clic AMP Content in
Cuilufed Fetal Rat Bone. . EndocriM R.ch.
Cornm.7: 189- 200. 1980.
77, Haldimann, B., Kaptein. E, M __ Singer, F. R.. Ni·
coloff. J. T .. and Ma."ry S. G. Intestinal Calcium
Al>$or-ption in Patients with Hyperthyroidism. J.
Clin, £nJocrjooi. Mtlab. 51: 995-1. 1980.
78. 11011. B. Bone in Cartilaginous Fishes. Nmu'e
198' 324. 198Z.
79. HarKIl.r. J. S .. and Orloff. J. The M.chanism of
Action of Antidiuretic Honn""e. Chap. 24. pp.
79\-814 of Orloff. J ... nd Berliner. R. W.. eds.
Handhwl: oj ny>ioIOgy. Soo. 8. Americ.n
iologio.1 Soci.ty. Washington. D.C .. 1973.
80. Harpe', E. C"nagenalO" Ann. Rev. Bioch,m, 49:
106)_78.1980.
81. Heany, R. P. F..$lrogen E/foo .. an the Skeicton.
pp. 493-502 of Tolmage et .1 .. eds .. reforetIC.
181.
82. H•• th. E, B.. and Zull. J. E, Activation of Bo,ine
R... I Cort.. Membrane Adenyl Cyel .." by Low
Concentrations of Parathyroid Hormone. t::ndo<:r.
•. 7: 87-98. 1980.
83. IICllh, H. P''''OCaliY< T",ts of Parathyroid and
C Cell FutlCtion in Adtenalectomi>cd and Chem.
icolly SympOlhCOtomi.ed Rats, Endoc,ilKli. 107:
911_81. )980.
84. Hirsch. P. F.• Cooptr, C. W., Pengo T ..C .. Bor·
ford. I!. J" Toverud. S. U.. Gray, T. K.. Juan. D..
Ontjeo, D, A., H.nne.,,)', J.P., and Munson. P. L.
Effects. Fune!;ons. and Endocrine Interrelations
Thyrocalcitonin. pp. 89_99 of Talmage et 01 ..
edo .• ,ererence 181.
85, Hirsch. P. F.. and Munson, P. L Thyrocalcitonin,
Physiol. R ... 49: 548--1i22, 1969,
86. Iloider. A T" Wallis. M .. B;gg$. P.. and Preece,
M, A. Effects of Growth Ilormone. Prolactin and
Thyro.itIC 01\ Body Wei8ht, Somatomcdin·like
Acti.ityand In-Vi.o Sulphation of Canilage in
Hypopituitary Dwa,f Mi«. J. "lUioc'. 85: 35_47,
\980.
81 . Jacobs. J, W.. Golllman. D.. and Ibbe.e,. J. f.
Abstnce of Detectable Calcitonin Synthe.is in the
Pituitary Using Cloned Complementary o.o.y.
ribonucleic Acid Probes. £nJ{J(',IIKli. III: 2014-
19.1982.
88, Jacobs. J. W .. Goodman. R. fl., Chin. W. W .•
o.e. P. c., Habene., J, F.. Boll, N. II., and Pm".
J, T .. Jt. Caloi,,,,,in Me...,nger RNA Encode,
Multiple Polypeptido. in a Single Precursor. Sci_
''''dlJ·451-9.1981.
89. Kllu. D. N .• Ihdji-Georgopoulos. A .. and Fost.r.
G. V. Acute Regulation "f Plasm. Calcium I>y
Parathyroid Hormon. in Rats: Effoot of Age. pp.
270-2 of Tllmage '" 01.. ed$., teferenco 181 .
'"
90. Kaptan. E. L.. Peskin. G. W., Hill, B. J .• T..". H.
S .• and Arnaud. C. O. An Adrenal Calciton;n-
Lih Principle. pp. 458_65 of Taylor, S .. • 00 fOil_
ler. G. V.. eds. IlItW PTQCnding. of rh.
1nd Inlm UlI. Symp. Heinemann, Lend"". 1970.
91. Keaton, J. A.. Ba'lO, J. A.. Moore. M. p.. G,ud.
J. 8.. and Ma)'.r, G. P. Alt .... d Parathyroid Re _
_pons< 10 Calc ium in HYP<'",.lcemic Noonatal
Calves. £nJoaIMi. /OJ: 216 1_67.1978.
92. Kcnl, G. N .. Jilka, R. L.. and Cohn. D. V. Ho-
mologous and HelerolO8,""s Control of Bone Cell
Adenosine )'-Y·Mooophosphale Re.""n ... 10
HOT1I\<lne. by Paralbormon<, PrOiltaglandin E,.
Calcitonin and 1.25-Dihydro.ychoiecalcirerol.
E:nd<xrlMl. 107: 1474-8 1. 1980.
93. Kha n, f .. Khan, A. J., Papag.roofali., C .• War-
man, J .. Khan. P., and E •• ns. H. E. Reversible
Otfe<:l of Neutrophil Chemotaxis .nd Random
Migrati"" in Primary Hypcrparathyroidi.m, j,
Clin. Endocri"";. 582-4. 1979,
94. Kl<eman. K. , and Kleeman. C. R. Parathyroid
H<>rmon •. Chap. 9. pp, 306-29 of Ingbar. S. II..
ed. C""'tmperory vol. I. Plenum.
Ne .. Yo>rk. 1979.
95 . Kleeman. K.• and Kleeman. C. R. Paralhyroid
Hormone ond Calcilonin. Chap, 4. pp. 109-60 of
Ingba., S. H.. ed. Yror lit Eltdocr;ne/ogy.
1977. PI.num. New York. 1978,
96. Klem.nI$Chil$Ch. P.. Kaplan. E. l.. Healh. H ..
HI. N<>rth. P.• and Lee. C. H. A Gutrie Factor.
Calcitonin•• nd the Hypocale<:mia Induced by
Gamoinl."inal Hormones. /05:
1243-47.1979.
97. Krieger. N. S .. Feldman. R. S .• and Tashjian, A.
H .. J r.• Paral hyroid Hormone and Colellonin In-
teractions in Bone: IrradiatiM·lnducod [nhibition
of Elcape in Vitro, Caldj T;jJue fm. 34: [97-
203,1982,
98. Krieger. N. S.. and T.,hjian. A. H .. Jr. Inhibition
of Paralhyroid Hormane-$timulated Bone Re-
sorption by Mono .. lem Cation lanophor... Caf·
TISS"t fn,. 239_244.1982.
99. Kronfeld. D, S., Mayer. G. P.. and Ramberg. C.
F .• jr, Calcium Homeosta.i. in Caule. Chop. 7.
pp. 169-81 of Aurbach .• d .. ref.renco 5.
100. Ku,.hora. S., and Sellra... H. CytOlogy and Au·
loradiagraphy of ESlragen-l nduced Different io·
tion of Avian EndO$'ea[ 0:11$. Chid! fnl.
14: 352-8. 1982.
101. Lambert.<. S . W. G .• Haekeng. W. H. L and Vi$-
ser. T. j , Di",,,,,iation and Associalion Between
Cak itonin and AdrenoconiCOlropin S.cretiM. j.
CIi". Endocrlnel. Mttab. 50: 565-8 . 1980.
102. Langman, J. Mtdlral Emwrology. 2d ed. Wil·
liam. &: Wilkins. Baltimore. 1972.
10). Lasker. R. D, and Spiegel. A. M. Endogeoous
Substrale. far cAM P-Depcndenl Phosphorylation
in Di'persed Bovine Parathyroid Cells. Ettdorri-
nel. III: 1412-14. 1982.
104. Loro)·er.Ali",n, E.. David. L . " nd Dubois. P. M.
PTIi. C... lCITONIN " NO OTl--lER REGlA.ATORS
for Calcitonin in the Thyroid Gland of
Normal and Anenceph.lic Human Felu,." 1m·
munocytological Locali u.tion, Rad ioimmunou.·
,ay. and Gel Fiilratian of Thyroid Ext .."ts. J.
Cfin, Endocri"";. Mtlab. :m: 31 5_21. 1980.
105, Lind, .. n. U .• and De Lu" •• H, F. Role of Para-
thyroid HotmQne and 1,2S.Dihydtoxyvitamin D,
in 'he Development af Osteopoenia in Oophorec-
tomittd Ral$, Chid! TJJu, fnt. H,'
1982.
106. Linehan. W. M .• Cooper.c. W .• Bolman, R. M ..
Il l.. ond Well •. S. A.• Jr. I nhibilion of in Vi,o Se-
"retion of Cakitonin in th" Pig by 5omatO$talin.
Eltdocrl"";, I(U: 1602- 7. 1979.
107. Lo CaStio. V., Adami, S .. A' i()li, LV., Comina·
cini. L. Galvonini. G.. Gennari. C .. Imbimho. B.•
and Seuro. L. A. S uppr<$Sive Effect of Chronic
Glucocorticoid Teeatment on Circulaling Colel-
lonin in Man. Chid/. TI"ut Int. 309_ 10.
1982,
108. Luben. R. A., and Cohn. D, V. Effects of Para·
thormone and Calcilonin on Cilrate and Hyalu·
rona,e Metaboli,m in Cultured Bone. t:ndocrinol.
98:413 - 19. 1976.
109. Luckey. T. D.• ed. Thymic H(H'mo"u. Uni'''r$i,y
Park Pr .... Baltimor •• 1973.
11 0, Mac lntryre, L. Colston. K. W., M., and
S"",..,.. E. A Survey of Ihe Harmonal Factors
That ContrOl Calcium Metabolism. Ann. NY.
Sri, 307: 345-54, 1978.
IIOA. Maci ntyre. I.. Hillyard. C, j" Murphy, P. K..
R.ynolds. j, J .• Da •• R. E.• and Craig. R. K. A
SeO)nd PI .. ma Calci um·Low"ring Peptide from
the Human Ca litonin Pr.cursor. 300:
460-2.1982.
111. Manette. L E .. Renfro. M.• Lemoncc lli. J .. and
R"","\>IW. M, Radioimmunoa .... y. for tbe 24-48
Region of Parath yroid H<>rmone Detecl Inlact
Hormone bUI NOt HornlOn< Fragment •. Cold!
TiJJUt Inl. JJ: 375-80.1981.
1[2. Mareu •. R .. A!"csen, G .. and Orner. F. B. Fluc-
tuation of 3',5' -Cyclic Adenosine Monaphosphate
Bindi ng Sitc Occupa ncy a, an Index of Hom>on ..
Dependenl Adenosine 3',5'· Mol>Opbosphatc For·
mation in Bone Cell$. Endoerinel. 104: 744_50.
1979.
113. Marcu,. R., Orner, F. R .• nd Brickm.n. A, S. Ef-
reclS in V;.o of Vilamn D. Metabolite< and 17(;.
EStradiOl on P.rathyroid Hormone-Dependenl
Formation of Adenos;ne 3',5'.),1ol>Ophosph.te in
R.t Bone. Endocrinol. /07: 1593-9. 1980.
114. Martin. K. J" Freitag. J. J" lkliori ... Font. 10..
Conradcs. M. B.• Klahr. S.. and Slatopolsky. E.
The EIf.. t of Acute Aeidosi, on the Upta ke of
Parathyr";d Hormone ond Ihe Production of
Adenosine )·S· MMophOilphatc by [sol. ted I'<r·
fused Bone. Eltdocrinol. 106: 1607- 11. 1980.
115. Marx. J. L. Osteoporosi" Ne,.. Help fo r Thin"ing
Bone •. 207: 628-30. 1980.
116. Marx. S. J .. and "urbach. G. D. Calcitonin Re·
 ceptOfl. pp. 163-71 of Talmage e\ 01 .. od •.• ref·
erence 181.
117. Mayer. G. P.. Keaton. J. A .. HUrSt, J. G., and Ha-
bener. J. F. Effect. of Plasma Calcium Concen_
Ir.tion on the Relative Proportion of Il ormone
and Corbo. yl Frogment' in Paralhyroid Venous
Blood. Endrx,/IIOI. 1778- 84. 1979.
118. McGowan. J. A, Chen, T. C. Fr.gola. J .. and Pu,-
chelt. J. B. Parathyroid Hormone: Effects of th.
3-)4 Fragment in Viv<>and In VitI"{> Sd.""e 219:
67-9,1983.
119 Mc Kinney, T. D., and MyerS. P. PTH InhibitiOn
of Bicarbonate Transport by Pro.imal C",wQ..
luted Tubule •. Amtr. J. Phy<io/. 139: fl27 _ F I 34.
1980.
120. S . A .• DdtO$. L. J., B.ylink, D. J.. and
Robemon. R. P. Neuroendocrine Modulation of
Calcitonin and Parathyroid Horm""" in Man. J.
Clin. Endoc,illOl. Mtlab. 47: 151-9. 1978.
121. Meyer. R. A,. Jr, . and Meyor, M . H. Parathyroid
Hormone, Thyrocalcitonin. and Sofl Tissue Phos·
phate Metabolism, pp. 125_6 of Talmage.t .1"
eds,. referenee 181.
122- Mi,utani, A. A. Thymic Hypocalcemic Compo-
nenl. Chap. 10. pp. 193_24 of Luckey. od., refer_
ence 109.
121. Moran. J. R .. Sorn. W .. Tuchschmid,C. R" .nd
Fischer, J. fl. Cllc ium-Rcgulatod Bia;ynth",i. of
the Parathyroid Secretory Protein. Proparathy_
roid Hormone, and ParathyrOid Hormo"" in Di ..
p<""d Bovine Parathyroid Cells, J:,·ndrxr/IIOI. 108:
2264_8.1981.
124. M<>rel. F.. Imbert·Tebou l. M.. and Chabardo!s. D.
Distribution of Hormono.l><:pendent Adenylate
Cyclase in the Nephron and iu Physiological S ig.
nificanee, Ann. Ph,-,jo/. 569-81. 198L
125. Morrissey. J. J .. and Cohn. D. V. The Elrects of
Calcium and M'ine.ium on thc Secret ion of Par_
.. honoone Ind Parathyroid Secretor)' Protein by
Isolated Parathyroid Cell.. t"ndoc,/rJOr. 103:
2081-9(1. 1980
126, M",ri...,y. J. J.. Hamilton. J. W. , MacGregor. R,
R .. and Cohn. D. V. The Secretion of Parathor-
mane Fragment> 340M and by lli'p<t'SCd
Porcine Parathyroid Cells. Endor,j""l. 107: 164_
71,1980.
127. Mundy. G , V.. Varanmi. J.. 0", W., Gondek. M.
D.. and Ward. P. A- Resorbing Bone is Chemo-
tactic for Monocytes, Nalu,e ]75.- 132-4. 1975.
128. MUll$On, P. L. Ph)'Sioiogy and Pharamcolol\Y of
T hyrocalcitonin , Chap. 20. pp. 443-64 of Aur_
baCh. cd .. relerence 5.
129, Neuman. W. F. The P..... nce of a Soluble "RcS-
ulator Phasc" (Secondary Cakium Phosphate) in
Bone, pp, 297-302 of Talmage et. al .. ed, .. refcr_
oll<e 181.
130. Ng. B.. Hekkclm.n, J. W.. and Hcers<he. J. N.
M. The Effect of Cortisol on the Adenosi"" 3',5'-
MQnophosphate Response to Parathyroid H<>r_
mone of Bo.. in Vitro. Endocrjnol. lJo- 5,
1979.
lJl. Nordi n. B. E, C .. M.rSh.ll. D. H __ P<aoock, M.
and Robertson. W. G. Plasm. Calcium Hom",,""
ot.. i•. pp. 239_53 of Talmage et al.. ed •.. refer-
ence 181.
132, Nordquist. R, E ... nd Palmieri. G. M. A. Intra-
cellular Lo<:aliutlon of Parllhyro;d Hormo"" in
the Kid""y. Endoct/nol. 9j: 229-37. 1974.
133. Olgiali. V, R., Netti, C, Guidobono. F, Ind Po.
die. A. High Sensitivity to Calcitonin of ProIa ..
tin-S<:crcting Control in Lactating Rats. Endorri-
1lOI. III: 641-4. 1982.
134. Palmieri. G, M. A., Hawrylko. J .• and Hinton. A.
llypercalcemic Effect of Insulin in the Chick. E,..
dorrllIOI. 1774_7.1979,
1H. Pang. P. K. T, Kenny, A. D.. and Oguro, C. Evo-
lution of Endocrine Conlrol of Calcium Regul.-
lion. pp, 323-72 of Pans. P. K, T.. and Epple. A..
ed •. t.·YOIulfon of Endorrine Systtm J.
Te ••• Tech Pres.<. Lubbock. 1980.
136. Parthemore. J. G .. and Deft",. L. J. Calcitonin
Secretion in Normal Human Sub';'cts, J. Clin,
End"", inol. Umbo 184-8. 1978.
137. p.rthemore. J. G.. and Deft"". L. J. Calcitonin
Secretion in Primary Hyp<rparathyroidi'm. J .
crln, Endrx,jllOl. Mtlab, 223-6. 1979,
138. Pa)'ne. J. M., and Chaming •. J. The Effect of
Thy,-o.parath)'roidectomy in the Goat with Par·
ticular Respect to Clinical Effect< and Ch.nge; in
the Concentrations of Plasma Calcium. loorSanie
PhO$phorus and Magnc,ium. J. t.·ndoc,inoi. 29.-
19-28,1964,
139. Pca"". A. G. E. M<>rpholog)' and Cytochemistry
of Thyroid and Ultimobranehial C Cells. Chap.
17, Pl". 411_21 of Ambach. od .. reference S,
140, Peck, W. A., and Klahr. S . CycliC Nucle<>tides in
Sone and Mineral Mctaboli.m , pp, 89- 130 of
Talmage et II.. eds. refcrenco lSI.
141. Peck. W. fl .• Kohler. G .. and Ba". S. Calcium-
Enhancement of the CycliC AMP Re-
spon.e in Cultu",d Bonc Cells, Culd/- T;JSwe Int ,
33:409_\6.1981.
142. Peng, T-C .. and Garner, S. C. Hyp<,calcitoni-
nemia Associated with Return of Serum Calcium
ConcentratiOn toward Norm.1 in Chronically
Parathyroideetomi,.e<I Ran. ElUiornllOl,
1624_30.1979.
143. Pc",. T-C .. and Garner, S. C. Se. Difference in
Serum Cakitonin level. in Rats as ReI.ted to
Feeding. Fasting and Age. Endrx,;noi. 107: 289-
93.1980,
144. Pcrault..staub. fl. M .• Staub, J. F .. and Mulhaud.
G, A New Concept of Plasma Calcium Home<,>-
st.. i. in the Ral. Endoc,jnoi. 9j: 480_4. 1974.
145. Pera"lt_Staub. A. M .. Staub. J, F... nd Milhaud.
G. Constancy and Rhythmicity. A Dual Concept
for Homeosta.i. E. emplified by 24-llo"r Plasma
Calcium Regulation in the Ral. pp. 229-38 of
Tal""'ge et al., od •. , reference 181.
146, Perris, A. 0 .. Whitfield, J. F. and H IlS. P. K.
Role of Calcium in the Control of Growth and
cen Divi.lon. NalUr< 119: 527_9, 1965.
147. Pitkin. R. M.. Reynold •• W, A.. William •. G, A..
Kawaharl. W.. Bauman, A. F .. and Hargi., G. K.
... Mate,nal and Fet.1 Parathyroid H<>rmone Re-
SpOnsivene.. in Pregnant Prim."", J. Ciin. Ert-
doc,,/tOI. 51: 1044-47. 1980.
148. POIU;, J. T .. Jr .. al'ld Au,bach. G. D. Chomistry of
1!1e Calcitonin •. Chap. 18, pp. 423-30 of Au,·
bach. ed •. , reference 5.
149. Prien, E. 1.... Jr .• Pyle. E. R., aod Krane. S. M.
Hype'p.1ralh)',oidism. Chap. 16. pp.
383-410 of Au,ba.h, ed ., reforcnce S.
ISO. Pu,.... J. E .. and Brand. J. S. Parathyroid liar-
m(ln<: Slim"lalioo of Co!lagena .. Secretion by
Isol.tro Bon. Cell •. £ltIioCFino/. lIN: 559-62.
1979.
lSI. Rai.., L. G . Mechani,m. of Bon. Reso'ption,
Chap. 4. pp. 117_3601 Aurbach. ed .• reference S.
152. Rai .., L. G .. C •• ali., E M. Dimkh. J. W.o
Krt.m. B- E., and Gword. S. C. H<>rmonal Reg.
ulation of Bo.. Formation. Re<:. PN)I. lIorm.
Rs,•. 14: 335-348. 1978.
153. Raj .., L. G .• and K,um. B. E. H<>r""",aICootroi
or S ktletal Gro .... th. Ann. Physloi.
8.1981.
154. Raill. L. G .. Mundy. G. R .. Dietrich. J . W. a nd
Canalis. E. M. H<>rmo",,1 Rellulation of Mineral
Metaboli.m. Chap. 6. PI'. of McCann. S.
M .• cd. Physj%gy If. UniverSit)· Park
Pre.<$. Baltimore. 1977.
155. Rain. L. G .. Simmon •. H. A .. Sandberg, A. L .
and Ctnali., E. Direct Stimulation of Oone Reo
""ption by E"id<rmal Grow th F.otor. /:'ndoui-
no/. 107. 1980.
156. Rai... L. 0 .. Trommel. C. L.. Mundy. O. R., and
Luben, R. A. Immunol"llic Factors Influencing
Bone Resorption; Role of O<toocl.o." Activati",
Factor from Human Lymphocytes and Comple·
ment Mediated Pn)$t.a,landin Synthesis. PI'.
53 of Talmage ot al ., cd! .• ",rerentt 181.
157, Raman. A. Effect of Ad",n.leetomyon Ionic and
Total Plasma Calcium in Rats. Horrn. Me/ab.
Rsch. 2: 181-3.1910.
158. Ralmu$$tn, H , Parathyroid Hormone. Calcit,,"in
and ttle Calciferol •. Chap. II, PI'. 660-773 of
Williams. R.H .. cd. Tn/book of End«, jn%gy.
Philadelphi., 1974.
159. Rasmu$$tn. H .• and Bordier. P. The PhYJi%giCQI
"nd Cellula, Basi. of Me/abolit: /JoN
William &: Wilkin •. Balti"""". 1974.
160. Rumumn. H,. O(X)<\man. D. B. P., Friedmann.
N .• Allen. J, E,. and Kurok.wa. K. lonio Cont'ol
of Metaboli.m. Chop. I. PI'. of Aurbach.
ed"> ref.",nce 5.
161. Raymond, J. P .• Isaac. R,. Mereeron. R. E.. and
Wahbe. F. ComparilOn Bet...,en the Plasma C""-
centratio.. of Prol.ctin and Parathyroid Hor-
mone in N(H"mal Subjeou and in Patienu "i,h
Hyperparothyroidi.m or Hyperprolactinemia. J.
Clin. En<I""'inol. M.rab. 55: 1982.
162. Reddi. A. H .. and Sulliv. n. N. E. Mwix·lnduccd
EndOChondral Bone Oi!ferentiatio", lnft.enee of
Hypophysectomy. Gro .... th Hoc,""nc and Thy.
PTH. c,o,lCtTOJ<m AND OTHER REGULA TOIlS
,oid.stimu1ating Hormone. £'I(/"",Inol. 107:
1980
163. Reynold •. W. A.. Pitkin. R. M.. Williams. G . A,.
B.uman. A. F .. Hargi •. G, K.. Ikluhan. F. Z .•
ond Kawahara. W. Calcit<>nin Re.ponsi"""" .. in
the Primate Fetu. J. Clin. £nd""rino/, l/:
1980.
1M. Rich, C. Effect of Eltrugen. on The Slructure of
Bone. pp. 5 of Salhanic k et al .. ed$ .. ,ef.r·
entt 17),
165. ROOinson. M. F .. Body, J . J .• Offord. K. P .. and
Hoath. H.• II I. Vori.lion of Pla,m. Immunore ....
tive Parathyroid Hormonc .nd Cakitonin in Nor·
m.1 and Hype,parathyroid M.n during D.ylighl
Hours. J . Clin. /:·nJorrinoi. Mtrob. 55:
1982.
166. Rodan, O. A.. and Martin. J. T. R<>Ie of O<t«>-
bl.st. in Horm<>nal Control or Bone RC$Orption-
A Hypothe.i •. Cakif. Ti.. In/. 3J: 349_51.
1981.
161. ROOi!, B. A.. Bailoy. R.. Oka"". K.. and Deftos. L.
J. Calcitonin Biosynthesis; E.idcncefor. P,ecu,_
sor. pp. of Tolmage et .1 .. ed •.. reference
181.
168, ROOi!. B. A .• Cooper. C. W.. F.. linger. A. L.. and
Deftos, L. J. Acute and Chronic Fluctu.tion. of
Immunoreactive and Biologically AClivo Calci·
toni n in lhe Rat. EnJ«rlnoi. IQ3: 2180--86. 1918.
169. ROOi!. B. A.. Yoon. M.. Cul$ha ..... S. V.. and Kalu.
D. N. Calcium ROiulato,y Action of Endolle."".
Rat Calcitonin Demonllraled by Pa"ive Immu·
ni.ation .... ith Coleitoni" Antibodies. End«rlnoi.
107: 1321)-6. 1980.
170. ROOi!, B. A.. Yoon. M. J .. Frelinger. A. L" Pen·
. ky. A. E., Birnbaum, R. S,. ond Lambert. p, W.
Tumor Growth .nd Calcit""i. Du ring $cri,1
Transplant.tion of Ral Medullary Thyroid Ca,·
einoma. t:nd«,IIWi, 105: 1979.
170A. Rosenfeld. M. G ,. Mermod. J ,.J .. Amara, S, G..
Sw. n$O" . L. W., Sa ... enchko. P. E,. Ri.ior. J..
Vale. W. W.• and E.. n,. R. M, Production of I
Novel Neuropeptide Encoded by lhe Calcitonin
Gene vi a Ti'lu...spccific RNA Proce<sing. Na-
J(u: 129- 35. 1983.
171. Roth. S. I .• and $chille', A. L. Camparati.e
Anotomy of the Parathyroid Gland •. Chap. 12.
pp. of Au,baeh . • d,. reference 5.
112, Rothstein. M,. Mot,i .. ey. J .. Slatopol,ky. E,. and
Klahr. S. The Role of N. ··C. " E>-ohangc in
Parathyroid Horm""e Secretion , EnJoc, ino/. III:
1982.
173. Salhanick. H. A.. Kipni •. D. M.. and V,nde
Wiele. R. L.. ed., of Gonadal
1/000monts ".J Com,aup(i", S",QiJs, Plenum
Pre ... Ne .... York. 1%9.
114 , Sh.monki. L M.. Frumar. A. M., Tata'yn, I. V..
Meldrum. D. R.. David..",. B. H.. Panhemore. J.
0 .• J udd. H. L.•• nd Deft"", L. J. Age. Relaled
Change. of C.leit""in Secretion in Female,. J.
Clin. EnJa<rinol, M<Mb. 50: 437_9. 1980.
175. Shlouman. M .• Brown. 1>1.. Shapiro, E., and
Dziak. R. Calcitonin Effecl' on 1..,laled Bone
Cell •. Coldf. Int. 34: 190-6. 1982.
176. $c ,e ",en. O. H.. and Hindberg. I. Influ·
ence of Gon,d.1 Hormone, on the AClton of Cal·
citonin in Ihe Ral . ANO ENlOCT;IIOI. 68: 585-96.
197 1.
177. SU1l0n. R. A. L.. ,nd Dirks. J. H. Renal H,ndling
of Cakium. P,oc. 37:21 12-19. 1978.
178. T.lm'ge. R. Y.. Grubb. S. A., Norimat' u. H. "nd
YanderWiel. C. J . E.idencc for on Impon,nl
Role for Ca lcilonin. P"",. Nail. Ara<!. Sri. USA
77:609-13.1980.
179. T.lmag". R. Y.. Manhe"s. J. L., Martin. J . H..
Kennedy. J. W. Il l. Da.i,. W. L.. and Roycrofl.
J . H .• Jr .. Caiciionin. Phosphate and Ihe O<tC<>-
qte.a.leobla'i Unit. pp. 284-% of Talm'4\e et.
al.. ed •.. 181.
180. Talmage. R. V.. and Me)·er. R. A.. Jr. Physiolog.
ical Rolo of Paralhyroid Hormonc. Chap. 14. pp.
343-51 of Aurbach. ed .. reference 5.
181. nlm.ge. R. v. , Owen. M.. lind J. A .•
ed,. H()I"ttlOnn EI .. v"'r.
New York . 1975.
182. Talmage. R. Y.. VandcrWiel . C. J .. Decker. S. A.
and Grubb. S. A. ChangCl Produced in I'o>tp ran'
dial Urinary Calcium EXCrelion by Thyroidec.
tomy and Calcilonin Administralion in Ra" On
Diffe,..,nt Calci um Regimes. t:rrdo(t;noi. 105:
459-64.1979.
183. Tannenbaum. G. S .. Rorstad. 0 .. and Brazeau. P.
of Prolons.d Food Dopri •• tion on th. UI ·
tradian Growth Hormone Rhythm and Immuoo-
reacti"e Som'los,"lin Tissue Level. in Ihe Ral.
Endocrinol. 104: 1133-8. 1979.
18 4. Tashji .., A. H .. Jr .. Voel keL L F.. Wolfe. H. J ..
Gagcl, P., Dc Lellis. R. A .. Fra nk li n. R.. and
Jacbon. E. C., Calcitonin and Prosl.glandins:
S igni ficance. Rtle •• n<:e and Uncertaintie,. pp.
135-48 of Talmage el al.. ed •.. reference 181.
Tashjian, A. H .. J, .. Wright. D. R.. I.ey. J. L.
and POOl. A. Calcilonin Bindins Site. in Sone :
Relationships to Biologic,l R<;$pOn .. and ·'Eo·
eapc··. R«. Prot. Hom,. Rsch. 14: 285-332.
1978-
186. Taylor. T. G .. Balderston.. 0 .. Baimbridge. K.
G .• and Lewi" P. E. Changes in the Coocentra·
tion of Calcium and Calcilooin in Ihe Plasma of
Chick Embryos During Incubalioo. pp. \ 16-18 of
Talmage el al.. ed •.. reference 18!.
187. Thorn)$, M. L, and Forte. L. R. Serum Caloium
and Par.thyroid Hormone during the Reproduc.
li. e in Normal and Vitamin D-Defiden1
Rats. ENloe',,""'. I/O: 703- 7.1982.
188. Thompson. J. S .. Palmieri, G. M. A .. Eliel. L. P..
A·1. AI","ndre, C. 1.1 .• Chapuy. M. c.. Yisnon. L,
Edouard. C. Eng. B.S .• Johnston. C. c., and
Meunier. P. J. T,..,atme nt of Pasel', Di..a,e of
Bonc wilh Ethane· l . Hydro'yl· l.l Diphospbo-
nale (tHDP) al • Low Dosage (5 ms / kg/day).
and Cutler. G. A. Effects of Cortisone .nd Adre·
naleclomy on the Re,ponses to Thyrocalcitonin .
Errdoc,inoi. 81: 470-4. 1968.
189. To.erud. S . U.• Harper. c.. and Munson. P. L
Calcium Metabolism During LaClation: En·
hanced Effects of Thyrocalc itonin. Endoe;inoi.
99: 371-8, 1976
190. Vande rWiel. C. J .. a nd Talmage. R. V. Compar·
i>on of the Effects of Prostaglandin E, and Para·
thyroid Bo,mone 00 Pla.ma Calcium Concen lra·
,ion and 0$10«1, ,, Function . /OJ :
588_94, 1979.
191. VanderWit l. C. J.. and T almage. R. V. Ultra·
s"uctural and Physiological E.idence fo, Calci·
tonin·lnduced !'()stprandial Calcium Storage in
Bone! of Rat$. Caldf. Inr. H· 417_24.
1981.
192. Van 1I0ulon. M .. Rizzo. A. J .• Goltzman. D.• and
Posner. II. l. Brain ReceptOl"$ for Blood·Borne
Calcilonin in Rats: Circumvenlrkular Locali,,,,·
lion and Vasopre.sin.Re.istant Dcficien<:y in He·
reditary Diabetes In.ipidus. Errdrx,inol. III:
1704_10.1982.
193. Wal .. r. M. Divalenl Cltion. : Ph)·, icochemical
Sta te in Glomerular Filtrato and Urine and Renal
E""lion. Ch.p. 18. pp. 555-86 of Orloff J .. and
Berliner, R. W.• ed •. Ifandbook Physiology.
.. c. 8. American Physioiogic.1 Sociely. W ashing·
tQn. D. C., 19 n
194. W hil>on . S. W.• Dawson . L. R.. and Jee. W. S. S.
A Tetr,cyline Siudy of Cyclie L008iludinal Sone
Growth in tho Femal. Rat. Endoc'i/lOl. /OJ:
2006-10.1978-
Windeck. R .. Br",,·n. E. M .. Gardner. D. G., and
Aurbach. G. D. Effect of Galtr'ointestinal Hor·
mone. on lsolaled Bo,ine Parathyroid Cell,. En·
d",,";nol. IQ3: 2020-26. \ 978
196. Woog. G. L. . Kenl.G. N.• Ku. K. Y.• and Cohn.
D. V. The lntetaotion of Parathormone and Cal·
cium on lhe Hormone-Regulated Synthe,i, of
Hyalurooic Acid and Citrate D«arbo.ylation in
lsola .. d Bone Cell •. Endoer/noi. /OJ.- 2274_82.
1978.
\97 . Wong, G. L.. Luben. R. A .• and Cohn. D. V. I .25·
Dihydro. ycholecalci fer<>1 and P:\talhormone: Ef.
feclS on Isola led Osteoclast·Like and Osleoblast·
Like Celli. 197: U3-5. 1977.
198 . Yamamoto. T., Schu.dziarra, T. V.. and Unger.
R. H. Pancreatic and Gastrc D Cell FUll(:lion in
Hypophy><:clomi,.ed Dog.. Endoc,inoi. 104:
IH9-62.1979.
199. Yooeda. T., and Mundy, G. R. Rei"" .. of the
Lymphokine 0<10«1.., AClivaling Factor Re·
qUire< Cyclic AMP Acoumulatioo. Colrtf. TiJSU'
1m. J4.- 204-8, 1982.
Clitt. Orthop. IN: 19)_205. 1984 .
A·2. Cohn. D. Y.. Elting. J. J .. Frick. M .• and Elde . R.
Selecli . e Local i7-'rlion of the Parathyroid
tory Prolein . I/ Adrenal Medulla Chromogranin
A Protein Family in a Wide Variety of Endocrin.

Cell$ of the R .., Endof'I""", 114: 1963 - 74. 1984,
" -3. Gennari. c.. Toccafondi. R,. ROielia. C. M .•
franCini. G .• Brandi. M. L.. and Maioli. E,
Salmon Calcitonin and cGMP Production by
Human Kidney: Sludi., in Vivo and in Vitro.
Calc. Ti.. 1m. jJ: 273_8. 1983.
"-4, Heinrich. G .. Kronenborg. H. M .. Potts. J. T .. Jr, .
and Haboner. J. f. Gcne Enooding Paralhyroid
Hormone. J. BioJ, eh,m. 259: 3320_9.1984.
A-S. Lopez. E .• Tisscrand.Jochem. I;:-M .. i!yqucm. " ..
Milel. c.. Hili}'.rd. c.. lallier. r .. Vidal. B.. and
Mac Inlyre. I. Immunocytochemical Doteclion in
Eel Cor-pu,ek, of Slanni • • i•• Mammalian !'at.-
Ihyroid.like Hormone. Gen. ,{ Comp"r. Endocr;_
nolo53: 28-36, 1984.
PH... CALCITONIN ANO OrnER REGULATORS
A-6, Mnndy. G. R ... nd Poser. J. W. Chemolactic Ac-
tivilY of the ),-Carboxyglulamic Acid Con'aining
Protein in Bone. Cak T;.. 1m, 53: 164_8.
198).
A·7. Oldham, S. IL Moloy, C, T .• and Lipson. L. G.
C.lcinn, Inhibition of Par. thyroid Adenylate Cy-
cl."'. t.'ndocriool, 114: 2<11-14, 1984.
A·8. Rif.,. L.. She •. V.. Mitchell. K .. and Peck. W. ".
M"croph. sc-derivcd Growth Flctor for O$t<>r
blast-like Cen. and ChondrocY'e' p,oc, Nml,
ACtld. Sri USA 81: 4558-62. 1984.
"·9. Soonerman. M .. Hewilt. A. T .• Varner. H, H..
S<:hi{fmann, E.• Termine. J .• and R.ddi. A. H,
ldenlir.ca,ion of a Bone M.tri.-deriv.d Chemo-
tactic Factor. Cole. 1m. JS.- 481_5. 1983,
_ __ PART V _ __

Hormones and Reproduction

 13
Sex Determination and Differentiation of the Reproductive
System
The term "scx" is used in very different by ge-
netecis!s, cytologists. endocrinologists. immunolo>-
gists. embryologists, psychologists.
sociologists. lawyers, clothing designers. and adver-
tising agems. While an of thc meanings arc related
in some way loa form ofrcproduction. lhc vagueness
of Ihc association beoomcs apparent when One hears
high school biology students describe Ihc proccs.c.
of gamete formation and fertili7.ation in dam. and
plants as "001 vcry sew" ""hile applying the adjcc-
tive "sexy"" to inanimate objects.
T his chapter examines the interrelationships
among Ihc following "forms" of sex: chromosomal
(or genetic). gonadal, hormonal, phenotypic, psycho-
logic, behavioral, and legal. II surveys me<:hanisms
whereby cell, and complex organisms produce morc
of their kind and considers the humoral regulato"
that provide direction. Sections are also devoted to
the problem, that can ari", whcn wmething disrupts
the usual course of events.
ASEXUAL VS. SEXUAL REPRODUCTION :
FUNDAMENTAL DIFFERENCES
Reproouction is thc formation of new biological en·
tities (cells or whole organisms) that closely resem-
blc the parent specics. The asexual mechanisms uli-
a $!lIgle $ouret of heredilory !nmtriol that is
replicated and then apportioned eqllol/y among the
progeny. As a result. the new individuals tha t
emerge arc genetically idenlical with each other
(and wilh Ihe original parenl) , Thus. population ho-
mogeneity is maintained. exccpt when something
goes amiss during replication or distribution of the
macromolecules.
By contraSI. Ihe lerm ,exuol implies nolhing mOre
(or less) Ihan lhe imerminglillg of nucleic acid com-
ponents derived from IWO 'ouren and Ihe production
of progeny that possess cambiliOlion.r of hereditary
entities donated by both of the parents. In most
cases. the offspring differ. at least in small ways.
from the progenitors.
Most higher animals Ul ili?e asexual methods for
rcnewal of somalic cells and sexual ones for the for-
mation of new individuals. whereas simple unicellu_
lar organisms widely employ asexual reproduction
For perpetuation of the species. Exc<:ptioos 10 this
rule are discussed later.
ASEXUAL REPRODUCTION OF THE
SOMATIC CELLS OF HIGHER ANIMALS
MOSI of the tissues of animals undergo oon-
tinuous (or regularly recurring cycles (1) cell re-
newal. Usually, Ihis is accomplished via the highly
Or<:kred p=ss of mitosis.
(al The Ihat f«m protective on external
and intern.1 body ."rfa"...Iough ofT and must be re-
Then: is. for example. regular rene".. al of Ihe ep-
idermis of the epithelial component' of thc gawoi.-
te'liMI and respiraIM)' mucosae; (b) erythrocyte. have
limited life .pans, in pIIrt bec,usc of the puni.hment in_
meted on Ihem during cardiac s)'5lole and passage
through MrrOw eapillarie,. Rapidty protife"'ting precur_
sors "'ithin the bone mar"",' keep pace wilb the fotc'" of
destruCtion , (e) " new utorine lining forms in '''''ju nction
with each nonferlile ovarian eycle of the adult mammal;
(d) the mounting of ....... ful immune ,"ponsc. re-
quire. the rapid formation of ,pecifie type. of I)'mph"..
qte" (e) wOllnd healin,.1Id lbe watling olf of inre<:tion,
usually involve proliferation of fLbrobla ...; (I) .perm .."..
gonia form new cells for .3eh ",ave: of ,permot",e.e.i •.
while follicular cells of Ihe ovary grow and divide during
the prepllration. f01' ovulation; (g) when endocrine gland,
are ,",lied upon 10 markedly inere."" their ,at'" of hor_
mone ... retion. newly fo>rmed cells usuall)' provide Ihe
ne ..... ry machinery; (h) normal bon<; undergoes a ""n_

linu".. process "f remodding which i""ludes of
Ihe ".Iooprogcnilot cell. Ihat give rise 10 collagcn-f",,,,-
ing ".10<>1>10,1.; (i) dO.lr"Clion of portions of vital organs
,uch a, lbe liver and kidney i. counlored by rapid "oom-
pen,""ory" formatiM of new tissu.; and (j) proliferalini
cell. 80 through cydo. of =t. gro"'lh. DNA synlhtsi •.
and division lhal .re aWlCialed wilh sequenlial change.
in lhe seMilivilie. 10 e.lernol r.gulol<><$. C.".in kind. of
,peciali711t\on can be accomplished ooly when cell. are in
Ihe appropriate ph... ,
Neurons and skelelal muscle fibers arc cxamples
of body oomponents Ibal have losl thc abilily to en-
gage in
AS EXUAL PERPETUATION OF THE
SPECIES
Unicellular organisms rapidly increase Iheir num_
bers by dividing asexually. In addilion 10 providing
for oonlinuily of Ihe species_ Ibe processes serve
otber purposes. By inCl'<'asing the .urface:volume
ratio. cach division facililates adequale excbange 1»
lWeen Ihc cells a nd their environments of respiralOry
gases. nulrienlS, and waSle malerials. In mosl cascs.
Ihe daughler cens are of equal size, but Ibe "bud-
ding" of yeasl involves uneven apportionment of Ihe
cylOpl.,m ,
Coelenlerates and SOme other simpic mClazoons
split olf groups of cells. and cach clump (or bud) can
give rise to a whole new individual, en-
gage in Iransw rse binary fission. following which the
"head" portion grows a new "Iail" while the caudal
fragment acquil'<'s a new head. Some wormS also
split longitudinally. S.Hlars (.larflSh) usually re-
produce .e.ually. Howeve r, if an adull is cut into
large pieces, each f ragmenl can "regenerate" into a
whole animal. The vegetalive propagation of plants
is a relaled form of ase.ual reproduclion.
Social inse<:ls may make yet a1lOlher uSC of this
Iype of division. Honeybees, for example, produce
large numbers of genetically identical males via par-
thenogenesis (which is whereas their fe-
arise from fertilized eggs.
Parlhenogenesis and related forms of a,nual 1'<'-
production also proceed in verlebrates, as discussed
later.
ADVANTAGES AND DISADVANTAGES OF
ASEXUAL REPRODUCTION
The ability of a .i ngle member of a species 10 pro-
more of it. kind bypasses Ihe need 10 seek out
other individuals of ils group, In times of isolalion,
this can spell OUI Ihe differences bc:twecn perpelUa-
Sfx DIFFERENTIATION
tion and extinction. In some (but not all) cases, such
reproduction is asexual.
There are Ihree obvious disadvantage.: (a) no 0t>-
portunily is afforded for the DNA recombinations
thaI comribule 10 versatilily, evolution, and the
emergcnce of charactcristics that faeililate adapta-
tion 10 environmcmal changes; (b) undesirable mu-
lations can be passed On to all of Ihe progeny; and
(c) a form of Slagnalion is built inlo Ihe s)lSlems,
This last factor scems 10 have been "recogni7.ed" by
even very simple organisms. Many have developed
"stralegics" such as conjugalion that provide for ex-
changes of genelic material between individuals.
GAMETES, GONADS , AND GENDER
reproduelion in multicellular organisms typ-
ically involves Ihe formation of specialiud eclls or
gametes. Usually. each comain, one-half Ihe chro-
mosomc number Ihal characlerizes the somatic cell.
of the same species.
When all of Ihe cell, are morphologically sim·
ilar, they are known as isogamnes. Higher plants
and animals make heler<>gamelts, The OneS pro-
duced by animals thai arC smaller and marc mOlile
arc sperm cells Or spermil/Oz(}(J. whereas Ihe larger,
usually nonmolile counterpart. arc the ",,11. or
Gonads are organs specialized for Ihe produclion
of gameles. (The term is also applied to immature
siruelures that will later develop the capabilily.)
Those Ihal make only spermat01.oa are /estes. while
ones producing only egg cells arc ovaries.
In higher animals, the gonads also sccrete hu-
moral regulators thaI dil'<'ci the developmenl and
mainlain the funClions of acuJSory reprod,,(/ive
structures. i.e._ organs involved in Ihe protection,
nurturing, stOl'llge, and transpon of the gametes and
oonceplUses. Although tbey ar<: di'inguishable from
the primary repradu,riw .Iructures or gonad" Ibey
arc oflen essenlial for realization of gamete function.
Gonadal hormones may additionally promote
emergence of secom/ary chaf'llcltrislics. These
are body eomponems nol diTeClly involved in Ihe re-
productive processcs per SO, Ihal play imporlant roles
in Ihe :selcclion of males . In some species_ Ihe indi-
viduals Ihal possess ICSICS are markedly dilTcrent in
cXlernal appearance from lhose endowed with ova-
ries. As win be discussed, Ihere i. 00 dil'<'ct relation-
ship oolwccn "reproductive efficiency" (Ihe ability to
produce adequale numbers of offspring) and the
magnilude of "scxual dimorphism".
Gonadal bormones arc further capable of bringing
about "sex dilTercnlialion" of the brain in a manner
thai affe<:ls behavior. and they Can dicil sex-relaled
differences in metabolic funclions and in the serrsi.
tivities of certain types of rtteptors.
The term, male and masculitll! are applied to
'permalOzoa, to te,tes. 10 Ihe associated accessory
",pnxiuctivestructures and secondary sex characler-
istic, of dimorphic species. and to the lestieular hor-
mone,. They are also used to designate rdated forms
of behavior. Traditionally, aggression, lerrilorial de-
fense. courtship, and copulalion have been included
in Ihis calegory. More modern concepts are consid-
ered later in Ihe chapter , The whole individual pos-
scssing the described features is also known as male.
Similarly. Ihe lermS and a rc used
for egg celis, ovaries. the associaled accessory organs
and phenotypic characteristies. the ovarian hor·
mones. forms of behavior tha t include Ihe assump-
tion of eharacterislic postures when slim ulated by
males. and the whole indi vidual.
GENDER IDENTITY AND GENDER ROLE
At a very early age. humans come to rccogni7-e their
membership in one of the two Sex groups , The ac-
e<:ptance of "gender identity" usually docs not pose
problems. but conditions under which it can are con-
sidered later,
The phenotype imposes e<:rtain components of the
"gender role" (i,e., Ihe behavior expected of the
of the group), Obviously, for example. only
those endowed with uteri Can support pregnancies,
only female birds can lay eggs; and only individuals
possessing copulatory organs and testes can
insef,liMte.
Among nonhuman animal!, SOme sex-related sep-
arations of activities are common. In mOSt (but not
all) cases. the female assumes the major responsibil·
ity for care of the young whereas the male is the pri·
mary defender of ihe territory. The males of some
,pecies are also the major providers of food. How-
ever, female hyenas hunt in packs along with ihe
males, while lionesses a re more likely tllan their
mates to bring home dinner for the immature
offspring.
Human societies impose different kind, of expec-
tations. but these vary widely from one culture to an-
other. A child's acceptance of gender identity docs
not necessarily carry with it total conformit}' with
the behavior normS. Thus, a young female growing
up in a "dc_eloped country" may not question ihe
appropriateness of lining up with the girls at school.
using the assigned washroom. or entertaining
thoughts of eventually bearing and caring for an in-
fant. At the Same time, she may engage in form, of
play considered more appropriate for boys and look
forward to assumption of an occupation traditionally
reserved for males. Similarly, a male can defy pre-
vailing customs by expressing interests in cooking
and the Care of children wh ile accepting other com-
ponents of the imposed gender role. Most aspects of
gender role are culturally determined. and behavior
regarded as deviant by one group may be perfe<::tly
acceptable in another. There arc controversies con-
cerning whether gelUfer preferew::e (sexua l interest in
one's own Or the opposite gender) is oonditioned by
the hormonal milieus present early in life.
SEXUAL REPRODUCTION THAT DOES NOT
INVOLVE GAMETE FORMATION
Tesl<s, ovaries, and gametes are not .... ntiat for .""uat
r.production, Th. only rcquiromento ... mechanism. for
the uChang. of h.reditary materials from t"'o sources
prior to the formation of new individuats.
IJ.clerial cell' .... 001 partners for ,ueh ..change.. In
a .. n... Ihe entire organi,m funcli(m, temporarity ., bolh
gonad and gam.le. Parnmecia eng"3e in ronjugaliOl!, a
p = that in",l_ excb.nge of mic ronuete i. Filamen_
IOU' ptan" , uch as 'pirogyra line up and form conjuga-
tion tube$lhrough whith genelie intcrmingling is aCCOm·
pli'hed. Following the eneounIO.... the individual,
s' parale . reorgani"" inlr.lcet\utar components. and elUlgc
in milosis,
Allhough it is possible 10 distinguish "mating Iype,"
(oom<times designated plus and minus). lhe coneepls of
male "nd female (or of sperma lozoa and egs c.II.) cannot
be applied 10 such species, A singte paramecium ean al$O
rcorganil. its o"'n stores of DNA a nd Ihen produce prog-
en), Ihal are stightty differenl from lhe t),pe OIbcrw i..
formed,
ZYGOTES , EMBRYOS , LARVAE , AND
FETUSES
True gamete.< unite during fertilization to form a zy-
gote. The lauer soon begins cleavage, and an embryo
emerges as newly formed cells engage in migration
and in specializations that invol_e selcctive expres-
sion of specific DNA component s.
The embryos of many oviparous spo:des develop
into /afWle that fr. e themselves of the prote<::tive
cootings of the egg as soon as Ihey capable
of independent The larvae are usually very
different from mature individuals. and they must go
through a process of mttarnorphosis that can involve
substantial changes in structure and functions. Rep-
tilian and avian embryos generally undergo mOrC ex-
tensive development prior to hatching.
In eutherian mammals. the young arc retained
within the ulerus for widdy varying time periods
(ranging from 16 days for hamsters to as many as
641 for elephants). Once the embryos have aC<juired
features clearly recognized as species characleristie.
'"
they 3rC asfelUses. The developmental siage
is attained by the cnd of the second week in many of
lhe rodents, and at around eight weeks pootCOllC<'P-
lion for humans. While thc term melOmOfphosi" i.
not applied (0 mammals. juveniles undergo very
marked changes in appearance during pu\>crtal
maturation.
All of the cell replications thai follow ,_ygote for-
mation 3f<' accomplished On occasion,
cells formed during early cleavage slagcs $Cpam!c,
and each component develops into a whole new ;n-
dividual. Twinning of Ihis kind is aCluall)' a form of
asexual reproduction. An interesting variation On Ihc
theme is the regular production by armadillos of
identical quadruplets.
HERMAPHRODITISM
MO!iI animal species arc diotcious (or gonochorist);
Ihal is, they rumprise two kinds of individual., male
and female. The term monoecious i. applied when
the formalion of both spermal07.03 and OVa within
the same animal is the rule.
A trut po!'Sesses lissucs of both
testicular and ovarian types. either in separalc and
distineuish.hle OTg;ln< or in complex structures
known as (In some cases, thcrc is an ovo-
teslis on one side and either an ovary or tcslis on Ihe
other.)
Hcrmaphroditism (hermaphrodism) regu-
larl in some species. It can arise under pathological
condilion$ or following intervenlion in
Sym;hr(m()us hermaphrodites produce spermato-
zoa and ova al the same lime. The arrangement
markedly facilitates the ability of cerlain animal
types to engage in sexual reproduction. The earth-
worm provides a good example, since it is a solitary
cl"<'alUl"<' that only se ldom makes contael with
of its kind. Any two adults that happen to meet can
engage in the formation of zygotes. via a process of
cross-ftrtiU·w tion in which spermatozoa from each
partner combine with Ova produced by the other. It
is nol neeessary for a "boy worm·· to seck out a "girt
worm" (or vice versa), since clearly Ihere are IKl boys
Or girls in sueh a setup.
Tunicates (sea squim) are unable to make evcn
limited of sexual since each
adult lives alone anchored 10 thcccean noor. The ga-
metes arc released directly inlo the surrounding
water. Since they lravel only short distances and
haY<' brief life spans, it is obvious that only neigh-
boring animals can cooperate in 7.ygOte formation.
Cross-futilization i$ the rule. because arrangemcnts
SEX AND DIFFERENTIATION
of the genital duelS preclude the simultaneou s re·
lease of sperm and ova by one individuaL &If_fenil.
i7.alion is avoided in differenl ways by some of Ihe
synchronous marine leleostS. Those animals engage
in spawning behavior that encourages discharge of
male gametes by one partner and of female ones by
theolher(119).
A different arrangement is needed by the lape-
worm. since the adult has no opportunity whatever
10 inleract wilh ils conspecifics. Fortunately for this
beast (if not for the future hoom). self-fertili7.ation is
the rule. Here, some of the advantagC!i of genetic
mixing nnd the ability to minimize the consequences
of undesirable mutations are traded ofT in the inter.
ests of perpetuation of the species in the only manner
of sexual reproduction that is available . Self-fertil.
ization also contributes to tlte survival of some of Ihe
fishes that find themselves trapped alone in puddles
during water shortages. It has additionally been de-
scribed for fish species that could theoretically re·
produce in other ways (139).
Two kinds of asynchronous hermaphrodites arc
recognized. The prof(mdrous ones funclion firsl as
"males" and laler as ··females."' while prOlogynous
forms begin their ",productive1ivcs as '"females."
0yslers.• Iugs, and some of lhe fi,hes and frogs
'''But.''y fun"'ion in "' A, ,h.,
time, they produce spermatozoa and also engage in
'·male-type" behavior. Afterward. they develop the
ability to release fenilizable ova. A transitional state
has been described for some. There are also fish spe·
cies in which an individual maintains female func·
hOM throughout the life span undcr normal circum-
stances but retains the potemial to become
transformed into a '"male" under adverse environ·
mental conditions such as total isolation from males.
SEX CHROMOSOMES, AUTOSOMES,
GENES, AND ALLELES
The hereditary material of higher animals is orga-
ni,cd into discrcte structures or chromosomes. each
of which conlains DNA segments (· ·genes") thaI
cod. for specific functions. The nucleus of a typical
"resting" (i.e., nondividing) somatic cdl of the
human contains 46 chromosomes that arc present in
the form of homologous pairJ. Wilh the exception of
the sex chromosomes described later. each member
of a homologous pair resembles ils eounlerpan in
morphology and gene conlent. Thus. for example,
both members can bear a DNA sequence that spec·
ifies eye color. Corresponding genes of this kind are
aI/drs. Since one is derived from the male parent
and Ihe olher from the female. the are often
nonidentical. For example. one can specify brown
whereas the other dictatcs blue. The phcnoty[lC thai
eme rgcs in the presence of diffe"'n( alleles depends
on the kind5 of interaction" In some C35es one form
dominant, whereas in others both contri bute,
One pair of chromosomes is mo.., d irectly con-
cerned with sex differences than the others, a nd its
components are called ux •. Female
mammals have tWQ morphologically and function·
ally similar X chromosomes, whereas males have One
X a nd one usually much smaller Y sex chromosome.
All of the other pairs ar<: autOSOmeS. It cannot be
emphasized tOO strongly tha t "sex" chromosomes af·
fect soma tic functions. while autosomes play eSSen·
tial roles in reproduction. Th us. the human X chro-
mosOme contains SOme 91 separate genetic loci
(116). and it codes for several vital functions. "'hile
autosomcs di rcctly regulate the biosynthesis of en·
zymes controlling the formation of gonadal
hormones.
Since the single X chromosome of males is ade-
qua te for maintaining somatic functions. the female
requ ires special mechanisms for acq uisition of ge·
netic balance. This is ac<:ompiished through "inae·
tivation'" of mos t of one of the X chromosomes in
somatic cells. In SOme respects, the female has an
advantage. The presence of one healthy X Can often
"dil ute out" or "compensatc for" ' the existence of a
def""tive one. Control of color vision provides a fa·
miliar example. Males with one type of X mutation
suffer a form of "oolor blindn"'-,_" Females with one
such entily enjoy normal vision (although they retain
the ability to pass on the defecI to their wns). The
defective X is ofte n (but not consistently) the one
Ihat undergoes inactivation.
CHROMOSOME SEPARATION DURING
MITOSIS
Since resting somatic contain pairs of chromo-
somes. they a re said to be diploid. As they gel ready
for division. Ihc thread·like chromosomes condense.
When prepared wilh suitable I""hniques, they ap-
pear as banded ro,k The chromosomes then repli·
cate, and the sister dromatids thus formed remain
joined at the centromeres as they become al igned
along Ihe equatorial plate (Figs. \3·1) When separa·
tions occur. each daughter cell acquires one copy of
every chromosome that was present in Ihe
parem ,
CHROMOSOME SEPARATION DURING
MEIOSIS
A different mechanism for separalion of genetic rna·
terial is obviously needed for the formation of 8'"
metes. In this case. reducriOfl division leads to pro-
d uction of cells that contain just one
representati'-c of each homologou_' pair. The fusion
or gametes during rertilirution re'tores the diploid
oondition in Ihe 1.ygole_(I f gamele' were diploid, the

, , XK
, , , ,
1l, 1\, II, iji
,
qa, X3
,
II
, , !I
,
18
,
H
, II
,
II

!X I'
"
'"" I! t. ,. '""
"
"" ••"
"
"" "
"
.-
"
.
" "
"" . . .
" " "
"
.- ,. II
"
•
"
•• .." "
(,
" "
I " " I," "
FIV. 13·1. M etApI>II'" mitOlic 01 • I>umtIn
10m. " (") arid A mole (9) .rrArl(/6d in 1'Iom<>Iogou'
(Reprinted wllh ,*"",,',,,
Irom V. ", Humlln
P,""tic. Hall. EngIe .. OO<I Ctills. N.J" 1964 . )
 DEl"£RMINATION AND DIFFERE NTIATION

MEIOS IS I MEIOSIS II

f\J LCl'lole n..

! Proph«:>e II

Melaph"s " i Am.ph",.e I Melaphase II Anap hase [l

Telophase I Telophas e IT
FlO. 13-3. PtcphtJH I. LOj)lot_: The oNOtI'Osomes oj the t>omoIogou. OilrOmOoom8S ""'y 0,00' 0 . ... 00&
bee"....,. 1pj)8.' on' as ,lWlllnear o"l>C/uru. Zy;ol_: or>Otl>e/. lorming I 0/1;0"""' . OiplOt_: The
Hornotooou. Chromosomes I.... up .nd po.ir willi 00& Iurtht< shorlon and broaden: they 1100 coil. I tomoiogoIJ.
MOl .... point to point Plc:Ioy'_: Wilh poirOlg bOogjn to moW! _ .. 001 1' . hetd 1<>geti>Of .t
completed. ,he ch,omooom8' b9oom4o short ... .... 1M chil""". Dll ki"" .. " The chromosomes .. broad....
and ea ch OpIits ",10 chromalic! •. Ih/I trNck.... more tigl1tty cooed ; they mo • • lurn- .PI".
"""',0I'Mfe _ining ling ... TM 10<11" c:Ioromotic!. 01 tM IwO I. The <:t.-omooom8u,e on the equatoria l
c:Ioromo&Otl\K OOI'st;!Uf<t • !);.... nt. CI>romotic!. Ir¢m eac:lo plat •.
 P'imary spe,malOCyte
S::oodary
"I"'nnalOCylM " W
oocyie
, Third
SpermalWO,
Fig. 13·4. Me;ot;c divisk>ns 01 _
oocytes. Only to. sex
zygote formoo during the first fertilization woold be
tetraploid. If tetraploid individuals could .urvi,·. to
produce gametes in a similar manner. the next gen-
eration would hav. four limes the chromosome num-
ber. Continuation of the pr<.>cess WQuld eventually
lead to the appearance of cells as large as calS.)
Telraploidy io lnlorated by ",me of the amphibian,.
T he aSS<Xlated ,o<r.as< In ce llo",:" oot oompaHblc >l"Llh
central .. ,vou, 'yOlcm dc"Clopmcnt in mammals. When
it oceu". the ,.,uitin& emb,yo i, .",," aborled (18S).
Rare e.ampl.. of human triploid)' a,e menlioned laler.
Reduction divisicn is acoomplishcd by meiosis
which re4uircs IwO stages. The homclogous chro-
mosomes first associate with each other. and dupli-
cation of the DNA leads to the formation cf bi..a-
lems (double sets of homologous p;!irs. Fig. 13·3).
Some "crossing over"" of gcnctic material OC\:urs at
this Slage. so that Ihe chromosomes that evcntually
form arc different from the oncs present in thc par-
cnl cell. Unlike the process for mitosis. separation
docs not occur at the centromeres. T he first division
I. TO. Chrom<;>SOme. di_ge . e xCl>aoginQ
chromosomal _ I s at ,he .. te <>! {he Chia ......
TtIIOpMSit I. eac:fl ""'<>mlltid pai'. joj...., Dy •
'*""'.... 'rv.1iH in. <laUQl"tt ... cell . TO. ""'omalid. LlIlCOi1
and lengthtn to ....,.. . xleo\.
Chromatid. in theloll·hand <lauvht.f cd pass llvough the
100Iowing suoges in mIIiO ... II:
PropMSit II. Thi. Sloge is {fan"""" and aD...,I.
..""" lhe chromalids may move d;,ectly '0 ...... Iapha .. H.
II. Chr<>mll'ids ohon.... t."0adG<. and
ooil8<l. The CMI,,,,,,,,,"" di.idM.
". .. II. ChI"Om8lids separat8 and mo •• 10
FilSI polar body
and
poIa' bodies
fourIh
(9
...... Iocytes and
or. shown.
yields IWO daughter cell •. each of which oomains
double oopies of OtW homologous chromQ:lOme of
cach type. (The oopies are nol identical Ixcausc of
the cr=ing over.) The daughler cells divide again to
form haploid gameles.
Spermatogenesis
The diploid primary sfH'rmawcyle contai", one X
and one Y sex chromosome. Both are replicated.
alO11g wilh Ihe autosome,. The first division yic1ds
SfCondary spermatocyte•. One oontains l\<"O X
chromosomes. while Ihe mh.r haslWQ orthc Y type.
Division cf Ihe !Coondary spermatocy tes results in
Ihe formaticn of four spt'rmatids. each conlaining
eilher an X or a Y (Fig. 13-4). Thc spermatids sub-
malure into spermatozoa.
Oogenesis (8)
Although sperma lOzoa contribute mostly DNA to
the 1.ygote. Ihe egg cells must also furnish cyto-
II. Each <>! the chom.tid. i. now in a do. .... h' ...
Too •. in the COurMI of 1 _ two di.ision. lhe fOur
""'''''''''lids lorming 10. bOYlleol of prophall8 I I r.
$&paroloc!. first inlO two daogill'" cells of leIop/1 ... I. ""on
coota.,iIIg two ch<oma'id' (.n - 2n). and ,'- into 'WO
<laug/1tOf cell. again in loIophaS. II. each cootairing one
c"'''''''''lid (2n - In) . IOlai of I.,... doughter cells is
produotd. Nch to. haploid (In) '"""'*' 01
chromooomu. In a malo indivldu.all.,... """""" "'"
p<oduced; in. I_alft. one Ovum a Tld Ihr.... pOIa, bOdies. On
1",{ili",,{OO tlHl dipolOid (20) .........- is resto/oc!. (W"; ... "-
Gteep. ,.r. (87)

plasmic componcnt$ that support early cleavage.
The diploid primary o<xpie replicates its chrom<>-
somes. When it divides. half of the gcnelic material
of the nudeus (including IwO copies of one of the X
chromosomes) is passed on 10 a oocyle.
which also receives mosl of the cytoplasm. The other
half goes into the firSI ""lor body. a very small cell
that can degenerate directly Or give rise 10 the Ihird
and fourth polar bodies which deleriorate. The sec-
ondary oocyte divides. and il passes half of its ch"'"
mosomc complement (including One X) to the ovum
or egg cell, along with most of Ihc cytoplasm. The
remaining chromosomes arc sent into the uconJ
polar body, which also deteriorates. Thus. oogenesis
culminates in the formation of a single. large ovum
from each initial diploid cell. whereas spermatogen·
esis yidds four spermatozoa from each primary
spermau)Cyle.
FERTILIZATION ANO SEX OETERMINATIO N
Fertilizalion (syngamy) is the fusion of genetic rna·
terial. of Ihe egg and sperm that results in Ihe for·
mation of a diploid zygote. The chrOt>WSomal sex of
the 7.ygOic is determined at that time,
------- 0 Male
Sperm
Since thc
'''''
arc of two kinds, it i. some-
times said that genetic (chromosomal) sex is deter-
mined exclusively by the male. There is the unex-
plored possiblity that the ovum is endowed with
some ability 10 preferentially accept One type of
sperm,
Sex Rat io s
As spermatids mature inlo spermat07.0a, the head
portions become highly condensed and ultimately
consist of httle more than pachges of genetic rna·
teriaL Those of the Y type are slightly smaner.
they swim more rapidly through dense media. thcy
can Ix concentrated in the laboratory. Y-spermato-
zoo may gain access to oocytes in greater numlxrs.
and it has been suggestcd that the more XY zygotcs
wit! form when insemination occurs dose to Ihe time
of ovulation. The X-sperma tmoo are believed to be
SE X DETERMINATION ANO OlFFERENTIATION
hardier, and 10 have the advantage when gamete<
musl survive for many hours before accomplishing
fertili7.3tion, However, couples altcmpling to use
timing to predetermine the sexes of their offspring
have nOt been uniformly It is lherefore
likely that other faclors aSSume importance in vivo.
These can include Ihe compOSitions of uterine and
tubular Auids and of cervical gland secretions.
A Sex ratio of 106 boy to 100 girl births is widely
qUOted. but the proportions vary wilh geographical
loca le and with parental ages. The popular nolions
Ihal "boys run in SOme families", and Ihal "young
mothers are more likely to bear sons than older
ones" hve not been supported by exacting "Iatistical
studies.
ACC<lrding to some authors. XX and XY
arc formed in equal numbers, but fewer of Ihe for-
mer Iype survive the gestation period (146). Limited
support for Ihe idea i. provided by SOme karyotype
determinations made on spontaneously awrted fe-
tuses. On the other hand, other investigators have
ob:.erved that thcre arc mOre males among chromo-
somally oormal abortuses, and that more males Ihan
females suceumb during the perinatal period (107).
The exaCI numbers are difficult tn estimale. si ncc as
many as 50%0f conceptuses may die too early in Ibe
of development to be included in the aborted
groups.
CHROMO SOMAL SEX IN NONMAMMALIAN
VERTEBRATES
Since male mammals produce both X· and Y·type
spcrmat071)O., they are said to be the he/eragamttic.
Analagous chromosome pallerns are Sten in many of
the amphibians and ftshes, and Ihe term Y is also
applied 10 the special chromosomes in males of those
groups. It has been found, however, that the Y chro-
mosomes of such exotherms (poikilotherms) are con-
siderably larger: Ihey can even closely resemble the
X chromosomes of the same species.
In birds and many of the reptiles, and in some of
the amphibians and fishes, the is heteroga-
metic . Her sex chromosomes are designated Wand
Z, wher= males pOSsess IWO of the Z type. The dif-
ferences in chromosome patlerns profoundly alTect
the mechanisms for differentiation of thc reproduc-
tive structures,
PARTHENOGENESI S
The development of new from unfertil-
ized egg (parthenogenesis) is a form of
Male wasps and honcybcCl; arise in
 this way. and the pi'QCC:SS is utili7.cd regularly by a
few of the vertebrates. I n some of the fi shes and li1.-
acds, the: entire population;s said to be "female." "n
interesti", variation 00 the theme iI presented by the
Amawn mollie. T he: fema les "mate" with males of
a clo5ely re lated sp'"ics. However. the sf'C rmaI01.D1
simply provide the stimulus for egg develupment
witOOuI contribuling to the genetic make up of tl>c:
offspring ( 12 1).
It ha.< bc:cn c5timaled thaI more lhan 40% of the
eggs laid by .irgin turkeys (1 0) a nd a subslantial
perccnlage of a rtificia ll y incuba ted hen eggs (119)
undergo spontUlcous pa rthenogencsa.. n.cell cells
of ma ny invertebrates and oomc: e_hermie vene-
brates respond to nonsp«ific "'mul i Ihat alTeet lhe:
cell sur(accs. "ctivation has been achieved by prick.
ina thc cc:lIs with sharp needles or bY"' pOSing lhem
In !.all solut ions. heat, cold . acids. alhlies. ultravi.
olel radiation, lipid solvems. or ca lcium ionophorcs
(1 0, 190). In.orne cafeS. adulu posscssingthe phe-
notypic characteristics or thc parent have developed
from the e£l$.
Ma mmal ian <IOC)·tCS arc rna«: T he birth
of live young following Ihe impla nw.tioo 0( partllo>
genetically-derived rabbit blastot:ysts into normal fo-
males has been described . but numerous a llempts to
reproduce: the have been unsut:a:»(ul
( 190).
Studies o( artif,cial induct ion of pa rthenogenesis
have been utilized to obIain information on mocha.
nisms 0( fertililllllion and on the functions of tbe
ch romosomes.
When an ovum undergoes cleavlles, the resu lting
individuals a rc baploid. Fusioo of an ovum with I
second pOiar body. or ae tivati01l of a secondary ex>-
tyte, Cln lead to the development of diploid a nimal •.
Triploid parthenogcnomes arc obtained from the:
union of an ovum with a first pOiar body.
snmal studi ... rcvealed that parthenogenesis in
hens a nd turkeys that culminates in the deveiopmt:nt
of living birds a lmost always involves cell fusion!:
(119).
ZZ /Nics an be obtall\Cd from fusion of a z,tyI'C
OVUm .. ith a Z-iYI'C SC<lOiod poIa. body. ZZW 1M.... reo
luhins from 1"" union of a W.ty,," OVU m .nd a ZZ ('rsl
polar body uuaity acquir. OVOl." ... WW Z)'JOtCS a.n"'"
..ni.....in<;<: the Z fDr" vj,.1 fu,"",ionJ.
Sin« the "",urn and th. scwnd poLar body have 11M: same
$<;. chromosome: m. keup. it i. 001 $u .pri$ing thll no ZW
IMrds "-",, •••••n """"'.rcd.
TlIc:rc has bc:cn considerable OVer the
possibility lhal spontaneous parthenogenesis Can
lead to the birth of viable )"OO"g in mammals. but
lhere is 00 CYi!kncc: 10 Mlppoo1 it$ occurrence. Since:
lhe germinal cells have only X chromosomes. all or
the progeny would be expected to be (emale.
ACESSORY REPRODUCTIVE STRUCTURES
Gooads are primary roprnductive organs. T he <l«rJ -
SOf')' struCtures increase: reproductive efficiency and
they ma ke it jIO:\Ilibie for animals to breed on land.
Spee ics dilT.r widely in th.ir needs for .ueh
Sltuet urcs.
J a wlc:ss vertebrates (cyd:)stornes) rclease both ova
and spermat07.03 into Iheir body cavities. from
which the cell. migrate through pores in the body
wall to the surrounding .nvironment ( 156). They
have no ne<d for accessory reproducti ve: Ofga ns. but
they pay a high price for Ihe simplification of body
form. Enormous of pmetes onUS! be pr0-
duced .• ince oomc: arc: lost wit hin the body ClIvity and
m051 of th. others SUCCumb SQ()n aftcr they escape to
the w rrounding water.
Some of the fishes get around the fi rst problem
with tubular 0( the gonads that direct the
sex cells 10 openings. Ilowc vc:r. the: gametes
arc still CIItapulted into a less than ideal environ-
ment. Relat;vo:ly few find parlncrs for (.reili1.11tioo.
There is also of the limited numbers
or
o( delicate l)'&O!cs that do form. and most ehe em.
bryOS that survive carly de."Ciopmeneal staacs KTVC
as f()(X.! for prcdaw ....
Fishes ;nctcaSC the cbano.:cs that fertilization will
OCCur when they enwe in <:oorting and spawning
beha viors Ihat sy ncht<lnilC tbe rclea", or spermat'"
WOI and "" •. Tu acoompti.h lhi •• men, be .. or bolh
sexes req uire structures for temporary storage or the
gametes in viable form and meehan;srm for regulae_
ing their releaK . Some am pllibia ns further improve
the efficiency with Qmplrxus. in which the male
graspslhe female 300 discharges his spermatozoa as
she releas.s her egg Cell s. In such species, very large
thumbs on the: ma le are included among the ICCCS-
90ry reproducei'" structures.
Some of the: "'rtebnlICSIhal depend upOn extern al
fertilizalion have alS<) developed s trategies (or pro-
tecting the devo:lopin& embryos a nd newly hatched
progeny.
"nimals tha t reproduce on la nd provide
moi$1 sitcs (or fert il ization (usually partsor the J'(:.
productive trael that a re pro!ccted against the exter-
nal environment and removed from the ovary) . The
(emale then requires oomc: kind o( flVidurf for recep-
tion of the: male gametes. for the f. rtilization. and
for su b$c:quent utrusion of the conceptuses. whcreas
the male need s an organ for tlflivtry of the sperma .
tozoa. By increasing the probability tbat the female
gametes will be exposed to sperma tozoa. interna l
(e"mution sub$tantia lly reduces thc need to pro-
ducc large numbers of egg cells. E ffICiency is furt"",
inereased if there: a re mechanisms for assuring that
copUlation will oceur close 10 the time of ovulalion.
When Ihe femal. traet ad ditio<ut lly has uructurcs

thai nurture and protect thc young conceptuses. evcn
fewcr egg cells are require{!. IXlicate cmbryos and
felUses can be shielded if there is a u/rruJ to suppon
their growth and then participate in thcir expulsion
when Ihe appropriate stage of maturity has been al·
tained. Strategies of this kind are employed by
sharh, some leo!eosts and snakes, and certain other
ectotherms. Eutherian mammals have acquired
elaborate mechanisms for nourishing and reta ining
intrauterine young. Under such oonditions. the prog·
cny can slowly develop oomplex cenlral nervous sys-
tems. However, the mother must carry around
heavy. bul ky fetuses. make numerous metabolic ad·
justments. and undergo painful panurilion that can
involve oonsiderable loss of blood. Marsupials over·
come these problems by delivering immature young
which are. in most species. carrie{! in pouches. Both
eutherian! and marsupials oontribute further to the
survival of their young by producing milk in spe<:ial.
ized mammary glands.
Birds Ihat Ay must maintain low body weights.
They enclose Iheir zygotes in yol k.laden. shell...,.,v-
ered eggs, and they warm and protect the eggs
throughout the incubalion period. Both males and
females of some species provide special nutrients for
the hatchlings. MOllOlremes. which are regarded as
the mosl primitive of mammals. also lay and prolect
ew. and they posse'" primitive mammary gland_
like struCtures. Mosl of the reptiles produce eggs
with leathery coverings Ihat are resista nt to mechan-
ical injury and dehydration. However. although the
females make allemptS to shield the ew from pred-
ators, e.g. by laying them in seclude{! places or bury-
ing them in soil. the mortality rale is high.
Copula to ry Organs
Structures spe<:ialized for the delivery of spermata.
zoa to the female tract come in many forms. Thc
human peniS is very short by comparison with the
analogous organs of zebras and elephants (even
when allowance is made for body (33). and it
lach the bony support seen in carnivores and ro.
dents. The opossum has a bifurcated penis. snakes
and li7.amS have two copulalory organs (hemipenes),
while fishes can have paired claspers or a single gon-
opodium. In some of the bims. an extension of Ihe
fem(1le tract direct.! Ihe transfer of spermatozoa
from the male to Ihe female cloaca (I S).
The cloaca is a common receplacle for the lermi-
nations of the genital. urinary. and digestive tracts
of nonmammalian vertebrates and of egg-laying
mammals. It houses Ihe penis of SOme eClotherms
(e.g. lUrtles). Some salamauders have no need for a
copulatory organ, since Ihe female uSeS her cloaca 10
$l;X oeTERMtNATtON AND DtFFERENTIATION
pick up sperm packets deposited on rocks or twigs by
the male (IS6).
Structures Specialized for Sperm Maturetlon
end Sto rage
Spermatozoa ejected from Ihe mammalian tC5tis
undergo a prolonged period of maturation and stor·
age in Ihe epididymiJ. where they acquire Ihe ability
to become independenlly motile. In humans and in
many Others, both the testes and epididymides are
housed in JCf'0I0/ sacs which mainlain a temperatuTC
considerably cooler than thaI of Ihe abdominal cav-
ity. The scrotum is equipped with a special set of
blood vessels (Ihe pampinlform plrxus) that converts
the arterial now from pulsalile to continuous. and
also provides for cooling of Ihe blood as il leaves the
abdomen and rewarming as it returns. The scrotum
has sweat glands that are activated by high external
temperatures. and contractile elemenls that afford
some protection against exce",ive cooling. The testes
of humans remain permanently within lhe scrotal
sacs. However. the relatively large and vulnerable
organs of the rat can be temporarily retracted when
Ihe animal engages in combat or is exposed 10 cold
environments. A more prolonged period of retemion
wilhin Ihe abdominal cavity is the rule durilli pe-
riods of sexual quiescence in many of the seasonal
breeders.
C'yptorchism is the failure to accomplish normal
descent of the testis aud epididymis into the scrotal
sac. It can result from blockage of the inguinal canal
(Ihrough which the testes migrale) or from other deo
velopmenlal problems. Cryptorchism thaI OCcurs
spontaneously or is accomplished experimentally.
and excessive warming of the sacs oontaining the
leslCS. are associated with failure of spermatoroa to
malure and survive.
It is widely believed that heat damages the ger-
minal cells. and some evidence h(U; been presented
for additional deleterious on the Serloli
cells (15). Moreover, local faclors released by the
damaged li",ue may adversely affect the formation
of gonadotropin receptors by testosterone-sccroting
cells (143). However, since whales. dugongs. cle·
phant., rhil>OCerQ!;es. and other mammals lack sera.
tal saCS (29) and yet manage to produce fertile
spe rm at relatively high temperatures within Ihe ab-
dominal cavity(14), it has ocen speculated that the
scrotum is needed primarily by the species that !/OF(
spermalozoa for relatively long time periods and en·
gage in repeated ejaculations when the opporlUnitiC$
presenl themselves.
The female lracts of many a nimals also contain
devices for sperm Storage. In some, a single iosemi-
nation for fertilization of female gametes
that mature during subsequently recurring ovarian
cycles.
Glanda of the Male Tract
Prostate glands provide nutrients. !Iuids. buffers.
and other components of seminal !Iuid that support
su rvival and transport of lhe: spermatozoa. They vary
widely in appearance. bul some kind of Ihe gland is
presenl in all male mammals (189). (A few females
have similar struclures. but no functions have been
ascribed to them.) MCllt eutherian mammals also
have seminal wSldes that make different conslitu·
enlS of the seminal !Iuid, bUI no such organs have
been found in whales and carniYOn'S (180). or in
marsupials and monotremes (189). Wilen present.
the more distally locatoo bulbouwhral (Cowper's)
glands provide lubricants for copulation. There are
controversies concerning the function, of the prepu-
tia/ glands that Can OC<:ur in females as well as in
males. It has been suggested that they seCTCte sex
attractants Or phero!l1()nes.
The accessory structures of a "typical" eutherian
male mammal are sbown diagrammatically in Fig.
I 3-5.
Major Accenory Organa In Females
The OI#UClS (fallopian lUbes) of female eutherian
mammals facilitate both the upward transport of
spermatOlOO prior to ovulation and the downward
passage of young conceptuses. They also provide a
favorable environment at appropriate times of the
ovarian cycle for sperm capacitation (the final stage
of maturation required for fertilization). Soon after-
ward, the secretions support fertilization and the
survival of young oocytes. r.ygOtes. and developing
blastocysts. In some vertebrates. however. oviducts
are liltle mOre than passageways for the ova. By con-
trast with the bilateral arrangements of most ani·
50",,,,.1 .t
,
V.. f
" glorw:l
Pon ..
IProPUI,. 1 9t.rw:l1
twhon
epododym ••
mall;, the right oviduct (and ovary) of the bird usu-
ally regresses. as the lower part of the left one
enlarges and bouSC$ the shell gland.
The mammalian uterus provides an e nvironment
that favors sperm survival and capacitation during
the preovulatory phase of the ovarian cycle, and it
becomes receptive for blastocyst implantation to-
ward the end of the luteal phase. It grows to accom-
modate the developing embryo and fetus. and it
plays an active role in partutition. The glands of the
ulerine ct/'liix secrete a watery nuid tbal facilitates
sperm entry into the body of the uterus around the
time of ovulation. and a one that retards
sperm motility some days later (when there is danger
that an "overripe" OVum will be fertilir.W). In some
species. the cervi. provides a site for sperm storage
and controlloo release.
A large, single< hambered uterus is charaeterinic
of females that carry One Or two young for relati""ly
long gestation periods. whereas double-horned uter;
a rc beller suitoo to the nurturing of large lilters for
shorter times. The bicornate uterus of tatS and of
many of the domesticated mammals leads into a sin-
gle cervix. but the duplex uterus of the rabbit has
tWO cervical openings into a single vagina. Marsu·
pials have separate uteri ne openings into blind ends
of vaginae that are joined more caudally (156).
Eutherian mammals utilize the same passageways
for sperm entry and fetal e>tpulsion. Some marsupi-
als have a separate birth canal that clClles after each
parturition.
The clitoris i, a sensory struCture derived from an-
lagen similar to thOOie giving rise to pans of the penis.
It is more prominent in some animal types than in
others.
The general appearance of the ovaries. fallopian
tubes. uterus, and vagina of primates is show n in
fig. 13·6.
Highly specialized accessory organs. depend on go-
nadal hormones for maturation and function. In a
sense. some also perform as endocrine glands. They
P", . . ot) t3·5. :scr-atic
,,,,""_t&fion of str"""_",,. IhrO<flll1
... ni<fllll*m.to.OI It.... &rw:I gl"l'KIs
conlr;b\Jling to _allluid.

'"
lake up regulatory molecules of one type and convert
them to others with different biological properties.
For example. the prostate glands reduce ICSIQSICI'On<'
to dihydrotcstostcronc. Much of the produ,\ is u,cd
directly "'ilh;n Ihe prostate, bUI some is released intQ
lhe blco:lstrcam 10 aCI on the kidney and other lar-
gel organs.
SECONDARY SEX CHARACTERISTICS
Males can of'lcn be distinguished from femal.s by
Iheir seCQ/\dary sex charaCleristics. The Structures
are not essential for formation of gametes, fenili,,;!-
lion, or nu"uring of the young. However. they play
roles in "Stxual allraclion" and the choice Gf maling
partners. The mane of the lion and the elaborate
adornments of t he peacock provide striking exam·
pies. Olhers, such as Ihe spurs of the rOOSler and the
anllers of the stag, contribute to Ihe ability of a male
to fight with others of for re«plive mates.
Sexual diMOTphism oorrdates wilh lifestyle.
rnlher Ihan wilh reproductive "success" (Ihc num·
bers of offspring sired) (119). and it i'l the InOIit
highly developed in spedes in which polygamous
males establish harems. Al!hough male competition
for limited numbers of females i'l said to accomplish
trnnsmission of the "fittest" genetic chracteri!tics.
success in CQItlbat is not necessarily associated with
genes that enhance adaptability to changing
environments.
Sexual dimorphism is vinually nonexistent among
species in which reproductive success ",quires long-
term cooperation between members of monogamous
pairs, Or in which there arc very marked specializa-
tions for survival. Even zookeepers cannot distin-
guish the sexes of harpy eagles (highly specialized
for predation) or of hyenas (in which the fema le
hunts alongside the ma le).
It is not surprising that nocturnal animals display
SEX OETERMINA,TION A,NO DtFFERENTIA, l ION
few diffe",nces that can be detected by visual recep-
tors. Thus, the male mouse looks very much like th.
female, and he is often the same size or smaller.
However, the male pheromolU's that pro-
voke aggr=ion in other males_ contribute to terri-
torial defense. Or affect the ability of fcmales to sus-
tain a pregnancy.
Human males are generally larger than females.
have broader shoulders. narrower hips. stronger skel-
etal muscles, deeper voices. and characteristic pat-
terns of body hair distribution. Females usua\\y have
softer skins, more rounded contours, and breast com-
ponents that are not essential for lactation. There
have been inte",sting discussions oonccrmng
whether such dimorphism provides support for the
notion that humans are "basically" polygamous
(1 19). A more widely acc<:pted concept is that the
distinguishing features contribute to "pair bonding"
in a speeies that mOre effectively accomplishes long-
term nurturing of offspring when both parents
participate.
PSEUDOHERMAPHRODITISM
During the normal course of cvenlS. the mammal ian
XY conceptus eventually forms testes and a full set
of malMype
socondary se;o: characteristics, while the XX zygote
becomes a fully rcoognizable female.
Since Ihe factors governing the development of
the gonads. the accessory structures. and the second-
ary characteristics are aU different, il is possible for
an individual to acquire cerlain features associated
with female syStems and others considered male.
The condition is distinguishable from true hermaph-
roditism by the presence of just one type of gonad.
The cireumstanCC$ under whieh it occurs in mam-
mals (including humans) are considered later in Ibis
cbapter.
For legal and social purposes_ it is customary to
assign a gender at the time of birth. The decision is
usually made on the basis of the appea"''''''' of the
cxternal geni talia. a neonate properly classi-
fied as a malt pseudohermaphrodite because of Ihe
presence of an X Y chromosome pane rn and testCS
may be assumed to be a girl if "her" external fea-
tures a", feminine. A form of the disorder in which
the individual undergoes pubenal maturation and
acquires female-type breasts and other secondary
characteristics is described later. The abnormal-
ity may be detected only after failure to establish
menstrual cycles. Similarly. a female pseudoher-
maphrodi te (with ovaries) can show very marked
signs of prenatal virilil.3tion, present tlte appearance
of, and be classified as a boy.
Interestingly_ the subje<:ts usually adapt nicely to
Ihe assigned gender role. Femini'",d childll'n wilh
XY chrolnOiSOmes regard as girls. and
many laler enjoy happy wilh normal
males.
Assignmenl of gender is WI always a simplc maI-
ler, since pseudoh ermaphrodiles can hvc eXlernal
featuI"CS Ihal arc besl described as "ambiguous." An
auempl may Ihen be made 10 delermine Ihe genelie
sex and 10 tll'al Ihe infanl with Ihe appropriate hor-
mones and surgical Usually. however,
major consideralion is given 10 Ihc analomical po.
lenlial of Ihe exlernal organs_ Neither hormoncs nOr
surgical procedures can elfect formation of a normal
penis in an individ ual wilh severely impa ired phallus
development.
EARLY DIFFERENTIATION OF THE
MAMMALIAN REPRODUCTIVE SYSTEM; THE
AMBISEXUAL OR "INDIFFERENT " STAGE
Mammalian embryos are said 10 go through a "sex-
ually indilfcrenl slagc:' since Ihc forerunners of the
f ulurC re produclive organs are morphologically sim-
ilar in XX and X V individuals and Ihcy possess the
potenlial for acquiring either maseuline Or feminine
cha racteristics (9 ,77).
AI Ihat lime, each embryo posse$SCs; (a) the be-
ginnings of a pair of gonads; (b) One pair of ducts
capable of forming the inlernal male-Iype accessory
reprod uclive organ.: (c) a second pair of ducls lha,
can differentiate imo a uteruS and fallopian lubeS;
(d) the undeveloped precursors of Ihe f ulurc exlernal
genitalia; and (e) pituilary. hypolhaiamic. and
higher brain.. enler components whose: maluralion
can be condilioned by gonadal hormones.
The lighl microscope cannot be used \0 reveal dif·
ferences between gonads of young XX and X V em_
bryos. It is possible. however, 10 idenlify Ihe kary(>-
types and t- demonslrale Ihe presence on Ihe
surfaces of male (bul 1\01 of female) cdls of a prolein
..
,0:1,.
o o
Fill. 1 J - 7 . A. OieIl"fM"IO.t;e tron•• _ _ tion tlv-o<Jg/l
t"" t"",bar r8giOn of OI"",_-oId flmb<yo. $IIowintI
rOdge. Iocatflod bo!_ !"" _ ... f "'f"'' n1f1fy or.:! Itle
Ihat is be lieved \0 direCI differentialion of lhe gonads
inlO leSles.
There are indications that gonads de"ined to become
t.. te' mOre rapid growth than presumptive ova·
rics of the same age. and that they acquire larger num·
bers of ge rminal cells (110). However, thi S pha", <>ceurs
just prior to the onset of cell speciali'.3tion and its detec-
lion require. accurate timing. The female gonad ",main.
undifferentiated for a longer period and il e,-entualiy Sur_
p''''' Ihe male counterpart in overall .i.e.
The descriptions thl follow apply moslly 10 hu-
mans. IXve\opmcn1al paucrns for olher euthe rian
mamma ls arc qualitatively similar, bUI species va ri·
alions are encounlered.
The time cou""s are condcn,ed for many of the sul>-
primates. Thus. whe",.s the gonad of a t4-<la)"..,td male
rat fetu, . hows . ign, of organizing into . testis. and the
bios)'nthesi, of st"'Oid hormones ca n be det<x:ted two daY"
later (101). analogou, changes in the human are seen
. round day. 42 and r.speCl ivcly . Ra" are .1.., known
to accomplish certain 'SptCIS of reproductive sy<tem dif-
ferenliation during the first postn".1 week (which f<>l-
IO"'S a gestalion period of 21_23 da)". ), whereas compa·
rable evenls tran.pire during the third trime>tCT in
humans, Speeies 'ariation. in the dot. ii, of testicular and
ovarian differenl;ation. in Ihe development of Ihe parts of
the hypothalamus inv<>lvtd in control of reproouetion.
and in some chromosome·related evcnts have also been
described,
Formation of the " Indifferent Gonads"
Wilhin four weeh afler conception, a genital ridge
forms on each side of the embryo. It is medial and
"cntralto the mesonephros (Iemporary kidney. Wolf_
fian body) and close 10 Ihe developing adrenal gland.
It al firsl comprises and under_
lying mesenchyme. bUI it soon becomespopulaled by
germinal elemenrs Iha t migra te in from the yol \': sac
entoderm (Figs. I J- 7A and 13-SA). and it is invaded
_B. Similar MC1ion, as In A. 01 • " .-w_-oId
fT ....... lJh!"o.
flmb<yo. snowing I"" incIin ...,,, I/f)nad Itle ",;mitl.o ...
cords (mo<Hlied .tt... (Longman. rel .."""" a6J
 I
.1

/
,
••

B. Earty 01a\lO ot male din.",n';",ion

--"., ""ie'"".

- - Ute,",
Urinnry
Dla<I<Ie, -
!-- vagona

E. lalnr stago oltemate d&WtIOp""""

F ig . 1:HI. o;R ...nt;ollon 01 lho ""' ........1;00 _ . 00<1

duCts .

'"
 13·9. .... SchMnatic<l<ewing 01 a U',,_ _-oI<l
""'"""Y<> _wing IfIfI prImordial lje,m cells ;" tile .... 11 oj tile
sac. 010 .. 10 I.. anao",""", 01 the (. !lor
Wi,,,,,,). 8. Dr .... ing '0 .. _ , . . m'WatiOn p"th 01 t . .
by mesoncphric cclls. Thc resulling structure is said
to be an "indifferent gonad:' Under normal circum·
stances. it dc"clops into a leslis in XV fetuses and
into an ovary in XX individuals: however, it JXlS-
selSe. some polcntial for assuming the charactcris-
tics of the gonad aSSOCiated with the opposite sex.
GER MINAL CEllS
The g<l'kX"y te., all: diploid ""II.will ._<musHy
mature into gamete precursors. They can be idemi_
lied in the region ofth. sac epithdium when the
embr)'Q is I.,... than I mm in length and barely two
wC"ks postconccptkln. Because of their large si,.c
and eharacleristic staining propenies, they Can be
traced in animal embryos as they proliferate by mi-
losis and utili,c pseudopods to migrate through the
hindgut to the gonadal region (Fig. 13·9).
The gonocylcs reach Iheir destination by the
day. It is believed that they Rre attracted
by a chemotaClic subslanc. (Ielopheron [9.20): but
it is possible that they accumulate selectivdy within
the fulur. gonads because Ihe cells that wander clse·
where fail to survi,·c. Autosomal defects can impair
both the proliferation and Ihe migration (62).
Mitotic division continues for some time after the
migration is completed. Eventually. ho"",,ver, the
germinal cells associate with somatic components of
the gonad that exert inhibitory innutnces (fig. 13-
lOA).
The Duc ts (194)
Bilateral WoIffian (mesonephric) ducts develop in
conjunction wilh th. lemporary kidney (mesone·
phros. Wolffian body). They provide components of
the future urinary systems in both sexes. but some
oell. olo<>g the w811 oj tile I\indgut and t. .
ga<m
_ sal _sentery intQ the geoit81 ridge. Not. the potoltior1 oj
the genital ridge and rM""""p/lrOS. (Langman . ret.rena
portions undergo further development only in males.
In response to hormones secreted by the testes of Ihe
embryo and young fetus, thc steroid·sensitive parts
become the forerunners of the epididymides and of
other internal accessory reproductive StruclUres. The
relaled portions undergo atrophy in normal femalcs.
The uppermOllt parts of the MilIlerion (para meso-
nephric) ducts arC derived from the coelomic epithe·
lium. while the lower regions eilher separatc from
tl,e Wolman duel> 0, ,equi,c thc p,c"""",,, of Wolf-
fian duelS for differentiation ( 192). In females. Ihese
give rise to the fallopian lubes (oviducts), ulerus.
and parIS of Ihe vagina . In males. the MUllerian
duelS undcrgo regression and all bul completely
disappear.
External Features
Toward the end of Ihe "indifferent Slage·'. Ihc em-
bryo has s genital t"Mrcle with Ihe potential for de·
velopment into either a clitoris or the antcrior port
of Ihe The tuberde is eonlinuous with thc "'I)-
geniraljolds that will be involved in developmcnt of
the ,.re/hra and (in the female) thc labia mirwra.
The surrounding genital swellings will becomc either
the scrotum or the labia majora (fig. lJ_ll). At
first. a urogenital membrane covers the external sur-
face of the urogenital sinus. The sinu, serves as the
foreruner of the prostate gland of the male, mOllt of
Ihe vagina of the female, and parts of the urinary
bladder of both sexcs.
DIFFERENTIATION OF THE TESTI S
In human XY embryos. Ihe gonad, show signs of or-
ganiling into te,les before the end of the sixth week.
AI thai time, the embryo has attained a crown-rump

'"
PI ....... ...
o •
, EOIIy ...,-..
length of around 10 mm (193), and the IOtal gollO-
cyte population is estimated \0 be belween 300 and
1000 (57). The developme nt invohu inlcl'lI"ions
-mont the various gonadal oomponcnlS (gc-rmina1.
epithelial, and rnesench)'mal cells),
Role ol l he H·Y Antigen
The following hypothesis for regulation of gonadal
differentiation in mammals has gained wide ac.:cp-
tarn.:c: T he Y chrol1105Omc directs the formation of a
malc-spccific cell surface proIein (the tl . Y antigen).
Inttraction of the prOIein with its rc« ptoI'$ leads 10
organi7..ttlion <.If the "indifferent gonad- inlO a lC$li$.
When no H-Y a ntigen is present (Ill! in XX em-
bryos), the &Onad malum into an ovary-like
5\l\Ietll'<:.
se x DETERMINATION ... NO
FIg. n - I o . • • _ _ _
,.1... '.., ... ,t ol .... ooy,
...... 1. C . e.""
DISCOVERY OF THE H·Y ANTIGEN (119)
The e. ist.l\Ce of a maiM.p«tftc minor histocompatibility
InliS"ft w;l$ dcrn<)n$Ir1I,cd .fLer il ..... oboerved lhal
.dull fem." miff 01 hi, hly inbr«! ..... i.. reject st.ift
.... flj from miles of Iheurne .... in. whereas ani.... b of
booh oe.CI "cuP! anfts from fe"",lo$. TlIe protein wu
IPI'"'f.riald y ... med H·Y anlil<n (II for hi.u)c:ompal;·
bililY. Y for Ih. chl'OlllOOOme ",ilh .. hich i15 appea .. nce
i. . ."",i"ed). The moIeeul. oo<uo;.. fe,.·., l ban 200
.ml"" lcid moi.li ••. [I , •• m. 10 I•• k . peei •• 'peeificily
Ind may"" idenlical for human. Ind I wide variety of
o.htr ••• Ieb.ales .... ilh XY so . chromosome pallern •.
Some: of 1"" findin&, coosill.nl wilh I major role in
di reclion of JOfI3da[ difref(:nlillion 'f(: C;led ""r•. Ind
ot""" Ire po_,ued Iller in llIe chlp'e •.
1. II· Y Inl1gcn is pra<nl 011 ,be .... f . ... of .1Ie <;<:Ib of
Idull mak$ bu. not Oft lh. «[bof f. .... .Ies (unde • ..,...,.1
oondilioM).
 Genil. I .....11ing
Ij \1c Cloacal membt.""
C<>acal l<>Id
3 Wee • •
4 Wee ••

A. -'-";I!ereni" S139"

lJrel"'al

\ Glans penis

.
".::>.
"

,
'.',
'.'
I scrotal !old.
' . 0 ,..,

4 Month.

B . DiHer"r>l;;'hon 0 1 male eXlernal

, ,
,
l a bial lOld

9W"",.

C. Diffe renliation of lema" \II'flilalia

Fig. 13·1 I . For""'tOn of mo'" And 1......1• • • teI ....1

peJ1it. li• .

2. The .nli,on Can bo d<tccted long btrore [o,lkul.,
dilf.",nli.lion begin" It i. p", .. nl 00 moo .. embr)'''' .1
!he 8-cell ,tago (prior 10 the tim. of ;mplantalioo) (62).
Laler. il build. up in highe't concentrations in dovtloping
lts'tS ( 119).
3. Antibodies directed ogain'l lhe an!igon con block
,<,lieul'r diff....:n\;alion of gooad. taken from very yoonS
XV .mb.},,," thai ar. majntained in culture.
4. When tho gonad. of very Y<'U"g XX embryos a,.
pm.mod in vilro with lh. Intigen. tbey begin [0 .«urn.
testicular form .
S. The molecule, are reversibly .nchore<! to coli ' .r_
f."". by fJ·2 microglQbuiin, (121). A condition th at
sometimes occur> in cattle is attributed to transfer of the
.ntigen from l m.le retU. 10. remale twin. The female
is then virilized ("'. p_ 550) ,
STRUCTURA L GENES COD)NG FOR THE H·Y
ANTIGEN PRODUCTION
It proven technically difficult to determine the
location of the DNA that codes for production of the
H·Y antigen (51). The concept that multiple copics
of the structural Ilene are present on either the shorl
arm or the pericontne region of the Y chromosome
is consisten t with ",veral observations (5 2). The an·
tigen i. not pre",nt in normal mammals lacking Ihe
Y (I.e. in XX females). It is made in relatively large
quantities by individuals "'ith s upernumerary Ys
(XY Y. XXYY . XXYYY. and ol her patterns) .
Another possibility is that the Y ch romosome oon·
tains rtgulolOry genes Ihat direct the transcription
."
of DNA segments on X No
quanlitali>'c r<:lad()lI$hips bel ween the numbers of X
chrOl\'lOlSOmCS and tile amounts of H. Y an ligen have
been established fQl" mtmmals wilh muhiple Xs, but
some X 6dc:cts llavc been linked ,,-jth
male in fertility.
Yel a different is Iha1 the Y chl'Orl'106Olllc pro-
moces trans<:rip1ion of autosomal gCne$, while nor-
mal X chl'lJRlOl$Orr>O; o:JIcn inhibitory ( 16).
In panicliLar. a gene: on the short Irm of Ihe X chro-
mo5OOIC 1Il001 ordinarily escapes inactivation is im-
plK:alcd (51). Th is I'l0l;011 can be rttOIICilcd wilh 11K:
prtUn<;C of small amounl$ of H-Y a"li&e" in some
XO female$. II is alw known lllal XXV. XXXV.
and XXYY males usually suffer gonadal dysgenesis.
excessive numbers 0( X chromosomes <:an
imerfe'" wilh spermatogenesis in OIlier ways. It
$eCITI$ II) be necessary 10 achieve IrallSienl X inacli·
vation in primary spcrm:lloc:ylCS, al>d the mecha-
nisms utilized may 001 be capable of coping wilh
more lhan one such cnlily.
FaClO<S 1hal have delayed progress in Ihis arca of
invtstigation include (I) tht facl Ihal anima ls can·
not survivt without at least ant X chl"Oll'lQ:lQll1e; (b)
tht neo:<! for regulatory genes tha I are nol directly
involvo:<! in H·Y synthesis; (e) the absence of known
spoc ics-spcci fic differences in 1-1. Y chcmiwy; (d) the
slrong lendency for Y chromosomes to unde rgo dele-
tions. Iransloca lions. and inversions; (c) une<:rtain.
tics rega rding Ihe rdalionship$ bell'o'cen molecules
sludied wilh serological methods and ones involved
in CrIOlo, icily: (0 the low antibody tilers obtained
when attempts are mack 10 immuni .. e animal.
againsl the H·Y; (I) difficulties el>OO\lntcrod in
bioassays: and (h) somc problems of Sludyinglhe an-
tigens Ihat have been linko:<! wilh o;arbohydrJte o;om.
ponents{LSS).
It is unlikely that the: II.Y ,nlia<:n mercly $Crves
as a marker for OIher Y faclOfS
IlIat direct leslicular difi"el'<:nlialion. the
po5Sibilily will not be ruled OUI unlilthcre bttn
suca'ss in puriflCalion of the si ructural gene. Re«nl
studies or nonropctili"" DNA 5Cquenecs from
mou5«lcrived « 11$ OQnt.ini na ' human Y chTOll'llJ..
some ( I!JA) nisc hopes liull this will soon be
accoollplishc:d.
RECEPTQf'IS FOR Tl-IE H·Y AN TIGEN
If il is 10 fur.ction as lhe: inducer or lesticular differ·
entiation. Ihe H· Y antigen mUSI combine wilh spe.
cific receptors on Ihe surflces of t ile largtl OriOl n•.
In this and other respecls. ils mechanism of lei ion
hormone.like. The antigen can also pass from one
sex TION ANO
ce ll type to another both directly a nd via Ihe
bloodstream.
Receptors have been idcntiAo:<! un Ihe cells su r·
facc:s of Ihe "indiffe rent gonads" of bolh XX and
XY em bryos. However. Ihey may remain nonfunc-
lional in lhe female. sinee neither Ihe embryoi nor
lheir mothers produce Ihe anlilen. (Sec the _lion
00 ovarian differentialion fOf addilional discussion of
Ihis poi nt. )
Evidenlly, som:uic cel l$ lack specific r-.:teplM,
The abilily of adult females to rejecl skin &nof"
from males l"QIui= mechanisms ""'Y different from
Ihe ones involved in gonadal difJC"rt1Ilial ion.
Differentiation of the Gonadal Epithelial
Cent
The epithelial cells of Ihe gonad are im-
portant sourcc:s of H· Y antilen. They may also pro-
vide Ihe primary largel5. In lhe presence of lhe an·
tigen. thc)' proliferale rapidly. penttnle the
mesenchyme. and advaoce toward Ihe inocr (med·
ullary) regions. These or mesonephric oclls malure
inlo young Smo/i cells Ihal cocirclc Ihe gono<.:ylcs
and enter inlo Ihe formalion of primary sex ronIs
(Fig. 13·12B). The laller arc soli d struClures in Inc
f""". "flcr Ihe onsel of pUberty. they undera<! fur.
Iher growlh. develop lumina, incorporale myoid cle-
menlS. and become Ihe seminiferous tubules of Ihe
malure lest is.
Fine s lrands of epilhelium also from II!c
cords 10 the cenlers of the gonads. The" or,ani1.e
into the relio leSltS Ihat make dircclwnlaci with Ibc
tubules of the temporary kid ney of Ihe young felus
(Fig. 13· 12A). The mesonephric lubules gi"" risot: 10
the epididymides as the permanenl kidney form$.
The teslis functions as an endocrioc ,land even
bdOJ-.: the morphological Ch,naClen.t1cs al'<: fully de-
fined. Sertal; cells a.>nCCnlrale II·Y anligen. They
relell" it ;nlO cullure media and are thel'<:fore be-
licYo:d 10 provide Ihe glyWjiiOlein 10 OIher cclllypcs.
Soon arterward, production of. hormone Ihat ar·
fecu Ihe Mollenan duct.s can be demonslralo:<! •• nd
Ihe effecls of tllal hormone are Ijlpilrenl by the Sih
",-.:ek. They 1100 ""en localized inftucnecs Ihal pro-
long survival of the germinal ccll$ bUI inhibil mitO$is
and enll")' inln reduction division.
Differentiation of the Germinal Cells
The gonocytes malure inlO noomotile
thaI a rc smaller Ihan Iheir precurson. Th e sperma·
togonia divide by mitosis up 10 Ihe lime they come
 Fig. , 3· ,2. A. Trans ...... """,;on 10r0ugh lhe
1M eigtllh week 01
'''' 1.00is e<><ds. _r>d the ,"'.
NOI& tll<t
,u tis. T'"
'LIn"_.,bt>girlfla.
Bowman's cop ...... oj , ... -.p!vic . XCfoto<y
'OQ",»ion. B. ,_asent.,ion 01 ,he , • .,;••r>d
under {he influence of (he devek'ping Scnoli cells.
Their accumulalion within the medullary region
portends future functions (ha( involve transpon of
gameles 10 Ihe relia teSteS.
After Ihe primilive sex cords have formed. spcr·
malogonia remain un(il the onset of pu·
berty. No new germinal cells arc formed in Ihe fetus.
It is often stated (hal (he germinal cells play es·
sential roles in dircction of epithelial cell dilTcren(i,,·
lion (86.164). and SOme studies of mouse chimeras
(animals lhat develop following fusion of cells from
Iwo different sources) provide support for (he con·
cept of an ··orga nil.er"-I}·pc action (62). They do nOlo
however. supply H·Y antigen (since lhe prolein docs
nol appear on the surfaecs of eilher gonocyles or
spermatogonia and has not been found prior 10 the
postpubertal spermalOC}'lc 'Iage).
nifcrOlls luhules made up primarily of Ser(oli cclls
Can form under spceial circumstances (44). and Ser-
toli c.:lIs undergo maturation in mice wilh autosomal
defects that impair gonocyte proliferalion and mi-
gration (59) .
Mesenchymal Cells
Some of the mesenchymal cells differcn(iate into iff-
Itrs/i/ial (Leydig) cells (hal and secrete
the steroid hormone /tS/OSlrront (115). The efTec(s
of (hat on (he gonadal ducls are demon-
strable by Ihe end of (he 8th week. Other mesenchy·
mal cells beoome oonnceti"e tissue oomponems that
direct the invasion of blood and lympha(ie ve;scls
and of nerve endings. In humans and in some other
in 'he _;10 1 d uel. in t ... ,..... lh mon1h oI_.Iopmen1. 1he
. nd
""'_"""fled t ... tis COlds a ,e conti"""". with lhe ' e l.
,e.ti. co-ds. Note t'" ductul; """,.."teo ( •• "'.to<)'
lUbe Of. ", mosoneph,ic '''''''''0). which ..""" "'" WoIl&an duel
a lt'" GilOUO). (Langman. , e l..."""" 86)
mammals. Ihe connective tissue forms pan i·
lions Ihal of developing seminifer·
ous tuhules from each other.
The peripheral (conical) regions of the gonads be·
C<tme depleted of both epilhelial and germinal com·
and a dense connective lissue memb,"nc.
'he tunica albugim"a. nppoar< . It i. lined by 'he ,,,,,.
iea .asculosa. and it is soon surrounded by another
membrane of pcritoneal origin. the tunicu l"aginalis
(fig. 13-IOB).
The imeractions be(ween meseflChymal and epi·
Ihelial C<tmponen(s are not well understood. Some·
Ihing wilhin the environment (possibly supplied by
Ihe Senoli cells) facilitates induelion of an enzyme
dehyd rogenase) that ca(alyles
Ihe C<tnvcrsion of steroid precursors to tCl;tOS(Crone .
It is unlikely that the H-Y antigen plays a direct role
in the induction process. since embryonic and fetal
U:}'d ig cells do not bind the antigen (although rna-
Ime ones do) (62). The factor seems 10 be missing
from XX gonads. si nce (he latter ma ke de·
lecmbk amountS of lestosterone.
Mesenchymal cells arc known (0 play essential
roles in direction of (he dilTcrenlia(ion of ep ilhelial
C<tmponems of (he urogenilal sinus ("'hich conlrib-
utes (0 (he Formation of the pl"05tatc gland and the
external genitalia) (32). It is possible thai Ihey per·
form analogous funttions in (he de"eloping lo.,les.
1n(eractions with epithelial may in parI
for the failure of the XX-(ype gonocyles of humans
and of many olher mammals to survive and malure
in the testicular environmenl.
Thue arc indications Ihat steroid hormoflCS ro-

'"
leased by lh. cells promote growth of Ihc
wrds (19J). After puberty onset. lhey are known
\0 contribute to maturalioo of Ihe semin ircrous
tubules.
DIFFERENTIATION OF THE MALE
REPRODUCTIVE S YSTEM DUCTS
The major work of thc H-Y antigen seems to be
completed when Ihc lesti. has assumed ils eharac-
leristic felal arehileclUre. Humoral faclors released
by the embryonic and f.taltestis direct funher de-
velopment of Ihc ,eproductive system . The regula·
tors are C;IOO briefly in Ihis sec1ion. and they arc di,-
cussed in moT<: delaillsl •• in the chapler.
Regression 01 the MOlierlan Duetl
By thc end of the 71h wcd, lhc SerloH cells begin 10
secrete a hormone that was initially called medul-
laria (or meduliarin.). sine<: it is made in lhe inner
portions of lhc gonad (77). The regulator is now
common ly known under names that describe its
function: Millierian duct regression factor (MRF).
MUllerian duct inhibitor (MO l). MUllerian Inhibi_
tory Substance (MIS). or anti-Milllerian hormone
(A MH). II h.. Ihe propcrti"" uf a glywprotcin with
a molecular "'eight of something li ke 200.000 (76).
Although the chemicalstrUClUre has not been deter-
mined. the existence and fUllClions have been dem-
onstratoo in sc"eral ways. Steroid hormones cannot
s ubstitute for M DI (77).
As the name implics. MOl promotcs degeneration
of structures thai would otherwise form fcm ale ac-
cessory reproductive organs. The process begins dur-
ing the second monlh. and it requires about 2:\ weeks
for complelion_ SinC<' the MUllerian ducts almost to.
lally disappear, the effects are irreversible_
Evidently. Ihe distance over which MO l diffuses
is limiled. If Ihe gonad of a very young XY embryo
i. removoo on one side. the MUllerian d uel persists
and develops on thaI side.
Congenital defects have been described in which
failure to release or to r.. pond 10 M Ol permilS pcr-
sistence of Ihe MUllerian duelS in males. This can
occur even when Ihe leSI.. assume a normal mor·
phological appearance and retain the ability 10 se_
crete steroid hormones (44).
The MUllerian duelS of females have Ihe potential
for responding 10 M Ol. and tissues ta ken from
young XX fetuses s how the effects when they are co.
cultured wilh felal testes. However. nO MOl is syn_
thesized by normal female feluses.
SEX DETERMINATION ... NO OIFFERENTIATION
Maturation 01 t he Wolffian Ducts and
WOlfflan Bodies
Unlike Ihe M!1l1erian ducts. which develop only in
[emales. Ihc Wolman ducts have dual functions.
They are required for formation of Ihe urinary sys·
tems of embryos of both sexes. bUi Ihe)' also contain
androgen·responsive components Ihat develop only
in males. T he excretory ponions are considered first.
RELATIONSHIPS TO THE URINARY SYSTEM
The mammalian kidney develops in Ihree stagcs_ A
small. primitive pronephros form, by the end of the
Ihird wee k. It somewhal resembles the permanent
excretory organ of jawle", verlebrates. but it
never funclions in mammals (and it fails to make as·
sociations with the gonads that devolop laler). The
pronephros is SOOn replaced by lhe mesotu>phro.
(Wolffian body). which acquires glomeruli. IUbules.
and also collecting ducts thai empty into Ihe Wolf·
fian duct.
At first, the Wolffian duelS terminale in Ihe parI
of the cloaca Ihat becomes the urogenital ,inus (Fig.
13oS). The sinus interaels wilh the caudal portions
of the duelS 10 form the urinary bladder and part. of
the urf/hra.
A. the permanent kidney (mera""phro.<! emerecs
on each side. Ihc lower end of Ihe Wolman duel ex·
tends a ureteric (ureteral) bud loward it. The buds
Ihen give rise to Ihe u",Urs and rollffting ducts of
Ihe metanephros_
The permanent kidney enlarges. migrale. crani-
ally. and assumes excretory functions. as pariS of the
mesonephros undergo atrophy. Certain ponions a",
retained in males, bUI the mesonephros is almost to-
lally lost in female feluses .
VIRILIZATION OF THE WOLFFIAN
STRUCTURES
Under Ihe influence of the testosterone sccreled by
the felal teslis. some <If the tubules of Ihe mesone·
phros persist. grow loward Ihe relia lestes and be-
come the ejJeren/ due/ults Ihal drain into Ihe col-
lecling dUCls. The laller join 10 form a coiled
epididymis Ihal lead s inlO a Wolffian duel.
Most of Ihc original Wolffian duct develop< into a
highly muscular vas deferens (Ihe most prom;nenl
component of Ihe plumbing system ). Near ils caudal
end . each vas deferens sends out an ampulla that
gives rise to a glandular seminol vesicle. Ducts
draining that organ fuse with the vasa deferentia to
form Ihe ejacula/ory duCls. The laller penelrate Ihe
C<'ntrally located pl'Qj/ale gland and join up with the
prostatic un:thra . Although most of the prostate de.
from the urogenital sinus, the Wolman ducts
may make a CQIltribution.
The roic of testosterone in promoting vi,ilil.ation
of the Wolman structul"<'S is easily demonstraled. Ir
the gonads are removed jusl after MUllerian duct
regression has started, the aCl'cssory struclures de-
scribed in the preceding two paragraphs fail 10 de-
velop. Unilateral gonadectomy usually blocks dc,·c!·
opmcm on the affected side only.
The ducts of XX embryos have the potenlial to
repond to tcstostcrone. bUI they do IlQt recci"e
enough of the stcroid to be stimulated under normal
conditions, The emerges
when a genetically defective adrena l gland n:iease.
excessive quantities of gonadal steroids. If large
amounts of androgen are secreted early in fetal life,
the Wolman struclul"<'s of XX embryos al"<' virihe<!
(even when Ihe ovaries have formed in a normal
manner). Female embryos injected with testosterone
also undergo maseulini7.ation of the Wolffian struc'
tures. (Ho\\'ever. the MO llerian duct. al"<' not af·
fected.) In normal fcmale embry", and fetuses, the
Wolman st ructures not involved in development of
the urinary s)"ltem degenerate,
DIFFERENTIATION OF THE MALE EXTERNAL
GENITALIA
The eloaca is a common receptade for the terminal
ends of the digestive, urinary. and genital tracts. A
permanent structure of this kind is found in egg_lay.
ing mammals and in hirds. reptiles. and fishes. The
beginnings of one appear brieAy in mammalian
embryos.
At threc weeks po:<tconC<'ption. the sur-
face of the cloaca is covered by a membrane. and it
is Aanked by r/I)(l(tli ftlld5 (Fig. 1).11). T he anterior
portion' of the fold, fu,c 10 form the
An anal plate soon separates the cloaca into a p0s-
terior anus and the anterior urogenital sinus (which
receives the Wolman ducts and is continuous with
thc externally urogenital folds), T he folds are
Aankcd by urogeni/rll swelling5.
Both XX and XY embr)'", advance to
What happ<ns afterward depends upon secretions
from the gonads.
Masculinization of the External Genitalia
The urogenital sinus and its associatcd struelu res
contain an enzyme that converts test"'tcrone to di-
hydrotest"'terone (DHT ). Genetic defec ts that im·
pair the formation of the enzyme or the ability to
respond to DHT can block virilization of the
nal genitalia , even when tho test"" and reproductive
ducts have developed in the usual mannor.
Under the influence of DHT. the genilal tuberclc
matures into Ihe anterior part of the {lfnis, thc uro-
gcnital sinus gives risc to lhe prOJ/tlle and bulbour-
ethral glands and parts of Ihe r.relhr(J, the urogenital
folds make a contribution to the urethra and penis.
and Ihe genital swellings fuse to form the .<rrO/llm
(Fig. 13-1 1B). (There are controversies conc<:rning
whether the caudal ends of Ihe Wolman dUet,< are
involved in formation of the prostate,)
Similar changes can occur in XX embryos when
malfunctioning adrenal glands secrete large quan·
tit ies of androgenic steroids. and in experimental an-
imals given test"'terone or DHT at an early stage.
of the external genitalia has also
been observed in human fetuses whose mothers fe'
ceived synthetic progestogens that can be metaboli·
cally con.'erled to androgens.
Although the phallus is still very small and the
and urethra "re incomplete. the few.1 be-
COmeS externally rceogninblc as mate as early as the
12th wee k po:<tconception. After that. androgenic
steroids are needed to promote continuc<:l growth of
the external genitalia and descent of Ihe testes into
the scrotum. The descent begins during the 7th week
and it is usually completed close to the time of birth
(193).
Althouih there are indications tha t androstancdio/s
released from the fetal testis play role, in stimulation
of prostate gland cell prol iferation (95), DHT is t hc
major hormone required For virilization of the exter·
nal genitalia (12. 119).
Individuals with genetic defects that impair the
conversion of teStOSterone to DHT but permit testos-
terone synthesis to proceed at a normal rate undergo
Wolman duet development bUI fail to accomplish
maseulini,.ation of the urogenital sinus and related
5lruelUres. Infants with severely impaired DHT for_
mation are the n born with fomale-typ< external or·
gans. while XY fetuscs with limited ability to ma ke
the regulator form incompletely masculinized or
"ambiguous" slructures,
It has been proposed thaI DHT .stimulated mes-
enchymal cells provide the epithelium with morpho-
genelic signals. When mesenchyme and urinary
bladder epitheli um from normal miC<' are cocu lt ured
in the presence of androgens, prostalHypc differ-
entiation occurs. Moreover, the quantity of differ·
entiated epi thel iu m varies directly with the amOunt
of mesenchyme. I n the absence of androgen, vaginal·
type epithelium forms. Epithelium ta ken from Tfm
mutants that lack androgen receptors also differen_
tiates into prostate-li ke tissue, if normal mese n-
chyme and hormone are provided. However. mes-
enchyme from Tfm mutants ca nnot support the
."
male-type differentimion of bladder epithelium
taken from normal mice (32).
DIFFERENTIATION OF THE OVARY
II will be re<:alled thaI the of XV embryos
begin 10 organize inlO testes by the end of the 6th
week afler conception. By contrast, lhe p,..,surnpt;ve
ovaries are said 10 ""lain their "indifferent" appear-
ance for al l.aSl 14 additional days, and to be mor-
phologically identifiable as female-type gonads only
by their failure to undergo obvious change. The
"donnancy'" may. however. be superficial. There is
an early tendency for the germinal components \0
accumulate in the periphrry of Ihe gonads (as con·
trasted with the medullary buildup of gonocytes in
the embryonic testis). and. as discussed later, steroid
hormone biosynthesis commences in XX and XV go.
nads a1 about the same lime.
During weeks 6-8, the gonads of XX embryos
tend to lag behind IhO&<: of their XY contemporaries
in size, weighl, and germinal cel l population, proJ:>.
ably because Ihey fail to oome under the stimulalory
influences of Ihe 11-Y antigen. 1I0we''Cr. growth and
cell proliferalion oontinue for a longer lime in the
pr<:sumptive ovaries. and the lauer soon surpass the
tesles in the parametel'l ciled .
Germinal Cell Maturation ( 6)
The gonocytes first differentiate inlo nonmolile 00-
gonia with large nuclei. Unli ke the spermatogonia
that come under early inhibilory innuenccs exerted
by the Serloli cells. Ihe oogonia actively engage in
mitosis, The rate of proliferalion is bet wcen
Ihe 81h and 20th weeks (66). and the cortical regions
soon beCllme "stuffed" with germinal cell s.
Around the 15th week. some of Ihe oogonia ad-
vance 10 primary oocyrts (primary ovocylcs). The
process begins slowly and seems to peak around
week 28 (66). Many oocytes Ihen initi3te the pro-
phase of meiosis [ and complele the diplotene stage.
Faclors re [eased by the epithelial cel[s (discussed
laler) evident[y inhibit further progression of cell di-
vision. The oocytes COler a resting Or "d iely"tc"
slase that seems to be compatible with long-term
survival (39). Some resume the meiosis shortly after
the onset of puberty. others go into diakinesis follow-
ing a lag period of up 10 50 years. while the majority
die off without eomp[eting the division.
Germina[ cell proliferation [cads 10 Inc aCCum u·
[alion of some 6-7 million cells by the lime Ihe felus
is 25-28 we<:1:s old , The population Ihen begins a
lifelong decline that is vcry mpid at first and slo,,"er
during the later ycars. At birth, the two ovaries COn·
SEX DETERMI NATION ANO DIFFERENTIATION
tain around 1- 2 million primary oocytes. of which
only 300,000-400,000 make it to Inc time of pu-
berty. Ultimately. $Omcthing like 400 fi nally attain
a of maluration tnal permits fcrlili7.ation.
There are individual as """II a•• pecie. di!fere""" •.
Som" WOmen are 101.l1y deplcled of """yle. by lhe end
of Iheir 40th year. whereas OIhe ... till have some cells
when 'hey arc ,wo decade, <>Ider, The lime_honored con_
cept Ihal germinal cell proliferali"" lerminales during
Ihe felal period has rce<:nlly been queslioned for hum.n •.
tn .nim.t, wi,h .herl geSlaliQn period •. the de<:line in cell
populalion usually commence, postnatally. A few,peei ...
•. g. dom."i. ea, •. evidently r<lain a popul.'ion of "",0-
ni •• s adult •.
The iniliat ropid reduclion of germin.t coil populalion
during felal life i, attribuled in port 10 the .xlru.ion of
oogoni. 10 the ,u,fae<: of Ihe developing ov,rie" Late,. a
process of alreJia (which begin. in hum.n felu,"" arournl
lhc 51h monih and inc ludes opi,heli.1 cell,) .cenunlo for
most of the 100•.
Germinal cell maluralion in",,"'es ,peeiat conlrols OVOr
function, of ,he X chromClSOmes. In the .omalic cell' of
XX embryos. one of the ehrorr>050mes is ,aid '0 be "in_
a.tiva ted" pri", to the lime of implanlalion (62). and lhc
lrophoblasl i. belie,,,d 10 play 0 role in dir«IHln of Ihe
phenomenon. (Evidently. howeyer. I . mall porlioo of the
genome continue. 10 be Inl ,) Gonoe)"le' ,",em
10 be to 'he ,arne influences. but lhe ,",cond X
i. reaclivated won afler the cells hove tak"n up re,idence
in lb. gonadat ,idges. tn human. and in man)" olher
mammals. both of Ihe X chrorr>050me. ar<: rcquir<:d f",
Ihe prodUClion of f.rtiliUlble Ovo. Female, ooe of
Ihem (lhose with Ihe XO genetic ddccI' described 1.I.r)
.r. sterile although Ibey $Orne ovarian ditfcr<ntia_
lion. Mice and $Om"olher mammal. wilh the XO pallero
have. limiled obit it), to produce mature Ova, It is possble
thai Ihe chrorr>050me that is relained in mice conl.i", ,.-
netic inf"'mation Ih.1 i. unavailable in XO wOmen. but
the .hort in,o rv:o.l between ovarian di!fcrentiation and Ihe
fo ..1 appearance of gamete. may .«:ounl for lit< .biti'y
of the mie<: 10 become tran,iently fertile.
Epithelial Cel[ Maturat[on and Follicle
Formation
Around Ihe 8th "'Cek, there is some indicatiQn Ihal
Ihe epithelial celis will form medullary cords of Ihe
kind described for the embryonic testis. Howe'·er.
Ihe cell ciuslers are soon broken up by me<cnch}'mc
Ihal invades the medulla, commences formation of
Ihe ovarian Siroma. and advances 10 Ihe (Fig.
[3-13).
Medullary cord formation i. more obvi"", in the
nads of ",me of 'he subprimale •. However. Ihc pr"'ump-
live ovary never a"um •• the appea,anee of Ihe embry-
onic le.ti.,
 , ,

o ill
13·1 3. A. T,an._.. sec,"" U"""'Ilh "'" ovary.t Note ''''' lhel'M<lul l.'Y 0<1<<1 •• ThO
. he ,ov""th ... HI< ot development. ohowing the I xer. lory meoonoophrle IUb<oIe. efI ...<>ntes) <Ie not
d<!geMf.tiQn <)1 thO primitive (mfldull'ry) sex C<>f<l' and the commoJniCat. witll tn. ,et._
Tne cortat ,one oj the o..ry-
10<""";",, o. ,... 0001",., <:<>«Is. B. df. .... iog Of the <:on'''''o groop" 01 <>ogoni .. ...-,ounded by t",,",ula' cell._
of\d gee;' " """.. ... the mo'''" 01 eM ,"I I _ 1 . (La_n. ,et .......,. 86)

The oogonia congregate in the regions.
and by the 12th ",<,ok it is possible to the
beginnings of cortical cord' wmposed of irregular
rows of epithelial and germinal cells that "re sepa-
,.,ed from each other by strand. of mesenchyme
{f ig. 13_14).
Certain of the epithelial cells mature into nat-
lened pregr(1nulWI1 (folliwlnr) cells that make inti-
mate associalion, with the oocyte •. Gradually, (hey
enter into the formation of primordial jollidt." each
made up of an O<X}'tc surrounded by a single layer
of Aaltcncli pr.granulosa cells (fig. 13·15 and 13·
10). Oocytes that escape inoorporation are less likely
10 survive.
Limitcd numbers of primordial follicles undergo
maturation into primary jollities. involves en-
largemen t (but not division) of the oocyte. as well as
growth and prolifenuion of the follicular cells. The
more advanced follicles have a highcr mtc of alTNia.
which in death of the oocyte.10l'S of epi-
thelial cells. and replacement of the follicle with SCar
ti!Sue.
The follicular cells seem to release an oocyte mat-
uration inhibitor (OM I) lhal maintains the germinal

Fig . 13- 14 . Corlical cord. bol",.

Ilurnan lelUs, 3 """" liS.
The oogonia a""""r clear. X '00.
(T.cfIma",,-Oupl . ..i• • , al .. ,el..-....,.
'U)

cells in the dictyate stage. A peptide with a moloo-
ular weight of less than 2000 has bet:n recooered
from the fluids of small (bul not of more
follicles of the pig (30.173). and it is known that 00-
eytes artificially remove<! from the influences of the
epithelial cclls and ma;ntainoo in culture soon re·
sume reduction division.
Controlled atresia seems to a physiological pro-
cess that is e=ntial for maintaining normal ovarian
function. poosibly because the ovary cannot support
more than an optimum number of germinal cclls.
Factors that interfere with normal atresia seem to
bring about ultimatc impairment of fertility. Ullie
is knQwn about the mechanisms for "selection." It
hu been suggestOO that large numbers of germinal
cdls with chromusumal defects a'" formed, and Ihat
the'" are the ones preferentially excluded.
Regulation 01 Ovarian Dlffarentlatlon
Conflicting interp,.,tatiom have attached 10 OD-
.ervlltions that the presumptive ovaries possess sur·
face components that bind the H-Y antigen . One
coneept is Ihal Ihe formalion of reeeplo", is fortui_
IOUS (and no purpose is served). Similar thinking is
SEX DETERMINATION ... ND DIFFERENTIATION
Fill. ' 3· IS. f'rimordiallolliele •.
IIumon o.ary, letu". 9 """,thi. X775.
(Tuehmann-o...pa.SS<1 et at .. 1111..""""
applied to the finding of estrogen receplors in Ihe
mammary glands of males and of Olher apparently
nonfunctional molecules in dilTcrent ceillypes.
A second suggestion is thaI XX embryos make a
faclor dilTerenl from Ihe H-Y antigen thaI interaets
with Ihe surface molecules. No such faClor has
identified, bUI Ihe,., is evidence for the formalinn of
a diffusible SUb'l18nce that inhibilS the bindi ng of H-
Y 10 Ihe ovary (62). A third idea is thaI differentia-
lion is direcled by ullOtXupied H·Y ,.,e.ptors (183).
Observations that gonads of XY embryos tend to de-
velop ovarian-type archileclure in the presence of
antibodies di,.,cled against th. H-Y have Ilccn cited
in support of the first and third ootions. They dn 001
necessarily rule OUt the second. sinee tissues of males
may synthesi7.c ovarian organi?.crs that do oot fune-
tion in the presene. of Ihe H-Y antigen ,
The situation could more complicaled. The
thymus gland is known to play key roles in dilTer-
enlialion of Ihe immune s)lStem. and il is dearly in-
volvoo in the rejection by females of highly inbred
strains of sxin grafts from malcs of the same strain
(119). As discussed later. Ihymus gland deprivation
at an early age impairs maturation of the ovary .
Thymeclomy does oot seem to interfere with testie--
ular maturation. but ;t alTcct dcYclopmcm of
<ome androgen.<!cpendent accessory reproductive
structulX'S in oomplex (63.97.109).
Mesenchymsl Cells
Although epithelial and germinal cell different iation
begin later in the ovary than in the the mes-
enchymal acquire the ability to secrete steroid
hormones at the same age in both sexes (a round the
8th week). In the developing ovaries. the amounts of
testOSlerone produced are minute when compared
with those formed by the testes, The present<: within
the ovary of sharply limited amounts of
sleroid dehydrogenase 3e<:ounts in pmt for the dif·
ference. but thc cells also contain aromatase en-
zymes that rJpidly convcrt the androgens that a,."
formed to estrogens,
Thc role of cstrogens in ovarian dilTcremiation is
diflicult to determine. since thc steroids arc '''ential
for sustaining the lives of both XX and XV fetuses.
In males. the estrogens are formed mostly by lhe
placental system. They never reach high OOncentra·
tions within the gonads. This implies that high le.'cls
within the developing ovary perform SOme function.
The XV ge rminal cells of most mammals do not
form gametes in the oyarian environment ,
Development of the MUllerisn Ducts
In lhe absence of the MUllerian dUCI inhibitory fac·
lor (secreted by lhe embryonic testis). the M ullcrian
ducts persist and give ri", to the fallopian I14beS.
uterl/S. and upptr vagina. The cranial end. of the
acquilX' fonger-like projections (fimbriae) lhat
will later enYelop the ,urlace of th. ovary and dir.ct
oocytes to the ostium (the entry into the tubular
lumen). ThclX' is. howe,·er. no di,."ct oonncction be-
twecn the ovary and the tube. and lhe ostium ac·
tually communicates with the abdominal cavity. The
caudal ends of the MUllerian ducts fuse in lhe mid·
line 10 form a uttrQ"uginal canal. Init ia lly. there is a
uterovaginal septum_ but thi' disappears by lhe 9th
weck. Thc canal enlarges anteriorly to form the body
of the uterus (which is continuous with the fallopian
tubes). as the more caudal portions interact with the
urogenital sinus in the formation of the vagina and
related structures.
It is widely believed that MUllerian duct dilfer-
entiation proceed. without the benefit of hormonal
stimulation (120). Th. changes occur in XY fetuses
dcpriVt:d vcry carly of MOl and also in gonadecta.
mized XX animals. of ductal tis-
sUe undergo simi la r deYelopmcnt in vitro.
However. all mammalian embryos develop in an
environment that rich in hormones supplied by the
placeta and the maternal system. and most in vitro
culture utili}'c serum that conlains an as-
sortment of IX'gulators.
The term CQl'ticiM a hypothetical fac-
tor formcd in diffclX'ntialing ovaries that pcrforms
analogous to those deseribed for medullar.
inc in males (77). Insulin. EGf. and ATP promote
tyrO'Sinc phosphorylation of membrane proteins and
stimulale growth (A·2).
The fallopian tubes and utCrus arC formed before
the end of the third month (prior to th. appearance
of ovarian follicles). Vaginal development begins
SOOn after the initiation of steroid hormone synthesis
in lhe gonad. but it is IIOt completed until the middle
of lhe second trimester (193).
Fate 01 the Wolfflan Siructure s in Females
The oomponents of the Wolflian Struclures that give
rise to essential parts of lhe urinary systems 01 both
sexes have been described.
The androgen-sensitive portions of lhe Wolman
structures deteriorate and almost totally di sappear
in normal XX fetuses. The process commence, at an
age when lhe ducts of XV fetuses hayc almost com-
pleted their early differentiation (around 7S-80 day,
posteaneeption). At this stage. the oyary has only
begun morphologically yisiblc differentiation but it is
producing estrogens.
It is not known whether estrogens facilitate Wol f-
nan due! IX'grcssion. Explants from both XX and
XV embryos undergo virilization when androgcn.
arc presenled and atropby when they are withheld ,
Differentiation of the Female Externsl
Genitalia
Although the ovary dilTerentiates later than the tes-
tis. the extcrnal genitalia of XX embryO!; .how dis-
tinct tendencies to develop alo ng female lines al
about the same time thc analogous structures of
males begin to rcspond to DHT. The maturation
process continues Over a period o f months. but the
fetus is reoognizable as a female toward the end of
the first trimester.
The uterovaginal canal that arises from the Mol-
ducts makes contact with the urogenital sinus.
A vaginal plate forms and then develops a lumen.
There are unsettled questions concerning the relative
cont ributions of the M nllerian duets and uroge nital
sinus to the vagina. A membrane (the hymen) ini·
tially ",als the external open ing. but an orifice de-
velops within it before th. time of birth.
In mal.s, the urogenital membrane disappears.
but the opening is SOOn ooVt:red by the growing and
converging urethral folds. In lemales. an ciongated
urogenital slit (open to the extcrior) is soon Aan ked
by the labia minora that form from the urogeni tal

'"
folds. The: genital swellings fuse po$leriorly. as the
anlerior pam enlarge into the labia mojO'a. The
urogenital sinus contributes \0 the and pam
or the urinary bladder.
l1le tubercle uoderg<Je$ very limi":d
growth. WIns Qludally. and beC()lIOC$ the:
(Fit- ] )·1 1). For a brief lime. the phallus is equal in
size 10 lilal or an XY fet u$, but t he <>rpn soon
rommcncc:s a prolonged pI'OC" IS of enlargemcm.
The tissues Irt: believed to pon=u In Minnat,," po-
lentialto develop along female exttpl "'hen di-
[0 doOlhc:rwisc by regulators by the
testis. XY fetuses deprive of either InlO$ICI'Of>C or
the ability to rnpond [0 the steroid acquirc female-
type external genilalia (even when the testCS have ai-
tained their "hal1lelenslw; morphology and the M Ul-
lerian !Ia_"
regruKd). Normal females poos-
SCM both sensitivity to testosterone and lhe
u'<Jgcni\al sinus enzyme that promotes conversion of
testosterone \0 OliT.
SEX DETERMINATION IN NONMAMMALIAN
VERTEBRATeS
By providing the means for distinguishing
what is from what must necessarily be. «Imparative
studies «Intribu te substantially to our understandina
of the specia l fUnctions of regulators. Tbc com parl-
§Ons arc especially illum inating in the field of repro-
ductive endocrinology.
WZ Chromosomes end the H-Y Antigen
In birds. many of the repliles. and iOtTK: 0( the am-
phibians and fishes. the female IIln W and Z 5cx
ehromcl5ClmC$, a nd 5he produo:s en cdl5containina
either. W (W a z.. n.c male has two Z chromosomes
and therefore makes only Z-IYpe
n.c /mwlr bird the: H· Y antigen. and
in animals the antigen promoles dfferentia tioo
of the indilfcn:nt gonad into a n O>'/lry. n.c antigen
SCCms 10 be idcnHcal with t he Dne made by male
mammal!. If. developing avian ovary is cocu lturcd
with an indifferent gonad taken from a mammal. the
ovary rcla iflS its form as the mammalian gonad or·
gani •.C$ inlD a test;'!ike Jlructu n: . TIle effeets a n: at·
tributed tD pam,e or the antiacn from the avian
DVlIry to the mammalian indiffe rent aonad. If the
embryonic mammalian lesl;s (with H·Y anligen) ;"
cocuhured with an avian indifferent aonad. the test;"
retains its male character;"tics while the avian gOl1ad
organi1.c5 inlD an ovary·li ke
In moll of Ih. birds. only Ihe left do",loj"l$, The
l<Ha.d on Ihe righl .ide pcrsllll in v., li/li.1 form. If Ih.
$EX DETERMINATION AND DIFFERENTIATION
len gonad is removed "'ry early in the C<lOINC of
opment. 'he righ' one be<:ome< a les,i. or ovoteslis..nd
li>c bird acquires I male pber.otype (49). If ti>c .ursery
;,; delaye<l for a ro-... day<. tbe rilh, conad beCCO".1 an
OVOIesti. or ovary·like orpn (179). The obKrvl1ioM lug·
&CSI lhal tbe rith' conad <:(HItai", a very timiled number
or H·Y reooeptors. and ,hat;1 is Iffected by li>c ant;,. ..
only .. ·bcn lhe til.1S build 10.
is """';ble thaI tbe len ovary Iw already sccreled ."M.
eieRI ""mg'''' 10 V'CSlieial ao ... d. In ZZ
birds. two functioooinllesles or «lui oj", ... ually clcvclop.
The germi ...1 «lis Df lbe VCSt;,;a1 (nlhl) ovary .Io>oly
deler;"""I • . If the orpns removed from )'0'1'"
Ire ""mplanted ;,,.0 10 day old eatlra,.d maiO$. the 10"-
oq"tes malure inlO """rmal"l""la. When Ihe fCcipioo ....
..... Ie .. ith _mal ' .....1... birds .. i,b WZ and Zl SC>.
chromosomes from the Z)"JOI ....
.. ,hootkl form i" 1 , I : 1 ra'iotr..
WZ. Zz. aDd WW
lI(1\O'Cvcr. al lea.! one Z i ...... ntial for 'UN;""I.)
Oeve1opment 01 the Avian Reproductive
Oucts (133)
WOlFFIAN OERIV ATlVES
Tbc mesonephros of the bird funClions as a urinary
organ aim()St to the time Df hatching (al-
though Ihe metanephros begins dilTerenliatiOl1 by
Ihe l1 1h day afler fertilization and gradually devel·
op' in'D the permanenl kidney). It i. IherdDr< no!
su rprising thaI the embryonic Wolffian structures of
birds arc hormone-independent in both sens. and
thaI adult females us ually retain Wolnian remnants.
later. <Xlmponen\5. of the WDIIf,an structures be·
come respoosive 10 testosterone. In ZZ birds (with
testes) these portions develop intD mile acrcssory re-
prodUctive structures the metanephros begins tD
take over the urinary fu netions. In fema les. the an-
drogcn-scnsitive portions undergo atrophy that is not
always compkte.
WoIfftan duC!. regression in femaks seems to re-
sult from the absence: Df testosterone. The persis-
tenee of the ducu in females deprived of the left
ovary could be CJlplained in pan by the prc:$Cnce: of
an DVQ\CSt;" lhal rci",,_ the androgen.
ovarian nlrogrru evidently contribute 101 the reves-
sion in normal females. since bilaterally gOll3dcc:to-
mi7.cd WZ birds reta in W oIffian ducts that do not
complele masculine·type development. (It is 1150
possible lhat the Dvaries secrete 1 Wolman reves-
sion prOlein or peptide. but 110 M:h regulator has
been found.)
AVI AN MOLLERIAN DUCTS
Chick gonads diffcn:nliatc during days 7-9 of Ihe
Ihrce·week incubation period. In males. the MOller-
ian duets begin to regress around tnc 9th day. and
they complete the process by day ] 3 or 14. Since ex-
ogenous androgens aceelerate tne atrophy. and gon·
adcetomy leads 10 MOlierian duct persistence. it
scerns reasonable \0 conclude that the testis prOOuces
a steroid duct inhibitor.
However. Ihcre is also evidence for extra·gonadal
produclion of a resression factor that is under inhib-
itory control by the pituitary s land (133).
In females, the righl MOllerian duct stops srowing
al an early stase (around day II in chick embryos).
but il does nol lotally deteriorale. Since IW{) ducls
persisl in ovariectomized birds. Ihe gonad probably
seCreles a regr=ion factor.
The extensive development of the left dUCI, which
includes formation of a shell gland. i$ probably es·
trogen-<lependen\. Intere.<tingly, removal
of just the left ovary perm its development of the left
duel.
Studies on Viviparou s Repliles
Although Ihe described speeializations suppon pr()-
duction of nutrient-laden. shell·protected eggs and
mechanisms for de.lins with cenain metabolic prob-
lems during Ihe incubation period. sex determination
in avian vertebmtes can be viewed as a "step back-
ward" in evolution. since (3) the Wolnian strueures
are retained for a relatively long time and they show
only limiled hormone dependene<:. and (b) steroId
hormones. rather than specific peptide-type faclors.
secm to be primary resulators.
The limited information available Ihal
viviparous are lower ye( on Ihe evolu(ionary
scale. The mesonephros conlinues 10 func(ion until
aner binh. MUllerian ducIs persist and undergo hor-
mone-independent differentialion in Ixuh and
(he Wolffian Slructures of both males and females
develop without benefil of hormones durins Ihe pre-
natal period. Later. SOme teSlosterone is needed to
promole formalion of Ihe epididymis and vas defcr·
ens, and a testicular regulator (which SCems to be an
androgenic steroid) promoles partial regression of
Ihe MUtteria n ducts in males.
Conc lUSions from the Preceding Findings
The observations indicate that (a) the H·Y antigen
is formed by the members of tne species that have
two differenl kinds of chromosomes (male mam·
mals. bul female birds and some female r<:ptilcs); (b)
the H· Y antigen dir<:cts differentiation of (he type of
gonad that produces two kinds of gameles (Ihe lesti,
of the mammal. but the ovary of the bird): (c) reo
gardless of the role played by the H-Y antigen. Ihe
lestis prOOuces IClltOSlcrone while the ovary secreles
estrogens; (d) Wolflian duel relention. hormone de·
pendence. and development are closely lin ked wi th
the roles of Ihe Wolffian slructures in maintaining
urinary system functions; however. formalion of the
male accessory reproductive structures is androgen·
dependenl; (e) although MOllerian duel regression is
regulaled by gonadal hormones, only mammals have
been shown 10 produce a specific regulator that is 1101
known 10 affect other reproductive functions; and (0
unlike the Situalion for eutherian mammals.
gens by WZ nonmammalian vertebrale
ovaries play obvious roles in early development of
the female phenotype.
SEX REVERSAL
Eutherian mammalian embryos and of both
sexes develop in an estrogen-rich environmenl. It is
therefore forlunate thaI gonadal differentiation is
controlled by the presence (or absence) of Ihe H-Y
antisen. and that it is independent of the concentra-
tions of estrogens .
Mosl of Ihe other ,'erlcbmtes do nO! require such
freedom from hormonal control Although sex chro-
mosomes and H_Y antigens are involved in devel·
opment of the phenotype. the processes are innu·
enced by environmental factors. The phenomena
described nexl are most easily demonstrated in bony
fishes. but all classes of vertebrates respond in vary-
ing degrees 10 external stimuli.
Under ordinary circumstances. X X IishC!i devetop
into females that prOOuc.: X-type egg cells. while
XY fishes become males that ma ke both X· and Y-
type spermatoma. However, in many leleost species.
of very young embryos to cold environmen-
tal temperatures, In very shorl photoperiods. or 10
androgenic steroids. leads 10 Ihe emersence of Ihe
male phenotype regardless of chromosomal makeup.
whereas warm lemperatures. food deprivation . and
C!llrogcnie steroids favor different iation along female
pallcrns(1)9).
When XX animals become "males:' they develop
leSles. prOOuce spermat07.03 of the X type. and may
acquire sc x characteristic.< and behavioral
pallerns usually expressed by XY malc.<_Similarly.
XY "females" form ovaries that produce egg cells
containing either an X or a Y chromosome.
The environmental factors affect only thc phen()-
Iype (not Ihe chromosomes) _Thus all of Ihe progeny
of an XX "male" and a normal female have XX sex
chromosomes_ Under most condilions. all develop
into females . When an XY "female" males wilh a
normal male. Ihe ralios for XV. XX. and YY off·
sprins approach 2: I; I. Un like mammals. fishes wi th
YY patterns survi.·c. Their unions with IIOrmal fe-
males yield all XY progeny.
Since Ihe aceessory rcprOOuclive organs of most
fishC$ are simple. adults can undergo sex reversal.

'"
Damsdfi ,h regularly function first as males and
later as females, whereas clownfosh arc among Ihc
SpeCIes thaI begin ""proouclive ac(ivil)' as males
( 139),
"SOCIAL" CONTROL OF SEX INVERSION
When large numbers of female coral rcef fish live in
the presence of males Ihc adult population is slable.
Howe,-er. if all Ihc males arc removed. some of Ih.
females become "transformed," In some cases, on.
new "male" emerges for each one Iha\ is removed
(15 4). II has been suggested 1hal females have a
"na lural tendcIlCY" 10 change sex, but that lhc pm.
cess is ;n"ibiled by the presence of males. Another
idea is thaI removal of the males provides a special
"stimulus" fn, sex reversal. Responses of the kind
described arc elicited in only c"nain of Ihc fishes.
Sex reversals can be acoomplishcd wilh hormones
and other agems in amphibia ns. reptiles. and birds
manipulated during time·limited "sen,itive" 'tages
of devclopmenl.
I n mammals. steroid hormon"" aIT<:<:t soma/k but
not germinal cells , Estrogens cannot promote the
formation of ovaries in XY embryos of any age. Tes-
tooterone interfere, with ovarian development. but it
cannot bring about testicie formation in XX em·
bryos , Mamma lia n germ cells have very ,peclal re-
quirements (183). XY ty""s will not emer into sper-
matogenesis if they are surrounded by XX somatic
ails. and XX germinal :lements fail to yield OVa in
XY somatic environments,
HORMONAL REGULATION OF
REPRODUCTIVE SYSTEM DEVELOPMENT IN
MALE MAMMALS
Sertoll Cell Funcllone: An Overview
After differentiating from the epithelial components
of the "indifferent gonad'" the Sertoli cells undergo
a seri"" of 3ge-dependcnt changcs in structure and
fun.tions. During the embryonic and early fetal
stag"". thc cells prOtect the germinal components
against premature maturation. and they promote in-
volution of the MUllerian ducts, T he protective fune-
tions continue through the late felnl and the post_
natal juvenile ""riods. After the onset of puberty,
Sertoli cells mature and aSSume major roles in the
support of spermatogenesis. They a lso produce reg·
ulators that contribute to ,,,,,rm maturation in the
epididymis and to the control of gonadotropin
secretion.
SEX DETERMINATION ANO OIFFERENTtATION
Eerly Influences of Serloil Cells on Germinal
Components of the Emerging Testis
II is not known whether epithelial ceils of the ger·
minal ridge (or the Serloli cells that SOOn dilTeren·
tialc from them) play roles in the armurion of gon-
to the emerging embryonic testis. in
facilita tion of germinal cell accumu/ariOl! within the
regions. or in the mall/ralion of thos.c
componen ts to spermatogonia , It is clear that very
young Sertol; cells encircle the spermatogonia . and
that they inhibit both spermatogonial rrolifcration
and the advancement of the cells to the primary
spermatocyte slage They may additionally contrib-
Ule to long·term survival of spermatogonia.
Fotlicutar ceUs of Ihc ovary arc derivcl from the &ame
components of the indHk .. nt gooad thatli"e rise to thc
Sertot; cell •. An oocylc ma'uration inhibilor has been
identified in small ovorian follicles (173). It blocks dcvcl·
oprfltnl of primary """),Ies. but favors oocylc ,u"iv.t.
Since no analog,,", Senoli coil peptide has been identi-
fied, it i. poo.sible that eontrol in the emerging ,""is i.
exerted in dilTercnt "'ay,. for via e' trogens th.t
are discussed later.
Mllllerien Duct Inhibllor
The sec retion of MUllerian duct inhibitor (MO [;
MUllerian inhibitory substance. M[S; anti-Maller-
ian hormone. AM H) begins even before morpholog-
ical differentiation of the Sertoli cells is completed .
FUNCTIONS
The ducts involute undcr the influence of MOl duro
ing a sharply limited time period that extends from
the 7th to 10th week after conception in the human.
Duct.< ""rrnil(ed to develop for a time without the
"'8ulator soon become refractory to its influences.
The pos$ibililY that MOl .ct< on the mesonephros even
e.,t;e! i, rai,ed by observations that mouse undifferen·
tiated gonad. oocuhured with mesonephros fail to
undergo the u,ual masculinization (26). MOl ma)' there-
fore inhibit the release 0< oppo:st the . etion, of. me<o-
nephric celt product. However. it h.. oot been demon·
strated that 'nch • ,ubstance is made. MOI'W"er. the
po;«ibility th., mesoocphric cell. in cuhure aUTOct H-Y
"nligen "nd thereby deprive the Sertoli cells of il5 inHu·
cnces has not been ruled out.
MDl i. secreted for a considerable time peri<>d after
Mullerian duct re8ression has been a<:eompli,hed (44). h
has been dete<:ted in ehild",n up to ''''0 years of ag" and
in ral5 of 2t day. (I"" u. u.t time of we.ning), Ex"aet.
oontaining the motecules inhibit the growth of o"arian tu·
mors. and roles in differentiation of . trUCIUTe, "'her than
tho MUlleri"n hov. b«n p""","d. An i"Ouenee on
Se rloli «11 mOlu ... l;"n hos .Iso been ccnsider.d (172).
I'crh.p$. bow.""r. Senoli «11 •• imply conlinuo 10 mo ke
MOl unl;l Ihey ad.anto 10 lheir I\C'U Ilase of
de •• lopm.nl.
CHEMISTRY AN D ACTIONS
T he: bas JlyCOptOleln·llke proper-
lia (16). may consist of a mixlure of ehemically re-
lated suMtaD«!. cstirmued moI.:.:ular " 'eights
arc in the ranges 01120.001>-195.000 and 200.001>-
395.000. rap:<;tivcly. whell density
and gellil\ration tcchniques arc use4 (IJ 1).
Oo:.:aUK or the la'l. $il')(: and watCf soIubilily.
a "KOJIld m<:5oKnger"" c:oncept has been illvoked .
M [)I rna)' actlvale Mill' -der.ndelll fIOOsphalasc.
eAMP (43). MIX. ATP. Zn ' . and \l;lrudale 0p-
pose. whereas EOTA and F par1lally mimic lhe d-
reCII (A.2).
REGULATION OF MOl FORMATION
Til<: c.rly appe .... "". of lhe mokeul.,.lh. riel thaI 'hey
arc foond in the lUlU of m.mmall and t"" oyarieo of
bird •.• nd observalion. Ih.1 lhey ..crt inhibitory in"u,
."" •• <>II ovari.n """,pOnents of ma mmals. afC all COMi ...
lenl ... ilh ,It<: pouibilil)" that MOl producliQn is dopen.
dent upon lit<: II·Y anti,en. It il .nlikol)· Ih.1 '0."1'''0''
from di". "1 , ile •• r<: InVQlved in inili.lion of
MOl .yn,hesl •. ,Ince the e!fecl> of 1M IIOrmone arc * by the
ali,ed before dirrcr<: "lialiQn of the piluitary aland. tho
steroidogenic tissuos. and ""mponcnlJ or lhe vascul.r .yl-
le m is compleled.
SteroId Hormone Mete boll, m In th e Sertotl
Cell
Adult SertQ/i cells uli!ilC androgen-dependcnt ....... h.
a nisms u) support Tbcy re«:ivc
lheir hormone supply from Mighborlng
cells lbal synlhcsilC trslMerone from choleslcrol
aoo other precufSOfS (Fig. IJ.l6).
Felal So:r101i cells perform vcry fullCllon5
Ih.al include protection 01 the spcrmalOSOflia against
premalure enlry into meiosis. They mUll limir lheir
eJlpolure 10 lestosterone. Tbc «lis poocss
IMt rapidly convert androgens released in their .i-
einily 10 ocher meUlbolitcs.
SERTOU CELL SYNTHESIS Of" ESTROGENS
Arornal1l$e$ "Ialyle the OI)IIversion of androgens to
cstrogens (Fig. 13-17). Tbc reactions $ern: $everal
(I) they prevenl accum ulation of testoste r·
one within Ihe Sc: rloli cell$.• nd thereby block the
maturalion-Ind ucing effeclS of Iha l steroid: (b) es.
lragens directly retard Sc:rloli cd l maturation: <lnd
esuosens directly suppress lestosterone:
lion by neighboring inte!""Stitial cells (93). and Ihey
diminish sensitivity to gonadotropins (13).
In adult ... al$(J inhibil Ih. occr<:lion of IUI.i ...
i';1IA hormone (,"" major stimulanl f.,.. 1..,.,.le' OtIC pro-
d.... ion). Bo...."'-.:r. ,h,,,. is "" e.ideroc<: f.,.. felal cell re-
leaK 01 ... fficicn, ..eroid to.el in Ibis _y.
SERTOU CELL Sa-REDUCTASE
Adult SenGlI cells contain a Sa-redu= Ihat eat·
al)"':cs formaiion of OHT from leslOSlerone. Since
DlIT is by many eritena far more poIent than its
pr-.:cursor. lhe presence of lite en1O)''''''' in fetal cells
mighl appear 10 be: counterproduclive. However.
D HT proba.bly acU vel}' dilTerenlly in lhe ret us:
1. Some Icslosteror.e-tcsponsive edb insensi-
live to OHT (115). and immalure Sertol; cell. may
fan inln Ihi. calegory.
2. Androstanediols ba"" biological propenies very
differenl from lhose of OHT. They exen some eslro-
gel>-l ike actions, and Ihe large quanlilie. made by
ralS during t he juvenil. period c.n dola)' puberly
onsel (al leasl in females) (84). DHT as Ihc
pr-.:curror (Fig. 13-1 8).
3. DHT and olher or reaclions catalY1.ed
Me rnpidTy
lerone, a molccule that lacks androgeniC poleney
" n<l ... ",_
(Fig. 13-19). Therefore. Ihe cnzymc may play an im-
porlant role in slercid ltormonc degradalioo.
ANDROGEN BIOSYNTHESIS AND FUNCTIONS
IN MATURE SERTOU CELLS
Adull Sc:noli "" lis 3"'1uire lhe abili ly 10 ma ke small
01 teslOSlerone from bolh progc:stet(N)C aoo
prcgncnnlone (72). The quantities formed arc min-
Ule when compared ",ilb the eornribulions of Ihe in-
lerstitial cells (39). bUI they probably par1ielpa le
.i8"if..:antly in localized buildup nf the high andro-
gen concenlralions tCqui, ed 10 su pport spormatoscn-
ali The cells also pos.m receptors thaI
bind OH T "'ilh hi'" affinity. The Sa-reduelasc
serYCS as a ll androgen amplifier (as il conlin ucs In
r.ciliulle formalion nf androslanediols). JII addilion.
Sc:n o11 ceHs synlhesize and secrete a spceialiw:l pro-
lein tbat enncentrates androgens ",ithin both the tes-
lis and tile epididymis.
The: inlenlitial cells conlinue to be the major pro-
vmen nf androgens. They beeome highly dependent
on hormone stimuillion. and Sc:noli cells
In some ... ay faci litate their aeeumulation 01 LH
r<:ccptors.
 ,",
,C=O
I

"0 , ,'"
,c=o
, ",
,C.: O
'",
I ,I-
, T
" '" P'OO"Sleron<>
"0
'"
17,, ·OH.P'egnonolone

,
,",
,"
tiel
L -0" o

" '"
Oehydtocp;."",o".,,,,,,, (DHA)
o
I(0) 0

I
" I

o"

"
I'"
o

"Jo
" I

T."oOle,,,,,,, /
" Testosterone

Fig . 13' 16 . .l.' ( fell ) a M.l.' ( right ) po.lh"'. YSlor IS) '7h ·hycko.yl.... Ie) C I T, CZO ....... ( D) lTfJ-
01 les' ''''' '''''''''. (A) .I' ,"mid hydroXY"Ofoi<l <l&l>ydr"""",,". ( Btok.., ."OWI sI>ow
... + ",', ;,.' , 3-U tO£leroid i_ .... .11 ...."'''e palhwoyS. )
 o
• ;co"
--

o'l
'"
I
- . I

4'

\ 7-DIONE TESTOSTERONE

j 1
o"

0 "0
"
9 , »
'9-0H· T COlO'''' r<,,,,,
o' l '" "
o j o
.l
"00 "
'"
0
'l
'"
17/I·QH.Andr""a. 'A-die ..... 3-one
o'l -J

\ "
0

\
\ o' l '"

'["
0
•
7 -
I
-
I[
'" ESTRONE ESTRAOIOL-17;J
Fig. 13-17. Co,,, .....,., of 8nd,o.ttnedione and
1••toolet¢ne 10 Propose<! int"'m«Ii8tes in
pothwa y. are shown in 1ig/1t ...
'" SEX DET ERMINATION AND DIFFERENTIATION

"Ao

o
TESTOSTERONE
'"
o"

,,
o ,,
"
5a·DIHYDAOTESTOSTERONE
(DHT )

o"

, I'"
,, 00"/
•
"
3/l,!;<,·ANDAOSTAN E0 tOl "
3<. ,S<. ·"N DROST "'HE DIOL
«i<.- Andro"a".,·3,17/I·cIioI) (5wAndrOSla"".J", ,7/I-<fuI)

Fig. 13· 18. Me1.boIie 00<1 . .... ..", o' ,,,.te.,..,,,,,, to Sa·
...oid._

Fo ilitro pin ( FSH ) Regulation 01 Sertoll Cell
Functions
Follitropin (follicle stimulating hormone. FSH) is an
adcoohypophysial hormone that derives ils name
from functions performed in the female. Its g1yco-
prolein com(XlSition and physicochemical and bio-
logical properties are described in Chapters 14 and
15,
FSH can first be dcte<:lcd within the pituitary
gland of the human fetus around day 70. and se<:re·
lion into the bloodstream becomes evident by day 90
(41), Since Sertol; cdls begin to rorm fOCCplors
toward the end of the third m(lnth. it is reasonable
to conclude that thcir earliest functions (M DI secre·
tion and some estrogen biosynthesis) do not require
stimulation by that regulator, FSH docs induce am-
matase enzymes. and it increases 5a·reductase and
dehydrogenase activities.
Within the testis. only the Sertoli cells respond to
FSH . The sensitivities and reactivities change with
age. and they are: modified by other regulators, Be·
havior of the cells in culture: s uggests that either
there: are subpopulations that differ from each other
in functions. or else cells undergo asynchronous
changes in responsivity (39).
FSH st imulates growth. proliferation. and malu·
ration during the prepubertal period. The cells don·
 .1

6"
.l.· ·ANDR05TENE-3, \ 7-01ONE
S... ANOROST AN£DIONE

"
ysterGid
1
"'-
3<, 'Hydro xyS'.foi<!
"'00
(3<,.Kel <>tteroicl
, .? ,educt •

TESTOSTERONE

s,,·R!)duClase l "o
.1
0

"
A
• •

o •
•
"
ANDROSTERONE

"
5,,·DIHVOROTESTOSTERONE (DHT)

"eroid "0

• · •

"
5"."" DROSTANE -3.,. 1711.0101.
Fig. 13-19. Oegr.<Io.'ion 01 Aooroven> to .""'''S'tiotlfl,

gale. and they establish light junctions that form a
"blood-testis barrier". [n Ihis way. a compartment
thaI docs not communicate with Ihe bulk interstitial
nuid is crealed. 1\ provides a highly specialized en-
.. ironment thaI supports gamete development (42),
and it pmt«:ls lhe haplQid gametes against attacks
by the immune system (152). (Spermatozoa ha,'c
unique surface CQmponents that may be needed for
fertilization {5SA]. The cells are antigenic when in-
jected ;n\o Ih. bloodstream.)
Because of the diflicuhies involved in studying
large mammals , much nf ()ur knowledge derives
from laborat()ry rodcnts, A 15.700 M, peptide
(SGF) believed to act "ia paracrine or autocrine
mechanisms to regulate mitosis. and \0 be FSH_in_
dependent, has becn obtained from the cells
of juvenile mice (A_I). Rats are widely used. since
they are born after a gestation period of only three
weeks, S<:veral aspects of their reproducti" system
maturation that go on during the forst postnatal days

'"are oomparable 10 processes in human fe-
tuses. Development during the ensuing weeks pro-
vides insights into roles of FSH during the prepu-
bertal period,
In these rodents. FSH stimulation of testicular
growth is most obvious during Ihe sc<:ond postnatal
week. DNA, RNA, and protein synthesis are mark-
edly augmented at first. Sert()ii coli, proliferate rap-
idly for a time. comple!e thi, phase SOme tim.
octween day 15 (103) and day 20 (137) of postnatal
life. Once maturity is auained. they no longer divide
under normal conditions.
Hemic,mralion performed during the first few
days after birth does not choge the time schedule.
However. the remaining tcsticle undergoes "wm-
pcnsalory hypertrophy" that is a$OCiated wilh in-
creases in <;ell nurnbors. FSH secrelion is also aug-
mented . If the surgery is delayed tothe 20th day. the
cell' can no longer engage in mitosis. and the co m-
pensatory growth docs not oc<:ur (103) despite the
elevated plasma FSH levels,
FSH aetivatcs Serloli cell adenylate eyelase, and
it promotes the formation of at least seven different
proteins (37). It stimulate< secretion of some of the
prod ucts and inc reasc< the phosphorylation of sev-
eral protcins (at least OIle of which is implicated in
the morphological specializations). Most carly re-
sponses to Fsn decline with age. and maximal 105-'
of sc:nsitivity coincides with the appearance of the
tight junctions a nd the in itiation of meiosis (104).
The changes Jre permanent in intact animals, but
hypophysectomy performed during the 4th postnatal
week partially restores the sc:nsitivity to exogenou,
FSH.
Thc numbers of FS!-I receptors increase progres-
sively from birth to day 15 (during the phase of
rapid Scrtoli cell proliferation ). Re<:cptor numbers
then decline to adult levels and remain stabili7.cd
thereafter. According to some authors, the a )location
per cell docs not change after day 20 (132), but oth-
ers describe the emergence of a new popu lation of
surface components and some secondary inerea"es in
receptor numbers up 10 day 60 (80) (when the ani·
mals assume adult reproductive functions). FSH is
known to play an important role in induction of its
own rece ptors in the ovary (127 ), and it may per_
form comparable functions in the maturing testis of
the juvenile.
The dec reased binding of FSH to &noH cell s of
older animals may depend on both synthesis of a
substance tha t inhibits hormone-receptor association
and increao;ed production of en7ymes that promote
FSII degradation (124). Desensitization involves
1= of phosphodiestcrases , A cAMP-<lependent pro-
tein kinase inhibitor also made (37). At the same
SEX DETERMtNATION "00 DtFFERENTIHION
time. mice synthesil.<l less SGF. a mitogenic peptide
implicaled in germinal cell proliferation (45).
FSH Stimulation of ESlrogen Biosynthesis
Exogenous FSH markedly increases estrogen pro-
duction in 5-1 ().day-<>Id rats. Thc cffecu fall off rap-
idly by day 18 (In), and they are no longer delect·
able by da)' 30 (39) (after spermatogenesis has
begun bu t the accessory reproductive structu res are
still infantile). Observations con,istent with the con-
cept that FSH ind uces aromalase include
the long latent period that elapses beforc
synthesis increases. and the inhibition of
stimula tion by actinomycin D or puromycin (39). In
addition to functions cited earlier, estrogens may fa.
cilitate FSH induction of FSH receptors.
Although such responscs to the pituitary hormone
stimula tion are lost in adults. some e,trogen biosyn·
thesis continucs, probably on a constitutive basis,
There are controversies concerning whether Se rtoli
cells release sufficient quantities into the blood-
Stream to contribute to negative feedback control of
gonadotropin secret ion .
Androge n alndlng Proteins
Undcr the inlluence of FSH (and of other regulators
cited la ter). Senoli cells synthesize a cytoplasmic
protcin that Can be distinguished from the androgen
receptor by ilS molecu lar weight of 85,000-90,000
(60), its c1e<:trophoretic mobility, and other proper·
ties. It is similar to but also distinguishable from the
testosterone..,strogen binding globul in (TeBG .
SSBG) found in the blood plasma of humans and
some other species (but not rats) (113). Rat andro-
gen binding prote in (ABP) seems to be a
helerod imer.
ABP accumulates within SOme of the Senoli cells.
The protein is secreted in substantial amounts into
testicular nuid. in whic h it travels to the epididymis
(129). Small amounts also enter the blood plasma.
Functions attributed to ASP includc concentration
of testosterone and DHT within mature Sertoli cells.
transport of androgens from the lestis to the epidid-
ym is. and facilitation of androgen and con·
centration by the capUI e pididymis (191 ). Since il
binds to epididymal 'permat02oa, it may also play
role.. in gamete mat uration ,
When presented in vitro to young Se rtoli cells.
FS H stimulates dosc-dcpcndenl buildup of AB P. In
intact rats. formation of the prolein begins around
day 15 after birth, Androgen binding probably com·
mences immediately aFterward. since Ihe sc:minifer·
ous tubules grow and develop lumina during days
16-11. The protein concentration falls to undctect-
able levels in thc testes of animals that are hypoph_
ysectomized, but it ean be restored with exogenous
FSH.
T cstosterone evidently contributes to main/mana
of established ABP biosynthesis, and it stabilizes the
androgen·binding sites of the molecules (l02) . Al-
though the steroid alone is elfective when it is given
to recently hypophysectomized rats. it cannot il1;ll-
ale ASP production or promote its .<f"crelion into the
lesticular Auids of FSH-deprived animals. Both
DHT and 5a-androstanediol mimic testOSterone ae-
tions (137). (FSH also to be needed to pro-
mote the secretion of SOme olher proleins whose syn-
thesis can be accomplished with cAMP and its
analogs as well as with FSH (36].)
Th)',oid stimutating IIorrnon< can promote the biosyn-
the, i, of flOP. but it. mode of .etion diffe ... from th.t of
FSIi (12) . However. purified preparation. of LH .nd of
OIhtr pituitary re8ul.10", Stem to be in<ffcclive. Peritu·
bul.. (myoid) componen\$of the testi, cnho""c ABP ac-
cumulati.", via mcchanisms differenl from lho« «crted
by thc other hormonel (71).
Inhib;n
Plasma FSH and luteinizing hormone (LH) levels
risc after castration. Exogenous androgens or estro-
gens usually lowcr the LH but have little errect on
the FSH. Tltese and OIher considerations led \0 for-
mulation of the concept that the testi! produces i"..
hibin. a hormone Ihat suppresse, FSH sccretion.
Peptides with such biological activity have been
found. The ones recovered from Sertoli cell cultures
are al!O known as Smoll cell jacror (SCF). and
those from sem inal plasma a! un/inal plasma inhi_
bin The term jolliruhmatin has been applied to a
related regulator made in ovaries.
At least one form of the hormone is a water·sol-
uble heat-Iahile, 19.000 dalton peptide that inhibits
FSH symhesis as well as release (117). However.
molecular weights ranging from 5.000 to over
100,000 have been reponed by other investigato ...
(135). Some of the larger entities may be hormones
bound to other proleins. It has al!O been suggested
that the testis makes a lipid inhihin (165). Bioassays
arc dimcult to perform because gonadal extracts
contain an LRH·like peptide (75) and substances
that nonspccifocally inhibit the pituitary gonado-
tropcs. Some recent progress wi th radioimmunoas-
says may soon resolve queslions regarding tile struc·
ture and function5.
Inhibin acl.'i on piluitary glands both in vivo and
in vitro. and possibly also on the hypothalamus (35.
90). Several hour:; are required to achieve
errccts (151) . It has been claimed that low conccn·
trations do not affccI LH secretion. but some inves-
tigators state that Ihe effecl.'i arc not thaI specific.
The regulator may be more important in immature
tha n in adult animals. since the peptide evidently has
a longer half-life and binds with higher affinity to
pituitary gonadotropcs of Ihe young (177). On the
OIher hand. larger amounts arc produced hy older
animals. and Sertoli cell defects in adults a re asso-
ciated with augmented FSH (but nOi LI-I) levels
(150).
Tlte pineal gland mediates many effects of cnvi·
ronmental lighting and other external signal. on the
reproductive system, and it suppres.... s gonadal fune·
tions during certain times of the year in seasonal
broeder:; (lg6). h. too. contains high·affinity recep-
tor:; or inhibin (177).
Although FSH may be the major stimulant for in-
hibin production. testosteronc probably makes an
important contribution. The "'inhibin hypothcsis" for
FSH regulation is not universally accepted. 11 has
been pointed Out that testOSter01te can. under lile
right circumstances. inhibit FSH secrelion (34) and
tllat testostcronc:estrogen rntios Can be important
dClermioams of tile relative amOUntS of FSH and
LH Found in Ihe blood plasma (159).
Other Effects of FSH ( 104 )
Some effccts of the gonadotropin pcrsi't into adult·
hood. The hormone continues to stimulate Ihc pr(l-
duetion and secretion of ABP. plasmiTlOgcn activa·
tor. transferrin. !Omatomcdin. and twO Sertoli cell·
specific intracellular proteins with molecular weights
of around 25.000 It also promotes gcncralit.ed
inc reases in protein and RNA synthesis.
In addition, FSH regulales tile mo"cmcnts of cal-
cium ions. and it affects calmodulin-related pro-
cc$scs. microtubule polymer;7.3tion. microfilamcnt
functions. and the establishment of tight junctions.
It evidently acts indirectly to increase the numbers
of inlc ... titial cell L H recepto ... (74). since testicular
fSH receptors arc confined to Ihe Sertoli cells.
Mec hanism 0 1 Action Of FSH ( 13, 169 )
FSH combines with plasma membrane-associated
r.ceptors and it elicits prompt. dose-related elevation
of the cellular cAMP. The nucleotide stems to se,,'e
as 3 mediator of many of the action. of the pituitary
hormone. including induction of specifIC Scrtoli cell
protein •. However. morphological responsc' to FSH
arc more transient than one, \0 cAMP. ils analogs,
or combinations of FSI! with phosphodieslerase io·
ibitor:; (36). Moreover, although the nUclcotide pro-
motes protein synthesis. only the hormone has been
shown 10 invoke protein secretion (39).
FSH is the only hormone kno ..·o to aClivate SeT'

'"
wi; <;:ell cAMP-dcpcndent protein kinasc,s. Its ability
\0 increase the RNA polymerase activity (85) may
be rdated 10 elevation of intracellular cAMP. How-
ever. direct links between protein kinase activation.
phosphorylations of specific cell camponenlS, and Ihc
apJI"3rJnce of FSH-spccif,c proteins have 001 yet
been satisfactorily established( 102).
The age.associaled decline in ",,"sitiv;ty to FSI-! is
acoompllnied by diminished rates of cAMP ae<:um-
131ion. Changes in re""plOr-<:yclasc coupling could
partially aCcoum for lhe cffe<ots. but lhc catalytic
properie. of Ihc enzyme may also be lessened (103).
An as }'Cl uncharactcrir.<:d "unooup]ing faclor" has
been found in preparations of adult Serlo]; cells
(104).
More rapid cA M P degrGdation may be even more
important. Although infantile and adult Serlol; cells
cantain simila r lotal quantilies of cyclic nucleotide
phosphodiesterases (PDE). part of thc of
immature (FSH,scnsitive) cdls is present as a cal·
cium-dependcnt isozyme , FSH affccts calcium ion
distribution and and it can lo"'<:r the activity
of that iso7.ymc.
Pro leln Klnes e InhIb itor ( 169 )
when the cells arc exposed to
cAMP analogs or agents such as isoproterenol that
increase cAMP gencratioo. In older SertoH eells.
FSH alone fails to induce the PKI. butlhe combi·
nation of FSH plus a phosphodiesterase inhibitor is
effective. Neither lestoslerone nor thc pituitary hor.
mo""s other than FSI-! lhat have been tesled affect
formation of the prolein. Presumably. only cAMp·
dependent functions are antagonized by thc PKI.
Interstitial Cell Ho rm o nes
I nterstilial (Leydig) cells differentiatc from the mes-
enchyme of the indiffcT<:Ol gonad (180). They rap-
idly acquire 3/l·hydroxysteroid dehydrogenase. and
they make detectable 3mot1nts of testO<iterone (Fig.
13· 16) by the end of the 81h wee k after conception
(192), Steroid hormone production then accelerates
for a time and it peaks around week I 5 (168). The
secretory rate declines thereafter. but SOme testos·
terone is made throughoul the second and third
tr;mesters; and neonatal blood plasma contains mod·
erate amounts of the steroi d. A few perinatal
"bursts" of aClivity are followed by prolonged juve·
nile quiescence. finally. testOSlerone levels rise
shonly before tho onset ofpubeny and the establish.
SEX DETEFIM IN.... TION .... ND DIFFERENTtA TION
ment of fairly constant adult rates of hormone
production.
According to SOme observe",. the felal and fICC)-
natal interstitial cells die off. to be rcplac<:d after pu ·
berly onset by whole new populations, Othe", belicve
that fctal cells survive. go through a prolonged pe-
riod of quiescence, and are then reactivated (134).
In human fetalte<te •. most of Ihe androgen i. formed
from J,-' intermc,)i,t.s_ Prognenoton. is hydroxylated to
t7".oH'pregncoolone. and the laller i. sMrtened to de·
hp:l roepia ndro:<tcronc (OHEA. OHA). Allhough 3p·hy·
dro. y.leroid dchyrogena", accept' .. veral .ubstra tes
(fig. 13· (6). much of 'he PHA i. rcduocd to ",'.. ndroo-
Icn.-<Iiol. which <cr...... he prOOUr$Or of t.. t",terone.
Ther. arc indications that all of the intermediate< can
k ••• the eclt., Some ,.tf. te> of pr<:gi\enolonc. it. t7<>-
011 derival;.e .• nd of OIlA arc a lso f"'mcd. and adult
'e, te, ar. Known to release ,.bstanlial .mount, of PHA·
.utfate_ Dog. and $Om<: Other mammab ma ke their .n·
droge n, in" 'imilar manner, lIy contrast. raU arc repre·
sentat ive of groups .ha' "prefer" .he ",' path,,·.y .• t leas!
., adult •. Such an imals con.crl pregn<no\one to proge,·
terone. "nd they tht" use the product to synth.si,_" ,...
tosteroll< via 17.-.-0H-progcSl.rone and J,'.. n<lrQOtene.
dion. (t65)_
Gon adotropin Contro l 0 1 Androg en
Blo"y nUn,,, I,,
l uteinizing hormone (lH) is the major regubtor of
testosterone biO<iynlbesis in the adult tcstis, Its ac-
tions resemble tbose decribcd for ACnl control of
glucocorticoid production by Ihe 7.0113 fasciculata
cell. of the adrenal cortex (Chapter 7). Although
both piluitary hormones affect other enzymes. they
most obviously accelerate sleroid .ynthesi. by en·
hancing the rale of conversion of chole.terol to
pregnenolone.
Several kinds of observations support the concc:pt
that very young interstitial cells begin to f unclion be·
fore they are presented wilh substantial amounts of
lH. and that they later respond to a gonadotropin
of placental origin (165). Evidently.lH does not as·
sume importance untillale in fetal life.
When testosterone biosynthesis is forst
(around eight weeks postconception), the cclls utilize
preg""nolone und progesterone supplied by Ihe pia·
centa and maternal S)'Slem_ They arc unable 10
cleave the cholesterol side chain. They soon acquire
gonadotropin recepto"" and the rapidly accelera ting
rate of androgen biO<iynthesis during weeks 10 to 16
is associated with testicular accumulation of proges-
tero"", Similar changes occur in anencephalic fe·
IU>CS (which lack pituitary glands)_ A ""ed for UI
of pituitary origin bas been demonstrated for only
some of Ihe mammals.
 Human chorionic gonadotropin (hCG) is a gly-
coprotein thaI shares many propertics "'ith LH. in_
cluding abilily 10 interacI wilh tne same reccp-
10rs, It is secreled by the preimplantation
trophoblasl. and levels of the "'gulalor build up dur-
ing lhe lime whcn Ihe chorion form, and Ihe inter_
slilial cells acquire lhc abilily 10 cleave choiesleroL
In common wilh Ihe piluilary hormone. hCG pro-
males lhe conversion of eooleslerollo p"'grICnolone
and il also augmenls 3j1-h)'droAy5teroid dehydroge_
nase aClivity (132).
Hiih concentrations of heG (and of UI) promot. the
g... ration of cAM P. and. role fOf the nucleotide in thc
"iulation of androgen production i. sugge. ted by obser-
vatOn$\Ml exogenous nucleotides .nd pho;pbodiesterase
inhibitors mimic some of th. act ions. However. rcl.tion-
, hipS belwccn lhe gl),coprOtein. and cAMP arc not as
Slr. ightfor,,"'ard as 11>= d.",ribed for FSH
Gonadotropins evidently participate in lin,i/alion a.
,,"'ell as >t;mulation .of . teroid production . They
induo< arom.l ... enz)'m.. in lhe inlerslilia l cell., and lhe
emogen th.t i. formed rna)' contribUle l<' locali,ed
inhibition,
Some addit;.onal po$itiv. and nega,ive controls are ex_
ertod indrtclly. a. FSH act. 00 lhe Serloli cell. , The".
fClic.ll)·_.,le'''. FSH can enh.nce androgen prodUClion
in 1"'.0 "'ayo: (a) it does not combine with reo
on interstiti.1 cdl •. FSH in some .... y f.ci lilat..
lhe formation of lH and (b) by promOling Ser-
loli c<ll uptalc and utili'-,,-tion of andrQi:ens, FSII de_
creases the conc.nn.,ion, of "eroid. "'ithin th. in·
t.rstitial cell microenvironment . It m.)' lhoref.ore
diminish steroid inhibition. (Loo.li7.cd inhibition of glu.
cocooicoid p,<><\uetion by glucocorticoid, w.' dcs.cibed in
Chaplor 7.) On the olher hand. Sertoli cell. m.y rcle.",
enou&h estrogen '0 dimini, h inlerslitial cell ,esponsive_
ness to heG and lit (lit t.
Role of Testostero ne in Mascu linltaUon of
the Wolfflan Du cts
Some aspect. of testosterone action are considered
here. and others are presented in Chapter 14.
The U"U. of thc Wolffian duelS possess leSloster-
one receplors, The sieroid is believed to act upon
them in a manncr regarded as "Iypical" for hor-
mones .of Ihis kind, Traditionally. this means for-
mation of a cytosolie complex,
processing of thaI oomplex. and transport of Ihe
prodUCI 10 the nucleus for auachment 10 acceptor
This is followed by effects on RNA transcrip-
tion thaI \cad 10 the biosynthesis .of proteins nceded
for growlh and differentialion of Ihe androgen-scn-
silive componenl' of the ducts, The U"lls do not oon-
lain measurable amounl. of Ihe 5«-reduclasc en-
zyme, and it is believed lhat teStOSterone aelS
directly. I.e. with.out prior metabolic lransformalion,
The epididymis and seminal ve.icle develop from
the superior and inferior portions. respe<:liveiy. of lhe
Wolffian dUCI, TestOSlerone promotes lhe pubertal
maturation .of lh<lSCorgan,. and it;s needed to mnin-
lain adult structure and The mature- epi-
didymis convens substantial amounts of teslosterone
10 DHT and 10 By compariwn with
other reproductive s)'Stem slructures, the epididymis
requires high .Ieroid concentralions
(60). Accumulation of lhe androgen i. facilitated by
andrOllen binding protein lhat is supplied by the Ser-
toli cell,
Virilizatio n of the Extern al Genitalia
By contrasl wilh the Wolffian duct cells. those of lhe
urogenital sinus and related strUClures oontain sub-
stantial amounls of 5«-reduclasc. and the develop-
ment is dependent on DHT. Very high levels of lhe
enzyme are also found in the prostate gland (which
is dcri,-ed from lhe urogenilal sinus).
Interestingly. androgens acting on lhe prostate
gland promole the formalion of proteins specific for
thaI organ. whcrea. androgen .timuation of the ""m_
inal vesieles involves more generali7ed increases in
RNA and protein synthesis (68). There arc indica-
tion. that DHT is of major importance for the pro-
motion of cell growth and secretoT)' funclions.
different teS1OSterone melabolitcs (andros-
tanediols) mediate cell proliferalion (95) ,
Importance of Conversion of Te sto sterone
to OHT ( 12,74, 119)
Individuals with genetic defecls th"t permil le.tos-
,erOOe to be produced bUl impair lhc conversion of
the steroid 10 OHT undergo normal Wolman duct
developmen\ while failing to acoomplish masculini-
7.3tion of the cxcrnal genilalia, XY infants with sc-
vere forms of the d isorder arc born wilh female-type
genitalia . whereas those with limited ability to make
DHT usualiy have ex'ernal organs described as
"ambiguous", DefeclSimpairing the abilil)' to uliliu
DHT elicit similar symploms.
To explain findings. il was at one time sug-
gesled lhat the urogenital struclures contain
DHT receplors that differ qualitatively from lhe /e5-
IOS/frone receplors of tne Wolffian ducts. Certain
observations made on mature tissues seem to provide
support for the ooneept. Kidney and ,kcletal muscle
cells do not oontain measurahle amOunt. of Ihe 5«-
reductase. and they are highly responsive to teSIOS-
lerone. In contrast . cells of the skin Ihat do possess
the enzyme can be stimulated with low concentra-
tions .of DIIT (but not with equimoiar quantities of
testOSlerone).
Closer scrUliny reveals the inadequacy of lhe hy-
PJlhesis. The androsen receptors of lhe kidncy av-
'"
idly bind DHT. and thc cells arc
\() DHT. Morrover. high concentrations
of testosterone inleraC! directly with the "DHT re·
ceptors" Qf the and urogenital sinus-<lcrivcd
organs.
A different kind of explanation for the DHT re·
quirement of the urogenital sinus into account
Ihc anatomical localions of lhe androgen largel cells
and thc fact that steroid, arrive at their destinations
via diffusion in Ihc embryo and young fetus. Since
the Wolman d uelS are close 10 Ihc leSles. they are
exposed to relatively high concentrations of le,IOS-
tcrone-evidently sufficient for stimulation. The
more distantly located urogenital sinus probably re-
ceives much lower concentrations. The ability to
ronyen testosterone 10 the more potent DHT may
therefore serve as an amplir.cation mechanism
(119). A concept of tbis kind does not rule Out co-
existence of factors that affe<:t ccll sensitivities. for
example. (a) differences in tbe plasma membrane Or
the cytosolic receptor that determine the concentm·
tion of steroid required to elicit a response: or (b)
dilTerences in the cytosolic receptor or nuclear ac-
ceptor site that affect the retemion tinle of Ihc ste-
roid complex within the nucleus (11).
The "testosterone-sensitive" cells may employ
supplementary st ••ilegies to obtain sulrLcient andnr
gen . Those that lack Ih. Sa-reductase take up SOme
of Ihe minute amountS of OHT present within blood
plasma. They Can also utilize androstanediols. since
they pOSsess the enzymes nceded to eonven those
steroids to DHT.
Studies of androgen'responsivenes' arc compli.
cated by the fact that testosterone promotes the bic-
synthesis of 5a·reductase in some of its target cdls.
Therefore. if testosterone secretion proceeds at a
suboptimal rate. OHT deficiency is exaggerated.
Testosterone also serves as the precursor of estrogens
in some of its target ,,<,Ils. and in those it interacts
with estrogen receptors.
Testosterone Regulation of
SpermatogeneSiS, Spermio genesis, and
Sperm Maturation
Although some evidence for androgen binding has
been presented (148). most authors state that ger-
minal cells do IIQI p<>S.,eS$ steroid hormone re<:eptors
(74). Testosterone and its metabolites arc essential
for spermatogenesis , but (hey exert their effects in·
directly by acting On the Sertoli cells. The)" synergi"lC
with FSH to promote both structural malUration
and the maimenance of adC<juate level s of androgen
binding protei"".
Prccociou, Onset of spermatogeno,i. can be
SEX DETERMtNATION AND DtFFEAENTI"TlON
achieved in the larger experimental animals by ad·
ministering pharmacological doses of testosterone:
and children with androgcn-secreting tumors have
been kllQwn to produce spermatozoa before the age
of tbrec years.
Not surprisingly. however, attempts to reproduce
the phellQmena in rats and related small mammals
have been unsucceS$ful. S uch species produce their
first spermatozoa as early as 45 days postoonccption
(122) (barely 3)0 weeks after the usual time of
weaning).
Testosterone alone can maintain spe rmatogenesis
in rats thai are subjected to hypophyseclomy after
attaining adulthood. provided Ireatment is instituted
promptly after the surgery. However. FSH replace-
ment is required if tbe testes are permitted to
There arc indications that humans
to maintain fer(ility.
leave the testis in an immature state.
undergo further mslUratl<m in the cpidid-
14). Androgens are needed to maintain
structure and functions. They arc also
sustaining thc activities of the seminal
vesicles and other accessory reproductive organs.
Other Actions 01 Testosterone (94 )
In addition to the already cited testis. accessory re-
productive structures. kidney. skin. skdetal muscles.
and pituitary gland. the targe t organs for tcst():$ter-
one and its metabolites indudc the liver, the thymus
gland. the bones and bone marrow. and the brain.
The steroid plays major roles in the regulation of LH
se<:retion. and in the emergence of secondary sex
characteristies. its anabolic actions alTe<:t appetite
and electrolyte balance as well as RNA and protein
synthesis. Some innuenccs on the brain are consid-
ered later in tbis chapter. and metabolic effects are
treated in Chap. 14.
Altbough the release of MO l probably precedes
the establiShment of steroidogenesis within tbe fetal
testis. there is some evidence for androgen synergism
with that regulator.
CONTROL OF REPRODUCTIVE SYSTEM
DEVELOPMENT IN FEMALE MAMMALS
Many of the techniques used to define control sys-
tems in the male cannot be applied 10 the female. h
is not I'O'sible. for example. to study animals that
lac k an X chromosome (since at least one is essential
for SUfi/ivai). There is also no way toeliminate estnr
gens from an;mal systems. since large amounts of
lhe steroid arC produced by the placenta. Moreover.
there are strong indications that estrogens are abso-
lutely by b<)lh XY and XX
Amibodics directed against the hormone can impair
implamation. fetal devciopment . and parturition in
at least species (96). It has been pointed out .
in this connection. that many kinds of congenital de-
fccts diminish or bl<x:k the ability to secrete or utilizc
androgens. whereas no neonate., lacking the ma-
chioc!)' for cstrogen biosynthesis or uSC have ever
been found (192).
The testis is reoognized as a source of at leaS! two
important of sex differentiation (M DI
and testosterone). and castration imposes clearly de·
fined, reproducible consequences. Factors of
Ihc ovary may be of major importance for oontro] of
female development.
Much of the information on female systems is ob-
ta ined indirectly , Accordingly. the literature on hu-
moral regulation of reproductive sys tem dcvelop-
ment oonl3ins a relativciy high "speeulation: faet
ratio."
Is There an Ovarian Inducer Comparable to
the H·Y Antigen ?
As has been discussed. it is widciy believed that the
"indifferent" gonads of eutherian mammals have an
"inherent tendency" to develop into ovar ies. ucept
when the H·Y antigen dirccts otherwise. The IlOtion
is supported by observations made on explants grown
in cuhure. and in studies employing either a ntibodies
directed agai nst the H-Y or pl'QCedures devised for
"stripping" H·Y from cell surfaces (119).
A problem wi th the ooncept is that it fails to ex·
plain why the gonadal precursor develops into an
ovary (rather than into an adrena l gland. splcen. Or
some other ki nd of internal organ). Obviously. some
form of i""truction is r<:quircd.
One suggestion h3:i been that XX embryos pro-
duce an organi,-er lhal combines with lhe "H·Y re-
ceptors" on the surfaces of the cells of the pre,ump-
tive ova ry. No such inducer has been identified , A
second thought is that. si nce only gonadal cell, of
both sexes ar<: equipped with the appropriate recep-
tors. it is the rc.:eptor itself that provides
the needed information . The idea rece ive.' some sup-
port from ot>scrvations that ovarian extracts oontain
somcthing that impairs lhe specific binding of the J.!.
Y an1igen (162). On the other hand. the differences
in time COUrses for d"'elopmem of ovaries as com·
pared with testcs raise the possibility that very dif·
ferent kinds of oontro! mechan isms arc inV<llvcd,
The embryonic testis assumcs recogni13ble form
very soon after the emergence of the genital ridge
and the accumulat ion within it of the migra ting gon·
ocytes. The f,rst stages of differentiation become ev·
ident before format ion of the circulatory system is
completed. and prior to the time when Ihe pituilary
glands and other putative regulatory organs ha vc as-
sumed their functions, The germi nal cell popu lation
beoomes stabilized soon after the Sertoli cclls begin
to encirde the spermatogonia. Only later docs the
show signs of coming under the influence of
gonadotropins. In oontrast. presumpti"e ovaries re-
tain their "indiffer<:nt" appea rance until after the
end of the 8th They then undergo a protracted
period of development that rcquir<:s many month •.
The observations imply (but do not prove) that ovar-
ian differem iation;s dependem on influences exerted
by blood·borne chemical regulators that are pro-
duccd elsewhere within the organism.
The germinal cell population of the ovary under·
goes changes throughout gestation and the juvenile
period thaI follows. At first. there is an eXlended
time during which cell proliferalion lead, to the ac·
cumulation of vcry large numbers of oogonia and of
primary <x>cytcs , The maximum numbers are al'
tained around the end of the 6th prenatal month. Be-
fore the period of rapid proliferation is oomplcted.
mechanisms for red uction of germinal cd l numbers
become operative. Oogonia that are I>Ot intimately
associated with epithelial cells are cxt!1lded from the
ovarian surface. and primary <x>cytes endosed in pri-
mordial follicles succumb during follicular atresia ,
The factors controlling atrcsia are only pmtially un·
derstood. There are indications that gonadotropins
promote advanccment of primordial follicles to the
primary follicle slage. and that the more mature
oomponents are preferentially destl'Q)'ed.
Ooqte loss and follicular alresia continue post·
natally. albeit at a slol'o'er rate. There are (, million
germinal cells at the cnd of the second trimester. but
only around I million around the time of birth. A
further reduction to something like 400.000 is ac·
complished during the juvenile period. Studies made
after therapeutic gonadc.:tomy and at autopsy indio
cate that most women ha ve lost all of their germinal
cells bofore the end of the fifth decade .
Atresia appears to be a phy,io/ogiml pl'QCess that
is eJun/ial for IlOrmal ovarian dc,'Clopmcnt and
function. At least some conditions that retard the
ecilloss arc associated with delayed onset of ovarian
dysgenesi s (89) .
There has bocn much specula tion about what is
accomplishd by atrcsia: (a) it may provide a mech.
anism for elimination of germ cells wi th air
normal Chromosomal ma keu ps. Or of ones that have
begun to deteriorate: (b) since more germinal than
fOllicular cells are lost. it may cstablish a favorable
("til ratio; (c) follic ular cells take
up androgens produccd by the stromal cells. and
they oonvert the steroids to cstrogens. In the adult.
the Follicular cells bring about regularly recurring
cyclic changes in blood "'tradiol concentrations.
Some follicular atresia may be needed to achieve an

'"
optimal hormonal (d) the quantities of go-
nadotropins available 10 lhe adult follicle. arc lim-
iled. Loss of some ovarian cells may iocr.ase the
chances that Ihe survivors receive odequarr pituitary
hart/writ slimulation: (0) it is important for ovaries
\0 release numbers of fertilizable cell, thaI arc ap-
propriate for Ihe species during each 9'de. Atresia
may reduce the incidences of supernumerary ooncep-
lions. (The human ute,u, d"", 001 easily accommo-
date more than onc fClus at a lime. and ",ually only
one germinal cell allain, maturity each month): and
(I) programmed reduction of follicle and oocyte
numbers can tessen and eventually eliminate the
likelihood thaI females who have grown too old \0
provide adequale prenatal and postnatal care will
become pregnant.
A quite different thought is that atl"<'sia is an
obligatory, but II<)t ne","s.'larily desirable COIl""quencc
of the influences uerted by the intraovarian andro-
gens , T he 'teroids Serve other functions (e.g. they
arc substrate, for estrogen biosynthesis).
Since atresia f'TSt becomes apparent afler most
other organs have undergone differentiation. it may
be controlled by humoral factors that 31"<' synthe-
sized outside the gonad5.
Possltlle tnvolve ment of t ne Tnymus Gtana
In Ovarian Development
Several different reaSOnS for suspecting that the thy_
mus gland plays important roles in ovarian differ_
entiation and maturation arc cited.
The gtand begins to diffel"<'nt iate bef.,.. the
pre,umptive gonad, show .ign, of organi zina into testes
Or o... i... It $lIOn become. colonized with lymphocytes.
Ind it then provid.. a micl'OCn-ironment sui tattle few pr<).
liferat ion of those cell, .nd for their maturation into thy-
mocytcl (T cell.). I.. crueill role, in the establi,hment of
cellular immunity involve both the of thymocytCS
a nd the rei .... of humoral ractOl'5 into the dr<ulation.
The concept that the thymus i. especially during
an .arly. "eritieal" phase of d.velopm.nt .. ise, from ob-
servltion, that rats and mice . ubjected to th)'mcclOmy
during tbe firs, postnatal ...... ,uffer permanent
of Ihe immune .yst.m. wherea, those permincd to retain
Ih.ir ,land. for an additional ",cek display only mioor
imp.irment. Thero arc indication, that a comparable
crilkal pha .. octurs durin, the last trim .. t., <>f lCstation
in humans and in many other large mammals ,
The immune .yst.m is involved. among oth.r thing •. in
the recognition and destruction of thaI -do not be-
long" (e.g. foreign One. introduced artificially. ,h<>«: of
inf.cting mic,oor... nisnu. eel" thaI have bt<:Qme tran,·
formed by vir ..... a nd tum"" cells wilh abnormal mah·
ups). 11 also promot.. acceptance (toleranc.) of normal
body compo""nl$. and il "built·in" control. that pro-
SEX DETERMtNA TtON AND DtFFERENTtATION
vide protection 'gai nst Ih. mounting of all.d. on
h•• llhy li"u •• ,
S.x diffe,ences in immune funclions havc becn de-
scribed . Fem.les have higher incidence. of .utoimmune
disord.rs. and the r.. ulting dam.,. can be more seVerC.
C.stration e.acerbates the problem. in when il i,
performed prepubertally. Testo".",,,,, administration i.
,uppressi•• (I (5),
The rejeclion by fem.1e rodents of highl)' inbred
stra ins of .kin grafts from male (but OOt female) mem·
ber< of the "me e.idently invol ... lhymocytes that
are activat.d in the prescnce of It-Y .ntig.n. The obser·
vations bear some rclati(>nshi", to phy'iologic.1
pro<:.sse> in fem.I., related 10 the rr=nce of H-Y
receptor< ,
RooenlS .ubjee led to thymectom}' during the first few
postna tal da)'. later develop ovarian dy'genesi. (117)
Ihat is associated wilh lymphOCYlic i"fil"'lion of the pi-
tuitary and thyroid il.nd. (63). m• .,i.e Iymphocytie aC·
cumulation. in.ide and around the ovarian follicle •. and
the pre.ence of autoantibodies again" oocyte. (I (6). The
findings are con.istenl with some impairmenl of the func·
tion. of ",uppr.,sor"·type T cells,
RELATIONSHIPS TO GROWTH HORMONE
In addition to ovarian dygene,is. animals th.t are Ih)'.
mectomized n""""tally (and tbose suffering genetic de-
f«" thaI blo<' "«lui.ilion of a Ihymu, gland) have mor·
phologically demon..... ble pituiEa,y gland .bnormali·
tioo(I7 ). The ",matOln)pe$ are the cell' moot obviously
.ffected. and growth hormone secretion is suboormal.
Thc pituitary hormone is implicated a, a I"<',ul.tew of
oo.rian development and function (106). 11 also stimu·
late. thymus gland and som3tic growth. Although they
are re<ponsivc to o.og.oou. G H (160). athymic .nim3ls
suffer growth retardation. Since hypophysectomy olows
fet.1 growth in """"ey< (58) ao well as in rodents (167).
somatotropin deficiency is implicated. On Ihe OIher hand.
of hypophYSCClomi7.cd animal. io more .asily ac-
«ieratcd with a-MSH.
RELATIONSHIPS TO GONADOTROPINS
Both th. pituitary gland and the blood concentration. of
gonadotropins are lowered by neonatallhymCCtomy in r0-
dents. and tbe concentrationo can be restored by implant·
ing Ihymu, glands from OIhcr animals (136). The dcoel·
opm.nt of ovarian dy".n .. is has been allributed to
pi,uilary ho,mon. ill$uff,cieney (89). On. possible COn·
'"'IUene. of the low.re<l gonadotropin levels may be Ihe
failure of foil ides to attain full maturation and to ovulate.
Th;. could lower the .S1rogen:androgcn ralios within the
0.. " (I 16) and al'" a<:<:O\lnt for Ih. f.ilu,. to form cor-
pora lut •• Ind 10 Iher.by achicve _mal level, of pla'm.
prog.sterone and of I (63). (A.
discussed in Chap. 16. prog«togcn. seem to be regulator<
of Ih. immune 'y<tom.)
Som. effects of Ihyme<:tomy may be indirect, ,,-MSII
• rreclS l""ad<>lropin ",crelion ( In). II inleracI' wilh Ihe
pineal gland 10 affCCI ,ep,oou,'i.. sy.. em funcli"",
(181) •• nd il is al"" beH.,·ed 10 inieraci in ",veral wa)·s
wilh Ihe Ihymus lland . Thymus·pine.1 i", .. relalionship;
h..e been described by se....l in"e'ligalo".
THYMUS INTERACTIONS WITH GONADAL
STEROIDS
The Ihymus acquires 'pecific. hikh .... mnily reccplors for
bolh and,ogen, and e'trogen. at an e..ly , t.ge of de.d·
opmen, and it relains them Ihroughout life. The glands
of females contain larger numbers of ,ee<:pt"" than those
of m.le$. Orchiectomy augments the numberS (112).
Pharmacological cone<:nlralions of either androgens or
e'trogens invoke ra pid reduclion in lbe , i>c. we ighl. and
cell c<>IInlS of Ihymu, gland •. There is u.uaily prompI re.·
lor.,i"" of Ihc initi.1 coodilion follo,"ing .. ilhd,.",. 1 of
Ih. "c""d •. Phy.iological afll()um. lower thymus gland
•• eightS in .uuatl)' malure adullS. {The gland, of ea,·
trales enlarge .) Th)'mu>C$ a l"" eootain estrogen.indueible
progeSlcrone rc<:eplOl'l' (A·)),
When female ra" arc injecled wilh androgens during
Ihe firSt day or tw<> afler birth. Ihey fail to 1.lcr establish
normal ovarian cycles. II ha$ been repOned Ihallhe)" can
bc protecled against the consequences of androgeni'"tion
wilh ,u.pen.ion. of thymocyte. (81 J.
Prolactin and th)'roid hormone. exert influence. on go-
nadal " c,,"d hormone formatioo and functions, They
al"" ael on the thymus gland. but Ihe secondary C<>nSO-
quencos have not been investigated. It is not known
whether Ihe Ihymu. innervation (24) i. relaled 10
influences .'."ed on e;ther the Or gonadutropin
.e.relion.
Follicular Cell Functions
Follicular cells differenliale from analo-
gous to the OneS Ihat give rise 10 the Serloli cells.
Some of Ihe functions arc similar.
INFLUENCES EXERTED ON GERMINAL CELLS
Gonocytes migrate to the genita l ridges, proliferate
rapidly, and (hen mature into oogonia. The latter
also proliferate for a time. but they soon advane<: to
the primary oocy te slage and enter inlo Ihe propbase
of moiosis I. Follicular cens surround many of the
oocylcs and Ihereby form Ihe primordial follicles.
This has twO consequences: (a) The germinal celts
are protecled (relalively large numbers of free 00-
gonia and oocyte> are extruded from the ovarian sur·
fae<:s. but only small numbers of germinal cells en-
closed in follicles are losl al this stage); and (b)
meiosis is arre.ted al th e "diclyate'· stage in many
spec ies. Cerlain of the oocytes resume meiosis
shortly afler the onset of puberly, olhers do SO dur-
ing Ihe ensuing four decades in humans, and Ihe rCo.
mainder deleriorale.
As noted . Senoli cells also proieci germinal cells .
Howe,'er, Ihe male gamele precursors do not pro-
gress beyond Ihc spermalogonia slage in feluses Or
juveniles.
A peptide of low molecular weight (oocyle matu-
ration inhibilor. OMI) has been idenlified in Ihe
nuid of small follicles of the pig (173). and a sub-
stance of this kind may be produced by fetal cells.
Oocyles thai are removed artificially from Iheir fol·
licles are said to undergo ··sponlaneous·· resumption
of meiOllis, and the proee.. can be blocked wilh cx-
lracts containing the OMI. A probtcm "'ith inler-
preling tnis finding is that Ihc procedures requirW
10 remove Ihe oocyles may also <timulate cell
division.
In aduli ovaries. follicular cells providc nutrients.
protection. regulators. and a microenvironmenl th'lI
suppons oocyte maluralion. Follicular Auids also fa·
cililate IranSporl of Ihe secondary oocyte 10 Ihe fal·
lopian lubes afler ovulalion has occurred.
STEROID HORMONE METABOLISM
In common wilh the Sorloli cells. follicular onos ac·
quire aroma/au Ihal promole conversion of
androgens 10 estrogens. a needed 10
transform teSloslerone to DHT, dehy-
rogenases that calalyze Ihe fOrmalion of androsla·
nediols and androslerone from andrOgen precursors.
and a /lJj-hyd'oxySltrOid (I 7-keto-
steroid reduelase) thai is necdC<i for lile inlerconver-
sion of lesl<lerone and androstenedione (see Figs. 13.
16. 17-19).
Ho",'evcr_ as tne follicles malure, Ihey also ma ke
substanlial amounts of cnolesterol side-chain eleav.
age enzymes and some 3p..hydroxysleroid dehydro-
genase, Therefore. Ihey can synlhesize pregnenolone
and oonveri some of il 10 progesterone. However.
they conlinue 10 depend on the surrounding slroma
to supply Ihe teSlOliterone prec ursor of eslrad iol,
HORMONE RECEPTORS
Foilicular cells acqui re FSH. lestOSlerollC, and eslro-
gen receptors. FSH promoles growth, proliferalion,
and maluralion of Ihe follicular cells. and il aug·
ments the conversion of androgen< 10 eSlrogcns , As
in Ihe leslis. the aClions are aswcialcd wilh genera·
tion of cAMP, and Ihe responses decline with age
(142).
Estrogens induce Iheir own receplOI'S in follicular
cells. T hey support FS H inAuences on cAMP accu·
muialion and also on induction of LH rtteptors
(137). They may addilionally be needed 10 create
Ihe environmenl essenlial for progression of gono-
eytes to oogonia (157) .

aoccleralcs follicular atresia, and in
this scnse it can be said 10 cxcrl inhibilory infiucnccs.
On Ihe olher hand. leslostcrone sy"ergiles with FSH
in augmcntaling the S)'nlhesis of cholesterol side-
chain eleavage en?yme,. It thereby accderatcs pro-
geslerone biosynthc<.is (39).
FOLLICULOSTA TIN
FSH increases Ihe formalion of substances Ihal in-
hibit FSH release but have limiled or negligiblc in-
fluences on LH release when prescnt in low cOnccn-
lrations. Relalionships belween Ihe chcmical
struCIUrcs of foll iculoslalins and the inhibins al ready
described remain to be defined.
FOLLICULAR CELL INFLUENCES ON
REPRODUCTIVE SYSTEM DUCT MATU RATION
The folliclcs do not. of COOrs<:. make MO L There is
no evidence for production of an inhibitor of Wol f_
nan duct virilil.ation. but there arc controversies con·
cerning whcther cstrogens contribute to MUllerian
duct differentiation.
Since estrogens arc dTectivc in low CQnccntra-
tions. there may be no nttd for a protein that facil-
itate, Ihe accumulation of thc stcroid (compa'J.ble
to thc AB P thaI binds androgcns in mal",,). An ('(.
felOprOlci" that binds estrogcns with high am nity
and performs special funclions in female rodems is
described later. Humans. monkeys. and many other
mammals ma ke proteins Ihat are chemically related.
but these do not strongly bind the cstrogens Or per-
form similar funclions.
Stromal Celt Horm ones
Same dilTercntiation from Ihe mcscnch)'mc. along
with the beginning of steroid hormonc production. is
evident by thc cnd of the 8th prenata l wcek (157.
192). At n!'l;t. the cells utilize pregnenolone (from
the placenla) 10 which
erts some aclions (11 2). Since thcre are
only limited of dehydro-
genase. very littie testos«<>oc is synthesized. (There-
fore. no stimu lant is a"ailable for virHirution of the
Wolman ducts or external genitalia .)
Steroidogenesis begins withoul bener.t of gonado-
tropic .timulation. Latcr, Ille cclls accumulatc re-
ccptors for glycoprotein hormones, and they proba-
bly respond to hCG before coming under Ihe
inAuencc of fetal pituitary LH . The hCG is impli -
cated in induction of cho\csterol eleavage en?ymes.
and therefore in promoting the formation of preg·
DETERM INATION .o.ND OIFFERENT,.o.TION
n.nolone and then progesterone. By the time Ihe
stroma l cells can synthesize signifocant quanlities of
lestoslerone. the follicular ones are ready to CQnvcrt
thc androgen to estrogens.
Neonatal rat ovaries go through a phase in which
Iheyare insensitive to exogenous gonadotropiTlS and
only mimimal quantities of steroids are synthesized.
A comparable event may not oem, during late ges-
lalion in humans. sincc much higher CQncentrations
of progesterone and of its I 7",-hydroxy derivative are
found in the am niotic fluids of than of males
(44). I n both animal types. steroid production during
the juvenile period is low.
Stromal cells of adult ovaries make large quan-
tities of androgens. Throughout the reproductively
competent years. thcy are mostly converted to estro-
gens by Ihe follicular cells. After the menopause, an-
drogens are released into the bloodstream in largcr
amounts. They are laken up by several of lis·
sues for CQnvc!'l;ion to other steroids. Adipose tissue
is rich in Ihc aromalaso system needed to ma ke
estrogcns.
The fetal uterus has receptors for androgens as
wcll as for estrogens. It is not known whether both
hormone lypeS CQntribute to it, development.
Other Aetions of Steroid Ho. mone ..
In addition to the uterus. oviduct. mammary sland.
and other structures aSSOCiated with reproduction.
cells equipped with estrogen receptors are found
(among OIhor places) within the pituitary gland.
brain. liver. skin, and ske\ctal syste m. Some elTeet.
On the central nervOuS system will be cited later in
this chapter, and additional rol.s are considered in
Cnapter 15.
DISORDERS OF SEX DIFFERENTIATION
The processes involved in sex dilTcrenliation arc
highly complex. and they therefore offer numerous
for disruption. Often. the resulting conditions
are totally compatible with long-term survival.
Many of the anatomical and functional abnormali-
ties are apparent to who lack scie nti fic
lraining. and mOSt are of a kind thaI molivates the
victim to scc k professional help. It is therefor. oot
surprising Ihat the clinical literalure abounds with
descriptions of a wide variety of CQnditions.
The problems that arise arc conveniently divided
imo three general categorie.: (a) aneuploidy. or the
acquisition of wrong """,be,s of chromosome.
(this can occur during gamctogenesis. fcrtili7.mion.
or cleavagc): (b) chromosomal deJms Ihat resuit
from lranslocalions. delelions. or mu-
lalions: and (c) conditions in which external ja(/l}f".r
(hormones sccreled by nonreproductiyc system
or \Urnors. yiral agents.
autoimmune diwrders. and nutritional deficiencies)
interfere with the funclions of normal chromosomes.
The categorics arc not mutually exclusive. They cut
clinical classifications Ihat are bascd On
symptomatology.
Alleuploldy Ilivolving the Sex Chromoso mes
Du ring Ihe normal course of evenlS. thc primary
spermatocyle its aUtosome.' and bolh X
and Y as it prepares for the nrst "'-
dUClion division. It then donates one sct Ihal includes
a pai r of XS 10 a seCQndary spermatocyte and the
remainder of Ihc genetic material (including a pair
of V,) 10 the other secondary spermatocyte. Dur-
ing meiosis II. each of the secondary . permato.
cytes gives rise to two haploid spermatids. each COn-
laining. either a singlc X or a singlc Y (Fig.
13-4).
The primary oocyle sends two of its four X chro-
mosomcs to a secondary oocyte. while the remaining
two are discarded with the first polar body. Meiosis
II in the female sy'tem culminates in the formation
of an ovum containing one X. plus a second polar
body thai ..:rves to remove Ihe excess DNA.
Evidently. the process of meiosis is fraught ,,'ith
hazards that do not apply to mitosis. Chromosomes
thai enter into the formation of telr:lds during the
first phase do not always sep<or3te in a normal man-
ner. Problems can also arise during meiosis II.
Nondisj"m:tioll is the failure o[ the chromosomes
to separate properly. When it alTects the sex chom-
osomes during meiosis I in the testis. a secondary
spermatocyte can acquire any of following com-
binalions: XXYY. XXV. XYY. XV. X. Y. or 0
(Fig. 13-20). Spermalid, wilh abnormal sex chro-
mosome numbers can form from secondary
spermatocyles. and il is also possible for Ihem 10 ac-
quire any Oflhe following combinations when Ihe in-
termediate cellsare XX or YY: XX. YY. Or O. Sim-
ilarly. ddectiv. ,cpa ration during oogenesis can lead
to the [ormation of ova containing XXXX. XXX.
XX. or O.
Chromosomal/ag is the term applied ,,·hen sepa-
ration dots occur. but one or more of the chromo-
somes fails to migrate in the u,ual manncr. If an X
or Y is alTccted in this way. it is oftcn extruded from
thc The resulting gamete i, deprived of its sex
chromosome.
PROBLEMS ARISING DURING FERTILIZATION
Obviously. 'ygmes wilh abnormal chromosome pat_
lerM Can be produced when [enili,ation is accom-
plished by defcclive gametes. Only lypeS resuiting
from panieipation of One healthy sex cdl and one
with an unusual chromosome ma keup are sllown in
fig. 13-21.
Abnormal conceptuses can also form from the
union of gametes with conventional numbers of
chromosomes. Two distinct mechanism' arc
recognized.
1. Following of a spermatozoan. a sec_
ondary oocytc soon undergoes a wno renClion that
allcrs the properties of the plasma membrane in a
manner that preclude. the entry of addilional male
gametes (sec Chapter 15). It then compiele. meiosis
II . extrudes the second polar body. and underg"".
changes preliminary to cnlfy into cleavage.
If a second spermatozoan dOt's gain access to the

Primary spermatocyte XXVY

with reP"ca:ed
chromosome. // \ ......

//\
.perm.tOC)1es /
rxvy
I
+0 XXY\- Y x +; m
XY . Xy

XXXV

,•
0
•
,
YX
XY ·' ., •
0
,,',
• o _ Xy o
'",• '" ,
• ,
•
m
Sperma';.:!'
". " , ,
• ,•
,,.
"m Fig. 13-20.
o! rooodisjuncr;on <II.o"ino
 SEX DETERMINATION AND OIFFERENTIATION
'" No<mal Ocl",,,,,,, Normal Abnoml.1
,,,,,,m,fO'O. zyqotes 'pe,maloz<>a
0 , " -- ,
,
• 0

•
" ,
0

"
, '" •
"
•
" '" "
m
m • XXVy

'"
, . .-- ,, '"
XXXX .-- '"
XXyy XXXYV
XXXXX .- ,, XXXX
Fig. 13·21,
01 partcip.t ..... QI one defeetw. gl rMle
XXXXY • XXXX in 1000''''0Iion.

oocyte. the product will a1 least transiently contain
the triploid number of chromosomes.
2. aU of the polar bodies formed during
oogenesis deteriorate. I{ is possible, however. for One
\0 persist and 10 r<:lain its allachmern to Ihe oocyte.
The polar body may even be fcrhli?ed . In Ih. ex-
treme case the conceptus will camain Sromple!c sets
of chrorno:s<>mes (two from a first polar body. one
from each of the spermatozoa. and onc
from Ih. oocyte). Tctraploids can arise when the
double fertilization involV<'s a sewnd polar body, or
when a flfs! one escapes sperm penetration, but ad-
heres to the fertilized ovum.
Events of this kind may not be as unCOmmOn as
was once believed . Rare CaseS of ITiploidy have bttn
described for living humans (25). They display a va-
riety of somatic defects, and moot succumb soon
after birth (146). Triploidy has been found in around
4% of spontaneously abortcd embryos and
that have been examined. It has been estimated that
50%-80% of all conceptuses die within the first
month, many at a stage so immature that their for-
mation is not detected by the mother (185). and it is
likely that the majority of them have chromooomal
aberrations. Telraploidy is encountered Ie .. often
among aborted This has been attributed to
loss of most of the affected during early
cleavage stages.
Polyploidy impairs the proce..es of chromosome
duplication and Deletions and redistri-
butions of the retained oomponcnts lead to Ihe ap-
pearanCe of different kinds of anomalies during the
mitotic divisions.
PROBlEMS THAT CAN ARISE DURING
CLEAVAGE
The normal (diploid) zygote divides by mitoois and
starts to form an embryo in "'hich each cell oontains
a complete copy or the chromosomes derived rrom
both the spermatozoan and the ovum. Separation of
the two daughter cells that arise from the first cleav-
age, or of small groups of cells that are formed soon
afterward, can be followed by the development of
normal identical (homozygotic) twins and more
rarely of larger numbers of identical s iblingS. Sepa-
ration.s of this kind seem to be partially under ge-
netic oontrol, since they occur with greater fre·
quency in some families than in others. regular
formation of identical quadruplicate armadill()S waS
mentioned carlier.) The mechanism is obviously dif·
ferent from the one in which separate fertilizations
lead 10 the developmenl of nonidentical siblings.
Nondisjunction . chromooomal lag. duplications.
and uneven distributions of the genetic material can
occur during cleavage The "inactivated" X chro-
mosomcs (all in exce.. of OIle) replicale later thn
others, and they are the ones most often affected.
The end of abnormal chromosome distribu·
tions during cleavage depends in part on the slage at
whiCh the problem arises. One possibility is that the
1.ygote loses an X, and all subseq uently produced
«lis of the oonceptus are of Ihe XO type. Another
is that the X is duplicated and the progeny are XXV
or XXX. When two or more different kinds of c<:lIs
arc formed during cleavage. the resulting individual
becomes a gtnelic mosaic possessing SOme cells of
 XOIXV
Mosa'" XX/XO

XO! XXV
XOIXXX
Fig. 13·22. Some tYp<Kot genetic
XV/XVY
mo..;c;sm t""t can "' .... t from
(luplico!ion or deletion of ...
xX/xxx x O/XVV
""''''''''»Orne'<luring e..... ge.

one kind and some of the other. for example. 45X/
46 XX. 45X/4?XXY. and so forth (fig. 13-22).
Polyspermy and the retention of polar t..:.dies lead
to formation of conceptuses that aT<: chimera•. that
is. indiyiduals possessing cells with genetic oompo.
nents derived from diverse sourccs . The usual oon-
'iCquene<: of chromosomal redistributions during
deavage is the appearance of 'iCveral different cell
lypes (Fig. \3-2]). Since the events occur long be-
fore maturation ofth. immune system. all of the cell
types are tolerated.
Some Generallullons Concerning the
Presence of Abnormal Sex Chromosome
Patterns
1. Any kind of chromosomal aberration can lead 10
dysfunction of both reproductive and somatic pro-
cesscs. Usually, there is a diT<:ct T<:lationship bet ween
the extent of the deviation from the XX or XY pat-
tern and the 'iCverity of the symptoms.
2. The mOSt cOmmOn finding is mental retarda-
tion. However. there is a high incidence of gonadal
d)'Sgencsis and sterility. and some of the defects are
associated wilh characteristic types of somatic struc_
ture malformation.
]. Mammals require tbe presence of at least one
X chromosome. Since the X aCOJunts for about 5%
of tbe total genome. tbis is not surprising. Mamma-
lian YO zygotes that form do not survi"e beyond the
first cleavage ,
YO and YY fi'hes can de>clop into ftflile ,d ult . (119) ,
Thoir ability to do SO is amibuled primarily 10 the pres-
ence of relalively iafie Y ehromo«lmcs that bear genetic
compo"""" I""forming function. "nalogou. to ones rei·
egatt:<! to the mammali.n X,
4. Somatic defects usually arise in individuals
with only one sex chromosome (45 X. or XO pat-
lern) that arc not seen in either XX Or XY s. This
suggests that cerlain essenlial kinds of genetic infor-
mation affecting Ihe structures aT<: oontributcd by
either the second X or the Y.
5. Further indication. that the y .ffcc" >omatie
Slructures come from the observations of Ihe tall
of most individ"al s possessing more than onc
such entity (X YY. XXYYY . and related pattcrns),
6. The Y chromosome is sa id to confer "male·
ness." In its presence, there is usually some testicular
differentiation and release of both MDI and teStOS-
terone. Al least certain features of the male pheno-
type emerge in all possessing a complete Y> includ·
ing those with supernumerary Xs (XXY. XXXV.
XXXXY. and others).
7. Spermatogenesis evidently invoh-cs trans ient in-
activation of the X chromosome. possibly because a

$perm81oz0a
,
,
0"
,
,
,--, Zygote

'"
So"", pos. ible mosiao forms
x X/XC Xx/XC xX/xx XX/XO
XXXX XXiXX xxX/xx xxX/xx
, , ", XXiXV XOlXV
, , '" xX/xv XXVIXX xx X/xv
,., , " xxxv

'" XX/XO XX/XO xX/xx

,., , m xX/xv xX/xv XYIXO
, ., , m XV(YO XVIXO

ftg, 13-2J. Some poO$lbleconsequenonol _m.tow. ore shown in bo!d type tor pUrposes of
irwO"'iog _ . And pOly_my. Oniy ideotific.tion. )
.... s!Iowrt. (X mromoO<>fl1Hdonotlod by

fully active X interferes with transcription of DNA
present on the Y. The inactivation proeess may not
be capable of dealing with supernumerary Xs. XXV
individualS usually fail to undergo normal pubertal
malUralion. They suffer gonadal dysgenesis and 100s
of ferlility. and Ihe problems are when
more than twO Xs are present.
8. Oogenesis in humans and in many of the Olher
large mammals requires the lemporary panicipation
of IWO X chromosomes. XO women often s uffer
ovarian dysgenesis and sterility.
XO members of some of Ihe smaU.. species with
short life SpallS, e.g. mice, can develop into tran-
siently f.nile females. It is possible Ihat thc diffc-
ences are rdated 10 the shon interval thaI clap«e<
between the appcarancc of the ovarian follicles and
the onset of puberty . XO mice produce fewer ferti-
lizable oocytell_ and they terminale their reproduc-
tive functions earlier Ihan XX indiyiduals of the
sa me species (183).
9. The consequences of gcneac mosaicism depend
on the kinds of cells presenl, the relmiVl' numbers of
thc various types, and the dis/ribu/ion ""lIerltS.
At one end of the 'pectrum, one finds symptom-
free adults that have. for example. mostly XX cclls
and a small number of the XO type, Or mostly XY
XXV. When the XO nr XXV
cells are confined 10 lhe gonads. the consequences
are gonadal dysgencsis with linle impairment or s0-
matic funclion. Sevcrt: problems arise if. for exam-
ple, XX cells appear mostly on the left side of the
body whereas XY types predominale on the right. In
such cases, an ovary and MUllerian ducts develop on
the lefl side as androgen.,.,n,ilive compQnents of Ihe
Wolffian ducts atrophy, and a testis and masculine-
Iype internal organs differentiate on Ihe right. It is
poSSible, bowever. for XY ceUs to release sufficient
H-Y anligen to affeci th. gonad on the XX side. T he
appearance of the eXlernal gcnitalia depends mostly
on the quantities of testosterone sent 10 the urogen-
ital sinus region. The structures arc usually (but not
always) incompletely viril ized in XX/X V mosaics.
10. Chromosomes interaci in ways to
achieve oormal differentialion. It is therefore nOI
logical to conclude that the association of tOO few or
tOO many of anyone type with a specific s)'m ptom
demonslrales that the chromosome in question di·
rertly controls Ihc related functions. M(lreover, lhe
detection or an abnormal sex chromClWffie panern
does nOI cSlablish Ihe finding as Ihe of Ihe as-
sociatoo abl1Ormality_ The concomitant presence of
aUlosomes with normal morphological characleris-
tics that bear defectivegcnes Or deletions is not eas-
ily ruled out, and Ihe failure to "Iurn on·· Or to "turn
SEX OETERMINATION AND OIFFERENTIATION
off"· Olherwise healthy DNA segments al just the
right limes mu,t also be considered .
Relation ship s between Age of the Gamet es
and Incidence of Chrom osoma l
Abnorma1lt les
It has long bc:<:n recognized that young mothers bear
relatively few infants wilh chromosomal derects.
whereas the incidence of such problems riscs dra-
matically with advancing age in Ihose ITI(Ire than 35
years old at the lime of conception. Th rcc explana-
lions have been advanced , Fim, oocyte, that even-
lually mature ha,.., undergone a phase of "arrested
development" that was initiated during fetal life. By
Ihe time meiosis I is rCl;umoo. the oocyte can be
Ihree months older than the recorded age of the
mother. There mu)' be an upper limit to the time
that primary oocytC& can remain in good condition.
Second. it has been proposed that a se lection proces..
favors the maturalion of heal/h" oocytes during
ovarian cycles_ If this is true, the chances lhal a de-
fective oocyle will mature late in li fe arc increased
(since the total numbers availahle for selection are
low and the proportion of unhealthy on.s may be
higher.) Third . changes in the microenvironment
.."",,,ntling wi'hin
the sensitivities of follicles to ovulalion-indueing hor-
mones, Or the ahility of the hypQthalamohypophysial
s)'stem \0 present a sufficient and optimally tim«l
prcovulatory "surge·· can affecI Ihe condilion of 00-
eytcs re1eastd, Changes in the secretions of fallopian
tube Ruids may adverscly innucncc the proccs<cs of
sperm capacilation and fertilization.
It is likely, however, that aging impai", postfertil-
ization events as well, The observation that chro-
mosomal aberrations in neonales are more common
when older mOlhers have nOI previously borne sib-
lings suppQrts thi, concept. It is pOSSible. for exam-
ple. that altered respQnses of oviduclal muscle retard
Or aecelerale the passage of the conceptus to thc
uteruS for implantation. and that an inadequately
preparoo endometrium presents less tlmn oplimal
conditions for implantalion,
Since spermatogonia renew themselves by mitosi"
and the cells that mature into primary spermate-
cytes can be formoo only days before the wave of
spermalogencsis commences, little attention was a t
first directed al the possible innuence. of paternal
age. However. in most cases thc falhers arc atleasl
as old as the mOl hers, and il has reccnlly been shown
that offspring with XXV chromosome palle,"s usu-
ally acquire the second X from the male parent.
Gamelc age may also be a factor for children born
to younger oouplcs. Wherea s arresled al Ihe
dictyate stage (and spermatogonia formed during
f.tallife) can survive for decades. the ]ife span of
matuff g.rminal cells ii sharply limited. Spermato-
zoa that arrive in the femak tract lWO days before
the time of ovulation. and oocyle! thai reside in the
oviduct for mOrC than 20 hours Ixforc engaging in
fertilization. are far more likdy Ihan "fresh" ga-
metes to enter into the formalion of defective zy-
gotes . "Overripencss" of oocytcs can also result from
eXlernally imposed factors that delay their reica<;e
from the follicles .
The importance of gamete age has been demon-
straled in Siudies utilizing in "itro cultures of sex
cells prior to fertilillltion, and in others in which ovu-
lation has becn delayed by artificial mean. (20.196).
It is also Ixli.,'ed that couples employing the
"rhythm method of contraception". in which coitus
is avoided during the days immediately preccding
and immedialely fol1owing the predicted time of
ovulation. have a higher than otherwise expected
number of children with chromosomal defects. Evi·
denl ly. practices of this kind increase thc chances
Ihal zygoles will form from aging spermalol.Oa or
ova (sec Chapter 16), In subprimates. there are safe-
guards againM fertilization< al inappropri"tc limes.
since female sexual receplivity hormonally linked
with the ovarian cycles. Humans have less cffecli,·c
mecoh, "i.m. (.e<: Charter I S)
S o me Diag nos tic Proced u re s
Information on the nature of the sex chromOSJmes
Can be useful for determining the causes of infertil·
ity. and when decisions concerning assignment of
gender and Ihe institution of surgical or hormonal
treatmcnt mu>! be made for infants born wilh "am-
biguous" external genitalia. Separation. visuali7.a-
tion. and counting of chromosomes are of greatesl
value, and reccntly de,'eloped techniques make it
possible to diagTlOSC abnormalities of Ihe individual
entities. Unfortuna tely. the processes are time-con·
suming and expensive. The)' require special equip-
ment available to JUSt a few laboratories and cxpcr-
tise possessed by only limited numbers of
investigalors.
Simpler teslS can Ix used ,,'hen dctermination of
the numlxrs of X and Y chromosomcs is sufficient.
Thcy can bc performed on readily accessible cells.
such as ones scraped from the inside of the check.
Inactivation of X chromosomes in cxcess of one is
reAecled in the presence of chromatin condensations
or "Barr bodies" Ihal arc visible within Ihe nuclei of
Ihe epithelial cells of the buccal murosa . Normal
(XX) femal es. wilh one inaClivated X have one sueh
body. and Ihey are said to be "chromatin positivc."
Those with XXX and XXXX palterns ha"" Iwo and
three. respectively. In contrast. normal (XY) males
do nol inactivate the X in somatic cells. and they arc
therefore said to bc "chromatin negati",," (since no
such bodies are present). On thc other hand. the cells
of XXV and of XXXV males have one and twO, re-
spectively, and such males arc dromatin positive. X
chromosomes in e xcess of one can also be detected
by examining ncutrophilie (polymorphonuclear) leu·
kocytes of the cireulating blood. Many such cells of
normal females. and those of males with more than
one X. possess "drumsticks" tht are absenl from
Ihe nuclei of normal male leukocytes (Fig. 13-24).
The short arm of the Y chromosome exhibits in-
lense Auorescencc when cell preparations arc treated
with quinacrine hydrochloride. S killed observers can
determine the numbers of Y chromosomes per cell
by counting thc Auoreseenl points within Ihe nuclei.
The techniques have obvioul' limitations: (a) Only
of Ihe cells show Barr bodies or drumsticks.
e""n in individuals with uniform presence of more
than one X chromosome: (b) in genetic mosaics. it is
possible to have extra X chromosomes in SOme parts
of Ihe body (e.g. just Ihe gonads). while eclls of the
buccal mucosa and circulating blood are normal in
appearance: and (cJ Ihe methods cannot pick up chi·
merism associated with normal chromosomc mlln-
lx" and they fail to detect mUlations and related
chrorno<omal (22).
Sp o nta neous ly Oc c urri ng Chro mosoma l
Ano ma lies in Huma ne
A brief survey of the more widely rccosnized disor-
dcrs follow$. No allempt is made to present compre-
hcnsive treatment of the subject.
KLINEFELTER'S SYNDROME (87,128)
In the "classical form." a phenotypic male with 47
XX Y chromosomes undergoes le'licular differentia-
tion and seCreleS sufficient MD I and testOSlerone to
bring aboul masculinization of the dUClS and virili_
7lItion of th. urogenital ,inu, and genilal tubcrele_
However. the phallus is . mall. descent of the testes
is dela}'ed. and subseq uent pulxrtal maturation is in·
complete. The su bnormal teStOSlerOne level, proba-
bly account for the failure of the penis and SCrotum
10 achieve adult proportions. the pc:x:>r developmcnt
of the skeletal muscles. the sparseness of facial. ax-
illary and pulxrtal hair. the high gonadotropin lev-
cis. and the delayed calcification of the epiphyses.
Additional factors mJY contribute to the tall stature.
since the leg bones a re elongaled in juveniles.
Gonadal dysgenesis and inability to produce ma-
ture spermatozoa are the most common findings.

'"
,
,
" -"
, ,
t Fig. 1344 . Sex ""roml !ln in humanl. " , Sa" body in
Underdevelopment of the SenoH cells probably ac-
oounts for the elevated plasma FSH. 11 also contrib-
utes to the azoospermia, but the CXII'lI X chrom(>-
SOme in the germinal cells further impairs gamete
production.
Small percentages of patients with Kleinfelter',
syndrome seCrete normal quantities of androgens.
SEX DETERMINATION 4ND OlFFERENTIATION
,
"
"""_ of • sq"""""'s epil!lftlio l ".11 from the t>uccol
muooMI. 01 I lfImale. 8. 1.... "'omst"" in I
poiymorp/>onljclMr !eukocyt. oj • I........ , C.
Polymorphonuclear 1.....c<>cY'. of • more. (Courtesy ot
Ca rGl,"" Supply Cotnpony.)
They have fu lly developed external genitalia and
abundant body hair. but the testes are atrophied and
the breaslS are enlarged.
Although most XXV males auain normal intelli.
gence (87), the incidence of mild forms of menial
retardation is higher than in XY men . There arc
controversies over the etiologies of "antisocial behav.
ior" and psychiatric Some allribute them
to the deleterious influences of supernumerary X
on brain developmen\. Others suggest
that the subjoxtive reactions during the ea rl y )'ears
arc of primary importance. Amicled children can
the differences in body fealures thai SCI
them apart from eonlemporaries, and their poor
skeletal muscle development lmpall'S athlelic
performance.
Many variant forms are recognized , Some XY I
XXV mosaics with mostly normal cells a re symp-
tom-fr<:<= and fertiic. Others accumulate Ihe XXV
cells almosl exclusively within the gonad. They can
Ihcn have normal somatic features and only chro-
matin-negative cells in the blood and buccal mucosa.
In XXXV subjects, Ihe symptoms are qualilatively
similar but pronounced. Most of Ihe individu·
als a re over 6 f..llall, have espoxially long legs
in proportion 10 Ihe arms), and breast enlargement
that in.elves intraductal tissue. (In different disor_
ders secretion of too much estrogen affeclS mostly
the ducts ,) The rare individuals with XXXXY and
some olher pallern! suffer severe mental retardation,
more pronounced skelelal system I.,ions. and
"st reak" gonads that consist mostly of connective
tissue ,
Approximately 0.2% of newly born male infants
have extra X chromosomes. Since Ihe incidence is
similar in men. the condition evidently does not af·
feCI survival during perinatal and juvenile periods
(12S). The chromosomal aberra tions arc present in
0.5%-2.4% of mentally relarded males (128) but in
mOre tha n half the patients also suffering from go-
nadal dysgenesis tI76). All subjocts have a predom·
inantly male phenotype. evcn when there are many
X chromosomes,
CONDITIONS ASSOCIATED WITH M ULTIPLE Y
CHROMOSOMES
Humans with more Ihan one Y chromowme tend to
be tall. It has been estimaled thai about 0.02% of
adult males have an XYY palieTn, but that lhe fig-
ure is closer to 0.3% when only those wen ovor 6 f"" t
in height are examined . The condition is associated
with varying desrees of testicular dysfunction (rang-
ing from undetectable to <evere) and wilh a moder-
ate incidence of subnormal intelligence. Many pa·
tients have acne (12S), and at least some male more
of the H·Y antisen Ihan XY males (52.183). The
discussion that follows demonstrates OUr need to
learn more about the consequences of having tOO
many Y Chromosomes. It also illustra tes the case
with which it is possible to draw erroneouS conclu-
sions from limiled data.
The males of many vertebrate species display
more aggression than the females. The effccls are
logically anributed (at least in pan) to Ihe higher
teslOSlerOne levels in males. The concept is sup-
ported by observa tions that dominant members of
animal societies oflen ha." plasma concentrations of
the sieroid that are greater than Ihose of the subor.
dinates. and also by studies in which and rogen injec-
tions ha." increased aggressive behavior. The Y
chromosome may also exert androgen-independent
inAuences on central nervOUS sySlem development.
The greater tendency of XYY than XY fishes to
fight sc<:ms to be related to this.
The notion that humans with morc than one Y
chromosome tend to engage in violent behavior prob-
ably grew OUi of considerations of this kind . An a t-
torney contended that his client could not he held
accountable for criminal behavior because he suf-
fered the defect. Soon afterward. there werc reports
of high incidences of XYY pallern. among individ-
uals confined to penal institulions.
The findings wCre put into mOre realistic perspec-
tive when it was demonstrated that a fair number of
"upright citiuns" harDored the ddec\. Attempts
were then made to conserve the hypothesis by sug·
gesting that the XYY men who appeared to be nOr-
mal were able to inaeth-ate the extra chromowmc.
(Some subhuman mammals can eliminate a Y chro-
mosome from the germ cells [1191,)
More exacting studies on large numbers of sub-
jects led to different ronclusioos (ahhoueh it should
be mentioned that because funds were limited only
tall men were examined [70. 1951). The incidence of
XYY was indeed high in penal institution popula·
but the affiicted individuals failed to display
increased tendencies to engage in violent behavior.
Most members of the group had been apprehcnded
for then and related infringements. The o.'erwhclm_
ing majority were of subnormal intelligence. and the
incidence of criminality was no grealer than among
others with similar mental equipmen!. The obvious
conclusion is that the XYY males were not Skillful
al cvadins capture (125.195). (It shOUld be pointed
out, in this connection. Ihat the XYY condilion is
often associated wilh low rates of teslosterone secre-
tion. and that human Y chromosomes arc quite dif-
ferent from fIsh Y chromosomes.)
When Ihe numbers of X as well as Y chromo-
somes are excessive (XXYY. XXXYY. and related
patterns), the individual, usualty have sign, of Kline-
felter's diwrder (57),
TURNER'S SY NDROME
In XO fetuses that survive the gestation period. the
chromosome deletion can usually be linked with a
defeetivespenn cell (161). The typical subject is a
poorly developed of short stature. The char-
acteristic features include rudimentary ("streak")

conads lhal cannot SIIppon ""ebbing of
1M n«k, chest ",ilh incomplctely ma-
tured mammary glands and "'idely spaced nipples.
facial deformities involving Ihe jaws, earl. and e)"e'
lids. 10", nuch31 hairline. oUI "'aro bendi", of tile
forearms (cubilus valgus). shorlcning of one Or morc
melacarpa ls, and hypopl asia or malformation of the
fi",crnails. There a!"C hiah il1l;idences of coarctation
of Ihe IOTUI. !"Cnal syste m dc fects (c.,. ··Itorscshoc
kidney" and duplication of the urctcrs). and of visual
and l uditOO')' sensory defta$. Additiona l common
findings induck pigmenled nevi, and mental retar·
dalion that is associaled "";th "Ipace-form blind-
ness." Varianl forms include XX/ XO mosaics
($()rne of which escope al! of the prc«ding), and
women with onc norma l and one defeclive X
chromosome.
The incidence among live births is around I in
2000 (7). It approach"'l $% in aborted feluses thaI
come to a utop$y. It is bclit-ved Ihal very few XO em·
bfyos surviYC 10 the fetalilage. The!"C is also high
neonalal a nd infant monalit y among humans suffer.
ing lhe defcet (St. ).
Sin« males "";th just one X ehrorn(l8OmC do not
have rdated problems. il is possible that two 5cx
chromosonles ael in conce rt \ 0 accomplish certain
aSpeCls of normal female differentia tion.
" s al ready noted. XO micr ca n beQ}flle fert ile fe-
males. [t is not known "'oct he r they suffer menIal
dcfccu. " curious varialion on the tocrne is secn in
ereeping..oles. Female somalie cells a rc XO. bUllhe
X undergoes du pliution du ring
"'lis. Normal somatic cells of some marsupials a re all
XO.
A "mole form of Turner'. Iyndromc" is ottributed 10
trl.aiocalion to Ihe . i",le X ehromO$Omc of genetic mo·
leri.1 normolly f"" n<! on Ihc Y. The vklim, ma ke H·Y
I nliscn Ind form lesl"'l. bUI lhey l ulTer IQnU.lic dcfecl$
lItCh I t ,.bil.' ...18. '- ""rdiOO'a..,ular anomalies. and fa·
eial dcformilies. llonl wllh 'f)"plorchism. pOOr l cydi&
« II f.""IOon.. imp;airc<i spennalOlCnoesis, and ..... nl.1 rc-
tardaliool. CMriously ...... ny have tyll«()ma<lia.
"SUPERFEM ALES"
Th is lerm is applied when tbere are three or more X
c hromosomes but no Vs. It a misnomer. XXX
women can have regular fea tures, but most
are menIally retarded and $Ieril •. Some XXXX
women whoappcar normal Mvcal$o been described.
The fe'" kflO\>ll 10 have In XXXXX pallern are se-
verely retarded. a nd lite)' 11$0 s t.o... cireulatOO')' sys.-
tem defeclS.
SEX OETERMtNATION...ml DlFFEReNTIA.TION
He lmaphrodit lc MOfS.8le.
Around onc-thinl ofhuman INC hermaphroditeure
XX/ XV mosaics. When the XV cells accumulalcon
one side of Ille body. a leslis forms Ihere and il \LIU'
ally secretes suffIcient MOl and testostcrone 10 viril·
izc the ipsilateral ducts. The contralatera l gonad can
becomc a n ovary if il is PQPulalcd predom inantly by
XX cells and is shielded from H·V anl igen and tes-
licular hormones. More commonly. t he second
tonad rccciVC5 wmc H-V aoo il clcvclop< into an
ovoteslis. In lhe uternal genilalia arc at
least partially virili""d. Tlw:y sometimes a5.$umc
fully masculine forlfl5. HO"'Cver, 5i nc;e gonadal duct
de,'elopmcnl begiM befon: Ihe circulalory syslem is
oom plcl cd. the WoIffia n and Mall.rian ducts Can be
"remi ni1.cd" on Ihe XX s ide. An ovotestis does not
ofte n provide an environment tbat supports oocyte
maturation. It can, ho",ever. secrcle suflicicm estro-
gen 10 prom<.lIe subslant;al mamm:l f)" gland grO'<l·th.
When XX cells predominale, Ihe conse-
quence is development of a n oval')' on one side. an
OI'OIcstis on lite otller. and mostly female·type dif·
ferenlia tion of tilt duclS and ellcrnal genitalia. Hcr·
maj'lhrod ism tan al$() arise in XV / XO, XXV / XO,
.nd ot he r forms of mosaicism. nnd when an XXV
individua l loses V during embryogen·
esls. Other causes are OXlMldercd
DI' Ofd e r. Re.u ltln g fro m Chromosomal
Dele ct.
"tlealt 19 different genes contribute to normal
diffcrentiation (1 9 3). Some are on autosomcs.
"'''''rcal othcrs are 00 the X. " normal X is essent;al
for ",,,Ie as wcll as femalc development .
Two ex pbnatioo. have been offcred for Ihe wide-
spread occurre nce of sex chrOln()$()llle defects: (a)
MOSt o f the disorders arc compatible with s urvival;
100 (b) the su chromosomes are more li kel y 10 be-
come altered lhan lhe autOl!Oll>CS. (The second X of
femalc:s replicatcs laiC. while the Y ehro"""""",,c
ca nnot synapse complelely with Ihe X and is often
altered du ring the "crossing<lver" pIIasc of meiosis).
Techniques are availabl e for detection of chn:.>-
I\lO$OmD I duplication •. delctions. in,'crsions, lra"",lo-
ca tions. n nd fragmentations. and w "'e individuals
harbor "rini··type However. suc h
mel!>Ods eanoot usually pick up mU lalKmS a ..... i·
ated with normal chrolTlOSOllUl ,i7.t or s hape. Cer·
tain mUIDtions affect the bios)'nthcsis of enzymes
...:cded to make eillM:r gonadal hormones or Ihc re-
«ptors for those: regula tors. Otocrs tan impair the
ability of genital ridges to accv.mu1ate adequat e
numbers of gonocytes. Or the differentiation of the
epithelial and mesenchymal components of the in-
diffen:nt gonads.
" XV Females" and "XX Males " ( 16)
The H_ Y antigen (rather than the Y chromosome)
seems to be the major determinant of the emcrgence
of "maleness" (22). An mutatioo that sup-
presses 1.j_Y synthesis ha' bc<:n found in XY fertile
femak wood lemmings (119). Iluman 46 XY fe-
males that do not ma le H-Y an tigen may have a
rdated mutation . but anmher possibility is thatthcir
Y chromosomes have lost a camponent that is pres-
ent in norma! males.
"XX males" may have an X chromosome or au·
tosome thaI has acquired DNA sequences normally
located on Y chromosomes, or a mutatiol1that per·
mits H-Y antigen synthesis in some other way.
In "XO males" one possibililY is Ihat the sinsle
sex ch romosome comains Y determinants. Another
is that the zygote and young embryo were XV, but
the Y chromosome was 1001 during fetal life.
!n a species of mongoose. "XO males" make H-Y
amigen. whereas "XO females" do no!. In SOme XX
male and XX hermaphroditic goats. a defective au·
tosomal recessive gene is held responsible for the
anomalies. whereas an aUlosomal dominant gene has
heM linlocl wi, h eme'eenc. of XX m, I. mice ( t 19)
Problems Relaled 10 Oelectlve Synthesis
and / or Use 01 Oihydrotestosterone
It will be recalled thaI lestosterone directl)' on
the Wolman duct •• but ,·iri!i7.3tion of thc urogenital
and tubercle can OCCur only when a 5a·redue·
tase con"crsion of that steroid to DHT. In
and also in rats and mice. genetic defects
Iht impair Ihe following have been detected: (a)
production of adequate quantities of the cnl.yme: (b)
formation of an cnl.),me with normal prop-
erties: (c) both of the preceding; and (d) syn thesis of
DHT receptors (193).
Sa-REOUCTASE OEFICIENCY
Three different single·gene mutalions that lead 10
partial or completc deficiency are
(193). None alfects H·Y synthesis. testicular dilfer·
cmialion. 11.1 DI release. testostcrone secrelion. or in-
terstilial cell responsiveness 10 LH .
In XY males producing the usual amounts of tcs-
tosterone. the testes and ae«ssory reproduclive or-
gans develop and the Mullerian ducts regress. How·
ever. when Ihe enl.)'me defect is severe. the
genitalia a,"ume fcmale form (with Wolman duclS
lerminating in a "blind" vagina). When somewhat
more of the enzyme is made. tbe external structures
undergo incomplete _irili7.ation and they arC "am-
biguous" in the infant. An interesting variant is the
"penis at twel'e" syndromc (130). The infants arc
often judged 10 be females at Ihc time of birth, de-
spite a somewhat enlarged phallus and partially
fused labia. At puberty. LH secretion increases. and
this stimulates production of enough testosterone to
accomplish inductiCKl of subslantial quanlities of the
5<>-reductase. The consequenc.s include growt h of
the pen is. enlargement of the larynx. full develop-
ment of the musculature. and thc appear-
ane<: of abundant facial. axi\!ary. and pubic hair.
Most of the affected individuals then make satisfac-
tory adjustments to male gender roles . The disorder
is prcvalcnt in some geographical locales, and at·
tempts arc now made to rccognile the eondilion at
the time of binh. The children are Ihen raised from
infancy boys and they are given appropriate hor·
mone
ANDROGEN RECEPTOR OEFECTS
Three of defects that impair respo/lSN to DHT
are recogniu:d (SS): (a) failure 10 maxe hormone re-
""ptors: (b) formation of !"<'ceptors that do not bind
the stcroid wilh high affinilY and translocate il to lbe
nndell" (e) iMhility to m'r<mrl rn hn,m<mrr''''
c<:ptor complexes that translocate.
In human "complete testicular feminil.ation," the
testes form and they promote regression of the MUl-
lerian However. there is no virili7.ation of
either the Wolman or urogenital organs. Infants
born wilh tbe condition look like perfectly norOlal fe-
males al birth. Gonadotropin seerelion increases at
puberty. and estrogen is released in quantities suffi·
cient to support maturation of the breasts and othe r
female secondary sex characteristics. The only ex·
ternal indicalions that somelhing is wrong arc the
failures to grow axillary and pubic hair and 10 eslab.-
lish menstrual cydes. At such times. the individual
may cansu\! an endocrinologist and soon learn that
"she" nas a 46 XY chromooome pattern. In other
cases, the diagnosis made because Ihc patient de-
velops an inguinal hernia. There is cancern oV<'r the
delayed deteclion of Ihe problem, since thc incidence
of testicular neoplasia is much higher in pseudoher·
maphrodites than in XY males.
When there arc limited numbers of OHT re«p-
tors. defects recognizable at birth can include hypo.
spadias (in which tbe urethral o,ifi<;:e is located on
the undersurface of a poorly de,cloped penis) and
incomplete fusion of the SCrotum (55. lOa). Breast
developmenl may be extensive at puberty. The term
'"Rein/ensleit':r syndrome" is applied to the clinical

'"
picture. but it can also designate problems arising
From inability 10 ","crete sufficient testosterone.
Related disorders OCCur spontanoously in labora-
lory animals. Tfm (testicular femini'.al;on m"tan(j
a'nimal! are phenotypic but sterile females that are
resistant!O exogenous androgens. M ice evidently .uf·
fer more complete defects than lhe ralS (12). Previ-
ously healthy XY rodents treated wi th androgen re-
ceptor antagonists a1 a very carly devdopmcn lal
stage acquire similar characteristics.
Mutations Affecting Steroid Hormone
Biosynthesis
The steps leading from cholesterol 10 pregnenolone
and [0 17a-hydroxyprogeslcrone 31"<' similar in the
adrenal cortex and gonads. Some genetic defects im-
pa ir steroidogenesis in both. whereas others afTect
only the 1cstts and ovaries. Deficiencies of either the
C 17 .C20 lyase Or the 17,8-hydroxy.teroid dehydrog-
enase (17-<>xokctore<:!uctase) lead to incomplete vi_
rilization of the Wolffian ducts and "feminization"
of the external geni talia. XY individuals form teSte.
and Mllilerian duct TCg ression. However.
testosterone deficiency precludes sperm maturation.
and pubertal maturatioo proceeds along "female"
lin ....
There are no known eases in which testosterone
can be made. but its ar(lmati7.ation i. bkx:kcd (192).
This has led 10 speculation that estrogens a re essen·
tial for su .. iva!. (Aromatasc enzyme inhibitors have
been given to experimental animals, but they do not
lotally abolish estrogen production.)
Ra re cases of 17a-hydroxylase deficiency have
been found. They a re associated wilh sexual infan-
lil ism. and with inability to make the
lated glucocorticoids. Therefore, replacement ther·
apy must be inSl iluted $OOn after birth. Exogenous
cortisol and SOme of the synthetic glucocort icoids
ca n be util ized for testoslerone syn thesis.
The devasta ting consequences of failure 10 ma kc
3/t· hydroxysteroid dehydrogenase or pregnenokme
synthase were considered in Chapter 6. Sieroids sup-
pl ied by Ihe mate rnal system support su ..ival but fc-
luses with XY chromosomes and testes cannot ac·
complish different iation of the Wolflian duc\$_
I ofants succumb to adrenocortical insufficiency if reo
placement Iherapy is not soon afler birth.
Extragonadal Hormonel Affecting Sex
DifferentIation
The adrenal glands devclop io dose proximity to the
The they release may be major reg-
ulaton; of re product ive S)'stem diff.reotiation in
SEX DETERr.ttNA, TION A,N D DIFFERENTtA, lION
male marsupials (28). but they probably do not exert
important infl uences in normal eutherian fetuses.
21-hydroxylase deficiency impair< the coovcnoion
of pregnenolone to glucocorticoids> diminishes the
glucocorticoid inhibilion of ACfl-1 ,""erelion . and ac-
celerates ACTH ,""cretion. Pregnenolone then accu -
mulates in the adrenal glands. and most of it is made
into androgens that travel 10 thc reproductive organs
(145). Afflicted XX fetuses dcvelop ovarics (sincc
they do oot make H_Y antigen). and they retain
their MUllerian ducts there are no testes).
However. if the androgens are released early in the
gestation period. the Wolffian ducts are stim ulate<:!
and the external genilalia undergo virili,.ation .
Therefore, the individual becomes a female
pseudo he r rna ph rod ite.
An "adrenogcnilal syndrome" can also develop
latcr in life . if adreflOCOrtical tumor!> Or adrenal
glands overstimulated by ACTH begin to make
cessive androgen. Boys then undergo precociou< pu-
berty. whereas girls become Female repro-
ductive structures cannot be totaliy
aftcr a "cri tical slage" of development i. completed ,
However, Ihe androgens promotc growth of the cli-
toris. enlargement of the larynx> and hypertrophy of
the skeletal muscles. They also Slimulate the ,""ba-
glands of the ' ki n and C'In hir<" i.i,m
They aCI on Ihe pitUitary gland to interfere with es-
tablishment of menslrual cycles. and they promote
premature closure of the cpiphyses of Ihc long bones.
MATERNALLY DERIVED AN DROGENS
Sieroids made by ovarian Or adrenal gland tumors of
the mot her can cross the placenta. Female fctuses
have also been adversely affected by synthetic pro-
gestogens Ihat interact wilh androgen reccptor< or
are metabolized to such steroids. Fortuna tely, it is no
longer the custom to adminisler the progestogens to
wonten with a history of spontaneous abortions.
TRANSFE R OF H·Y ANTIGEN
When mu lti ple fertilizalions OCcur in humans. each
conce ptus establiShes its own private placental ar·
rangemcn\$. It is therefore possible for male and fe-
male sibling fCluses to simultaneously undergo nor·
mal development_
In catt le, vascular anastomoses conn""ling the
placentas aro often eSlablished. and these permil
fetal exchanges of cells as well as of molecules. An
XX twin can accomplish normal preliminary devcl.
opment of the ovaries. gonadal ducts, and urogenita l
sinu before coming under the inAuencc of H-Y an-
tigen and germinal cells releascd by a male sibling.
Afterward, one or both ovaries arc transformed into
testosterone-secreting OV(llestes and the external
genitalia become virilized. The affected calf is
known as ajrunmrlin. Depending ullOn the Stage at
which the exchanges begin, she becomes either a
true or a pseudohermaphrodite. The observations
demonstrate that even a partially differentiated
ovary Can be markedly altered by the antigen (119).
In ralS and mice. the placentas remain separated,
but androgens made by XY fetuses can travel to XX
siblings. Females that develop in close proximity to
males show mild virili7.ation of the external geni.
talia. At binh. the anogenital spacings arc greatcr
than in unaffected females. latcr. there are differ.
enttS in Ihe timing of puberty onset and in the
lengtns of the ovarian cycles. Howe,·cr. the .Iightly
masculini7.cd females arc fcrtile (182).
ADDITIONAL FACTORS AFFECTI NG
REPRODUCTIVE SYSTEM DEVELOPM ENT
The '"persistent MUllerian duct syndrome" is a rare
condition seen in XY individual. with testosterone·
secreting testes (108). Presumably. it is caused by
either inadequate or delayed secretion of MOL or a
receptor defect. The wmmon a"ociation wilh asper.
matogenesis suggests thaI the mutation simulla·
neously affects several Sertoli cell functions. Al_
though there arc indications that pituitary hormones
affect MO l secretion (153). the developmental stage
during which duct regrc$ ion normally OCCUrs is not
wnsistem with pituitary etiology of thc disorder.
Tbe syndrome is distinguishable from one in which
the genital ridge fails \0 form and hormonc secretion
is never established.
When the interstitial cells do not acquire normal
gonadotropin the testes makc sufficient
androgen to promote Wolffian duct maturation but
the external genitalia arc 001 fully virilized. In
human infants. the can include hypo.-
spadias and microphallus. Postnatal androgen injec·
tions alleviate the metabolic consequences of testos·
terone deficiency. but they cannot normali7.c the
malformed structures.
In humans and in some other large mammals.
chorionic gonadotropins act on the t H receptors.
Therefore, inability to secr<:te adequate amounts of
pituitary LEI n""d not impair early differentiation.
Some lH seems to be nceded during the third
trimester to achieve adequate testOSterone produc-
lion. Dcficiencies impair the later stages of gonadal
and phallus growth. and they delay or block descen t
of tbe t .. t .. (153). Androgen administration can
wrrect some of the problems that arise postnatally.
but gonadotropins are usually given (since they pro-
mote interstitial cell proliferation and maturation)
(3g.58). Sometimes. gOllOC}1CS migrate to the een-
tral nervOus system and establish germinomas (162).
They then impili r gonadotropin secretion during the
second decade. (By wntrast with humans. rabbits
and some other small mammals require pituitary
lH during the gestation period (381.)
Maternal diets that are calorically inadequate im_
pose generalized problems that can include interfer_
ence with normal differentiation of the r<:productive
organs. Caloric dcficicnciesduring infancy delay tes-
ticular and seminal vesicle growth and the onset of
spermatogenesis (152) . In rodents. the pineal gland
mediates some of the cffeclS (I 86). The concept tht
females must acquire an adequate fat:lean body
mar.s ratio before they establish ovarian cycles is dis-
cussed in Chapter 15.
Zinc is needed in relatively large amounts during
early development. and it is known \0 affect proper-
tie.< of androgen receptors (79, I 75). Infants born to
zinc-<ieprived mothers ar<: likely to .uffer a ,,'ide va-
riety of somatic disorders as well. Iodine deficiency
impairs maternal a nd fetal production of the thyroid
hormones needed for central nervous system matu·
ration early in life and for de,'clopment of other or·
gans. Prostaglandins arc from
jally acids. Since they play numerous role< in repro-
duction (69.157) it is safe to assume that maternal
diets lacking such molecules are harmful. However.
it is diffIcult to study the problem since dietary ma·
nipulations have yielded a bewildering array of
wnsequenees.
Testosterone production in felUses ,an be de-
pressed by maternal st,us (21) . and males subjected
to stress·invoking procedures after birth show simi·
lar effects (152).
Autoimmune disorders and viral infections are as·
SQ<;iated with tissue destruction and a variety of hor·
mone receptor problems (149). They n<>1 uncom-
monly affeet both adrenoconical and reproductive
proce!.S" within the same individual (73).
SEX DIFFERENTIATI ON OF THE C ENTRAL
NERVOUS SYSTEM
Much of Our knowlcdge of reproductive system de-
velopment is wnsistent with the wneeptthal mam-
mals have an '"inherently female" body makeup.
upon which testicular can impose maSCu-
linity. The notion can be applied only with reserva-
tions to sex differentiation of the central nervous
system.
The most obvious gender·related differences in
neuron-controlled processes arc jun("lional (rather
than morphological) and quantillllivt (rather than
qualitative). Males secrete more androgen and less
estrogen and progesterone than females. but the
members of both sexes have central nervous system
receptors for all of those hormones. The sensitivities
 DETERMINATION AND OIFFEFl'ENTI" lION
'"

Fig. 13·25. TIIiooi...,ained hi. ' <>IOQi<:a1wetion. ( 00 OIienlal;on, . <>d _,,,,,, C arod 0 pro."" gr..".r
1"'0<41 ,he oexoally _phic """""'" (a rrow,) 01 r.;.toloQic1>1 do..il. AbI;>r ....lions: AC, ant..ior commissure ,
,.,. medi.ol preoptic . ' . . 0' the po;nl 01 itl ""' • ...,urn OC. <>ptic Chi .. Ufltum; 00 , ouprtehiosma,ie no.ocr.u •.
d ,."eI<>prneol in twO gonIIdeClom;zed ma r. ( A. C).nd (Reprinted I,,,,,, Gor.ki. 1978, r.'"""", s.4)
1.....,. (B. 0) ed"" rals. SeotOon. " aM B Pf""ido _ . ,
of certa in neuron groups IQ endogenQU$ and admin-
istered regulators also differ. but the ranges ove rlap.
Certain forms of behavior have been classified as
masculine or feminine. a nd those related to copula-
tion are similar aCro" the various vertebrate species.
Yet. populations of normal animals con tain fully fer-
tile females that are motivated to mOUnt conspeciflcs
of ei ther sex. and also males that display "rcceptiv-
iW'· The tendencies of both males and females to
engage in either form of behavior can be enhanced
by manipulating social as well as oormonal factors.
Morcover. testostcrQne is an aroosal stimulant for fe-
males. while estrogens bring OUt ma.<culinc·type re-
sponses in both males and females (I).
Even greater difficulties are enrountered in delin-
eating sexual dimorphism when forms of beha vior
thaI an: 00\ directly related to reproduction arc stud-
ied. It is ge nerally expected that males will be IIlQI"C
aggressive . eSJlCc ially when they are defending ha·
rems or territory: yet aggression is regarded as "nor·
mal" for females whose lilters are threatened . Sub-
missiveness has been c1assifi«l as a female trait, but
most animal societies contain subordinate males.
The gender roles vary widely with the spe<:ies. In
some groups, the females assume full care of the
young, whereas the males are the predators. In oth·
ers, males participa te in "maternal" activities. and
females either join them in the hunt or serve as the
major food providers.
Morphological Differences in the Central
Nervous System
Since behavioral responses can Ix: unpredictable and
dillicult to quantitate, "objectively verifiable" mor·
phological sex differenccs have Ix:en eagerly sought.
In some cases, relationships bet,,"cen speciali1.cd
characteristics of some neuron clusters and repro-
ductive functions have been demonstrated.
The spinal nucleus of the cave'no&u< is nccded ror
the motor activities inVQived in intromission
and ejaculation. It undergoes androgen-<lependent
development in male (but not in normal female) ratS
(92). Females castrated soon after birth and then
gi,·en repeated testosterone injections acquire large
phalluses and male-type nuclei that support their
ability to engage in intromission.
Spinal cord motor neurons of male animals accu·
mulate amOuntS of teStOSterone and of
DHT. Intraspinal administration of thc androgens
has sti mulatory effects on penile Estrogens
inereasc the of sensory neurons that innervate
perineal regions (3 ). Normal adult female rJlS tend
to have larger ventrom«lial hypothalamic neuron
clusters than adult males. and the synapo;c patterns
in the preoptic regions also show sexual dimorphism .
Both regions facilitate ovulatory reftexes . T he amyg-
daloid CQmplexe:o; modulate ",productive Ix:hav ior,
and sex-linked differences in electrical activity fol-
lowing stimulation have bee n described (21).
The mast obvious morphological differences have
been found in a part of the brain whose functions
have nQt been defined. The medial prwptie area on
each side contains a neuron group tilat has been
named the sexually dimorphi( nucleus (SON) (5 4)
beeause it is some 8 times greater in sile in castrated
males than in female rats (4) (Fig.
13-25). The nucleus enlarges during the first IOdays
after birth in the males (92). Neonatal orch iectomy
diminishes. ,,"hile neonatal ovariectomy augments
the SON: however, the sex differences are not abol_
ished by .uch surgery. It seems. therefore, that
either the ncuronS that go into it are established be-
fore the time of bi rth, or factors other than gonadal
hormones direct S ON maturation.
Mascu linization vs. Dalamlnlzatlon
The "'()ros ma.«IllinizQtiQtl and viriliwtiQtl were
used to deseribe t he effects of Y chromosom"811S<>-
eiated regulators (H .Y antigen. testosterone , MDI,
etc.) on the gonads. gonadal ducts, accessory repro-
ductive structures, and secondary sex char·
acteristics.
More complex terminology i. applied 10 neuron-
regulated functions. Here, mas(ulinizariM desig-
nale. androgen-linked establishment and augmen-
tation of the inclination to engage in copulatory and
related behaviors. Dejemini;;aNQtI refers to supprcs·
sion of "inherently" female gonadotropin relea ..
pallerns as well as tendencies to display sexual re-
ceptivity. Investigators who believe that fcmale-type
development is inherent seldom usc the term
jeminiwliM.
Under normal conditions. most male nonprimate
mammals undergo both masculini7-'!tion a nd defem_
inization. However, the processes can be separately
manipulated in rats, mice and other spe<:ies. Males
and females subjected to certain carefully timed hor-
mOne treatments will engage in mounting, intromis-
sion, and ejaculation , and also in lordosis (assump..
tion of the posture assumed by rec<:ptivc
females when stimulated by ma les). They arc some-
times said to be bisexual (21). Primates show maS·
culini7.8tion but they are not believed to undergo de·
feminization (100).
OrganlzetlQnel VB. Aetlvetlonel Effects of
Hormonas
Organizational (cond it ioning, imprinting) influer>CeS
are exerted duri ng an early "critical" phase of dc-
velQpment . The major consequences arc oot ma ni-
fested until long afterward. For example, androgens

secreted Or administered perinatally in nus affect g.,.
nadolropin secretion pallern! and behavioral re.
sponses that emerge after the onset of puberty.
The effe<:ls take time 10 develop. and Ihey are usu·
ally permanent. Since Ihey involve induction of spe·
eif,c macromolecules, Ihey can be bloeked with pr.,.
lein and RNA synthesis inhibi tOr!. Usually.
preexisting arc affected. Certain neuron dus·
lers within the brain of the rat fe tus that regulate
reproductive functions complete mitosis by day 14.
and some Olhers continue to divide until day 16 or
17 (10 1), whereas organi7.ational influences arc
known to be exerted after day 18. However, the jXI<I'
sibility thai estrogens exert some very early influ·
ences on mitosis has not been ruled out .
The survival of developing neurons determined
to a great extent by the kinds of cell-to-eell com·
munications established . Gonadal steroids addoo to
culture systems affect the outgrowth of axonal and
dendritic processes (170.171). Sinec only some of
the cells respond, the hormones can prolong (or
shorten) the live,s of neurons wilhin brain
loei,
hormones can also affeci cell
growlh, nuclear and nucleolar volumes, a nd lhe
CQmpOSitions of membranes, They exen influences
on mechanisms for regulating lhc uptakc of inor·
gank as well as organiC components of Ihe microen-
vironment. and they Can in this way affect sponta-
neOuS firing rates and electrical activity responses to
st imu lation. In addition, they modulate the ma-
chine ry involved in the synthesis. storage. degrada-
tion. and release of neurotransmitter and hormones.
Their long-range effects include differences in the
numbers of hormone receptors in region. of
the brain, Sex differences in the binding of serotonin
(45A), as well as of gonadal steroids are known .
AClivaliOtWI stimulation is more proximally re-
lated to overt responses , Can act on fully
developed brains to reversibly modulate the func-
lions , The regulators do not actually elicit Ihe be-
havior, bUllhey facilitate its expression .
Several forms of aetivational stimulation arC rec-
ognized. (a) Those with brief latencics and durations
seem to involve direct infiucnccs of hormones on
plasma membranes. Estrogens can alter the firing
rates of some preoptic neurons within milli<eCQnds
(100). The meehanisms must differ from ones in-
voked by ncurotransmillers. since the responses per·
sist for a time after withdrawal of the Slimulus_ (b)
Reactions seen after somewhat longer latent periods
can involve hormonal inftuences on rates of uplake
or release of secondary regulators. (c) Some behav-
ioral changes OCCur within half an hour after hor·
presentation. Thcy probably depend on new
SEX OETt:RMtN" T'ON " NO OIFFt:RENTI"TION
protein (but not RNA) ProgCSlerone fa-
cilitation of estrogen-invoked lordosis has such a
time course. Its effects are blocked with anisomyein
(a protein s)'nthesis inhibitor) (100.126). but not
with actinomycin D. (d) Changes resulting from
"classical"' mechanisms of action of hor-
mones require alleast One hou r to develop. These are
susceplible to actinomycin D block. (e) Estrogen·in-
duced lordosis in ovarie<:tomizcd animals peaks after
several days. and the effects persist long afterward.
Stimulation of this kind may require complex alter-
ations of Ihe cellular machinery,
The need for activational hormones is modified by
teaming and experience. Thus, normal bUI "narvc"
adult male rats initiate copulatory behavior when
they arc presented with receptive females, whereas
androgetH!cfident ones do 1101. Ho....,ver. sexually
experienced males copulate long afler has
lowered the androgen levels, cues Can
trigger the release of hormones regulating both
learning and bebavior (78). Aetivational hormones
alYcet lhe responses elicited (38,61).
The TImIng of " CrItical Slages" for
Responses 10 OrganlzaUonallnfluenees
The .se a' which.n "'""1";."0 O<Vni,., ....... l
hormoRC$ depend. on Ihe slage <>f central ne .. oo. ')'Slem
development, The'. ar •• pe.iel difference,. and each
form of response has ils own time·table , In r.i •. maseu·
lini,.ing influences On ,,,".al beha.ior lxgin as earty as 18
day< poslconception. hormones mooulalel.e meehani,ms
conI rolling son..d<>lropin "cr<'ion . ho<tly b<for< and f<>r
• few d.y. following binh on day< 20-22. but .. x differ·
enec. in tUt. preference «(84) can be condilioned after
Vieaning (1 Sl), H.m.le .... wilh ge.,al;on period, of only
16 day$, ,how sensilivities during 'he first lwo week. after
birth Ihat .r< comparable to ones found perin.tally in
rat,. Guinu pigs seem 10 unde'go '""'.euli ni.... ,io. during
d.y< 30-)7 of a 63-70 day ges'ation period (92) . Since
thyroid h<>rmones are major usulolors of central ne1"OOS
.y<lem rnaluralion. Ihe "crilical period."' can be length.
ened by e .... ling def,ciencies. and Ihey can be ,h"'tened
by imposing hyperthyroidi.m (48.tOl)_
Evidenlly. neuronat CQmponents of Ihe b.. in and .pin.1
cord go IhfOllah • brief 'Iage during which mi,osi. OCcurS
but Ihere i. lillie Or no response 10 agem, thai promote
speci.li .... lion or cell groMh. If barmone. affccI prolifer_
a'ion. ,hey mu,' acl a, ,ha, ' ime . Somewh .. later. Ihe
eclls enlarge and acquire Iheir specialized ",uclural and
furt(:tionat fU'ures Ih., indude .."",iatio", wilh OIhor
cell •. Thi, i, probably the .,age <>f maximal "n';livi,y 10
<>rganialional hormQne •. Onty later dou il be<Xlmc p0s-
sible to demonstrale ;n/luenec, of activalionalhorm""" •.
In rats .• uch rc.pon.ivity begi •• 10 emerge a, the end of
Ihe first pOItnllll week (99),
Some pla'licily may be uI.ined . It ha, bun observed
tbat cenain 0<11$ <>f the ral bypotbalamu< 1= tbeir $t n-
. iti.iti •• to organizational df«" onc •• du1!hood i, at·
tained. How".r. if the connection, between them and
other neuro .. are .... red. is regained (54).
Maturation of Mechanisms for Regulating
Gonadotropin Secretion
Th. hypothalamus of the adult male send. Out reg-
ularly recurring ··pulses·· of luteinizing hormone·re·
leasing hormone (LR H). Pituitary gland gonado-
tropes resp::>nd by emitting tcmporally relatcd pulses
of luteinizing hormonc. The LH. in turn. provides
physiological stimulation for the testOStCrOnMCcrct-
ing cells of the testis. In humans and othcr mammals
that maintain reproductive functions throughout the
year. the n«,d for LH docs not cbange very much
from day to day or from wed to week (sec Chapter
14).
Ad"lt female. require more elaborate mecha_
nisms for oontrolling of gOJl3.dotropin secretion. and
they rapidly discharge massive quantities shortly be·
fore ovulation (Chapter IS) . Gonadal steroids regu-
late LH release in all eutherian mammals. bUI there
are ma rked variations in Ihe for
acoomplishing the LH "surges"'. The control systems
wcre first studied intensively in rats. and it was oncc
believed Ihat Ihe findings could be applied to mam-
mals in general. It has recenlly been recognized that
although penatn In many 01 thc
(21). humans and most mon kcys solve
their biological problems in dilTerent ways.
GONADOTROPlN CONTROL IN AATS
Ncurons wilhin thc arCuate and yentromedial hy·
p::>thalamic nudei synthesize and ((,.ically rolease
peptides that stimula te the LH-secreting cells of the
pituitary gland. The term gonodorropin "leasing
hormone (GnRH) is used to designate Ihc hypotha-
lamic regulator. The Guestion of its idcntity with lu-
hormone releasing hormone (LRH) is con-
sidered in Chaplers 14 and 15. Gn RH mUSt be
presented on a ...,gular basis 10 maintain Ihe struc-
tures, secretory funcliollS, and s'''lSil;vilies of the pi-
lUitary cells.
In female rats, Ihe arcuale nuclei eslablish func_
lional relationships wilh neurons of Ihe preoptic reo
gions of the brain. The conne<:tions arc essential for
acoomplishing preovulatory LH ··surges:· and they
synchroni?.c the events with environmental c ues that
indude diurnal variations in lighting. Rats exposed
\0 natural illumination have 4 or 5 (but never 4"')
ovarian cycles. EXTKlSure to contin uous brighl
light ean block ovulation.
Ovarian follicles ··ripen·· during the first phase of
the est rous cycle. When they release sufficienl estro-
gen to '·sensitile" the prroptie me<:hanisms
leading to rapid discharge ofGn RH are sct in mo-
tion. The lH surge and ovulation follow .
If the arcuate nuclei and their connections wilh
the hypothalamo-hypophysial portal eirculalion are
left intaci. but connections betw«'n the nuclei and
other pans of Ihe brain are severed. sufficient GnR H
is released to sUpp::>r1 limited maturation of Ihc ovar-
ian follicles. However. ovulation does not occur since
there are no lH surges. (Ovulation can also be dis-
rupted if are made in the preoptic region,
when pharmacological agents sueh as
impair neuron f"nctions. following destruction of
GnRU·secreting cells. and wilh eSlrogen =ptor
antagonists.)
The hormonal meeh.nisms compte,. When e>!ro-
Ben, arc first released by the o... i.n follicle •. tllcy act
mOStly on tile pituitary gl.nd to inbibit LH rde.",. Ho...·
ever. they also increa.e lhe sen. itivities of tile pituitary
coils 10 LRI I. and L11 . yntb ..i. continue •. Thoref<>r<:. pi·
tuitary $tOres of LH huild up for. 'ime. Continued rc·
lea.. of .'''OS"ns lead. ultimately to ..erotion <>f I.rger
quantiti<1ofGnRH and thiS i. followed by lhe LH $Urge.
GnRI! i. pr.sent in th. preoplic as well •• '.n"omedial
brain relions (3). It seems to function as botb a neuro-
tran,mitter and a hormon •.
The concept that Ihe rat brain has an ·'inherent"'
tcndency to develop along female lines i$ supported
by lhe "bI;.rvalion that neonatal o •• ,iectomy
nol prevent establishment of the machinery required
10 mOunt LH surges. If Ibe ,}Varies of .!lOlh.r animal
are subsequently implanted. Ihe hypothalamus and
pituitary gland support ils cyclic functions. females
Irea ted in this way can ovulale. oonceivc. and bear
young. On the othcr hand. if a previously normal fc·
malc is given a single. moderatl>-Sized dose of testos-
terone soon after birth. the hyp::>thalamus be<:omes
··dcfcmini7.cd.·· After the onset of puberty. a paltern
for GnRH and LH release resembling that of nor-
mal males emerges, and the abililY to mount LH
surges in r(l;ponse to physiological slimuli i$ lost.
The time period during which the system is suscep-
tible to such manipulation is limi ted . I f the androgen
administration is delayed for two Or three days, a
dose is required . The sensitivity is totally lost
by the end of the 6th TKlSlnata\ day.
If dooe. too .mall to invoke lotal d.femini ... tion arc:
used. the females develop. ··del.yed anovulatory . yn_
drom.:· They bav. several cy<:le. soon after puberty
onsel before becoming anovul. tory. and they r.t.in the
ability to accomplisb LH , urge, in responK 10 .kClrical
' limullli"n of tbe bypoth.l.mu,. The defemin ization
,"""" to invol ••• ndrogen influenc...,ert.d on both the
pituitary gland and the goo.d. (21).
Whe n males arc castrated on the first or second
day after birth. the hypothalamus develops along re-

male lincs. Ovaries that are laler implantoo display
activity. The effccts of orchiectomy are casily
reversoo by administering a single dose of testoster-
one, Both cailTation and androgen "replacement"
responSCli are lost after the first postnatal week.
THE AROMATIZATION HYPOTHESIS
When thc effects of perinatal gonadectomy and hor-
mone injection were first observed. it seemed reawn-
able to conclude that testosterone interacts with an·
drogen in the brain to bring about
defeminization , However. Ihe concepl nad to be re-
vised when it was found Ihal tslrOgellS mimic leslo<-
lerone. whereas does nOI.
II was soon revealed that estrogen receplors begin
to appear in the around tne time of
birth, and that they increase in numbers during the
first few postnatal days (99) . MOre<l''Cr. neurons in·
volved in defeminization contain aromatasc enzymcs
that convert tCS!C)Sterone (bul nol DHD to eSlrogen.
The conclusion Ihat tJll"OgtllS are Ihe defemini1.ing
agents is supporled by several finding$ (SS).
The effect' '" testosterone e.n be blocked with oro-
m.ta", en'.ymc inhibitors such IS 1.3.5-0ndr""t.t.i....
3.17-<1ion. (A TO. Fia. I 3-26). :l,'.Andr.. tene-)-<)ne e.r·
• ..-I,iet, .. i,l, ""'"0'';''''' uf .. U>-
torOne to DIIT. is ineffecti.e. Nonsteroidal .gen .. such
as di.thylstilbestrol (DES) that interact with e'trogen re·
«pt"'" mimic the teSt",terone. Estrogen ,eceptor ant.g.
oniS!.< (e ,g. M£R_25) abolish the effects of both teltO$-
terOne and the naturally occurrinjl e,t,ogens.
Cyprot.rone acetate (CPA) competes ,,·i,h both teSlO$-
leron. and DHT for androgen binding $ite •. It> too. im·
pai .. the defeminizing influence, of the <teroid (88).
flow ••••. CPA eannot be regarded .. a "pure"' andre,en
ant.gOl1ist. si"".;t exem some progesterone.like aClions
.nd it inhibits lrom.t.", en>.ymeo (98).
Estro gen-Slndlng Proteins ( 88 ,99 )
The obvious question raised by the preceding obser·
vations is "What prolects Ihe young female against
estrogens secreted by her own ovaries and by the
placenta?"
Young rodents produce ..,Ialively large quanlilies
nr a protein (or a group of closely related ones) Ihat
binds estrogen. with high affinity. The molecules.r.
known under several names. including alpha-foto-
protein. AFP. "...FP. fetonconatal cstrogen-binding
protein> and FEBP. They are formed first in the yolk
sac. Later. Ihey are made in tne liver. from which
they are released into the bloodstream. The concen·
trations of circulating AFP are especially high dur-
ing the "critical period" for org.niution of hypotha-
sex OETEAMtNA TION AND DtFFERENTIA lION
control of GnRH. By binding estrogens. they
sharply limit the ability nr those steroids to gain ac-
cess to cells equipped with receptors. The lauer in·
clude brain neurons affecling defem inization, as well
as accessory reproductive structure components.
During the juocnile period (after thc hypolhalamus
has become "",\"'). AFP levels decline rapidly. The
uterus Ihen undergoes maturation.
Since the proteins do IlQI bind appreciable
amounts of testosterone, tney do not imerfere wilh
lestosterone uptake and aromatization in the
neurons,
Most of the srmMlic e'trogen, and the non'teroidal
aClivatorS of estrogen receptors do not bind to AFP ,,·ith
high affi nity, Therefore. minute dose, aro highly crf«:ti""
... hen admini,t.r.d systemically. Th. naturally occu"in,
gOnadal will defeminize only when given in
amounts that exceed 1he bindin, copacity of AFP.
It is likely that some AFP i. synthesiz.d extrah.pati_
cally (99). Sm.1I amount. are found in the e<:rebrospinal
fluid, and in cert.in neuron, of th. brain that are not in·
vol.ed in the ddemini,.ation . It has been propOSed th.,
'hey provide for accumulation of e>trogens in
certain regions (92). Uterine AFPs may .1"" di •• rt ""me
e;rc"13til\& estrogens away from defemini7.il\& of
the central nervou. syStem.
Th< pl.sma concentration, of AFP roll rapidl}' towaN
the end of the first week and more , lowly thereaft." The
I•• el. are barely detectable by day 20. and the prote in
m.y tOlally disappear from the cir<:ulation by th •• nd of
the first mooth.
APPLICABILITY OF THE AROMATIZATIO N
HYPOTHESIS
It is important to point out Ihat many influences of
androgens On neurons do /WI depend upon aromati-
za tion . Only limited numbers of .. lis contain estro-
gen ree<:ptors. and only some of lhose possess aro-
matase enzymes. (The ones lading the enzyme are
not stimulated by estrogens.) Rat brain contains dif-
fe rent neurons with androgm receptors. Some are
equipped with Sa-reduelases. In guinea pigs and sev-
eral other spe.:ies. androgen receptors mediate some
r<:sponses that require estrogens in the rat (1.99) ,
TESTOSTERONE LEVELS IN NEONATAL
MALES
Since the testis sy nthesi"", androgens and releases
them in to Ihe bloodstream. whereas the immature
ovary has very (i mited ability to ma ke those steroids.
it nas been widely assumed that the male:female dif-
ferences in hypothalamic differentiation in ratS and
related species can be explainoo on the basis of
higner circulating testosterone concenlrations in
 ,
,",
c=o o
o .1. ___
"- "
O- C - Cfl,

'",
i',>-
c/
COOl!
0 0 /- /-
,m
(81""""a .. ;"hi bOOf)
"
CYP"""r""" """,a,e
(OHT "",cpt"" anlag""" ' )

4-Ar><lro"" ""-3_,",,,. 2O-e a rbO<y1ic ocod

(S... ,edu<'.se _ bi'or)

o"
,I - ," --,--?'
"

I
ME A·25 (",ha mo'ylfiphc'oIl
(O'''''9<'n ,,,,,,,p(O, .",' ago.n;ot)

H,c, Ii
N- C- C- O
H
c/
" "
H,c' Ii H

"-
I

I '"
H,c,- H H
/
N_C_ C_N Nalo' '''irlc
H,C/
FMomi<\e
10HT roc<:plOr antagonist)

Fig. 13·26. 5o<M pIoormooologicll l ogeo,s used Ie

$'udy otIfeets 011."0$' ...0<>1 "" the bla 'n .

males during the first postnatal wcd. The dala 001- nave higher , •• ,os,.rOOe k .. I. ,han females during da)'s
Iccted by some investigators support the 11 through 27 .r'er concept;"" has b«n f<>und. ,h.
plasma ore cie>.,ed only on
How.,.r, ,tudi., on large numbers <>f relal and peri· day 18 (the tim. ""hen ro, al androgen p,<>ductioo pea k.
nalal animal, Ihal Ihe m«hani, m, m(lre and neurons wilhi" speCialized brain regions hay. jU.1
Although lendency r<>r male fel use, 10 completed mi'osi.). It has tx:on proposed Ihat dcfcmini_
...
Ziltion o<cu" in lwO nagc$. On day' 18-19, ,,,,,,>s,e,,,ne
JtMilius lhe neurons in males. Ao. resuh. only moder-
ate CQIIcc.u'lioll$ an: required for perinol.1 defemini_
"'tion (188). Neonalal ca.tration depri ••• male, of the
$mall a<nOll"" needed.
The blood pl .. ma of fetal and neonatal female< OOn-
.. in<'0_ 'e,tosterone. However .• ince the le,'.I. arc not
high on days 18-19. Ihe .. n,;\;""tion does no\ o<cur. Tho
animal. therefon: remain un'''pon,;ye,o thei, OW" small
amount. of androgen._ Tho)' .r<;, how',"e' .• rr«'cd by
la ' ge d""es that ar. injecled. (Souren of and"".n, in fc-
male reI""" ha, . I'IOt b«n dct<rmined. T he >toroid; do
not .. om to originate in eithe, ,n . maternal sy'tem or the
r... lo>ar;e$.)
T W<>-sICP mechan;,m. ha"" beon propo>od by oth."
(48), Androgen. can in'ok. seque ntial ch"nses in the
"umbe .. of 't<r<>id re<:eptO« in ,;><oi(,o brain and
in arQmatue and .sc....od"ct... activities (21.9')). The}'
may contral the duration of the critical period.
Although sen.itization requires ooly limited 'moIInt,
of androgen. there i, a Ihr<'$I>old oon<:ontration b<low
which it cannot occur. Female rat fetuses devcio>pi"3 in
close pro,imily 10 male sibling.< bave bigher blood and
amniOlic fluid testosterone colI<entratioo. than """'" lo-
c.. ed b<lween t;v(l fem.le< (182).
SEX DIFFERENTIATION OF THE PRI MATE
HYPOTHALAMUS
The menstrual cycles of most primates dilfer in ob-
vious ways from the estrous cycles of rodents (23).
The former arc usually longer (avcraging around 28
days for humans and some of the monkeys. com·
pared with 4 or 5 days for Ihe rat), Ihey include a
protracled luteal phase during which the ovary ....
CreleS substantial amoums of protesterone. and Ihe
preovulatory surges show no obvious links "ith diur-
nal changes in environmenlal lighting. Moreover.
Ihere is no primate equivalent of Ihe "behavioral es-
trus" Ihat is discussed later.
Unlike Ihe situation deseribed for rodents. pri_
mates mainlain ova rian cycles when connectlom be-
Iween the areuale nuclei and Ihe Olhe r pans of Ihe
brain are seve,""d, or when lesions .'" made in
the preoplie regions (118). Gn R H sli mulation of Ihe
gonadOlropes is requi,""d, but amoun ts dolivcrcd
to the adenohypophysis need not increase on a pcri-
odic basis 10 elicit the LH surges. When the arCuate
nuclei of adult female monkeys are destroyed, the
animals can conlinue to ovulale in a seemingly nor-
mal manner if hourly pulses of synthetic LRH are
provided in dosages that do not vary from day to
day. (A similar pattern of LR H administration
maintains lesticular function in males with lesions
Ihat impair endogenous Gn RH secretion.) It seem$,
Iherefo,"", that Ihe LH surges in Ihese mammals a",
SEX DETERM INATION ANO OIFFEf1l;NTIATIQN
regulated primarily by the ()varies. and that Ihe
GnRH plays the "pcrmissivc" role of mainlaining
Ihe strueturCS and secretory capabililies of Ihe gon·
adotropcs (82,83).
II " ... recon tly demonstrated that rem.l. monkeY'
have fewer dendrilic bifurtation. and .pine. in the preop-
tic region than male. Thi. contr.. ts with the greater
numbe .. in female than in male rats. The preoplie rcgion
i. evidently required f.". normal sexual behavior in male
monkey., bUlllOl for oY"talioo in fern. I...
Since hypolhalamic mecbanisms for GnRH re-
lease are similar in males and females. it is not Sur-
prising thaI no evidence has bc<:n presented for "de-
in male primatcs . .". for a protective
influence of AFPs in the females.
AFPs are made and secreted, but the pr<llein' do rIOt
bind sub$l.ntial quantiti" of emegens. Rei .. in immu_
norellulotion and in e<>ntroi of Ihe rate< of grOWth of ....
tr<lgen .... nsitive nellroos have been proposed from some
of Ihe mammals (163.166). PrimatO$ hove plasm. pro-
teins not flHlnd in rodents Ihat bind testoslerone and es-
trogen •. It i. Iherefore li kely th.1 AFPs perform fllOC-
tioos unrtl.ted to the reproduclive system. (Even in mi<:o.
Ihey may have multiple role<. Quantitative relation,hips
bct""een AFP levels and r.l .. of felal growth have been
de.eribed [641-)
r Uflner indications Ihal gonadal , tcroid •• '" not
important "'gulalors of hypotha la mic , ex differen-
tialion in primales come from observ31iollS made on
human infants cxpo:sed prenatally to high androgcn
concentralions. Female infants born with moder-
alely virilized eXlernal genilalia often undergo flOr·
mal pubertal development. and they subsequently
establish menstrual cycles (40).
HORMONAL REGULATION OF
REPRODUCTIVE BEHAVIOR
In species Ihat display stereotypcd behavioral re-
sponses 10 naturally occurring s timuli. it is easy to
demonSlrate regulatory roles for the hormones.
However. eve n in these. environmental cues and s0-
cial factors contribute to the aClivities (78). Male r0-
dents emit high-frequency sounds Ihal encourage Ihe
display of sexual receptivily by females (47). The
sight and odor of females in can promote re-
lease of hypolhalamic and gonada l hormones in
males. and these arouse sexual interesl (61). Lll lcv-
cis rise in males jusl prior 10 and during coitus (3S).
while vaSinocervical Sl imulation alfeets metabolic
activities in the brains of females (2). Hormones re-
leased in ,""sponse to social and environmental cues
conlribute 10 the behaviors. (Androgens prepare
males for the precopulatory vocaliT.ations, wherews
estrogellli and progestogen. are important determi-
nants of female reactivity.)
Monkey. have more highly developed cerebral
cartice. than rodenlS. and social stimuli a nd learning
are at least as imponant as hormones for de termin_
ing behaviors. Although men release GnR li, LH.
and testosterone in anticipation of sexual activity
(61), behavior in humans is controlled mOStly on a
canscious levd
Hormonal Control of Reproductive Behavior
In the Rat
Adull females undergo regularly recurring changes
in sensitivities 10 stimuli thaI are clearly linked with
the phases of Ihe estrous cycles. The animals beoome
"proceptive" when the foUides and oocytes arc ma-
turing and the estrogen tite rs in the blood begin 10
rise. As the time for ovulation approaches. Ihey i!l-
crease Iheir motor activitie •. (If an exercise wheel is
provided, they use it more often at this time.) As the
blood estrogen levels reach their pcaks. tile females
darl about and orten wiggle their cars. They become
highly receptive to males. and they will assume a
posture that faeililales insertion of the penis into the
vagina if they arc stimulaled. The lordosis response
involves dorsa"ection of the spine . elevation of the
head and rump. extension of the hind leiS. and
movement of the tail away from the vaginal orifice,
It can be elieiled by artificial lactile sl imulation of
the vulva l region (21).
The of females to enter into "behav-
ioral estms" (beeorne ma,imally rcsponsi"e 10 males
during Ihe periovulatory period). and to fight off lhe
at OIller limes. asSure that oopulalion will
OC<:ur only during times optimal for oocyte
fertilization ,
[n contrast. healthy adult males mainta in conlin-
uous motivalion to engage in reproductive behavior.
There have been suggestions that their uninler-
rupted prodUction of very large numbers of spe r-
matoroa is "wasteful." but il has been pointed OUI
thaI a sustained state of readiness a vcrts the need for
highly camplcx mechanisms that synchroni1-c sper-
in one anima l wilh ovulation in aoother
(114).
The behavioral cycles of females depend on the es-
tablishment of neural circuilS. the acquisition of
highly sensilive receptors for CStrogc ns and otller
stimuli. and til. development of camplcx hypotha·
lamic. pituitary. and gonadal mechanisms for hor-
mOne release. The processes are initiated before
birth. bUI Ihey arC susceptible to manipulation dur·
ing Ihe early postnatal period.
Some insighlS inlo the .lfeelS of prenatal hor-
mones are obtained from comparisons of caesarian-
delivered fewses developing in close proximity to
sib lings of the same sex with those exposed to sib-
lings of the opposite sex. The amniotic Auids of fe-
rnales cantiguous with other females contain mOre
estrogen and less testosterone than those of males
implanted nex t to males. The steroids can dilfuse
from One fclus to the neXI. and the eoocentration<
are somewhat modified in this way. Female rnice oc-
cupying uterine sites between twa males have been
reportcd to develop into ad ults thaI arc aggressive
and less allrac tive to males than females developing
belween t "'0 females. However. despite mild urogcn -
ital virilizalion. they relain full fcrtility. Males de·
veloping between Iwo females mature into adults
Ihat are sexually more active than controls develop-
ing between males. but less agg ressive toward olher
males(182A).
Prenatal additionally affecl the central
runclions of se rotonin. a neuroVansmiller thaI can-
tributes to the regulation of lH surges as wen as re-
productive behavior. Gonadal steroids regulalc thc
activities in adult animals. but sex differences in
binding have been demonstrated for gonadectomized
rats (4SA).
OrganiT.ational influences cantinue to be mani_
fested after binh. The medial preoptic area of Ihe
rat plays esse ntial roles in the expression of male sex_
ual behavior. It is pOOrI}' differentiated durin£ the
first 5 postnatal da),s, and it makes fewsynaptie can-
ncctions at that time. Infant females receiving intra-
cerebral transplants of medial preoptic tissue from
males mature inlo females with responsiv-
ity to estrogens and greater tendencies to display lor-
dosis. Progesterone-facililated behavior is not. how-
ever. affectoo. Tlte females also have
tendencies 10 engage in copUlation. The effecls are
at least partially allributed to the formation of large
numbers of estrogen receplors (2A).
The behavioral responses require aClivational hor-
mones. They subside in untreated gonadectomized
females. and they Can be restored by administration
of the appropriate chemical regulators.
When given alone. only large doses of estrogen a rc
effective in ovariectomized females. Much smaller
amoo.mts are needed if progesterone is also provided.
Progesterone alone: Can invoke proceptivity. and it is
believed to cantribute to the physiological onset of
behavioral estrus. h is also implicaled in termination
of that phase. Both effects seem 10 depend on Ihe
induction of spec ific proteins (126). GnRH promotcs
secretion of gonadotropins and thereby of ovarian
steroids. It (or a closely related peplide) additionally
aclS directly on neurons involved in behavior, (lnjcc-
tions of synthetic LRH can invoke sexual rec<:ptivity
even in hypophysectomized females.) An LRH -li\.:c

wilhin the ovary affc<:u lhe responses 10 g0-
nadotropin slimulalion (75). ACli>'alienal hormones
can also inhibit Ihe rcspJNeS. Molecules wilh coni-
cocropin relu si ng hor!TlOnC-like prol'C'nic:s di"..
tribulrotO discrete brain sites. and ;t hal been shown
thai microin fu sion of C RH in to Ihe arcu.le-ventro-
medi.l regions of the hypOthalamus si multaneousl y
suppresses sexual rceeptivity and invokes aggr<:Sl!ion
(16 IA ).
TIle concept lhal the lendency 10 accomplish the
deyclopment is "inhercnt" is. e asily
sUpPOl1ed. Neonatally gonadeetomittd males and
females retti¥ing no steroid I'<:plaament ..apon<! 10
hormonal and mechanical slimulation when thcy al'<:
ad ulls. Even inlaCI males display fOOlC lordotic 1'<:-
SpOnses when they arc kepi in observation "arcna'"
in the compa ny of olher males for protracted pe-
riods. Eslroge n injections the inlensi lies and
fl'<:qucneies of the activilies.
TeslOSterone has defem ini1';nl inlluern;es on the
behuior. females given small a mounts soon afler
binh af(: laler less rcspJfISive to males. even when
It.eyare injected with estrogens IS adults. Although
at leasl some or the effeets del'C'nd on aromati711lion.
is more effective than ewogen in noo-
nalnl anima ls of both species Ihal have been
castra ted.
Males with androgen receptor defc<:ts but lestus-
le!'OM secretion show liule lendency to engage in
lordOISis. even when Ihey art injected wilh estroge ns
dllrina adulthood. The obscmltion has been cited as
support for Ihe conr.:ept lhat estrogen reeeplOl$
(wh ic h are flll>Clional in these rats) mcdi.ale ddtm-
inization. It should be pOinled OIIC. however. that
hleh .ninuJ. a", also deprived of anJrovn influ·
cnces on Ihe brain. Th.y also fail 10 copulate .
SY C<Jntrast with Iheir effec ls in nconalCs. low dos-
agcs of f"dlii"it estrogen_medialed be-
havior in adults. Intact malcs are much"""" likely
to display lordosis tban caslratcs (118).
Ahhough normal male rats lotally Iooc the abil ilY
to mou nl U I surges. tbeir dcfeminiz;a·
lioo" is incomplete. InlaCt ad u1t$ respond 10 both es-
lrogen injections a nd manWil slimulallon. They
quire larger doses of Ihe steroid tban females. a nd
Ihey display lower "lurdosis quOtients" (33) (lor·
dosit:mount ratiOlS), Some authors $laiC Ihat intac t
ma les fail 10 show progeslcrone facilitalion (33). but
OIhers disagrc<: (178 ).
f emales are generally more sensilive 10 estrogcns.
Uowever. members of . pOplllation differ ...·idcly in
behavioral respon5C$ 10 o:1O$enous and rndogcnoos
Stcroids. Some r<:Spond only when given dosages Ihat
.'" effec:tiv.: in males. HorrTlOflCS can act on prwplic
"'gions 10 invoke inh ibition (171). as wcll as on lhe
sex OETERMINA l ION AHO D1ff ERENTJ,t,.TlQN
venlromedial hypOthalamic areas involved in
stimulation.
BEHAVIORAL MASCULINIZATION IN RATS
Preoptic regions of Ihe brain media te mounl ing. in·
trom ission. and ejacul alory behaviors. The aClivilies
B'" bU I il has 001 been eslai).
lishcd tlLat the steroids mllst be during lhe
felal period. In addition 10 aifeeti", Ihe brain. male
conadal hormones increase the taetile sensitivily of
the penis..
Ma ny normal females in mount ing behav-
iors. T he aetivily is increa$Cd if androgens an: i...
jecled . The Ircatments are especially elfoc\ive wben
females arc ovaric<:lomi1.ed soon afte r birth and a rc
Ilten give n "conditioning" dosagcs of tC'5IOSlerone,
Electrica l of the preoptic brain also
brings out Ihe teoocl>Cics.
Some effects I\a .,c been linked with a romali711tion.
Reccnt ly castrated males that an:
seldom a u empt OIlplllation. They can be encouraged
10 do so if thcy an: trealed ..·;th eslrogens. HO....,YCr.
an estrogen·DHT <.:Qmbination is more effeeti,.., (I).
MASCULINIZATION VS . DEFEMINIZATlON:
SOME COMPARISONS
lordosis is elicited in a nima h only
when the dosages of eslrogens given arc in lhe range
required for mainlenana of ulerine weight Tbe J ...
imllb respond wilhin 1&-24 IloIIrs each lime lhe
trcllmenl is inslituted ( 100). The behavior lhen sui).
sides unlil the next injocllons are given. The intervals
between injeclions do nOt nffc<:1 Ihe dosage
f(:Q,ui",ments.
In contrast. dosages tllal restore copulatory be·
havior in recently castrated male adUlts arc insuffi.
eienl 10 promote growt h of Ihe aecCMOry reproduc-
tive OTgans. HO\fI..,ver. if Ihe .nimab a", deprived of
androgens for a protracled I'C'riod. the behavioral cr-
fects can be clicited only after repealed injections of
larse d05C$_ Inle..atingly. however. sexually experi-
enced males that al'<: CaStraled late in life continue
10 mounl females for monlhs al'ler the surgery. The
lime period during which Ihe activilY I'C'rsists i$ im·
pressive. since Ihe average li fe-span in the laboratory
is some thing li ke 2)1 years,
differenlialion of the rodent brain is rr>OI"C
<.:Qmplex than the prcecdinl discussion suggestS.
Some of the faclors Ihal modify beha"ioral respOllSCS
II'<: eiled.
I . NOI .11 ............ ' ions I'" wholly coouisIon, wi. h lhe
arom.tiU.lion hypOlhnil, AnlicstfQg .... do not oons;$'
 lenlly block le,'oslerone-in"Ol:ed behavior. even in cas·
traled mal< ralo. 19·oo.leslO:;le,,,,,e evidently .xeno
grealer influenceo Ihan would be expected solely on the
basis of iI, a'omatiubilily. DHT (which is nol conY. ni·
bl. to estrog.ns) has som. aClivity in castrated male<. E.·
trog.no implanted inlO the preOplic area. of castrat.d
mal. rats stimulate ..,ual behavior only when som.
DHT i. given .y<lemically , J<>.reduced DHT melabolites
can act .1"". to stimulat...,ual behavior in ca,tr.,.d.
st <ually in.. pe,ieneed male mic •. It i. likely. Iher.for •.
thaI occupalion of bolh eSlrogen and androg.n rec.plo",
i. rtquired for run ",pre»ion of male behavior (971\).
2, Progest.rone bind. with 10'" .ffInily 10 androgen ....
ceptor.. Depending upon the ooncenlration. relative 10
tesloster""e. proge".rone can funelion a, .ith.r an 'g'"
Or antag<>niR It can also .treel le.tosle,one metab-
oIi.m by compelinll with Ihat steroid for Sa·reductases.
The 5a-dih)'droprogestuone that is formed may e<crt di·
rect influence. of its own (122) ,
It has botn prQj)OO<d Ihat prOg<Slerone protce .. the
brains of felal primales against potentially deloteriou. in·
ftuencos of androgen. (141). Since progeSterone kveh.re
higher in female Ihan in male rat felu,"s (40). Ih. hor-
mono may play comparable roto. in rodcn". A report
Ihal progesle,,,,,,, injection. protecI ag.in't Ihe d.f.min-
i,ing effects of neonatal androgen ad min i"'ation in fe·
male .... i. oon,i"cot wilh (hi. notion (40),
3. In add ition to acting on th.ir own receptors lind in·
ducing progeslerone r.ccpto ... estrollcns .ffectlh. secre·
tions and f"nction. of prol.ctin. ,r",... h hormone. o'yto-
cin. LH. prO$laglandin.. and hi".mine. Prolactin
mooul.". t .. ticul.r.nd ovori.n ."'roidogcno.i•• nd e,.
erlS neurotran.mit1er·likc aCI;"". in Ihe brain (100). Ox-
ytocin. LH. and prostaglandin, '100 aot at multiple , ite.
to affecl both reproduction and beh.vior •• OO GH con-
tribut.s 10 Ih. regulation of gonod.1 funetions.
ESlradiol i. by many crit.ria Ihe most potenl 01 tho
naturally occurring estrogen •. It i. interoonvcrlibl. with
estrone in many t.rgCI cell •. and it ",rve. a,. precursor
of estriol . We hav. only limited informalion on Ihe spe'
cific role. of some of the metabolite •.
4. Norepin.phrine stimulates pulsalile GnRH .. cre·
lion. [}<)pamine somc of ilS effcetS. and it i,
al"" a major inhibitor of prolactin rele ..e. Estrogen, in·
leract with Ihe oatecholamines in se,'eral w.)" (127) that
include modulation of Ihe luncti"". of catecholamincrgk
ncurOn' (AOOrogens have been .hown to act at somc
of Ihe sam •• il •• ,) Substantial quantities 01 e"rogcn, are
convcrted to catechol derivativ .. in the h),pot ha lamu.
(Fig. 13·27). and al least some products of Ihe ,eaction,
$C",e .. nourotran.mi llers. It ha. be.n report.d that 2-
hydrox)·.stradiol .. cultured gonadotropos to
LRH, and th.t il enhances GnRH in .dult animals (75),
However. bolh 2·hydroxye"radiol , od 2·hydro<yCII'"""
&tern to inh ibil gonadotropin "c""ion in newborn female
rats (21). and 2·h)'droxye".. diol can ouppre" proiaclin
$Cerotion in women (46). Cateehol estrogen. compote
with epinephrine. norepinephrine .00 dopamine for the
oatechol.()..meth)'itransfera.e (COMT) Ihat ",as dc·
,cribed in Chapler 8.
S, Interrelation.hip. bet",ccn tho Ihymus gl.OO aOO the
gonads wcre cilcd earlier. and it "''''" notcd that cstroge",
and ,ndrogen' promOte Ihymic involution. 8y cont,"st.
prog.sterone.OO prolaclin administration c.n O'Ust en·
largement of the gland , Su.pens ion.of Ihymu, Iland ceil.
are reporl.d 10 protecl neonat.1 female. againsl th. dc-
feminiUlion th.t WOuld otherwise <>ccur follOwing andro-
Ben injeclion (81).
6. The oondition. undcr which repTOduetive beh.1vior is
studied in Ihe laboratory .r•• niftcial. and Ih.", arc se-
riou. qu'"ion, coneerning the applicability of the ob>cr·
,,"lions 10 Ihe und .... I.nding of nalurally <>ccurring
evonlS. Animal, are often taken from the ir oages and
placed in an unf.miliar setting. Members of one sex oom.
in Oontact ""ilh those of thc othe r when the inve"igalor
chooses to make ,uch .rrangements. The numbe .. wilhin
each group are arbitr;ttily $Clected. and u.ually th, par·
licipants of the eXperim.nl have no opportunily to ....,a1'"
from the '"a",na:· Nocturnal ani mals .ueh as ralS arc
commonly studied du,ing d.)i ight hou ... (",'he n Ihey
would olhcrwi.e be relatively inaotive). and they .re
mainlained under lighling cood ition. determine<! by con-
unrelated to ones eneountered by f"al ani.
mal>. (··Light> on" at 8 A.M .• nd ·' Iillht' 011". ot 6 P.M.
or 8 P.M. du,ing both summer and winter are f"'quently
emplo),.d.) The pineal gland exert. a variety or influences
on the reproducli'" syst.m. and il i. profoundly affected
by the photoperiod. There i. little unde"tanding of Ihe
differene.s bet"' •• n ··,ummer" vs. "wintor·· .nimals
maintained under COn.tant temperature. humidity. di·
etary and tillhtinll condilions. t>t of the importance of por·
millinll animals to inter.. t ",ith Changing cnvironmenl'.
HORMONAL CONTROL OF REPRODUC TIVE
BEHAVIOR IN PRIMATES
Techniques used 10 rodents are IIQI easily ap-
plied 10 Ihe inveSligation of organizational and aCli.
vational hormones in primate •. Although yoong in·
fam male have higher leslOSlerone level.
Ihan females of the same ages (144). Ihe long ges--
lalion periods and Ihe oomplcxities of the noonale
brains suggest Ihal ··condilioning" OCcurs long be-
fore birth. The mechanism. dilfer from those of ro-
dems. and both Ihe distribulions and funclions of re·
CeplOrs for progesterone and olher hormones arc
dissimilar (91). Surgical and pharmacological ma-
nipulations of young fetuses arC Icchnically difficult
to accomplish. and they invariably traumalil.c both
the mother and the young. Androgens. estrogens.
a nd proge'logen! Can be injecled into pregnanl fe-
males. but affect much more than fetal brain
development. They are also converted
'" a varie(y of biologieally aelive wilh prop-
enies unlike those of the prccursors. Moroover. tlte
amounts that enler the fc(os can only be roughly
cs(imated,
Postnalal behavior ean be modified wilh exoge-
nouS hormones. but it is strongly influcnced by social
cues. learning. psychological conditioning. and other
factors that are nol casily defined or conI rolled. An·
 SH DETERMINATION AND DIFF ERENTIATION

"
o "
o
A J..

OOM'
• c7
I I
"0
'"
"
o
/

"0 "
o "o
A
C-
c7
OO"' •
I I
"0
'"To
H

o o
" "
'c7
I
ESirone
-+ '"
'c7
I
"0 '"
Fig. 13-21. Some .." """", """ a bo!;I•• l¢<med in lhe
c,","'., n.,IIOUS sy&lem.
 deprived of ordinary substi tute aller-
nate cues. are also numerous species and in-
dividual difference •.
Although ddeminization probably does not occur.
males are believed 10 undergo behavioral masculin-
i1.alion . The are. however. mostly quantita-
Juvenile males tend to be more activc than fe-
males of the s.ame but some females are
friskier. The lendency 10 mount Qlher animals i. re-
garded as a male attribu te. bUI SOme females do this
more frequently than their male counterparts. More-
over. Ih. behavior Can be invoked by slimuli unre-
la ted to reproduction. It is used by both sexcs 10 ex-
press dominance. and all healthy juveniles
frequently jump on the backs of their parents. "Psy·
chosocial deprivalion" during infancy blunts Or abol·
ishes overlly interactions wilh other ntent·
bers of the species. even when Ihe animals are gi"en
exogenous hormones.
T he effects of activational hormones dilTer from
those described for rodents. even when rescm blane<:s
in end resulls are observed. Thus, for example. fe-
male monkeys living under natural conditions. and
ones maintained out of doors in large colonies. usu-
ally engage in copulation only during the follicular
or periovulatory phases of their menstrual cycles
(53). They terminate Iheir displays of inlerest in
males as the progesterone le"els rise during the lu-
teat phue •. 11owever. there i. no lrue "behavioral
estrus". Unlike rodents. female rhe,u, mon keys
maintained in laboratories display ., cxual "recep!i,·,
ity" and extend invitalions during all phase' of their
ovarian cycles , A previously isolated healthy male
given aeee" 10 an adult will copulate without
regard to the phase of Ihe cycle. On the other hand .
when given the choie<:. male, select periovulalory fe-
males. The cone<:pt that female, with high
levels are attractive to males because they release
pheromones i010 their vaginal fluids wa, discu.scd in
Chapter 1. It has been widely promulgated by SOme
investigators and refuted by others (50) ,
Organl:Ultlonal and Actlvatlonal Hormones in
Humana
Most of our informalion has been oblained indi-
rectly. Girls exposed prenatally 10 high androgen
levels are said to display more "tomboyism" and
strong interest in physically demanding sports (7).
They do OOt seem to have ,pecial "gender identity"
problems. As children. Ihey regard themselves as
girls. When they altain adulthood, Ihey marry and
bear children in ,uflkient numbers 10 refule the con-
eepttna t prenatal androgen;zalion is a major deter_
minant of postnalal behavior. It has been suggested
Ihat tne lessened tendeneies of prenatally androgen_
ized girls to engage in forms of play considered by
10 be "appropriate" for young females is un-
related to hormonal status. Since androgens arc an-
abolic. girls exposed to thcm tend to be larger and
stronger Ihan other children of the same age. They
may therefore be belter equipped 10 perform athleti.
fealS and 10 resi.t attempts by adults to persuade
Ihem 10 be satisfied with dolls and other toys,
The re arc controversies concerning the elTecls of
prenatal exposure to excessive amount-I of progester-
one. This may be rela ted to observations that natu-
rally occurring progestins comJlC'le weakly with an-
drogens for receptors. They Can serve a,
either agonislS or anlagonists. Synthetic steroids
may aCI directly as potent agoni'" or be melaboli7.ed
10 products Ihat do so.
Some authors state th"t progestcrone protects fe-
male fetuses against androgens (141). and reports
that both male and female iofanl s born to progesto.
gen-treated mothers have reduced activity levels and
la ck aggressive tendencies (40) have been cited in
support, Others fInd elTects of this kind in Sirls but
not in boys (7). Yet dilferent studies indicate that
aggression i. increased (140). It should be pointed
oul that androgen levels are not closely correlated
with behavior in humans. and only devia·
tions from the norm have been as<ociated wilh con-
sistent conscquencc.l, Plasma tcstosterone levels vary
"'idely among Olen wilh similar personality charac-
leri"j"" ( (47).
The ac""ptanc. of gender identity seems 10 deter-
mined mostly by learning during infancy and child-
hood. and by th. anatomical fealures of Ih. geni-
lalia. It may not be subslantially influenced by either
chrolllOWme palleros or hormones. XY individual,
with androgen receptor defcctsare usually raised as
girls. and man)" go On to marry and adopt children.
Strongly virili,ed XX persons have often assumed
male roles wilhout difficulty. It can be argued. how-
ever. tnat XY "females" arC androgen-<leprived.
whereas XX "malcs" have been conditioned by their
sex hormones.
The factors that wntribute to gender identity
problems and homosexual preferences in anatomi-
cally normal humans are unknown. Attempts to
"correct" the condilions with exogenous hormones
have been. almosl uniformly U,ually.
androseos exaggerate (while blunt) preex-
isting tendencies wilhout changing their directions.
Human brains probably remain highly plastic
(147). A. noled. children with XY chromosomes
and limited ahility to Convert tCStOSlerone to Dl·IT
have been observed 10 adjust well 10 childhood rolcs
as girls and to assume masculine behavior patterns
whe n hormonal ehanges during puberty bring about
vi ri Iiz.a t ion.
Sex diffe rentiation of nonreproductive struclures
is considered in Chapters 14 and 15.
".
REFERENCES
I . Adki •. Rcgan, E. Hormone Spccificity,Androgen
Metabolism, and Social Behavior. Amer, Zoot.
11:2S7_11. 1981.
2. Allon, T. 0 .. Adler. N. T" Greenberg, J. II .. and
Rei.ioh. M. V'llinoccrvkal Stimulation Scloo-
li"oly Metabolic Activity in the Rat
Brain. 211: 1070-2. 1981.
2A. Art"dash. G. W.O and Gors.i. R. A. Enhance·
ment of Sexual Beha.ior in Female R.u by Nco.
natal Transplantation of Brain Tissue from
Male,. SrienN 217' 1216-8. 1982.
3. ArllQld. A. P. Logical Level. of Steroid Il<>rmlmc
Action in the Conlrol of V"",:brotc Bchavior.
Amtr. Zool. 11: 2))_42. 1981.
4. Arnold. A. P. Se.ual in ,h. Br.in.
Am", 68:165-73.1980.
S. Ayoub, O. M., Cree"""tb , W. T .• and Ju,aska. j.
M. St. DitTerence. in Dendritic StruCture in the
PreoptiC Area of the Juv"nil. Monkey
Brain. 219: 197-8. 1983.
6. O. P.. and Moyle. W. R. Role of Carbohy.
drate in the Action of Gon.dotropin,. Chap. 9. pp.
261-89 of Birnbaum.. and O·Malley. cds .. ref·
erence 19.
7. S. W. Ps)·eoo.o.<ual Differentiation in the
Human. Bioi. R.prod. 21: 61-72. 1980.
8. Baker. T. G. C!Qgene.i. and O"UI'lion. Chap. 2.
pp. 14-45 of Austin. C. R.• and Short, R. V .• cd •.
in Mammals . • ol. I. Cambridge
Uni •• "ily Pre". New York. 1972.
9. T. G. Primordial Germ Cell •. Chap. I. pp.
1-13 of Austin. C. R .. ud Short. R. V. ed •. Gum
C.U. and F."i/i,ariott. Cambridgo Uni.o"ity
Pr.... New York. 1912-
10. Balill$ky. B. I. An Inlro<iuclion to Embryology.
5th ed. Saund.rs. New York. 1981.
II. Bardin. C. W .• BullOCk. L P .• Mill •. N. c.. Lin.
Y..c.. and Jaoob. S. T. The Role of Receptors in
th. Anabolic Action of Androgcns. Chap. 4. pp.
83-103 of O'Malley and Birnbaumer. ed •.. ref-
crellC< 123.
12. a.rdin. W.. and Cauorall. J. F. Te<toslcrono: A
Major Determinanl of Ex"agenital Se .. ual De·
vdopment. Sci.net ]/1: 1285_94. 1981.
13. Bart ke . A .• William •. K. L H .. and Dalterio. S.
EI1"«.. of 8 t roee", on Te<ticular Teslostcrooe
Production in Vilro. Bioi R.pro<!. /7: 645_9.
19i7.
14. Bedford. J. M. Evolulioo of Ihe Scrotum: Ttte
Epididymi. a. Iho Prime Mover"? pp. 171-82 of
Cal.by and Tyndak·Bi$<oc, cd •.. ",ference 27.
15. Bergh. A. Morphological Si,n. or a Direct Effecl
or Experimental Cryptorchidi"n On the Scrtoli
Cell. in Rat. Irradiated •• Fel"""'. Bioi. Rtp'od.
14: 145-5 2. 1981.
16. Bernstein. R.. Koo. G . C..and Wachlel. S . S. Ab-
normalilY of Ihe X Chromosome in Hum.n 46.
DETERMINATION AND DIFFERENTt"TIO N
XY Female Sibling. wilh D)'.senelic O•• rie •.
107. 768-9. 1980.
11. Bianchi. E .. Pierapaoli. W.. and Sorkin. E. Cylo-
logical Change< in the Mou.o Anle,ior Pituitary
after Noonalal Thymeclomy; r\ Light and Elec--
tron Microscopic.1 Study . J. t:ndrxrirtol. 51.- 1_6.
1971.
18. Biology Today. CRM, Del Mar. Calir.. 1972.
19. Birnbaumer. t .. and O· Malicy. B- W.• cd •. Rt-
IVplors and HormoM IIf. Academic Pre ...
New Yo, • . 1978.
19A. Bi.hop. C. E.. Guellaen. G" Geldwerth. D.. Voss.
R.. Fellow<. M., and Weissenbach. J. Single--Copy
DNA Sequence.Specific f", Ihe Human Y Chro-
mosome. Nmurt 303: 831_2.1983 .
20. Blanda •. R. J. Biology of EU' and Impl, ntation.
Chap. 14. pp. 797_882 of Young. W. c..cd. Sn
and S"mkm,. lrd cd. Wmiam. &: Wil·
kin •. Baltimore. 1961.
21. Boolh. J. E. Se .. u.l Differenliation of the Brain .
Chap. 2. pp. 58_IS8 of Finn. C. A.. ed. Oxford
Rt.;rws of R. p,odutliw Bio/I'tY. vol. I. Oxford
University Pre ... New York. 1979.
22. Brcs, W. R .. Genel. M., Koo. G. c.. Wachtel. S.
5.. K.. and Miller. O. J. H-Y An-
li,en and Human Se .. ChrOmOSQll,.1 Abnorm.li·
tic •. pp. 279- 92 of VaUel and Po .. er. cd, .. refer-
ence 176.
23. Brinkley. H. J. Endocrine Si,naling and Female
Reproduclion . Bioi. Rcprod. ]4: 22_43. 1981.
24. Bulloch. K.. and Moore. R. Y. Thymu. GI.nd In·
ncrv .. ion by Brainstem and Spinal Cord in
Mou", and Ral. Am.,. J. Anal. /6]: 57-61 . 1981.
25. BUY$<. M .• and reingold. M . Syndrome. Associ·
ated with Abnormal Extern.l Genitalia. pp. 425-
35 of Vallet and Porter. ed •.. reference 176.
26. Bysko'. A. G .. and GrinSled. J. Feminizing Effeel
of Mesonephros 00 Cuilurod Differentiating
Mou"" Gonad. and Due ... Sci."" ]1]: 817-18 .
1981.
21. Calaby. J. H .. and Tyndale.Bi$COC. C. H .• cd,.
RtproducliOlt and t"volulion. Aumali.n Acad-
emyofScion<:c.Ca n berr •. 1917.
2S. Carrick. F. N., and Cox . R. I. Testicu lar Endo-
cri""logy or MaT>upial. and Monotreme<. Pl'·
137_4 1 of Cal.by and T)'ndal".Biscoc. cd ... ref-
eronce 27.
Carrick. F. N .. and Setchell. B. P. The Evolution
of 1ho ScrOlum. PI'. 165-70 of Calaby and Tyn.
d.l".Oi<eoe. cd •.. ,efcre1l<e 27.
30. Channing. C. P. In Search of Ihe Porfect Contra-
cepti ••. Sc;."", /9; 14_ I 5. 20-21. 1979.
31. Chowdhury, M.• Steinberger. A..• nd Sleinber·
ger. E. Inhibition of de o'Iovo Synth csi<of fS H by
Sertol; Cell Faclor (SC F). EndIX';IIoI. /OJ: 644 _
7.1978.
32. Cunha, G. R .• Chung. L W. K" Shannon. J. M..
Tasuchi, 0 ..• nd Fujii. II . Hormone·lnduced
Morphogo ... ,;' .nd Growlh: Role of Mesenchy-
 mal -Epithelial Inleraclion,. Rtf.:. Pro:. I/orm.
39.' 559_95.1983.
33. Davidson. J, M. Ho,mone, and Reproduclive lie-
havior. Chap, 3. pp. 64_103 of L.vi .... S.. ed.
HormoMs ond B.ha.'i",. Academic Pr=. New
York. 1972.
34. Decker, M. H.. Loriau,. D. L-. and CUller. G. B..
Jr. Seminiferou, Tubular Factor i, Not Obl iga·
IO,y for Regulation of Plasma Follielc-Slimulal-
ing Ilormon. in Ih. Rat. EndlXrilWi. 108: 1035-
9.1981.
35. DePaolo. L. V.. Anderson. L. D.. and Hirshfield.
A. N. £Xi,t."'" of a Long.Lwp feed·
back S)"tcm botWttn FSH and Inhibin in Female
Rat>, Amr'. J. 140; £544_ES49. 1981.
36. I>ePhilip. R. M.. Feldman, M .. Spruill. W. 1\ ..
French. F, S .. and Kierszenbaum. A. L. The Se-
cretion of Androgen·Binding Protein.nd Olher
Prole ins by Rat Serl"'i Cell' in Culture: A Slruc--
lural and ElectrOphoretic Study. Ann. N. Y. A<:t1d.
Sci. 383.' 3110-7 1. 1982,
37, DePhilip, R. M.. and Kier<'.cnbaum. A. L. Hor·
monal Regulalion of Protein Synthesi .. Secrelion.
and Phosphorylation in Cuitured Rat Settoli
Cell. , Proc. Nail, Arad, Sri. USA 79: 655 1-5.
1982.
38. Desjardins. C. End""ri"e Signaling and Male Rc--
proouction. Bioi. RtpraJ. U' 1- 21. 1981,
39, Dorrington. J . II...nd Armstrong. D. T. Effect<
<>f FSH on Gon.dal Function,. R«. Prog. /lorm.
R'ch, 35: 301-32: di.cussion. pp. 332-42. 1979 .
40. f.hrhardt. 1\. 1\ .• • nd Me),er.Sahlb"rll. F. L. F.f-
f<ct. of Prenatal Se, Hormone. On Uender·Re·
lated aeha.ior. 211: I 3 I 2-1 8. 1981.
41. !: ik·N... K, B. .. i•• nd SecretionofTe'l-
Sieroid,. Chap. 4. pp. 95-115 of Hamil·
ton. D. W.. and Gr«p. R. 0 .. cds, lIalldbook of
sec, 7, vol. 5. American Ph}-.iologic.1
Sociel)'. Washington. D.C. 1975.
42. Fawc<lt. D. W. Til< Uhr"l ,uct"rt and Functions
of the Settoli Cell. Chap. 28. pp, 302- 20 of
Greep, R. 0 .. and Kobl in,ky, M. 1\., <XlI. Fro".
lit' s Reproduction and F"nility COItlro!. MI T
Press. Cambridge, Mass .. 1977.
43, f.derman . D. D. The Te.lis. Chap, S. pp. 109- 42
of Ingbar, S. H.• <Xl. Th, Y,ar in endocrinology
197j-1976, Plenum. New York. 1976.
44. Fedorman, D. D. Th''''.li •. Chap. 5. pp. 135-1 I
of l"3ba r. S. H .. ed. COItUmpoFory Endoc,llWi·
ogy. Plenum. New York. 1979.
45. Feig. L. A. Bell,·e, A. R .. Erickson. N, Ii.. and
Kl agsbrun. M. Sertoli Cell. Conl.in • Milogenic
Peptide. Proc. NOli. Acad, Sri. USA 77: 4774_8,
1980,
45A. Fi"'heue. C. T .. Biell"" . A .• and MoE,.·on. B. S.
Se, Differen«. in Serotonin Receplor Binding in
Rat Brain. Srit ".. 122: ll3-5. 1983,
46. fishman. J.• and Tu lehins\:.y. D. of
Prolaclin Secrtl;On in Normal Y(>Ung Women by
2.Hydroxyeslrone. 210: 73-4 . 1980.
47 . Floody. O. R. The Hormonal Control of Ultra·
sonic Communication in Rodenn. Am.,. Zoo/. 21:
129-42.1981.
48. Fox. T. 0 .. Vilo. C, C. and Wieland, S . J . Ewo-
gen and Androgen Re .. ptor Protein. in Embry.
onic a nd Neon .. al Brain: Hypothe$C' for Role. in
Se, ual Differenliation and Beha.ior. ZOO/.
18: 525-31.1978.
49. Fran kenbui •. M. T.. and Kapper1. H. J. E.peri·
menial Trlnsformalion of Rillhl Gonads of Fe-
male fowl inlO Fertik Te.te •. BiO/, Rel"od, 13:
526-9,1980.
50. Goldfoot. D. I\. Olfaction. Sexual 8.ha"ior. and
tho Pheromont 1I)'pothesi. in Rhesu. Monkeys: A
Crilique. Am.,. Zoo/, 21: 153-64. 1981.
51. GO<.>dfenow. P. N.. arid Andrew •. P. W. S.. u.1
Pilferenlialion ond the H· Y Anlillen. Nalu' e 195:
11-13.1 982 ,
52. Gordon. J. W.. and Ruddle. F. II. Mammalian
Gon.dal Delermin'lion and Gamelogene,i,. St:!.
0"" 1//: 1265-1. 1981.
53, Gordon. T. P. ReproduCli". Behnior in the Rh o-
$"' Monkey; Soc i.1 and Endocrine Variables.
Am'F. ZOO/, 21: 185-95. 1981 ,
54. Gorski. R. A. The NouroerldocrinQIogy of Rcpro-
duetion, An Bioi. 20: 111_21.
1979,
55. Griffin, J. E .. and Wiloon. J. D. Gon.lie and Mo-
leeular Characterilalion of Androgen Re.i'la nce
Synd rom« in Man. pp. 129_47 of Yallet and Por·
I.r. eds,. reference 176.
56. Grumb.eh. M. M. GerlCtic of Se. ·
ual Developmen" pp, ll-1J of Vallet and Pofter.
cd, .. referenee 176.
51. Grumbach. M. M.. and Van W)"k. J . J . Disorders
of Seu.1 Diffe r.nti.tion, Ch.p. 8. pp. 42J-5IJI of
William •. R. H.. ed. Tex/book of I:;MdlX' iM/Ogy.
5th ed, Saunders. Philadelphi • . 1914.
58. B. 1-. Tullner. W. W .. and lloogen,G . D.
Felal or Malernal H)"pophyseclOO1)" in Rhe,us
Mon"')'$ (MO<;t1<;t1 mularUJ!: Effect< on the Dc--
vclopment <>f Tesle. Ind Olher Endocrine Organs,
Bio/. Rtprod. Ii: 650_60. 1977.
58A. Haneod. R, J. T. Im mune Respon",. to Sp<rm.
Oxford R. •. R,prod. Bioi. J: 182_208. 1981.
59. Handel. M, 1\. . and Eppig, J. J . Senoli Cell Dif-
feren liation in lb. T"les of Mi« GerIClically De·
r,dent in Germ Cell •. Bio/. R,prod.20: 1031-8.
1979.
60. Han"on. V.• Ritzen. E. M., French. F. S ., and
Noyfeh. S. N. Androgen Tr.nSporl and Receplor
in Testis and Epididymi$. C hap, 7,
pp. 113-201 of Ham ilton, D. W .. and Greep. R.
0 .. Handbook of Phy<iologJ', sec. 7. vol. S.
American Physiological Societ)', Was hington.
D.C., 1975.
61 , Hardi"3. C F. Social Mooul alion <>f Circu lating
Hormon" Lev<:l$ in the Male. Am". Zoo/. 11 __
223-31. 1981.
62 . Ha,eltine. F. P.. and Ohno. S. Mechani,m'ofGo-
nadal Dilferenliation. Scit"" 211: I 272-8. 1981 .
63. Haltori. M.. "nd Orandon . M. R. Thymus and the
'"
Endox.in.: Sys\cm: Ovarian Dysg""",;! in Neo-
natally Thymectomiled Rals, J. El!do",iooJ. 83:
101 _10. 1979.
64. Hau. J .. S •• nd",". P.. To;'n •• , B.> Pcdcrson. G.
T. and Kristi."..". B. Correlation aCI"· •• " Feta l
Weight and Malernal Serum L.,'.I> of Murine
«-Fe,opro«;n and Quanlilali"" of Four Mokcu "
lar F<>rm,_ Bioi. R.prod. 14: 683-9. In!.
M. Herilage, A. S.. Stumpf. W. E.. Sar, M.. and
Granl. L D. Brai",lcm C",cchoiam;nc Neuron,
lfC Targel Siles for Se, Steroid Ilormooc,. Sd-
,,,,,207: 1377-9.1980.
M. Herti,. A. T .. and Barloo, B. R. Fine Struclu'e
of Mammali.n OocytCS and O.a. Chap. 13, pp.
311-48 of Grecp. R. 0 .• cd. Halldb<>ok of Physi-
oIot)'. sec. 7, vol. 2. American Physiological S<.>-
dety. Washington. D.C.. 1975.
67. 110)'ncr, $. [mm.,""enc!ic Approaches to the
Slud)' of the Mammalian Egg and Eo.rly Embryo.
Oxford Rtv, Neprodur,jW' Bioi, J: 95 -1 26. 198 I .
68, Higgin,. S. L and Parker. M. G.
Regul.tion 01 Gonera liled and Specific Rosponse,
in Accessory S..1la1 Ti"ucs cor the Male Ral .
BiMh.ln. A ction, Horrn, 7: 287_309. 1980.
69. Hildeb .. ndt-Stark . H. E.. and F,.i<:<:tt. O. W. Ef·
ltet' 01 Deficicn<y of Essential Folly Acid, and
T,.. tmen1 .. ilb Pr<)$taglandin E, on tho Uh .. -
,truct"re of thc Rat Te'ti •. Bioi. 19: 736-
46. 1978-
10. Hook. E, 8. EUra S.. Chrom<)$()mesand Human
Bebavior: The Na,ur. of the Evidence Regarding
XYY. XXV. XXYY and XXX Genotypes. pp.
437-63 of van.t.nd Poner. ed, .. relerence 176.
71. llutson, J . C. and St<>e<:o. D. M. Peril"bu l.r Cell
Inngence on the Efficiency of Androgen.B inding
Protein Secretion by S.,(OI; Celt' in Cultu re. En-
dM,I""'. 108.- 1362_8. 19S1.
n. Hutson, J . C,. and Stocco. D. M. Speciftcity of
Hnrmont· lnduced Respon,es cor Testicular Cell,
in Cuhure. Bioi. R<p"J/I. 19: 768-72, 1978.
7), Irvine. W, J . Autoin,",unity in Endocrine Di ,·
eue. Prog, Horm. J6: 509-56. 1980.
74 , Jen",n. E. V.. Call. K, J .. Go ... ki. J .. and Wil·
liams-A,hman. H. G. HormoneoR=plor Inter·
action in the M.chanism 01 Reproductive Hor·
mone Action. Chap. 25. pp. of Greep. R.
0 .. and Koblin,ky. M, A .. eds. F' OIIlirr, in
produrrlon anJ Fmiliry Control, MIT Pre ...
Cambridg •. Mass .. 1971.
15. Jone •. P. B. C .. and H$ueh. "- J, W. DirecI Ef·
f«I' of Gonadotropin Hormooe and il<
AnlOgoni't upon CW.rion function, Stimulated
by FSH . Prolactin and LH . Bioi. R.prot/. 14:
747-59.1981.
16. JOIUQ. N .• Picard. J.·Y .. and Trao. D. The Anti·
mUlIerian prog. /form. JJ:
111_63.1971.
77. Jost, A. Hormonal Facto,. in Sex Differentiation
of tbo Mammalian FOClu" T"''''. Roy. Soc.
UmJ. B. 259: 119-30. 1970,
SEX OETERM IN ... TIQN ... NO OIFFERENTIATK:lN
18, Kolley. D. B. Social Signal" An O.e"iew. Am".
ZOO!. 21: 111-16. 1981.
79 . Kellokumpu.S" and Rajaniemi. H. EIf«t of Zinc
on the Uptake or Hum,n Chorionic GonadOiropin
(bCG) in Rat Te«i,.nd Te,tosterone Response
in vivo. Bioi. R.prod. 24: 298-305, 1981.
80. K.tdsleg..... J .. M.. Hetzel. W. 0 .. Sherins. R. J ..
and Cotto K. J. Dev<lopmcntal Changos in T."ie·
ular Gonadottopin Recepto ...: Plasma Gon"dOlro-
pin' and Plasma Te'loMorone in Ihe R.I . I;;ndo-
",inol. 101: 212_22. 1978,
81, Kind. F. A.. 0,;0\. A.. Pi. A. F.• and Maqu""" M.
Prevention 01 Steroid-Induced SterHity in Neo-
natal R.t$ with ThymiC Cell SU'J>On.ion. P'M.
Soc. Exp. Bioi. M.d, 120: 252-5. 1965.
82. Knobi!. E. Patlorn, of Hypoph)·.totropic Signal$
and Gonadotropin Secretion in the Rhe,u, M",,·
key. BiO/, Rt prod, U: 44_9.1981.
83 , Knobi!. E, The Neuf"OOnd""rine Control of Ihe
Men'tr",1 Cyclc. Rer. P,Ot. Horn •. R"h. J6: 53-
88. 1980,
84. Kraulis. I.. Na ish. S. J .. G ra .. ""r. 0 .. and Rul.
K. B, S.,·Androst.nc-x..17PDiol: Inhibitor cor
Sexual Moturation in the Female Rat. Bioi. Nt-
proJ, 24: 44 5-53, \981.
85. lamb. O. J .. T...<>. Y,-H .. Steinberger. A .. and
Sanbo,n. B. M . $ertOli Cell Nuo\o.r Transerip-
lional Activity: Stimulation by Follic\e·Stimulat·
ing Hormone and TcS\ostorone in ViITO.
nol. 108. 1020--6.1981.
86. Langman, J. 2d od. Wil·
liams &. Wilkins. Bahimore, 1969,
87. leonard. J . M .. Pauls. n. C. A .. O<pin •. L. F.. and
Burgess. E. C. The Cla .. of Klindeher'.
Syndromt. l'p. 401_19 or Vallet and Porter. cd, ..
refer.""" 11("
88. lio\x:,burg. L, and McEwen, B. S. Steroid Hor-
mone Receptors in the Central Nervous System,
BiMh.no. AN;oru H",,,,. 6: 4 15-59. 1919.
89. lintern·MOOI'O. S , Effect of Alh),n,;a on the Ini·
tiation of follicular Growth in Ihe Rat Ovary.
Bioi. of R<proJ 17: 155-61. 1977.
90. Lumpkin. M.. Negro-Vil.r. A., Franehimont. P..
and S. E'idcnce for a Hypothalamic
Sit. of AOlion of Inhibin to Suppress FSH Reo
lea",. t;ndM,jllOl. 108: 1101-8. 1981.
91. MaoLusky, N. J.. Lieborburg.1.. Krcy. L. C .. and
McE .... n. B. S. Progestin Ro<:<:plors in lhc Brain
. nd Pil"ita'Y of the Bonnet Monkey (MarIJra,a-
Jiata): Difference, bot ... een the Mon):e)" .nd th.
Rat in the Di,tribution 01 PfOjle'tin Reoeplors.
Endocri""'. 106: 185-91. 1981.
92 , MacLu,ky. N. J .. and Naltolin. F. Sexual Diffor·
of Ihe Central Ne .. ou, S)·""m. Sci.ne.
111: 1294_1302. 1981.
93. Magof\1n. D. A.. and Erickson. G. f. Mooh.ni'm
by which 17Il-Estrad iol Inhibits Ovarian And,o-
gen in Iho Rat. EndM,lnol. 108.- 962_
9. 1981.
94. Mainwaring. W. L P. And'OiOn Receptors and
 Biologic Re,pon.e" A Su"ey, Ch.p. 5. pp, 105-
10 of O·M .lIey and Birnbaumer. cd... refcreoc.
123.
Mainwari ng. W. I. P. of Acti""
of AnJ'OgellS, Springer-Verlag. Ne,,"' York. 1977,
96. Maflen>. N. D . Tho Bi<>logieal Effcct< of Immu-
ni,,,,ion again.t Stcroid. in Fen'al. Mamm.I •.
Ox/on! RfV. RepMJ. Bioi J: 239-262. 1980.
97. Mart in. C. R. Adrenoxortkal Innu""",. on
Growth of Re productive Struc,ure. of Thy""","
lom i,ed and Sham Th)'n, .. ,omiw;i Rats.
m'oo/. 75: 167_72. 1964,
97 A. Martini. L. Th. 5<>-Roouelion of TcstOSlerono in
'he Neuroendocrine S,rue,ure •. Biochemical and
ph),.iologkallmplication •. /:"nd""" Rn". J:
1982.
98. Mc Ewen. B. S. Gooa d.l Steroid Recep"'''' in
Neuroend<xrine Ti" ue•. Chap. 13. PI'. 354-400
of O'M alley and Bi rnbau mer. cd •.. reference
In
99 . McE"en. B. S. Gonadal Steroid. and Drain [)e.
velopme"!. BIoi, ReproJ, 11: 43 - 8. 1980.
100. McEwen. B. S, Neural Gonadal Sleroid A<tion •.
1303-11.1981 ,
101. McE""n. B. S , $e,u,1 Maluration and Differen·
tiation, The Role of to. Gonadal S,eroid •. Prof.
Bmin Ruh. fa: 291_307.1978 .
102. Meano. A. R. Biochemical EIl«t< of Follicle·
Slimu lating 1I0rmone. Chap. 8. PI', 203- 18 of
I/alldl>ook of Phyfiolo/:y. sec , 7. '01, S. American
Phy.ielogical Sociely. Washington. D.C " 19H.
10.1. Me,n,. A . R.. I)orlm'n . .1. R . F. b ,nrline . ! l ,
and Tindall. D. J. of Actioo of FSH
in the Male Ra'. Chap, 12. PI', 363_92 of Birn·
baumer and O· Malle)". eds.. refen:nco 19.
104. Mea",. A, R.. Dedman. J. R.. Tash. J. S .. Tindall.
D. J .. Yan Sickle, M.... d M. J. Regula·
tion of Ihe Teslis Sertoli Cell by Follicle Stimu·
laling Ilormone. Ann, Physiol. U : 59-70.
1980.
105. Mel ... K. A.. Rec'es. J. 1'" and Sle inbtrg. A. O.
Regulation of Ihe Exp.e"ion of Autoimmun ily in
NZB X NZW F, Mice b)' Sex Hormone •. J. 1m_
I: 27_42. 1979.
106, MiChael. S, D.. Taguehi. 0 .. and Nishi1.uka. Y .
Elleet of Neonatal Thymeclomy"" Ovarian [)e.
velopmenl and Pla. ma LH. FSH . Gil and PRL
in the Mou$<:. BiQI. 22: 343-50. 19S0.
107. Mig""n. B. R, X-Chromosomc lnac\iYa lion .. a
[)e,erminanl of Female PheOOlypc. pp, 293-303
of Vallel and Porter. ed ....eferenee 176.
108. Migeon. C. J" Amrh< in. J. A .. K.enan. B. S ..
Me)"er. W. J. II I. and M ig""n. B. T he Syndrome
of Androgen In.en,iti, ily in Man: I" Relation to
OUr UnderStanding of Mal e Se, Differentialion.
pp. 93- 128 of Vallel and Porter. od •.• rcfcn:nee
176,
109. Miller. L. K. Thymic I nfiuenC<:$ On 'he GrOWth or
Acccuory Rep roducti'e Slrueture. in Male
Hood ed Rats. Ph.D Thesi •. Hunter Collese. Cily
UniverSi'Y of New York. 1970,
110. Miltw<xh. U., and Delhanty. J. D. i\. Growth of
Dilferentiating Tesle' and Ov.. /I'D /un; 224:
1969.
III. Moger. W. H. Temporal Cha nges in Teslicular
"'tradiol and Testosterone Coneentralion•. Cy-
loplasmic r:Slradiol Binding. a nd [)e.en.i, i'.ation
after It um.n Chorionic Gonadotropin Adminis-
tration '" the Immat ure Rat. Entioc,;n"l. 106:
496- 503.1980.
112, Muldoon. T. G, Regul.'ion of Steroid Hormone
Receptor ACli'ity. Hndtx:'ilU' R,c. I: JJ9_64.
1980.
113, M USIO. N. A" l.."ea. F.. Cheng. S.-L.. KOIitc.
N .. Gunsalu •. G.• and Bardin. C. W. b lracellu·
lar Androgen·Bindi", Prolein" Specie. Compar·
ison. and S,ruc,un:·Func,ion RciatiMship$. A"".
N.Y. Acad. Sci, 383: 343 _55 .198 2,
114. NaftOlin. F. UnderStandin g the Base< of S'" Di f.
fere nce., ]1 I: I 263-4 . 1981.
Niemi. M.. Ikonen. M.•• nd /le.vo!\(n. A, Hi 'lo-
chemistry and Fine Structure of the Inte rslit ial
Ti"uc in I.. Human Foelal Tesl i•. pp, 31-52 of
Wolstenholme . G. E, W.. and O·Coo ner. M . cds.
End(>CrinoiOgy of /h, Little . Bmwn. Bo<.
too. 1967.
116. •. Y .. and T. O,·ari.n Dyste.
nosi. Induccd by Nronalal Thymeelom)' in Ihe
Mou ... EndoNi""'. 89: 886-93. 1971.
117. Ni.h izul<a. y" and Sal<akura. T. Thymu. and Re-
produclion' $e,·linked Dy.gene,i. of Ihe Gonad
after Neonatal Thymeelomy in Micc.
166: 1969.
I Nnrm. n. R. I ". And Sr;«. II. r.. R,.;n I.e.;"". in
Inf.nl Female Rhe.u. Monke}'" Effcct10n Mcn·
arche and FirSt Ovulation and on Diurnal
Rhylhms of Pmlaclin and Co"i",!. EnJ"",ino/,
108: 1981.
119. Ohno. S. Sprin.
ger·Veriag. New yo.k. 1979.
120. Ohno. S . The Development of Sexual Reproduc-
tion. Chap. I. pp. 1-31 of Au" in. C. R.. and
Shor,. R. V.. eds , Th' /:.·""/u/i",, of Rep,oduction.
Cambridge UniverSil)' pr ..... New York. 1976.
121 . Ohno. S .. NOllai . Y.. Ciccare... S"and H.
II·Y Antige n ond Primary
Se,·[)etermining Mochani,m of Mamn .. I•. R«.
Prot. J/orm. flsch. 35. 449- 70. 1979.
122. Oj eda. S . R" Andre,,"'s. W. W" Advis. J. p" and
Whil". S . S. Recent Ad,"' nccs in tho End""ri""l·
<>&y of Pubtrty. End"",.;1U' Reo. I: 228-51. 1980.
123, O·MaUey. B. W .. ond Birnbaumer. L.. cds , Re_
ceptors and Hormon. AClion [ I. Academic Pre".
New York. 1978,
124, O·Shaugh ne ... y. P. J. Age Dependenl Differenceo
in Te.tieular lnacti," ,ion of FSH and In hibition
of FSH Binding 10 Rat Te'li •. Bioi RtproJ. 10:
1009- 14.1 979.
125. Ow. n. D. R, P.ychological Studies in XYY Men.
pp. of Vallet and Porler. cd ... reference
176,
126. P:l rson. B" and McEwen. B, S. Sequenlial lnhi·
bilion or $e,ual Rcccpli ,ity by Progesterone i<
Preyemed by a Protein Synthe.i. Inhibilor and is

N01 C.usally Rela1ed 10 o.crused U>els of Hy.
po1halamic Proges1in Recep10 .. in 1he Female
Ra1. J. Neurosd. I: 527-31. 1981.
I 27, P.ul. S , M" Hoffm ... A. R" and Axelrod. J. Ca·
lcohol Estrogens: Synthesis and Melaboli.m in
Drain and Olher Endocrine ro .. ue •. From;",
Neu",.mi(,cTinoi. 6: 203_17, 198().
128. Paulsen. C. A. The Tesle •. Chap. 6. pp. 323-67
of W illiam •. R, H.• ed, Textbook 01 EndocrInol-
ogy, Slh .d. Saund .... Philadelphi • . 197 4.
129. PeUiniemi, L. J.• Dym, M .• Vunsalu •. v . L
MuSlo. N. A" Bardin. C. W .. and Fawccll. D. W.
Immunoeyux:hemical LocaliUlLon of Androgcn.
Binding Prolein in the Male R31 RerroduCli>e
Tract. Endo"I""', 108: 925_31. 1981,
130. Pe1erson. R. E., Imperato-Mcvinley. J., Gaulier.
T" and Slurla. E, Heredilary Sleroid Sa Reduc-
10$( o.ficie""y; A Newly Rceogniu:d Cause of
Male Pseudohermaphroditism, pp. 149-67 of
v.nel .nd I'Qrler. eds .• reference 176.
Ill. Picard. J .• y .. and JOM<>. N. The
Hormone: P",liminary Allcmp" at Purif,cation .
pp, 75-92 of Vallc1 and Porter. cd." .efcre""e
176.
132. Pomeran". D. K. Effect o f In Vi>o Gonadotropin
Treatmenl on f:.st rogen U.els in the Testis of t h.
Immalure R.t. Bioi. Rrrrod, 21: 1247-55.1979.
133. Price, D.. Zuijer, J. J. P .• Ort iz. E., and Brink·
mann. A. C. CUrrenl View. on Embryonic Sex
O;ff.,e n,;at;on;. Rep,; le., I:!; .d" and Mdmmab.
Arne•. Zoo,. 15 (Suppl. /): 173-95. 1975.
134. Ramaley. J. A. 1)e>c1opment of GonadOtropin
Regulalion in lhe: Prepube"al Mammal. Bioi. Nt-
prod. XJ: 1_21. 1979.
135, Ram.,barma. K.• and Sairam. M, R, Isolation
and Characteri"'l ion of l nbibin from lI uman
Seminal Pl asma Ann, N. Y. Acad, Sci. 383: 307-
26.1982 ,
136, Rebar. R. W .• Morandini, I. C .. Benirsch kc. K..
and Pel"". J. E. Reduccd GonadOlropi n. in
Alhymic Mice: Prevention by Thymic T",nspl.n-
lalion . £/ldo('r{!Iof, 107: 2130-2.1980.
137. ReiChe ... L. E.. Jr" and Abou· lssan H, Follil ro-
pin Receplo", in Ral Testi. Tubul. Mcmbra"""
Charac1erizalion. Solubilizalion. and Sludy of
Faclors A!fCCling Int. raclion " 'ith FS H. Chap.
II. pp. 341-61 <Of Birnbaum.. and O·M.lley.
ed, ,, reference 19.
138, Reid . R, L.. Ling. N .. and Yen, S. S. C. Melan-
ocyte Slimul.ting Hormone Induces Gonadotro-
pin Releau. J. Clln. £ndoc';noI, Mrlab. 51: 159-
61. 1981.
139. Reinbolh. R, Can Se. Inve",ioo Be Environmen-
lally Induced? Bioi. )2; 49_59,
140. Reini"'h. J. M. Prenalal Expos"'" 10 Synlhelic
Progeslin. Ine",as,,. POIenlial for AUrcs,ion ;n
H uman •. Sdml.'t 111 : I I 7 1-3. 1981 .
141. Resko,J. A. retalttormoncs and Their Elfeclon
1he Different ialion of the Central Nervous S)'S-
tern in Primale •. Proc, 34: 16S0_5, 1975.
S EX OETERMtN" lION " NO OIFF ERE Nll"llON
142, Richard •• J. S. Hormonal Control of O varian FoI·
licular Development: A 1978 Pe"'P<I<li>e. R..-.
Prot. Horm. R.ch. 35; 343-68, discu'$ion, 368_
73. 1979,
143, Ri.bridger. G. P .. Kerr. J . B.• and o. Kretur. D.
M. Evaluation of Leydig c.n Function and Go-
nadotropin Binding in Unilateral and Bilaleral
Cryptorchidi.m: E>ide""e for Local Conlrol of
Le)'dig Cell FUnclion by the Seminiferous Tu·
b ule•. Bioi. R.prod. U ' 534-40. 1981.
144. RobiMOn. J. A., and o ridson. W. E. Neon"al
Hormone !'alterns in 1he Ma<a<jue, L Sleroid •.
Bioi, RtprOd 19: 773_8, 1978,
14S , R""enf,eld. R. L. Heterogenei1Y in lhe Expr." ion
of Ooficie""y: venelic Implica.
tions. PP, I 7S- 87 of Val lel and Porle •• ed ... ",f·
erenCe 176.
146. Roth"'ell. N , V. Und.monrfi"l 2d cd .
Odord Univenily Ne'" York, 1979,
147, Rubin. R, T " Reiniseh. J. M .• and Hoskelt. R. F.
Poslnatal Gonad.1 Steroid Effectson lI um.n Be·
havior. S(I",,,, 1Jl: 1318-24. 198 1.
148, Sanborn. B. M., and Sleinberger. E. Androgen
Nucl •• r Exchange ACli>ily in Ral Te"i •. Endocr.
R.ch. Commun. 1: 335_44.
149, L.. and Rapola. J . COIIsmilal
11011. Rinchart and Winslon. New Yor' . 1%9.
150. $colt , R, S .. and Burger. H. G . An In>."" Rola·
tion.hip Exists belwocn $cminal Plasma In hibin
s."um FolI;c1. St;mu, .. ing Hormo .. in
M,n, J. CUn. End""rl""'. U<I"b, 51: 796- 803.
198 1.
151. SCOIl. R.S .. and Bu.ge •. H, G. Meehani.m of
Action of Inhibin . Bioi. R.prOd. 14: 54 1-50.
198 t.
152, Selchel l. l.l . p.. lhe Blood·T.,.l" Banier. Chap,
30. pp, 338 - n of vreep. R. 0 .. and Koblinsky
M" cd •. in R. prodycaOll and Fmilily
C<mlro/, M IT Pre ... C.mbridge. M ..... 1977.
153. Shapiro. B. H" and Goldman. A. S. New
Thooghts on Se,ual Differentiolion of the Brain ,
pp. 221-46 of Vanet and POrler. ed$.. reference
176.
154. Shapiro. O. Y. Serial Female Se, Change. After
Simultaneou. Remo .. 1 of M.les from Soci.1
Groups of. Coral Reef Fish, Sdrnce 2M: I I 36-
7.1980.
155. S hapiro. 1\-1" and Erickson. R. P. Evide""e lhat
the Serological o.lcrminant of Il-Y Anligen i.
Carboh),drate. NOluFe)()9: 503-5.1981.
156. Sharman, v . B. Evolution <Of Vi>ip.ril)' in Mant·
mal s. Chap. 2, pp. 32-70 of C. R.. and
Shorl. V.• ed •. Th. E""IUI;OIl 01
Cambridge Univenity Pr . ... New Vork. 1976.
157. Sheme.h. M. Estradiol.111l Bi",,),nthcsis b)' lhe
Early Bovine retal Ovar)" Du ring the A<tive and
Refractor)' Phase •. Bioi. R."rod. 23: 577_82.
1980.
158. Shemc. h, M" Ailenberg. ).\" Mileguir, F.. "nd
Ay.lon. N. Honnene Production by Cultured
 p,..,.. and I'O$t.lmplantation Gonad •. Riol. R..
prod, 19:761-1. 1978.
1$9, Shcril\$. R, J.• PatteTSOn. A. P .. Brigbtwdl. D.•
Udd,man. R.• and Sartor. J. Aheration in
Pla,m. Te't"'terone: Estradiol Ratio: An Aher·
nati,.., to the Inhib;n Hypothe.is, An". N.Y. Acad.
So/. PlJ: 29$_]06. 1982.
160. Shin. 5,·1.• Brown. A. L.. and Bancrofl. F. C.
Growth Re.!">"se in Ath)'mic Nude Mice to
Transplanted Growth Hormono&creting Rat Pi·
t"itary T"mor Cell •. t:ndrx,i""'. /OJ.- 223-8.
1978.
16 I. Simpson. J. L. Gonadal D)"gene. i, and Se. Chro-
mO$Qme Ab""rmali,ieo: PbeT>Ot}'j',i .. Karyotypie
Correlation •. pp. 365-405 of Vallet and Porter.
ed$,. reference 176.
161A. Sirinath,inghji. D. J, S .. Roc •. L. Ii .. Ri,ier. J ..
and Vale. W. C",t icOlropin.Rclca' ing FaelOt" i, a
Potent Inhibitor of S.xual Recepti'ity in the f.·
male R.t. J05: 232_5. 1983.
162. Skla,. C. A.. G,umbach, M. M .. Kaplan. S. L..
and Cont • . F. A. H(}fmon.1 and Mctabolic At>-
norm.litie. Associated with Central NeCV<)u. Sys-
tem Gorminoma in Children and Adol.scents and
the Effoct of Therapy: Repon of 10 Patiem •. J.
C/in. t:ndoai""'. MtMb. 52.- 9-16. 198 I ,
163. Sow. A. M.• and SonTlCn, cbe in. C. Control (If
Growlh of ESlrogen-Sen,iti"C Cells: Rol. f(}f,.,.
F.loprot.in. Pro", Nor. Acad, Sci. USA 77.- 2084_
7, 1980
164. SpcrolT. L. Gl .... R. H.. . nd K.... N. G . Clinical
GyMroJogic t:ndocril!OJog)' aruJ Il1jmili,,-, 2d cd.
Will iam, & Wilkins. Baltimore. 1979.
Steinberger. E" Swerdk.IT. R. S .. and Horton. R.
The Control OfTc"icul" function. Chap. 26. pr.
264-92 of Greer. R. 0" and Koblin,ky. M. A..
eds, in ReproduCliM aruJ F,rrilily C'<m-
trol. MIT P, . ... C. mbridge. M . .. " 1971.
166. Slone. R, T , In Vitro Live, Synthesis and Serum
Lc,'eI. of Alpha Fetop,ol.in and Albumi n in lhe
Fetal Pig. Bioi. R.pft>d. U. 573_80.1981.
167. Swaab. D. F.. Docr. G, K.. Docl. J .. Dog.rtroon.
J .• van Leeuwen. F. W .. and Vi""r . M, Fctal
Ncu'''''ndocrine Mechanism, in Dcvdopment and
Parturition. Prog. In Brain R,ch. 4J:
1978,
168. Tap.naiTlCn. J .. Keliokuonpu· Lehlin.n. P.. Polli·
niemi. L.. and Huhtaniemi. r. Ag.·Relatcd
Chang.. in Endogenou. Steroids of li"man f.tal
Te5ti$ dudng Early and Midp,egnancy. J. Clin.
t ·!!drxri""'. M"ab, 52: 98_ I 02. 1981 .
169. Tash. J. S .. We lsh. M. J .. and Mcans. A. R. Reg.
ulation of Prolein Kin ... Inhibilor by Follicle-
Slimulating Hormone in Sortoli Cells in Vilro.
t·!!drxri""'.I08:421_34.1981.
170. Toran·Allerand. C. D. Gonadal Hormones and
Brain De,dorment; Cellular Aspects of Stxual
Diff.rentiation . Am",. ZOO!. 18: 1978.
171. Toran·Alkrand. C. D. Gonadal St.roid. and
Bra in Dev.lopment. Trend, In Neurosci. 4: 118-
21. 1981.
172. Tran. D.. Mou.y·De,soll •. N" and Josso. N,
Waning of Anti·MUlled.n Aeli'ity' An Early
Sign of Sort(lli Cell MatUf3.1ion in the Developing
Pig, Biol. U ' 923-31. 1981.
173. T ... friri. A.. Pomer.ntz. S. H.. and Channing. C .
P. Inhibition of Oocyle Maturation by Porcine
Follicular Fluid: Partial Ch.ra... riution of the
I nhibilor. Bioi. 14: 511 -16. 1976.
174. Tuehmann.Duple$$i•. H.• David. G .. and HaegeL
P. f1/uwol . d /lwrnan Ernbr)'Olog)'. vol. 2, Sprin·
ger.Ve,I'g. New York. 1974.
175, Tymoe.ko. J . L.. Liang. T .. and Liao. S, Andro-
gcn ROC.plor Inl.raclion. in Target Cell" Bio-
chemical Evaluation. Chap. 6. pp. 122-56 of
O·Mall.yand Birnbaumer .• d ... r.fer.""e (2) .
176. Val let. H. L.. and Porte'. !. H .. cds.
M"hanIJ"" of Saual Academic
Prc$'. New York. 1979.
177. V.nage. G. R .. Thakur. A, N .. Kadaon. M. S..
and Shcth. A, Metabolic Clearancc Rate of In·
hi\>in in Mature and Immature Ma l. R. u . Biol,
R<pro<i. 2J. O. 1980,
118. Van de Poll. N, E.. De 8ruin. J. P. c.. Van Dis.
H .. and Van Oyen. H. G. Gonadal Hormones .nd
the Differ<nliation of Scxual and AU, . .. ive 8e·
ha-ior and Learning in th. Rat. PMg, Rsch.
48: 309-25.1978 .
119. Van Tienhoven. A. Endoctinoloi.\' of Rcproduc.
tion in 8ird>. Chap. 18. pp. 169 of Young.
W, C .. and Corner. G. W.. cd •. S.x and In"mo/
S<ffllioru. William, &: Wilkins. 8altimore. 1961.
180, Van Tienhoven. A. Rtprod"Ni'''' Ph)'<lolot y of
V.,.,n,rm,• . Saund .... Philadelphia. 1968.
18 I. Vcrn;kos-Dane lli •. J, EITccu of Hormone. on the
Central Nc,"ou, Syst.m. Chap. I . pr. 11-62 of
Levine, S.. ed. I/",m""" ond Brho"I"', Aca·
d.mie Pre ... New Yorl. 1972.
182, Vom Saa!. F. S .. and Bronson. F. H. S.,ual Char·
aCloristics of Adult Female Mice are Correlatoo
with th.i, 8100d TeStOSlerone I.e'ci. during Pre·
natal Development. Sci",,,, 208: 1980.
182A. V"", Saal. F. S .. Grant. W. M" McMullen. C.
W.. and La,es. K. S. High Fctal Estrogen Con.
centr.tion" C",relalion wilh Incre ... d Adull
Sexual Acti'ity and Decreased Aggre$$ion in
M.le Micc. nf): 1306-9. 1983.
183. Wacht.l. S . S, Th. Dysgcnetie Gonad : Abc"ant
Testicular Differenliation. Biol. R,p,od, 2].- 1_8.
1980.
184. G. N .• and Zucker. r. Taste Prefercnce<of
Fem.le Rats: Modification by Neonal!l Hor·
mone<. Food Deprivation and Prior Experience.
Ph,-,Io!, &. Bthav. 4.- 9)5-43. 1969.
185. Wagner. R. P.• Judd. B. H.• SanMrS. B. G .. and
Richardson. R. H, ImrodwUitm 10 Mod, m Gr--
Mli". Wiley. New York. 1980.
186, Walk.r. R. F.. and Belh.a. C. Gonada l Funcl ion
in Underfed Rat,: I. Erreet of Pinoal Gland and
Con".nt Light on Malural ion and Focundily.
Biol. /1.. 623_9.1977.
187. Wei ... L. .• nd G,cep. R, O. lIiSiolOt)', 4th cd.
McGra",·Hill. Ncw Yorl:. 1971.
188. W.i ... J.. and Ward. J. L. PI .. m. Test",tc",".

'"
and Progc>lCrone Tile", of Prcgnan' Ra t>. lhei'
Male and Female re'u,.., and Neona,al Off-
,pring. Endocr;no/. hid: 306_16. 1981,
\89, While. L G_. Rooge •. J. C. Morris, S. R .. and
Marley. P. R The Role of 'he Secro,ion. of tlH:
Male Acc<:,sory Sex 0,1""' of Mammal., PI'.
183-92 <>f R""oJu",jon and f."wurion . Austra"
Ii. n AcadonlY of Science. Canberra Cit)'.
1971.
190. Whitlinghan . D. G. Parthenogenesis in Mam_
mal" OxfOl'd Rn'. Herrod. Bioi, 1: 205-31. 1981.
191. Wilwn. E. M. Lea, O. 1\" and French. F. S. An-
drogen-Binding P,o'ein. of the Male Rat Repro.
dUCI;ve T meL Chap. 17. PI'. 491-53 1 of O'Mailoy
and Birnbaume •. ed •., rdere""" 123.
192. Wil""" J . D. S.,"", DitT.rc",j:llion . All", Rt1',
PhJ",if>l. 40: 279-306. 1978.
1\.1. Iklh'" A. R.. and Fe ig. L. 1\. Cell Prolif'rlnion
in lh. Mo"'m.'i." Testi" Bioi,,!)' of lhe Semin·
feroo' Growth Factor {SU F). R« . Prof!. lI",m.
4(); 531_61.1984 .
"'·2. Donaboc. p, K.. lIunt son. J. M.. Falla'. M. E,.
S ., and BuMik. G. P. Mechani.m of
SEX DETERMINATION AND DIFFERENTIATION
193, Wil..,.,. J. D.. GC<)rge, F. W.. and Grim •. J. E.
The 11",",,,,,.1 Control of 5<:,"al [)c"elopment,
&itrlu )/1: I 278_34. 1981 .
194. Wilson, J. D., Grimn, J. L arid George. F. W.
Sexual Dillerenti.,io", Hormone S),n, h<,i,
.rId Action, Bioi. Rerrod, U: 9-17.1980,
Wilkin. H. A .. Mednit<. S. A .• $chl • • inger. F.•
Ba He,1,.,m. £.. Cnd,ti • .,..,n. K. 0 .. GoOO,n·
ough. D. R.. l,ti"ehOOrn. K.. LurldSlOCn. C ..
O..-en. D. R .. Phil ip, J .. Rubin. D. B.. and Stock-
ing. M. C,iminality in XYY and XX V Men, Sci·
193: 547_55. 1976.
196. WilSeni. E. Teratogcnic Effects f,ont O,c"ipe.
nc .. of the Egg, Proceeding.. of the Third Inte,-
natioo.' Conference "" Congenital Malform.·
Th. Hague. Net herlandS. 204: 157-169.
1969.
Act ion of Mul ler i•• Innibiting Subst.nce. Anlt.
R ... /'h),.';{)/. 46: 53-65. 1984.
A·3. Poareo. P. T .. Khalid. S. A. K.• and Funder. J. W.
Progosterone Receptor< in R", Th}'",u" f;,,,Jori_
noI, II): 1287-91. 1983.
 14
The Male Reproductive System
The mammalian testes profoundly affcct "v<:'y as-
peCI of the ph)'sioiogy of lh. individuals in which
they reside. and they do 50 from carly embryoni. life
\0 the lime of death. Th ey pro,-ide the spcrmalQ7.00
that are =cntial for perpetuation of the specics. and
lhey lleerc\o hormones thaI (a) promote development
and maimain the f ""clions of ac.:cssory reproductive
organs nceded for reali7.alion of Ihe roles of lhe ga-
metes; (b) bring 001 lhe phcOOlypic features thal
"'nrlM "tr.ctive tn the fern. Ie; (e) <en,iti,,,
the organism as a whole 10 slimuli that spark and
sustain sexual intcres! and support Ihe performance;
(d) contribute to control of gonadotropin synthesis
and release; and (e) CAC'I in"ucnoes on a wide vari-
cly of " nonreproductive" body components that in·
clude the liver. kidneys. skin, skeletal muscles. thy.
mw; gland. bone and bone marrow. and of the
brain that modulate food intake. mood. and the in·
clination to engage in motor activity.
COMPONENTS OF THE ADULT TESTIS
lubules containing the germinal ele-
mentS and the Sertoli cells that nurlure them. make
up the bulk of the adult gonad , The long. hollow,
convoluted. looped portions originate and terminate
in straight lubuli rteli, Spermatozoa leaving the tub-
uli recti pass through a fine network of channels (the
retia testes) into efferenl duclU{ts as they journe)' to
the epididymis (Fig. 14·1).
The tubules are envclopc<J by a basal lamina. just
beyond which there are fusiform (myoid) cells that
resemble smooth muscle fibers, The latter are. in
turn, invested wjth the
The surrounding interstitium carries the Icstoster·
one-producing Leydig (interstitial) cells, blood and
lymphatic capillaries. finc nerve ending>;, callagen-
ous fibers. macrophage •. and some fibroblasts (179).
'"
" Ihick. connective tissue layer, the luniM Illb,,·
ginea. encloses the testis as a whole, It is lined by the
mniCIl vll$cuiosa. which provides the site for enlry of
branches of the imernal spormalic artery and Ihe in·
lernal spermalic nerve plexus. The tuniM vaginali,
is a double serous membrane. thc visceral ponion of
",hich covers the tunica albuginea. The pmiclal
layer of the tunica vaginalis lines Ihe scrotum. A
shcath of smooth muscle (the lunica dartos). and Ihe
<t,iMed rr'mll.fler mu.<r/" on,,,,]op the ,,,,,,matic
cord as "'ell as the teslis.
Minor sptcico .. rialioo,;n t.. tieular ,trueture arc de·
",ribed for Ihe mammal •. Human organ, 8re 4_5 em in
length and 2- 3 em in diameter. bUI one ;, ge ....11)'
larger than the other (126). The tubule. are 0 . 12-0.3 mm
in diameter, and they , how «tens;.. aMSlOlTlO<C<. Con.
nective tiM"" "'ptulae "'parate the parench)'nt. inlo
",me 250 lobul ... each .oot.;ning 4_ 10 Iubul¢<. Th.
teSt .. of rat •• nd other ,mall mamrn.ls lack seplulac and
an.,lomose •.
PRODUC TION AND MATURATION OF
SPERMATOZOA
The migralion of primordial germ cells (gonocytes)
10 the genilal that later enters into formation
of the leSlis, Ihe maturation of the gonocytes 10 spor·
matogonia, and Ihe early differentialion of the male
gonad were described in detail in Chap. 13.
Most investigators believe that Ih •• perm.log",,;.
formed during fetal life remain dormant throughout tbe
juvenile pcriGd and tben become the prallenitors of the
mature gamol.. (179). bUI OQrne oay th .t gonocyte. arid
their early ,"c"...sors dio off, to be replaced by I\CW .per·
malOgonia that differenliate from th. "germinal
epithelium ."
 - •
--
.- ." ,
c
,

•
- ••
I
... • •
.
•
• ••
• \

,• 1
,.
·"i:. ..
, ..,
o • ,.•

,• .
.
. ': - •.
. '
Spermatogonia 01 the Mature Te stl.
All mammals have two classes of spermatogonia.
along wilh subtypes (hat show spedes variations (33.
49).
TYPE A SPERMATOGONIA
These somewhat oblong cells are fouM in Ihe basal
rcgions of the tubules. allaehed broadly to the basal
lamina. They are said to be ··dust·like"· because the
chromatin appears finely granulated (33).
Primates have darkly staining A. cells that do not
divide or take up labeled thymidine under ord inary
conditions. They arc believed to be r tserW Slem Cf'lIs
that can renew the populations when infections.
drugs. radiation. or nutritional defocieneies damage
the pa ler Iype A spermatogonia. Thcy a rc almost de-
void of cytoplasmic organelles olhu than limited
numbers of mitochondria. They also may lac k
nucleoli .
Less intensely s\a ining pale (A.) cell, are
rounde<:!. contain numerous organelies. and ofte n
jXl5Scss one oT two nucleoli close to the nuclear en-
velope (Fig. 14-2). They divide on a regular basis
(every 16 hours in the monkey and every 12 in the
rat [33]) to support the recurring wa.·cs of sperma-
logenesis. These are, therefore. /'f>newing stem (ells
thatgiv. rise: 10 B type spermatogonia. Usually. they
occur in groups Of four.
Th. A, are believed to release a (halane that
inhibits division of th. dar k cells , (Extracts of nor-
mal testes diminish proliferative activity of lhe dark
of a radiated testis 1144).) It is 001 known if
mitot ic slimulanls arc also made (16).
The very la rge numbers of germinal cells wilhin
each tubule. and SOffIe overlapping morphological
features. make it difficult to follow the stages of cell
division and specialization. It is koown that several
generatiom; of type A spermatogonia must be
formed 10 provide adequale number1; of gamete
precu rsors.
Si, A .ubt)'pes havo beon described for the r.' (179).
According to. widely .ccoplcd .c hcmo. the cell. aro
lhe «/ui.alenl. orth. primate A. cell. , Thc A, 'XlIsgive
rise 10 progeny in the follo"'i", ordcr. (Only one d,ughler
tttl from each divi.ion i •• hown.)
.- -------------------------------
FIg. 14·1. A . Sec1ion ot (a bblt le.ti • . (') Te .ti •• (2)
oft"'""1 ductulM. (3) hOOd of epi<t<lymi •. (4) 'un>eo
.,buQi........X 5. B. Enl'''gemenl 01 a,u simi .., l<> '''''ta""",
., A. Soction 01 fO<)( _"..",, of """,;";f... oo.oo 'ubuIes.
human IMli• . ( I ) l u,,*,ot _ il"O\I$I_. (2)
WOlified ""ilhelium 01 spermatogenic 00II1• • (3) inl ... ..1
I; ••"". (4) cello of l e y<;l;g. X 168. C. Ento'oen,""1 01 a, ...
10 'ecla"" l. in B. Cro •• section of oeminife'"".
Iubull. ,al fe ' lis. oleCtron mi<:<ogo-aph, (1) l"""'" of
", ___ A, ___ ", ___ A. / "
" A, __ 8_ _ Primary
spelmalocyte
Thus. A, celt •• re of the succeS$iveiy more
differentiated t)'pes. but they al5<1 iodirc<:tly form new A,
cell •.
A problcm ... ilh lhe hypothesi, is Ihal il '«Iuire. an
ad>a nced cell type (A,) 10 .. rve a. Ihe prc<:UfSO( of ""e
Ih" i, Ie .. well differcnli"ed (3J.52). Another concepl i.
Ihal A. (stem cell.) proliferate dirc<:tty and al"" se",e.,
Iho progcn;tOf1, of $C.eral other Iypc< of ,pe rmalogoni.
Ihal include form. (A,,) more "primili"'" Ih.n Ihe A,.
11..-- 11.,-11.,,-11.,,-11.,,-11.,- A,- A,- A.-A,- B
TYPE 8 SPERMATOGONIA
These germinal arc "committed" to entry in to
spermatoge nesi,. They arc S<t id \0 be "crust-like" be·
cause of the Aaky appearance of chromatin ,\\lached
to the nuclear membrane (33). They are spherical.
possess more org.nelles that Ihe ty pe A spermalO-
gonia. and usually show small dumps of ehromalin
elose \0 Ihe nuclear envelope in addition \0 one or
two cent rally located nuelcoli. There is only limiled
altachmem 10 the basal lamina .
Monkeys may have fewer kinds of type A cells
Ihan «It •. Four .ucce.. ive gonemllon. of B sperma-
togonia have been described. the last of which gives
rise to primary
B,-B,- B,-B,-P,im'rY'pe,matocyte
CYTOPLASMIC BRIDGES
All but the mast primitive of the germinal
undergo incomplete cytoplasmic separation. and
spermatogonia in chains of as many as 80 have been
found (55). The c}'loplasmic bridges contain organ-
elles. and they may be siles for inlercellular com·
munica lion (55) , The concept is supported by obse r-
valions that all compone nls of a "clonc" undergo
synchronous developmenl according to a time scale
that can be different from the one governing neigh-
boring groups. Spermatogenesis is also accompan ied
by a rate of deterioration and dea(h Ihal is spc-
""""nil"""'" tubule. (2) S8rtQl; celiS. (3)
type B c< ve<y .arty primary _IOOY'''. (4)
S!>O' "",loeyt.... lhe pac""" _ . ,age of cllromosomal
,..,-rangement {IOta prOphase ot meiotic dO,'sion}.
O&fly _,malido. (6) inte'stiti.1 coli. of l e yd;O. (1)
poti'ubu\a' capilloo';o, . n<! ,,,,,"1<'1'. (8 ) on ... _. (9 )
tympMlic "",ce. X 580, (Rrtodin. ,ele ,"""o
150 )
Fig. 14· 2. Er.e1rOtl m;c,ogr_pI\S Oily.,. A da",. type A <Iepi<;t cmoma,in clumps II "'" 01 t .... nuoIt;r • . N.
pate . and IypO B Inset. or. light """"","",s. X 3900. In.." X 9SO . (Dym ond C..IocNI .
micrograp/1' 01 tM ..."'" ""R • . 1M . "owhead. in (3) reference .9)
des characteristic. The signa ls for destruction ""em
to pass from one member of a chain to another. It
been estimated that anywhere from 25% (55) to
61% (16) fe",<:r are produced thHn
would otheN·ise be expected from the rate of prolif-
eration of the preeul1lQl"S. The e<:11 destruction may
serve to selectively eliminate defe<:ti\"e ··clones" as
well as to provide appropriate numbers of new ga-
mete precursors. The bridges may also account for
the IIOt infrequent formation of with
IwO heads or two tails (154).
Spe rma togen esis
This lerm usually designates the scries of events in·
volved in Ihe transformation of spermatogonia to im-
mature spermatozoa. It can be divided into thre<:
stages: (formation of the pri-
mary spermatocytcs). meiosis (two-stage reduction
division that culminalc.. in the production of spero
matid,). a nd spermiogell("_. f. (maturation of sper-
matids into spermatozoa). Some authors regard
spermiogene'is as a prOC<'s< distinct from the firsl
twO stages.
$PERMATOCYTOGE NESIS
When first formed. primary spermatocyte. arc indis-
tinguishable from type B spermatogonia. Gradual
increases in nuclear and cytoplasm,c volumes and
preparations for entry into meiosis take several days_
MEIOSIS
The cells undcrgo a prolongcd period of DNA rep-
lication and chromosome pairing, during which nu-
cleic acid chains arc broken and repaired and CA-
changes between the segments (,·crossing over··)
OC<'ur. The term "seA vesicle" designates a chromo-
philic mass allached to Ihe nuclear envelope thai
contains the X and Y chromosomes. (It is not appm-
priatc, sine<: there is 110 enclosing membrane.) A
dark-staining chromatoid body is also reCOgni7.able
in primary spermatocyteS and their progeny. Bio-
chemical preparations for spe rmiogenesis occur dur_
ing meiosis (16).
Each primary spermatocyte divides to form two of
the secondary type, Each secondary spermatocyte
then yiel ds two spermatids (see Chapter I 3 and Figs.
I).J and 13-4),
SPERM IOGENESIS
When first formed. the spermatid is a small. round
cdl with a spherical. centrally located nudeus that
houses granular chromatin. The pale·staining cyto-
plasm contains numerou_. mitochondria, a compact
Golgi close to the nucleus. some free ribosonlcs, N'O
clearly visible centrioles. and a chromatoid body_
The remarkable transformation that follows has
been referred 10 as a metamorphosis. Figure 14_3
provides a si mplified representmion.
TI ME REQUIRED FOR SPERMATOGENESIS
Each change in acrosome structure is called a 5lOge,
As a spermatid matures. it makes repeated associa-
tions with s pecific kinds of less advanced germinal
ceils. The timc required for a particu lar type of as·
sociation to reappear within One region of a scminif-
erouS tubule is called a cycle. S.<'eral cycles must
recur before a spermato?Oan attains the status that
it to be: extruded from the tubul. (55),
In rats. 19 stages arc recognil.d. Depending on
the st rain . it Can take 4g-53 days for a type B spcr·
matogonium to be Imns[urmcd into a spe rmato,-<"n .
The intcrval for mice is 34.5 days. and it is 49 dHYs
for bulls and rams (179). Human spermatO?01I arc
said to require 74 + 5 days. The timing is geneti-
cally detcrmined, Hormones affect the numbers of
gametes formed but not the rates at which they pa'"
through the maturation stages.
S ertnll C"ll Rn leR tn Sperm a togeneSiS
In the fetus, Sertoli and germinal e<:lIs aggregate
to.:>sely to form scx cords_ The latter are plate·like at
first, but they soon thicken into c)·linders. Toward
the end of the gestation period. they elongate and
I><comc canalized_ Fell'll Sertoli C<'lls do IIOt have
specialized ccll-to-cell interactions. They protect the
spe rmatogonia and block premature entry into
meiosis.
As tlle time of puberly approaches. tlle Sertoli
C<'lIs proliferate rapidly for a time. and they increase
1D-20-fold in volume (16). Although their numbers
arc small when compared with the germinal elc·
ments, they occupy one-fourth to one·third of the tu·
buies (49). At this stuge. they can be removed and
slimulated to continue proliferalion. As they become
more specialilcd , they lose the ability \0 divide, [n
time. the sex cords become the long. hollow, tortuous
convoluted seminiferous tubules of the adult lestis.
SertOli cells are remarkably resistant to high tcm-
peratures. radiation. and other that destroy
germinal cells. (It is therefore possible to obtain Ser-
toli cell preparations for investigative purposes.) Se-
vere vitamin A deficiency and some pharmacological
agents disrupt the functions (57). Evidently. rcti-
tIOids interact with F'SI-I, stimulate milosis, and pm-
mote germinal cell differentiation (A.4).
'" REP!1OOUCTIVE SYSTEM

0;..,.,_ P,o.oe'osomal STRUCT URE OF MATURE $ERTOU CELLS

golgi ..
The fully difJel"<'nlialed extends from lhe basal
lamina 10 the tubular lumen (Fig. 14.4). It has
highly irregular contours. wilh processes eXlending
around the germinal elements. The cytoplasm is
richly supplied wilh organelles that include tubular
mitochondria, primary and seoondary IY'iOSOntcs.
lipid droplets. microtubules. and scancred groups of
Golg; vesicles. Pigment particles are generally
ent, but crystalline inclusions have been described
only for human testes. The smooth endoplasmic re-
ticulum is well developed. and SOme free ribosomes
as well as rough endoplasmic reticulum a re also
present. However. although Sonoli cells release sev-
eral products. there are no secretory granules. The
multilobulatcd nudeus contains a prominent nuelca.
lUI, but the heterochromatin seems to be confmcd to
tWO paranuclear inclusions (57).

D. Cop ph...
-, THE " Bl.ooD-TESTlS BARRIER"
Contiguous Senoli cells form tight junctions thai ef-
fccti.'ely separa te a "basal compartment" in which
spermatogonia nestle. proliferate. and give rise to the
prclcptotcnc primary spermatocytes. from an "ad·
luminal wmpanmcm" that houses germinal cens in
mO .... odvonced stag", of development. A. a resuh,
substances broughl in by Ihe bl<X>d capillaries can
gain access 10 the regiom; oc<:upicd by spermalC>-
gonia. bUI they must pass through lhe Sertoli cell q-
I p""e loplasm to reach the dividing spermatocytes. sper-
matids. and spermatozoa.
The lransfer is actually made between tile Sertoli cells
" and the lymph th.t bathes their b...1surf.= . • nd there_
Acrosom., !>hO.. fore it is probably more appropriate to usc the term "tes-
lis-lymph barri,r" (61). The cffcctiven... of the 'TranSe-
ment i. demonstrated by the exclusion of acridine dyes.
jlCTQJ;.idascs, lanlhanum, and other molc<:ulC$ from Ih.
adluminal compartment. when .uch subslances arc pr.-
:le nted in a ma nn", that p<rmil< tbem 10 enler the "'lie-
ular lymph and come in c""tacl with the 'p<rmatog""ia.
The selectiveness of the Iransport processes is re-
flected in differences in the ionic composition or the
luminal, compared with Ihe bul k interstitial Auids.
However. testicula r Auid also contains components
that a re secreled by Ihe Se rtoli cells.
The barrier makes it possible for Ihe Sertoli cells
p;o,oo to maintain a highly specialized microenvironment
P'ifI<;p.l." " thaI supports meiosis and the maturalion of sper-
, lOl. matids. Since the lalter are sma ll when first formed
and undergo s ubstantial loss of Ihe remaining allot-
Fig. 14-3. (CyloplasmOc bricltal ment of cytoplasm as they become transformed 10
connecting tOe _molid •• (. 1'>01 ShOwn .)
spermatozoa. the Senoli cel ls must provide both sup-
 -
, ;.,
;,'
" ..

--.

Fig. 14·4. D;aQrammatio '6P'0ser>1at"" 01 potIioe. 01 lwO oompie' bet"'....., two IdIaet<>t s.rtoH c.lts: ll. I;po:!
OO<I.;guou. e.!Is ar>d "*'
aS$OC;ated dfO\lleto , ly •. lysosome: M. m;to<:hondr;,,, MI, micfo,ubulM;
_ _ to, Tho bold _ . show .he contours o11he Serto1i
c.ll • . TIM cytopl" '" i.
shown
s.......1 opeormotozoo .t.
t ..... I.il. projeeti"lllnlO 11><0 lublJ l... 1<0,,-. Go,
N. ....,(@u. con'airliog8nucIeOlU •• "" Iw<l pa!IOUCi<l8'
"w' ogation. 01 REIl, 'Old> ' ''''oplum;c
,.'k>JI<Jm: Seyt. _""'!OCYIo: Sgm, """",,,,'01IO"ium:
GoIgi , . ""'les, IS. inter<al!LJla, """e.o: JC. iun<1iona1 SmEA , smoolh endopI.omi<; reliculum: Std , _m.tjd.

port and nutrients. (They have therefore been called
"sustentacular" or "nurse" cells.) Serlol; cells also
ingest and dispose of lhe germinal cytoplasm.
and (hey are believed to provide prole<:\ion against
(he mounting of imm une reactions against dC"elop-
ing gameles. It is nOt known whether haploid gene<
are transcribed or whether the <:ells support such a
process (52A).
Half the ""conda.)" 'pcrmo'''''yl« and 'p<nnalid. lac k
an X chromosome. and the .. i. some evidence for X in·
aCtivalion in the (61). Senoli ceil. may provide
sub>ton«.th .. V-type g.metes need but <aonot ma ke .
O1her possibilitie, arc Ihal Ihe cell. do not require X
ehromowme, .,Ihose .tages. or lhal X.IYpe gamete. "'"
,.in 'heir chromosomal fUn<:lion. and I""'mit Ihe ,",c-
essary molecule, a.,..,.. C)'lopla,mic bridge,.
Spermatogonia and preleplolcnc 'permalocytcs
are confined to the basal portions of the tubules (Out·
side the bl<X>d-testis barrier). Germinal cell, in mere
advanced reside above the junctions, The ul>"
ward migration of maturing spermalocytCS must in-
volY(: opening and closing of galeS. A "zipper-unzil>"
per"' mechanism (52A) with reduction s in
adhesiveness. di sengagemen t. and subsequent clo-

Sure of the same passagewlI)'$ has been proposed. [t
is also possible that some junct i01l$ are totally de-
stroyed as new ones form (44 ).
Bundles of thick (100-,\ diameter), aClin-ronlain-
ing filaments within the junctional regions probably
contribute to formation of the barrier. Thinner ones
(60_70 A) in other parts of the cell are said to in-
teract with microtubules to redistribute cylOpla'm_
bring about regularly recurring changes in contou rs.
aid in upward uanspon of thc germinal cells. pro-
vide support for the spermato7.oa. and contribute to
spermiation (33). Contractions of peritubular myoid
cells. and fluid "currents" generate<! by absorption
and secretion. add it ionally facili tate ceU migrations.
SpermIatIon
As imratesticular maturation approaches comple-
lion, the spermalO7.0a become positioned with their
acrosome, and nuclei deeply embedded within r0-
cesses of the apical portions of the Scrtoli celh , Mo.t
of the remaining cytoplasmic masses are displaced to
the bases of the flageUae that project into the lumen.
Since each syncytial duster now spans the uppe r
portions of several Serlol; o.:U,. the latter must co-
operate to accomplish gamete eXlrusion.
The Senoli cell, take up fluid . elongate. Jnd swell.
Widening of the cisternae and channels of the en-
doplasmic reticulum is attributed to lowering of
ATPase (and therefore of sodium pump) activity.
As spermiation proc.:e<!s, Ihe acrosome,. nuclei.
middle pieces. and tails move toward the lumen. but
mo.t of Ihe cytoplasm is held within the Sertol; cell
recesscs (Fig_ [4_5B). With continued displacement
of the ends of the tails, the cytoplasm constric ts and
each sperma(W03n is connecte<! to its cytoplasmic
mass by a slender ned (f ig. !4-5C). When Ihe
brea k occurs. the cytoplasmic bulk is retained by the
Sertoli 0.:11 as a r..sidual body. bu t a small cyto-
plasmiC drople/ adheres to the middle piece of the
spermatozoan (fig. 14-50).
Germinal cells may play active roles in spermia-
tion. The regular rcCurrenCe of spermatogenic cycles
suggests that they communicate with one another.
Spermatozoa scem to initiate destruction of their
own residual bodies and contribute to aetivalion of
the phagocytic and [ywsomal functions of the Sertoli
ecU,. The [ipofusein pigment that ao.:umulatcs in the
laner is probably made up of indige;uible residues
(33,122)_ It may also contain material salvaged from
One wave of spe rmatogenesis that can be re-
n1ilized for the next (140). It has been suggested
that residual bodies release regulators that initiale
the next wave of spermatogenesis.
THE MALE REPRODUCTtVE SYSTEM
I "
,
)
)J
,
"
, 0
Ftg . 14-5. SUoc.w•••t8l/<1.1n _m 'fl ... _.l ,
ElOnQat&d 'pMffilltid. dHflly . . . . - .. lhO' SerlOli cell
w;tfIcytoptu.m Cludal to lhO' middte pi..,., B. bttu ....... of
uiol oomponents of ",*"",11d. wI1i" 10/)'"'' of eyt<>p!asm
" 0 in thO' o pilhO'lium. C. Conlir>t>O<l oxtru ....... 01 Sperm
l><Iad roOtJlt1ng in attonuotior1 01 .lenda.- 'laII, connocling
cyl<>p!Osm to necI< ' OQioo, D. o10!Ooik wiV,
'et'action Qf 110 proxlmol PQ(1ioo to n<JCk fo<,.,;"g tl><l
cytoplasmic <lrople1 and Iea.iog _ rounded ",sidu.ilt
bOd;"" ot ilt hekl in l/Ie opitr>elium. (F.wce1l. ",t""""" 57)
TESTICULAR FLUID
SerlOli 0.:111 a vidly take up waler a nd sol utes. and
they make copious quant ities of a speciali7.cd fluid
that bathes germinal cells and facilitates their deliv-
ery to the epididymis. The hypero<motic secretion i,
rich in K ' and 0 - but low in Na '. It contains sub-
stantia[ quantities of myoinosi to[, testOSterOne and
other steroids. along with androgen binding protein
and other described in Chapter [3 _
Sperm Maturation wlth[n the Epididymis
The young spermatozoa now have condensed nuclei,
weU.,jevdoped tai ls, and other morphological fea-
tures of mature gametes. However. they ca nnot as
yet either swim or fertilize. They embark upon a
long, tortuous journey through the caput (head).
upper (proximal) and lower (distal) corpus. and
proximal and distal cauda of the epididymis. during
whiCh they undergo "ripening." Spermatozoa taken
from the caput Or upper corpus of experimental an-
imal, engage in random circular movements if they
are placed in aqueous m«lia. Ones ta ken from the
cauda can swim ;n a forward direction. Acquisition
of motility is essential but nOl sufficient for (lOCyte
penetrat ion ,
Epididymal transit time varies with lhc species.
Human spermatozoa complete (he journey in [2
days (15). but (hey can be stored in the cauda for
several ,,"eeks. Afterward, they may be catapulted
through the deferens during ejaculation. or re-
leased during reHex nocturnal emission •.
SPERM TRANSPORT
Contractions of the myoid cells al Ihe base. of the
seminiferous tubules. and of Ihc muscular wall. of
Ihe efferent ductule •. iniliate movements of sper_
matOloo Ihrough the epididymis. Muscles of Ihe
scrolal ",·all. also promote oontraction of the testis.
Large quantilies of lesticuiar Auid arc injected into
Ihe CapUI. and both progressive absorplion of more
Ihan 90'% of il and the bealing of cilia on epidid)'mal
cell s Ihat border the lumen facilitate the passage.
Muscles of the epididymal walls engage in bolh pen-
dular movementS thul mix the Auidsand increase ex_
]JOSure of Ihe spermalOzoa 10 Ihcir oontents. and
peristaltic oontractions. Their aClivitie. are under
adrenergic oontrol (15). Since radiopaque ioon par-
ticles inserted into Ihe caput arc sent 10 Ihc cauda.
active participation of Ihc spermat07.oo is probably
not needed.
FUNCTIONS OF THE EPIDIDYMAL
EPITHELIUM
The cytological features of the epididymal cells have
been described in detail (71), but we have only li m-
ited information on the functions. The "cry large
surfaces presented by microvilli. the oxll speciali711-
lions that differ from one oompartmcnt to thc next.
and the many biochemical processes identified. cast
doubt on the va lidity of suggestions thaI the epidid-
ymis simply provides a Suilable enviro"ment fot re-
alizalion of Ihe "inherenl" polential of the spcrma_
1O'.oa. Normal development may require a period of
residence within the capul region beFore more ad-
vanced stages of maturation can be accomplished.
(Cells placed direclly in lO Ih. cauda becomc defec-
tive [37),)
Sp<rmOlozoa. laken from the rete Icsli, Can undergo
maturllion in slulamal..rich. defined media, However.
tltere i. a high dealh .... ,e and m.ny of lhe , urvivors have
morphologic. 1 abnormalili ... Th. fertili7.3lioo ....1. i.
very low.• nd fOTma lion of lhe pronucku' i. delayed
when il;, aC<Xlmpli,hcd. MOOI of the embr)'", do 1101 at-
tain malurily (t5). The possibili ly lh.l impro"emonl' in
the cuit.", media can inc",= lh. producti"'" of IIOrmal
game Ie. has 1101 been fully e<plOTed.
Epididymal cells sho,," eXlensive pinocyl;c acti vity.
This accomplishes Auid absorption, and there i, an
associaled bidireclional transport of t>oth inorganic
ions (86) and large molecules. Phagocylosis and ly-
sosomal digestion dispose of sub:\.tances by
Ihe maturing spermatOlOO. and they rid Ihe lumina
of dead and degenerating cells. There may be se lec-
tive destruction of abnormal gametes, Far fewer
spermatoroa appear in ejaculates and emissions than
in lhe caput. and lower percenlages of gametes with
swollen heads and other defcets cnler the ca uda , Ep-
ididymal contains spermatozoal fragments
(15). and fewer polyploid cmbryos form from ga-
meles thaI have spent the usual times in the epidid-
ymis than from ones coll ected prematurely.
Large quantities of glyccrylpholSphorylcholine
(GPC) a", synthesized and discharged inlO the
lumen, G PC contrihutes 10 the high osmotic pressure
and il stabilizes Ihe plasma membranes of thc sper_
matOzoa. It probably also inhibits capa,ilalion (a
process thaI prepares gamel.. for fertili'.ation bUI
rende rs them highly susceplible 10 delerioralion
[28]). Capacilation normally occurs ... ithin Ihe fr:>-
male tract (Chapter 16). and oviductal Auids acquire
high of G PC esterase clos.c to the time of ovu-
lalion (99). GPC has additionally been implicaled in
removal of phospholipids discarded by Ihe
spermatozoa.
Carniti ne is also released. Spermatozoa absorb
the molecules. and they utilize them for mitochon_
drial uptake of fatty acid fuels. The cells have high
carnityl trans ferase activity.
Much of thc sialic acid-rich carbohydrale made
by epithelial cells is protein bound. It may play roles
in reducing friction bet"'oxn Ihc closely crowded
spermalOloo. The high rale of glycoprotein synthesis
has been linked with supporl or the acquisilion of
fertilizability (194). A 37.QOO.dalton glyooprOlcin
attaches firmly to the sperm plasma membranes in
the cauda (where ability to fertilize is acquired)
(128). Epididymal cells also provide Ihe spe rmnto-
1.oa with surface antigens. These replace some gly-
ooproteins acquired in the lestis , T hey affcct the Sur-
fa.., charges and may also inhibit capacitation (93).
The epid idymis requires higher androgcn ooncen-
trations lhan other "'prodUctive organs
(122). Considerable quantities enter with testicular
Auid, along wilh androgen binding proteins. Addi_
tional steroid may be supplied by testicular blOXKl
and lymphatic vessels . I n some species. androgen can
also be syn thes;,.ed from ,holesterol (100). The cells
have a 5a--reduclase that promotes conversion of tes-
tosterone to DHT. and other en>:ymes Ihat ,ataly".
Ihe formation of androstanediols and related regu-
lators. Some of thc products are transferred 10 Ihe
prostale gland and sem inal vesicles (129).
MATURATlONAl CHANGES IN T HE
SPERMATOZOA
These involvc alteralions and redistributions of sur-
face charges. changes in the kinds of carbohydrate
groups that are exposed on the surfaces. a nd internal
'"
modifications (I 28). The most obvious morphologi·
cal change is caudal migration of Ihe cytoplasmic
drople! (70). The structure contains iysosom,,1 cn·
zymes thai dispose of cerlain spcrmatoroal oompo-
nem• . bUI a nutrilive function has also been consid-
ered (15). Relationships 10 acquisition of moti lity
arc controversial. Rabbit spermatozoa swim before
Ihe process is accomplished. In humans and many
olhers. the droplet is eventually discarded. but there
are species in which il persi$\s (I 5).
AC<juisition of motility has been linked with in_
creased ability to generale cAMP. with rising
cAMP-<lepcndcnl pM.in kinase activity. and with
olher responses to Ihe nucleotide. SperrnalQ7.Qa
laKen from Ihe rCiC lestis engage in Ihrashing move-
menlS when phO$phodieSlcrase inhibil<N'S are added
10 the fluids. They rna)' require exposure to a "for.
ward mobility (F MP) idemified in epidi-
dymal fluid to achieve more mature locomotor aCliv-
ity FMP binds tightly to thc spcrmato7.()3 ,
and cells eXpO$Cd to it respond in an all-<lNlOne fash-
ion (1). The lail must be stiffened, Mat uration in-
volves Ihe formation of intramolecular disulfide
bonds between the OUter dense-fiber proteins, along
with reductions in thc numbers of f= sulfhydryl
groups (15,74).
Even after aequiring the potential for indepe ndent
motil ity. spe rmatozoa remain quieseent throughout
their oonfinement within the epididymis. (This is just
as well. sinee it eonserves encrgy.) Allhaugh it has
been speeulated that steroid hormones within the
lumen inhibit motility. it seems mOT<: liKcly that cdl
crowding. low oxygen tension. low sugar content. low
pH, and the ionic makeup of the epididymal fluids
are more important. Cells bcwme motile as """n as
they leave the cauda and oome into OOI1taet with
fluids from the other accessory reproductive organs
or wi,h culture media.
Acquisition of the ability to fcrtilize is associated
with changes in the nucleus and aCl"O'lome. The head
becomes more oondensed and cell specific gravity in-
creaSCS. More disulfide bonds form between nuclear
histone Conversion of proo,rosin 10 ac-
rosin (74). and the appearance of hyaluronidase and
othe r en7.ymes may occur at this time (56).
The gametes of rau and sorne other species p0s-
sess "perferatoria" (dense structures that devclop in
the subacrosomal space). and in these obviou, aher-
ations in the sizes. shapes. and internal structures of
the acrosome! can be demonstrated (56). Prirnate
spermat01.Oa lack such speeial i711tions, but there is
considerable for acrosomal mooi-
flcation. There arc progr:ssivc changes in the light
se311cring pallerns. in electrophoretic mobility, in
agglutination behavior, and in protein composition.
THf MjI,lf REPRODUCTIV£ SySTEM
As the gametes progress toward the ITII,}I"e distal re-
gions of the epididyrnis, they IO$C SOme of their phos-
pholipids and cholesterol, show increased tendencies
to take up dyes, and become mOre susceptible to heat
and oold shock.
The spermat07.03 gradually acquire the ability to
ntihc a wider variety of nutrients , The higher Tate
of glycolysis shown by gamctes taken from the distal
epididymis has been allributed to the synthesis of
en?yrnes of the glycolytic pathway (but other factors
within the epididymis may account for the low rate
of sugar utilization in the more proximal regions).
STORAGE OF SPERMATOZOA
The cauda is the only oompartment that can main-
tain the sperm in good oondition, In addition to pr(>-
viding a receptacle for cells p=ssed in the upper
parts of the epididymis, it can ",,,,,ive spcrmat01.03
that have enter«! the vas deferens but have not been
ewuded during ejaculation (146). The life spans are
limited. Cells that deteriorate are destroyed, and this
provides protection against release of "overripe"' ga-
metes that can still engage in fenili7.ation but are
likely to cause formation of defective 7.ygote5.
Sperrnatozoa that leave the cauda of the human
epididyrn is pass successively through the muS-
cular V05 the somewhat dilated ampulla
(in which some shon-term storage can occur). the
inch_long eja(u/orary duer. and the prosrori( and pe-
nile poniom of the On the way. they oome
in oontaet with the fluids released from accessory re-
productive glands.
The ejaculatory duct is formed by the union of the
ampulla and the seminal vesicie duets. and it there-
fore receives Auid from the seminal vesicles. Numer-
ous small tubules carry the prostatic fluid into the
urethra. and spermut01.03 leaving this region are
with tWO kinds of secretions. The bulboureth-
ral (Cowpers) glands discharge their product into
the penile urethra.
Although substantial nurnbers of sperrnatozoa arc
lost along the way. the ejaculate of a healthy
adult contains SOme 20-100 million cells in each of
the 2-6 rnl of semen released (51),
SEMINAL FLUID S
The accessory reproductive glands provide most of
the seminal fluid (seminal plasma) that, togcther
wilh the spcrmatowa. makes up the sernen. The
Auids contain nutrients. butTers, and other sut>.
stances that contribute to the transport and .urvival
of the garneles. Species variation' in the structures
were cited in Chapter 13 (..e Fig. 13-5),
THE SEM INAL VES ICLES
Although the human glands are small relative to
body weight when compa red with those of rodems.
they supply around two-thirds of the seminal
plasma. An obsolete that they store spero
matowa has been discarded.
The secretions are especially rkh in [rue/ow (with
CQncentrations in the neighborhood of 315 mg/iOO
ml). while inositol and sorbitol are found in
amounts (26) . The is utilized by spero
matowa as a major energy souree. and reductions in
the rate of its metabolism have been correlated "'ith
dege nerati ve danges in the ,,<,lis (IOS) _ Seminal
plasma CQntaill$ exceedingly large quantities of
proslagfandillS. and at least 13 different varieties
have been identified (64). 5<lmc are smooth muscle
stimulants believed to facilitate transport of sper_
ma toloa through the female
The enzymes include acid and alkaline phospha-
tascs and nuclcotidases. The presence of large num-
bers of Iysosomes supports the belief that seminal
vesicles cont ribute to of abnormal and
deteriorating spcrmatozoo.
THE PROSTATE GLANDS
Although prostaglandiru were first identir,ed in
semen and named for their purported origin in the
p"»la'" glalLd. 111" "pi,hdial rolease onl)' min·
ute quantities of these fauy acids. Human secretions
comain components analogous to those of the
uiating glands of rodents.
Prostatic Auid is slightly al l aline. and it is rich in
cilrate and acid phosphalau . The citrate is impli.
cated in the binding of calcium ions and therefore in
regu lation of coagulation and subsequent lique.
faction of the seme n. It may a lso be an activator of
phosphatases and of hyaluronidase.
for prostate gland accumulation of
very la rge amoums of zinc not been deter-
mined. Positive correlations among the eOnC{:ntta-
in seminal plasma. the prolactin content of the
nuid. and spe rm count and Jll<)\ility have been
reported. but the fmdings are cont roversial (II) ,
Zinc enhances testQl;terone within the tes-
tis. and this has linked with a delaying effect
on receptor degradat ion (88). The metal is a cof"c-
tor or constituent of prostatic but
the amounts n""dod for are small by comparison
with the quantitiC$ accumulated.
The possibility that 1.inc released into the female
is utili7.cd by young is consi,tent
with knowledge that embryos avidly take up the
mineral. and that fetuse.< developing in zinc.defocient
environment' have high incidences of severe somatic
abnormalities_ On the other hand. only limited
amounts of zinc may actually find their way into the
Semen , Very high conC{:ntrations arc correlated with
low fertility and the presence of large numbers of
spermatozoa with coiled tails (51).
Prostatic ftuid also contains antigens. SOme of
which adhere to spe rmat07.03. and many en1.y mes
(lOS). There are a lso substances that affect sperm
motility. "Decopacitation factors" have been said to
origi nate in the epididymis (28). the prostate gland.
or both.
THE BULBOURETHRAL GLANDS
These small structures rdease a somewhat alkaline
fiuid that is rich in glyeosaminoglyeans. The primary
function seems to be lubrication of the tip of thc
pen" .
OTHER CO MPO NENTS OF SEMEN
Sub'itan,,<,s that have not been locali7.cd to a specific
gland include phosphate and bicarbonate buJJtFS
that provide protection against the low pH of the fe·
mate Iract. phlNpholipids and cholesuml that ac-
COunt for the opalescent appearance and in part for
the high viscosity, (w hich is probably re-
leased from deteriorati ng spermatozoa and serves as
a useful ma rler for detection of semen). and an as-
sortment of amino ocids and "ilomi/lj.
STEROID BIOSYNTHESIS AND METABOLISM
Sites of Androgen Production
The lestes of healthy young human adults release
around? mg of testosterone to the cireulation each
day. along with smaller amountS of tcstosterone-sul·
fate, androstened ione. dehydrocpiandrosterone
COliA). (D II AS).
dihydrotestQSterone and related sleroids
(Fig. 14·6) (50, I 04 , 145). All of the molecules in the
pathways be)'ood D H A ha.'e potency,
a nd some of the others Can be con.erted peripherally
to biologically active regulators. Most of the andro-
gens a re produC{:d by the ;mer!1itinl cells.
The steroids arc sent into the extracellular spaecs.
and a substamial fraction finds its way into the tes-
ticular lymph that b.1thes the basal portions of the
seminiferous tubules. Some androgen is ta ken up by
ScrtoH but the rich network di,'crts
much of the hormone to the systemic btood .-essels.
Sertoli C{:lls metabolize 'he androgens supplied to
them. and they transport large amounts of testos,er-
one and DHT to the rete testis Auid. T hey do not
se<:m to have choleslcrol si dc-chain deav.ge en-
zyme.' (44 ,4 5.104). androgen can be made
from pregnenolone . but the production rale is c.'ti-
 THE MALE REPROOOCTIVE SYSTEM

Plasma CMleS!e' oI $oo«.s

I ,
Ace¥-CoA Senoli CHOLESTEROL

,.

Fig . 14-&. Alldrogen biosyrttnesil in """'." tdlJlt

...t ... 0.11 1. Malo< paTnw. y snown ... bold A"ows
pointing outwa ,d show product.

mated at K.. thai of Ihe interstitial cells (119). Tu·
bular myoid cells engage in androgen metaboli5m.
and thcy affect transport. Accordi ng 10 some
observcrs. free-noating spcrmatoloa Can make somo
androgcn (104) and convert leStOllterone to DHT
(190).
Adrenocortical cells share embryological heritage
with the interstitial cells. They are not believed to
make significant contributions to reproductive func·
tions of unstressed. healthy male adults. Adrenal an·
drogens are. however. implicated in the timing of pu-
berty onset. Thcy Slimulate libido and the growth of
axillary and pubic hair in women, are major regu·
lators after menopause. and assume imporlltnce
under pathological conditions. Some low·potency
steroids regularly released can be converted periph·
erally \0 molecules that have high biological activi.
lies (133).
Blosyothet lc Palhways 10 Iha lolerslltls l
Calls
Cholesterol is the major precursor. Most of it is de-
livered by the circulating blood as a component of
lipoprotein complexes. Cholesteryl esters and choles·
terol that is free Or loosely a<sociated wilh Ihe
plasma proteins can also be taken up (52).
Reserves arc stored in lipid droplets Ihat increase
in sizes and numbers during times of reduced andro-
gen output but become depleled following mong
stimulation of the cells. At least some of the droplet
content is in the form of cholesleryl esters that can·
not be used until esterases liberate free choleslerol.
the case for the adrenal cortex. however.
much of the stored lipid seem. to serve purposes
otheTlhan hormone synthesis (I22J.)
Until re.:ently. it was generally staled thaI the in_
terstitial cells make their cholesterol from acetyl-
coenzyme A (50.190). Pathways for the conversion,
and the negative inAuenees exerted on the
rate·timiting cntyme (HMG-COA reductaSe) were
described in Chapler 5 (= Figs. 5-1 and 5-8). A
problem with lhe concept is lhat interstitial cells do
not seem 10 have that en1.ymc (52) . However.
cells have a HMG-CoA reductase. They may. there-
fore, synthesize cholesterol and pass it on to the in·
terstitial cells. (As noted. Serloli cells cannot use
cholesterol to ma ke pregnenolone.) If the concept i.
valid. then we have one more example of cooperation
between neighboring cells of differcnl types within
gonads. Cholesterol synthesis could serve as a '·baek·
up" mechanism for coping with ,ubstrate shortage.
There are sprxies variations in the ratios of
frce:eslerified cholesterol aoxumulated and in the
quantitative impOrtance of the various metabolic
pathways leading to androgen production (52 .122).
In human adult testes. up to 95% of the cholesterol
is in the free form .
CONVERSION OF CHOLESTEROL TO
PREG NENOLONE
Although thc possibility of ahernate pathways has
bcen considered. it is now ge nemlly agreed that rTlOl;t
or all of the cholesterol used for androgen biClSyn·
thesi s is oonverted directly to pregnenolone. Sinec
the reactions take place within the mitochondria.
cholesterol recruited from cytoplasmic "pools" must
f'rst be tranSpOrted across the membranes of the or-
ganelles_ The required protein carrier (cholesterol
binding protein, CBP) is distinguishable from a dif·
ferent substance that facilitates pregenolone egress
(52),
The sidc--chain cleavage is si milar 10 Or identical
with the reaction described fo r the adrenal COrtex
(122). Moreover, the comrols exerted Over it by lu·
tropin resemble the infiuenees of ACTtl on the
fascieulata.
CONVERSION OF PREGNENOLONE TO
ANDROGENS
The fate of the pregnenolone varies with both tne
species and the stage of reproductive system devel -
opment (145). Some uncertainties concerning the
events are difficult to resolve. si nce steroidogenic tis·
sues oontain enzymes that can catalyze tra nsforma·
lions along more thn one pathway. Much of OUr un·
derstanding of the bi(l<;hemislry oomes from studies
involving the administralion of labeled precursors
and the measurement of labeled prodUCIS_ The ad-
dition of supraphysiological concentrations of pre-
cursors, the "xlracellw/ar presentation of intermedi-
ates. and SOme of the conditions required for
ma intaining in vilro systems. may cause interslitial
cells to demonstrate what thcy ("1m do. ralher than
how they ope rate in the healthy, intact animal.
It has been suggesled Ihat the tI' palhway, whiCh
predominaleS in human adult male testes. is highu
on the evolulionary scale than Ihe tI' used by rats.
motl keys. and mosl other mammals (sec Figs. I 3-17
and 14{i). Orangutans resemble humans in many
respecls, and Ihey make some tI' intermediales
{122). However, rabbil' and some other nonpri-
mateS a lso usc the.;l' syslem (52)_
Acoording to one h)'pothe,i., Ihe kind. of intermedi"<$
formed arc determined by thc rel ati_e affinities of the
l1",hydroxylase and C17, C20 I)"ase en'ymes for ,h.
,ubstrate._ Another pOint of view i, that intormediales
.... ne_er free within the ceU •. The ,ubstrale allad,e, to
a p,rlicula,., rnut,i-<:n'yme e<>mpte. that ,hull Ie, the
produe, of One r•• c,iQn di=tty '0 the enzyme ,h.,
.IYles Ihe ne ,t on. (104), Tto. ... f_. the oompo ... nts of
the particle< de,ermi ... the fatei of 'he various me'abo-
lites. Th. secretion of large quami'ie, of tesl<><te,,,,,,, but
only minute amounts of .. veral other lipid.soluble , teo
roid< b«n ciled in . upporl. Ho",._er, some C21 and
01' intermedi.tes .,e also ... Ie ..ed on ••• sula. basi •. and
it has been suggested thaI both pla.ma prot.ins and Ser·
'oti cell, rtmove Other I'eroidl .
SULFATE CONJUGATES
The cells take up .ulfat., and the molecute<
see m to be proc .... d by en,_}'me. ,h., differ from the one,
"ting on UnCOniu8ated 'teroids (104) , Since the ,e'ti.
. tso con,.in, .ut fa,ase; th., froe >leroid. i, i, poS-
,ible Ih.t the I"'th ...'ays permit the ... of ,hernale ,ul>-
. lrates ... hen 'he .Itolcst.r<>\ .upply i. timitcd (501_ Ac_
cording 10 Ihi' concept. the ' teroid <.Ifates regularly
found in int .... titial .ell incubate ••,e byproduct' of
However. <teroid. conjugated at poIIition t 7 and son><
anuros'enedi<>\_3.17..:1isulfate or•• tso pr•• en, in 'he in·
cub'les (50). h i, therefore ti kely that t«tieular ,u lfo-
kina ... and .ulfa t.d <teroid. perform . pe.iat functiono.
0 ... possibilily i'th.t the Itormone. protect SpermatOlAl
again't prema,ure cop.citation_a process tha' ",u,lIy
occurs in the oviduct ,ince il .hone", the life·span, of lhe
gametes. The ,.Ifo"" activity of the o_idu., is ctos.I}'
regul.led, and it ri .., around Ihe lime of ovulolioo (99),
The remov.1 of .ulfate i'''''PS could 'hen .. rve to provide
f""h ly c.pacitated '""rm at the optimum time for f.rtil·
i,.atiQn (and low <ulfota .. activit)" during other ph ..., of
'he ovarian cycle may alf¢fd protection '8ainst fenih>.. -
lion of "overri",," oo<ytes).
Th. acquisi,ion ¢f sutfokin ... ae'ivi'y in 'he adrenat
cortex during the p... puben.1 ""riod and th.
secretion of . ubst"n,ial .moun" of DHAS may II<: re-
lated to reproduclive .y<tem maluration (",e end of thi'
chapter). and possibly al.., to the initi.. ion and mainte-
nant<: of .",,'malogcnc, i,. tn fet .t .dIC•• b. te. tos'erone
inhibits the , ulfokina ... whe,e •• DHAS (but not DHA)
reduc<$th. aClivity of the ltl-h}'dro'Y'teroid deh}'d ' OS",
na .. (t 33). Fetal ,u lfot ..., rna}' .Iso oonlribule to Ih.
con"ot of e"'adiol forma'ion {I 81_
other SterOid s Produced by Interstitial Celis
The blood plasma of human male adults oontains
somelhing like SO pg/dl of estrogens. According 10
various C$timates. the teste! deliver one-fourlh (I 3)
to one-third (104) of Ihe sleroid. or up 10 50 ug/day
(In)_ The remainder oomC$ from liver, Ihe adipose
tissue, and other sites tbat take up and aromali'e
sleroids relea ..d from the adrenal g lands and
gonads.
The Serloli cells of very young TaIS have high aro-
matase aClivity. and FSH can further augmcnt il.
... THE REPRODUCTIVE SVSl EM

Some obsem:rs believe that older S<:rLoIi <:<:11$ <.>Jfl- ANOROGEN RELEASE ANO OIS TRIBUTIO N
(;nue to make substantial fractions 0( the LC$!icular
cells laek the kinds of mcmbrane-(:n-
estrogen (I ().t). O llie,.., suggCSt Iha1 maturat;"n il as-
Iranu1<:$ found in cells that store.
lIOCialcd wilh I shift 0( most of the aroffiluasc activ-
and secrete the horntones. T hey lecU'
ity to the inlc,,(ilial «lis LH and hen can
mulate very li1l1e finished product. Stimuli Ihal au,-
;""""11<: 11'QnI.I1UC in tile Leydig cells of older tCStes
ment androgen release aCCllmplish this by a«dcr·
( 188), and Lerdia cell lumen oFten very
ating biosynthesis (122).
large amounts 01 estrogen (190). Subpopula tions 0{
The concept that the steroids dilfU$C out of Ihe
mature interstitial cells of ral testes lhal respond 10
cells is consistent with the high inside:ouuidc wn-
gooadolropinsand alSOlocAM P analop by increas-
ccntration gradient and " 'ith the lipid solubili.y of
ing lr0nt3Wot: production haY<: been dcKribed
the molceules (190). Microlubules may di«:C1 the
(US).
stcroids 10 the cell peripltoeries (104).
Estrogens can aCI locally 10 dccrca$e andl'08cn
The IIormoncs arc CXlruded inlO Ihe cxlracellular
biosynlhesis(42.12S). Someoflhc
spllca, from which Ihey a", laken up by Iymphalic
discusse<l in Chaple r 13. Under baS31 conditions. lil-
ves5C1s. Since 1M /low rate is only ,," Ihal of lhe blood
lie e:urogcn is made, 300 estrogen rttepl<ln '"' ca pillaries. it is not ... rpmin,that leslicula' lymph
II'IOJlly ullOOXupied. When JOIIadOiropill5 Slimulalc
concentralions arc 10 lirrtoC$ g1"<:3 Ie. Ihan tho sys-
tesl(ll'ltcronc produ ction, estrogen symhesis also
temic blood level. (I 22). However, concentralions in
accelerates,
t he testicular Qrlnin are al.o very high. This is al·
Iributed to COUnter...:u rn::nt u c hanges\>ctwccn sper-
Small al'!>O!.lnll of 16o>-OH.p"".. tcfOllC ent.. the
matic vei"", and contiguous arteries (104).
, pe,malic •• in •. l&"hydffl.O)'luc is an impol'1'nI r.tal
cnlyme. but no ' u"c lioll$ rOf 1M metabolite produced
have b«n for Idults. A •• se in the ,esti.
al", .. 'he formo ' ion or minute . ,nount. 01" .te- Varlatlona In Blood Androgen
roids wi,h double bond, " ' 'he po$itlon (SO). Concentrations
con"a,1 with 'he in,crSt;t;al «II. of hum. n. and
Thc Icvels vary with aae. lime of day. and !Cason of
most other$. tMSe or ,he s,"\\lon >cere,. lariC
the year (52). Secretory ra tes peak in men 25-30
amount. or "Irosen-like 18-(:'rOOn stcroid . "ilh Un""
ur.. A rin• •. These inc lude emiol (m.d. by nlO$' pre.·
yeaI'$ old. The plasma levels do not rail off as rapidly
nln, fe","le.) Ind equilin . ftC1cquilcnin. not known be '0 u the synt hesis. since m.,ta'oolic clearance 31.0 slows
in older . ubjects. Young adults have highest concen·
secreted by oth<r mammll, (F1,. 1• •7).
Ri ll ma ke more 7..... 'han tco.too- trations in the moming$. Mean daily values during
lerone I 190). Their "'tU 1110 syn,heai.., '",-OI I·and.os- Ihe rail approach goo ngjdl, but they arc closc:r to
,<<One. al in _itro. The steroid •• re de"o'Oid 01" In' 600 ngjdl in the spring.
d""enic pote",,)'. bII. .... y be "'• • 1.'.... (a.) . Rhesus mon keys li.ing OIIt of doors in coIonie$
l a-OH· ...,os,c""", • .la•• nd usually mate in tM fall. and lhey lIaY<: their hiJJ,hest
dehy<l""elWC$ I nd S<>·reduClasc .• nd t.. tos'e""", low· androgen levels at IMt time. HO\O·cver. unlike hu,
erS activi.y. 7...oIl ... nd..,.,ett«l""," de-
mans. they secrele mort during the nighl than dur-
creases . he ..,;"i.i« of ,he dehyd....
ing <bylighl boors. The diffcrences may be related
ICfWC and 01" ,he l-ketOlI.nlid dehydf'Oll'fWC.
ioomcrase coonpIel: (190). to social interactions lbat indude copulalion d uri",
With , he u«ption of birds ( 1-tO) ......t _ ...."'..... ,. Seasonal brccderscan have
ian ",,"cbrat.. ha.-e hi,hCf''''OI'Crortoe than ........ 1_ levels during lheir periods.
mals. Some 01" ,he lis,," produco ... .. 01" TeslOilterone is n::1casc:d in "bursu spaced 2 to 4
M

II /1-OH·' ....,...ro.... ,bey a n .... ke _ I I·k .....
tCSlOSterone , .... ' ..'01 ....".. IS2).
Phc'Oi'K .t Ire importut reluLalOtf 01" «producti""
bchayioo Ind 01" endot;.i ... systems .Irce. in, P"'I""IIC)' in
mict Ind _ OIher noe,., ... l ln'mal .. A'oma'" rnoIc·
cui.. thaI exe" circe" ... made by a
.... r..,y 01" othe, speci.. (sec Chapter I). The t ..t<$ ar.
impot'tantlotl'ces ol ci'lIe. the rca.Lat .... tllemsel ... ot
.s...
of pn::cur>QoS that ... "'.eti'·lIed"' clsc",'IIen:: . and,Qll'
lk ....:k>nc formed by tile In'trS,it;"l «II! olt he boa,
secm. to pc.rorm luch fun.,km •. (It is devoid 01 .nd..,.
ICnic potency.)
hours apart. Tbe amplitudes an:: g.r<:alcr in the morn-
ing in humans. Concenlralions "ilhin a single sub-
jecl can §pan the range ol200- 1000 ngjdl durina a
24-Il00. pe.iod. The patterns aK conlrolled moslly
by the changes in L11 levels.
Sllttial anatomical arrange menls assure a contino
uously rich supply 10 Ihe epididymis at all times. 100
'ooth seminal vesicles and prOlt3te glands enjoy some
protection against wide ftuctuations. O the r androgen
targell . re more directly affected by systemic blood
levels of androgens.
 o"
J-
o
.< ,
'"
, o• • ,,
o 0 '"
0"

],,·OH· Testosterone
'" '" "OH o

I 6-.",,·3..,....,

"
o "1o
I

o , o•
11jl-OH·TCSIOilcrone 11 . Kc'o,eSloste""'"

o o"
1
" (" -
/

I I
/
\
" / I
'" Equilenio
" '"
,c=o

Fig . 14·7. Somo "",oid. """,.,ed by inl",sti'ial cell. o!

.e<!eb<,'. lute• .
Plasma Proteins Thai Bind Ste roid
Hormones
Sex steroid binding g]obul;t\S (SSBG. testosterone-
estrogen binding proteins. TcBG) are glycoprote ins
originate in the liver. The oneS made by pri-
mates bind (cstostcrollC. DHT. andr()Stcncdiol, and
androstancdiol (but I\Q! u·... ndroslcncdiOllc) wilh
high afllnity (47) .
!:orlier suggestions ,h., C"", dogs. rodent'. and some
<>Iho, speci.. do no1 make such pro,e;n, oro irlCO",j'len'

with the k...,,,,n pfesence of mol<:"ule. ,hat bind gonadal
".roid, "'i'h mode"'tcly high .mnity. Th ... do...,t cr".,·
fcact with .n'ibodies dif<:",e<l ag.in" primate TellO.
(9).
Microhoterose"eities within each 'peci •• oro .ttril>.
uted to vori .. ion. in ,ial ic acid CQntenl. Largo molecular
weight difference, probably re,ult from .... mbly and
di ...... mbly of .ubunit compOnen', (9).
ROLES IN TESTOSTERONE SECRETION
By binding androgcns. the plasma proteins lower Ihc
concen trations of fret in thc blood. They
thereby create a steep intcrstitial cell:plasmu con-
centl'lttion gradient that facilitates testootcronc
egreSii (52). Plasma albumins contributc to this.
They bind wit h lower affinity. but t hey present vcry
large numbers of anac hment 'ites.
·'BUFFER" FUNCTIONS
In health)' adult men, some 44% of thc circulating
testosterone is bound to TcBG. Another 50% asso-
ciates with and an additkmal 3.6% at-
taches to COfticooteroid binding globulin, Therefore.
only a lillIe over 2% is present in the "free"' form. If
a large dose of Witooterone is injected, moot of it is
ta kcn up by the albumins. Consequently. only rna ...
sive doses can substant ially rai", the fre<: hormone
level (47). Under physkllogical conditions. the bind-
ing of testOSterone to album ins increases during
times of the day when the sec retory rate peaks.
When the IOlal testooteronc falls, albumins release
some of thc steroid.
ROLES IN REGULATION OF ANDROGEN
CLEARANCE
Protein binding retards steroid uptake by hepa to-
cytes and othcrcells that degrade the hormc)nes. The
rapid clearance of androotenedione is attributed to
low affinity for the proteins.
REGULATION OF TARGET CELL UPTA KE
Only frec stcroids can rapidly enter target cells and
interact with receptors. Te BG has higher affinity for
teSIOOteronc and DHT tban for estrogens. In males,
wi th high tC$tootcrone:estrogcn ratios, the selectivity
uptake of tbe small quantities of estro-
gen that are available. In females, the binding pro-
vides protection agaiTlSt entry of cxccSiiive amounts
of the circulating androgens.
Androgens retard produetkln of TcBGs, whereas
estrogcns enhance it (42.132). When the testes arc
THE M ALE REPIlOOUCTtVE SYSTEM
called upon to release larger amounts of the hor-
mones, reductions in TcBG increasc the availability
of the stcroids to thc targets. When physiological
oondilions require lowering of androgen production.
increases in the TeBG retard steroid entry.
Serloli cells ma ke androgen binding proteins
(ASPs) and seerete them into testicular nuid (185)
(see Chapter I 3). The proteins arc believed to con-
tribu te substantially to the maintenance of '"Cry high
androgen concentrations within the epididymis.
CeUs of the eaput region ta ke up ABP by pinocyto-
sis. Since the sites on the stcroid molecules that bind
to ABP differ from thc oncs that associate with thc
hormone receptors, it is li kely that transfcr.< of OHT
from ASP to receptor are easily made. Conforma_
tional changcs in the receptor protein that follow
hormone binding block reassociation of thc steroid
wit h ABP. Arrangements of thi' kind protect epidi_
dymal cells when plasma androgen levels are tran_
siently lowered,
Sertoll Cell Metabolism 01 Steroid Hormones
Serloli cells avidly take up steroids from the lymph
tha t bathes their basal su rfaces (185). They contain
a .x..reductase tbat oonverts testosterone to DHT
and accepts other substrates sueh as PrQicsterooc. 3-
Ketosteroid reductascs (3a- and
dehydrogenascs) catalyze both eonvcr.<ion of DHT
to androstanediols and thc formation of androstcr-
one (Figs. 13-19 and 13-20). The CCIIS have andro-
gen receptors and androgen binding proteins, and
they ne<:d thc steroid. to support spermatogenesis.
However. they alw release large quamitie, of andro-
gens into the testicula r Auid and send them on to the
epididymis.
Aromstasc activity and the "imulatory inAuence.
of FSH are Substanlial in fetuse, and you ng juve·
niles. They decline markedly as tbc cells mature.
However. as noted, some believe that Serloli celiS
conti nue to produce most of the testicular estrogen
in mature tCSteS (104).
Progesterone is metaboli7.<:d to several steroids
that includc testosterone and the androgen deriva-
tives previously cited (184). 20a_Hyd roxysteroid de-
hydrogenases catalyze the formation of 2CJa.<lihy-
dropregneoolone. 2CJa.<lihydroprogeSlerone. and
17a.2Qa..dihydroxyprogestcrone from pregneoolone.
progesterone, and 17"'progesterone, respectively
(Fig. 14-8), Questions have been rai",d about Ihe
importanee of the high rate of activity. sincc malUre
Serloli cells neither make oor receive large quan-
tities of the substrates (190). It is known. however.
that Ihe steroids can regulate androgen biosynthesis
(84. 145). and they probably "avelto the nearby in-
 ,
,",

HC -OH
. 1--'-

P'eg<>o!lOiOOe - - - - - - - -- _._
I
0./
ZO<, .QH·p'''9neOOIO<le
(ZOo,· I

.l

P'OQo""" ooe • .I

0' ,.,;c
ZO<, ·OH· P!09'"'1&,o<>e
(ZO<, I

, ",
,
HC_OH
.
-"
1. . ' "
- - - - - - -. ,_

o. " ,.,;c

Fig. 1.·8. R• • catalyzed s.rto1i ""II 2(1<,.

hyd cox y51<. ,,,", deIIyd,ogena ....

tcrstitial ccll •. The enzyme itself compete. with 17a
hydroxylase for substrate. within the Serloli cells,
and it the«,by retards con version of pregn<:nolonc
and progesterone to their 17a--hydroxylated deri-
vate •. The 20a-hydroxy metabolites arc inhihitors of
the 17a--hydrox}·lasc. In ralS. 17a.20a--dihydroxy·
progesterone can inhibit the C 11. C20 lyase. hut th is
does rIOt seem to OCcur in the human testis (145).
Peptide-type regulators produced by Sertoli cells
were described in Chapter 13. These include MUl-
lerian duct inhibitory factor. w'hich i. rcleased in
largest amounts during weeks 7-9 aftcr conception.
It is detectable up to the time of wcaning in rats and
up to the end of the second I""lnatal year in humans
(43). but it has not been shown to perform functions
aftcr the MUllerian duelS have atrophied. Plasmill{>-
gcn activator i, a protease implicatcd in opening of
the tight junctions between Sertoli ceils during spero
malogo"",i, (158). and it may also be involved in
spermiation. Inhibin Can indirectly arreet ste roid me-
tabolism. since it participates in «'8ulation of folli-
tropin secrct;on in the adult.
REGULATORS MAOE BY OTHER CELL TYPES
are claims that germinal cells (especially sper-
matocytes) produce testosterone (104) and that they
possess dehydrogenase activity
(52). Progesterone-binding prOleins have been iden·
tified in both Sertoli and germinal cells. and proges-
terone is reported to affect DHT binding (168).
M)'oid cells of the seminiferous tubules seem to
...
differentiate from p",curwr.; that alro give rise \0
the inle.Slitial cells. Thcy may be sources or new
Leydig cell populations that appear during Ihe pre-
pubertal period (193) . They are hormone r<:SlXlnsi,'C
(61) and capable of engaging in steroid hormone
metabolism. but they do nol aroma!asc ac-
tivity (45). It has been proposed Ihat they produce
regulators of Serlol; <;<;11 functions (52).
ANDROGEN DEGRADATION AND EXCRETION
Hepatocyte> avidly remOve androgens from the
blood. Some of the molecules arC sent directly into
lhe bile, from which Ihey tnwd 10 the intestine to be
either or reabsorbed. Others 31"<' conjugated
with sulfate or glue"ronal. prior 10 excretion. Most
arC converted \0 st eroids thaI poss ... lillie or no an-
drogenic potency. The products include cpiand!'C6-
[crone, epitestosterone. 5a·and",.taoolone and
J«.17t1.... ndmstanediol (fig. 14-9) . Etiochola nolone
is usuall y a minor metabolite. but there are patho-
logical conditions under which it accumulates and
acts centfJlly to elevate the body temperature. Fecal
steroids include produet.1 into the bile that
are acted on by bacterial
The urinary "1 7.ketooteroids" include mostly me-
tabolites formed in the liver. but also small quan·
lities of hormones that arc directly filtered by the
glomeruli.
THE GONADOTROPINS; BIOCHEMISTRY,
BIOSYNTHESIS, AND SEC RETION
Follicle stimulatins hormone (FSH, follit",pin) and
hormone (lH. lutropin) are species-spe-
cific pituitary gland hormones. Chorionic gonadotro-
pins arc chemically r<:lated regulators produced in
largest amounts by the ("'phoblast and placenta.
The forms found in humans (hCGs) exert mostly
LH-likc activity. Glycoproteins with similar biolog·
ical and immunological properties have been idemi·
fied in several cell types of healthy. ,..,npregnant fe-
males. and also in males. Morwver, certain kinds of
tumor cells secrete large quantities (23). Pregnant
mare's ser um gonadotropin (PMSG) is yet another
member of this group. It interacts almost equally
with FSH and UI reccptors.
He tero dlmeric Structure
Each molecule comprises t"t> dissimilar Sl)'cosyiated
peptides (subunits) held together in ooncovalem
linkage. Thyrotropin (thyroid-stimulating OOrrnonc.
TSH) has a similar makeup (139)_
Within a giV<'n species. all of the alpha .ubunits
THE M A LE Al:PRODUCT IVE SYSTEM
have almost identical amino acid sequences. Homol-
ogous resions have also been found for alpha com-
ponents of dilTcrent types_The human alphas
derive from a si ngle gene (A-I). The ones found in
largeS! amounts in the circulation have molecular
weights of around 14.000.
Each of the hormones has its kind of beta
subunit. The chain lengths in lH. FSH. and TSH
are similar to those of the alpha compone nls. but
hCG and PMSG beta subunits contain additional C-
terminal sequences_
When precautions are taken to avoid denatura-
tion. the subunits can be reversibly dissoci"ted and
recombined. Morcover. alpha components from one
kind of hormollC ean be united with beta, from an_
other. and subunits f",m dilTcre nt species also asso-
ciate. The processes bring about changc.' in molec·
ular configurations that involve, for example.
masking and reexposure of tho samo tyrosyl resi-
dues. The conformation of a re<:onstitutod hormone
is determined by the nature of the beta component
( 19).
When presented in "physiological"' oonccntra-
tions. neither the alpha nor the beta alone displa}'s
biological activity , The whole molecule seem, to be
nceded for functional binding to the receptor, Tho
associa tion must be made before administering the
glycopephdcs. Injection of first one subunit and then
the other is not elTectivc (l02).
Biological properties and speeics dilTerenccs in re-
ceptor affinity ar<: alwa)'S dctermined by the beta
(139). Thus. for example. rat fSH alpha
plus bovine lH beta behaves like t>ovine lH.
s.c,'en differenl gono:< or pseudoge"", coding for heG
bolO. but just one for hlH beta h.ve been identified
(A-t). Rats f!O>,<:«a retated ge"" for rLH beta. but 00
DNA codi"8 for • comparable cllo'ionie
(A-9), Somc subunil properties .'cre """"ribed in Chap-
ter 3_ There have bo<n 'oporlS that vcry high <onCenlr.,
tions <>f beta subunilS and of lheir fragmen .. can act
aiM< lQ slimutale . t"roidollenosis (119). and lhat mam-
ma lian FSIl bela is as potent os "'holo IIon""ne' for in,
"oking spe rmialion i" ti'ard, ( 102)_ On the other h.nd.
lhe addit ion of excessive numbers of beta ,ubunit< 10
",hole Can impair bi"ding to receptors
(tt9)_
Substantial numbers of homolog ies among lhe
"unique" beta subunils have been fou nd (83.139).
and these probably aCCOUnt for o,-erlapping p"'per-
tics. Thus. for TSH has somc gonadotro-
pin-like activity whereas hCG can stimulate thyroid
Species differences in receptor properties are
koown. and snaxc:s are among the vertebrates be-
lieved to make only one form of gonadotropin. Ob-
servat;ons of such kinds ha>-c been cited in support
 o o
'-I- " "

. ,, ,,

o
, o
"
"
I

, o•
•

""
D. Dehydtoepianclroslerone (DHEA)

"J..
o "J.
o

, ,
o" " ' - . /
.
"
E. 5)j·Ar>d,,,,,aoolone

o"•
,
. I A

o
, h

G. Epilesto$le'"""
Fill. 14-11. products of " ..Io",,,,one. A. 8, C,
o<>d D are 17-Xe'o"oroi<l.: G i. a stereoisonw of
..""". en. iog t"o...gh aoclrostoned_ . s an
•.

of Ihc m:uion thai all of Ihc gl}'coprotcin hormones Biosynthesis

evolved from One kind of parcrn molecule ( I 02. \31) .
Progress has been made in defi ning thc amino acid
sequences and carbohydmlc com]XIncnts of FS I1
(195). I.H (291\. 91). and heG (83). and the species
variations (161). Disulfide bonds have similar loca-
tions in all of Ihc mole<: ulcs wjlh COmmOn biological
activities (1 39).
All hormones of the group scem to be made in Ihc
SlIme way (29A,41) . More is known about thymI...,.
ihan about gonadotropin biosyn\hcsi5 (189).
Proxr and pre-p chains at<: assembled on separate
ribosomcs. each under the direction of its own RNA.
Hybridi7.a(ion studies indicatc that the genes cOOing

for the RNAs are on different (8).
Translations in cell·free systems
confo.mance with the "signal sequence"
(105) (Chapte. 3).
Mannos<:·.ich "core" oligosacchuridCl; arc at-
tached to asparagine re.iduCI; of both subunits while
the are still u\\achcd to their ribosomes. but
probably after removal of signal sequence (83).
processing i",'OI"s the '"trimming"' of the
oligosaccharide •. release of 'Onle gluc<>sc and
mannosc. This is followed by sequential additions of
glucosarnine, galactosamine, gaiactos<:, fucose. and
sialic acid.
Pre" and prc /J chain, or" , hortcncd.nd thcrcby coo·
'''rlcd to the" and {J cMlponent •. Most oboe ..... beli..·•
that 110 intcrmC<lialc ··prohormon •• ·• arc madc. High m<>-
kcui>r weighl mol«ule< ha.e been iMntified in gon.d<>-
trope'. including nonglycosylatcd on« of S2.000 and
21.000 daltoo. and glycosy!ated form. with app"ent
weigh" of 2t.OOO a nd Ii .000. Although it has been , ug·
ge<ted thaI 1.1-1 is an immature CQrnponent rormed
before the . ubunit. an ocilt •. the possibility that it i.
"immature lH" Or "immature beta .ubunit·· al1achcd to
Other p"'teill$ ho. b«n oon. idered (1061. Some large cn·
titie. may be aggregate, or hcavily gl)'cosylated peptide<.
(The high we ight of hCG is rel.ted to th.
presence or a 30 amino acid Cte,minal peptide glycosy·
On ,h. <c rioe moictios ,hat is not p",,,nt ;n Lit
[831 ·)
The final .tep is usociation or the alpha and beta sub-
unit •. Some ",cess alpha is evidently r",med on • regular
bui., to addition.1 gly<:osyl.tions. and
secreted.
Gene duplic3lion. m.y account for 'he production or
h",mone. with •• rying amino acid CQmposition. within
th. samc 'pecie<. and r", the ,)·nthesi. of more alpha Ihan
beta subunit. (I 89). Howe",r. nonunirorm posHran, la·
tional p"",essing can have .imilar consequence<.
Altemp', ha •• been made to determine the receptor·
binding e<>mpon.nt •. Acylation. guanidation, and carba·
mylation of Iy.ine residUe<. ni!r.tion or iodination or th.
t)·l"Q$ine$. Ind carbo.ymethyl.tion or the methionine. are
among tbe amino acid 31ter.tlol\$ ,ho ... n '0 reduce the or·
finitie< (139). The C·termi""1 peptide or hCG doc. not
oompete with the LH bet ••"bunit for $ites (119).
CARBOHYDRATE COMPONENTS
Variations are encountered when Ihe following are
compared: (a) the alpha and beta subunits of the
same hormonc; (b) the analogous hormones of dif·
ferent specie< (161); and (c) piluitary gland and cir·
culating hormones. Some free alpha subunits are
prescnt in blood plasma. and t hese are
more glycosylated than Ihe subunits of
the whole hormone. Gonadotropins made by lumOr
cells can be •• ceedinaly sugar content (177).
THE M ALE REPIlOOUCT IVE SYSTEM
"Functional pleomorphism" has a lso been de·
scribed. It has been observed adult male ratS
a nd androgen-treated gonadectomized animals of
bolh sexes secrete FSHs with molecular
weights. sialic aeid contcnts. and bioassay:im·
munoasS3y ratios than the FSHs made by aduh fe-
males or estrogen-treated castnl1es. Untreated cas-
Irates make FSHs with intermediate propenies. The
m,mes andm... g)'tW-. and have been
given to thc threc variant forms (24. 25).
Some in.igba into the importance of tbe carbohydrate
CQmponenu bave been obtained rrom studies of (a) mol·
eculcs reconstituted from tho ricbly gIYCOS)'lated free
alpha subuni" ptus beta subuni's Obtained from whole
hormone,: (b) tumor cell 800adot"'pin.: (cl hormone,
pr.treated ",ith en.yme. suoh .. galactosidase and ncur-
aminidase ("'hieb remo"" .ialic acid groupsI: (dl prep-
or.tion. obtained rrom cell' expOsed to tunicam)'cin (an
.ntibiotic that block> the . ynth ..i. or N·.cetyl$lucosa·
min)'I'phosphor)'I-dolichol cOOlponenl of the m.nnose·
ricb oligos.ccharide "oore"): and (01 mRNA-diroeled
proteins ,ynthe, il.e<I by cclt-rrce s)·'tems that lack
the membrane. required accompli,h the glye<>-
,yl.tion •.
The carbohydrates evidently facilitate
chain/aIding prior to establ;shment of the disulfide
bond., and they affcct the obilit;c> or >ubullit> tu us-
socialr with each other. Carbohydratcs also protect
the amiltO acid chains against intracellular drgro-
daliOll and prolong the half-liws of circulating hor·
mones. LH. Which contains only around 16% Car-
bohydratc by "'cight (5. I 39). has a shorter duration
of action that hCG (in which carbohydrates that in·
clude 2-acetamidt>-2-dcoxyglucosc and 2-acetamidt>-
2-deoxygaiaclo.c aCC<lunt for 30% of the weights of
both and bela subunilsl. PMSG is also long·
acting, and it contains closer 10 40% carbohydrate.
Lim;ted deglycosylation can augment hormone-re-
ceptor binding. but cxtens;,·. carbohydrdte loss im-
pairs the interactions. This has dearly been demon·
strated from comparisons of the properties of natiYe.
desialized. and more extens;vely deglycosylatcd
preparations of hCGs.
Sites 01 Biosynthesis
gonadotropcs arc the major
sources in nonpregnant animals. The question of
whether thc pituitary gland contain. separate FSH ·
secreting folliculotropes and ime .. ti·
tiotropos does not yet have a satisfactory ans..-e.
(153). (The term Ittleotl'OfW is not used for LH cells.
because prolactin and some othcr hormones are lu·
tcotropic in cenain species.)
 In B pituitaI'}' gland prepara tKln . some ce lls
bind a ntibodies di r<:<:led agai nst the I;S He.
up anti.L.HP. al'd )'et differenl ones bind both
Iypes.of antibodies ( 121). TM two kinds of ,Iyeo-
protetns \:lin wilhin the sam<: see retory Ira n·
ule (67). One is lhat there are three
kinds of gonadOlropes. An(lIher ;s (hal a singk; <:<:11
type undergoC!o junrl/()tW./ c hanges in biosynthelic
and secrelory aclivilic$.
Eleetron micrographs p TC$CnC<: of a cell
type with special morpholOSical features and 1'<"
$flOIISCS 10 hormones th31 earncd il the ""me
folliru/o(ro(>t. and the of. separale kind
of intcrstil!Olrope. In the lar,e mammals il is pOSSi·
bIe to e1el5e gland scgmenls that Qtllllain just one
gonadotrope type and just one of the horrnonc:s.
Ho",'ever. th<:1'<' are other «lis wilh tWO d,fferent
ki nds or granules ... it h e)'loI08;';"1 fcal Ur0:5 of an
in(ermcdille t)·pe. MlXCO"Cr. hypothalamic hor·
mOneS prese nted in vitro alTee t the appea rances and
aetivitics of cultu red gonadotropc:s (S4).
The problems of interpretat ion al'<' furlher rom-
plica ted by the prese nce of go nadotropc·like cel ls in
Ihe pars lulKralis (I S3). along wilh J.l I in lhe blood
draining thai region. and the demonstralion that
some adenohypophysial types bind a ntibodies di·
rO:<:led agaill$l both ACTH and FS II (117).
An of lhe prcwding challenge the
fQrmerly highly respected "one cell·<.me hormone"
hypolhesiJ. l! is I'eUOnabk: 10 bcclic\'e Ihat ccns with
cQmm<Jn genetic huitage5 c an aC<juire overlapping
when develop wilhin the $p<.:c iali7.cd
prov.ded by the pillliUtI'}' gbnd.
Brain Gonadotropins
Substances Ihal bind antibodies dirwed agaillSl all
of the pituitary gland hormones are present in var·
ioIIs parlS of Ihe bnlin. and al$O in ccl'<'brospinal fluid
(90). Each Iype of antibody has ,1$ charaCteristic
distribulion pauern . lH·like molecules have been
fOlind in lhe lIyposhabmus. amYldaloid complu
hippocampus. thBbm lls. caudate nuc\cus. and
cerebell um.
The hypothabmo-hypophyMal blood IniOSpor1$
hormones in t ..'O directions ( 14 1). and regulat""
Iha t travel from Ihe pituituy gland to the hypothal ·
amus participate in "short·loop" neptive feed back
oontflll of hormone $CCrelion ( 10). Ho....cver. at lea$l
some of Ihe brain hormoneS are in the (emllli
ntrwus system. and these a re belkved 10 perform
ntulomo(l\tIatofy functions ( I7 S). The molecules
persist in brain and cerebrospinal auid lonl afle r hy·
The wncc:nlratio!ts do 001 vary in
parallel ,"Ith 11\0$( of the systemic: blood .• nd Ihe
"blood-brain barrie," restricls enlry of !>ormones
wilhin the o;apilla rics.
Gonad otropin Storege and SeeTeUo n
In pituitary aonadotropes. the hormone COOlent is
dosely correbted ";Ih lhe nllmbers of so:cretOf)'
glllnule •. There are findings consistenl wilh Ille e.·
;,teoct of an easily recruited hormone "pool" . a
second. less easily ''aClivated '' $lore of both <)\dcr
and freshly sy nthesi7.ed IlywpfOteins (41 ).
Hypothala mk hormones act in different ways to
synlhcsis as com pared with release. They
mcrease 10lal bormone production. but thei r stimu'
lation of beta sllbunit synt hesis _ms tOl be rale-l;m-
' ling for ;onadotropin seeretion, f.xo&enous L.R II e\..
evales the circlliating free alpha subunit :LH rat;o.
in hll ......n adults. The le"el.of frec alpha a re hi.h in
...-.xncn (ISO). and ther<: are patho-
logiCal cond.\tOns under ""hich they become mark·
edly elevated (20). Since both piluitary a nd plasma
'm.
Ilea"" )' 8'yO)l5),latOO (83. il
tS v\ftually certa.n tha t the changes result from in·
nuellCes CJlerted on 1M release of Ihe moloculcs.
high glucose eon«:ntralioM used in some in
v!lro can bring about artifactu al glycosyla·
tK)fl (83). bul tMre is no reason to bcc!levc that lhe
effects are exerted preferentially on alpha compo-
nents Ihat delach from LH ·1
Gonadotropcs ha\'e hormone rcceptors.
High eooccntnilionsof p13dalloor, , _ are almost
consistcntly inhibitory. Ones in the
Innucn«S tbat !lICludc " pre-
sens.ttzatlons a nd synergisms as well as 'nMMtion.
The steroids also ael on hypo. haiamic ceil, th" t se-
Cl'<'tc releasing hormones and on neurons tlUll mod·
ulllle tM functions of lhose «lis.
ce lls that produce IICG do not po5SCSS
secrcl tO:n granules. Ux:al factOlS with in tM placenta
arc believed IG regulate so:crction of Ihe hormone.
The pluma membranes pia)' roles in the secrelion
lhat differ from ones described for piluitary gona·
dotropes (U).
GonadotropIn Receptors
High.affinity associated with the plasma
membranes of testicular and ovarian cells ha\'e the
p. .n ics of g1ycoproteins (1l9), The hormone
specificities al'<' .n(lI absolute. When fS H is pl'<"
$tnled .n very h.gh cooeemrat1ons. it binds to U!
receptors (Ind pharmaoological . mounl$ of L.H
elicit !'S1I·I"e responses). The biological actions of
hCG mosl c1e»ely resemble 11\0$( of LH , bUI the !>or.
m<Jnc can tOl some Ulenl mimic FSH and slimulate
the thyroid glands. PMSG inlelllcts to appro.i·
Ihe same extent with fSH and l H receplors.
H.gh <XIIlCCnualions of TSti slimu late Ihe gonads
(119).
lH elic;!J half·muimal sleroidogenesis "'hen

only 1% of the interstitial cdl receptors is occupied,
The large numbers of "spare" r",eptors and the
abundant low-aflinity binding sites enhance the sen·
sitivity to low concentrations of gonadotropill5. since
they facilitate concentration of the regulators in the
immediate vicinity ,
Ovarian luteal cells evidently have t,,·o kinds of
high-affinity receptors. only one of which couples
hormone binding to activation of adcnylatc cyclase
(119). The possibility that interstitial cells have mul-
tiple types. including one for LH and another for
hCG. lias bc<:n considered. (The t we hormones excrt
similar actions. but hCG binds more tightly. disso-
dates m<}l". slowly. and brings about resport<es of
longer duration.)
The early effects of gonadotropins seem to be e._
erted directly On the target cdl plasma membranes.
The hormonc-",ceptor comple.es arc subsequently
internalized. The processes have been linked with
physiological limitation of the responses and with
"down regulation" of hormone rec.:ptor numbers. At
leasl some of the molecules are laken inlo lysosomes
and degraded there. Chloroquine and other lysoso-
mal inhibitors do not affect gonadotropin actions
with shorl latent periods .
Some observers belicve tliat delared innuence! of
the ,onadotmpins on protein synthesis. cell differ·
cntiation . and cell proliferation «,quire the binding
of (or fragments derived from them) to
cytoplasmic organelles. The fragmcnts may also be
involved in mechanisms that arc
not associated with reductions of «,ccplor numbers.
A different oolioo ;s that some portion of the glyco-
protein must pcnctrJte the plasma membrane to ae-
tivate the adenylatc cyclase. The amioo acid se-
quences shared in commoo by LHiJ and cholerJ
to.in (which is cleaved it activates the en-
zyme). and the blunting of .denylate cyclase actio
valion by serinc protease inhibitors. are consistent
with a need to dissociate the subunits and internahe
the beta One. On the other hand. carbOOiimide and
some other agents that establish covalent linkages do
not abolish the hormone actions (119. 139). Studies
heG preparations labeled on JUSt the alpha
or just the bela show that nondissociated
hormone is internalized. However. dissociation
within the cells may precede degradation. The beta
components of the preparations are more rapidly de-
stroyed than the alphas (4).
Regulation of Gonadotropin Receptor
Numbers
The numbers of receptors pcr cell affect the sen,itiv·
ity to gonadotropin stimulation. but response> arc
THE MALE SYSTeM
also regulated at levels. Hypothalamic hor-
mones affect receptor numbers in ways.
Although chronically elevated of LH bring
about down regulation. some of the hormone is
nceded to maimain normal numbcrsof LH receptors
(82). Similarly. fSH o.'erdosage down ",gulates
FSH reccptors. but some of the hormone is needed
to relain sensitivity to FSH . The testes of untreatcd
hypophysectomized animals rapidly lose their re-
sponsiveness to gonadotropins. and rogain it
slowly aftcr rc-e.posure.
FSlI also induces LH receptors. At least in the
ovary. the actions are facilitatcd by estrogens. Pro-
lactin and growth horITlO!le increase the numbers of
gonadotropin receptors (79). and prolactin addition·
ally potentiates tlte cfTeets of gonadotropin stimula·
tion, Estrogens and androgens act in indirect "'llYS to
afTc.:t thc numbers of receptors. PlateleHlerived
gro,,·th factor (PDGF) potentiates. while epidermal
gro"'th factor (EGF) antagonizes FSH induction of
UI receptors ( 115).
Stress and the associated increases in ACTH and
81uCQCortiooid secretion can have biphasic cffeets.
There is usually a transien1 increase in LH and tes-
tosterone ( I 12). and it has bc<:n suggested that this
contribU1es to the ability to cope with certain forms
of stress (e ., . r.,htin, an auressor). The carli,,-'t <te-
roid ,<,sponse is evidently dependent on the testicular
innervation (although nervous inpU1 is not known to
afTeet basal ralcs of testosteronc sccretion) (59).
Continued release of the "St'<',," hormones leads to
a decline in LRH ,ec'<'tion (68,166). Glucocorti·
coids also decrease the rclease of prolactin and they
can Ll1 receptor numbers (6).
GONADOTROPIN RELEASING HORMON ES
Hormones synthesiled in the hypothalamus and re-
leased into the hypothaiamo-hypophysial blood ves-
sels arc major «'gulators of the adenohypophysis
(sec Chapter 2). If the neurons ma king the peptides
arc destroycd. or if the vaseular oonnections are in·
terrupted. pituitary cells producing gonadotropins.
TSH. ACTH, and GH undergo atrophy and the hor·
mone secretion rates rapidly (30.110). In in·
taCt animals. electrical stimulation of restriCled loci
within the hypothalamus affects the release of spe-
cific pituitary gland hormones. Cenain
dependent eventS (e.g, ovulation) changc the electri-
cal activities of the neurons (110).
The belief that the .,on ending. di,eh"ge the hypo-
tbal,mic rcgutatorS to the direct vicinity of the poTlal ,ys_
tem capillaries ha$ been qu .. tioned because of r.ilure 10
iden!if), hormone. "'ithin ",on. by immuooc)'tochcmical
 technique •. The ho!"mo"", ore pr.,.,nt in tane)',es (oeu·
rOSli.1 cell. that communicate with both the blood and
the ccrebrO$pin.1 nuid), Ta ne)' te. of the medi.n emi·
ncn"" rna)' therefore tak up the reg"llIon and transfer
them to the blood ,...,.,1. (199).
Luteinizing Hormone-ReleaSing Hormone
( LRH , LHRH, Lullberln)
A decapeptidc "'ith the following amino acid se-
quence ha' been identified in hypothalamic curacts
prcp",ed from numerou, vertebrale species:
pyro-Glu·His-Trp-Scr.Tyr-Glu-Leu·Arg·Pro-Gly·NH,
It is a potent Slimulant ror the release of both
FSH and LH when it is prcsenlcd to either whole
animals or pituilary gland prcparalions, and anti.
bodies direcled against the peplide innibit rclease of
those hormones (159). Becau se of its dual effeclS.
some .utho", prefer the name f'Slf/UI-Rdcasi/lg
homkJl!e (FSH-LH·RH). There arc those who be-
lieve that the hypothalamu. additionally makcs an
FSH·RH (68.197)_ Component, of hypothalamic
extract, have been reported to p<>5SC" such activity,
bUl no peptide has been identified {I 10). The exis-
tence of yet a third hormone affecting just LH is
doubtful. bUlthe possibility has not been ruled oul.
Plasma FSH: LH ratios vary with physiological
.tatu<. and there are conditions under which just one
of the gonadtropins is released. Juvenile rats secrete
mostly FSIi. As they mature . the LH levels rise and
FSII conccntratiQns fall (149). Cycling femalC!>
undergo regularly recurring change. in the FSH 'LlI
ratiQS(198).
Arguments in Favor 01 the Secrellon of Just
One Gonadotropin-ReleaSing Hormone
Proponents of the concept thaI LRH i, the only hI"
pothalamic hormone needed to regulate both F$H
and LH secretion have suggested several ways in
which differential control Can be accomplished.
I. trallSport of LR 1/ to just ct'rtain of the
pilUitaryalls: In at 1ea,t some species. certain of the
LRH·secreting neurOnS discharge their products
into blood vessels supplying one part or the pituitary
gland. "'hercas other neuron' establish chemical
wmmunicatiQns "'ith different parts of the pituitary
(3.143)_ The neuron dusteN can differ from each
other in the kinds of ..ceplors tne), JlO5-SC5S and in
their syna ptic relalionships with olher neurons of the
brain. Tnerefore. it may be possibl . al any given
tim. to stimulate just fol1ieulotropcs (or just inter·
stitiotropcs). and at other limes 10 affect both kind,
or gonadotropes. Electrical stimulation of the do"",1
anteriQr portions of Ihe hypolhalamu, (10.198) (und
of the paraventricular nudei) can in''(Ike just FSH
sec retion, whereas stimulation of the arCuate nudei
increases the release of both FSH and LH. (The
finding' do not rule 001 the possibility that the dorsal
anterior neurons make an FSH.RH.)
2. of changing UI release pat-
Under physiological conditions. LRH i, re·
leased "episodically." Concentrations in the pOrtal
blood can vary Over the range of20-800 pM in a 24·
hour period (30). LRH exerts "priming cffects:'
Wnen the levels have been low for a time. a small
dose elicits the release of SOme gonadotropin. A see-
ond dose of the same size presen1ed an hour later
invokes a quantitalively grcater response.
Gonadolropes arc affected by the frequencics and
ampli tudes of Ihe pulse •. by Ihe mean LRH concen·
tratiorrs over an extended time period. and by extra-
hypothalamic factors that alter Ihe sensitivities. The
re.pon.e paller", of folliculotropes differ from Ihose
of interstil;olroJ'C'! (58).
Rapid intravenous injection of LRH into adult'
elicits just I.H release. whereas slow. sus-
tained infusion or subcutaneou, injection increases
FSH levels as well (3 .164). Long·term administra.
lion of LRH tends to elevate the blood FSH:LlI
ratio. One inlerprclation is Inat intefStiliotrope' are
"rapid responders" that easily become "exhausted"
(3). Prepubertal animals re'pond differently. In
Ihese. rapid LRH injection elicits mostly FSH rc·
le.s<: , Other 'ind. of manipulat;Qn. that alter re·
sponses 10 LRH have been described (198)_
Whcn pituitary gland preparations arc main-
tained in vitro without LRH. the rate of LH release
into Ihc mcdium soon declines to undetectable Icveb.
FSH rclea'e off mOre .Iowly and Ie,s com·
pletely, 11 has therefore been ,uggested th at SOme
component of FS I-l secretion is "autooomous" (i .• ,
hypothalamic hormone-independent) (171). On the
other hand. when I. RH is con1inuously prc.<ent for
long time periods. LH release is 8reater under SOme
conditions (54) and relca5.c undcrothcrs
Estrogens affect the responses to LRH. In a study
of cultured pituitary gland cells, il I'o'aS observed thaI
LRH.invoked FSH release ,oon declined and stim-
ulatory inAucnces of e'trogen were lost within six
days. By contrast. LH release persisted for at least
20 days and thc responses to cst rosen were ret<lincd
during that time (97).
3. !::x/rahypolnalamic regularor5 .decrively alur
gonado/rGp<! rcsponst.t: Selective inAuences of inhi·
bin (folliculostatin) on fSH secretion have been dis·
cU'iSCd. GonadOlTOpeS seem to wntain insulin re<"p"
IOrs. and the hormone is .aid to be: a physiological
stimulant (2). However. seleclivit y remains to be
demOnstraled.
LH acts via short·loop f«:dhack to innibit just LH
sec retion. whereas FSH dccr<:ases the secrelion of
just FSH. It is possible thaI each of the hormones

accumulates within its own special region of the hy·
pothalamus and thereby selectively affects LRH
stimulation of one kind of gonadotrope (see item I
in this list). Alternatively. FSH may aCt on neurons
that ma);e an FSH·RH.
The pineal gland exerts diverse innuences on the
rcproductiY<' system (152) . There are conditions
under which it inhibits FSH and LH secretion. and
others in which it acts at ewapituitary sites to pro-
mote gonadal involution without lowering the
plasma gonadotropins. Differential effects of both pi.
nealoctomy and melatonin adminimation on FSH
and LIl ",cretion have been cited by SOme as mech -
anisms for changing respon",s of the tWQ cdl types
to LRH. but othe", believe that Ihcy irtdieate the
presence of a distincl FSH·RH.
Gonadal stcroids are major regulators of gQnado-
tropin se<:retion (30) . They directly affect LRH-sc·
crcting neuro"" the functiono; of different neurons
that synapse with them. 300 the turnover ratc., of
neurotrano;miuo",. They also act directly on the pi.
tuitary glands tQ control hormone biosynthesis. hor·
mone release. receptor numbers. and r<>Stre<:eptor
",nsitivities (58). Some effects arc cited here. and
others in Chaps, I 5 and 16,
Responses to the steroids vary wilh the chemical
nature of the hormone . the
the concentration relative to (hat or other regulators,
the eXr<>Surc time. and the endocrine history of 'he
In adults, in<;reases plasma and pitu-
itary 81and gonadotropin concentrations and the
numbe", of pituitary gland LR 1-1 receptors (30). At
least SOme of the effects are exerted directly on thc
pituitary 8land, and androgens can act directly to re·
duce the receptor numbers (62). Sex differences in
quantitative responses to androgens are known, but
in both males and females it i. easier to block the
elevations by instituting steroid re·
placement soon after surgery than it is to restore the
levels at a later time (164).
In intact adult male rats. LH turnover time in the
pituitary gland is around 22 days. It falls to 4 after
castration. By contrast, there is a decline of from 4
to 2 days for FSH. "Physiolo8ical"· doses of testos·
terone lower the plasma lH of castrates to the nor·
mal ran8e, but only ma$.Sive amounts inhibit FS H
release. If small amounts of e.trogen arc added to
the low tcstosterone dose. both FSH and LH levds
deeline (110.164). In intact animals. 80nadal ste·
roids also show stimulatory effects Qn FSH M:erct;on
(3.46) . Mixtures containing high estrogen :androgen
ratios usually elevate plasma FSH but not LH
(164).
THE M.... LE REPIlOOO..O:::TtVE SYSTEM
The blood androgens of normal females never at·
tain the concentrations required to suppress gona·
dQ1ropin secretion in castrate.<. They do. however,
play facilitatory roles in the regulation of FSH <c-
erction. By contrast with the LR H-<:omrolled preo-
vulatory gonadQ1ropin "sur8es'· that involve dis-
charge of both FSI-! and LH and can be blocked
with ami·LRH sera. the follicular phase FSH ele-
vations in rats are belie,'ed to be androscn-dcpen·
dent (75). They arc not ntither blunted by the same
antibodies. nor associated with substantial LI-I
elevations.
Facilitatory innuences of gonadal steroid. on LH
release occur in females but not in males. The sex
differences are attributed to neuron-neuron inter·
a"ions acquired durin8 an early developmcntal
stage and possibly also to the distributions of estro-
gen receptors. The effccts of estrogen alone arc com·
plex and triphasic (10). Durin8 thc follicular phase
of the ovarian estrogen., inhibit LH release,
They may do so by actin8 on one "pool" of pi.
tuitary 81and stores (41). Since they do not diminish
LH synthesis, the hormone accumulates for a time
in Ihe 80nadotropes. Shortly before the time of ovu·
lation, estr08ens promote LH discharge. possibly by
synergizing with LRH to activatc a different LH
pool. The estrogen< also facilitmc formation of LRH
receptors (165). and they act on brain neurons in.
volved in initiation of tne H I sur8e.
Some of thc obscrv«l effects of androgens depend
on aromati7.lttions. DHT (which cannot be aroma-
tized) r«luces thc frcquencies of LH pnlses. whereas
testostcrone and eslrogen can both lower the ampli·
wdes(42).
Althou8h it has been implicated in facilitation of
LR 1/ receptor induction in fcmales (165), progester.
one aets On thc c.:ntral nervous system to suppress
LRH release. Progesterone may also compete with
LRH for actions on the pituitary 8lands. (In its pres-
ence.low concentrations of LRH are ineffective but
larger ones stimulate the gQnadotropes 13].) S,,-{!i·
hydroprogesterone and 17""OH·pro8eSterone are
more potent inhibitors than progesterone. and they
haY<' greater effects on FSH than on LH release
(161).
G<>nodotropin secrelion in .udling inf.nts rna)' be ,ut>-
to impOrl.nt controls. tn addition 10 lhe
pituitar)" gland hormone, kn""n to be present in milk. on
LRH·like peptide has becn found. tn humans. concentra·
tion. ,"crage 107 ps/ml (compared with only 17
for blood ptasm') The SQuree i. unknown. Sinee
LRII;' effe"i"e when given orally. the peptide nlay ptay
phy.iological roles. It seems to be • more pOlent FSI1
Ihan LH .. im"lanl (7).
 4. Differencu in metabolic uff« 1
plasma FSH:LH rmio.,: FSH has a plasma half.life
of around 110 minutes in rats. while Ihe 1)1 for LH
is closer 10 22 minutes (110). If both hormones are
simultaneously released. an obvious consequence is
aeeumulalion of more fSH Ihan LH. Ilowever. if
Ihis continues for an extended time period. Ihe seC-
ondary events can include feedback inhibilion of
FSH secrelion and down regulation of FSH
When healthy human adu lls ale given addilional
hOlmones. similar diffe rences in clearance rales arc
found ( 199). The LH concentrations rise wilhin 2
minutes afler intravenous injection of LRH. the
peak is attained at 25 minutes. and the plasma III is
around 92 minutes. FS H concentrations ri se slowly.
rea l: at 45 minutes. and have a III of minutes.
Ce ntral Nervous Sy stem Co ntrol 01 LRH
Release
Olfactory. visual. tactile. thermal. ps)·chological. and
other stimuli modify LRII release rates. A bewildcr·
ing array of neurotransmitters and neuromodulators
becomes involved.
Explanation, can be olf.red f<>r ,he "umerOu, conflict·
ing rep:)I"\S <les<ribing the COn1ro! mechanisms. tn many
cases. LRII has 1101 been <liree,ly meMured. and tho
ehan8<' in 1.11 or I<"<»'.'on< "><d '0 "'Iill"« LRII 3fC
alfcctod by factors acting al ,ites "'her Ih.n Ihe hormQn..
",ereling neUrQnS (58) . The re'pon ... of whole .nimals
to pharmacological and phy,iologic.1 .genl. can .. ry
wilh Ihe .pteios. age. "'x, hormonal .n<l "ullilional ,to,
tu •. ,ime of day. and ",aron of the year. The)" . re alfecled
by sl ...... nd anelt hetie •. MO<l acl a' mulliplo
• ites. and only high coneenll.tions .lfecl the Ie" .. n,ilive
ones. The roo.tc of adminiStration i. imparl •• t bc<:ause il
determine. thc rate 01 which the regulalOr g.ins ..CO'-$
10 Ihe largel ' iteS and Ihe kind. of «II. alfccled . (Inlr"
«,..,bral injoe'ion. of Ion elic;1 elfeel. ver)' dilferen, from
ptripheral ones.) When br.in i. stud ied in vilro. Ihe influ·
enees on isolaled cannot be a"umed to mimic Ihe
on cell. making Iheir full complemen' of ,yMp'ic
conneelion,. Moreover. incubation mcdi. are nevcr iden·
tical wilh the physi<>logieal fluid •.
Thel<' is general agreement Ihat calecholamillts
.rc major regulatora (3, 123). They may act on tan-
eyt.s of the median eminence (199). as "'ell as al
synapses. [ntraventricular (bul not syslemic) admin-
istralion of either dopamine or apomorphine (a do:>-
pami ne agonist) lead, to rapid clevalion of plasma
LH (123). The dire<:! effeCls are probably all Slim_
ulatory and medialed by a receplor type dilfercnl
from the kind in"olved in inhibition of prolactin re-
lease (109) (see Cbap. 8). When DA decreases LH
I<'lease (3.68.199). il probably docs SO either by pro-
mating seoon<lary <lischarge of serownin or by aCling
on gonadotrores to decrease the sensitivity to LRH
(123).
Norepillt'pkrine is implicaled in me<liation of the
LH elevation Ihal fOllows castrat ion. Median emi_
nenCe concentralions of th. ne"rolransminer rise
SOOn aftcr castralion. and this Can be reversed by giv-
ing teslOSterone (123). In females. inlraventricular
adminislralion of norepinephrine increases Ihe LH
levels. whereas norepinephrine reccptor a nlagonisls
block lhe postcastration elevation. The I.H reiease
associaled with COilus in males may in,"Olv. bolh
norepinephrine and dopamine.
Proslaglandins of E type (especially PGE l )
act direclly on the hypolhalamu, (3 .64) . They may
be more effecti"e for increasing FSH than LH levels
(68). bUI direct on the gonadOlropes arc
nOI apparent. PGs may be mediator:; of catecllol-
amine aClions.
Su'''''' promO/es pituitary gland secrelion of
do'phin. The peptide . and enkephalin,. seem 10 exert
tonic inhibilOry COntrols o,'er gonadotropin secretion
and mediate some of Ihe effects of Slr= on the re-
productive sySlem ( 14. 150.1 92). Roles in protection
against tho premalur" Onsel of pubcny have been
propOSed (l27).
lIistamirw is present in high concentralions in COr-
lain parIS of the hypothalamus. In humans. exoge-
nous amine inte racts wilh H,·type receplOTS 10 in·
Crease LH release in mCn bul 10 decrease il in
women (1 42). It docs not seem to directly affecI gon·
adolropes. but it may dilate the bl<XXl vessels Ihat
supply Ihem. T he difference in response is op-
posilc in direclion for ralS.
ct-MSIf is found in both the pituilaty gland and
hypothalamus of many species. including humans.
Inlravcnous injeclion promptly augments FSH and
LH release in but nOI in females (151). Me-
Iolonln antagoni7.cs n-MS n inHuences on the pig.
men! cellsof exothcrms. It is I>Ot known whether me·
latonin inh ibilion of LRH seerelion (68) involves
sim ilar antagonism. The pineal glands of hamslers
and other seasonal breeders rclcase large quantilies
when the days become shorter in autumn. and it is
suspected that melalonin conlributes 10 prolaetin·as-
socialed regression of the reproductive organs al Ihat
time (65) . (However. as discussed in Chapter 20.
melalonin affects much more than LR H.)
is a melalonin precursor. but it is also
produced 31 olher sites. Altllough """'t reports in.
dicale inhibitory effects on LRH secretion. the data
are conflicting (123) (possibly because the amine
acts at several brain loci).
Alroplm (an acclylcholinc antagonist) i. said 10
lower both basal and stimulaled LRH secrelion.
However, both stimulatory and biphasic clTeels have

been deseribed for Additional pro-
po$od include gamma-aminobutyric acid
and glycine (which stimulate) and Ihe acidic amino
acids (especia lly glutamic and aspartic). which in-
hibit {12l).
LRH Bi osynthe sis and Metaboli sm
LRH is probably cleaved from a larger peptide. but
the precursors are oot known. Since it tra,'<:ls rapidly
through a very restricted portion of the cireulatory
it does oot require protection against hepatic
or renal degradation and excretion (199). Therefore.
no plasma binding proteins may be needed. and oone
has been identified. The pituitary gland docs. how-
ever, contain proteascs.
When LRH is injected intravenously. m()l;t of it
rapidly disappears from the bl<.>Jdstream {I)! = 4
minutes), but the fraction that remains has a half-
life closer to 50 minutes. The hormone is taken up
by liver, kidney. pineal gland, and neurohypophysis.
as well as by adenohypophysial cells (199).
MECH ANISMS OF LRH ACTION
The target cells have low-affinity binding sitC$
that concenlrate the hormone. as well as spectnc.
high-allinity receptors. Ca" is needed for LRH
stimulation of LH release. but oot for either 00..
mone_receptor binding or the inlluences exerted 011
gonadotropin bi()l;ynthesis. The binding in some way
opens a "calcium channel" that permits the ions to
enter and to alfeet microtubular and othcr intracel-
lular functions (36). and it brings about calmodulin
redistribution (35). Calcium iooopltores mimic the
effects on gonadotropin release.
Although LRH increases the cAMP. and cAMP
analogs can some"'hat augment LH secretion. lhe
nuclcotide probably docs not serve as an obligllWY
second messenger. Low concentrations of LRI1 Can
promote LI1 release without bringing about detect-
able elevalion of the cAMP le,·els. Innuences of
higher concentrations of LR H on cAM P generation
hvc been shown for hemipiluilaries of male {but nOl.
of female) animals. When the rise occurs, it oflen
follows (rather than prccedes) initiation of LH re-
lea .... Phosphodiesterase inhibilors have nOi been
shown to affect the rale of LH secretion (36). On the
Olher hand, cAMP Can potentiale the errcets of
LRH. possibly hy interacting with SOme other regu-
lator made in the hypothalamus (107).
Internalization of LRH has been lin\.:ed with hor-
mone degradation. Agents that block the uptah do
not abolish the stimulatory errect' on gonadotropin
THE M"'lE REPRODUCTIVE SVSTEM
release. However_ LR H is said 10 bind to eyler
plasmic components other than lysosomes.
Low levels of LRH may preferentially arrcet go-
nadotropin bi()l;ynthesis (107). Concentrations too
low 10 invoke LH release accelerate glycooylation of
the pituitary gland peptides. cAMP is said to exert
effect •.
EXTRA-HYPOTHALAMIC LRH
Molecules that bind LRH antibodies wilh high allin-
ity are present in several parts of the cxtra-hypotha-
lamie brain. and they arc believed to be synthesized
in neurons that do nol directly regulate the pituitary
gland (173). LRH can elicit of
reproductive behavior when it is injected into intact
or animals. Endogenous peptide
released from the brain neurons in response to psy-
chosexual stimulation may amplify the effects of hy-
pothalamic LRH.
Go nadal " LRH "
Exogenous LRH binds wilh high allinity to the in-
lerstitial cells of the tcstis (31). It decreases testos-
terone synthesis and reduces Ihe numbers of LH and
prolactin receptors in both intact and hypophysec-
tomi7ed rat, when given in large doses. It Can also
decrease 17 ,.,-hydroxylase activity (79). Some ef-
fects of the peptide on extra-gonadal structures can
be prevented with exogeoous testosterone (3). Ho .....
ever, LRH and its agonist! interfere wilh lhe actions
of that steroid on prostate glands. seminal vesieles.
and the kidneys of male (but not of female) mice
(9S).
When the observations were first made. there
wCre two reaSOnS for sospeeti ng tha( the LRH was
interacting wi(h receptors For some other hormonc:
(a) The quantities of hypothalamic LR H thaI eseape
into thc circulation arc too small to directly
affcct the reproductive structures; and (b) numerous
examples can be cited of molecules of one chemical
makeup binding wilh high affinity to receptors for a
hormone of very different composilion (200). (Mor-
phine has a struCture very different from the endog-
enous opioids. and diethylstilbestrol is dissimilar
from estradioL) Ther. is now g<.>Jd evidence for the
production within the gonads of a peptide that Can
be distinguished immuoologieally from LRH (169) .
It evidently has similar biological activity. i\ related
peptide has been found in reproductive tract st rue-
lures of males (8). The name has been
siven to a n analogous regulator in females (Chapter
15). Luteal cells of the ovary interact with LRH,
and the hormone decreases progesterone seer<:tion
(80),
It waS initially proposed that testo:nerone-stimu-
bted Sertoli cells excrt negative fe.::dback control
o,-er steroidogenesis by releasing the peptide (169).
Ne"-er studies indicate the gonadal LRII interacts
with LH and other to regulate capillary
permeability. testicular fluid volume. and steriod
concentrations within localized regions of the testis.
It augments testosterone secretion when LH le",,1$
JrC low to moderate (A-8). Other regulators made
in the tcstis include roMC (A-6).
PROLACTIN
While the term gonadOlrOf1ill is usually applied to
just the glycoplotein hormones that intel'llct with fol-
litropin and lutropin receptors, there is ample justi-
fication for inclusion of prolactin (PRL) in the
group. The hormone derives its name from its roles
in lactation (Chapler 16). but it ;s needed to main-
tain the corpora lutea of pregnancy in rodents and is
therefore also known as l!IItO/Top;II.
PRL is an important regulator of reproducti"e
functions in males. and it affects much more than
the corpora lutea and mammary glands of females
(175, 176). It modulates steroidogenesis in the go-
nads of both sexes and also in the adrenal cortex. and
it affects both the rdease of and the responses to the
gonadotropins. It Is Involved In rotal development
and ;n the timing of puberty onset It is also evi_
dently an important mediator of the effects of stress
on the reproductive system. In seasonal breeders it
contributes in major ways to the "reawakening" of
the dormant gonads (152), and in cycling females its
concentrations in the blood rise and fatl with the var-
ious stages of the ovarian cycles.
Unlike the glycoprotein hormones. PRLs have
high-affmity receptors in liver. kidney. accessory re-
productive glands, and other tissues. Influences on
water and e\cctrolyte metabolism were cited in Part
III and on calcium metabolism in Pan IV. The hor-
mone exerts SO many different kinds of actions (85
ci ted by one author [156]) that the name .",.rSalilill
has been proposed (I 24),
Although dire<t effects on the kidney and some
other targets haV<' been described. PR Ls usually
serve as modulators of the actions of other hormones
(60.78). The responses vary with the spec ies. the cell
type. and the physiological StatuS. High concentra-
tions invoke changes very different from low ones.
and even triphasic responses have been described.
PRLs are species-specific proteins that exist in
multiple forms within the same individual , They arc
devoid of carbohydrate. and they are chemically re-
lated to growth hormones and placemal lactogens
(somatomammotropins).
The laetotropes of the adenohypophysis are the
major sites for bio&ynthesis. storage, and release. At
least some of the PRL in the hypothalamus origi-
natcs in the pituitary gland. but additional molecules
are probably made in the brain. The hormone fune-
lions there M a neurotransmitter or neuromodulator,
Among other things. it affe.::ts behavior.
Reguletlon of Secretion
Unli ke gonadotropcs. thyrotropcs. corti cot ropes. and
somatotropeS, the laetotrope, retain their morpho-
logical features a nd secretory functions without ben-
efit of hypothalamic hormones. In the hy·
polhalamus exertS mostly inhibitory controls.
(Pituitary glands removed from the ponal vessels re-
lease supe rnormal quantities or PRL.) In birds. how-
ever. hypothalamic hormones stimulate.
PROLACTIN INH IBITORY FACTOR (PIF)
Hypothalamic extracts and portal blood contain
something that inhibits PR L synthesis and secretion.
Dopamine (OA) is widely believed to be the major
regulator. However. there have been reports that in-
hibitors other than OA are present. and the possibil-
ity that the hypothalamus produces a specific PJF
has not been ruled OUI (32). OA may even facilitate
the release of PIF. Prolactin secretion is a complex
process. and OA evident ly affects just one aspect of
it (sec Chapter 16).
Portal blood CQIltains OA in concentratioltS that
are adequate for suppressing PRL rdease (32). The
pituitary gland has high-affinity I)A and
the neurotransmitter is effective when it is presented
to the cells in vitro, In intact animals. exogenous OA
and its agonists reduce PRL secretion. while DA re-
ceptor antagonists and agents that impair OA syn-
thesis increase i\. Some of the DA that acts under
physiological conditions may originate in the neuro-
hypophysis (1JS).
PROLACTIN RELEASING FACTOR (PRF)
During the early stages of lactation, blood PRL lev-
els rise rapidly in response to a suckling stimulu s,
This may be One condition under which the hypo-
Ihalamus releases a PRF. There is SOmc cvidence for
the presence of such a factor in hypothalamic ex-
tracts. but 110 peptide has been identified, Thyrotro-
pin releasing hormone (TRH) can stimulate the lac-
tot ropes. However. PRL and T$1I Ie"els do not
usually rise in parallel and there are several other
rea.>OltS for believing that something other than
TRH is invol>-ed in PRL release (32.199).
,..
MODULATORS OF PAl SECRETION
Plasma PRL concentrations undergo diurnal _arm·
lions that include sle<:p-associalcd elevations. The
levels also rise in response 10 demanding ac-
tivity and some forms of stress, and sharp peaks have
been obse ..... ed following food ingestion (147). Em.,.
gens are pote nt stimulants that affecl DA turllQvcr
in Ih. brain. In cycli ng females. plasma PRL
reaches its highesl levels during thc times of rna,i-
mal estrogen secretion.
Endogenous opioid peptidcs may mediate both Ihc
stress and estrogen efTecls by inleracling wilh Ihc
DA system. Ii·Endorphin and opiates arc polent
rRL releaser< (and met-enkephalin sho,,", similar
aClivity but lower polency) (48). They probably
oombinc direct ly with their own receptors, si ne<: thc
stimulation is prevented "' il h receptor antagonists.
Those alone also lower the plasma PRL of
intact subje\:ts.
OA promotes ,coum"lotion of acolyloholine in "'me
parIS of lhe brain. Pa"'}'mpalhomimClic .gen" admin·
i$lerod to region, in which they can act on dopom inergic
ncur.,." bloxk the opiale Ilimutati.,., (I 70). The .ndoge·
noo, opioids mooulatc DA turn<I'"et in the brain (192).
and apOm(Kj>hillC (a OA a gooiil) abolishes lh. effcclS of
morphine ,.Ifate on PRL ...1•• ", (170). Em<>jlen, affect
the mOI-<:nkeph.lin conten, o>f brain "'gion, lhat conlrol
gonadotropin and prol,clin sec"'lion ( 48). S, ..... can in·
crea", endorphin ... Iease.
Serotonin probably contributes to PRL releasc
during lactation (32) and sleep. It dOl'S not act di-
rectly on the pituitary gland. but ex!"'rimental rna·
nipulation, affecti ng brain serotonin can increase
PRL release even when changes in DA arc a\'Oided.
Prostaglandins scem to both mediate PRL action,
and regulate hormone reloase (64).
In intact . ubjects. PR L exerts negative feedback
control over its own secretion. h probably acts on the
hypothalamus, ,ince intracel"<'bral ad ministration of
J> RL is When multiple pitUitary implants
arc made at extrahypothalamic sites. the plasma
PR L concentrations vary directly with the numbers.
Th is suggests that lactot ropos are not directly sensi -
tive to PRL
Norepinephrine seems to exert mostly stimu latory
effects. These arc d ifficult 10 study. because natu·
rally occurring and pharmacological agents in teract
with both presyna ptic and poStsynaptic receptors.
Other regulators implicated in PR L control indude
histamine. vasoactive imestinal peptide.neurotensin.
gamma-aminobutyric acid. and melatonin (32).
THE MALE Rl:PROOlICTtVE SYSTEM
HO RMONAL REG ULATI ON O F INTERSTITIAL
CELL FUN C TIO N S
The interstitial cells arc dependent on tonic stimu-
lation by IUlropin to maintain St rUCture. numbers.
functions. and the ability to respond to other regu-
lators. They undergo atrophy if the hormone is with·
drawn. and they regain com!"'tency if it replaced.
Cell, tbat ha vc established their secretory capac-
ities under the influence of LH relcase "'basa l" '
amountS of testosterone when the)" are tran,iently
deprived of the stimulation. When LH is again pre-
sented. increase.:! androgen output becomes obvious
within 15 minutes (122). Over a limited range. the
response is dose related.
The most obvious short·range influences are ex·
erted over the enzymes that promote the conversion
of cl1olesterol to pregneoolone. The mechanisms for
ACTH control Over the sid<xha in cleavage in the
adrenal cortex have been described in detail (Chap.
ter 7). and they appear to be similar for LH regu-
lation in the testis. The stimulation IS depende nt
upon the
The steroidogenic
of plotein (but oot DNA) biosynthesis. Fairly
high concentrations of LH promote the generation of
cAM P. and the nucleotide mimics the inft uenees on
protein formation and cholesterol cloavage. There is
an associated activation of cA M P..:!c!"' ndent prote in
kinase and phosphorylation of ",veral proteins.
The roles of the phosphorylaled proteins a re still
being debated. as are other purported functions of
cAMP.
LH supports steroidogenesis in scyeral other ways.
It enhances cholesterol Uptake. the activities of eho-
lesteryl esterases. the rale of cholesterol entry into
the mitochondria. and the activities of 3iJ·hydroxy-
steroid dehydrogenase. C17 ,C20 lyase, 17a.hydrox_
ylase. and Sa-reductase (179). It may also hasten
pregnenolone egress from the mitochondria. The re-
lease of 17,... :l'-androstene-
dione. S,,·reduced molecules and steroid sulfates is
accelerated (S2 A) . LH add itionally promotes proJ-
I"g/aruiin generation. PGs amplify LH stimulation,
mediate prolactin effects (156). and contribute to
the regulation of LH receptor numbe rs.
The long·range effects of Ul include
of cell growth, elaboration of the smooth endo-
plasmic rcticulum, biosynthesis of steroidogenic en-
zymes. and production of new prolactin and LH re-
ceplors (89). The influences on the smooth
endoplasmic reticulum may be especially important .
since they affect the poSit ioning of the steroidogenic
enzymes. Within a s!",cies. the extent to which this
structure is dcveloped determines the quantitative ef-
fectsof an LH dose. Across the species. variatiOlls in
the amounts of smooth (but 001 rough) endoplasmic
reticulum closely correlated "'ith the quantities
of testosterone released. Guinea pig testes have
highly developed membranes. and they produc<: un·
usually large quantities of the hormone.
ma ke smaller amounts than most Olher mammal ••
and they have low smooth:rough endoplasmic relic-
ulum ralios (52) .
Chronicallyelevaled LH levels inV{)kc very dilTcr·
ent changes that include ""down regulation" of LH
receptor numbers and ""biochemieallcsions" thai di·
minish steroidogenic responses to both gonadou<>-
pins and c AMP. The elTeets arc complex and dose·
rdated. At least some are believed to be mediated
via estrogens and prostaglandins.
When interstitial cells from
rats are exposed to the already subnormal
rates of I"'tostemm: produclion fun her decline. Th;,
is associated with lowering of tlte activities of 17<>-
hydroxylase and C I 7.C20 desmolase. and of the cy·
tochrome P-4S0 content. but enzymes that conven
pregnenolone to progeslerone are not affected (12S).
When hypophysectom;7.cd anima" are treated with
moderate amounts of hCG (which acceleralesestl"O-
gen produclion), testosterone wtput risc. (ransiently
and then declines 10 levels below Ihose initiall)'
found. The ch.nge< in enzyme act ivitic> and P.450
content are 'im ilar 10 Ihe Ones observed in cells ex·
posed 10 estrogen in vitro. Two proteins with molec-
ular weight. of 27.000 and 40.000 are induced. S ince
lamoxifen (an estrogen amagonist) blocks formation
of the one w;t h the lower molecular weighl and s;·
multaneously prevenls the cn>.yme and 1'-450
changes. it has b«n thai descnsitization to
hCG (a nd to LH) results from estrogen induction of
that prOlein, High doses of ItCG additionally impair
cholesterol conversion to but Ihi, ef·
fect is not blocked by estrogen antagonisls.
Tlte enzyme changes precede LH receptor down
regulation. Receptor numbers tend to increase
aculely before undergoing sustained redUClion. The
concentration, of PGE, and PGF", rise around the
time that rec<:ptor numbers begin to decline, and the
high levels persist until receptor recove ry begins. It
has bttn suggesled Iltat PCs mediale receptor deple-
tion via meeltanisms nOt directly linked willt testos-
terone production. si nce indomethacin blocks PG
generalion without affeeling testosterone secretion ,
However. although Ihe inhibitor delays down regu·
lalion, il docs not prevent il . PGs may interael "' ith
vitamin C, The early effects of vitam in E deficiency
;nclude accelerated generation of PGs, but also im·
paired testosterone syntltesis. Chronic deprivalion
leads 10 cell deterioration (73).
Influences 01 Other Regulators
LRlf agonim decrease LH receptor numbers. an-
tagonize the effects of Olher hormones on receptor
induction. lower the numbers of testicular PRL re-
ceptors (175), and decreasc 17a·ltydroxylasc activo
ity. T hey do not. however. mimic the elTeclS of ex·
cessive bCG or LH On lite C 17.C20 dcsmolase (19).
The changes in steroidogenesis can secondarily innu·
cnce FSH receptor induction in the testis.
TeslOSltrOlW can act locally to inhibit steroidoge n·
esis if it accumulates in substantial amountS (S2). It
also inhibits LH release. but;t can accelerate pRL
secretion (76) ,
Prolac/in interacts directly with high·affinity re-
ceptors on the interslilial cells. It has negligible in_
nuenees on steroidogene,i, when it is administered
alone to hypophyscctomi1.ed a nimals deprived of
LH. I-Iowe,·er. even in ratS trea ted this wa)". il in-
creases Ihe numbers of LH receptors. In the pres-
cnce of il augments androgen produelion. In in·
lact animals. PRL promotes the accumulation of
esterified cholesterol stores. and it increases lhe ac-
tivities of dehydrogena.'<C and of
dchydrogeMsc (12.175). (Al_
though il regulates adrenocortical 5".. hydroxylasc
[133] , no comparable effect on the ICSI;, is known.)
GH mimics some PRL effeclS on steroidogenesis
(127).
Nocturnal elevations of plasma pRL in primates
contribute to diurnal varialions in tlte testosterone
level, (120) , Copulation promotes pRL secrelion.
and the hormone may impro"e perFormance. PRL
and consequent testosterone release du ring stress arc
sai d to increase the ability to cope .
In hamsters, Ihe lesticular regression in response
toslton photoperiods is associaled with low PRL lev-
els (I 20). while tlte recrudescence seems to be me-
dialed in pan by risinS le.'cls.
pltarmacologicai amounts inhibil LRH release.
probably by exerting effects on dopamine turnOver
(II ,116). In men. prolactin-sccreting tumors a re as-
sociated with loss of libido, su bnormal plasma tes-
tOSlerone , and infertility, PRL aelS either directly or
via LRH to affect neuron funclions. When the hy-
perprolaetinemia is corrected. libido can be restored
before Ihe testOSlerone concentrations risc (12). In
women. the tumors eausc amenorrhea that oflen re-
sponds to pRL secretion inhibitors.
[t has been stated th at PRL lowers gonadotrope
5cnsilivity 10 LRH (12), Tltis may hold true only for
males and for estrogen-deprived females (176). In
women wilh PRlAeereting tumors. unstimulated
gonadotropin le,'cis tend to be low and estrogen p0s-
itive feedback is impaired (I 16). but pituitary gland
responses to exosenous LRH are either normal or

exaggerated. PRL is implicated in the delayed rees-
tabliShment of ovarian cycles following parturition
seen in lactating women, but it cannot wholly ac-
oount for the effects (176) ,
Some of the inhibition is evidently mediated via
the adrenal oortex. since adrenalectomy can lessen it
(12.1 75). Glucocorticoid secretion increases in hy-
perprolactinemic states and during stress. High oon-
centrations of the steroids depress testicu lar func-
tions. and reproduction is impaired by se"ere forms
of stress.
Although some authors speak of FSH actions OIl
interstitial cells (149). it is widely believe..:! that only
Sertoli c.:lls have receptors for the hormone. FSH
cannot act alone to measurnbly stimulate androgen
production. but it enhances responses to LH and in·
duces LH roccplors (122). The actions may be me·
dia ted by estrogens. FSH additionally accelerates
Sertoli ceil uptake of testosterone. It can in this way
blunt the inhibitor), actions of the androgen that
arc exerted both locally and on the pituitary gland
(as it elevatcs both testi<;ular and epididymal
testosterone).
The importance of FSH acc.:leration of estrogen
production is oomro"ersiaL If large amounts of the
steroid are. in fact, made. they would be expected to
aCt 1<)(;:llIy u> .Iow tcuo< terone produc,ion, and to
also lower LH The possibili ty tht they
promote release of inhibitory amounts of prolactin
h.as also been suggested (187). High "tr<r
gen:androgen levds may also disrupt other intersti-
tial cell functions. (Chronic estrogen overdosage in-
vokes formation of Leydig cell tumors in some
mOuse strains [163].)
Denervated testes produce ba&al amounts of tes-
tosterone and they respond (0 hormonal stimulants,
However, it been obscflled that adreaergic
ulation increases testosterone se<:retion (179). and
this may be important during responses to SOme
forms of Stress,
Reproductive system functions are impaired by
both hyptr and Thyroid hormones
are not known to act dirC<:tly On the gonads. They
do. however. affect androgen metabolism in the li .. er
(179) and the rdease of both TR H and PR L
(11.116). The possibility that Sertoli cells make I'(:g'
ulat= (IIhe, than the ones cited is raised by obser.
vations (hat Leydig c.:lls situated close (0 atrophic
tubules undergo hyperlrophy (S2A). The pul&atile
I'(:iease of LH can bring about changes of up to 50%
in consecutive plasma samples drawn from the same
individual (173). The reasons for failure of lestoster-
One levels 10 vary in parallel (113) arc only partially
understood.
THE MALE RE?ROOUCTIVE SYSTE M
HORMONAL REGULATION OF
SPERMATOGENESIS, SPERMIOGENESIS.
AND SPERMIATION
The Impo rts nee 0 1 Androge ns
Spermatogonia prolifemte and advance to pl'(:lept(l-
tene primary spermatocytes within the basal por-
tions of the seminiferous tubules (outside the "blood·
testis barrier"). They can continue such activity
without benefit of androgens. gonadotropins. Or
other known hormones. Processes beyond this stage
are accomplished within the "privileged" environ-
ment provided by the SerlO)i cells. and these are
blocked by androgen deprivation,
Although therc have been reports that some of the
germinal cells directly bind androgens and oonvert
small amounts of testosterone to DHT (190). and
that androgens Can act alone to facilitate complction
of meiosis and some parts of spermiogenesis (S2A).
it is widely agrc.:d that testosterone acts indirectly
(i.e. on the Sertoli cells). Most observers do not find
high_aninilY receptors on the germinal cells or an-
drogen transl<)(;ation to the nuelei (52A). In Tfm r0-
dents. inability to make effective androgen receptors
scems to account for failure to complete s1"'rmat<r
genesis, The germinal cells of such animals undergo
normal maturation if Ihey come under the inHuen".,.
of Sertoli c.:lIs from healthy members of the same
strain (SIA) ,
LH is nceded to maintain testosterone production.
(A proposed role in stimulation of Serloli cell growth
has been questioned. since the cells evidently lack
LH receptors [178].) [n rec.:ntly hypophy=to-
animals. alone can support sper-
matogenesis if it is given in very large doses. If
tesles of hypophysectomilcd animals :II'(: permitted
to regress. testosterone injections do not reestablish
the functions (158.179). FSH is then needed to re-
store the Sertoli cells.
The roles of FSH in promoting growth. prolifera-
tion. and maturation of Sertoli cells have been de-
scribed. FSH accelerates the production of 3a-an·
drostanediol in at least some species. and the steroid
is implicated as an initiator of the r,rsl waVe of spero
matogenesis (127).
Some in"cstigators state thaI FSH binds diroctly
to germinal c.:l1s (127,1]0) and that it (alone) pro-
motes advancement of spermatogonia to pachytene
primary spermatocytes. The hormone has also been
implicated in maintaining optimum numbers of type
" sperma togonia by prolonging the lives of the c.:11s.
hastening their entry into mitosis. or both (179). "
nced for FSH to complcte the late stages of spe r-
miogenesis has also been proposed. However. a morC
widespt"<'ad belief is thai FSH acts only on Serloli
cells (44 ,45)_
Altltough mature Sertoli cells do not respond to
FSH in the same ways as younger cells (94), SOme
of Ih. hormone may be ne<:ded Ihroughout adult·
hood to maintain optimum functions_ One role may
be acceleration of the production of 5a--reduced ste-
roid,. Interstitial cdl androgen is the usual preeur.
sor, but Sertoli cdls can uSc other substrates. Preg·
nenolone, 17a--hydroxYPt"<'gnenolone. progesterone.
or ! 7a--hydroxyprogesterone can maintain sperma·
togenesis in hypophysectomi'.cd rats e"en when the
circulaling androgens are inadequate for achieving
normal stimulation of the accessory reproductive
gland, (178). The observations may be related in
some way to the presence of high·aflinity progester·
one binding sites (168).
Contro l of Sp ermiation
The "frog" test for human pregnancy was initially
based on the coneepl that hCG promotes spermia·
tion in non mammalian vertebrates because it e.enS
LlI-like elfeclS (191). However, we now Know that
FSH can act alone to stimulate spermiation in sev·
eral of the amphibians (102). an<lthat hCG exerts
some FSH·]jke actions (22). lIypophysectomi,ed
animals totally deprived of LH release spermatozoa.
if testosterone treatment is immediately after
the surge,)'. Since spermiation is a function of Ser-
toli cells (which lack LH receptors). it seems reason·
able to conclude that FSH control$ the proces.•.
HORMON AL REGULATION OF ACCESSORY
REPRODUCTIVE GLAND S
For each of the aceessory reproductive organs, there
is a "critical period" early in life during which pre-
liminary development proceeds. 1n males. androgens
are needed during that lime. The changes they pro-
mote are for the most part irt"<'versiblc_ They persist
even if the ICSies at"<' removOO . No amount of hor·
presentoo latcr can make up for deficieneies
during the critical phase. When the changes arc
completed, the organs arc small and immature, but
Ihey have receptors for hormones that will later pre-
pare them to assume adult functions,
The maturation thaI begins close to the time of
puberty is qualitati"ely dilfet"<'nt . Hormones thcn
promote cell growth. proliferation and speciali,..•
tion_ The androgens arc neooed on a regular basis \0
maintain the structures and functions_ When the
hormones arc withdrawn. the organs regress. If the
hormones an: again administered. restoration
occurs.
The mature epididymis, seminal ","siele, and pros·
tate ha"," some common features (103). All possess
a secretory epithelium. high-affinity OHT receptors.
prolactin receptors. and Sa-reductase. that calaly,..
the metabolism of testosterone. (There have been
claims that DIH promotes cell proliferation,
whereas androotanediols stimulate secretory func-
tions, but the concept is not universally accepted
{196].) Androgen requirements are very much
greater than those of nonreproducti"e organs such as
the liver. thymus gland, and brain_ The epithelium is
supporled by a fibrovascular stroma that contains
myoid elements and estrogen receptors. The eslro-
gens exerl mostly stimulatory influences on the
stroma. and androgens in some CM'" antagoniz"
this. In contrast. estrogens are mostly inhibitory for
the epithelium. Some of their effects seem to be ae-
complishoo "ia binding to androgen receptors, (Oth·
ers result from inhibition of LH and therefore of te<-
100terone produclion.)
The organs differ from each other in hormone re'
quirements, receptor affinities. epithelial·stromal in·
teractions. and properties of the chromatin that de-
termine the responses to the hormones (8,77). A
recently formulalcd hypothesis may explain obser·
vations that testosterone invokes one kind of re-
sponse in some of its largets and different effects in
other cells pos=ing simi lar or identical steroid re-
ceptors. It has been proposed that de,,<:loping cells
acqUire '" maSking protciru;" tllat specific ac-
ceptor site. within the nudeus. In their presence,
only certain DNA segments can be activated by ste-
roid-receptor complcxes (177 A).
The Epld ldymla
The caput has the highest known androgen require-
ments. In monkeys, concentrations that rully support
the functions of the seminal vesicles and prostate
gland arc only SO'll) effective for the caput region
(129), and mice seem to need four limes as much
androgen here as in the other organs (77). Andro-
geru; and ABP are secreled into the testicular Ouid
that is delivered to the capul. Countercurrent c.-
changes provide additional androgen from the inter·
nal spermatic artery_ The epithelial cells also sy nthe-
, i'.e androgens from aectale . cholesterol, and other
precursors.
In elderl)' men. """"e,-':mc eoncenlrOlion. (nS/ml
serum or n,/g weI li"uo) ... ""rlcd." test i•. 669:
spermatic "ein. 448; epididym; •. 37; and per ipheral vein.
3_7 (100) , In Ihe ... me . ubj.eu. epididymal c.)Mcn'",·
tions of pregne nolone were almost .. high a. the testos-
,crone . and 'here ... a. half as much lIa-bydroxyproge.-
tcrorIC •• pregrICnoIonc_ Peripberal blood had only O_S
"i/ml of pl"<'snenolone. The data are ron';otent ",ith ,h.
."
belie( th31 the epididymis deptnd, mostly on
.ynth.,i, and ,..,icular Ouid (whe, ••• pcri!, ..... 1 blood
contribute< 001)' minima l amounts). In rabbi, •. ret. t.,,;.
nuid contoinc<l 69 nglml of te,tQSlerone. but the blood
level "'as 1.9 "g/ ml (129), Te.licular nuld i. a lso rich in
fniA .
The high »rc:ductasc activity and DHT content
(9.7 ng/g oomparcd wilh 0.4 ng/ml in human pe-
ripheral blood) indicale (hal DHT is the majQr hQr-
mQne. However, other regulators arc alro needed
(70,103).
The cells make 5a-androslanc-.J.a,17a-diol and es-
trogens_Some arc: transferred 10 spcrma lo7.oo.. which
bind (but do IIOl wncemrate) lhe molecules. The
diol is 3. effective,," DHT for maintaining epididy_
mal SlruClure and sperm viability. hUI it may
undergo conversion to DHT. Some of the epidid}'mal
steroid is passed \0 the prostate gland and seminal
vesicles .
There are limiled numbers of estradiol re.:eptoo>.
but the hormone is tightly bound (13). Estrogens arc
believed to promote stromal growth. but binding
to androgen receptors can affect the responses to
DHT.
Semtnal Ve51c185
These g lands arc very large in rodents. small in hu-
mans. and nonexistent in canines. When present.
they empty their products into ampullary glands in
some animal types and into the urethra in OIhers.
There are species differences in the secretory
products.
Steroid dependency is marked. DHT seems to be
the major regulator, but can convert it to
other molecules. If the cell. are androgen deprived.
reductions in epithelial cell height and impairment
of functions can be detected within 6 hours (26).
Androgens affect the appearances of the cells and
the rates of release of secretory products. They bring
about generaliud stimulation of protein and R NA
and D NA and the quantities of seminal
vesicle specific proteins formed vary with total pro-
tein content (77).
Aging (which is associated with reduced rates of
androgcn delivery) and estrogen administration in·
crease the IY!0050mal activities, and they depress se-
cretory functions in most species. In hamsters, estro-
gens have been observed to invoke degeneration and
the accumulation of lipooromal pigments (26) . (In
oontrast, cmadiol-17(j and diethylstilbestrol have
been reported 10 exert weak androgen·like actions in
guinea pigs [!O3!.)
MALE REPRODUCTIVE SYSTEM
Prostate Gland s
Although early differentiation of the prostate gland
is androgen-<lepe ndent. most of the DHT receptors
arc acquired during prepubertal Stages. at least in
ratio The critieal time for development into mature
structures occurs long after weaning. The ree.:ptor
numbers rise in parallel wi th plasma teslosterune
concentrations. and maximum levels arc attained
during early adulthood. Tho receptors continue to be
androgen-<lependem. but the numbers decl ine some·
what after spe rmatogenesi s is fully established. It
has becn proposed that the rec<:ptor proteins of the
adult gland exert negative feedback influences over
th.ir Own production (148). Unlike the influences
exerted On the scmiMI "",ides (in which there i,
generalized stimu lalion of protein synthesis). andro-
gcns preferentially promote Ihc formation of
prostate gland secretory products (77).
The glands tend to enlarge late in life. At thaI
time. androgen production slows. but rising TeBG
le"els minimize the in blood androgen levels.
It has been estimated that 50% of human males de-
velop benign prostatic hypertrophy (BPH) by the
age of 50, and that the incidencc of prostatic cancer
approaches 100% in elderly white males {SI). Most
prostatic cancers are metastat;e when first diaa·
nosed, and close to 80% of them are androgen de-
pendant (6IA). The neoplasms vary widely in his-
tological appearances.
PRJ. contributes to tumorigenisis in several kinds
of tissue. and androgens induce PR l receptors (29) .
However. although increased sensitivities to prolac-
tin. insulin. growth hormone. PDGF. and other
growth st imu lants may be importanl, it is likely that
a bener understanding of the causes of prostatic dis-
ease will derive from current research on Ihe rela-
tionship to androgens. As discussed in Chap. 13. em·
bryonic mesenchyme may be the primary target for
DHT. Testosterone induces the 5a-reduetase en-
1.yme_ and it is probably the major stimulant for the
formation of androgen receptors during the prepu-
bertal period. In the adult, androgens evidently
maintain optimum numbers of cystolic and nuclear
androgen "'''''ptOTS by regu lating receptor synthesis.
the "activat;on" required for translocation to the nu-
clei_ and degradation (20A). as they oontinue to in-
duce the reductase. The clinical responses of patients
with prostatic cancer to hormonal therapy seem to
be most closely related to tissue DHT levels (61 A).
Enzyme inhibitors markedly diminish prostate si:ee
in experimental ani mals (I93A).
H ighly differentiated human tumor tisiue retains
its responsiveness to androgens and estrogens . Ex-
ogenous c:strogens sometimes provide tmnsicnt ame-
liormion when sensi tivity is retained. but they may
act mostly via suppression of LH secretion (13). The
stcroids arC not effective on a long-range basis. and
they may not be useful at all when mOSt of the cells
have limitoo numbers of receptors.
Dos' arid lion, are among the rew nonprimate. koown
'0 undergo prostatic hypertrophy late in life. In <lop. the
gland, arc moK easily maintained with
diol than with either te.tosterone <>r DHT. Al1cmpt' have
been made to understand the eoodition. under which
prostate glands enlarge in rodents. but those anim.l. do
not <>rdinarily ,how the hypertrophy. The ,iuue, of )'oong
mice regress more rapidly than those from older .n imal.
",hen .ndrogen, aTe withheld. wherea. gland, of older
mice arc more .. nsitive to .ubseq ucnt hormone presen_
t.tion . E.trone il reponed to invoke epithelial hypcrpla-
.i. and metapla.ia in "-.an lings. but epithelial .trophy
and . tromal hypertrophy arc $«n in older animal. (103).
Insulin olone provide, ",me support for epithelial ce ll, in
culture. and it moy be needed to accompli.h .ndr<.>gen-
stimulated cell proliferation, Similar age-related chang""
do not seem to occur in r.t •. Hydr<K:<lrtisone e.n pre$<fY<'
<pithdi.1 cdl height and .uppr= stromal i\rowth.
whereas ""trone and ""t,adi<>l invoke epitheli.1 cell
"gr.";",,. Low "'ncentration, of PR L exert weak andr<>-
gen·like oction, when presented alone. and they .ync'lIi,c
with .ubthre.hold dOlago. of androgeni (possibly by in·
c.... ing androgen uptake and binding). High CQIICCntra-
tion, of PRl inhibiL Although .U 5a·,.ducod metabo-
li,o. t .... d mimic ,h. eifec" of and DHT On
coli growth .nd secretory .ctivity. only DHT itimulat<>
cell proliferation. The rat prostate ha. higher *redue-
ta.e activity thon any <>ther .pccie •• tudied_ It. r.ilure,o
undergo age-related hypertrophy may be related to the
observation that the rate of .ndrogen uptake declines
wilhage(16O).
Mat uration of the Pen is
Since Ihe peni, i, made up mostly of nonglandular
tissue. it is not surprising that Ihe responses to an-
drogens differ from Ihe ones described for the acces-
sory glands. The organ undergoes preliminary dif_
ferentialion early in felal life. h continues 10 grow
during the remainder of the gestation period and in
young juveniles. Androgen...Iealled much later pr<>-
mOle further growth and maturation, and they are
needed to maintain Ihe functions , However. OnCe
adult status is attainoo. high androgen levels do not
bring about greater enlargement. I'lormon. deficien-
cie, impair the function,. but they exert only limitoo
influences on the si"" of the relaxoo organ,
OTHER ANDROGEN TARGET ORGAN S
Virtually every cell type ;. affected directly or indi_
rectly by androgens (196),
S econdsry So)!. Chsra cte rl s t lca
These st ructures do not mature before puberty.
Many show reversible effects of androgen,_ For ex-
ample. hair growth increases in some part, of the
body as the androgen le,.. ls rise. and it becomes
more sparse if the hormones are withdrawn. Seba-
ccous gland activities rise and fall with changing
hormone levels. The malc-type fat distribution pat-
tern and the skeletal muscle developmcnt are not
fully maintained in deficiency states.
Other changes arc more permanent. Once growth
of the larynx has been accomplished. the voicc re-
mains deep. The effects on bone structure persist,
and some androgen-invoked influenc"" on skin re<:cp-
tors are stabilized (118).
Ne rvo u s Syste m
Androgen. contribute to maintenanc.:: of libido.
Physiological amOunts invoke a "sense of well
being." and they can increase the inclination to Cn-
gage in athletic activities.
Influences on the secretion of hypothalamic hor-
mones have been cited. Some of the seX differences
in brain functions unrelated to reproduction (85) a1'(:
androgen-linked. but others seem to be more closely
related to the chromosomal pallerns.
The Kidne ys
In most species. males have larger kidneys Ihan fe-
males. The activities of certain of Ihe enzymes arc
higher, the mtes of RNA and protein synthe'is are
greater. and (at leallt in rodents) some male-.;pecific
proleins are released into the urine when the andr<>-
gen levels are in the physiological range.
The di fferences have been swdied most inten-
sively in mice. The cell, of the proximal tubular ep-
ithelium are larger. th. mitochondria have greater
dimensions and electron lucidity. and the lysosome,
are more numerous in males. While the most anen-
tion has been dircctoo at the the ae-
tivities of p -galaetosidase. cyt<>-
chrome oxidase, and alcohol dehydrogenase arC also
affected_ Castration leads to "feminization" in
males, ... lteren Ihe administration of testosterone
propionate to fema\c, brings all parameters into or
above Ihe ranges for untreated adull males (92)_
Tlte effects of androgens are blunted in hypophy-
sectomized animals, and only partial restoration of
the sensitivity can be achieved with Ihc following
hormones presented alone or in combinations: Pf{)-
lac tin. glucocorticoid" thyroxine. and growth hor-
mOne (8). 11 has therefore been suggested that SOme

pituitary gland factor of a d illerent nature contril>-
utes 10 Ihe oonlrob.
The kidney receives its androgen from the circu-
lating blood, and it is one of thc few targcts that can
utilize te,tOSterone di=tly (i.c. witbout prior oon-
version tc DHT). The kidney also converts DH T
presented to it to androstanediols. Ho,,·evcr. sugges·
tions that the androgen receptors arc different from
the ones in most other targets are difficuh to recon·
cile with Ihe tighter binding of Din (con, pared with
testosterone) to Ihe receptors. The horntone. do not
promote cdl proliferation in the kid ney.
Skeletal Mu scle
Mature musele fibers do nOI proliferate. In most
parts of the body. androgens stimulate RNA and
protein synthesis and cell growth. The effeel. on in-
dividual fibers are small, but overall inAuence. on
the body acoount for most of the sex differences in
muscle and strength.
The numbers of eytsolic receptors per gram of
DNA are the smallest of all known androgen targets
(112), and there are indications that they arc quol-
ilaliwly different. Artificial steroids that exert
mostly "anabolic" actions without invoking marked
virili7.ation have been synthesized and shown to act
On the museles (sec Fig. 14-10). The molecules differ
from the natural hormones in that they have substi-
lUtions at the I 7 positioo. lack a C-I" methyl group.
or both. The agents ha'.. been used with some suc·
cess to hasten oonvalescence following debilitating
illness and to accelerate growth in prema ture in-
fants. They have been given to young athletes to im·
prove performance. and this has created legal prob-
lems. High dosages have mru;culinizing ellects on
fe males. and they can disrupt ovarian cycles. Muscle
tissue is !lOt strongly affected by cyproterone acetate.
an agent that antagonizes androgcn inAuenees on ac-
cessory reproductive structures (112).
It has been proposed tbat many of the effects on
skeletal muscle are accomplished indirect ly. The
possibilities include influences exerted 00 oonnecti ve
tissue components. induction of a "m)'otropic hor.
mone,"' stimulation of the appetite along with effects
on the liver that bring aoout a "positive nitrogen bal-
ance." and behavioral effects involving muscle
strengthening through exercise. The concept tnat the
androgens the catabolic ellects of glucocorti-
coids is !lOt easily reconciled with demonstrations of
the nistence of distinct receptor types for the twO
kinds of steroids and the failurc of one to affect the
binding of the other ( 112).
Testosterone binds directly 10 the receptors. Mu s-
cle has low 5a-reductasc but high Ja- and JiJ-hy-
THE M "lE REPRODUCTIVE SYSTE M
droxyste roid oxoreductase activities. Therefore, very
little testosterone is convened to DH T, whi le the
DHT in Ihe cells is rapidly made into an·
drostanediols.
Since the met.bolism oomplicate, Ihe problems of
Sl udying small numberS of androgen reetpt"",. studies
are usually condUtled wilh s)'nthetic androgens (e.j!.
methytlr itl'lOlon<) which .re "'" acted"" by the cn.ym ...
The agents h.ve been used 10 distinguish between andro-
gen and glucocorticoid reccpt""'. but they are "'" wholly
,alisfactory. Methyltrienotone binds to a greater exlen'
in ftmalethan in male Sprague-Dawley rals. The bindinj!
incre.",' after Iong.term eamation. and i, is al"" .ffected
by ,dren.leclomy. Muscle li",ue i. reporled to c"" .. in
eSlrog<n roe<ptol"$ (40). and the ,,<.
roid. may interact wilh them.
Androgens may exert special influences on im-
mature cells. They myoblasts in several
anima l types. and they oon tinuc to have effects on
species that grow after attaining sexual maturity. In
at least some strains of rats, the androgen receptors
of the quadriceps femoris are more numerous in
adult males than in equal weigh ts of the muscle of
eilher adult females Or immature animals of both
sexes. Castration has been ,..ported to decrease
(112) or increase (1\-7) Ihe reeeptor numbers.
Some of the muscles in the perinea! regions arc
related to the reproductive system. and these show
unique hormone responsiveness. The levator an i
muse les of rodents have large numbers of receptors
a nd they are highly sensitive to androgen adminis-
tration. Estrogens are also anabolic at these sites (8).
It is perhaps unfortunate that thcse muscle groups
have been widely used to study the "anabolic" or
"myotropic" actions of androgens.
Cardiae Muscle
Androge n receptors have bee n identified in both
atrial and ventricular myocardial celis (I I I). The
steroids a re reported to augment the right ventrieu·
lar hypertrophy that occurs in rats exposed to high
altitudes, to diminish Ihe pressor effects of arachi-
donic acid in ralS. and to potentiate the pressor ef-
feets of norepinephrine in F.strogen rCC<'ptors
ha"e been found only in the atria. h has been spec·
ulated that the fmdings arc related to sex differences
in the incidences of 'lOme forms of heart disease and
to the deleterious effects of oral contraccptivC5 ob-
served in SOme women.
The liver
Hepatocytcs secrete plasma proteins. includ ing al-
bumins and mokeules that bind hormonC5 wilh high
 "k-- o"
'" o"
-' ---
o
- _I A ---

"
/'

// // //
o
Nor."haodfolone Elhyles"enol
(N;i(!"ar) IM•• iboIin.O,atlOlin) IO.nobol)

"
o
L -

"
,
o o
" "
Nor>dro1One
phC""''''''''''''e
IDuraOOltn)

"o "
o
1 --0 ", A ---

'"
0
",I
o , ,

IAnava,)
"
S,ar.;,c>IoI
(Te •• t>oI;nl

Fig. 14-1 0 . Synlhel;C .""boIic 01..<>O:Is ,elated to

I..l<>s'''''''' .

affinity (TcBG. eBG. thyronine binding prolein and
others). They also ma ke subslanc;e< '!uch as glQb. «""
ulins in rats and major urinary prolei", (M UPs) in
mke lhal appear in Ihc urincs of adult males bU11I(I1
females or juveniles of either $eX.
The liver is a major site for coojugation and deg·
radation of the steroid hormones and for "detoxifi·
cation" of pharmacological agents. The processes in-
v<llvc a wide assortment of enzymes whose levels and
substrate affinilies differ in adult males oompar<:d
with adull females. The sexual dimorphism is re-
flected in dissimilar dearan.e rale!;. II is kno,,·n. for
•• ample. that the cffects of barbiturates persist
longer in females. whereas glucocorticoid. are de.
graded more slowly in males.
The mecbanisms involved in establishment and
maintenance of the dimorphism are complex. Some
aspects dcpend on gonadal steroid interactions with
billh.affinity receptors of tbe hepatocytes. These arc
usually affected by gonadectomy in both sexes. and
by exogenous androgens and estrogens. Others re.
quire "pr iming" that is accomplished early in devel·
opment . and these can involve hormonal innucnces
excrted on pituitary gland cells and neurons.
Tfm ralS and mice do not have physiologically ef-
fcelive androgen receptors. The males form testes
and they :;eercte testostcrone. Ilowevcr. they fail to
undergo androgcn-<lependent development of tbe ac-
cessory reprodUctive organs and cxternal genitalia .
do IIOt display androgcn·stim ulated behavior. and
arc unable to respond in a normal mannCr to even
large doses of testosterone Or DHT. Sexual dimorph-

ism of the liver is not established (8). The most ob-
vious interpretation is Ihat Ihe changes in the li"cr
are mediated via androgen receplors. However. Ihc
possibilily tnal the genetic defect impairs funclions
other than androgen receplor formalion be
coru;iderod.
Explanations are needed for the ability of andro-
gens to stimulate growth of the liver and clevate thc
microsomal protein contcnt . One possibili ty is that
Tfm rodents make a protein that can function as an
androgen roceplor in liver but nol ;n reproductive or-
gans. [The animals make a renal androgen binding
prolein (40)]. Another;s Ihatlhe stimulatory effects
of androgens on the liver are not mediatcd via a
"true" androgen reeeptor, even in normal animals
(8).
RAT "' •• MICROGLOBULIN
The protein is discussed hero because thc control
mechanisms may shed light On the ways in which
sexual dimorphism of the liver is controlled in other
species.
a ",Microgiobulin has a molecular weighl of
21 .000. The liver of the young male produces 25- 30
mg daily. At least 80% of it is e"croted inlO the urine
(where it for h,tf The.
functions are not known, but a role in protcction
against estrogen-mediated inhibition of spermato-
genesis has been proposed (96). Small amounts of
the globulin are also made by salivary glands (160).
The protein first appears around the time of pu·
berty onset (six weds after birth). It is oot found in
younger animals of either se x, in normal females, or
in ovariectomized animals. CaM ration markedly
lowers Ihe output in males, Injection. of DHT or tes·
tosterone restore the protein, and the androgen. Can
induce it in ovariectomized females. Androsterone is
also effective. if less potent (altbough that steroid
does not mimic testosterone aClioll$ on reproductive
organs), The lIormonal manipulations affect the lev-
els of the a&sociated mRNA, InAuences on transcrip-
tion are likely. but it i'l not known whether Ihe ste·
roids the RNA processing (96).
Cyproterone acetate blocks DHT actions. proba·
bly by competing with it for lhe receptor. Estradiol·
is a potent suppressor in intact males. Estrone.
estriol, diethylstilbestrol. and eslradiol-17a arc also
effeclive, although eSlradiol-17", docl; not mimic the
actions of thc others on female reproductive organs
(160). While some effects of estrogens invol ve inhi-
bition of LH secrelion. they persist in the presence
of androgens. Estrogens aro believed to interact with
their own rocoplors to impair formation of androgen
",ceptors. also competes with DHT
THE MALE REPRODUCTIVE SYSTEM
for its own binding sites. but the other steroids cited
do not.
AndrogefLS do not induce the protein in juveniles,
and a very long lalenl period precedes the effects in
adult males subjected to either long·term castration
or long_term e.strogen treatment. Evidently, a sub-
stantial time period is required for androgen induc-
lion of new androgen receptors (160). The estrogens
suppress formation of the roceptors as well as induc-
tion of the liver protein when they arC present. No
preliminary '"priming" effects during early develop-
ment seem 10 be invol"ed, since neonatally castratcd
animal s can later respond to androgens.
Although all of the proccding findings point to di-
rocl control by gonadal steroids. the regulation is
more complicated. Androgens cannot induce the
proteins in hypophysectomized or thyroidectomized
rodent5. and they have only limited effects in adro_
nalectomized animals. Thyroid hormones fully re-
store the responses of thyroidectomized animals. and
they stimulate production of the globulin when pre-
scnted in vitro to liver tumor cells that retain hor-
monal sell$itivities. They are believed to interact di_
rectly witb their own receptors in lhe liver. Growth
hormone alone and glucocorticoid. alone each pro-
vide some stimulation for cultured cells. and the ef-
fect< of thc fOHr hormone type< are additive. All arc
needed to fully restore pMein production ;n hypo-
physectomired animals (96.160). Insulin is llso re-
quired. (Alloxan tro3tment scverely impairs this
liver function.)
As they approach the ends of their life spans, un-
troated adult males stop making the "2 globulin and
they lose the responsiveness \() androgell$,
STEROID·METABOLIZING ENZYMES
The conlrol of steroid-metabolizing enlymes de-
pends on "priming" as well as on Ihe presence of ap-
propriate hormone levels in the adult (34,69).
The activiti.. of several hydroxylases that affect
the metabolism of pharmacological agems and most
endogenous hormones are higber in males than in fe-
males. However, the 5a-rcductase tbat aCtS on glu·
cocorticoids is lower, and this accounts ror the longer
half-life of that hormone in the males.
Some invesligators use the term '"femin;,.ation·· to
describe increases in ratiOIS.
In this sense, it can be stated that (a) IIC()natal cas·
tration feminizes males (it prevents the gradual
onset of "masculinization" that becomes apparent al
puberty); (b) neonatal androgen treatment blocks
thc poslcastration fem inization , Animals treated this
way become rully responsive to hormones presented
during adulthood. When neonatal animals arC per-
mined 10 go for a time wilhout hormone replace-
memo injeclion of androgens al a later time is far less
effe<:tive; (c) when males arc pcrmi(ted to develop
into normal adults. subsequent gonadC<:lomy brings
about limited femini1.ation that can be reversed wilh
androgens; and (d) estrogens given in dosages that
inhibil LH release can feminize adult males.
In females advancing from juvenile to adult
stages. 110 marked changes in the steroid-metaboh,.-
ing enzymes are seen. Neither ovariectomy nor es-
trogen injec tion ha, much effect.
It ""ems. Iherefore. Ihal this of sexual di-
morphism depends on androgen "priming" during
the prenatal period plus exposure a t a later lime to
physiological level s of androgens. The priming has
no diseernible direct innuence on juvenile" but it is
manifesled in Ih. form of increased sensitivity 10 an-
drogens after puberty. Normal female neOMleS do
not unde rgo priming. and they do not require estro-
gens to eslablish Ihe usual enzyme ralios.
Since the sex differences do not emerge in hy-
pophysectomized animals. it has been proposed that
pituitary glands re\case aftmirtinotrorirt (feminizing
factor. FF). and that androgens prevent this during
tne neonalal period. Pituitary glands removed from
thei. usual sites and transplanted into the same an-
imals release Ihe factor. and glands cocultured wilh
hepatoma cells feminize coil •.
Since transplanted pituilary glands aloo make
substantial amounts or protaeltn. allempts have been
made to idenlify Ihe FF with that hormone . How-
ever. a lthough hepatocytes have PR L receplOrs. the
hormone canoot mimic the effects of tbe pituitary
gland transplan15 . (PR L has been found to exert
very limited inHuences on 5a-reductase activity in
some studies. bUI to havc 00 innuence on thc hy_
droxylases [34].) Another notion is Ihal FF differs
from PRL but is made hy the laetotropcs (69). Ac-
cording to one hYl'Othesis. androgens act on the een-
lral nervous sySlem 10 promole secretion of a factor
that inhibils FF release.
There arc sex differences in the pallerns for
gro"'th hormone release in rats. Males have peaks
spaced 3-4 hours apart. wilh very low levels between
the pea ks. whereas femaks release the hormone
more irregularly and tend to have high lrough values
(114) . It has recent ly been demonstrated thai to,..
IInuQus of GH alone brings about femini-
zat;on of the li vers of hypophyseclomi1.cd animals
(114A).
Bone and Bone Marro w
Males usually have higher hemoglobin conccntra·
tions and erylhrocyle countS than females. Some of
the differences are undoubtedly related 10 physical
aClivity pallerns lhat increase oxygen need in the
males. hut others have been linlcd wilh the gonadal
steroids.
Erythropoielin is koown to play key roles. and
both tcslOIllerone and DHT can augment the eryth-
ropoietin influences via mechani.mS lhat arc blocked
wilh antibodies direcled against Ihat regulator .
(Among other things. androgens increase erythro-
poietin se<:;retion.)
Sone marrow may have special steroid re<:eplors
oot present in other ··androgen targelii" (8). These
interact with Se·redueed steroid, (and 5t1-<lihydro-
testosterone is at least 20 times as potent as OUT
for the actions). The hormones induce porphyrins
and o.amioolevulinic acid synthetasc. and they ac-
celerate iron utili7.alion by the erythrocytes of poly-
cythemic mice. The effects persist under conditions
in which the usual androgens arc not effective . They
are se<:n in Tfm rodents and in the presence of an-
drogen receptor antagonists that block DHT effects.
The mechanisms are unrelated to the one.. depen-
dent upon erythropoietin. and they are unaffected by
either antibodies directed against that regulator or
high oxygen tensions thaI de<:reasc erythropoietin
production_ tI·Redueed progestogcns and eliocllobn-
olone are amCKlg Ihe additional agcnts thai act on
bone marrow but not on male accessory reproductive
organs (87).
"'N'
Androgen' exert anabolic actions on bone. and the)"
contribute to the preadolescent growth spun. They
also interact with thyroid Ilormoncs to promote cal-
cifIcation of the epiphyses. Infiuences on food intake,
mineral and vitamin ntetaboHsnt. nilrogen balance.
sensilivities to olher regulators. and on behav ior con_
tribute to the anabolic actions.
Skin and Ralatad Strucluraa
Androgens bring about coarsening of the skin tex-
ture. activation of Ihe sebaCC<lUS glands. and hor-
monc-specific pallernS of hair growln. The effects
are evidently ntedialed via specific. high-affinity rc-
e<:plOrs thai interact primarily wilh DI·I T. The re-
ceplor concentrations vary from one part of the body
to aoother. They arc especially high ill Ihe genital
regions, and »redUClase activity builds up there
before puberty. The receptor numbers arc not known
to be affected by age. sex. Or gonadal hormoncs. bUI
androgens increase the enzyme activity and there-
fore the responsivcness to tcstostcrone. Hair growth
in mOSI parts of Ihe body (pubertal regions. face.
chest. uilla. and parts of the scalp) is strongly de-
pendent On both androgens and Ihe ability 10 reduce
testoslerone 10 DHT. In some OIher locations (e.g.
eyebrows and eyelashes). it is unaffected by the stc-

roids. Male-type baldness ha; been lllributed to ge-
netic factors that require thc permissive actions of
androgens.
Other Androgen Targe ts
These include several oomponents of the immune
system (/\·3). the salivary glands of rodents. and the
scent glands of some species.
MECHANIS MS OF ANDROGEN ACTIONS
Many of the actions can be fItted into the "classical"'
concept for steroid hormones. The androgens can
cross plasma membranes. and they sc<:umu!ate in
cells that conlain high-affinity binding .ites. Hor-
mone-,""ceplOr complexes form. undcrgo time- and
temperaturc-<:lependent ··activation." and translo.
eatc to the nuclei. Their associations wilh the chro.
matin lead to accelerated production of RNAs that
di,""ct protein synthesis. Many of the actions Can be
blocked wilh agents that interfere with hormone-rc-
e<:ptor binding (c.g . cyproterone and Ilutamide, Fig.
13-27) and with inhibitors of RNA and protein syn-
thesis (87).
Some of the unanswered questions regarding an-
drogen actio", pertain to . teroid hormone. in gen-
erat (177AJ82) (se<: Chapter 4). Others apply 10
androgens in particular.
Relationships between Q uantitie s o f Steroid
Retained and Responses Elicited
Whcn radioaclively labeled andragert' are injecled
into whole animals. target organs that do nOI prolif-
erate in response to the hormones (kidncy. skeletal
muscle . skin. pituitary gland. neurons) ta ke up very
limited quantilies of the steroid. the ac<:es-
sory reprodUClive glands accumulatc largc amOUnts
( 101 . 196). Some maximal responses require oc<:u-
1'-1tion of only small numboc" of nuclear ree<:ptors.
High d"""s increase nuclear relcntion times and
,hortcn laterlCies (A-S) . Perhaps proliferJtivc re-
sponscs requi re conversion of testosterone 10 other
steroids .
Active Forms 01 the Ho rmone
TestOSlerone is Ihe major d rmlaling androgen in
male adults. Reproductive organs rapidly convert
the hormone to DHT. and there i; lillie doubt that
is thc most important hormone in such organs.
It binds with high affinilY 10 Ihe receptors. and 5<<-
reductase inhibitors impair the response, to te,ta.--
terone. The conversion also facil itates testoste rone
THE MALE REPI1OO\.ICTIVE SYSTEM
uptake. sine<: it towers Ihe intracellular COIle<:ntra-
tions of that steroid.
Skeletal muscle has lillie 5a-reductase activity. It
COIlverlS testosterone to cpittstoslcronc. and the
small amoums of DHT Ihal enter the cells arc
mostly transformcd to androsta nediols. Testosterone
binds directly to the rc<:eptors. and it may be thc
major androgen in skeletal muscle.
The embryonic Wolffian ducts also bind lestOSler-
one directly. They do not make DHT. and tbey de-
velop normally in animals with senctic defects that
impair DHT production.
In bone marrow. the principlc androgell$ may be
5,6·reduccd steroids. Unlike the reproducti.·c organs.
Ihe e<:lIs have an aClive 5.6-rcduetase. and the cells
respond to exogenous steroids of this kind.
Many of the neurons that respond to Icslosterone
have aromatasc enzymes and "Strogcn receplors.
Animals with impaired responses to DHT mainlain
functions that depend upon aromati71uion of
testosterone.
Intracellular Binding Sites lor Steroid
Hormones
When low concentrations of DHT arc pres<:nted to
ventral prostate glands of species that depend di-
re<:tlyon the steroid. there is rapid and tight associ-
alion with a ,6 prolein or androphilin. AS a result. a
'"complex II " is formed tnal SOXIn becomes '"acti-
valed'" and translocaled tl} the nucleus. Therefore.
the.6 seems to serve the funct ions of the spc-
cinc receptor.
HO"iever. proslatc glands rce<:ivc much of thcir
androgen supply from tbe syslemic blood. TCSloster_
one docs not bind wi th high affi nity to the.6 protein.
Rather, it attaches to an a protein with quite diffcr-
ent properties 10 form Hcomplex I" . When DHT is
presenled in moderate amounts. some of il. 100. com-
bin.. with the <"< prOiein; and tstradiol-17,6 can a lso
ma ke Ihe 3113chmcm. It is not known whether COm-
plex I mediates some special actions of lhe steroids
(101). II could serve in a '"rc.<ervoir capacity."' that
is, as a means for relaining a recruitable supply of
DHT rrc<:ursor to be used when blood Icstosterone
levels arc low.
Some androgen actions evidently do OOt require
translocations of hormone-receptor complexes to the
nuclei. Effects on protein synlhesis that are blocked
with q"Cioheximide but nol with actinomycin D may
be exerted at the level of trimslation. Certain OneS
are apparent within to minutes after hormone pre-
sentation. Dilfcrenl mecbanism' mu,t be involved in
Ihe innuene<:s on cytoplasmic proleins that ,upporl
the binding of mcthionyl-tRNA to ribosomes. Pros-
tate gland initiation factor actIvity declines after
castration. and it can be restored with fairly high
DHT ooneentrations. but the changes are not af-
fected by cycloheximide (101). A few androgen aC-
tions have been linked to steroid associations with
nude", membraTICS or nucleoplasm.
There are also some as yet undefined interrela·
tionships with the cydic nUc/f'Olid.s. Ahhough nei-
ther castration nOr the in vivo adminislration of
moderale amounts of DHT has been observed 10
substanlially alfc<ol cAMP levels in proslate glands
of rats. injeClions of large amounts of DHT into cas-
lrated rats have elevaled Ihe levels within one hoor
in SOme upc:riments. and the prolein kinase activity
within Ihe nuclei is 'imillrly affecled (101).
Andlogens can exen cAMP-like innuences on
carbohydrate metabolism. They Can also affeel ca-
lion transport. and in Ihat way affect Ihe adenylale
cyclase and phosphodiestcrase
The Co ns equ e nce s 01 Hormon e-Re cepto r
Co mplell Bind ing 10 Nuc lear " Accepto r
$lles"
AI least some observations ar<: Consislenl wilh Ihe
OOnccpl Ihal Ihc steroid_r<:ccptor oomplex brings
aboul "unmasking" of tranSCriplion inilialion silCS.
The proposed mc<:hanisms include direcI inlcrac-
lions wilh specific DNA segments. removal of re·
pressors. and interactions wilh nudear proleins that
would OIherwise maintain the DNA segment' in a
superooiled stale. The rna)' also aifcet Ihe
processing of "gianl" RNA or stabili>.. the mRNA
products.
Temporal pallerns for augmentation of RNA p0.:>-
lymerase I and II have been worked Out for estro-
gens. but the)' arc less well defined for the andro-
gens. Early effects of Ihe hormones seem 10 be
exerted on pr<:formed "reserve" enzymes, and One
idea is Ihal Ihe complexes bring about con-
formalional changes in Ihc proteins thaI faeililate
binding to DNA sites (101). Delayed effects include
synthesis of new enlyme. Androgen_receptor com-
plexes have also been observed to allach 10 ribono_
clear parlicles (196) and to travel wilh lhem 10 Ihe
e)'loplasm. It has addilionally been reporled Ihat
DHT exerts some direel aClions on Ihe nudei (wilh-
OUI prior binding 10 Ihe hormone receptor).
The influences of DHT on cell proliferation take
days to develop. Long-tcrm relention of Ihe hor-
monc-r<:ceptor complex wilhin Ihe nucleus. cell
growlh, and lhe formation of several proteins occur
during Ihe lalenl period, It is possible Ihal the hor-
mone aclS indireelly. by "pr<:paring" Ihe cell for rc-
a]i7.ation of its "innale" ability 10 cnler into mitosis.
Anolher sUgjlcstion is Ihal Ihe oomplex indu<X's ami-
100ie stimulant Or remOveS a chalone .
AGE-RELATED CHANGES IN TESTICULAR
FUNCTIONS
Interstitial Cells
Soon aflcr differentialing from the mesenchyme, Ihe
cells begin 10 synthesize toSlOSlerone from pr<:gnen-
olone. LUlropin receplors are acquired early in felal
life. and Ihere is SOme cvidence Ihatlhey are induced
by Ihe H-Y antigen (119) . Felal receptors interacl
with chorionic gonadolropin before the pituitary
gland is sufficienlly developed to secrete LH . In hu-
mans. malernal plasma heG ri""s rapidly during
early pregnane)' and il peaks during weeks 8-10.
FClal blood Icvels rise more slowly and Ihe)' peak
during weeks 11-14 (53) (Ihree Or mOre weeks after
Ihc lestes secrele sufficienllestosterone 10 masculin-
ize the Wolman duclS). The interslitial cells respond
10 Ihe stimulation by undergoing growlh and prolif_
eration. and they acquire Ihc ability 10 usc choles-
Icrol. TestOSlerone biosynthesis a<X'elerales and the
felal blood IC"ds show peaks around Ihe 13lh wee k
(when the hormone is needed to virilize Ihe exlernal
genitalia.) Concentrations can Ihen reach lev-
els of WO ngjml (53).
Soon afterward, hCG secretion declines. It
reaches a low point during ..-eeks I 7-1 9 and r<:mains
there for the rest of the geslalion period. Felal teS-
tosterone secrelion also falls oif 10 around 40 n8lm!.
{Evidenll}, Ihe ooncenlralions are adequalc for sup-
porting c-onlinued reproduelive system maturation.)
The felal pituilary and hypothalamus malure
laler Ihan Ihe tcstis. Although tissue lakcn fronl 5-
7-wcek-old embryos and mainlained in culture can
respond to LRH by releasing SOme gonadotropin. Ihe
basophilic C(!lIs thaI make the hormone are said 10
be morpoolQ8ically dislinguishable only after ..-C(!ks
S (63) or !0-13 (127), and the gland docs not take
on ilS charaelerislic form unlillhc 141h wcck . Go-
nadotropins have been dctected in fctal blood as
carly as days. and LRH appears in lhe hypothal-
amus 31aboullhe same lime (127). Some LRH may
reach the pituitary cells via diifusion. bUI il is un-
likely that the gonadotropes receive SUbstanlial Slim-
ulation until after the portal blood system compleles
formation (belween weeks 20 and 28). The felal pi.
luilary undergoes a Jl).fold incr<:ase in si"e bel..-c<on
Ihe 141h week and Ihe time of birth (63). These ob-
servalions. plus evidence thaI the gonadotropes
"learn" to make «-subunits before Ihey can produce
LH {I 53). suggesl thaI only heG is an important
stimulanl before midgestation .
Ncverlheless. Ihere arc clear indicntions thaI Ihe
older felus needs some LH (127). The blood levcls
are quite high during days 120-150. and anence-
phalic feluscs display a speCtrum of developmental
defects that Can include micropenis. reduced si'.e of
the Icstes and seminal vesicles. paocity of inlerstitial
."
cells. and failure of Ihe testes to undergo normal de-
scent into the scrotum.
There is a need 10 limif as well as 10 stimulate
androgen production. so that Serlol; do 1>01
undergo precocious maturation. Negalive fe<:dback
control is established after midge!51alion. The lower
blood oonc.::nlrations of gonadotropins in male than
in female fetuses (53, 63) wilh 00 concomitant low.
ering of pituitary COntent (127) is attributed to an-
drogen inhibition of LH release but not synthesi,_
Tne rising prolactin levels may contribute \0 the
controls.
During the final prenatal weeks. the hYJIOlhalalTlO-
hypophysial system becomes ,-cry scruli!;ve to the in-
hibitory effects of the steroids. Pituitary secretion of
gonadotropins is minimal. and the interstitial cdls
arc probably stimulated rn<)Sliy by thc low heG
levels,
With loss of the placental influences. the testOIS'
teronc concentrations in the blood of thc neonate fall
rapidly to bal"<'ly dclcctable level •. LH rises Iran·
sienlly during the second Or third ]KIStnatal month.
possibly becau,,", of the lifting of inhibitory influ-
enCCS. (An lRH·likc factor in milk was cited. earlier
and it may contribute to Ihe lH change.) There is
an associated brief "bur1I" of androstenedi011e and
te<t""temne <ecrelion. Afterward. bolh LH and an_
drogen secrelion fall off, and the levels of bolh rCoo
main very low Ihrough(}llt childhood. The decline
probably explains the marked reduclion in the si7.cs
and number1 of interstitial cells. The .... trahypotha-
lamic brain is believed to make importanl contribu-
tions \0 sUPPl"<'ssion of LRH (and Iherefore of LH)
-ecretion. Pl"<'mature infants have _SQmewhat differ-
ent hormone patterns during the first few ]KIStnatal
weeks. bUI they SOOn make the necessa ry adjust·
mcnlS (I g3).
Similar agNdated change.. in testOISterone sec!"C-
lion have been described for other mammals. How.
eVer. in ones with very short juvenile period., there
is 00 obvious loss of interstitial c<:11 populations. (The
period during which testosteronele,.. ls arc very low
in mlS and mice is measured in days. whereas such
changes last for a de<:ade or more in humans.)
The operation of negative feedback controls is eas-
ily demonstrated in v<:ry )'QUog rat$. If castration is
performed. the plasma gonadotropin rises. Devdop-
mental changes in pituitary gland sensitivities to the
steroids are demonstrated by determining Quan·
tities of steroids required tG lower lH levels. Roles
of thc extra-hypothalamic brain in determining the
duration of the juvenile period are indicated by 00.
servatiGns that lesioM placed at cerlain sites advance
puberty onset. whereas lesions at Gtber loci can delay
i\.
As Ihe time of puberty approaches. the pituitary
THE MALE REPRODUCTIVE SYSTEM
gland begins to release increasing amounts f>f LII.
mostly in the form of nocturnal "bursts" of gradu·
ally rising amplitudes. It has been demonstrated in
rats that the numbers of LRH receptors peak during
the period in which the gonadotropin Icvelsare max·
imany elevated (27). Many factors may account for
Ihe changes. One ]KISsibility is the hypothalatn(>-hy-
poph)'sial system becomes less sensitive I<l the neg·
ative feedback influences of gonadal steroid •. 1\ rCoo
lated event may be LRH induction of its own
receptors. In addition 10 "reselling of the gonado.
SIal", there may be a reduction in the release of in--
hibitory factors by extf3·hypothalamic neurons
(l80). Or accelerated presentation of stimulants.
Norepinephrine is believed to be a major stimulant.
and its turOOver in the brain ac<:elerales short ly be·
fore the onset of nocturnallH surges ( 18 1).
I\s Ihe UI concentrations rise. the interstitial cells
incl"<'ase in $i,.e. number. and steroidogenic capabil -
ity. I\dult hormone conC<:ntrations are allained dur-
ing years 14-16. There arc controversies concerning
whether lH brings arout differentiation of new cells
from the lesticular stroma or activales quiescent
ones belonging to Ihc population that was prescnt in
the fetus, It is ]KISsible Ihal bolh processes (Ire in·
volved. The ,ec ret;on of relativ<:ly large amounts of
androstenedione prior I<l establi.hment of the ma-
ture pallerns for steroid hormone secretion has been
cited a. evidence thaI the cells are newly differen-
tiated. However. it may be equally reasonable to
suggesl that cells Ihat remain quiescenl for many
year1 regress and must undergo maturation befol"<'
they can produce substantial quantities of
testosterone.
The timing of puberty onset is affe<:ted by genetic
factors. nutritional status. and environmental inputs.
ScaSQnal variations 31"<' obvious for many species
(136), and SQITle influences are secn in humans. En-
vironmentallighting is probably a major controlling
component. (Blind males often have abnormal LH
and testosterone secretory patterns. and blind girls
tend 10 enter puberty earlier than sighttd one..
11SI].)
Once the adult levels arc attained. the plasma tes-
tosteronc is usually stabilized for several decades.
Ultimately. lestosterone =retion de<:lincs. but in·
dividuals show very marked diffcl"<'nccs in the ages
at whicb this happens. The numbers or interstitial
cells alSQ decrease (52). Since the metaoolie clear·
ance rate also becomes prolonged. plasma steroid
concenlrations fall more slowly than the =retory
rates. In aging mice. evidence ltas been prescnted for
a slowing of the neural "gonadotropin releasing hor-
mOne generator" and co ... equent reduction in the
numbers of LH pulses (38). It is likely that similar
changes occur in olher mammals.
SertoU Cells
Embryonic SenoH cells begin (O ,function before the
"indifferent gonad" bewmos recogni1.ablo as an im-
mature testi., They associate with the germinal cell'
to form the "sex wrds". II has been suggested that
there are twO types: dark cells that promote prol if·
eration and preliminary maturation. and light ones
that block the entry of prespermatogonia into
meiosis (193). The cells acquire aromatase enlymcs,
When the interstitial cells begin to ,<,lease testoster·
they ta ke up some of the ste roid and cOnvert it
to estrogen., They in thi s way dircctl y protect them·
sci ..." against premature exposure to high androgen
levols. Estrogens released to the surroundi ng ftuids
also exe rt inhibitory influences O,'er testostc rone pro-
duction by the interstitial cells.
The Sertoli cells acquire FSH ,<,c<:ptors. Around
midgcstation. cnough of the pitUitary hormone is re-
leased to promote $Orne growth and maturation . T he
""" cords dongate. become canali7.ed. and begin to
look like immat ure seminiferous tubules. At somc
stago , the Sertoli cells begin to secrete inhibin. and
the peptide may comribute to the fall in FSH leveis
that occurs later in gestation,
During the late juvenile period, plasma FSH lev_
els rise before the increases in Lli arc marked. fS11
promotes growth. proliferation. and speciali7.ation of
the sem iniferous tubules. After al1aining maturity.
Scrtoli cells no longer proliferate and they lose many
of their earlier responses to the pituitary hormone.
M(lS1 of the functions can thcn be maintained byan-
drogens from the interstitial cells. but $Ome FSH
may be needed to promote the production of andro-
gen binding proteins. inhibin. and other regulators.
The seminiferous tubules continue to support sper-
matogenesis for s",-eral decades. but the functions
deeline when testosterone production falls .ub-
stantially.
The Timing 01 Puberty Onset
Long before the usual time of puberty onset. the
testcs acqu ire the ability to mature in response to go-
nadotropins and testosterone. the pituitary gland has
the machinery for secreting ilS hormones and react-
ing to hypothalamic stimulation. and the hypotha_
lamic neurOnS can release lRH.
tn laboratory animals with long juvenile periods.
it is easy to invoke precocious development. Even in
rodents that bewrnc reproductively wmpete nt in
less than a month after weaning, the testcs and ae-
cessory reproductive organs can be made to grow
rapidly. and a pituitary gland taken from a recently
wea ned animal will support gonadal functions if it is
transplanted to a site within an adult where it is ex·
posed to hypothalamic hormones. In human children
with hormone-se<;reting tumors. seconda ry sex char-
acteristies as well as prima ry and accessory repro-
duct ive organs have b\:on known to mature as early
as Ihe third ycar after birth, and even behavioral
changes have been observed ,
Considerations of Ihis kind underlie lite "trigger"
concept of pUbert y onset. aocording to which fully
prepared components of Ihe system a"'3 it reception
of tlte appropriate signa l,
More modern views state that reprod uctive mat-
uration involves a gradual progression of complex.
intricately rela ted events. S tep by step. the individ-
ual begins to function less and less like a juvenile and
mOre like an adult. until finally the abilities to en-
gage in mature patterns of hormone sec ret ion and
produce a nd diseharge fe rtilizable germinal cells are
reahed (1 49.18 1).
1\ common feature of the preparation is a "'<'set-
ting of the gonadostat." The Itypothalamus a nd pi-
tuitary gland bowme gradually less sensitive to ncg-
ative fe<:<lbaek inftuenees of the steroid hormones. In
at teast some species. Ihe earliest change occurs in
the central nervOuS system. Some of the inhibition
over lRH release is lifted. More of the hypotha-
lamic hormone is secreted. and this soon leads 10 in-
ereascd 'iecretion of LH, The pituitary gonadotrupcs
acquire larger numbers of lRH rccepto['l; when they
are stimulated. and they therefore become mOrt sen-
sitive as well as more productive. Gonadal hormones
Can accelerate maturation of the central st ruclU,<,s.
but accelerated LH release is also demonstrated in
castrated animals lhat attain the age a t which the
events normally occur. LH additionally acts on neu·
rons to promote further development (I 81).
The prepubertal adenohypophysis secretes much
more fS H than LH. As it matures. the LH:FS II
ratio rises. One effect o f the FSH is induClion of UI
receptors. When the plasma LI'! wncentrations in-
c'<'ase . the sonads put out more steroid hormones
and changes in their enzyme complements bring
about maturation of tlte secretory capabilities. Al-
though immat ure interstitial cells release substantial
quantities of androstencdiorlC and androstancdiols.
adult tcstes secrete mostly testosterone. Some 5,,-re-
duc tase activity is acquired carly. but the rising lev·
els of testosteronc lead to of mOre of the
enzyme and therefore to production of more DII T.
In central factors Seem to be the major
initiators of the events under normal cond itions, A
reduc tion in the rate of release of endogenous opiate-
like peptidcs that tend to depress LRH secretion has
been implicated (127). In rats and other mammals
with less highly developed brains. gonadal matura-
t;on may be of primary importance ( 181). However.
even Itere. changing pallerns of neuron fu nction arC
known to occur during the peri pubertal period. Le-
sions placed in diserete brain regions can cLther ad-
vanC<: Or delay the maturation (149).
The developmental pallerns are inAuenced by a
.n
wide variety of modulators. The rales of inhibin se-
cretion and the sensitivities to ilS actions change
(136). Nocturnal GH pul.. amplitudes incr<:ase.
T he hormone invokes a "growth spurt" by exerting
infiucnc:<=s on nonreproductive organs. but il also
modulates pituitary and gonadal funCliOft>.
The adrenal cortex undergoes a series of develop-
mental changes. at leasl some of which oontribulC to
puberty The felal gland is of adult si,.c. since
;1 C<)ntains an "X" wne that underg0e5 atrophy soon
after birth. During the fetal period. it secretes mostly
DHA and DHAS. and its major stimulant may be
a- MSH (133). The gluoocorticoid:DHAS Tali<> rises
before involution of Ihe X 7.one is accomplished. b-
posure \0 higher concentrations of ACTH and ac-
quisition of sensitivity to Ihe hormone arc probably
involved.
The term designates changes in the
adrenal cortex thaI usually precede the gonarche
(maturation of the gonad.). The phenomenon has
been mostly in femaie,. but some ma turation
occurs in males (39). The zona reticu laris becomes
mOre specialized. .. activity rises. and the "'.
lease of substantial quantities of OHA and of DHA S
account for SOme of the elevation of urinary
tosteroid " content (42). According to some observ.
ers. ACTH exertS the major tropic influences On this
as well as on the (mostly
7.on3 fas<;;eula ta (ISS). Others favor the concept that
ACTH exens generalized '"permissive" effects.
while some OIhu regulator acts directly. It is
claimed that a cOTtical androgen ",creting hormone
(CASH) (133.134) Or adrenal androgen seeTOling
hormone (AASH) (174) is made in relatively large
amounts at this time.
The growth of axillary and pubic hair in females
is dependent on Ihe secretion of adrenal androge ns.
Steroi ds of thi, kind can affect reproductive s)'Stem
maturation when they are given to experimental an-
imals. but tlt.ir !"(lIes in normal maturation have not
been ddined. There are dinic.1 conditions under
which adrenarche and gonarche can be dissociated
(174).
In females. ovarian steroids play signi ficant rol""
in reproductive ,ystem maturation. The control sys-
tems and tbe effects of nutrition (A_2) may differ
from those found in males (Chapter I 5).
REFERENCES
I. ACOll. T . S .• and H<>skins. D. D. Bovine Forward
Motility Protein: Binding to Epididymal Spor-
m.(oroa. Bioi. 24: 234-40.1981.
2. Adashi. E. Y.. Hscuh. A. J . W.. and Yen . S. S. C.
Enhancement of Luteini,in8 Hormone
and FollicilO-Stimul.ting Hormone R.I .... by
THE MALE REPRODUCTtVE
Cultured CeliS. t:mJ"''',;III)/. 1(J8: 1441_
49.1981.
1. Arimu ..... A. Hypothalamic Gon.<iotr(>pin_Re-
leasing Hormone and Chap. 1. pp.
1-21 of R. 0 .. ed. Physiol-
ogy II. Uniyo"ity Park Pr.",. lIahitl\Ofe. 1977.
4. Ascoli. M. R""epl<>r-Mediated Uptake and Deg-
radation of Human Chorionic Gonadotropin: Fatc
of th. H(>rmGnc Subunit •. Ann. N. Y. A("Qd. Sci.
383: 151-69. 1982.
S. Bahl. O. P. Thc Chemi.try and lIiQI¢gy (>f
Chorionic GonadOlropin and it> Subunit •. Chap.
20 pp. 11_24 of G,eep and Kobli"".)". ed •.. refer_
enoc 66.
6. Bambino. T . H.. and H",uh. A. J. W. Diroct In-
hibilory Effect of Gluc<x:orticoids T c51ieulac
Hormone Recepl0r and Steroidogen·
esis in Vi"" and in Vitro. t:nJlX,inoJ. lOtI: 2142_
8.1981
7. Baram. T .• Koch. Y.• Huum. E.• and Fi,dkin. M.
Gonadotropin-Rel.asing Hormo .. in Milk. Sci-
19$: 300-2. 1977.
8. Bardin. C. W.. and Callemll. F. F. To.tost.ronc:
A Major Determinon( of Extragen ital Sexual Di_
morphism. Sd."u 211: I 28S-94. 1981 .
9 . B.rdin. C. W .. N .• .. lus. G .• KQti(o.
N., Cheng. S.-L.. bm:a. F.. and R. E,·
traocllula, Androg.n Binding Protein •. Ann. •.
43: Ig9_98. 1981.
10. C . 1\ .• WI..,. P. M .. Turgeon. J .•
Shander. D.. D.Paulo. L.. and R..... N. Recen.
Slud ie. on lhe Regul.ti(>n (>f Piluitary LH a nd
FSH Secrol;on. BiO/. Rrprod. 20: 86-97. 1919.
11 . B. nh. A. Role of Proi.Olin in Reproduction 0/
M.le Ma mmals. Proc. 39: 2SJi- 2S81. 1980.
12. B.nke. A., Haficz , 1\. A.. Bex. f . J.. and Daile rio.
S. Hormonal lme'a<lion. in Regulation of And,,,"
gen Secre(ion. Bio/. /l.tprod. 18: 44_S4. 1978.
13. Bashi'clahi. N .. and Sidh. S. M . Estrogen Recep-
tors in Mal. Genit.l O'gan,. Ad>. Stx 1I000m.
4: 1_26. 1980.
14. Beaumont. 1\.. and Hughes. J. Biology of Opioid
P.ptide •. Ann. Rtv. Fha'maw. 19: 245_67. 1979.
15. Bedford. J. M. M.tu,ation. Transport. and Fa(e
of Spe,ma(oroo in (h. Epididymi •. Ch.p. 14. pp.
303- 17 of Hamihon .nd Grcop. od •.• ref.ronc.
n
16. Bellv •. A. R. The Molecular Biology of Mam·
ma li.n Sperm'lOgo ... i, . Ox/<"d Rn'. Rep,ad.
Riol. I : 1979.
17. Berger. H.. and De K'.'ter. D.. ed •. TAr TtJri•.
Rayen PreS$. N.w Yorl:. 1981.
18. S.rgner. E. A .• and Shapiro. L. J. In,roa",d Ch,,"
1•• te,oI Sulfat. in Plasma and R.d Siood Cell
Membran.. of Steroid Sulfat.", Defldont Pa-
tient •. J. Clin. Elllioa/noJ. Mr,ab. 51: 221 _3.
1981
19. Bewley. T. A. C;rcular Dichroi.m of Piluit ..y
Hormon ••. R.N". Prog. /lorm. R«h. )5: ISS- 210.
1979.
20. Blackman. M. R.. Weintraub. B. D.• Kourides. I.
 A .. Solano. J, T .. Santner. T .. and Rosen. S, W,
Discorda"1 Ele' a,ion$ of Ihe Common ,,-Subun il
of 'he Glyeoprolein H<>rmone, Compared '0 p_
Subunits in S.rum of Uremic Pati.nl$. J.
t:ndrx,iIWI. Me/ab. 53: 39- 48 . 198 1.
20A. Blo nd.au, J .-P.. Baulieu. E.-E. and Robel. P. An·
droge",,[)(,pend.nl Regulotion of Androg.n Nu·
cI.ar Roceptor in 'ho Rat Venlral Prosta'o . En-
drx,il\()l. II(); 1926_32. 1982
21. Bloom. W .• and FU'cell. D. W . A TUlbook of
I/j"%g)', 1Oth ed. Saund .... Philadelphia. 19n.
22. Blu.. 'ein. B. L.. and Vai,.hi'i•. J . L Affinity
Chromatography Purification of Soiubi li""d FSH
T."icular Membrane Recep'or. Bio/, Reprod, 14:
661 - 9.1981.
23. Body. J. J .. Muquard t. C .. and Bor"",·. ki . A,
Human Chorionic Gonado'ropin·Like Subsunce
in ' he Pla,ma of Normal Nonpregnant Subjects i.
No' M<.>du lau;d by 'he Gonadolropi .. ReI.a.ing
Hormone , J. Clin. Endrx,;nol. H: 1249-
1981.
24. IIogd.oo ••• E. M.. Campbell. G. T.. and Peck-
ham. W. D. FSH Pl oom<>rphi.m in 'he Ra,_
Regulalion by Gonadal Steroid •. /;.'nd()l;'. R,d,.
Corum, /: 87_9'9. 1974.
25 . Bogdaoove. E .. Nolin. J. M .• and C.mpbell. G, T.
Qualitat ive and Quantitative Gonad·Pituitary
Feedback. R«, Pro8, /form. Rsth. 31: 567-619.
1975.
26, Cava_. L. F, The Mam malian Accc!.SQ'y Sex
G I.nd" A Morpholog ical and Fun c,ional An.ly-
, i•. Ch.p. n. pp .• 02- ,0 of G reep and Ko>blin,ky.
.d$.. refere"". 66.
27. Ch an , V.. CI,yton. R. N.. Kno" G ... nd Call . K.
J. Ontogeny of Piluitary GoRH Rec. ptors in the
R.I. Eltdoc, ;no/. 108: 2086-92, 1981.
28. Cha ng. M. c.. Au"in. C. R.. Ikdford . }, M ..
Brad:.u. B. G .. Hunt ... R. Ii. F.. and Yanagi·
machi R. Capacitation of Sperma,o",. and Fer_
, ili'.alion in M.mmah. Chap, )6. pp. 434-5 1 of
Groep and Kobl insky. cd ... refer.nce 66.
29, Charr.au . E, H.• A'tramadal. A .. Torn...,n. P.
A.. Colandra, R .. PuT' i•• K .. "nd Han,wn. V. An_
drogen S,imul.tion of ProlaCti n Rc«p'ors in Rat
Prostate. Mo/, « Cell. t:ndor,ino/. 7: 1_7.
19n.
29k Chin. W. W " Godine. J. E .. Klein. D, R .. Chang.
A , S .. Tan. L K.. and ll.bener. J. F, Nucleolidc
$cquence of ,h. cDNA Endcoding ,h. P,o<ursor
of the /l-Subu ni, of Rat LUlfopin. Pror, Natl.
Acad. Sci. USA 80.' 4649- 53. 1983.
30. Cla)"on. R. N .. a nd Cllt. K, J. GonadOl,opin.R.·
leasing Hormone Rccep,."..: Cbaracteri'.a, ion.
Physiologic.1 Regulation. and Rela,ion,hip to Re"
produeti'e Function. £ndor,in. R••. 1: 186_209.
198 1-
31. Cla)'ton. R, N .. Kati kineni. M .. Chan. V.. Dufau.
M .. and Can . K. J. Direc, Inhibi' ion of Testicular
Function by Gonadotropin·Releasi". Hormone:
Mediation I>y Specifie Gonadotropin-Relcasing
Hormon. Recep,ors in In'o .. ,it i.1 Cell,. P'Ol'.
Nal /, Acad. Sci. USA 77: 4459_63.1980.
32, Clemen,. J . A.. and Shaar. C. J. Control of P,o.
lo.. in $ccretion in Mammal,. Fed. PNX. 39:
2588-92. 1980.
33. Clermon'. Y. Spermatogenesis, Chap. 27. pp.
293- 301 of and Koblin.ky. cds.. reference
34. Colby. H. D. R.gulation of Hepalic Drug and
Steroid Metabolism by Andrege .. and E"rogcns,
Adv. Sn lIorm. R.,h 4: 27-71- 1980.
35. Conn. P. M.. Chafoule.s. J. G.. Roge ... D.. and
Mean•. A. R, GooadotrOpin Rel... ing Hormone
Stimulates Calmod ul in Redistribution in Rat Pi·
tuita ry. 192: 264_5.1981.
36. Conn. P. M .. Mar;.n. J .. McMillian. M .. Siorn.
J .• Rogo ... D.. Hamby. M .. Penna. A.. and Grant.
E. Gonadotropin-Rele .. ing Hormone Roceplors :
C haraetcri>a tion. Physiological Regulation. and
Relationship 10 Reproduclive Funclion •. £ndor'.
Rev. 2: 186- 21)9, 1980,
)7, Coope r. T. G .. and Orgcbin_Cri.,. M .-C . Effec, of
Aging on the Fertilizing Capacit)' of Testicular
from 'he Rabbit, Bioi, R.p,od. 16:
258-66.1977.
38. C"'Iuelin. A .. and Desjardins. C. Luteinizing 11o,·
mone ,nd Secretion in Young and
Old Ma le Mice. Aim". J. f'hyJiol. U3: E257_
E263. 1982.
39. Cutlcr. G. B.. Jf .. "nd Lorioux. D. L. Adrenarche
ond itS ReiatiOlllhip to Ihe On",t of Puberty. Fw.
Pro<. 39: 2384-90. 1980,
40. Dahlbe rg. E.. Snoc ho","ski. M.. and GUSlaf.",n.
J.-A. Regulation of the And rogen and Glue""or"
.i""id Recep'O<' in ['(a' ."d M""", Skele'al M u,"
d. CytosoL £ltdrx,ino/, lOll: 1431-40. 1981.
4 1. Daughaday. W, II . Anlerior Pituitary. Ch.p. 2.
pp. 21 - 76 of I ngbar. S. H ... d. Conrempm w y
dor';IWlogy, ,01. I. Plonum. No'" York. 1979.
42. DiZcrcga. G. S .. ond Sberin$. R. J. Endocrine
Con,rol of Adu lt Testicular Function. Chap. 6.
pp. 127_40 of Berger and DcK,es'.r. cds .. refcr_
.nee 17.
43. Donahoe. P. K .• Ito. Y .• Pri... J M .. and Hen_
dren. W. H. III. MUlte rian I"hibi,ing Substance
Activi,y in Bo.ine Fetal. N...·born and Prepuber_
tal TC$'C$. Bioi. Rep,ad, 16: 238-43. 1977.
44, Darrington. J . II .. and A rm.trong. D, T. Effects
of FS H on Gonadal Funelion$. P,Ot. lIorm .
fUch . 35: 301 - 33, and D iscussion 333-42. 1979.
45. Darrington. J. H .. Fri" .. L B .. and A,mst rong. D.
T. Conlrol of Te"icular Emoten $ccre,ioo. Bioi.
R.prod. 18: 1978,
46. Droui n. J ... nd Lo brie. F. Selocti.e Effect of A..
drogen. on LH .nd FSH Relea .. in Anterior Pi·
tuitary Cell. in Cultur •. Endoc,illOi. WI: 1528-34.
1976.
47. Dunn. J . F.. Nisula. D. C .. and R<.>dbafd. D.
T ransport of S,eroid 1·lormon ..: Binding of 21
Endogenous Steroid. to lIo,h Tes'O$lcronc_ Bind_
ing Globulin .nd Corticosteroid·Binding Globulin
in Human J. Clin. Endrx,if/OJ, M"ab. 53:
58-68.1981.
48, Dupont . A .. Ba,don. N .. Cusano L-. M¢rand. Y..
L.brie. F.. and V.udry. H. ,i·Endorphin and M.t·
en keph,li"S: Thei, Distribution. Modulation by
'"
Estrogen. and and Role in Nco'oe.-
d<)CrillO ConlrC>!. Ftd. Pmc. )9: 2544_SO. 1980.
49. Dym, M.. and C. vi«hi •• J. C. Fu",,!;"".1 Mar-
phol"3Y of the Te.lis. 8iol. 18: 1-\ 5,
t 978.
SO. Eik-N ... K. Biosynth .. is and Secretion of Te.tic-
ular Steroid•. Chap. 4, pr. 95-115 of Hamilton
and Greep. ed.,. ",ference 72.
51- Eli • ..., • . R. Analy.i, of Semen. Chap. 16. pp.
of Berger and D<: K,esler. ed •. . refer."""
".
52. Ewing, l. l.. a nd Zirkin. Lcydi& Cell Struoture
S2A.
and Steroidogenic Fu nction •. R«. Prog. Horm.
RscA. J9: 599-632, 1983.
E"'ina. L. L.. Davi •. J. C .. and Zirkin. B. R. Reg·
ulation of Te' ticul'r fu nction; A Spatial and
Temporal Vicw. Chap. 2. pr· 41_ 1 I S of G,O<'p. R.
0 .. cd. R'proJucl/vt Physiology Ill. University
Park Pr .... Baltimore. 1980.
S3. F.iman, C. W inlor, J. S. D .• and Roy<>. F. I. En-
doo:ril"lOlogy of ,hi: FOIal Testi l. Chap. 4. pp. 81-
105 of Berger and DeKrester. eds .. rderonce 17.
54. Farquhar. M. G .. Skutoll ky. E. H .• and Hopkin>.
C. R. S"uoture and Fu"",ion of the Anterior Pi-
tuitary and Pituitary Celli. In Vitro
Studi... pp. 83-135 of Ti.ier· Vidal. A.. and For·
quhar. M. G. edl. TM pjluilary. Ae.·
demic Pr=. New York. 1915.
55. Fawcett. D. W. Tho Male Rcprodueti.o System.
S. vv. 16S-277 ul R. 0 ..
M. A.. and Jaffe. F. S .• eds. and
I/uman MIT Pre$$, Cambridge. Mas>.
1976.
56. Fawcett. D. W. The Strueture of th. Sperm ot<)-
won. Chap. 31. pp. 353-78 of Greep.nd Koblin·
n.
. ky. eds .. reference 66.
Fawcett. D. W. The Ultrastmcture and Funct io",
of the Serloli Cell. Chap. 28. pp. 302- 20 of Greep
and Kobli .. ky. eds .• roferenee 66.
58. Ferland. L. . Maroh<lti. B.. Seguin. C.. Lefeb.re.
F. A.• Reeves. J . J..• nd Labrie. F. Dissociated
Chongos of Pitui'ary Luteinizing Hormone·R o·
le.si", Hormone ( LHRI I) Receptors and Re·
lpOnsi ...... to ,he NeuroltQrm()JIe Indueed by
17P·&tradiol and LlIRH in Vi", in th. Rat. En-
Jocrioo/. 109. 87-93. 1981.
59. Fran kel. A. I.. and R)·. n. E. L. Testieul.r Inner·
•• tion il NecC$$llry f,.. the ResjXln", of Plasm.
T est""uono Le.ol> to Acu'e StrO$$. Bio/. Hrprod.
24: 491 - 5.1981.
60. Frie"'n. H. G. ProlaCtin. Chap. 3. pp. 25-32 of
Greep and Koblin,ky. cds .• refere""e 66.
61. Fritz, I. 8. Silel of Action of Androgen< and Fol·
licle Slimulating HO!"mone on Colis of the Semi·
niferous Tubule. An /lorm. j : 249_81.
1918.
61A. J" IXLa Vega. D. J .. Albeit. J. D.. and
N.eh"heim. O. A. Ti$$ue DihydroltstO$tcrone
le..l.. nd Clinical Responses to Ho,"\On. l Ther·
a py in Palionll with Ad",nced Prostate Cancer.
J. Clin. End"",,-,,,,,. 58: 36-40. 1984.
THE MALE AEf'ROWCTtVE SVSTEM
62 . Giguere. V .. Lefebvre. F. A.. and Labrie. F. An·
drogcns Dccr<.", LlIRH Sites in Rat
Amcrior p,tu '1<"y Cel ls in Culture. t:ndoc'irooi.
108: 350-2. 198t.
63. Glue kman. P. D .• Grumb.ch. M. M .• and Kaplan.
S. L. The Humon Fetal HypOthalamus and Pitu·
itary Gland. Chap. II. pp. 196- 232 of T uichin·
sky. D .•• nd Ryan. K . J .• eds. Mnu ,rra/_Fl"Inl t:n·
docTillOiogy. Saunders. Philadelphi •. 1980.
64. Goldberg. V. J .. and Ramwell. P. W. The Roloof
Prostaglandins in Reproduction . Chap. 23 . pp.
219_35"," Gr<ep and Koblin,ky. eds .. refcronce
"
65. Goldm.n. B. D .• Matt. K. S .. RoyebOlldhury. P..
" nd S tet",". M . H. Proh,e'in Rde ... in Golden
Ham".rs: Photoperiod and Gonadal Influences.
Sia/. Hoprod. U. 287_92.1981.
66. Greep. R. 0 .. and Koblin,ky. M. A.. eds. Fron-
in Rop,<><iu(lil>fl and Corumi. MIT
Press. Cambridge. MasL 19H.
67. G uill.min. R. Peptides in lhe Brain : The New En·
docrinology of the Neuron . 101: 39-0-402.
1975.
68. Guillemin. R. , McC.nn. S . M .• C. H.•
and D.vidSOlt. J . M. Secrolion of Gonadotropins.
Chap. 9, pp. 90-102 of Greep and Kobli nsk)·.
cds .. refere""e 66.
69. Gu".f$$()n. J._I\.. Mode. A.• Norstedt. G .• HOk·
fcit. T .. Sonnenschein. c.. En<;r()1h. P.• and Skcll.
p. n,c IlYi><>'I ,alan>er- Pi,.it.ry.LiV<f A .i" A
New Hormonal S}'$'e m in Control 01 Hepatic
Stcroid .nd DI"g Metabolism. 8iocnml. AN.
1/","",. 7: 48-89. 1980.
10. Hamihon. D. W. The Epididymi,. Chap. 34. pp.
4 11-26 of Greep and Koblinsky. ods .. roforence
"
11. Hamihon. D. W. The Mammali.. Epididymil.
Chap. 5. pp. 268-337 of Balin. H.. and Glas.scr.
S .. eds .. H. produrlivt Bla/cgy. E..erpta Medic •.
Amnerdam.1972.
72. Hamilton. D. W.• and Greep. R. 0 .• eds. /land·
book of Physiology. ",c. 7. '-'01. 5. American Phy.·
iological$ociety. Washington. D.C..19H.
73. Haour. F.• Dray. F.. and Mather. J. P. In Vi.o
"nd I n Vitro Rel pOnse of Leyd ig Cells to Acute
Stimulation by HCG. Ann. N.Y. Arad. Sri . .18.1:
231_46.1 982.
74. Harr;son. R. A. P. The Melabolism of M.mm.·
li.n SptrmatOZO\l. Cha p. 32. pp. 37 9-401 of
Greep and Kobli nsky. eds .. roference 66.
15. Y.. Miyamoto. K., Ya,aki. C .. and
Igara,hi. M. Regulation of tho Second Surge
of Folliclwt;mulating Hor"""",: Effects of
Antiluteiniling Hormon<;-Rdeasin, Uormone
Se rum and "" ntobarbital. £Nlocr,.oo/. 109: 130- 5.
1981.
76. Herbert. D. C. Stimulation of Prolactin Secretion
by Te ..... lorone in Ju.onik Malo Rhesu' Mon·
keys. Bioi. 18: 448_5 3. 1978.
77. llinins. S. J .. and Parker. M. G. Androgenie
Re8ulat ion of Generalizcd and Respo ....
 in Accessory $e.ual TiS1u,S of the Rat.
A,t. H()I"m. 7: 287-309. 1980.
78. lI orrobin. D. F. Prol .clin os. R.sul.tor of F1uid
and Ekctrolyt. Metabolism in Mammals . Fd.
Pro<. 39: 2567-70.1980.
79. lI ,u.h. A, J. W . Di ... ct ElfeclS of Gon.dOl'Oflin
R.kasing Hormo/le on Test icula' Lcydig C.II
Functions, Ann, N.Y. Aro</, Sci. 18J: 249- 69.
1982,
80. Hsueh. A. J. W.. and E'khon. G, F, Em.pilui·
lary AClion of Gonad01ropin-Rele.silli ! IO/mo",,:
Direcl Inhibition of Ova,i,n Steroidogenesis, Sci·
204: 854-5. 1979.
81 . Huggins, C. Introduction. PI'· X I_X II of Vollmer.
E. P.. cl. Ott Bloloty of the PY()JIOU
and Ti:IJun N.tion.1 Cane<:r Inslilute.
12, WaShington. D.C .. 1963,
Huhtaniemi, l. T" Kalikin.ni. M" Chan. V... nd
Call, K. J. Gonadotropin-Induced Pos;t;.e Regu·
Ialion of Te.ticuIar lUlcini.ing Hormooe Recop-
I"", ElldorYIMi. lOll: 58_65. 1981,
83. l-Iu0$3, R. O. lIio<yntbc,is of I-Iuman Chorionk
Gonadotropin. Emforrjllt R,v. I: 268-94. 1980,
84. lno"", H.. SU'.uki, K" Wakabayashi. K... nd Ta·
maoki, MA . Biol08ic.1 ACti.itie. of 7".Hydrox·
yl.l.d C,.-Steroid, and Chanie, in Rat 1'."icu·
I.. 7,,·H}·d rox}'la:><: ACli.ity with Gonadal Smes,
Endor'/Mi. 01: 22-30. 1973.
85. [ngli •• J., .nd l aw","" J. S. Sex Diffcrence. in the
EIr.cls of Unilateral B,ain Damage"" 1"lelli·
gence. Srlena 111: 691_S. 1981,
Jen';.'. A ('>. r •.. C p .• nrl
S. Concenlralion of Se"en Element> in Ihe Inl,a'
lum inal Fluids of Ih. Rat Seminifcrou, Tubuie<,
Rele Testi< and Epididymh. !Jiol. Reprod. 11:
981-7.1980.
81. Jensen, E. v .. Call, K. J.. Gorski. J., and Wil·
liam"Ashman, II. G, Hormone·Reeeplor Int.r-
aClion in Ine Mechanism of Reproouctiv< I-Ior·
mone Action>. Chap. 25. pp. 245-63 of Grecp and
Koblin,ky, .d...... f.... "". 66.
88. Kellokumpu, S .. and Rajaniomi. H. Effeclof Zinc
on Ihe Uplake of Chorionic Gon.dolropin (lKG)
in Ral Te"i. and Testost.rone Re.pon:><: in Vi.o,
Blo/ R.prod, U : 298-305. 1981.
89. K.lly. P. A .. S/:guin, C" Cusan. l., and llbr ie.
F. Stimulalory Elrecl of lUleini,ing Hormon<
and Human Chorionic Gonadolropin on Testicu,
lar Prolaclin Receplor levels, Bioi,
924_8. 1980.
90. Kendall, J .. and Orwoll, E. Anterio, Piluilary
HO'mo/les in 'he Br.in and Other Ex".pituilary
Sile •. Front. 6: 33_6$, 1980,
91. Koutmann. H. T .. Da,....,n, 8., Bi.h<>p, W. 1-1 ..
and Ryan, R. F. Strucru ... of Human l Uleini.ing
lIormooe Alph. Subunil. Endorr. lUck, Com-
mun, J: 51-70, 1978.
92. Koenig. II" Goldstone. A" Blume. G .. and Lu. C.
y, T.stOSI.ron.·Medialed Sc>.ual Dimorphism of
Mil<xhondri. and lyso>omes in Moo"" Kidney
Prolimal Tubules. 109: 1023_6. 1980.
93. Kohane, A, C., Eche.erria. F. M. C. G" Pi,.,iro.
l.. and Blaqui.r. J. A. Inl.raclion of Proteins of
Epididymal Oligin with Sperm.tozoa. Bioi.
prod. 23: 137-42.1980.
94. KOlil', N, J .. Nayfeh, S.. and Frcnch. F. S. FSH
and Androgen Regulation of Sertoli C.II Funclion
in Ihe ImmalU ... R.I. BIoi. 18.- 6S-73.
19i5.
95. Kouride' , I. A .. Holfman, B. J .. and landon. M.
8. Difference in GI),cooyl.tion Iktween Secreted
and PiluitalY F.-.:e ...subunit of Ihe GI)'coprotcin
Hormones. 1. Clln, EmforrlMI. Mnab. 51: 1372_
7,1980.
96 . Kurt'.. D. T .. and Feigelson. p, Multihormonal
Control of Ihe Messenger RNA lor the Hepatic
Prot.in ""Globulin . BI«hem, Act. I/()I"m, f: 433_
55. [978.
97. lagocc. L., labric. F.. Antakly. T" and Pellelier,
G. SenSitivity of Ral Adenohypoph)',ial Cell' 10
furr.diol and lHRH During Long.Term Cui·
tu'e. Am. J, Phy<ioJ. 240: E602-E608, 1981.
98. lccomle, 1'.. Wang. N.-G .. Sundaram. K.. Rivicr.
J .. V.le. w .. and Bardin, C. W, The Anliandro-
genic Action of Gonadotropin·Rel.asing [[or-
morn: and 11' AS""i'I' on Ihe Mouse Kidney. En-
dor,IMi. 110. 1_6.1982.
99. Lepult, Y" BI.au. G" Chapelclain<, A" and
Robe't •. K. D, Steroid Sulf""$(: Acti.ity of the
Reproduclive TraCI Du,inithe EstrOll'
Cycle. Bioi. Reprod. 21: 720-5. 1980.
100. lei1\On<n, 1'., Hammond. G. l" and Vihko. R.
Te'toslerone and Some of ii' Precursors and Me·
loboliles in Ihe Hum.n Epididymi, J. Clln. En-
S d"",;,.,; 51'423_8. 1980
101. Liao, S. Moleeular AClion, of Androgcns.
Bi()(htm, An I/or-m. 4: 351-406,1977,
102. L;chl, P.. Papkoff,II .. Farmer. S" Muller,C. II ..
T.ui, H. W .. and C.-.:WS, D. Evolution of Gona·
d01ropin Structu ... and Function. R«, Prog.
"",m, R'Ch. JJ: 169-243 .• nd Di:><:u"ion 243_8.
19n
103. Liebe" M. M.. and V.n.,i.le. C. M. Cell and
Orgon Cultu ... of Male Ac"",,,,,ry Sex O,g.n.,
Ad •. Su I/()I"m. RS<"h. 4: 73-118. 1980.
104. Lieberman. S .. Gu'pide. E.. Lip:><:ll, M... nd Sal·
hanick, H. Sieroid Ho,mone Se<:rctions. Chap. 4,
pp. 33-9 of Gr«p and Koblin.ky. eds., reference
".
105. Lingoppa, V. R.. and Blobel. G. Early in
the Biosynlhe. ;. of Secretory and M.mbrane Pro-
11: I.i",: The Signal Hypothesis. Ret, p,O&.
R.ch.J6.-4S1_7S,1980.
106. Liu. T.-C " and J.ekson. G. l. Big lUleinizing
Hormone (BUI): PO$>ibl. Precursor of NOlive
LH (NlH) in Ame,ior Piluilary Glands of Ral.< ,
8101. U' 380-92,1981.
107. Liu. T.-C. , Wang, P. S .. and J ackson. G. L. Ef-
leelS 01 GnRH and Drull' thai Affecl cAMP I.e. ·
els on LH Synthesis and Release. II"",. J. Phys·
101. Uf: E14-E21. 1981.
108, Mann. T . Scmen: Me .. OOlism, Antigcnicity,
StOragc. and Arliflci.1 In""minalion. Chap. 35.
pp. 427-33 of G .... p and Koblin sky•• ds ..... fcr·
.nee 66.
109. Ma rtin. W. II .• Rogol. A. D.. K.i:><:r. D. I" and
."
ThQrner. M. O. Dopamin<'aic Mochani.m. and
Hormo .. (L H) II. Diffe,-
ential Effect< of Dopamine and Bromocriplin< ""
LH Rclea .. in Normal Women. j, Ciin. End"",;·
noI. 51:650-6. 198 1.
\ 10. McCann. S. M. Regul'li"" of $ccwi"" of FC>lli·
clNilimulaling Hormon<: and lut.iniling Hor-
mone. Chap, 40. pp_ 4$9_517 of Knobil. E .• arid
Sawyer. W. H.. cd •. Qf PhyJiololJ'.
SC<:_ 7. vQL 4. port 2. American Physiological So.-
ciely. Washington, D.C .. 1974.
III. McGill. H. c.. Jr .• An",lmo, V. C .. Buchanan. J.
M .. and Sheridan. P. 1. Tile Ilo.rt i•• Tartl.!
Orllan for Androgen. &i, ,,,, ]()7: 775-77.1980.
112. MicheL G .. and B,ulieu. E..I'. Androgen Rcccp"
lor in Rat Skeletal Mu",k Char"wori .... ,;on and
Physio"",i •• 1 Variati"" •. i::ndIX.;IIIJi, 107: 2088-
98.1980.
In. Miyalake, A .. Mo<;moIO, Y.. Oi,hi. T.. H.".. " ki.
N., Su,ila. Y.. lijima. S .. Te.hima. Y.. lii.hi-
kawa. Y.. arid Yamamura. T. Circadi • • Rhythm
of Serum Te,'o,aerone and ils Re l.,i"" 10 Sleep:
wilh Vari",ion in Serum Luteini,ini
IIormone. Prolaclin and Coni$(>! in Normal
Men . J. C/in. Mnab. 'I .. lJ6S_71.
1980.
114. Mode. A.. Nor>ledl. G.. Simie, B.. Enerolh . P..
and Gu'lafsson. J .. A. C<H\lin""u, Infusion of
Growth Hormone Femini,e, HcpalicSleroid Mo-
"ooli,m in tho R.t. 108.. 2103 - 8.
1981.
114A. Mode. A.. No .. ledl. G.. Enerolh. P. arid Gustar.·
""n. J .-A. Purificalion nf Liv¢r Fomini,in, Factor
From Rat Pituitario, and Demonm:uion of h .
Id entily wit h Growth H,..monc. Endl"iCrin<>i. II J:
1250_60. 1983.
liS. Mond,chein. J. S .. and Schomberg. D. W.
Growth Focto.. Modulate Gonadotropin Re""p..
tOr Induction in Granu lO$O. Con Cultur",. Sci.""
211: 1119-80. 1981.
116. Monro<:, S. E .. Levinc. L.. Chani. R. J .. Kcyc. W.
R .. J r.. Yamamoto, M .. and Jaffe. R. B. Prolac·
tin·Secrelin, Pituitary Adeoom ... V. Increaoed
GonadOlrOph R«pon<ivity in
Women with Pituitary Adeooma •. J. C/ln. f.:ndo--
51.- 1171_&. 1981.
111. Moriarty. G. C .. and G.",or. L. I. Immu""",ylo-
chemical Studies of Cells in the Rat Adcoohy-
pophy.i, Containing 80th ACTH and FSH. ,vQ.
165: 356-8.1911.
11 8. Mowszo",ie>. I.. Riahi. M.. Wright. f .. Bouchard.
P., KU llenn. F .• and Mauvaiworvi •. P. Androgen
Receptor in Human Skin CYlosol. J . Clin. End(}-
criool. M<lab. 5]: 338-44. 1981.
119. Moyle. W. R. Biochomistry o f Gonadotrophin
Receptor, . Oxford R ... 80"01. ; .. 123-21)4.
1980
120. Mukku. V. R., Murty. G. S. R. C., Srin'lh . B. R..
Ram •• harma, K.. Kotagi. S. G .. and MlHJgdal. N.
Regulation of Testosterone Rh)'lhmicity by Go-
THt: MALt: REPI100UCTIVE SYSTEM
nadotropin. in Bonnet Monkey$ (Mae"a ra·
dim). 8;0/. 24,' 814-19. 198 1.
121. Nakano. P. K. Identification of Anterior Pituitar)'
C.lls by Immu noclcelron Mic=«>py . pp. 45-61
of Tixier-Vidal. A .. and Farquhar, M . G .. eds.
PitUitary. Aoademic Pres<. New
York,1915.
122. Nea"os. W. B. Leydig Chap. 29. pp. 321-
31 of G=p "nd Koblin'ky. ed ... reference 66.
123. Negro-Villar. A., Ojeda. S. R., and MeCann. S.
M. Hy pothalamic Control of LH RH and Som.·
tostalin : Role of Con"al Neurotran,mille .. and
Inlracellular Messe",e ... AN. I/orm. J:
246-85.1980
124. Nicoll. C. S. Prolactin. Inlroduction to S)"n\p<>-
.ium. Ftd. PrIX. 39: 2561_62. 19S0.
125. No,u, K.. Del>cjia. A.. ZawiStpwich. L,C'll. K.
J., and Dufau, M. L Gooadotropin-Induced De·
sensiliUli"" of Leydis Cells I. Vi.oarld In Vilro:
Es"ogen Action in tho Te' lis. Ann. N. Y. Arod.
Sd. 383.- 212_29. 19S2.
126. Odoll, W. D.. and Moyer. D. L.
production. Mosby, St . lGuis. 1971.
121. Ojeda. S. R.. Andro"" s, W. W.. Advis. J . P.. and
White, S. S. Rcc<:m Ad.a""" in the Endocrinol·
ogy of Puberty. f:ndorri", /I.". I .. 228- 51. 1980.
128. Ol""n. G. £., and Orgebi •. Crist. M.·C. Sporn'
Surface Ch.nges During Epididymal Maturalion.
Ann. N. Y. Acad. &i. 383: 372- 390.1982 .
M. _C. n.elnfiuenccofTe,,;¢ol ••
Funclion on Related Reproductive Organ,. Chap.
I I, pp. 239_53 of Berger.nd DeKre"er. ed ... rof·
eren"" 17.
130. Orth. J .. and Chri.lensen. A. K. Aut"",dio-
graphic Locali7.ation of SpeCifically f!ot,nd "'I·
L.belod F<>Ilicle·SI;mu lat;ng Hormone on Sper-
m.totnia of the Rat TeOli •. f.·nd<x''-..m. /OJ:
1944_51. 1978-
131. Papkolf, II ., R)·.n. R. J ... nd Ward. D. N. The
GQn,dotropin Hormon«. UI (ICSII) .nd FS H.
Chap. 1. pp. 1-10 Of Greep and Koblin'ky, cd<.,
r.ference 66.
132. P,rdridgc. W. M. TranSpOrt of Pr01ein·f!ot,nd
Hormone, into Tissue. in Vivo. HndlXr;nt Hr>'. 1:
103-23.1981.
I n. Parker. L. 1'1.. and Odell. W. D. Con"<>1 of Adre-
n, l Androgen Secretion. t:ndlXrllll' Rtv. /: 392_
410.1980.
134. Parker. L. N., and Odell, W. D. E.iden"" f,..the
hi"en"" of Cortical Androgcn.$timuI3t; ng Hor·
mone. Am. r. J. Physlnf. 236: £6 16-E62O. 1979.
135. Payno. A. It.. O'Shaugh"""y, P. J .. Cha se. D. J ..
Oi,on. G. E.. ,od ChriSlensen, A- K. LH Retor-
lors and Sle",;dogene.i. in Dist incl Populalions
of leydig Cdl •. Ann. N. Y. Acad. Sd. 38J.- 114_
200.1982.
136. Peek. J . C., and Wat kins. W. B. Var;.ble Son.; ·
ti"ity of Prepube rtal M. lc R.ts to Inhibin·li ko
AClivity of Bull Seminal Plasma .nd to Tem.. ter-
one Propionate. Bioi. Rtprod. U : 198t.
131. Pellelier. G. Locali,,.>lion
of LHRH in Brain al Both Li,hl and EI«I1"011
Mlcrosoope Levds. Adv. lfwm. Ruh. 4: 181_
211. 1980.
138. Pelea. L. L.. Hoefer, M. T .. and Hen.Jonalhan.
N. The Posledor Piluil.ry: Resulation of Anle-
rior Piluilar)' Prolaclin Sc<;"'lion. 21J:
'"
139. Pier<:<:. J. G. and Pa"""s. T. F. GlycoprOlein Hor·
mones: Struelure and Funclion. R,".
Biodtm. 50: 465-95. 1981.
140. Pils"·orlh. L. M .• and Selehell. B. P. Spern,"lo-
genic and Endocrine funelions of tho Tesle, of
Invertebrale and Verlebrate An;mal •. Chap. 2.
pp. 9_38 of Herger "nd DeK .... ler. ed •.• ",ference
n.
141. Pomeront'. D. K. Elfecl. of I n Vivo GonadolTorin
Trealmenlon ESlrogen l¢vcl< in ,he Teslis of the
Immalu", Ral. 8iol. IItprod. 21: 1247-55.
1979.
142. Pontiroli. A. E.. Dc C.mo e Sil ••. E.• Mallolcni.
F.• Alhe",no. M .• Baio. G .. Pellicdotla. G .. De
Pasqua. A.• Siella. L., Girardi.A. M .•• nd Pozza.
G. The Elfect of Hi.umin. and H, and H, Re·
CeptorS on Prolactin and L"teinizi"3 Hormone
Relcase in Human$: St. Dilferences and the Role
of Stre". J. Clin. End<winol. j}: 924_8.
1981.
143. Porter. J. c.. Gudcl.ky. G. A.. Nan«!. O. D.. Pi l·
one. ". S .. and Foreman. M, M, Retrograde
Blood Flow in the Hypoph)"ial Vaseulal"'" and
i1< P.,.,ibk Rel"ion.hir '0 HYP',h,"m;c
tion of Dopamine. Ad". Stx /lorm . (: 213_
40. 1980.
)44, Prasad. M, R. N,. and R.j.l.k,hm;. M. Rccent
Ad .. nee' in the Control of M.lo Rcproducti"c
Function., Chap. S. pp. 153-99 of Greer. R_ 0_.
cd_ Ph}".i"/"lJ' II. Unive .. ity Park
P",,,. Baltimore. 1917_
14S. P.... iocx. J. P. Steroido,e ..,;<;n the Mom","I;a"
Te.ti._ f:ndaui"" R.v. I.- I J2-9. 1980,
146. Prin •. G_ So .• nd Zanevdd. L J, D. Contraction.
of lhe R.bbit Va, Deferen, Following &,ual Ac-
tivi'y: A Mechanism for Proximal Tr.n.port of
Sperm. 107m. Bioi. Reprod. 2J: 904 - 9. 1980.
147. Quigle)". M. E.• Ropert. J. F.•• nd Yen. S, S. C
Acule Prolact in Reins< Triggered by Feeding. J,
J:.ndlX,ilWl. $2: 1043 -4S. 1981.
148. Rajfer. J .• Nam kung. P. c.. and I'<tra. p, H, 0 ...
lO,eny of the Cylopla.mic Androgen Reoeptor in
the Rat Vent,.1 Pm'late Gland. 8io/, 21.-
518-21. 1980_
149, Ramale)". J, A. De"clopment of Gonadal Regu-
lation in the Prepubertal M.mmal. 8io/. Reprod.
10: 1-31. 1979.
I SO, Reid. R, L.. Hoff. J. D.• V'n, S. S .. and I.i. C. II.
Elfccl' of bog.nou, il.·Endorphin on Pituitary
Hormone See""ion and Its Disappearance Rate
in Norm.1 Human Subject<, J. Clin. End()aifJOi_
MeIOb, $l: 1179_84. 1981.
I S I. Roid. R.I... Ling. N .. and Yen. S. S, C. rr-Mel.n·
Stimuhting Horrnon< Ind"cc' Gonad"'ro-
pin R.lease.}, Uin. Endocrino/, $2: 159-
161. 1981.
IS2. R.iter. R, J. The Pin.al and it. in the
Control of Reproduclion in Mam mals.
/I.",. I: 109-31. 1980.
I H. Renn.I,. E, G .• and Herhell. D, C. Function.1
of Anterior Cylology, Chap_
I. pp. 1-40 of G",ep. R, 0,. cd.
Physiofogy III. Univc"ity Park Pro". Bal tirnor<.
1980.
154. Rhod in. J. A, G, Hi"'JI0I!)' _ Oxford University
Pre". New Vork. 1974.
ISS . Rich. B. H,. Rosenfield. R. L.. A, W.•
Helke. J_ C. and Ouo. P_ Adrenarch.: Changing
Adrenal Response to Ad",nocortic""opin, j,
Clin. End/X,;nol. M"ab. 51: 1129-36. 1981.
156, Rillom •. J. A. Mechani'm of Profactin Action,
hd. PrIX. J9: 2593- 8.
157. Risbrid,er, G. Po. Ilodgs.)n. V. M_ •• nd Dc·
Kre.ler. D, M. Mechani,m of I\cI;on of Gonado-
trophin on the Testi._ Chap. 9, pp_ 195_211 of
and DeKre.ter. eds .. refcrence 11,
158. Rit,en. E. M.. Han's.)n. V,. and French. F.S, The
Senoli Cdl. Chap_ S. pp. 171_94 of Ikrger and
DcK",mr. od',. reference 17.
159, Rivier. C .• Rivier. J,. and Vale. W, AntireprC).
ducti"e Elf.." of a Potcnt Gonadotropin·Relea.·
ing Hormone Antagonist in the Male Rat.
110:93-5.1980.
160. Roy. A. K. Hormonal Resulalion of "" Globulin
in Rat Live" Bi«hem, Au. lIor",. 482_517.
I q"lq
161. Sair.m. M, R.. and Papl:olf. H. Chemistr), of Pi-
tuitary Gqnad01rOphins_ Chap. 26. pp. 111_31 of
Koobil. E. and Sawyer. W. II. ed, .. lIa"dbook of
pn}"siology. sec. 7. vol, IV. Part 2. I\ meric"n
S(>Cicly. W.. hinglon. D_C .. 197 4.
162. Sarda. A, K.. and Nair. M, G. Elev.led Le"el.of
LRH in Human Milk, J, ("lin. t:mJlXrirroi. Mmrb.
51:%26-8. 1981.
16), SOlO. B.. Yamamu .... Y,. Huseby. R. A.. and
Matsumoto. K_ E$lrogen Rcceptor S)'<tcm' in
Normal and N"""la.tic Leydig Cell. of lhe
Mouse. Ad•. Sa Horrn. 4: 241_71. 1980.
164. SaVO}'·Moore. R. T ... nd Sthwart>. N. B. Differ·
ential Controf of FSH and LH Sec,etion, Chap.
4. pp. 203-48 of Groep. R_ 0 .. cd .
Ph}"sj%l!)' III. Uni"e .. ily Park Pre". Baltimore.
1980,
165_ Savoy·Moo",. R_T_. Sth ... N . B_. Dunc.n. J_
A.. and M.rshall. J. C. Pituitary Gonad""op;n·
RekUing HQrmonc Recepto" During the Rat
E.trous Cycle. Sd,,1U m: 942_4. 1980.
IU. Sch.II)'. A. V. A,pee" of i!ypolhalamic Regul.-
tion of Ihe Pituitary Gland_ 101: 18_28.
1918.
167_ V_. Rcddi"l!. T. W .• and Arimura . A.
Elfect of So. Sieroid. on Pitu;lary R..pon ••,. 10
Lil· and FSH.Relea,ing Hormone in Vitro. t:,...
d()C,ini)/_ 93: 893_902. 1913-
168. Sohmidt. W. N, .• nd D.nm. B_ Androgen and
Progesterone Bindins Component' in Cytosol
'"
Prepared from Cull.,., Enriched in Serlol; Cell'
from lmmOlur<O Rat T<;SIO •. Bioi. R<prod. lJ-
495- 51>6,1980.
169. R. M. Fr ••• r. H. M.• and Cooper. I. The
Scc"'I;on, Mc .. uremonl. and Funct ion of a Tes·
ticular LHRH-Uko Fact",., N. r. Arod. Sri.
383: 272_n. 1982.
170. Sh.rr. C. J .• and Clemon •. J. 11.. The EffoClS of
Opi",c Agonist. on Grow,h Hormone.OO 1''''lac_
lin Reka .. in Rat$_ PrOt:. 39: 2539-43 . 1980.
11l. Sheridan, R .. Loras. B., Surardl. L. EC10rs. F..
and P...«II. J . L l\.utQoomou. Scc •• tion of Fol·
lic1o-StimuJa!ing Hormone by Long Term Org.n
CuJtu.esofRai Pituitarie., Hndocrl>VJ/. /().t: 198-
204.1919.
112. Siego" R. /I. .. Weidcnfdd. J.. Feldman. S .. Con-
fOrli. N.• and Chow",'. J. Neural Pathw.ys Me_
di3!ing D.",] a nd SI"'""! "duC<:<! $ccretion of lu·
Icini,ing Hormone. Folticle-Stim"iating Hor·
mone. TCSIO<ltrone in til<: R.t. Emioc,j"",.
1(JIJ:B02-7.1981.
lB. Sil,tfm.n. A. J .. Krey. L. C .• and Zimmerman.
E. A. A Comparali,. Study of the Luteini,jng
Hnrmone Releasing Hormone (LH RB) Neuronal
Nctwnrh in Mammal •. Bioi. 20: 98_1 10.
1979.
114. Sk lar. C. A .• Kaplan. S. L.. and Grumb.1ch. M.
M. Evid.r><:e for Di$$OCi.tion Between Adren·
arche and Gonadarehe: Studie. in Patient. ,..ilh
Id,_,n,. Pui>c"y. Dy.!<.
nesis.l><>laled Gonadotropin Defici.ney.ond Con·
slitu lion.li)" Delayed Growlh and Adolescence. J .
Clin.EIt(/()Cf"inol. 51: 548-56.1980.
175. Smith. M. S. Rol. of Prolactin in Mamm alian
Reproduction. Ch.p. 5. pp. 249_76 of Greep R.
0 .. ed. III. University Park Pr ....
IJaltim",e.1980.
176. Smit". M. S. Role of Prolactin in Regulating G<>-
nado1ropin Secretion and Gonad Function in Fe-
male Rats. Fd. P,oc. 39: 2571_76. 1980.
177. Snyder. P. J .• Job"",n. J .. and MU'.yk• . R. Ab-
normal &crolion of GI)"coprotein ,,-Subuni, and
follicle-Stimulating Hormone (FSH) i$.subunit
in Men wilh Pituitary Ad.noma. and FSH Hy-
persecretion. J . Clin. Emiou"""'. Mnah. Ji: 579_
84.1980.
I17A. Spel,berg. T. c.. Lilliefieid. 8. A.• Seel'" R..
Doni. G. M .. Toyod •. Il .. Boyd.Uinen. P.,
Thrall. C. and K("r.. 0. L Rol. of Specific Chr<>-
mosom.1 Pr ·,.ins and DNA Sequen<:eo in Ihe
N"cle., Binding Site< fOJ" Ste.oid Receptors. R«.
P'<>6, H()f"m. 39: 463-513. 1983.
178. Steinbe'ger. E.. S,..erdlolf. R. S .• and Horton . R.
The Control of T. $ticular Function •. Chap. 26,
pp. 264-92 of Greep and Koblin.k)". ed •.. refer·
cnce 66.
119. Stc inbe,ger. E .• and Stcinbe'i\er, A. Spermalo-
genic Function of 'he Te"is, Chap. 1. pp. 1_19 in
Hamihon. D. W., and GT<ep, R. 0 .• ed •. Hami·
THE MillE FlEPROOUCTIYE SYSTEM
book of Phy,/o/Of)'. "'c, 7. vol. S. Amorican Phys-
iological Societ)". W""h ington. D.C.. 1915.
180. Styne. D, M" Kaplan. S. L. and G.umbach. M.
M. Pla.ma GI)'coprote;n Hormone ,,-Subunit in
the Neonate nnd in Prepubertal and Pubertal
Children: EIf.cts of Lut.ini,ing Ho'monc·Re·
lea,ing Hormone, J. C/;n. Emioc,;MI, Melab, 5Q:
450-5. 1980.
181. S"'erdlolf, R. S .. and IIcber. D. Endocrine Con·
trol of Testicula. Function frOOl Birth 10 Pubert)'.
Chap. 5, pp. 107-26 of Bergc. and l)e K.eSl...
cd,.. ,efere n<:<: 17 .
182, S"'80. C. M. Pa.allel, in th. Modc. of Action of
Pcplidc and Sieroid Hotmonoo: Membrane Ef·
f<OlI and Cellular Entry. Chap. 19. pp. 431 - 12 of
McKern,. K. W.. ed, SIr«Clur, ami Func,i{)n of
'h' G(m(jdOlroplllS. Plenum. New York . I97K
183. Tapa ...;nen. J .• K"',iSlO. M .• Vihko. R.• and
Iluhuniemi. I. Enh'nccd Acti,i!)" of the Pitu·
ita,y.Gonadal A.i. in Prematu,e Human Infants.
J. Clin. Endocri""'. Mmh. 51: 2)5_8. 1981,
184, Tilbe. K. S..• nd Wiebe. J. p, $erloli Cdl Capac--
it)" to MOlaboli,e Progesterone: V.riati"" wilh
Age and lhe Elfect of Foilicle-$timul.ling Ilot·
mono , Emiocr;tIoi. 108: 597-604.1981.
18S. Tindall, D. L .nd Me,n,. A, R, Propertie, and
Ilormonal Resulalion 01" Androgen Binding Pro-
tein,. A"". Sn I/orm. Rjch. f : 295_327.1980.
186. Th;er·Vidal. fl., and Farquhar. M. G.• ed<. Th,
A"urior P;,,,iI.:.ry. Ae. demk P", ... New Y"'k.
1975.
187, ne.guerre •. j , A. F.. Eoquir.no. 1\. L. Mendel. L
F. P., and Ihpcz.colderon. A. Possible Role of
Prolactin in the Inhibitory Elfect of Estr.diol on
the Hypothalamic.Pituitary.Teslicular A.i, in
the Ral, End()Cf"inoi. I(JIJ; 83_7.1981.
188. VoUadar... L. E.,and Pa)" ... A. H. Induction of
Ttilicul.. Aromalitation by Luteinizing II",·
mono in Mature Rats, Emioc,jnol. IOJ: 431-6.
1979,
189. Vamv,kopoul05. N. c.. and Kouride<. I, A, Iden·
tification of Separate mRNA. Coding for lhe "
.nd IJ Subunits of Thy.otropin. PrO<". Nor/. A,od,
Sf;. USA 76: 3809-18.1979 ,
190. Van der Molen. H, J.• ond Rommem. F, F. G,
T.,,;cul .. St.roidogene$i •. Chap. 10. PP, 213-38
of Berger and DeK.",t.., .d.,. refere".. 17.
191. Van Tienhoven, A. R'p'odu.rjv, Physiology of
S.unde ... Ph iladelphi •. 1968.
192. Van Vual. D. A.. and Meilc, . J. Influence of En-
dogertO\l$ Opi .. e. on Ante,ior Pituit.r), Function.
Ftd. P,oc, 39: 2533-8. 1980.
193. Wanenberg, H. Dilfcrenliati"" ud Developmenl
of the T.. t... Chap. 3, pp. 39-80 of Be'g.' and
DeK,ester. ed •.. refe,ence 11.
I93A. Wenderoth. U. K.• Ge",ge. F. W,. and Wil",n J.
D. The Effect ofa Sa·Reduetase Inhibiwon An·
drogen.Mcdioted Growth of the Dog PrOf tale .
Emioc,itloi. 113: S69-7). 1983,
194. Wen"..;>m. J. C .. and Hamillun. D. W. Doli.1to1
Conc<:mration and Dios}'nthe,i, in Rat To'ti' and
•. Bio/. Rtprod. 21: 1054_9. 1980.
195. Whitley. R. L Kentmann. H. T.. and Ryan. R. J.
Isolation and Ch.racteriUltion of the Subunil' of
Porcine Foliiele-Slimul.ting Hormone.
R.d•. Commun, 8: 61-81. 1981.
196. Wiliiams>A.hman. H, G. Mctabol ie Effect. of
TC<l icul. r Androgen<. C hap. 24. PI'. 473-90 of
Hamilton and Gr..,p. cd •.. 12,
197. Wilson. C. A Hypothalamic Nc urotran.mitter<
and Gonadotropin Relea,e. Oxjrmf R.", of Re-
rrod. Bioi. I: 383- 473.1979.
A-I. Fiddc,. J. C. and Talmadge. K. StruCtUfe.
bp",,,iQn and E.<>Intion of the Gene. for tho
Il uman Glycoprotein Ilo,mooe" R«. Prog.
J(u<m, /l.srh . 1_39. 1984.
A·2. GI ...<. A. R .• Andcrwn. J .. Herbert. D.• arK! Vi·
gersky. R. A, Rdat ioo,hip Ik,w<cn Pubertal
Timing and Body $i,,,, in Underfed Ma le Rat'.
t'nd{}(-rinoi. 115: 19- 24. 19a4,
A·3. Gr"'-'man. C. J. Regubtinn of thc Immune S}',·
tem by So, Stero;d,. t'ndacr, R<" 5: 435_5S.
A4, Ha""ji. T .. Mack,"·a. M .. and Ki.himu ne. Y.
Vi,ami n A and Follicle,Sli mnlaoing Hormone
S}'nergi,tic"l ly Induce Difforentiation of Type A
Sp,-"",atognni. in Adull Moo .. CrJptorehid
TeSte. In VI,ro. t'Macrtlwl, 114: 1954.
,\·5, Jlnnc. 0, A. . and B"rdin . C. W. Androgen and
198. Wi,c. P. M.. R.nee. N .. B.rr. G. I) .. and Barr.-
clough. C A. Funher Evidence that Luteinilinll
Ilo,mone-Reloa,ing Il ormone aho i< Follicle·
Stimulating HormOrlC-Rckasing Hormonc.
d"",;',ol. 104: 940- 7. 1979.
199, Yen. S. S, C. N.f,olin. F.. Le in. A.. Krieger. D ..
and Utiger. R. Ilypothalamic Innocnoe. nn pitu·
itary Function in HUman, . Chap. 11.]>]>. 108_27
of Greep and Koblin.ky. cd, ... oferonce 66.
200, Ying . S ,·Y .. Ling. No> Bohlen. P.• and Guiliemin.
R. Gooadc>c,inin" Pept ide< in O.. ,i.n Follicular
Fluid Stimulating the Secretion of Pituitary Go-
nad<)\ropins, Elldac'iMI. 107: 1206_15. 1980.
An, iandraten Recepto, Binding. Ann. N.". "hp -
iol 46: 107_18. ln4 .
,\·6. Pintar. J. E-. S.;haehte,. B. S .. Herman. A, 0 ..
Durgerian. S .. and Krieger. D, T , Charaete,i'a.
,ion "nd L""ali13tion t>f Proopiomclanoconin
o\-k''lCngcr RNA in the Adnlt Ra' Tc"i"
n5:632-4.1984 .
A-7. Rance. N. E-. and Ma,. S. R. ).1<,>dul.'ion mlhe
Cyt"",lk Androgen Rec<p'O' in S,ri.tcd Muscle
by Sex S'ero;d<. f.·ndo(',;I10/. 115: 862_6.1984.
,\·8. Sh"rpe. K. M, Inttatesticu l.. F.e,,,,, Contr<>llinll
Te.' t ieular Fune'ion. Bioi, Rtp'od. JO: 29_49.
In4 .
A·9, Tepper. ,\I, A.. and Ruben.. J. L Evidence for
Only One p'.Lu'e ini,;ng II <>rmone and No Il.(;ho-
rionie Qonad<>tropin Gene in the RaL t:Macnllo/,
115:385_91.1984,
 15
The Female Reproductive System
Tht reproductive system of the female is. of oeces-
sity. more elaborate Ihan thaI of Ihe male. In addi·
tion 10 contributing its share of chr<)ll105Omes to Ihe
'-ygotc, Ihe egg cell must provide mOM of the sut>-
stance. th.1 sustain the conceptus during ia first rew
days of life. Acoordingly. oocytes have larger diam-
elers Ihan all other cells of the body.
Since malure germinal cells have limited life-
spans. arrangements must be made for rontaet with
Op"rmaIO>.<la a\ Ihe optimum lime. In moot mam-
mals. the brain and ovary cooperale 10 assure syn_
chronization of ovulation wilh behavioral manifes-
tations of sexual rc<:cplivity. Primates are nO!
protected in Ihis way. but ovarian lIormones act on
the glands of the uterine cervix to promote the se-
cre,ion of substances favorable to sperm survival and
transport during the periovulatory period . In all
mammal" the uteri a nd fallopian tubcs provide en-
vironments that support 'perm capacitation during
thc of tlte cycles. The
lUbes also assist in upward transport of spermatozoa
10 Ihe fertilization sile, carly development ('f Ihe zy-
gote, and delivery of Ihe blawJCyst 10 Ihe Ulerus.
An elaboralely prepared endometrium then in-
vites implantalion. It soon actS in conjunclion with
the myometrium to support, nourish. and protect
embryos and fetuses . If implantation docs not occur.
the endometrium sloughs off and later renews itself
for another try.
The numbers of implanlations that occur alone
lime must bc appropriate for Ihe reproductive strat-
egy of the species. In a large mammal with. long
gestation period, the uleruS cannot properly accom-
adate more than One or two fetuses. In a small onc
with a short life-span. perpetuation of the species de-
pends upon the production of large litters. (This is
especially true if predators conlribute to the control
of the population.)
."
When the fetus is prepared for independenl exis·
tcnce, the birth canal softens and the uterus assumes
active roles in delivery of the infant, disposal of the
placenta and avoidance of postpartum hemorrhage.
In anticipation of future functions, thc mammary
glands undergo speciali'lIlions during the
period . Theile include acquisition of the ability 10 re-
spond rapidly to suckling stimuli. ReflexC!i associ-
ated with lactation pro_ide for release of preformed
m;lk. sy nlhesis or Ihe componenls of the noxl menl,
and conlractions of the uterus Ihat hclp 10 restore it
to iI, proper size. When lactalion makes heavy de-
mands on the metabolic resources of Ihe mother,
mechanisms for transiently suppressing ovarian cy_
des Or delaying implantation avert premature C!itab-
lishment of a new pregnancy.
COMMON CHARACTERISTICS OF MALE AND
fEMALE SYSTEMS
Despite the obvious differences in form and function.
the male and female systems are st rik ingly similar in
man)' respects.
In very young embry()!j of both sexes, a genital
ridge that forms On each side of the body serves as
thc forerunner of the gonad. Germinal cells (goll<'>-
cytes) Ihat are diploid originate in the yolk sac . They
proliferate rapidly by mitosis. migrate to Ihe genital
ridge, and continue 10 divide. Thc cells then advance
10 the next .tage of development as Ihcy continue 10
proliferate. In lime, milosis is arrested. ( It is later
re,umed in the male. but nO! in the female.)
The genital ridge become.. organized into an "in-
different gonad" that contaiM epithelial mes-
enchymal components. In the carly slages, it is im_
possible to dis tinguish the presumplive ovary from
the prcsunlptive testi, on the basis of morphological
criteria (see Chapter 13).
 The epithelial cells make intimate associations
with (he germinal elements, and they affect (he sur·
vival and maturation of the gamc(e precursors. At
first, (hey provide protection against premature ini·
tiation of gametogenesis. After the onset of puberty.
they play essential roles in the support of spermato-
genesis and oogenesis. Among other (hings. they cre-
ate an environment suitable for the progress of
meiosis and dilTerentiation. They arc also directly in·
volved in the processes of ovulation (in which cells
that will become ova are extruded from the gonad
and sent into fluid-containing oviducts) and of spero
miation (in which immature spcrmatolOa l.a,,, the
testis to enter fluid filled ductules that lead into the
epididymis) ,
The epithelial cells take up and metabolize steTOid
hormones providoo by the neighboring interstitial
cells, They also produce peptides that, among other
things. contribute to the regulation of follilTOpin se-
cretion. There are developmental stages during
which the epi thelial cells first function ... ithout ben·
efit of pituitary hormones. then become highly re-
sponsive to follitTOpin. and eventually show loss of
to the regulator.
At about Ihe same time pootconception. the mes-
enchymal derivatives of developing ovaries and
test.s aequire the ability to make steroid hormones
from precursors supplied by the placenta and mater·
nal 'y".m , Although the very young oelb poMCM lu-
tropin receptors. they function independently of the
pituitary hormone for some lime. Later. they re-
spond 10 a placental hormone and becomccapable of
utilizing cholesterol as the precursor, Afterward,
they become dependent OIl lutropin.
The gonadal steroids arc synthesi7.ed along similar
pathways in both sexes. The hormones arC neooed to
support gametogenesis. the growth. development.
and funetions of the aeeessory reproductive organs.
and the emergence of Ihe sccondary sex character·
istics. They are major regulators of hypothalamic
and pituitary gland functions. and they exert impor_
tant inHuences over a wide variety of other structures
that include the bones. the liver. the kidney. the skin.
the thymus gland. and the
brain. The mature testis seeretes m05lly teS(05terone.
but it also releases SOme estr0sens and progestogens.
and additional eSlrogen is formed peripherally. The
mature ovary .secretes mostly estrogen. and proges-
togens. but it makes considerable amounts of andro-
gen and secretes SOme of it; additional androgen is
formed peripherally. Sa-reduced steroids and steroid
sulfate conjugates are made in both types of gonads.
and androgens s(imulate sexual interest in both
males and females. Many aspects of the control sys-
tems (both internal and external to the gonads) are
similar. Androgens. estrogens. a nd progestins
undergo metabolic transformations in target cells
and they interact with receplors present in ma le and
female organs.
Follitropin and lutropin are chemically sim ilar in
both sexes. and they are produced by til< same kinds
of pituitary gland cells. The secretion is regu lated by
the identical hypothalamic LRH. and the laller is.
in turn. afTe<:ted by the same kinds of ncufo-
t,"nsmitters.
Young male and femaleembry05 possess two pairs
of ducts thaI give rise (0 the acccssol)' reproductive
structures. Although gonadal steroids SlX'm to be es-
sential for early dc,'elopment only in the male. the
female organs arc equipped with the same kinds of
receptors and they have th. potential for "maseulin·
i'-'ltion." P05tpubenal matu ration requires gonadal
steroids in botb sexes.
The forerunners of the external genitalia arc at
first indistinguishable;n male compared ... ith female
embl)·os. All are equipped with the same ki nds of
rce<:ptors and steroid-metabolizing e""ymes. The
full potential for virilization is prescnt in the female.
whereas the male Can assume a female form if spe-
cial hormonal environments are not provided ,
In at least some spe<:ies. gonadal steroids ac( duro
ins a sUige of devclopmcntto "condition'"
the brain so tha( it is prepared for expression of $Orne
forms of reproductive behavior. The effects seem to
be quantitative rather than qualitative. and experi·
mental animal; of 0"" >ox can engage in a(;tivitie,
traditionally assigned to the other.
The emerge nce of sexual dimorphi sm is altributoo
to the ability of the Y chromosome to direc( (he for_
mation of organi'.ers. (The concept that
Ihe H·Y antigen serves ;n this capacity was dis-
cussed in detail in Chapter 13.) If the gonadal pre-
cursor is deprived of the influences of such molecules
in the male. the gonad aSSumeS an o,'ary-like af>"
pcarancc. The gonad of the XX cmbryopossesses re-
ceptOIS for the and has (he potential for
acquisition of testicular featurcs. The maturation of
the germinal elements into spermato1.oa or ova has
been linked with til< possession of XY or XX sex
chromosomes, respeeti.ely. Other male vs. female
differences may be directly related to lhe production
of relatively larger amounts of androgens by the
males,
STRUCTURE OF THE ADULT OVARY
The ovary of the human ad ult has been li kened in
sile and shape to a shelled almond, a good-sized
olive. Or the stone of a peach. Since the organ under·
goes cyeiical variations in form. and since individual
differences are encountered among normal women.
perhaps each of the descriptions is as appropriate as
Iheothers.
In II<althy women. each ovary measures 2.5-5 cm
 THE FE MALE I1EPAOOVCTIVE SVSTEtd

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in lengln. 1.5-3 em in widtn. and 0.6-1.5 in
thickness (21).
A dense but narrow capsule CQn·
taining collagenQUs fibers and fibroblast_like
(the albughlM) tne outer boundary. It
is enveloped by a fold of peritoneum (mesothelium)
CQnsisting of a single layer of squamous to low cu-
boidal epilhelial cells. the muomdum. The lalter
rests on a thin basal lamina (Fig. 15·1). The lerm
"germinal Cpilnclium" nas been applied to Inc mes·
ovarium. It i, unfortunate. since no germinal cells
are present in Ihis region.
Attachments
One sidc of the me<ovariai ,urface projccts frcely
into the peritoneal cavity. and cell, in thi, region arc
equipped with microvilli. Tne 0pp06ite of the
mesovarium joins up with tnc po6terior portion of Ihe
bro<Jd ligamml. a large fold of periloneum that an·
chors Ihe uteruS 10 the hody wan (!'ig. 15·2). A thin.
fibrous cord within that membrane (the ovarian lig-
amtm) hinds the medial pori ion of the ovary to the
fundus of the Ulerus.
The suspensory (infundibulopelvic) lIgament runs
laterally bet"'Cen the layers of the broad ligament
em to thc fallopian tube . It altaches Ihe hilu, of
the ovary 10 the peritoneal wall and il provides the
passagewa'l1' for the large blood vessels and nerves.
AI ils medial cnd. the ova rian ligament becomes
CQntinuQUs with the round ligament thai extends
from Ihe uleruS toward the inguinal canal.
The round and ovarian ligaments are the female
CQunlerpart of the gubernaculum of tbe ICSli, that
undergoes extensi''C elongation as the male gonad
descends into the scrot um. Since the ovary migrates
just a Shorl distance downward from its original site.
the membranes remain short in the female.
The Ovarian Cortex
The cortical region parencbymatosa) is larger
Ihan and is often poorly demarcaled from Ihe inner
medulla. It contains all of tbe gl'rminal cells (each
enclosed within its private follicle). the products of
follicular development and degeneration. and a
closely packed interstilial tissue or Jlroma composed
of myoid. epithelioid. and ftbroblast-like cells. CQlla-
ienous fibers. and intercellular subslance.
The whiclr vary ireatly in size. are de-
,
Fig. IS-I. A. Ca l "". 'y. Con.,.
oI«:t<O<I micrograph . ( t)
(2) """"un•. (3) f<>11icI.'. corpor. Jutea. X 1 1. B.
Enla,_t of 'ocI"nule in A . ( ') Pr;mo.dla l 1<)\1",,". (2)
second ..... I<)\IiCle. (3) Otromll. corPUS Meum. (5)
inl ... glaOd. X Ie. C. e ... rgemont 01 a,1O& simila, to
.-.cla ng" ;" B. 'ot. eloctfOl"l micrograph. ( 1) P.. i\O<lHt
scribed la ter. The smallest arc made up of a primar)'
oocyte surrounded by a sinile layer of epithelial
cells. Somewhat larger one< have ,,'all, of <tralifled
epi thelium. As maluralion portions of lhe
ovarian stroma become organized CQncentrically
around the periphery of the epithelium. Thc corpora
atresia of the ovarian CQrtex form when follides
undergo incomplele maluration and then deterio-
rate. At certain phasc. of the ovarian cyclc. one or
more large rorpor<J luua can be readily distin-
guished. Several may be prescnt in .pecies that reg·
ularly produce litters (Fig. IS· IA). whereas the
human ovary often has just one. Corpora albicanlia
are scar-like slructureS derived from CQrpora lutea.
The tunica alhuginea is actually a CQmpact. con·
linuous ring of siromal tissue. The term "intemitial
gland"" is sometimes applied \{l clumps or cords of
epithelioid cells of the stroma that are not obviously
associated with oocyte-GQntaining fol licl es.
The Ovarian Medulla
This region (the wna vasculosa) is almost spongy in
appearance. It carries thc larger blood and Iym-
vessels and ovarian nen·eS. and it conlain,
true smooth muscle cells. epithelioid and fibroblast·
like and elaslic fibers. ctumpll of epilhelioid
cells may be loosely organized into a hilar gland.
Nonfunetioning remnants of a ductu le system
(the rete ovarii) arc often present. The.. are the
homolog. of the retia testes of Ihe male (220).
BlOOd and Lymphatic Venels
The circulatory system is rich and complex. Blood
""ssels that supply other parts of the pelvis and
undergo eXlensive anastomoses enter Ibe ovary from
two directions. The OI'Qrian artery Qn each side
arises directly from the abdominal aorta. and it
sends 10 the fallopian tube. The main uter-
ine artery originates in the nypogastric (internal
iliac) artery. Somc of the Iributaries pass throuih
the hroad ligament 10 make functional conneclions
wilh branches of the ovarian artery, while olhers go
to tnc vagina and componentsof Ihe urinary system.
The term gemlaf vascular (168) describes the
interlwinings of the vessel. Ihat supply the
gonad, fallopian tube. Ulerus. and related structures.
Blood from both the ovarian a nd uterine arteries
passes Ihrough Ihc mesovarium in the region of the
co.ity. (2) gemtio/It &j>iU.elium. (3) l"'icI otbuginea ... ith
intorslitial (') piimotdial toIic ... . (5) ooeyr. oI
secondary lolliele (nI>or"". i. ""' in pi""" of .... liO<l). (6)
.0<'18. pellu<;:ido. (7) totlicuto, eolls. (S) basal tlmina. (9)
theca I<)\JiouIi (;"I.. nol. (10) theca foIic<Jll (extema ).
(11) c.apilla,IN. X 860. (Rhodin. ",I .."""" t69)
hilus in helical arltrie$ thaI
the stroma of the medulla and send branches
(spiral arteries) toward the cortex. Coiled arteriolar
extensions of Ihe spiral arteries provide a rich capil-
lary circulation 10 the cortical stroma. including Ihe
portions of it Ihat make up the theca follkuli. The
arterioles undergo when the corpora
IUlea form, and the vasculature b<:comes evcn mo,e
eXlcnsive if conception occurs. Uncoiling of the ves-
sels permits maintenance of an even blO<"Xl flow to the
most active components of the ovary. and it supportS
the increased needs of the follicles that are preparing
for ovulation.
The blO<"Xl drains into a venou s genital arcade. On
the right side of the body, the uterine components of
Ihe 'ystem unite to form the central conducting veins
Ihal emply into the hypogaSlric veins, while the
ovarian OneS lead into the vena Cava. On the left side,
the ovarian vein joins up with the left renal vein. The
venous ')'"ltem includes a network of thin·walled ves-
sels. Ihe pampiniform plel"'$. Mechanisms for CO''''-
lucurrenl exchange Ihe ovarian artery and
vein facilitate the accumulation of high concentra·
tions of steroid hormones within the ovary (50).
The cortex comains numerous lymphatic capillar·
ies that un ite to form the larger vessels of the me-
dulla . The laller send Ihe lymph to nodes in the pel·
vic and lumbar regions, and eventually to the aortic
In common with the blO<"Xl capillaries, the finer
Iymphtic vessels undergo continuous roorganization
to provide for the needs of growing follicles. oorpora
IUlea. and glandular edls of the stroma. and for the
orderly transport of ovarian hormones.
Innervation
Allhough Sludies with pharmacological agents pro-
vide evidence for a neural contribution to the regu.
lation of steroidogenesis (77). and cholinergic pro-
jections have been idenlified. it was believed until
quile =ntly that the ovarian and uterine
neflles supply mO!itly unmyelinated sympathelic fi·
b<:rs to the blood ''esse/s and 10 the OOI1lraclile com·
of the Stroma. It is now that the
ovary contains sensory endings, and that the neurons
play importam roles in the regulation of divcrse
functions that include the "compensatory·· hypertro-
phy of one gonad when the other is removed. They
contribute 10 the feedback control of piluitary and
hypothalamic functions. Stimulation of cerlain loci
wilhin the brain augments (whereas stimulation of
others suppresses) some processes. even in females
that have been hypophysectomi1.ed and adrenalcc-
tomi1.ed (98) . Certain of the ovary-uterus interrela-
lionships also seem to depend on the innefll3tion.
OVARIAN CYCLES: MORPHOLOGICAL
ASPECTS
For lhe purpOSes of discussion, il is convenient to di·
vide Ihe ovarian cycles into three pha'iCs:follicular,
ovulatory. and lureal. Each phase is associated wilh
changes in the appearance of the ovary and with a
distinct pallern of steroid hormone accumulation
within both the ovary and the blO<"Xl plasma.
[n humans. the activitics of a single follicle can
dominate the evenlS for a limited time period, while
some support is provided by "cohons" that mature
Simultaneously. 11 is important to reCOgnize, how-
ever, that Ihe organ does not function as a synchro-
nized uni\. The growth and of follicles
and their germinal components proceed continu-
ously. Cells in one part of the cortex are very differ-
ent in appearance from those in another (Fig. lS-
I A).
Preliminary Pre paration of the Ovary
The gonocytes that migrale into Ihe embryonic
gonad soon mature into oogonia thaI actively engage
in milO!iis (Sec Chapter 13). T he proliferation peaks
aroond the 20th week, al which time the oogonia are
present as C<lrds of cells crowded into the C<lrtex. Be·
fore the process is completed (starting around week
IS), many of the germinal cells malUre into primary
oocyres and b<:come inlimately associated with cpi·
thelial components of the stroma. Germinal cell
changes include lhe lo:ss of rioonucleoprotein, gly-
cogen, and alkaline phosphatase {84}. The oocytes
enter the prophru;e of meiosis. but the division SOOn
becomes arrested at Ihe '·dictyate" stage. Some cells
compiele meiosis 1 during the interval b<:twecn the
first onset of adult functions and Ihe time of meno-
pause. Most others deteriorate b<:forc Ihis i5
accomplished.
A maximal germinal cell population of 6-7 mil-
lion is anaincd in the two ovaries when the fetus is
around months of age . Meanwhile. mechanisms
for reduction of the eelt are set in motion.
Oogonial disappearance results mostly from
sion al the ovarian surface during the final monlhs
of the gestation period (203). bUI some oocytes and
Iheir surrounding cells deteriorate within the gonad.
The lo:ss of germinal cen.continues into middle age .
Neonatal ovaries have some 1-2 million oocytes.
The population declines to 300-400.000 by pUb<:rty
onsel. Fewer Ihan 500 of those ever reach the preo-
vulatory stage. [n some women, gonads are totally
depleted of germinal cells by the time or menopause.
In others, a few sUfllivon; persist for one or mOre ad-
ditional decades.
 THE FEMALE REPAOOUCTIVE SYSTEM
'"
!lasal lamOn'
.. ... /
. ", Cytopla .... Of oocyle

,
l
'.. .. ..
.-
8. UniI.<Y\irnIr pr"",,\, 1000icie

C Mullllan'rMr 1>''''"')' !'"''''''

Fig. 15-3. <>I folli<:le mII,,,,ot",,,.

Formation of the simplest follicles begins around
(he fourth month ahcr corn;eplion. Very limited
numbers of the structures undergo malurat;on dur-
ing fClal life and childbood, and th= seem 10 be
preferentially des\royed.
By pubcny. most of lhe oocyles are contained
within primordial follicles, and structures of this
kind can be detected at all times during the period
or reproductive competence.
Prim ord ial Follicle s
Each of these liny structures is oomposed of one pri-
mary oocyte surrounded by a single layer of ftat-
l"ned epithelial (pregranulosa) The enlire
structure rest.! on a thin. acellular basal lamina
(Figs. 15-3A and 15-4A). The germinal cell has a
large and prominent nucleolus. Many small
ribosomes, and some small rounded mitochondria

Fill. 15-4. ". f.1 ovary. """'1fOO 1000iC .... ,al o.ory. eleCI,<>n mi<:rcgroph. (') N""""", 01
•
( I) N...:leu& 01 g«m oell. (2) """IooIUI in prima'Y oocyto (Ine oueIec4uo 10 not in ' Ile plano 01
'81.,.,1.,I""". (3) ooplasm. (') mitocI>or>cIOa. (5) GoI9i _ lien). (2) (3) oopl ...... (')
complex. (6) oort;cal g",.ul... (7) sligh'ly rl,Jflled surf."" ""'ochOnd,i •. ( 5) 00<tic&1 g,ranulH. (6) ... rlo.,., 01 000)'' '.
01 ptin>O<di.1 {I«nt cell . (8) ......,..,; oIIOI"""'.f <*IS. (9) (7) _ of _ . llo/lieu!o,coUo. (8) ""..11.-.... (9)
_ eytoplaorrio _ ' n oilolOeulo' ombraQng tile f"IOOIo; 01 .t,omal 0011. (I!>wo i. no IIWICIII000000i f",mIId . .
g«m cell. (10) s lrom&l ceIll. (11) _ 01 capillary. yltt). (10) 00II0_ 01 o .. ria. '''orna. X '400. (Ahodin.
( 12) n"" ..... 0/ oncIc1l>e1i1l cell. X 5_00. B. Prirnlry ,otItftf>OO 169 )
'"
and lipid droplets <:an be identifiw in Ihe narrow
ring of cytoplasm. n." Golg; apparatus i$ a t first
small, but it .oon undergoes elaW,sl;';'rr.
Prior to folliCle formation. the 008011'. resuhing from
a milotic division rem.in coonccle<llo each olher vi.
topl .. mic bridg<,_ It i. pOSSible 10 find on 0<""';0"01 [<>I.
lid. lhal has end=d ,wo
connected germi .. 1<:<:11 •.
Ther. are e<,>ntroverSi •• <Xlllcerning lhe ilage at which
me;"'i. of the human """ylc bc<omcs o"esled (84). In
some species with short ""a';on period,.oogoni. can
pe"i$l.nd continue to divide .her the lime of birth.
Unllamlnar Primary Follicles
Limited numbers of primary follicles are formed in
Ihe felUS, and olhers appear during childhood . The
ovaries of young aduhs always conlain structures of
this kind.
The most obvious changes occur in lhe epithelial
oomponenu. The pregranulosa cells proliferate, and
they gradually become transformed inlO cuboidal
granulosa cells that form a C(lminuQU$ ring (Fig. 15-
38 and 15-48). ColiageTlQus fibers occupy much of
basal lamina.
The oocyte grows and there is an increase in the
cytoplasmie:nuclear ratio. The mitochondria clon-
,ate ",mewho t and Ihey more
The endoplasmic reticulum undergoes spttiali7.a-
lion, and microvilli soon project from the plasma
membrane,
Multilamlnar Primary Follicles
The granulosa cells continue to proliferate, and they
eventually form a multilayered 5lrQ/um granulosum
(Fig. 15-3C), Since the legion is avascular. the ger-
minal cell cannol communicate with the capillaries
of the conical stroma and it is therefore more de-
pendent upon the granulosa cells. Gradually, a clcar.
noncellular gel-like ZOna pel/ucida (mucoid ooloma)
forms between it and the surrounding cell •. As the
oocyte matures. il sends microvillar projections into
the layer, and these interdigitate with processes em-
anating from the granulosa cells. There are conlrl>-
versies concerning whether the protein-pol)'saeehar-
Fig . 15-5. A. ,at ""O'Y,
e,-"""" micrOlJ'Oph. ( 1) Nucleus. (2) oocy,o,
(3) l orn. pelf"";,, •. (4) """"'" 'adiato. (51 ,n'"''''
(e) eflil. 01 _ana g,anulo". many 01 whiCh
a,. in ItOge. of mitooil (ci'cles). (n bu." I.minll
rMftIb.-a",,). (8) theca. 1011iCuIi. (9) perifoflicular
(10) ova,ion st,oma. X B. PO" 01
""""""_f"1 ""oicuI.' '., ""o'y. eleci,,,,, ,,,icrograph.
THE FEM .... LE AEPAO!>UCTIVE SYSTE M
ide-molecules of this region are secreted by the
granulosa cells. the Golgi of the oocyte. or both
(21,220).
The stroma immediately surrounding the granu-
losa commences organization inlo a theca
that contain$ capillaries.
SoUd Secondary Follicles
With further maturation. thc 1.ona pellucida
ens and the cellular processes extending into ;t be-
come longer and more numerous. According to some
observcrs, direct cytoplasmic communications bo-
t,,'ccn the two cell types are established (220).
The oocyte continues 10 enlarge and to urnkrgo
cytoplasm ic speciali7.ation. The mitochondria elon-
gate and increase in number. They migrate toward
Ihe periphery of the ce ll. as small. rounded organ-
dIes aeeumulale ncar Ihe nucieus-
The theca acquires more cell. and begins to sep-
arate into a vascularized. glandular Ih«o ImertW
and a more peripherally located Ihtco eXlerlUJ com-
poscd mostly of connectivc tissue. The term gia...y
membrane describes the now wdl.deveiopcd. trans-
parent basal lamina Ihat contains collagenou s and
reticular nbers (Fig. 15-5).
,,-, it emw<, .in k, rl""l"'r int" oor_
tex. Howc'"Cr. a wedge-shaped protru,ion (the thecal
cone) extends toward the tunica albuginea.
Veeicular Secondery Follicles
Spaces that appear between group< of granulosa
cells !iOOn become Auid-fined vesicle' (Call-Exner
bodies). The liquOI" folliculi within Ihem is dear and
rich in hyaluronic acid. It later aceumulates steroids.
foninopin. protease.. dchydrogenases. carbohy-
drases and other enzymes. proteins derived from the
bl()()Oj plasma. and SOme speciali7.cd peptide. pro-
duced by the follicular cells or released when the
cells deteriorate to be replaced by olhers.
As the vesicles enlarge, they coalesce. Eventually.
a single large cavity. the amrum. is formed (Figs.
15·5 and IHi).
T he Ihcca inlerna now contains epithelioid cells.
(1) Nocl.olus. (2) nucleus 01 WOOtId.,y oocyte. (3)
OOI1;cot g'."""'". (_I ....,.laC41 oocyte. (5) .ono p.Ullc;"a.
(5) nucte; 01 'Ile loIIiCuf ... cell. mIIke "" COftH\O
,adi.'a , (7) SIeMer celll'fOC"s .... j,,,,,, tM oocyte atld Ille
oorOnll ,adi." C411I1 _ " Ole ' Ile ..,.... pelloc;"o. (8)
with l'f&Cipila"'" liQuor 1<>lhcul i. X 1\1(1(l.
(AOOdin. ,et"'tnee 169)
·"
•• terna
FID. 1S·6. p,."....,..,.. y matu<.tiQn Of fOIliO'.. ,
and ils morpllological cha racteristics arc
", jlh I role in steroid hormone biosynthesis. II ae-
qui'Q' rich blood aocl lympb:uK capilhl'1' network.
The theca UICrna is romposc<l primarily of con-
«nl.ical1y amnged bands 01 fibroblasts thai aR"
held together by ooIlage_s fibrils embedded in a
muoopolysa«haridc grvund $ubstarKe (111).
Preovulatory (Graafian) Foltlclel
Allhough many follicles a pproach this stage. usually
only one completes full development during tach
human ovarian cydc.
Wilen maturation is completed. (he structure . , a
whole typically b3s a diameter of 20-25 mm
wilh 0.05 10m for primordial follicles ( 1281).
The oocyte has grown from In initial 25-30 ,. in di-
ameter 10 approximatc\y 125-1){) ,.. The ZOna pel·
lucid. is 5-10 !' in thickness, and lhe basal!amin.
;1 1-2 ,.,.;d •.
The ant rum accumulates additiona l fluid. As il
enla rgcs, i1 p.m againll the follicular walls and
es
this " U$CS some: s\r(:tchilll Ind th;nn;", of the gra ...
ulosa .nd lbeea. The stralitio:d epilhelium now ap-
11"<$ u • relatively narrow rim (Ihe membrana
&ra nulosa ).
THE FE ....... lE I!EFliiOCNClrvE$Y$TEM
T he oocyte is pushed to one side of the follicle. It
IIllIinlains ilS associalion wilh Ihe grnnulooa via a
narrow longue of epit hel ium 1....1 i$ conl;nuOWl wilh
• ring of (:ells immed ialely $Urroundi", Ihe OOtyte
and f;QV1:ri", ilS lumi nal surfatt ( Flg. 1S-6).
The term cumulu! oophorw i$ gencrall)' applio:d
10 lhe longue 0( epithelium by which the ooc)'!e is
suspended. "'hcrell the roroIIQ rodiota designates
the cell ring Ihat is eioo:ly associated with Ihe gcr·
minal cell. However. some aUlhol"$ use the IWO terms
inle rchangeably.
As the follicle prepa res for ovula tion. il 10-
WliI rd 11M: tunica albuginea II • slle devoid of capil·
l.ries. The nllCleus of Ihe OOtyte enlarges and apo
proe.chc:s lhe plasma membrane (oolemma). AI thi$
lillge. it is sometimes ""ferred \0 as the germinal VC$o
ide (or vesicular nucle us). The chromalin undergoes
rcorganiution. and the nuclear membrane disap-
Meiosis I is soon com pleted. This culminates
in Ihe Formalion of a serondory oorytt that is almost
as large as the primary one from which il is derived
and contains olle·half the ch romosollllli OJmplemcnt .
A small cytoplasmic bleb and lhe relllllinilli chro-
mosomes Ire inoorpol. ted inlO lhejim poilU body.
Eltccpl for the width of Ihe CI'IOJilasmic rim. the cell
resembles a min;"'ture oocyte. It f(IOO il"iOYCS into the
zona pcllucida. Under oormal conditions. it deterio-
rates rapidly after performing ;t5 function of renlQV_
ing (he excess chromatin. (On occasion. il divides
r"'sl 10 form even .maUer. shon·ii""d Ihird and
fourth polar bodies.)
The :;ccondary oocyle almosl immediately enters
into meiosis II. It ad"ances 10 Ihc melJpha:;c stage.
in which division is again arrested unlil after
ovulation.

Oyulatlon
The flrsl indicalion Ihal ovulalion will OCCur :;cern,
to be a rapid and substantial increase in (he blood
How \0 Ihc ovary. ne vessels supplying the fully pre- A . FOIoCIe '" 1_ of <>vIlla 1i<:<>
pared follicle dilate. and Ih. capillarie, become more
permeable. Gmnular leukocYles (including baso-
phils) and Ihrombocyles accumulate within thc fol·
licle,;. and erylhrOCYles may gain entr)" (59) . Tissue
macrophage, and masl cells soon add to Ihe
populalion.
A secondary pha'e of follicular fluid secrelion pro-
motes edema formation. augmenlalion of thc follic.
ular volume. and Hallening of thc walls. Osmolic
factors may be of primary importallC<:. prolein,
formerly relained by Ihe capillaries can now rcadily
pass into the anlrum. Morcover. hydrola.e. are a..
Uvated . and large molecules are converted to
S. FOIICltla f' e< 0 ......"' 1"",
smaUer. soluble ones within Ih. cavit)·. The cells of
the oorOna radiala loosen Iheir associations with Ihc
neighboring epilhelium. but they maintain oonlacl
wilh Ihe oocyte via the processes that penetrate Ihe
rona pellucida.
Since there are concomilant changes in thc follicle
walls, the fluid accumulation does nol raise the hy·
drostatic pressure within the antrum (117). Muoo-
polys.a<xharidcs of Ihe ground substance confer elas-
ticity and permil movement of Ihe collagen fibrils, as
proloolylic enzymes degrade Ihat
previously conferred rigidity. Granulosal cells in Ihe
vicinity of (he oocyte either move apart Or undergo
degeneration (Fig. 15-7 A). and the lunica
becomes W<'a kened in Ihat region. Locali7.ed necrosis Fig. 15·7. 0vII10I.,..1Id IOtmat;oo 01
probably results from the rapidly developing hypo>:ia Ihe co<pu. lutoum .
(since thero are n(l capillaries in the part of Ihe wall
(hat eventually ruplures).
A small. blister-like bulge (the stigma or macula
pellucidum) forms on the ovarian surface. When the Finger-like projections (fimbriae) of Ihe oviduct
wall is sum';enll)" weakened, nuid from the close 10 Ihe site of ovaria n wall rupture direct Ihc
follicle. The secondary oocyte Ihen leaves through oocyte and its surrounding celts \0 the lubular
the opening. and mOre fluid is extruded. Myoid cle- lumen. and cilia that line the surfaces move the cells
menlS of the Iheca and surrounding slroma contract. downward .
and Ihis aids in both oocyte extrusion and oolla)l5\' Meiosis 11 is nol usually compleled unlil afler a
of thc follicle. sperrna\07.oon penetrates (he oocyte. When ;t occurs.
 '"
the division culminates in the formation of a single
large Ovum and the second polar body. The latcr
soon deteriorates.
Formation of the Co rpus Luteu m
Corpus luteurn means yellow body. In humans and
some OIhcrs. lipofuscin granules thai accumulate in
the cells provide the color. (However. Ihe structure
is not yellow in all mammals.)
Afler ovulation, the follicular walls continue 10
contrac\. Most of the Huid that is nol extruded is'1>-
sorbed. Blood vessels and connective lissue then in-
vade the granulosa as the basement membrane de-
teriorates. B10Cld released from ruptured capillaries
forms a clOi that occludes whal liule is left of the
lumen. (Residual antral Auid also contains coagula-
lion proleins, and ;1 win dot if it is extracted.)
The granul0S3 cells are now exposed for the [,rst
lime to a capillary circulalion , They undergo hyper-
trophy along ""ith spe.:ializations that include clon-
gation of th e mitochondria, development of the
Golgi apparatus, proliferation of the endoplasmic re-
ticulum wilh Irandormalion of Ihe mostly smOOlh to
a moslly rough Iype, augmentalion of Ihc nudear
volume, and acquisition of a "cell wall " (172). Lipid
droplets and piament ar3nuics accum ulate in the
cytoplasm.
An elaborate blood vessel networ k supported by a
fine reticulum 500n permeates the entire structure
-(Fig.1 5-7C).
Such "luleinization" oceul'S in all species, In hu-
mans and $OIn<' others. thecal cells contribute, They
enlarge only slightly, as they fo rm wedges along the
periphery . Stromal cells from the surrounding region
may also be incorporated (I 28). I n many mammals.
only granulosal cells fonn the active components of
the oorpora lutea.
If fertilization and implantation occur, the "spu-
1'1';1. 15-8. A. Co<pu6 Iut...." oj Pf_ f'IC)'. """"'n ovary.
( 1) F<>IdO<l 1o.)'tII" oj granulou ... ,...., celli. (2) for..,...
fOll",utal (3) of If>eCI ""III . (.) ",..ca
. "&rna celli, (51 ova'ian surface, X 5,5. B.
01 al •• $imilol 10 ,..,ta nglo In II. Corws lot..." 01
Pf""nancy ......... n ova'y . (') Cord. 01 granulosa lulein
cell •. (21 of tf>eCI ...1..... celtl, (3) tl\oca ••160'..
cen • . (.) Cllpillary. fibrobla.ts arK! 100M conoor;t;ve
ti.sue in 1.,..",., fO/lic\Jta, ant"'"" X 100. C. Ental_nt 01
alea .. mila' to IOClang" in B. Corpu.loteum, fa' ovary,
elee""" mk:rograph. (I) Cord> 01 granulo .. eell$,
(2) eapilla,iH, (3) 1If";Je venous CIIp;IIa'ie'. (.) lhee.
. " &rna (!nI.1y _ I . (5) int..cellul., spaces, X D.
EnItIl_m of "'" Simila, to lectangle in C. Ral ova,y.
THE FEMIILE REPRODUCTIVE SYSTEM
rious" oorpuslUleum of ovulation is transformed intO
a more elaborate "true" corpus iuteum of pregnancy
(Fig. 15·8D). In some species. the oorpus lutcum is
needed throughout the gestation period. In humans
the placenta ta kes over most of the function arter the
second month.
The corpus luleum "'g""""s during "",nfertile cy,
d es. Signs of delerioralion arc apparent in the
human ovary within 10-12 days arter ovulalion. and
Ihe hormone secretion declines. During the next two
days. the ilfueture begins its transformation in to a
sear-like ClYpliS albicalU that can persisl for months
or even years (Fig. 15-l!E), Eventually. the corpus
albicaos 5inks into Ihe ovarian medulla. where il is
destroyed.
The lerm I!ileal phast designates the lime period
during which hormones sec reted by Ihc corpus lu-
tcum exert major oootrois over the reproductive sys-
tcm functions . However. many follicles undergo p"'-
liminary maturation at that time, and some advance
to the antral stage.
Atre81a
Follicles in all stagcs of development undergo atresia
(degeneration that indudes loss of the OOCYle). The
pr""es.' heain. durilli fetal life, and it continues until
all the remaining germinal die olf.
It has been suUe.<!ed Ihal Ihe produclion of millions of
oocY'''' by mammal. is.n "ovolu'iQnary •• "yo""r" from
aneo.l0.. tltal engaged in <"ernal fcrlilizalioo, Anolhe,
lhoughl is lhal l.rg< numbe .. of oocyle< "i,h ahoorm.1
ehrQlllOSOmc •• fOfm<:<i during meiosis and . .. /«1;""
P'''''"" favors Ihe maluration of only Ih. heal,hi." of Ihe
coil •. $om. proponenlS of llIe S«<lnd hypolhc<i, .t1ribule
thc high incidence of defecls in children b<>rn 10 older
moth .... to progressive reduetion in Ihc avail.bl. pool of
""'mal coils.
electron mi<:n>grOph. ( I) Nu::I<!i 01 granulOsa lIJtein cen •.
(2) lipid dr<>plOIS. (3) capillat .... (' I nucJe; oj _helill
.
eells, .'YlIvOCyt ••. (6) (no' . ll\ot tf>eCI lutein
eeli. 01. mi&$in; in "'to). (1) inlorcel""a, s paces, X
1700, E. CotPIJ$ albican$, n..n.n O'Iary, (' I CotP<lO
mode up Of . xllocellulll, hyalinft I1'IIIOSM _
"""'" lMiduOi celt. oj me lOt_ oorpus lu!eum, (2)
oV"ian WOtT\I. (3) border toword ovanan 0I10tT\I ;.
""alp on<) tho 110"'il;oo abrupt. X 43. F. Corpu> .'r.'i<:um.
human o •• ry. (1) o.a,ia" "roms. (21 loIcIed, thic<OMd
I_nl 01 11>0 ol. .. y membr.".. (3) fOt."., . _ona
granulo ... now l"OghIy d isorg."_ , (.) ",.;00., Of
cOi lapM<l ,ono pelluCid •. X a5. ( _in. "I&renee '69)
 ,
5
I

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,.,' - ,

-
•
1
• ""'. -
•

'" , ,
'. ,-,
•
•
'
'.

- •
•
.-. ..
"'
•
"

•

'"
Atresia can begin in lb. chromosomes Or spindle
fibers of the oocyte (I S). or in the follicular cells.
Substances released during the deterioration SlimY-
late phagocytic cells.
All components of primordial and primary folli.
des se<:m \0 be resorbed. The remnantS of vesicular
follicles become corpora airt,ia that resemble. but
can be distinguished from the corpora albicantia
(Fig. IS·SF). Follicular waU cells thaI remain viable
can enter in10 the formation of hormQoc·SC<'rcting
"interstitial glands."
OVARIAN CYSTS
Fluid-filled degenerating structures often form
within the ovaries when the androgen levels risc
above optimum values. Cym arc COrnmOO in older
women. but they appear in younger oneS that are fer.
tile. Those derived from the rete ovari; do n01 seem
to <;{lnlain hormone_secreting cell •. Others develop
from follicles that attain the GraafIan stage but do
nO! extrude their oocytes (157). When hormone lev·
cis in ratS are manipulated to encouragc cyst for-
mation. tbe capillaries of the thoca dilate and the
basal lamina deteriorates. This is soon followed by
macrophage invasion and the appearance of auto-
pha:ic vesicles within the membrane l!ranulosa. The
epithelial cells bordering the amra persist and form
the walls. Most cysts are evemua lly resorbed. Very
large ones call for surgical intervcmion.
Time Required to Complete the Ovarian
Cyclet
It is oonvenient to pretend that human ovarian cycles
are 2S days long and to tailor diagrams to the modcl.
!lowever, the interval. for healthy, fenile subjects
range from fewer than 24 to mOre than 42 da)·s. with
mean values close to 30 (91). The cycles are espe-
cially irregular during the first year after they be-
come established and again as the time of meno-
pause approaches. The follicular phase accounts for
much of the variation it' duration depends on
the devdopmental stages of th. follides at the time
of cycle initiation. Since it is innuenced by hormone
levels, it can be manipulated in experimental ani-
mals. The length of the luteal phase varies unde r
pathological conditions. and inadequate develof>"
ment of the corpus luteum is a major cause of
steri lity.
Nutritional and genetic factors affect many as-
pects of ovarian function. including the cyel.
lengths. Subjects who were obese at age 18 and
gained 5 or more pounds afterward arc reponed to
have longer 9cles and more irregularity during the
THE FEMALE REPROOUCTtVE SYSTEM
first seven years .fter menarche (the first menstrual
period) and again during the seven years preceding
menopause ( 192).
Although many small mammals have vcry short
cydes. there are no oonsi"cn! rel ationships between
body si?e and the duration of the ovarian events. For
example oows ovulate at 21-day while
fo,es require 90 days. The 4 or 5 day cycles of rats
and mice havc brief luteal ph$Cs. but the luteal
stage is prolonged in the dog. In "'reflex ovulators"
,uch as the cat. ma ting stimuli shorten the follicular
phase. Thc rhesus monkey is a favorite subject for
investigation because its 2S-day cycle is similar in
somc respects to that of the human. Other primates
have longer or shorter phases. Chimpan7-""S require
around 35 days.
Humbe" o f Follicles That Undergo
Simu ltaneous Ovulation
Women usually produce one fertilizable ,"",yte at a
time . (This is just well, since the human uterus
not easily acoom modate more than One felus.)
The incidences of of nonidentical twins, trif>"
lets. and larger numbers of infants provide some in·
dication of the frequencies for multiple ovulations.
However. it i. possible for one oocyte 10 und.r:o fer_
tili7.ation as others deteriorate. On rare o<xasions. a
polar body is fertili,ed and the 'ygote beoomes a
healthy fetus.
Follicle stimulating hormone (FSH) administered
carly in the follicular phase can increase the num·
bers of ,"",ytes that mature. SUbsequent inje<:tion of
lH (or hCG) can then invoke multiple ovulations.
It is relatively C3l;Y to achieve "'superovulation" if
the ovary contains large numbers of follicles (44). It
is much mOre difficult to estimate the a ppropriate
dosages of "'fertility drugs" for wOmen who would
like to conceive but do 001 ovulate regularly. Quan·
tities that just barely support establishment of a sin-
gle pregnancy in some subjects have been known to
invoke multiple implantations in others. Excessive
amounts defeat the purposes for which the agents
are used, since it is unusual for more than three COn·
ceptuses to survive the gestation and neQnatal pe-
riods. gonadotropins Can cause other
problems. as well. Sinee they disrupt endogenous
hormonal balance, they can inlcrfere with implan-
tation. it has been shown in
animals that there is substan(ial danser of producing
embryQS with chromo:somal defects (I 31). One p0s-
sibility is that the hormones encourage maturation
of unhealthy ,"",ytes that would not have survi,-ed
under normal conditions. Another is that incom-
pletely prepared germinal « lis will be released for
fertilization. BellOr control i, oflen achieved by ad-
mini$lering agen ts that aCI on hypothalamo-hy-
pophysial system 10 promole secretion of endogellO\ls
gonadotropins.
Breeder. of large .n;mal, sometimes i;ve g<>nadolro-
pin> to ioere'$<: Ibe inc idence of twinnins. Or to acqu ire
oocyte, from fema l.. wilh ·'good·· genelic eharacter;st;c.
for external feniliz.alion by 'p<rmalO'03 frQm sclocted
male •. Embryos of the de,;rod sex can then be ;mplanted
into ,u rrogate mol he" Ihat are healthy but Ie .. valuable
(1 $8). Reccntly devclop<d t""hniqu .. ha.e ev.n made it
possible to nurture embryos of endangered 'pe<:ie, in ol<>-
mestie anim.l, of. relatcd typ< ,
MOSI small animal, ha,·e reproductive strategics
different from Ihose of larger oneS, Since Iheir lim_
iled life span' arc often further shomned by preda-
lors. surv ival of Ihe species depends On Ihe produc·
tion of large lillers. A\though 8-12 pups a rc usually
born at one time, rals hav<: been known to carry 20
Ihrough lactalion . Mice are almosl as prolific, and
lillers of 8 and 6 are C\)mmon for foxes and ham_
sters. res!,«,livdy. Large numbers of oocyte< are 1'<'.
leased each ovulatory period . If fertilization
does nOl occur. it is only a matler of days before ralS.
mice. hamsters. and olher species produce a new
crop. fealures oflh. uteri account in par! for
Ihe abili!y 10 nurture many fctusc!. Probably mOre
important. the geslation periods are short. and the
tiny young grow rapidly afler birth.
Some inleresling , ..ialion, on the themes have b«n
di.cove,ed (135). The PrQng-hor ..d .nttlope. the ele_
phant $h,ew. and tl>< South Ame,ican Vi,cacha .11 reg·
ula.ly deliver two full-term infa.I<. Yet the numl><,. <>f
ooo)'t.. ,ele.sed during One cycle.re 5. 120, and 300-
700. reope<:lively_ The Ma lag.oyan hedgehog differs from
most mammal, in th.t its follicle. do not form .nt,o. and
fertiliulion is "cwmpli,hed with in the ovary.
STEROID HORMONE BIOSYNTHESIS IN TH E
OVARY
The ovaries make progeslogen .. androgcns. and es-
trogens that are chemically identical with hormones
made by the lesles. and they ulili,.., similar biochem-
ical pathways (see Chapter 13, and especially f igs.
I 3-16 and 13-17), However. Ihe relalive of
each thaI are formed, Ihe blood co"","nlralions at-
tained, and the major pathways for degradalion al'<'
all differenl in Ihe female. Moreover. complex. time-
dependenl secretory patterns are required to main-
tain the reproductive funclions.
The pituilary gland gonadotropins. lutropin (lu-
teinizing hormone, LH, inlerstilial cell-slimolating
hormone, ICSH), and follitropin (follicle-stimulal-
ing hormone. FSH) are major regulalors, but they
act in conjunction wilh a variety of other faelOrs.
The chcmimies. biosynthesis. and some as!,«,1S of
their mechanisms of aClion and secretory control
wcre discussed in Chapters 13 and 14.
Subs tra tes
In common with Olher steroidogenic lissue<. the ova-
ries usually uSe eholel;lerollbat is delivered by Ihe
blood vessels (56). The lipoprotein particles are Ihe
major sources. bot cholesterol bound to other mole-
cules or loosely associated with albumin is also taken
up_ Gonadotropins increase substrate availabilily by
augmenting the blood ,upply. inducing lipoprotein
receplors. and aClivating cholesteryi esterases and
olher en,ymcs.
When the cell, are presented wilh more choles-
lerol than they need for immediale use. the exce.. is
esterified and stored in lipid droplets. The intraccl·
lular cholesterol stores are lhe major regulalors of
the conlrolling miCfOilomal cn'.yme (coenzyme A
acyhran,ferase, ACAT) ( 183). According (0 some
(bul nol all) observers, progesterone lowers the ac-
livity and it thereby makes morc substrate available
for steroidogenesis.
When Ih. demands exceed the ,upply. the cells
utilize palhways described in Chapler 1 to make
cholesterol from acelyl..coenlymc A. The activily of
Ihe rate-limiting enzyme A reductase) is
decrca<Cd when cho!e.,(effil OR) . It
has been proposed that progesterone increases thc
aCli_ily, possibly by promOling phosphorylation of
Ihe enzyme (70). An action of Ihis kind could ac·
count for Ihe abilily of progesterone to accelerale its
own synthesis in corpora lutea.
Gonadotropins promote the generalion of prosta-
glandins. and .slrogens invoxe histamine rcleasc.
Both products are _asodilators. Prolactin increases
the effectiveness of gonadotropins in several ways
that include activation of cholesteryl
Side-Cha in Cleavago
There are many condilions under which conversion
of choleslerol to pregnenolone becomes rale-limiting
for steroidogenesis. LH inHuenccs on Ihc side.o;hain
cleavage enzymes of interstilial cells are sim ilar 10
Ihose: deseribed for the same hormone in the lesli.
and for ACfH in Ihe adrenal eortex (40). The hor·
mones promote formalion of One Or mOre labile pra-
leins required for delivery of cholcslerolto Ihe mi-
tochondrial cytochrome P-450 systcm. LH also
stimulates production of mitochondrial proteins
whose aprearance correlates well wilh Ihe accelera·
tion of progesterone formalion (173). In addition, it
markedly enhances the rate al which phosphate is
incorporated inlO membrane phosphalidylinositols.
Those phospholipids contribute 10 stimulation of

'"
sicriodogenesis (40). and they a rC implicated in 30:-
cderation of Ca" uptake. LH additionally acts on
lysosomal membranes in a manner Ihl culminatts
in augmentation of gonadal hormone production
(52). Emogen, also act on Ihe Iysosomcs (1)8). and
they may on Ihis way .yncrgize with Ihe
gonadmropins.
W hen present in sufficiently high cooC<:n1rations,
U1 accelerates the generation of cAMP. The action
has been linked with inHuences exerted on mierofil·
aments (42) as well as with activation of plasma
membrane-associated proteases that regulate Ihe ad-
cnylal. cyclase. In common wilh LH, cAMP eo-
hances steroidogenesis via cakium-<lependcnl mech.
anisms that can be blocked by inhibitors of prolein
(but 001 RNA) biOllynlhesis (46). The nucleotide
probably amplifies gonadotropin effects. but it docs
nol seem to be an obligalory medialor. 11 does 001
mimic all aelions of lH (e.g. on phosphate incor-
poration into plasma membrane phosphalidylinooi-
tols), but it can affect the phospholipid composition
of that membrane [40J.
Prostaglandin, of the E type are believed to me-
diate certain lH actions (e.g. Ones exerted on ovu-
lation). They increase the cAMP levels and stimu·
late sleroid hormone production. However, lH still
i the presence of
Additional Mechanis m s lor Regulstlon of
Steroidogenesis
In addition 10 exerting acu te inftuences, gonadotro-
pins promote cell growth and speciali7.ation, and
they induce enoymcs . They regulate their own recep-
tOr numbers and also the receptors for other hor-
mones. Product s of their actions contribute to the
controls. For example. there arc conditions under
which androgens depress eSirogen formation and
others in whi.h Ihey syoersize with FSH to increase
arontat;zation.
Growth factors in blood plasma interact with both
and steroids_ When Ihey increase cell
Ii numbers of .ells
hormones. Both
and fibrobla't
have been demonstrated to
i FSH i of LH I"<'ceptors (and EGF
also =ms to accelerate los.s of I"<'CCptors Ihat have
already been made). In contrast, platclet-derived
growth factor (PDGF) potentiates thc FS li clTecl5
(134). EGF i, also reported to depress FSI I stima-
lation of cstrogen production by acting at somc sile
distal to cAMP generation (89). The androgen in-
THE FEMALE REPRODUCTtVE SYSTEM
hibition may utili,e EGF a, a mediator, since andro-
gens promote EGF generation in some cell types.
A, diseussed in Chapter 13. hypothalamic gona.
dotropin releasing hormone (lRH ) probably affects
reproduction mostly by regulating the secretion of
FSH and LR Concenlrations in the peripheral
blood rarely exceed 10-" M (123). lRH
and its agonislS interact with receptors in the go-
nads, and they Can depress both and
cytodilTerentiation responses to the pituitary hor-
mones (7). However, concentrations of at least 10-'
M are required (158). For this and other reasons, it
is believed that exogenous LRH intcmels with re-
ceptors for a different peptide made in the reproduc-
tive system_Al\hough responses have been deseribed
for many mammalian species, they differ in rodents
and primate, ( II).
Steroidogenesis in the Fetus
The presumplive ovaries of female human fetuses
make measurable amounts of eSlrogcns from C21
by the end of the 8th week po5tcoTICCption.
(They cannot at this stage utili,e cholesterol.) The
oteroid, probably play localized roles. Thel"<' is no ev-
idence that the hormone is secreted. (Male fetal go-
nads make mostly t.. tosterone. but no sex differ-
ences in the estradiol concentrations of fetal blood or
amniotic naids havc been found [63].)
At the 8-we<lk stagc, the gonad of the fema le fetus
is not yet recogni7.able as an ovary. As dc.elopmem
procc<:ds, the mesenchymal (steroid-scereting) cells
ente r into the formation of the ovarian stroma. The
cells acquire lH I"<'coptors and the ability to
progesterone from cholesterol. Concomitantly, the
Cl? C20 lyase activity decliTlCS (190)_ Therefore,
the progesterone is not converted to CI7 'teroids.
The potential for eSlrogens from androgens
is retained, bullittle aromatase substrate is available
to the cells. A role for prolactin in induction of the
LH receptors has been demonslrated for immature
rat ovaries (90,142). but no requil"<'ment for PRL
has been established for human fetuses.
It is difficult to determine whether the fetal ovary
makes a contribution to the plasma progestogen lev-
els. since the quantities of steroid provided by th.
placcnta are so greal. Higher amniotic fluid concen-
trations of progesterone have been described for fe-
male than for male of some species. but thc
findings for humans al"<' conlroversial (197).
Simil" dc.clopmenlal ch,nge< ha.e been de;cril><d
for other mamm.I,. O""i.. ukn from ca lf fotu", up to
8 cm in crown·rump I.ngth r.I .....,trog.ns inlo culture
media when they are pro.ided with progo'lerone or ilO
11a-hydro.<y derivative. and they also make somt tost",,·
ttrone. The rateS of ,yntb«i. can be augmented with
either lutropin 0<' dibutyrykAMP. In contrast. ovaries
from f.tu<csiQ"ge, th'n 10 em do IIl>l sponta neouSly ,e.
least .ndrogen. Qr estrogen. (althougb Ihey can arom.,
li,e androge".lhat are added to Ihe media). In the llfier
gon.d •. lutropin and cyclic nucleotidc, can still enh.ne.
progesterone .ynthesi. (1 90).
SterOid Hormone Secretion In Juvenile s
Infants and children sterete only minute quantiti<$
of gonadal steroids. Ho",..,ver, the blood levels stem
to be sufficient for negative feedback oontrol Over the
pituitary gland , (When laboratory animals at a oom·
parable developmenlal slage are: ovarieclomized. Ihe
plasma gonadOlropin concenlrations risco Moreover,
one gonad undergO<$ compensatory hypertrophy if
tbe Olher is removed.) Since follicular development
is minimal, Ihe stromal cells are probably the 50IIrces
of the steroids.
The ... ,umplion lhat estrogen, mediate gon.d<>iropin
inhibition ha' betn qu«liooed. Stud ie' in ,.1, indie.te
that the imm.ture pituitary i, ",gulatod mostly by the
minule 'mounts of androllens in lhe eire.I'lioo. and thai
puberty OnKt il alSOCiattd with a Shift to eStrogen dopen.
denee (8).
Stromal Cells of the Adult Overy
Wben the follicks begin to mature, some of the
stromal cells form the thecal layers. A considerable
malS of stromal tissue not directly associated with
the foil ides persists. Many of the cells make andro-
gen, and pus them On to the follicles for conversion
10 estrogens. There is limited progesterone synthesis,
and small amounts of estrogens may also be released
during the fertile years_
After tht: menopause, the ovaries stop ma king «.
trogens. (Postmenopausal ovariectomy does not af-
fect the plasma estrogen [210].) The stromal cells
release androstenedione and other androgens to the
bloodstream. The molecules are: aromatized byadi-
pose lissue. in the liver. and al other eXlragonadal
sites, (Estrone then becomes the major circulating
estrogen.) Stromal celb that form ovarian tumors
sometimes secrete very large quantities of
androgens.
Stero ido genesis In the Ovarian Follicles
The squamous epithelium Ihat comprises the pre-
granulosa of prlmOtdlai follicles is obviously not
equipped for the biosynlhesis and secrelion of steroid
hormones. and it is virtually certain that even mul.
tilaminar primary follicles are not signiftcant sources
of the hormones ,
Steroidogenic ability emerges as the granulosa
cells grow. proliferate, and specialize. Vesicles form
within the layer, and the theca becomes organized
and vascular. The rale of hormonc scc"'tion in·
creases in direct proportion 10 the follicle si'.e (a po.
rameler directly linked with the numbers of cells
that form the walls) (129). Maximal rates of eslr<r
gen produt:tion are attained shortly before Ihe time
of ovulalion. There: are: sequential changes in the rel-
ative proportions of the various types of steroid mol-
ecule, produced (23.129).
The hormones are released into the follicular Auid,
the ovarian lymph, and the blood capillaries that are
drained by the ovarian veins. There is also a pcri.,.
vulatory discharge inlo the abdominal cavily and
probably into the fallopian tubes as well (205).
The ftuid of the smaller human follicles conlains
m()Stly 17",bydroxypregllCnolone, dehydrocpian-
drosterone. testosterone, and
The aromatization activity steadily increases as tbe
follicle matures. Soon. estradiol·17(J is made in large
amounts. along wilh some estrone. The Auid also
oonlains progeslerone. 17a-hydroxyprogeslcrone
(118), and small quantities of both Icstoslcrone and
DHT {I 29). Since il appears in the ovarian veins. it
is believed tha t 2(la-hydroxyprogestcrone is also syn·
thesized (210). Although conjugates have been iden-
tified (29). much of Ihe steroid is in the frce form.
The from 'nO rosen to «trogcn bio>yn-
the,;, has been "'porled fO<' a "'ide variet)' of mammali.n
'peei", Ho,.e.e,_ considtr.ble variation in the compOSi.
tion of the follieul.r fluid II encoontered. FO<' example.
Ihe mart a.. umutatts \ia.hydrO>.yestradiol·t1/:1. Ihe
guinea pi!. t \ia..,piestriot and e>tr.diol·17a. and the ra\>.
bit some .. tradiol-I 7-« (Fig. t5·9).
In humans and mOSI olher primates_ just One of
Ihe maluring follicles Ihen compleles maturalion. It
ma kes much more estrogen than tbe others and be-
comes the major contributor to Ihe circulating pool
of eStradiol. Shortly before ovulation (when follicu_
lar size and estradiol secretion arc maximal), the
granulosal cell mitotic index declines, Estradiol pro.
duct ion falls off, and a rapid increase in 3(J·hydroxy-
sleroid dehydrogenase activity coincides wilh a rise
in Ihe rale of progesterone synthesi s.
Follicles thai begin maturation at the same time
but are not '-selected -' to go On to ()lInlation. aCCu-
mulate androgens and become alretic.
Cell Types Engaged In Estrogen Producti on
It is generally agreed that granulosa cells ma ke pr<r
gesterone and that they convert androgens 10 estr.,.
gens. whereas the theca inlerna can usc both cllOles-
terol and progesterone 10 make androgens.
Controversies concerning whetber the thecal cell.
." THE FEt.!A,LE REPROOVCTIVE SYSTEM

"
o
-' C'

'" I '" I
>-
"" ESTRADlOl·Hi<
>-
"" ESTRONE

"9
'-J'" C' -, '" -0"

I I
ESTRADIOL- 17" l/;.,·EP IESTR:OL

"1o

I
y
,
o
"
(""OH· ESTF1AOK)l· 171l
Fig. 15-9. .,..,'i..... in lollioularlruid. 01
• • riOO. mam""";'. sptoCiH .

have a romatase activity remain unresolved, and fOllr
different hypotheses have heen advanced to explain
lhe very high rateS of estrogen production by the
large follicles.
Unoena;n,;., arise becau", (al ,he .. are
quanti,.'iv. 'pecies va,iatiQns in follicula, l'hysiology:
(b) 'he ovaries undergo ",que"'ial change. in . ,croido-
sonesi., and data collected., 00. "aae arc different from
,hose o b.. incd .,anothe" and Ie) each of lhe technique.
used imroduce, il' spedal problem. (30). Cell' isola\w
rrom mho. type$ with which they "$".lIy intenct. and
mointalncd in culture. may nol beh."" in a "physi<>logi·
cal" manner. This i•• specially t'ue for long_term stud i••
in whicb the cell, underg<> change$.. CO<:ulturing different
cell typel may oot pre.., ... the ulual kind. of relatton·
.bips. e'pecia liy if tb. medium i. more f,vorable f'" one
of Ihem. W he n anemp\5.re made to .electively de$.troy
certain ceillype< in the intact ovary. the injury inHicled
.lfec.. Ih .... ullS. I forgan suuetur' is pre ..... d and ....
roid. are collected from lhe veins, linle informalion i, ob-
I.ined on even" occurrins inside the follicles.
I. Tlte 'l'W(>-Cell Hypmltt sis": Majority opinion
seem, 10 favor this concept. at least for some of Ihe
species mOSt widely studied in laboratories. It ,tates
lbal Ihecal cells make androgen, and that tbey
Ihereby supply the substtott. The granulosa cells
lake up the androgens and conven them 10 QlrQgellS
(47 . 114). The prodUCI' (mostly Qlradiol·17p, but up
to 15% estrone) would Ihen have 10 be Iransported
back to the theca for secrelion into the b loodslream.
since tbe granulosa is d evoid of capillaries (Fig. 15·
lOA).
The hypothesi, is supported by obse,vation. thai th.cal
cell. of many specie. pOS$Cl<.1l of the enzym.. required
rOf lhe con .... ion of ehol.,t.,'" to testosterone and
 -
Cf"cIestcroi C"''''Sle,oI"", /
GrMuIOSa AIII'um

Q A NDROGE N , \ - _ ANDROGEN

ANDROGeN - [ - ANDROGEN j 0)
ESTROGEN " • ESTROGE N i-- - ESTROGE N
A. Two·cell hypo" .,.,.: 011."'09"" II made by granulo$a

C"""'"erol A N DROGEN , ,- - ANDROGEN

AN02GEN )r--I I
ESTA'aaEN ESTIIO(;EN' ESTROGE N

S. Thecal eSlf<>ge" g<>e$ ", \>Ioo<;I"",am: granulos" "'' 09<'" 90<" 10 an"",,,

Cholest.rol

OJ LANOROGEN ANDROGEN
ANDROGEN

L5TnOGCN ESTROG EN ESTROGEN

I eSTROGE N

"- /
C. Theca i. ""'i'" Oite 01 cs"ogen Ciosy'IIeSi$
....... .
CfloIe","OI ChoIe.Ie'" .---, A ND ROGEN , , -. ANDROGEN
OJ
ANDROGEN -j, ANDROGEN
I
I
ESTROGEN i-- ESTROGH I
ESTAOGEN ESTAOGEN
''.
, ,
'- . , !
, '

O. SterOId synlt>es,. inllOives oomplex ;"t.fact<>n.

t>et .. ,en dol!.ren' 00" I)'pes

Fig . 15-1 0. Proposed 0;1 •• tor

of .strogeno by pr_'ory 1_._
indicates .,.gnitudll, Brol<.., arrOw' indicll18 C. . .. r
ond ""'"'tion
Arrow ttHelo._

intO<t<t;ona Oll>et tl>an storoid uonsport


..I.'-androsleneoione, When eullurro alone and provided
,.-ilb prcour$Of, Ihey Telea"" and,ogen inlO Ihe .urround_
ing fluid., The ..... of androgen ""eretion can be aug-
menled ",ith ionadolropin,.
In cont,.>I. granulosa cell. of r.". ham.teT). sheep.
CO'"'. and some olh., mammals have lillIe Or no Cli.
C20 Iyo", ,clivity. and they do nol relnse dete<:tabl.
amOunts of arldroge n' even when e.posed 10 lhe gona_
dOlropin'. ThO)' ,OC rete $ub$,anlial amount< of e"rogen'
only when ..orogen, are provided .• nd thcir abilily 10 do
SQ increases "ilh maturalion of Ibe follicle from whieb
'hey were derived. Fu rther indical ion ,hal .ndrogcn i,
loken up (ralb" Iban synthe,ized) derive, from obler·
vation, that lc<tQOlerone anlise ... orre" ."radiol biooy._
th.,i, when Ih ..,1 cell' aT. pr.",nt, (Pre.umably. Ih.
sera would be ineffeclive if Ihe Indrogen Ind estrogen
weor. made with in Ih. confines of Ihe .. me coli II 18).)
2. SRrond HYf'OIhesis: Granu/Q5al cells
Ihm mleF IhR an/ra. bUllh«a/ cells
eSlrogens into the ovaFian "eins; It has been argued
that making androgens in the theca. transporting
Ihem to lhe granulosa for aromati1.8tion_ and then
transporting the estrogens to the theca for re-
lease into the blood.ueam is "physiologically ineffi-
dent" PO). Thcrc is poor correlation between anlTal
Auid and plasma estrogen coocentrations. and it has
been reported Ihat the s tcroid composition of o'arian
"cin blood is not affected by inje<:ting steroids into
thc liquor follicUli. KeffiO\lal of JUSt granulosal cells
docs not rapidly affect th. plasma androgen le,.ls,
whereas excising jusl thecal cells docs (30). More-
over. thecal cells obtained from humans and mon-
keys can estrogens when cultured alone, The
se<:ond hypolbesis has therefore gainw favor among
primate physiologists (sec Fig. IS-lOB).
J. Third Concepl: The Ihero is Ihf major Sile for
eSlrogen biosyMht'sis: This idea has been proposed
largely on the basis of 'ltudies of buman. monkey.
and mare follicular cells in culture (sec Fig. 15·
IOC). It is 00\ oonsistem with dala oblained from
rats. hamsteT). sheep. and cows. Same investigators
believe that it docs not apply 10 the pig. but others
reporl estrogen production by the thecal cell' of the
sow (78).
The h)'poln.sis does not rule 0111 limited emogen
production by follicular cells for release imo the an_
trum. Such aClivity may be required to maintain an·
drogen:cstrogcn ratios.
4. Modified Two-Cell I/ypothesis: Studies on
human and monkey cells 'upporllhc belicfthat both
cell Iypes make progeSlogens. androgens and eSlT<)-
gens. and Ihal each enhances (he functions of Ihe
other. Nonfollieular stromal cells may cootribute 10
tbe cell-to-cell interactions (127) (Fig. 15-10D). Co-
operative activities could include release by onc cell
type of growlh or proliferalion factors for another.
HIE FEMALE REI'ROOUCTIVE SVSTEM
Serloli_inlerstitial cell interaeti"", weore described in
Chapter 14. It i. pos$ib1e that granulosal coli. borderins
Ihe theca engose in 1M scheme summarize<! in Fig, 15-
11. Estradiol also appears to .limulate prosesterone bio-
synthesis during Ihe f<>llicular ph...., (217).
Although the author i. unaware of ,eports that gran-
ulO$ll cell. do, in fact. ,yn,hO$i:te more cbQlww:>l Ihan
they require 10 maintain theiT own o<ganeU.., 1M scheme
i, eonsi"enl wilb ,everal otber findings, (0) ChoIe"ero(
accumul),.s within the antrum (128); (b) "eroidogenesi,
accelerlle, in cuilure wben Ibec, .nd granu losa cells are
,imultanc"",ly preoenl. even in species in ,",'hieh Ihe Ibeca
alone Can make estrogen or when Ihe sranulosa cell. are
supplied with optimum amoun" of androgen substrate:
(c) eXlracellular androgen enhanc.. P'Of'''''1.'JN bjooyn_
the,i, by , .. nul= cell. (30): (d) progesterone inhibi"
its o"n biosynth..is if it .ceumul.tes in ..ce .. ive
.m""nl, (30): and (e) anlral nuid contain. progestcrone
metabolite.,
Additional synergism, may involve the germinal cells,
The foll icle' do nQl develop without Ihem. and a"esia
usually begins wilh oocyte deteri"'"lion. Oocyle, proba·
bly do OOt possess steroid hormone recepton. but they
oebieve run maluralion .,.Iy in follicle, whost anlr. are
ricb in e"rogen and 10'" in androgen contenl.
Ho rmone Production by the Co rpus Luteum
A< the granulosa cell. undergo luteinization. Ihey
v<;ry Iheir rato:> uf
produclion, while (hc ability to make eSlrogens de-
dines. A small rise in progestcrone biosynthesis pre-
cedes ovulation , After extrusion of the oocytc and its
oorona. the progesterone level, in thc o'ary and
blood plasm. rise 'Ieeply. A plateau is then main-
tained until the cells begin 10 show signs of detcrio-
ration. Progesterone biosynthesis (hcn falls off rap-
idly. and low levels persist from the lale IUleal phase
to the time of the next ovulation ,
RELATIONSHIPS BETWEEN FOLLICULAR
FLUID AND PLASMA GONADAL STEROIDS
I n reproductively competent females, the ovaries arc
the major souree. of plasma e.trogens and proges-
10geltS. The concentralions of those , teroids are
higher in ovarian veoous blood than in (he general
system ic circulation. and Ihey fall off rapidly if Ovar-
iectomy i, performed. Same androgen is also re-
leased on a rcgular basis.
The steroids perform certain functions wilhin the
ovaTi", and others outside those organs, There is
poor correlation between Ihe intraovorian and pe-
ripheral plasma ooneentrations, Same hormone is re-
tained within the follicles. "'hile a frac-
tion of Ihe circulating is obtained from
extragonadal sourees (195), Moreover, each molee.

_.
ESTROGEN
ular Iype: displays i\$ m'e 0( rcmova l
from Ihe circulatory pool.
Verletl o na In Pillsmll Eebo gen
Con ce ntra n o n s during the Mens trual C ye le
I S-12 is a stylized di.Srlm lhat pcorlrn)'s the
patterns of chango for cslradiol. cslrone. progc:ucr-
one. ,00 ] 7.... hydt"OJlyprogc:steroM. For convenience,
it is usumcd ,hat the cn'i re n:<juire:s 28 daY'
aOO lilal (/Yulation occurs on day 14 .... hen the Dmet
01 menstrual bleeding;s laken as day O. The Curves
have been "imOOlhed" 10 show D:)t\lrasts. f requenl
$ampling of individuals reveal s numerous brief. ir-
"'8ula rly recurring small peaks and troughs
throughoul both follicular and luteal pha5CS.
Sin<:e ptO/lcsleroM is prescnt in much higl>cr con·
«ntrlltions, ,he v.llucs arc cxpl"cssed in nanograms
per mimliler (while ,hose for CSlfO$eRS ,,'" ;n pico-
,rims per milliliter).
Sevenl dilfe",nt tcchniques are used 10 obtain the
data. and this probably "CC(l<mt$ for minor discrep-
Inci cs in the absol ute values ...::portcd by various lab-
oratories. There scem' '0 be I range of levels consis-
tenl with feni1ity. Peaks attained by yonnger
.ubjc:tl.! 'end '0 be higher than thOllC of old. r ones.
and tt..: concentralions can vary from one eycle '0
'he nUl.
PLASMA ESTRADIOL- 17{j: ROLES O F THE
DOMINANT FOl.UCLE AND CORPUS lUTE\JM
Throughout the fenile years. I single "dominan"·
follicle and Ihe corpus luteum ,hat forms from it pro-
vide nl()$l of the circulating estradiol in nonpregnant
females of monolOCl.lUS .pecies (ones in which a sin-
gle per cycle is the rule). A. will be dis-
cussed. Ihe follicle is before day 8 ;n
nlOflkeys.
"The blood vessels Ihat d rlin ,he ovary with 'he
dominant follicle have higher es,radiol concentra·
lions than the contralaleral Ot\C:I (210). Removal of
F'r"I ..... . . - ........
Fig. ' 5· " .
"" ."""*".,. . .
01 _oleic g.- .. oioo
1 1 ' _ '_ _.c,o.. I + 2.
Gr..-·. • I,.!If .... 01 _ , _
prow",,, _ ... "" ...-_"""
pooducIioft. 3. _
lO .... k... di"g." .• + 5. G f . _
""'" 10 "..ke . ., _ , ...,
.-. 01
0/11-". 8 . E"'Ir<>gen I."",
o.anul<>Sa "imullt.1 I!WCI
_,",,,''''''. 1. "to :01n fr"", , - . .
lIimu11'"II""'- 'J""
,.'1 01
_ , ...""". e. 131_ uptak • ...,
01
_ ..."... _ ..... 1.'
............ "'1""; 'w""" .... _ .
'he dominant follicle or ;IS corpus IUleum;s
by rapid d.cline of lhe steroid le,..I•. (Some estrog.n
is eviden'ly also produced by "rohorl" follicles. since
the eJllO&en eoment of the ovarian ve ins continues
to cx«cd that of Ihe peripheral blood plasma.)
After the mcoopllusc, tMr"C i. very lillie cslrndiol
in Ihe drtula,ion. The smalilmounts present ariso:
extrqonadally (195). (EstTOOC then be<:omes the
major plasma ,..Itogen.)
Sevcral follicles commclltC ,1OYo·,h during ,he firs,
we<:k of ,he C)"C1c. Those 'hat aequire antra accu·
mu late eslrogen. but they do 001 release it (and
plasma levels arc low). As ,h.
dominant fol licle de-
rapidly during th e sccond weelt. the increment
in antral es'rogen con,ent corr"Clates with Ihe num·
bers of s",nulooa layers added (129). A, 1M gor_
minal vC$icle s,age . val ues ,>-crage 465 n8lml. Es-
ltogen is ""dually released in amounu.
and 'his aceounts for ciCv.ltion of ,he plasma level.
Estradiol syn'hesis peaks shortly befo", ovulalion.
Anlral fluid conocntra,ions us..ally au ain oom<:thing
like 1019 na/ml when lhe polar body forms. bul con·
up to 40.000 times tbose of peripheral
blood plasma have been f{lund. (C{lhort follides ae-
cumu lal. much less.)
Si""" 1I0""d. lo..inl ,be owa,ics 'r"C dilu,ed by ,be
blood. J>C,ipberat _lei be '0 bc
low. o.he. fac:,ors ,hal a«oun' fo< ,he higb ....
tral: pl...... Cf'rot<n """'" indotdc ,h •• * ..... of biood
YCSS(I$ in ,be ,ranYIosa. II hM b«n suUCSted ,hal folli·
'ha,
eles con,. in pro ..;... bind ,be 1,<TOid wi,h h;lh allin·
i,y. 1I 0we •• r. the pn;>1cin'"Te no'"' known to ' CKmblc ,he
OtICS in ,be circula'ion. Mortevc •• ,be <t.roid •• ,.
cud th. b indi nS eapaci'y by 2o...100.fotd (! 2S).
Plasma estradiol peaks sbottl)· before Ihe onse' of
o. ula tion. T bil is attributed 10 "lea kage" of mole-
cules as ,h. fol licular walls under,o ch:tngcs. bul
blood flow is also modified al that ,im<:. Jus, before
the ooeyle is cx, rudcd. 1100 follicle begins 10 make
more proaesterone and \es$ es'rogen. Thc...:: is. usu·
ally a concomitant lowering of plasma eslradiol.
 THE FEM",LE REPRODUCTiVe SYSTEM

/ -,
II '\ "
,
I \
\ "
- - - - P'oge'l8fQOO
,,
I \
\
\
"
•
••••••

I
, , I
\
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•
, f
•0
I \
• I \
•n
h I
I
I \
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,
I \\ •
, ,-,,
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" 01,°,,"
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'- °0
.
-,
... ...... -.: ,
.
/
'00
' ' ' ' ':=::::: , / • ..
-------
_____ __ • / •J
___ _ _ _ _• _
, "i
--- °0 °
0
...
" 0"
,
, '•••••••••••••••
' •
••

, • • " ,.
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0 2Q 22 24

t Ovulation
Fig. 15·12. Oioll'ammatic rep<Mf>ntatOon of
blood COI'IU(IUotions of ewOQ8f1" IIId _
;"
(<>goon> <ll<inII
and .'"'''''' .r."'
pieogrom. po< m;t!;(;t6l". ,..,.,.••• tI>O. .
tor protllSt6l"""" and
'M """,$1",. 1ey<;Ie. Not. thaI lha unit. 1", tile eStfadiot-, 71l nanogram. pO< millm'6I".

A secondary, rise in plasma estrogen oc-
cnrs when (he corpus luteum begins to function . Fi.
nally, the CQrpus IUleum rogresses. and the plasma
estradiol falls 10 Ihe low lovels that a re maintained
until a new dominant follicle matures.
Very lillie of the estradiol derives from
other 5OU!'CCS. St romal cells can release small
amounts. EstrOIlC is a potential precursor, but the es-
tradiol = cs\ronc reaction proceeds mostly to the
righl under physiological conditions. Plasma lestos-
tcrone averages arou nd 0.3 nglml during mOSI of Ihe
cycle (91). Most of it is bound to protcil\S, and prot>-
ably no more than 0.2% of it is aroma ti zed (2 10).
Peripheral Metabo li sm of Eatradiol
Binding 10 plasma proleins retards uptake by deg-
radation si ttS as well as targel organs. ESlrogenS a re
major inducers of Ihe proleil1$ (153). II has Ixcn
stated that close to 60% of the steroid associates witb
albumin. and another 36'lt-39% binds to the testos-
tcrone-<:str<Jgcn binding globulin (Te BG. sec Chap .
14). The importan<;<, of Ihe binding 10 globulins has
I"<'ccmly been questioned (219).
Hcpatocytcs av id ly take up estrogens and uSc
them to ma ke most of tbe circulating metabolites.
(Target organs form estrone. catechol estrogens, and
other derivatives. but they rdease only small
amounls.) The hepatic en1.ymes calalyze hydroxyl-
ations at positions 2, 4. and 6: conjugalions with glu-
curonaie. sulfale. glutath ione, peptides, and othcr
substances, mostly at positions 3 and 17; and oxida_
lion to estrone (Fig. 15-13). Pr<:>ducts of the reac-
tions Can be acted on by secondary cn?ymes. (Fig.
15-14). {For example. cate<:hol estrogens al"<' often
methylated (1981. and much of the estrone is
conjugated.)
The catechol cstrogens are among the products
 "o
J-
"
J-
o "o
--Oil
, I J.
0"

'" I I '" I
" "'- 0' "'-
ESTRIOL 16-EPIEST AIOL
'7·EPIESTRIOL·3·SULF ... TE

"
o, o o
A " "
C -- 0
"
'" I
,,,,- I I "
0

16.17·EPIESTRlOl ,S,.-OH·ESTRONE 16!I·QH·E$TRQNE

o "
"o o

• o J. <,,0 ",A ,
"
o COOH

-0 I I
'"
,S·QXOESTRONE 16·QXQe$TRAOIOL· \ 711 16·QXOESTRAOIOL·' 7" GLUCURON ICE

o
" J.

o
"
1- '"
o
17·QXQ· pQUINQL· , Oi'
?,, ·OH-ESTRONE
"

o
o I",
" 4·METHQXYESTRONE

"0 "'-
I
2·METHEXYESTRONE
... THE FEMALE REPROOVCTIVE SYSTeM

1<. Widths 01 ."OWS ind"ate reial,'" quant"'"

01 Sler""'s ,"",''''''''
,,'
.,, - ----_. ,.I _ 2·C H,Q·E,
::- .f!·QH·E, - 4-CH,o-E,
6,, ·OH·E, 6,rI-OH-E,
7,,·QH
11
"
I
OKA E, _ _ _ _,
4!J"Of-J./;, _
_ 2·CH,O-E ,
4-CH,o·€,
i),, -OH -E. OO,o-E, 6jl-OH -E,
DHAS E,S

t
..\4·$

"
,.,
16/!·OH·E,

17·Epicslrio! / "
(1& ••17u-E5triol) ' / './' 16·EpieSlfioi
(1 6!J, 17/j ·E."ioI)

,f"
16,17-Ep;est<ioI
" "'-
IS-O,oestradiol·' 7" 16·0,,,,,'1, ;>dOll. 171J

ESTRIOl
I '6/1.1 7w Estrioll (I 50,. I 7 r'.::>I)

B. Major fC/lCliom iflVOlve<l;" e.II<>gerl Iorm.lio<1 a<>d deglaciation

(coni"llaloons olM, 011ll3IOO •• re not sI»wf»

Fig. 15· 14. Fact"'. """lrOOO1;og to ma;n'enaoc. oj

pia""", " 1<008f' le>Iell.

thai are biologically activo. They find '.,,<,pIOTS in
the uterus. mammary gland. liver. and pituitary.
The ones mad. in the brain Can act directly and also
compete with norepinephrine for catechoJ.()·meth-
yllransferase (I 54).
The liver releases mostly conjugates to the blood
(and close to 90% of circulating metabolites arc in
that form). Substantial quantities of the hormones
a nd their dcrivati""" al"<' secrcted into the bile. Some
are reclaimed by the "tntcrohepatic circuit," whi le
others arc scnt on to the large intestine. Some free
estrogen appears in tnc urine if a large dose is in-
jected. bUI the kidney usuany excretes mostly me-
tabolites that form in th. liver. It also has sulfatases
a nd other enzymes that act on the molecules. (Most
of thc urinary steroid s are sulfates. "'hereas most of
the OneS released by the liver arc glucuronates.)
Erythrocytes. gastrointestinal cells. adipose tissue.
and reproductive organs metabolize the estrogens.
Some derivatives recently identifIed in target organs
are not released (179). They may perform special bi·
ological functions.
OTHER CIRCULATI NG ESTROGENS
follicular cells ma ke estrone (E,) as well as estradiol
(E,). The E,: E, ralio in the dominant follicle is
around 20:1 shortly before ovulation. II i$ much
lower in Ihe oohorts and it declines to unily when
Ihey begin to undergo atresia.
E, roughly parallels E,. but it is moro var'
iahle. Concentrations during Ihe follicular phase can
be lower than. "<iuallo. or slightly greater Ihan those
of E,. T here are wide pfC<)vUlalOry "uel.lions. and
the preo,"ulalory peak is lower than that of E"
The oorpus luteum releases smail quantities of es·
triol (210), bUllhe ,mall amoum, in the follicular
phase plasma. and virtually all of Ihe minute
amounts of cpiestriols and other derivalives are pe-
ripheral melaholites.
PERIPHERAL PRODUCTION OF ESTROGENS
Adipose tissue is a major si le for aroma ti,.ation of
the DHA. DHAS. and ;l'-androstenedione (tl.') reo
leased from the adrenal oorlex. When Ihe aging
ovary Slops making E , . most of the circulaling estro-
gen is E, formed in this way. The steroid Icvels arc
hiih in obese human adults. They are rePOTted 10
decline during caloric reStriclion in
men. even whcn Ihcre i, jusl a small reduction of
body weight (204). However. since Ihe ae·
tivity is highest in Ihe stromal cells (ralher Ihan Ihe
adipocyles) (I). and stromal cells persi't, the eircu·
laling steroids do nol always return to the normal
range in obese women who lose weight. The mech·
ani'!rns whereby eslrogens affecl lumOr growth
(101). as well as interrelationships among hormone
Icvels. hormone receptor numbers, and the tenden.
cies to develop malignancies (187) are only dimly
underslood. Nevertheless, Ihere arc reasons to sus-
pect thaI Ihc high incidences of breasl and uterine
lumors in women who have hccn obese arc linked
with chronically elevated eSlrogen levels (39). Slress
is believed 10 be another predisposing faclor, and
glucocorticoid. arc implicaled as indu""rs of adipose
tissue aromalase (196).
Plasms Progestogen Changes during the
Ovarian Cycle
Very lillie progeslogen ac¢um.lates in ovary or
blood during most of the follicular phase. Granulosa
cells acquire the ability to makc large amounts
shorlly before ovulalion, and Ihe le.·cls within Ihe
folliclcs Ihcn increase lOO- 2{)().fold (22). Usually
Ihc plasma progeslerone rises somewhat al that
lime . When Ihe corpus luleum assumes ils secrelory
funelions. plasma progesterone builds up 10 a mid_
IUleal plateau Ihat is maintaincd for seveml days.
Wilh regre'!sion of Ihe corpus luteum. Ihe conceRlm-
tions decline rapidly. They remain low throughout
most of Ihe next follicular phase . Thc levels of
plasma 17a-OH·progeslerone can be equivalent 10
or grealer Ihan Ihose of progesterone during Ihc fol-
licular phase . bUI they do nol rise as high aflerward
(23).
Since bolh ovaries oontinue to release SOme pro-
gesterone after Ihe oorpus IUleum is cxcised. somc
plasma progeslerone probably dcrives from the
stroma (43). Although Ihe adrenal releases pregnen·
oIone su lfate and small amounts of pregnenolone
throughout the cycle. il probably has little inAuence
on the plasma progesterone. Most of Inc steroid is
rapidly mctaholizcd to prcgnanediol and excreted as
such (or aftcr oonjugalion) by Ihe kidney (sec figs.
15-15 and 15-1 6).
Nonpregn"l ra". mice. and Olher mammal, wilh
'hott ovarian cycl....cr.te very lillie proge"erone. U,u·
ally. ther. i, • 'mall preovulatory or Ihe pla,ma
levels and a limited. secondary one: during lhe abbre"i·
aled IUloal ph .... At the end of eaeh cycle. Ihe <<>rpora
lute. persiSt and $Core.. $(lme 20a-dihydroproge"eronc.
Circulating progeSterone anaches most closely to
e<>rtico<\croid binding globulin. and i.. cle.","c.
ra lC is affected by glucocortiooid as well as gonadal
hormones (IS). Somc also with the plasma
albumin The steroid is rapidly taken up by many
cell types. Mo.t of the urinary derivalives ha"e re-
duced A rings.
Luleal phase plasma 17«-OH-progeslerone origi·
nales primarily in Ihe ovary. Thc midphase platcau
is lower Ihan Ihat of progeslerone. bUI Ihe brief preo-
vu lalory rise can be of grealer magnilude.
The adrenal releases only minute quantilies
of 17«-OH-progesterone. but human glands put OUt
5 mg/day of 17a-OH-pregncnolone. The laller
serves as the precursor of 20%-100% or Ihe eircu-
laling 17-OH metaholilC during the follicular phase,
and the blood levelS can exceed Ihose of progesterone
(210). Mler the menopause, the adrenal pfOlIides al-
most all of Ihe 17«·OH-progesterone. Pregnanetriol
is Ihe major urinary melaholile.
Human ovaries seerele less 20a-dihydroprogesler·
one Ihan progesterone. but lhe amounts can be
cquiva lentto those of the 17«·O H metaoolile. Some
2O«-dihydroprogesterone is also made from eirculat·
ing progesterone. Although Ihe blood level changes
resemble those of progesteronc. thcre is a lowcr mid_
IUleal plateau. All of Ihe 2op-OH·progeslcrone i,
formed outside Ihe gonads (but oow ovaries secrele
Ihe melabotite).
...
·20I!·OL·3·01'1 E
\
zo..·DIHYDROPROOI:STERONE
avory
Ad<ooal -
<O<Iox
j
PA€GNENOLONE
SULFATE
PROGESTERONE
/
15_15. MMabolic """"",,sion.
OOt>OI<1trotiono, Allot
eorWgation.
The rabbil i, an "induced ovula«>r" whose inl ...!ilial
sto.nd, ..1... ", Io.'l!c 'l"u,;"" of 20a dihydroproS" 'ct
0110 in ''''ponle to maling "im"1i (73). Lillie progester_
one i. mad. o.for. establishmenl of a p"'Inancy or
pseudopregnancy.
BloOd Bod Foilleular Fluid Androgens
Ovaries secrete il.', testosterone (T). DliAS, and an-
drQSlencdiol (110). Usually, the plasma concentra-
tions show a preovulatory peak and a second eleva·
tion during the luteal phase (91).6,' is the major
precursor of estradiol (214). lis production rales
(aboolme and also relative to other sieroids) vary
with Ihc stage of follicular maluralion (23). Anlr31
H"ids of small vesicular follicles conlain approxi-
mately 167 ngjml. Thc concentrations rise 3-fold in
follides that undergo substantial development but
never anain Graafian sialus. This is attributed \0 a
malur3tion-linked increase in lhe.:al cell conversion
of progeslerone to 6,'. At Ibis slage. much of the 6,'
is made into E,. When atresia begins, Momatase ac-
livity declines sharply as the 6,' CQncentrations rise
10 times those of the sma ll vesicular follicles.
E,:6,' ratios tben fall from midfollicular values of 9
to as low as 0.5 ,
In contrast, aromatization ace(:\erates rapidly in
Ibe "selecled"follide, and Ihe E' ;il.' ratio can reach
32. The E,:progcslerone of a ntral Auid is also high
PRE ·2(ljI.{)l·3·0NE'
THE FEMALE REPROOUCTIVE SYSTEM
t 50,·
•
y---
5!l-PRE G NANEOION E
PREGNANEDIOL
• ALlOPREG NIIN EDIOL
• PAEGNANETRIOl
ESTROGENS
doolit>g pi..m.
.n. . _ . can ""-110
prior to resumption of meiosis. Progesterone forma·
ti,," >o<>n increase •• bu. the 10, remain. high,
The coneentr3tions of T and DHT in the antral
fluids are only 7%-9% and 0.4%-0.8%. respectively.
of those for ,).' (23). and very little DHA and an-
drostenediol a re accumulated or secreled. Stromal
cells rdcase sman amount. of the androgens and
lheir precursors throughoul lhe cycle and after the
meoopause.
The adrenal major contributions to
the cireulating androgens and their precursors ,
Pla,ma concentr3tions of DHAS fluctuate belween
1600 and 2600 ngfmlthroughout the .yde, with 00
consistent relationship to Ihc chang.. in other Ole-
roids. In women given dexamethasone t" ,uppress
the adrenal component. the values can fall as much
all 4O-fold , The ovarian contribution can then be es-
limated. A peak of 190-200 ngjml is atlainoo at
midcycle. whereas levels during thc early follicular
and late luteal phases are lower Ihan 100 (23) ,
In addition 10 servi ng as Ihe major eSlronc pre-
cursor. DHAS may provide sul fated steroids thaI
perform special funclions. (Androslanediol-sulfate is
reported to inhibit LH secrelions in some 'peci..
thaI do oot respond to androslanediol [49] .) DHA
CQncentrations range from 2.5 to 5.3 ngfmllhrOllgh-
OUt the cycle. Dexamelhasone rcduces them by
75%-80% (9 1).
Tbe adrenal continuously releases enough to
 ,
"c=o
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c
'"
! 7waH -PREGNENOLONE
" PREGNANETRIOL

,
, ",

He-OIl
,
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KG -OH

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"
PREGNANEDIO L
"
Al LOPREGNANEDIOL

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, ",
HO-CH
A

20,,·OIHYOROPROGESTEFlONE

, ,
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HC-0H c=o
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"I

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5., -PREGNANE ·3.ro.OIONE
15".OIHYDllOPAOGESTE ACNE)

FI;. 15·15. $10<01<1$ 10 "'_or_.

maintain plasma levels of 0.6 ngiml by itself.
Stromal celi, of the ovary add 10 this, and normal
plru;ma ooncemralions vary from I to l.5 ng/ml dur·
ing the follicular phase 10 2.1 at midcycte. A dccli""
in plasma tJ.' with advancing age is attributed to
more rapid conversion 10 E, (210).
Plasma testosterone rises from 0.2-0.3 n8lml dur-
ing the fnl1icular phase to O.S n&lml at midcyclc. A
second dcvation to 0.4-0.6 nslml often OCCurs 3-4
days before ,,",el of the menseS. Inhibitors of adre·
nO<.:ortical steroidogenesis have lillie innuenee. Cy·
cling women have something li ke 0 .2 ngjml of DH T.
half of whieh is released from the ovary.
Circulating androgens bind with higher affinity
than estrogen, to the TeBG. The metabolism was
described in Chapter 14.

• , • • •
Days 01 Cyele_
Fig . 15· 17 . PII""", ooncentratioo. of 1000 itrOpin aoo
,wop;.. dur;"g 11>0 mens'"'''' eye...
Gonadal Steroids In Peritoneal Fluid
Sh"p ;no,.O$<, in E, and Pros"".'''". ¢OnceOl,al;on. (10
44 and 3000 ni/ml. , •• ""eli"ely) soon .fter "v.IOIion arc
attributed to .. lea.. from the corpus lul.urn ,hat is
undergoing v..cula,izal;on (11)6). It has been propo>ed
Ih .. peritone.1 nuid sieroid, play rolo. in 'he fina l S1agC$
of oocyte mOluralion. in oocytc lran.porl, and in
f.rlili"';on.
PLASMA GONADOTROPIN LEVELS DURING
THE MENSTRUAL CYCLES
Figure IS-I 7 is a slyli?cd representation of lhe FSH
and LH changes lhat re<:ur during the menstrual cy-
cles. Smooth lines arc obtained when melon values
for large numlxl'S of subjects arc used. However,
sa mples ta ken a1 frequent inlofllals from the
subje<:( reveallhat the hormones are relea.ed episod.
ieally. and that numerOUS irregular peaks and
THE FEMAlE m:PRODUCTIVE SYSTEM
14 16 '8
I 0.,,1;01;00
troughs of small amplitude are superim posed on Ihe
general trends.
The concentrations are low al the beginning of the
follicular phase . T hey rise somewhal during the nrsl
week, and anal FSH plateau is often Scen during
days 4-6. GonadOlropin kvel. then rail and remain
low unlil afler Ihe estradiol pea k that occurs on days
10-12 (sec fig . 15·12). i\ sharp LH peak. accom·
panied by a less steep FSH devation. preecdesovu·
lation by one day. The gonadotropin levels then fan
off sharply at first and more slowly afterward.
Some obser>'ers of human and monkey cycles de·
seribe a brief elevalion of FSH shortly aflcr Ihe
omet of the menses (91). while others find either a
very gradual rise and fall (41.105) or an increase
during the laIc luteal phase followed by a continuous
dceline thl is completed just before the surge (30).
FSH levels during most of the foll icula r and luteal
phases a re variously repone<ilo be slighlly greater
(30) or a bit lower (91. I 05) than those of UI
HORMONAL REGULATION OF OVARIAN
CYCLES IN PRIMATES
Mosl of Ihe follieles of the adult. reproductively
competent ovary are of the primordial type. Some
primary follicles are universally pre)Cnt, along with
oe<:asional secondary ones. The cell s acquire limited
numbers of FSH receptors al an early slage of
development.
Recruitment
During every ovarian cyele, a small group of follicles
is ··recruiled." Each then enlarge, a. the cell, of the
granulosa grow, proliferate. develop vesieles into
which steroid hormones are secreled, and acquire
surrounding coalS of theca . FSH provides thc pri·
mary stimulus. Additional FSH administered during
the few days can increase the numbers of folli-
des recruited.
Only follides that have become ··competenl·' re-
spond fully to the FSH stimulus. Immature ones ar.
believed to undergo preparative procc!.Se, Ihal in-
elude acquis ition of FSH and estrogen rec<:ptors and
estrogen accumulation during the follicular phase,
Some never achieve Ihc state in ,,'hieh they can re·
spond, whereas others may require se.'ernl follicular
phases to do "".
Figure 15_18 summari"". currenl concept> of 'he
hormonal imeractions inV<llved in the maluralion of
FOlllT RQP IN IFS H)
New FSH ,e<:e ptots
Fig. 1 5·t8. Ho""on.1 rogtJla';o. of foJ;cutor grow"'.
o;.oc' eIIOC1. 0' FSH on gr. ""Io.. "-,,• • ,. ;n,t;ca1O'd b'! I....
<Iouble .,rows , Oy"..-g;. es with FSH to indu<:.
the recruited group during the early fo!!icular phase
(l70):
1. FSH binds to its granulosa cell receptors. It
then promoles grow/h. pol,/tra/ion (proliferation I
in Fig. IS·IS) and spedalizations Ihat indude the
inductioo of oromalOSt enzymes, One consequcnce
is an augmenled rate of t s/radio! production.
2. Estradiol alone can promote $Orne proliferation
of the granulosa cells (proliferation 2). The elfects
arc limited. but rapid increases in cell numbers are
achieved when the sleroid acts in concert wilh FSH.
3. FSH induces ils OWn recrp/Or$, Estradiol mark·
edly enhances its ability to do "". and it also pro-
motes formation of tSlrogen rtrtplors, Many of the
acti;)"s of FSH can be mimicked "'ith cAMP. Estra·
diol FSH-slimulaled cA MP generation.
but il cannot al'l alone to eilher increase cAMP or
induce FSH rec<:pto ....
4. At this stage. the granulosa cell docs IIOt con-
tain detectable LH receptors. and that hormone af·
fttts the granulosa only indirectly. It with
receptors on the theral cell s, and it stimulat es their
production of andmgens, The lalter are taken up by
the granulosa. in which they serve as eSlrogen pre·
cursors. In addition, testQ:Sterone enhances aroma_
la .. activity via mechanisms unrelated to its sub-
strate funclion (114). A direct interaction with
androgen receptors has been proposed (87),
When 'he follicle reaches • mOre advanced >lase
and acquires adequate E, st(>fes. the steroid supporls
LUTROP IN ILH I
ANDROGEN
FSH roco-p,,,, • . " n<!<og.., entOf$ .. cell. to
lynerQiz. wi'" FSH lor a,omat . .. induction. I, " 00 ........
as 1M . . tr. cIio! p!OCU'SOT.
."
ability of fSH \0 indue.:: granul()S;l cell ,«oplon;
for LH. One. Ihis process is well under way. lH
binds to those rce<:plQrs and ;\ furlher
numbers of LH receptors. ( I nhibilOrs of sleroido8cn.
csis impair receptor induction. Their effects are
counteracted by exogenous E" progesterone. (II"
DHT [164).)
The fUnc1ioo. of Ihe gonadotropins are supported by on
a$SO(lment of "growth facto"," and mitogens deliverod
by Ihe blood . O"oulO$<l. cell' maint.ined in monolaycr
cullure wi'",,"l serum require insulin. bul (hi, hormone
can b<; replaced by $Omatomedin C. FGF. EGF. and
high-deruily lil"'1',<)Io ;n. stimulale in lhe prekoc<: of
either insulin Or <Om.tomedi" (177). Ttan.ferrin (177)
and oortilCl (30) may .Iso be n:quiwi. of (hi,
kind seem to .(fecl mostly gro"'lh .nd proliferation.
("ood ividing ""Ii, .,posed 10 FSII in monolayer cullure
Can . urviv •• nd 'C<juire LH ,"""ptOfS when they are no!
, upplied (1081,) FSH and LH EGF receptors (A·
'l.
Thus. early maturalion steps involve gradually in·
creasing abilities to make eSlrogens. consequenl el·
evations of the sleroid hormone concemralions. and
the gradual of new hormone receptors,
Selection
U.ually. ju>! one <If Ihe maturing follicle. i•• ingled
oul 10 complete maturalion and go on 10 ovulation,
A prevailing hypolhesis Slates that the ""Icc led fol-
licle is initially mol'(: sensiliV<' to slimulalion, and
that illhel'(:fore more rapidly accumulales eSlrogens
and gonadotropin I'(:CCptors. It may be equipped 10
indirectly interfere with the maturation of neighbor·
ing foil ides. sinee il can more elfeetively "capturc"
Ihe limited numbers of FSH molecules presenled to
the ovary. Another concept is Ihal Ihe selected fol·
licle has a slightly greater blood flow. and it is there-
fol'(: presenled Yo'ith mol'(: stimulams. A diffe",nC<' of
this kind could occur by chance when the capillaries
proliferate. Or involve the release of vasculari1alion
promoters (230).
It has also been suggesled Ihat the dominant fe>!·
lieie I'(:ieases faCI01'5 that aCI bolh locally and on Ihe
contmlateral ovary to inhibil the maturalion of Ihe
other follicles (43). Alternalively (or in addition). it
may be endowed with Ihe abilily 10 overcome the ef·
fecls of intrafollicular inhibitors. The ftuid of small..
follides contains something that blocks the forma·
tion of Ul I'(:ceptors (30) and subslances Ihat
impede the binding of FSH (166).
Evidently. the selection is made belween days 5
and 7 (43). Although the reigning follicle is usually
larger than all others. it Can be identified before this
occurs by its ability to bind subslantial quantities of
THf FEMALE FrOf>AODUCTIVE SYSTEM
heG. Granulosal (ralher than Iheeal) cells are of
primary importance. since thesc make mosl of Ihe
estrogen (57). The ovary on lbal side has a richer
blood supply and it releases more estrogen Ihan Ihc
eonlralaleml organ.
Rapid conversion of androgens to estrogens strves
several purposes: (a) Protection is provided against
the atrCBia'promoting elTe<:ts of androgens; (b) eSIr<>-
gen released inlo the blood afler sdection contrib-
uteS to inbibition of exeessiV<' FSH and LH release.
Therefore. the gonadotropes can store up re<erves
for the LH surge (FSH suppression may also pre--
vent cohort follides fr<om completing maturalion
[229]); and (c) circulaling E, laler inVOkes the LH
surge. In the lale follicu lar phase. LH contributes 10
lowering of the androgen levels. since il reduces the
17,,·hydroxylase activity (122).
Gonadolropins can facilitate selection of addi·
lional follicles if given early. probably because Ihey
proteCI against atresia. They canoot "re<cue" folli·
cles thai have already begun delerioralion. If Ihe
dominant follicle is I'(:moved after it has undergone
substantial developmenl. il is nol ",placed by a co-
hon. In monkeys. ovulation is delayed for IWO weeks
(exactly the time required to complctc a new round
of recruilment. selection. and preovulatory prepara-
tion [43]).
Although some gonadolropin muSI be continu-
ously prescnt. Ihe plasma levcls arc low during Ihe
final stages of follicular maturalion. At Ihat time.
Ihe number of functional reaplar$ arc Ihe major de-
lerminants of the r,,-,pons ...
In al le.S! some species. prolactin facilitates in-
duclion of LH and estradiol receptors. and il cn·
hances gonadOlropin-stimulated progesterone pro-
duclion (5.142). Estrogens promole prolactin
secretion. They also act locally to al first suppress
and laler enhance PRL influences (218) .
Final Stages of Domlnent Follicle Maturation
In preparalion for ovulation. granulosa cells undergo
both morphological and biochemical changes, These
may require activation of a luleiniling stimulant. in·
activation of a luteinization inhibitor. or both (186).
The mechanisms whereby progesterone accumulales
as estrogen produClion declines arc complex.
Initially. both FSH and LH acl o>n Ih. granulosa cells
10 a""elerate cholesterol ,idc..:hain cleavage aod
fore progcslero!IC ,ynlhes;s. Som. o>f Ihe proge'terone ;,
released to th. antrum. but . ,ub"anlial fraction getS
inlo Ihe blood. LH also accelerales side .. h.in cleavage ;n
the<:a cells. but the proge. terone made Ihere i. rapidly
cOlwerted to androgen . The is tr,",ferred to the
granulo.. cells. in whkh with FSI!. The ",0-
,etid bind. 10 i" 0""'. reeep''''' within the granuk& cells.
aOO ;, dinai [Ollie cAMP generalion ,'ep (47), h ,
Off.cliven ... ;0<1'<:''''' a, 'he follicle mal ures (217) (Fig.
IS·19Aj
L.ter. the 'a'gtt coil 'O$pon= cha nge, The gonadot ro-
pin may ., fors, invoke limited "d... nsitizat;"n:' bUI
$<lme chang.. ore re,.,ed to. decline in !oo.dol ropin ,._
ere,;"", Now, LH cont inues 10 a=kr.to ,id«: h. in
clea"age, bu, ;1 also 10""." the J 7,..h)'drox)'I• .., and C 17.
C20 Iya .. activiti« in [be ,hcc. (30) . TttcrcfOfC. less of
lbe proge'te rone i. """,. rted 10 and"'l\<n, . nd f'OOI'<: ac-
curnulal" . "S ilS concentration. ,i,e, progesterone it..,lf
contributes 10 inhibilion of t hose cn,ym« (Fig. 1
g.. nul"", cell production of estrogen
dedine. for seve,ol .. uon •. The cell. now recei,. very
liltle androgen . ub$u'a le f,om the theca . and Ihe)' 10$<
Iheir . bilily to inc ...... romata.., aClivity in ,esponse 10
FSH . 1I0,",'.oe,. FSH . till accc!eral.ssid...,hain cle.v.ge
and il .1so incrc3S<:$ lhe 3/J·hydro,y>tC!oid dehyd roge-
nase aCli,ity. Therc!o ... even more progesterone accu-
mulate •. Thc decline in estrogen levels f.cilital<, lhi.
(.;0<0 estrogens i"nibit proge ...",.. prod uclion . p",ba·
bly by aCling on the 311·hyd""y.. eroid deh)'d rogcn ...
(217)). Some of the Change. in granul"", cell funclion
a .. attribUlc<i 10 ··down "8uialioo"' of FSH ..ceptor
numbo .. by FSH itselr. bUI also 10,",'<" the FSH re-
ceptor nu mbe,s, . nd;1 'educes e.trogcn .. ceplO' form.·

,, _ l UW;"''"t'"'' inr.itlitor
• lute,,",.t"'" Oli"",t3Ot

>'-',7 FSH
0<' .....
sec '§, PROGESTERONE

A. j
ANDROGEN

-
MI'U"'/!

""
17".hydroxyl .... ",
I FSH 'e<;ep\Or$ " ,

I j. C 17. C20 lyase, :

=0
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J PflOl.ACTIN recepl",'
"",
dehyd'oge\ / PROGESTERONE '
,//
I::::._/
s. PROGESTERONE ANDROGEN

\ +FSH ,,",op!<>!S-
j. lH ,,",eptols

FI; . 15·1;. "'og.st.,,,,,. biosynthesis in p@riOvul.l<>ry FSH. B. FSH incrN_ gra""IO" _'erone by . ctiog
II. "'<>11<1 ......one accumola'" In .. cella "" tI>o sec . ncl3j:i .... ydr"-'yot ....oKI TlI<I
_ou'" bOth FSH one! LH . cc.Jer .... """"sterol_ In _torono decr ....... FSH and lH 'oe.p1",'. LH
Clea"ao- (seC) , n.. p<oOII.I.,,,,,, is ....1 to lhf1 ... ,.,._ ptoge ......on.o syntheSi. in thO t"-"' . """'.....
"nt,,,,,, .nd 'hfI bloOd. LH .Iso sec ;" ,"-'" . ndrogen iO"""llon. and regula ••• roe.p1"" of thfl
cello. How ....... lhe ptoge<tor"". ;s mo.dO' into granulo .. , ProgeSlerono con1rib<J'•• to """y,.,.and
and'O\IIH1s tha, "allel1o ' 1100 gra""lo .. to Oy_;i!l .. iltl """'pt'" numt>or- contrors.

'"
lion as well (170). In addiliO/1, progesterone m.)' comrib-
ute !O Iow<ring of bot h FSI! and LH recep''''" "umbers
(2 11).
There is Srowing recognition of the impon oflC<' of pr.,.
lactin in regulation of ",producli •• funclions in the pri-
males (liS). The hormone i. a potent stimul.nt for pre).
S..ler"". production in many speci •• , and it has this
effcol when presented to cullured hum •• cell.
(200)_ lH ind"oes gronulool ""II prolactin '=ptou. and
FSH i. abo implica1«1 in thi' function.
Oocyte Maturation
The primary oocyte grows 3$ the follicle enlargo._
but il does !lOt yet resume meiosis. Studics of oocytcs
rCl11Qvcd from follicles !Usses! that the ""lis go
through a phase d uring which lhe)' are unable 10
mawre spontaneously. Later. Ihey acquire Ihe
"compel.nce" to resume meiosis, but oocyte malu_
ration inhibitors keep them from realizing Ibeir p0-
tential. Once freed of that inAuenee. tbey prepare for
di.ision but may have to go through an additional
maturation step before they can complete the pro-
CeSS (30). The cells are highly responsive 10 the mi·
cl'QCnvironment. and this seems 10 be conlrolled to
SOme extent by the cumulus oophorus.
Meiosis I is completed shortly before ovulalion.
T he secondary oocyte Ihcn proceeds to the met,,·
phase of rnetQ:$'S II . while the f,rsl polar body mi·
grates toward the zOna pellucida.
FACTORS REGULATING OOCYT E
MATURATION
A peptide with a molecular weighl of less than 2000
(oocyte maluration inhibitor. OMI) has been iden·
tified in the antral fluids of developing [<)j lieles. It
acts directly on oocytes in vilro 10 arrest meiosis. but
it may additionally exert influences on the cumulus.
It can also decrease prog"'terone accumulation even
under conditions Ihal permit meiosis 10 procecd
(30). It is likely thallhe peptide functions for a time
in all ma turing follicles. but something assoc ialed
wilh the gonadotropin surge renders it ineffcctive in
the dominant follicle preparing for ovulation.
LH stimulation of ooc)'te mawration may in.olve
OMI degradalion or inactivation. There is some ev-
idence thai it promotes Ihe biosym hesi s Or activation
of an oocyte maturation factor (OMF) that antago-
nizes OMI (30). The GnR H·li ke peptidc a lready de-
scribed may be this factor. GnRH an·
alogs i>OSSCss such acti.il)' (51). and the same or a
related pcp/ide is implicated ;n initiation of 'pcr_
malOgono,i, (155). LH d<IC' 0101 antagonize OMI if
it i. added 10 oocytes u p<l'ated from cumulus
rells,
THE FEMALE REPROOUCT'VE SYSTEM
O n Ihe other hand. oocyte maturation may be
cootrolled in different ways (161 A). cAM!' probably
act;vatesor caus", forrnation on OMI (A- I). It has
been dernonstrated that the nucleotide. it. analogs.
and phosphodiesterase inhibitors directly arrcst 0o-
cyte maturation even when presented to denuded 00-
cytcs. At least undcr SOme experimental conditions.
FSli inhibits ooc),te maturation when it is presented
to ovarian follides.1t has been proposed that the ac·
tions require palent gap junctions bet",,,,,n granulosa
cells. Estrogens Can retard oocyte maturation. and
Ihey are known to promole the formation and regu-
late the maintenance of such junctions. The path·
ways of communkation may in some way direct
cAM!' 10 the oolemma. Androgens antagon ize the
FSH inhibition . possibly by disrupting the coupling
bet",een oocyte and cumulus cdls and thereby bring-
ing about functional denudation. (The androgens en-
hance the cffe<:ts of cAM!' presented in vi1ro.) LH
de<:reases estrogen production. and it increascs an·
drogen concenlrations. It also aceelerate< progester-
one produclion, Pros"'tcrone facilitates ooc)' te mat-
uration. and it antagonizes estrogen influences On
gap junctions. Oocytes may also make cAMP (A·I).
Perloyulelory Chenges In the Cumulus Cells
The unJergu expansiUH and
tion when Ihe oocyle prepares 10 complete ils first
division. The cells possess bolh FSH and LH feeel>'
tors. bu t thcy differ from bolh mural and anlml
granulosa cells (A-2),
FSH is a potent stirnulant for progesteronc bio-
synthesi'. for produo;:tion of hyaluronic acid. and for
induction of morphological changes in Ihe cumulus
celts , The effects Can be demonstrated in .itro. Pro-
gesterone is a less poIent progeslerone stimulant. and
it fails to invoke the other changes in the cumulus
cells. However. it decreases their oxygen consump-
tion as it increaSC!l oxygen use by the oocyte (85 ).
There arc somc indications that relaxin is involvcd in
the cumulus changes, butlhe mecbanisms remain \0
be defined (24).
FSH accumulates in amral fluid prior to the onset
of the mucification. Howev<:r. it may not become ef.
fe<:ti>'e before the LH surge. since antral Huid hep-
arin and related gl)'cosamiooglycans seem to reduce
the ""nsitivity (58).
J ust prior 10 the lime of oocyte extrmion. the cu·
mulus cells arc highly responsive to gonadotropins.
The)' may stimulale prod uclion of prostaglandins in
the vicinity of the oocytc (but PGs do not acccierate
sleroidogenesis at this time),
Cumulus (coronal) cells oonlinue 10 perform en·
docrine funclions as thcy accompany the oocyte on
ils journey 10 the oviduct_ They now make PGEs
(but nol PGF .. [85]), and Ihe PGEs now Slimulatc
stcroidogentsis. Roles for PGEs in ()Xyte and sperm
transpOrt, sperm capacitation. and fcnili7.ation nave
betn proposed (182). The cells may also be involved
in the ()Xylc activalion that follo"'s fcrtili7.ation. in
creating condiliOnl; favorable for early cleavage. and
in promoting degeneration of ()Xyles that eseape
ferlili'.alion.
HORMONAL REGULATION OF OVULATION
Similarities between ovulation and inflammatory re·
actions have been cited (59). Both phenomena in·
volve (a) loealized hyperemia (which is not associ·
ated with increased cardiac OUtput or generalized
readjustments of the circulatory <ystem); (b) release
of proteolytic enzymes and of mediators lbat include
histamine . PGs. and ehemOluins; (e) increa..d
iIlary permeability. along wilh accumulation of
formed clements of Ihe blood: and (d) fibroblast
proliferation.
E, production is high during Ihe preparalive
phase. The steroid within Ihe anlrum protects
against at resia (22). and Ihe eireulaling hormone
promotes LH and FSH release. (Although estrogens
are pOtent mitogens for many cell types. they do I10t
seem to directly affect ()Xyte meiosis),
LI-I elevate.lhe cAMP I"'ck and nuciOOlidc that
escapes from the cells probably causes hislami"" re·
lease from the mast cells and basophilic leuk(lCyles
Ihat enter the follicle. There are good reason, for be-
lieving that histamine invokes most of the early hy-
peremia. Ihe increases in capillary permeabilily. and
the entry of both granular and thrombo-
cytes. Exogenous amine mimics the effects (226).
Moreover. Ihe levels of norepinephrine (a hi$tamine
antagoniSI) fall (14). and the ovary is graduall)' de-
pleted of hislamine.
Both gonadotropins and emogcns accelerate I'G
production. and estrogens also aClivate an
thaI converts PG Es 10 PG Fs. PG Es eontribute to tlle
vasodilalion and progestCTOlle production. and pro-
gesterone is implicated in ()Xyte maturation. (Roles
in germinal veside breakdown havc been established
for amphibians.) PGFs arc Ihen present in cquimo-
lar concentrations. and they Slimulate comraolion of
the myoid cells involved in oocyte eXlrusion. After
the Follicle ruptures. PG F Ie'-els drop precipitously.
bUI PGE synthcsis continucs_
Once begun, tlle events are self.perpeluating_ LH
and histamine activate thrombocyte$. granular leu·
kocytes. and fibroblasts. as Iculoeylc. release ma,ro-
phage activators and hydrolases that calalyze weak·
ening of Ihe follicular walls. More PG, are made.
and macrophages secrete a plasminogen aetivalor
that promotes conversion of f,broblasHlcri,-ed pro-
collagenase to collagenase. LH can to some eXlenl
increase plasminogen aelivalor aClivity. FSH is
more pOlenl. and cAMP mimic;s ils effects, PGEs in·
duce lhe entyme. bUl PGFs do not (17). LH pro-
mote, ilS secretion by granulosa cells (A·2).
The contractile effects of PGF .. include vaSOCOn·
str iction (which may contribute to the development
of hypoxia near Ihe site of stigma formation) and
contraction of the follicular walls. as well as ()Xyte
extrusion (231). Roles in thinning of the ",aHs have
also been describe<i (60). Scrolonin le,'c\, ris.e shorlly
before ovulalion is completed. and Ihe amine syner-
gi7.cS with the prostaglandin.
CORPUS LUTEUM FORMATION, FUNCTIONS,
AND REGRESSION
The term iUleinizatiOl1 is used by some au thors to
designate the morphological changes involved in
transformation of the follicle inlo Ihe corpus lutcum.
and by others 10 mean acquisition of the ability to
secrete copious quamities of progesterone.
When an ()Xyle premalurcly removed from its
follide. the granulosa cells begin 10 luteinize. It has
therefore been suggested Ihat Ihe germinal cells re-
tard Ihe events (137). Howe,-er. it is difficult to rule
OUI Ihe possibility thai either Ihe process of removing
Ihe oocyte Or something in thc culture medium pro-
vide< a <t imulus_(Oocyte.. are nol believed to make
luteinl'-"Iion inhibitor [301_)
LH Ihe =1 obvious regulator. but somc FSH
must "" present (186). "Luteal pbase defects" as-
socialed with inadequate progesterone production.
shortened and nonfertile c}'cles. and spOntaneous
abortions have been with preovulatory FSH
deficiencies (42). On the other hand. ... lvcly
high FSH: l H ratios may account for the reduced
progesterone secretion eharacleristic of perimellQ-
pau,al cycles (118).
So me Problems Involved In Dellnlng Corpus
Luteum Properties
The corpus Meum (eL) has been called "a fo!liele
whose alresia has been tempOrarily arrested " (172);
and Ihe lerm "corpus lutea of atresia '· is some ti mes
applied to follieles Ihat devclop bUI fail to extrude
tlleir OOCyles , It may be more constructive 10 regard
the CL as an organ that performs special functions
once ovulalion is accomplished_ In almost all of Ihe
mammals. the progesterone it seC'""teS contributes to
the preparations for implantation a nd tbe mat ura-
tion of Ihe mammary glands. In mOSt. progesterone
"quiets" Ihe myometrium and thereby protects
against premature expulsion of the fctus. The CL i.
a major site for production of relaxin (134). a hor-
mone that funcllons in both maintenance and ter·
...
mination of pregnancy_ The C l may additionally,;e_
crele foUid. maturation inhibitors (42). J n several of
Ih. repliles and other eClolherms. lh. CL is nceded
for retemion of young embryos wilhin Ihe female
lracl. Since birds release Iheir eggs soon afte r fcrtil-
izution. 00 CL are nceded and none arc formed.
The mammalian corpus lut.um may well deserve
ilS reputation as "Ih. weirdest endocrine gland of Ihe
body" (172). It undcrgocs II series of timc..:lepcndcnt
changes thai alfec! its ability tQ sccrete hormones.
and it is programmed to participate in its own de-
mise. Progesterone secretion is controlled mostly by
int rinsic factors that include positive feedback. The
steroid content is highest at the vel)' linte when the
release is maximaL When IWO "crops" of corpora
IUlea are present within the same ovary each behav,,",
in its Own way .
btrinsie hormones some inHuences. but nei-
ther dClSC-related stimulation of steroidogenesis nor
the operation of negative f«dback oootrol. can be
demonstrated . The «"ponses invoked by pituitary
gonadotropin. vary with the concentrations and the
time of presentation. A ,ingl e. chemically defined
extrin,ic regulator Can be "l uteotrophic:' " lute<>-
static:' or "Iuteolytic" when presented to the same
CI.. under different oonditions.
Specie. variation. are numerot... nd oom('lex.
The oorpora lutea of closely related animals such as
sheep and goats differ in important ways (38). For-
tunately. the CL of monkeys are similar to those of
women. and studics performed on them are broadly
applicable to human physiology. The following kinds
of species variations have been obseroed.
I. Tht numbers ofeL present 0/ any OM timt: In
primates and most other mammals in which a single
fetus i, commonly nurlured within the utenrs. there
is JUSt one C L. Rats are among the spccies in which
multiple ovulations are followed by the formation of
numerous CL during each nonferti\e cycle. The
structures persist throughout 2 01' more subsequent
eydes. The CI.. that suppon a pregnancy arc re-
tained until the end of the lactation period, and a
new set is added after the pOStpartum ovulation (86).
The mouse forms One CL for each follicle t ha t
completes ovulation. If conception does n<ll follow.
the CL r<:gress wit hin two days. In marsupials_ a CI..
is formed for each oocyte shed. but the numbers of
embryos that undergo de""lopmenl are limited. (In
One species of opossum, 22 germinal cells and 22 Ct..
but only 15 embryos complete maturation [121].)
Elephants release one germinal cell per cycle and
form one Cl. They must accumulate the CI.. from
several cycles before establishing a pregnancy (194).
2. The kinds of cells im:orporared: Granulosal de-
rivatives are universally present. and they seem to be
TflE REPROOUCTtVE
the sole sources of ste roid hormones in rabbits. cows.
IIorses. and shcep. The CL of humans and other pri-
mates. and probably also of rats. additionally 000-
lain thecal cells.
3. The mechanisms for increasing progesterone
production: This Can involve mostly hypertrophy of
the cells initially present. hyperplasia with limited
growth and specializat ion, 01' both h)'pertrophy and
hyperplasia.
4. Accessory u llt}'pu that .,imu/lanfflusly engage
in steroidogenesis: The rnbbit has especially well-de-
veloped interstilial glands. and these release copious
quantities of 2Oa-dihydroprogesterone evcn before
the corporn lutea are formed . Smaller amounts of
sim ilar tissue are found in mice, min k, and olh-
ers. but domestkated farm animals sllow little or no
hormona l dependence on such accessory cells (79).
When oonception occurs. the felOplaccntal unit
either ta kes Over 01' supplements the work of the COr-
pora lutel in humans and in guinea pigs. H"msters.
mbbits. and some other species depend on Ihe C L for
the entire gestation period, and rat. and micc n«d
it for most of the second trimester (86). In horses,
"endometrial of maternal origin sccrete
estroge ns.
.5. The kinds of steroids sN:mNi: The bovine CL
make. mO<tly proge<Ierone. along with some of it<
pregnenolone precursor and the 20a-dihydroproges-
terone metabolite. Rabbits_ sows. and mares addi-
tionally produce sma ll quantilies of 17a-OH_proges-
terone and (176). In humans and other
animals in wh ich thecal cell. are inoorpora ted. estro-
gens as well as progestogens arC secreted.
6. The of progeslerO'le made and Ihe
peak plasma com:tntration.,: Rats. micc. hamsters,
and other animals with very short estrous cycles
make only limited quantities of progesterone if they
do not mate. However. stimulation of the uterine
cervix during the periovulatory period invokes a
state of pseudopregnancy that i. as.wciated with 001)-
ious secrction of the hormonc. Primates. guinea pigs.
and other ,pecies with longcr luteal phases make
substantial amounts of progesterone during nonfer-
tile cycles. In domestic dogs and other carnivores.
high sec retory rates can be maintained for months
at a time. Each elephant CL probably synthesi?.cs
vcry small quantities. The animal accumulates cor-
porlliu tea for many months a pregnancy can
be cstablished. It has been stated that the
contains barely detectahle amounts of progesterone.
with no elevations during either lu teal phases or
pregnancy (81.194). but recent studies on Asian el·
ephants contradict this (84A) .
The pea k plasma concentra tions atlained a rc in
the neighborhood of 3 nglml for the guinea pig. 5-
 ngfml for the human. SO "tl ml for tlte mt .• 1>d
ovt:r 250 n'lml for the r.quirrel monkey (172). No
clear relationships bet .... .,.,n the progesterone
and either the lengths of the gestation the
numbers of developing embryt15 are apparent.
7. rondilions "'hkh rorf'O'o IUleil for", ."
I-Iu mans. rats. rarm animals. and many others
form C L durin, each eyde. In coo-
trail. domestic cat •. and ferret$ 80 throogh
1M follicular pn.se bul usually do not ""ulale .... hen
deprived or mlilling slimuli. (Their follicles event .....
ally deteriorate., "amsters are among the mammals
Ihat uadergn seasonal ehanges Ihat irw.:lude
in which no follicles form.
S. Tht /ijNP'JrI of CL tonupllon dOl!$ 'IOf
O«lIr : Thi. Can he as shorl as 1 days in the mouse
al>d hamster. al>d as long as 10 months in the roc
deer. Huma n SlruetP!l:S fu""'t ion well fOO' 12_ 1J
da ys. and they sbow regressive cha nges for 2
before undc:rtoing atresia. Guine. pig CL persist for
apprw;i matdy lhe same lime_ In hamsters (with 16-
day gestation periods). thc CL of pseudopregnancy
se<:rete progesterone fOO' 8- 10 da}'s. In mice (.... ith
19-20 day ,estalion periods). the secrelion is main-
tained for 10-12 da)'s. Carnivorn "ilh lu.
teal phllSc:! Spontane(lusly ul>dergo chan,t5 that in
many "'3.)"S rtscmble p$Cudopre&na"",y if lhey do 1101
mate. As discUSKd above. ele phanls a«:umulatt CL
from many successive eyclcs before conception be.
comes possible.
P. TM IIorn,,-s st-
(rtltd by Iht rorporo I,"M: These al"(: prominent
amoog Ihe eutherianl bUI may be of lilll. or 00 im.
portance in marsupials.
10. Thr rXlriNi( I/o,n!O#Jn rtqui;td 10 ntoi1lloilt
SlrurlU;t ond SltroidogrM$is: Most corpora lutea
displ.y "aulonomy"' (i.e . they CilIn persist for a lime
and ileCl"(:le progestetOi"lC: whon litprived of utemal
stimulati(lll). Lfi is "luteotrophic" for al l.a.n a lim.
time in most pla}"S
mapr role:. '" rodents and it _111$ 10 be or some
imporlarw.:e in most olher mammals. The rdbbit re.
quires estrogens, while some otho" necd FSH alone
or FSU plus est,..diol. Chorionic aonadotropins reg.
ulate tho CL of pn:gnancy in mOil mammals.
II . m«honism. involvtd ilt of Ihe ror-
pt)I"Q IUIN: The most marked dift"tr<,OCd are secn in
I"" upon the UI"u.J. Th is has been C$-
tablished for sheo p. guinea pigs. mice. rabbi!!.
pigs. aad CO""5. but not for primates.
Gen . ral Attrlbut.s
Lu i ••
0' Mammalian C o rpo ra
A universal cllal"llcteristM: is limited life "PIn
(172,231 ). Wilh fow .xceptions, the CL also display
autonomous ability to secrete P"'Jesterone (172).
LVTEOTROPINS
LH may be univt:rsa lly I"(:quired to achieve full de-
vt:IOpmenl in eutherian mammals. There arc Q)ntro-
vt:rsies Ovt:r tile lime period during ... hich it mlill be
pl"(:sent to maintain human CL for their usual 2.
.... life during nonfellik: e)-.:Jes. A ftcr hypophysco.
tomy. C L that form in response: to exogenous I'SII
and LH continue to make procesterone for 3-4 days
after the injection. are stOJlpcd. It is not kllO...-n
.... ""Iher this occurs because iIOfIIe gOnadotropin is
;tlointd in th. CL. The question of whether t1ll: d.
feCIS of hCG for a 10n8cr lime b«ause the
hormone ilKlf 1Ia. a Ion.gcr duration 01 action Iw
also 00\ been anN.red (172).
The need for LH is gl"(:3te5t SOOn dter Ihe C L
forms and commences proecslerone An
LR H analot: Ihat lowers gonadotropin le-.:ls invokes
lutcolysi. if it is given to !llO!lke}'5 days afler
ovulation. and it can do this without elevaling the
PGF: PGE ratio (IO). hCG «II{nteracls the effects.
The CL persisls if the 3r>aiott is gi-.:n 3t 7 days
JlO(itovulation.
LH can trans;cnily augment progestcrone sec .....
tKM:" It .poobobly Ille time period duri"t
whIch hIgh rntes of aCl1vi ty are maintain<:d. but il
doto$ not seem to direclly stimula te steroidogcncsi$.
The cells soon bewme Sil'lC1: proges-
terone I"(:leased to the bloodSll"(:am inhibilS LH re-
1C4K. it/v",• • reiatioruhipo bc:lwlOGn
and LH <:CIrt«nlralions In: usually found in intlct
fema les.
LH acceleratcs androgtn production in primates,
rats. and other species in which the CL contain theca
derivativu. TIle: 51oroid funct ioros as a n estradiol pre.-
cursor, and there al"(: conditions under which lestos-
terone can sUbstilute fOO' LH (71).
H i'" CUiKXntrnlions or lH Ire /ultOIflk. Ali",
corpora lutea or ral$. hamslers, ami are es-
pecially sensitive to Ihis influence . In LH
may contribute to physjologjcal C L regl"CS$ioo. Pro-
posed mccl\;tnisms '"",Iulit 5\imulal;on of PGF:r.
generntion. acceleration of enragen produclion or
usc:. and elevalion 01 the progesterone
within the CL. When hCG prolongs Ihe life of lhe
Pn:8n3""'Y, it may do so by eXCMing ac-
tions d,ffCl"(:nt from tho5c of LII. or by syncrgiling
wilh other K&ullltors.
EFFECTS OF ESTROGENS
Luteal cells ha vt: al>d CStroac n-rcccptor
complexes arc transported 10 the nuclei. The steroids
prOmOte growth and progesterone synthesis. and
they may be universally required . In some species.
estrogen is made direclly by gran ulosa-<lorived CL
ocll •. The rabbit C L cannot ma ke estrogens. and it

'"
;5 dependent on neighooring preovulatory follicles
for ilS supply. (Estrogens alone maintain the Cl in
hypophysectomized rabbits [88J.) In species requir.
ing FSH, 3 major function may be acceleration of
estrogen production.
It has been proposed thaI Ihe rabbit is especially
sensitive 10 the IUlcolylic influences nf LH because
the gonadotropin {al promotes ovulation and
thereby depletes the supply of estrogen·producing
follicles; (b) aclS on thecal cells 10 reduce estradiol;
and (e) lowers lhe numbers ()f CL estrogen recep-
IOrs. Exogenous estradiol can counteract the lUll»
lytic cffe<:\sQf heG (227).
In contrast, high concentration. of estrogens 3re
luteolytic. especially for aging corpora lutea (69).
Estrogens labil;,c lysosomal membranes and Ihe
consequenl releas<:: of hydrolase! may contribute di.
re<;lly to cdl destruction. High coneen!ratiollS of es-
trogens also clc'ate the PGf and progesterone Ie,·
els. and estrogens can synergi,e with progesterone to
inhibit LH SC<'!'Ction (181).
ROLES OF PROLACTIN
PRL has 1000g been recogniled as an "essential"
luteotropin in rats. T he levels rise during pseudO"
and exoee1>O'" PR t . C"fl """<,
of the responses. PRL provides the precursor for prO"
gesterone synthesis by activating cholesteryl ester-
ases. It decreases the activities of en7.ymes that uti-
lize progesterone as a substrate (20c>_hydroxysteroid
dehydrogenase. 17a·hydroxylasc. and 5a-redue-
tase). It stabilizes lysosomal membranes, and it in_
duces LH and estrogen rcceptors (5). PRL may be
more importan t for preserving the morphology and
SC<'retory capacity than for actually augmenting
steroidogenesis.
Hypophysectomized primates maintain their CL
when no PRL is injocted. However. the CL can re-
tain previously presented hormone for l(l!lg tilm" pe-
riods. and they may even maximize its elfectivcn=
via intercompartmental transfers (143). Agents that
block PRL secretion can bring about luteal phase
defects ( 118). J n most (but not all [IS]) mammals.
estrogens stimulate PR L secretion ,
PROGESTERONE INFLUENCES
Progesterone seems to exert positivc feedback con-
trol Over its own secretion (172). CL levels arc high-
est when the release rate peaks and when concentra-
tions of the pituitary lutcotropins are low. The
steroid increases the activities of lipoprotein lipase.
cholesteryl esterase. and dehydro-
THE FEMALE REPRODUCTIVE SYSTEM
genase. and it inhibits the 20a-hydroxysteroid de-
hydrogenase. Moderate amounts presented early de-
press POF .. generation, probably via stabilization of
membranes that contain the precursor.
In contrast. the long_term presence of high con-
centrations increases the ability of estrogens to pro-
mote POF .. synthesis (172). and it may also lo"",r
the numbers of gonadotropin receptors (211). It ad-
ditionally contributes to inhibilion of gonadotropin
secretion,
CORPUS LUTEUM REGRESSION
?GF.. is the major factor (112.231). It deprw,," gO"
nadotropin secretion. but it is also effective in hy·
pophysectomized animals. Although it does not
lower basal adenylate cyclase activity in the CL. it
blocks the UJ stimulation and also impairs the abil-
ity of cAMP to accelerate progesterone synthesis.
Since it is more effective in vi,othan when presented
to cultured cells. it may exert additiona l indirect ef-
fects (94).
Progesterone biosynthesis falls off markedly
within an hour or less aner ?GF .. presentation.
There is an associated decline in hCG binding un-
related to changes in receptor numbers. Altered
physical properties of microsomal membranes have
also been described (27). Although direct effects on
the blood flow 10 the CL have been ruled OUt, inAu-
ences on capillary permeability Or on diffusion
through the ovary may limit gonadotropin availabil-
ity(l52.231).
T he uterus is Ihe primary source of POF .. in
s heep, guinea pigs, rats, mice. rabbits, pigs. and
cows, and in these hysterectomy prolongs the life of
th e CL. In primates, most of the PO is made by the
eL
In addition to inhibiting PG synthesis. indometh-
acin interferes with PGE binding to receptors of the
C L (231). It prolongs pseudopregnancy and elevates
plasma progesterone in mice via mechanisms that
arc antagoniled by POF .. but not PGEs. At least
some of Ihe actions arc extra·uterine, since PO s
exert effects in hysterectomized animalS (37). In
rats, indomethacin Can block the rise in ovarian .'ein
hydroxyprogesterone:progesterone ratio that pre-
cedes CL regression (45). It also antagonizes estro-
geo-stimulated CL regression in monkeys. Related
inlluenees ha'e been reported for humans. but
women are less sensitive than most mammals to eX-
ogenous PGF .. (17).
Dcmise of the CL can probabty b< invoked by different
mechanisms. In pseudopregnant rabbits. h)'"erectomy
re",onSiven.., of C L .denylatt cyct.se to
heG. When corpora lut<a a« transplanted 10 the kidoey
capSule. they «,ress al Ihe ... me lime •• the ""e. in Ihe
ovary Ihal r•• eive PG. from th. ut.m. (although cireu·
lating PGF .. doe. not ri.e) (103) . Dome'licaled cals are
amo", th. f.... animals that may be insensit;.c to the PC.
Relaxin (RlX) is a name applied to a group of
clOISely r.lated peplides best known for Ihe effects
they exert on the birth canal prior to the onset of
parturition. Howc.er. these hormoncs perform othcr
functions (160.184) (:;.ce also Chapter 16).
Evidently. thc Cl must allain a certain age or
maturational state bef<>re it produces substantial
quantities of RlX. The hormone can be detected
during nonfertile cycles in humans and others ... ith
long luteal phases (193), and ovarian vein concen·
tralion. fall pr<:cipiloosly in monkeys subjOClcd to lu-
tcoctomy (160). In rats and many other species ... ith
short ovarian cyclc.o;. mcasurcablc amounts accu·
mulale during late gestation. Gonadotropins ae<:el·
crate RlX synthesis in pr<:gnant wamen (74). and
U I stimulates its production in cultured granulOS<l
cells obtained from large porcine follicles (120) .
Roles in ovulation and in prolongalion of thc li.cs of
the Cl h..e been suggested (A-4).
REGULATION OF PLA SMA CONADOTFIOPIN
CONCENTFIATIONS
Ovarian cycles depend upon rcgularly recurring
changcs in the plasma levels of FSH and lH. Our·
ing the follicular phase, small increments in the hor.
mone level! promote r<:cruitment. selection. and
maturation of the dominant folliCle and the secretion
of steroid hormones . A rapid and mass i.e gonado-
tropin "surge'· must pree<:de o.ulation and <!Stablish-
ment of the corpora lutea . In some species. a ·'second
FSH surge·' permits folliclcs that will ripen during a
subsequent cycle 10 undergo preliminary mat-
uration.
The prima ry r<:gulators of FSH and lH synthesis
and release are hypothalamic gonadotropin releasing
hormone (GnRH. lRH). and (Warian hormones.
GonadotropIn Relea sIng Hormone
The structure of LRH. the widely held belicf Ihat
this hormone serves as the major r<:gulator of both
FSH and lH secrelion. the me<:hanisms of lRH ae-
tion (34.199), and some orlhe influcnccs of LRH on
gonadOlrope r<:ceptors (139), Were discussed in
Chapter 14.
lRH seems to exert one influence on discharge of
a "readily r<:leasable poor· and another on transfer
of the gonadotropins from sequestration to :;.ccretory
sites within Ihe cells (100.139). The :;.ccond process
may involve changes in hormone glycosylation. lH
.tor<:d in the pituilary differs from the circulating
hormone. and a .hift in the ratios of twa FSH s!,«,ies
distinguishable from each other by concana.alin A
binding is reported to take place in namstcr glands
just prior to the proestrus gonadotropin surge (31).
Pulsatile pallerns for lRH release pr<::;.crve the
functions of the gonadotropes . In humans with hy·
pothalamic defects and in experimental animals with
hypothalamic lesions Or under the influcnce of
agents that block LRH secretion, continuous admin·
istration of the hypothalamic hormone descnsililcS
the cells. Reco.ery can be accomplished by present·
ing the lRH imermillently (105.199).
ha.e been .tudi.d inten,i.ely in mono
d(ll\ilge. of LRfI are continuously
, , .rise transiently. Both re-
f" hormone.rc<:op'or inter·
the gonadotropin COIl<:ontra·
tion. r.1I below 'he i I ..Iu ••. Modorato d""ago'gi"on
hourly can maintain high FSIl and LH lo.el. for days.
The same .mount< pro .. nted at half·hour inte..als first
.<Iimula(e ""d I... r • . Purther shor1ening of the
in, ..."I•• e<:olera,os tho desen.it;zation (223). Pulse. of
low fro<iucncy oI....e 'he FS fI :LfI '"'ico. This i. ex·
plained in p.tr( by the mueh longer plasma half·lir. of the
fSH (S3.223). flowc •• r, it h'$ also been sUUO<'ed that
,he Ul r<>j>OO"" i. m<lre ••• ily de,ivated.rtd m<lre '"p-
idly He.haustibk·· (9).
Gonadal steroids affect both thc amplitudes and
frequencieS of the lR H pulses . but they arC not eS-
sential for maintaining h)·pothalamic rhythmicity.
O,·ariectomized monkc)·s and sheep continue their
circhoral (approximately I-hour) and
ovarieetomilcd cats retain their 20-30-minute pat-
ternS (92).
Intracerebral administration of norrp;nel'hrine
and its agonists increases thc elcctrical aelivities of
neurOnS involved in lR11 discharge. Inhibitors of
norcpinephrine and a (but not fJ) adr<:_
nergic blocking agents abolish the rhythms in rats
and mon kcy. ( I02. 113). Pla.ma LH is not much af-
fected when warnen take a hlockers, but the dosages
uscd arc much smaller than the
keys (165). At leaSI in rats.
tion is presented
I to exert tonic
i and t ore evidently
accomplished at least partly via counteraction of the
effeclS (97). Morphine blockS ovulation, whereas na-
(a morphine antagooist) stimulates LH re-
lease. Altnougn the con:;.cquenccs of administering
apomorphine and other dopamine agooists have I10t

'"
been consistent (102). DA is believed \0 funclion a5
a physiological inhibitor (149), ScrOl()l!in is impli_
cated as a modulator_ Fibers ascending from Ihc
brain Slcm mediale inhibition (113) thai may in·
volve both dopamine and SCfQlonin.
Gonadotropin Surges
Under physiological OOIldition., Ihc mounting of
preovulatory gonadotropin surges involves complex
in!eractions between gonadal hormones and central
nervous system neurons_ Very marked 'pecies diffcr-
CII<:<'S in the mechanisms have been
(55J85).
RATS, HAMSTERS, AND RELATED MAMMALS
The mechanisms have been imensively studied in
small mammals, and especially in rats. The conclu-
sions drawn have profoundly inllucnced lhe work of
invcs\igatprS of ()\her species. and il has only re-
cently bocn recogni7_cd thai Ihe findings do not apply
to primates.
In these rodents, steroid hormones act on nCu rOnS
within the preoptie and antcrior hypothalam ic re-
gions that ma ke functional conne<:tions with Ihe
LRH cells. After appropriate hormonal prep.u"dtion
of bolh neurons and pituitary gland gonadOlropcs.
messages from Ihe rostral regions elicit a rapid preo-
vulatory diseharge of LRH into the portal blood ves·
sds. This is soon followed by a massive release of LH
into Ihe systemic circulation . The rise in portal blood
LRH is essential for accomplishmenl of the LH
surge. Lesions that interrupt communications be-
tween the medial basal hypothalamus and other
parts of the brain abolish the m idcyde surges. and
agents such as barbiturates that impair LRH dis-
charge h"e similar effe<:ts. In animals subjected to
such proccdul"<'s, the pituitary rctains responsiveness
10 LRH.
The neural circuits are complex . and it may be
necessary to activale more than one pathway (62).
The LR H l"<'lease can be accomplishcd only during
certain hours of the day. and this is atlributcd to rcg-
ulalOry inRuences exerted by thc suprachiasmatic
nuclei. DemonSlrated inRuences of estradiol and pro-
geslerone on muscarinic l"<'cepIOl'S imply involve-
ment of acetylchOline (201).
PAIMATES
In contrast. primales relain the ability 10 accomplish
LH surges when communica tion between Ihe medial
basal hypothalamus and other parts of the brain is
disrupted . Monkeys Can ovulate if they ar<: deprived
THE FEMALE REPRODUCTIVE SYSTEM
ofcndoge11Ous LR H and are then given LR H pulses
of unvarying amplitudes (105). The LR H is said to
exert ··pcrmis.ivc·· efTecls. The gonadotropcs cannol
funclion without it. bUl ovarian hormoncs regulale
Ihe scnsitivities of the gonadOlropcs and thereby the
quan tilies of LH thai arC released.
The observalions do 1101 rule OUI tha I possibility
that phy.<ioJogicol control of the menstrual cycles in-
volves some preovulatory elevation of the LRH lev-
el,. In One stud)" On monke)'s. the concentra tions of
tbe pcpt ide in portal blood rose from 23 pg/ml dur-
ing Ihe follicular phase to 103 pgJml following an
artificially eliciled gonadotropin surge (91 ).
In wOmen. the delic"te bal.nces arc e.sily disrupted.
Food deprivation can lower the LRH kvel' Ixlow the
threshold, requi",d to support ,onadotrope functions
without impair,", rospon ..s to e.ogenou. LRH (124).
Women who "'gul.rI)" engage in .. h'.Sli"3 exerci..
h."" Ix.n . hown to .uffer luteal ph..c defec!> Ih.t arc
associated with inadequate LRH rele ... and elevated
mel'lOnin level. (28). The pine.1 gland i. known to me-
di.te Ihe elf.. " of food deprivation on ",productive sys-
tem maturation in rodenlS. and mcl.,onin C.n inhibit
LRH relea .. in many 'pcei",.
"SPONTANEOUS'" VS. '"I NDUCED"
OVULATORS
Pdmates, rodents, ungulales. and SOme olhers are
classified as ",pOIttaneous ovulatorf' because .11
phases of the ovarian cycles are con trolled by intrin-
sic mechanisms. In contraSI . cats. fcrr<:ts. rabbits.
and llamas arc among Ihc "reAex" or "induced'" Ovu·
lators. Under natural conditions. they go through the
folliCular phase and then Tetain ripcned follicles for
a time Wi lhin the ovary. LH surges and ovulation do
not occur until mating and the associated stimula·
tion of = ptors of the uterine cervix leads to
activation of the LRH-secr<:ting neurons. Thc surges
can be artificially invoked by mechanically stimulat-
ing the l"<'CCptors with a glass rod. Ovulation can also
be accomplished by injecting LH without providing
such stimulation.
Differences between spontaneous and l"<'flex ovu·
lators may be qualitative rather than quantitatiV<'_
Rabbits have been known to ovulatc without the me-
chanical stimulation when they are str<:sscd. The 0b-
servation that conception often occurs at ina pprc>-
priatc times during the menstrual cycle in rape
victims has been cited as indil"<'c( evidence Ihal
WOmen ovulate in l"<'sponsc to stress. Conception also
OCCUl'S at times in women who practice
Ihe "rhythm method of birth conlrol." Rats cXjXlSI:d
to continuous bright lighl enter a Slatc of "pcrsislent
estrus" not unlike the condition !ecn in unmated
rabbits. and Ihey ovulate in response to cervical
stimulalion.
MEN STRUAL VS. ESTROUS CYCLES
Two differences belween the menSlrual cycles of pri_
males and the eslrous cycles of Olher mammal. are
known. Firsl, although mood, the level of sexual in_
Icrest. and behavior are innu.nced by hormones in
primates. members of such can be receptive
and engage in coitus at any phase of Ihe ovarian
cyde. In othe r mammals, a period of "behavioral es-
Irus" coincides wilh periovulalory events, and the fe-
males arc receptive only at Ihal time (sec Chapter
13). Second. in primates. Ihere is much more elab-
orate preparation of Ihe endometrium for implanta'
tion. If conception does 1101 occur. sloughing of I"e
uterine lining is acrompanied by rupture of small
blood ve...::ls and the blood no'" that constitutes the
menses .
Pitu itary Gland Reeeplof1l for LRH
Regularly recurring changes in receplor numbers
aC«lmpany the changes in ovarian activities. These
are imponant (but by 110 meanS sole) determinants
of Ihe sensitivities 10 LR H slimulation.
In reproduetivdy competcnt female rats. the maX-
im.1 n"",bers.re ochieve<i i"<t rrior '0 .he on"J or
the preovulatory gonadOlropin surge. A precipilouS
dedine soon follows. Similar patterns have been de-
scribed for the hamster (3). Lactating ralS ha,-e rel-
atively small numbe ... of LRH receptors. and they
s.ccrete only small amounts of gonadotropin (34).
AUTOREGULATION
LRH plays major roles in thc regUlation of its own
receplON. In castrated ewes. an injection of the hy-
pothalamic hormone is soon followed by the appear-
ance of larger numbers of functional receptors. T he
proleill$ have been identified on Ihe membranes of
the granules within and it
hu been prOp<.lS"d that the early "self_priming" ef_
fects involve translocations to the plasma membrane
(139).
When LRH is given repeatedly at appropriate in-
tervals. TCceptor numbers become chronically ele-
vated. The delayed responses are probably depen-
dent on new protein synthesis. Agents that
endogenous LRH relea,e, and hypothalamic lesions.
invoh LRH receptor deficiencies.
Although acu te administration of LR H i, SOOn
followed by LH discharge. the rate and magnitude
of the LH release depend on factors other than Ihe
numbers of LRH binding ,iles (3). LRH ean in-
crease the abilily of gonadolropes to respond to hor-
mone_receptor interactions. The innuc necs on
tion oflcn precede the OneS On receptOr numbe .... a nd
maximum ratcs of LH release Can be achieved when
LRH binding reaches a low point.
In" sludy of proeslrus rats, a low dose of LR H
invoked prompt release of LII. Soon afterward, a
second dose of Ihe same sile elicited a Io-fold
greater secrelory response, and a Ihird dQSC further
elevated Ihc rale. There was a concomitanl 30%-
40% reduction in receptor numbers (64). This
"down regulation" of receplor numbe ... docs not de-
pend on persistent receptor occupation. The half-
lime for dissociation of the LRH-receptor complex
in vitro is only 3 minules (64), and receptor loss can
follow occupation of fewer than of Ihc receptors.
LR H can also "uncouple" hormone binding to acti-
valion of the secretory re'ponses.
INFLUENCES OF LII ON RECEPTOR NUMBERS
LH and FSH negltive inAuenots on their
own secr.l;ons (109). h has been ,ugge'ted Ihal high
conotntration. of LH in the piluilary gland. portal blood.
or per;pheral cireulal;On.,m n.galive fcodbad control
over the LRH reCOPlO'" "' well (34). Obso""lion, con-
,i'tent with Ihe notion i"cludelhe following: (a) LRH r.-
cePlot numbers rail soon .fler the nalurally occurring
LH ,urge: (b) a barbilur.te .dministercd ,IIo'tly before
the ",ual lime of Ih. , urge blocks both the I.H relea,e
and lhe dectine in """'J>l'" numbeD; and Ie) """,alion
le.d.1O in reCePlor "umlx... wilh lTl"imal val_
uc, au.in,d after 24 hours.
There are .. rong .rgurnenl' QgQ;nsl the CQncopt Ihal
LH i. an important regulator. The .ffe<t' of b.. biluralc-<
Can be explained on the bui, of their inhibilion of LRH
r.l ..... and Ihe .elio", <.n be .nlagoni,-<d wilh exoge-
nou' hypothalam;c peptidc. Gonade<lomy liso affects
LR H secrelion. In a sludy of ",,"riCOlOrniud e... s. recep-
lot numbers were oot loweml by inje<ting hCG for 10
day. Slight reduction. c.n be acbic,'ed by giving
LH to int.ct animal •. bUllhi, i•• llribuled 10 Slimulalion
of pfOi.Olerone secr.lion and .teroid-mediated aug men-
l31iQn Qflhe LRIi rele.se (4).
Sub'lance. within lhe hypothalamus and Qlhcr part. of
lhe brain th. l have LH-lil:o propertie, (54) are impli-
cate<! in functions other th.n LRH COn1rol. The level< fall
after hypophy..ctomy. but removal of lh. pitU ilary doe.
nol1Olaily deplete the brain conlcnl.
Steroid Hormone Influences on
Gonadolrope Receptor Numbers and
Functions
Each of the storoids Can aCl at many sites to elicit
monophasic. biphasic, Or multiphasic responses. The
consequences of changing the concentrations of any
one of them depend on the magnitude of change . Ihe
duralion, the concentration, of other ,Ieroids, and
the endocrine hislory of the subject.

ANDROGENS
TcstOliterone is a major regu lator of plasma LH in
males. The earliest effect of uogenous hormone i,
inhibition of gonadotropin t hat is ae«>mpa.
nied by transient elevation of the pituitary ,land
content. Laler. ,onadotropin s,"tl,lttsis is deprew:d.
Sin«: DHT is "'lually eFrective, the D", not
bel ieved to rcqllire aromali7.lltion (115).
Castration of adults is soon fol lowed byelevalion
of Ih. plwna Lli. accelerated LH b;osynthcsis. a
rise: in porIal blood LRH, a nd augmentation of LRH
numbers. TlM: "down regulation'· cffecu of
LRH are diminished bill "<)I a bolished (48 ).
leronc injected soon after thc s urgery blocks a ll of
Ihe effecls. I r fil1t administered $Ome boul11aler. Ihe
flcreid revt:1'$CS changes thaI occurn:d. WIK:Il
tn:3tmenl is delayed for many days. only repeated
large doses reslore the parameters.
LRH is widdy dislributed throughout the brain
(20. 156), and Ihe hormone made by
lamic neurons is implicated in the regulation of r<:.
productive behavior. Highly potent. Iong-aeting
LRH agonisu impair tbe functions in nils. presum-
ably because Ihey I",,'''c r the receptor numbers. Tes-
tOliterQnC is not an important regulalorofsuch activ-
ities, and the effects of lite LR H-like peptidcs cannol
be overcome with tCSIOlilerone injcclions (4H).
The pituitary gland cells of females sbow similar
respollSCS to ellO&cnous DHT (34). HO'I''CVC1. pla$ma
tt::Mosteron<: 1....15 I re low in healthy adults. and the
steroid is not believed \0 be an important r<:gulalor
of either LH secretion or LRH ",eeptor numbers.
In Ihe species tha t have a Ii mall po$tovu latory in-
c ....."" in FS H secretion (M$«Ondary FSH s urgc··).
ovarian androgellS are believed to mediate the Iilim-
ulation (SO,11g). AndrogellS from both tbe adrenal
and ovary also increase inleresl (I 48).
ESTROG ENS
These steroids are evidently tbe major in
females. Tbe sensitivity of the pituitary ,000do-
Iropes 1(> estrogens varie. widely across Ihe s pecies
and at ditTerent limes in the !<'Ime individual ( 133).
T he acute effects of raising estrogen oonccntra.
lions durina the midfollicular phase resemble lilose
dc$cribed for a ndrogens. Since LH synthesis oonlin-
Ue$ bUI ilS release .. inhibiled. tbe: piluitary gland
acellmulates Ihe gonadotropin stOfU it will necd for
the preovulatory su rge. The,c responses are s«n in
both spon ta neous and roRex O\'ulalors (93).
However. fcmales build up high eslrosen levels
during the late follicular phase and lUSuin them
unlil !.ht>rdy befor.: ovulation. The steroids the ll act
THE FEMALE REPI'IODUCTlVE SYSTEM
in differ<:nt W>I)'$ 10 exen fccdbolck ronlrol
over LH .. Icue (2). They augment Ihe numbers of
pituitary binding sites and Ihe responses 10 hormone
binding. In primates. Ihey also curt inHu.
enccs on gonadotropc$ previously uposcd to but
t.mpo;nrily deprived of LRH (222). E.$trosellS ad-
ditionally promote LR H secretion. This effect .. es-
senlial for accomplishing the LH lurges in rodents
but not in primates.
TlM: positive feedback.;an be demonslraled in re-
rnales ova riectomized as adults. bul IlOl in nonnal
males. At ICI$\ in rodents. it evidently depends upon
ea rly '°oond itioninJ" of lhe hypothalamo-hypophy.
sia l sy$!em .
The faelors involved in terminalion of the gona.
dotropin surge evidenlly include down regulation of
LRH rcotptor numbers and lass of gonadotropc sen-
sitivity (100). During the IUleal pha$C. cstrogcllS
again actions s imilar to tltosc dcscribetf for an-
drQiellS. They aCI in eon«rt wilh progesterone to in-
hibit LH sy nthesis and r<:lease,
PAOGESTERONE
The elTccts of progesterone vary wilh Ihc slage of Ibe
ova rian cycle. in part because lbe responses arc m0d-
ified by the prior and concomiton! pre.en •• of estro-
gens. Estrogcns indUe(: J>rOieslerone receptors in Ibe
pituitary gland. hypothalamus. and eJttra-hypolha.
lamie brain (as "dill in (lIber target otgIns such
as the uterus and mammary glands) ( 136). AI-
lhough certain neurons do not r"'luire such ··.-stf()-
gen pri ming:· there ar(: others in which progesterone
receptor induclioo it a n _ r y (but not sulflcienl)
oondition ror achievin, sensitivity 10 pl'O$CSlerone
(61 ).
P'Q8.-sterone docs not bind 10 .-strOSCn
but il both directly and indirectly affects the re-
sponses 10 that . teroid. It Ca n impair tStr{)gen ind uc-
tion of its Own receptOfli and also interfere witb es-
trogen binding to those proteins. [ It has been
SU&/l.-sted thai Ih. eslfQ8en targets have tWO kinds of
higl\..aftinity siles. and that prtIIcslerone $<elcct ively
affeel$ one of them (32).1 In addilion.
exertl cen tral aClions th ai leeondarHy innuencc the
responses to estrogellli.
ift v<:ry hi.h C<W"""' ..... ioM. atradd
receptors. ..... i. is for
some of the .)"n!II<,;'" PfOIcst",ons
eltobli,hed 'hot Ihe ctreel$
,
.
, t be cONidered
;
'"
not con,i'tently associated with dimini'hed res""",ive_
ne$$ to Ihe hormone (136).
In primates. plasma progesterone is low during
the early and midfollieular phaw;. Exogenous hor-
mone can at Ihal time delay or tota ll y block Ihe
prwvulatory gonadot ropin surge. It acts centrally 10
decrease LR H !;tcretion (83). and il can direclly in_
hibi l gonadotropin secretion without cha nging Ihe
sensitivity to LRH. h also reduces Ih. nuclear reten-
tion for the occupied estrogen reccplor. possibly by
inducing an eslrogen ree<:ptor regulatory faclor
(l47).
Primale follicles begin IUleini7.ation s hortly before
Ihe lime of ovulalion and they Ih.n release small
amounts of progeslerone. The steroid now exens Ja-
cUirarMy inA utnees On the estrogen·prepared pitu-
itary gland (224). It is probably needcd to aS'ure re-
lease of sufficient quantities of LH to acoomplish
ovulation and the establishment of fully funetioning
oorpora lutea , Exogenous progesleronc presented
late in the follicular phase can advan .. the midcyde
su rge and increase its magnitude (212). The facili_
talion is probably excrled al several levels. In posl-
menopausal estrogen-primed ovariectomi7.cd WOmCn
(1 41). in monkcys wilh hypothalamic lesions rCl:eiv-
ing LRH pulses of unvarying ampliludes. and in es-
trogen-primed ovariectomi,-Crl animals. progester-
one-invoked LH surges probably depend hcavily on
augmentation of pituitary gland sensitivity to LRH .
However, addilional are evidently exened
centrally. In women. lhere is an associated elevalion
of prolactin levels which can be blocked wilh meth-
yldopa. In intaci rodents. progesterone has been 0b-
served to promotc LR H accUmulalion within Ihe hy_
pothalamus (97). It has been proposed that
progesterone elevales lhe norepinephrine levels and
thereby oountcracts opioid inhibition of LR I I (96).
During the phase Ihat follows, progeSlerom:
synergizes with 10 inhibit gonadotropin se-
cretion . The conditions created facilitate prolonga-
tion of Ihe life of t he oorpus lute um 10 the lime when
i! will be needed 10 support implantation if fcrtili1a-
tion occul's.
In cattle, increments in LRH are essential for ac-
oomplishing the mideycle surges. Therefore. the
stim ulatory cffc<:1S of estrogens on the hypothalamus
during the preovulatory period are of greater impor-
tance than in primates. However. the effeclSon gon-
adotrope sensilivity are also required (100). LH
surges arc not progesterone dependenl. and no facil-
ilalory elfects on Ihe pituitary cells of cows have
been observed during in vitro studies (15 1).
In rats. follicular-phase estrogens Ihe pi-
tuitary . They a rc also bel ieved to invoke sufficient
LRH release 10 acoomplish "self-priming" elTC<:ls of
Ihe hypothalamic hormone on Ihe gonadotropcs.
They additionally indu.. hypothalamic progesterone
receplors. Shortly before the LH surge, estrogen Icv-
cls decline a nd progeslerom: is released in small
amounts. The estrogen change probably lifts Ihe in-
hibition Over gonadotropin release. as the progester-
one amplifies the effects of GnRH on the pituitary
(215). Proovulatory progesterone also oonlributes to
Ihe estrogen-invoked behavioral eSlrus.
Rats have very shorlluteal phases. and the ovaries
secrete very lillie progeSlerone during nonfertile cy-
cles. Gonadotropin se<:retion is not inhibiled 10 Ihe
same extent "-' in primal", and il is therefore pos-
sible to acoomplish preliminary maturation of new
follicles. This is important. since the follicular phase
is very slmrt.
In calS, cSl radiol level! rise as the animals prepare
for ovulalion, bUI there is no increase in plasma pro-
gesleTOne. The animals release LRH in response 10
mating stimuli. and an LH surge SOOn follows . Pro-
geslerone neither enhances nor diminishes the elfeels
of estrogen and neural stimuli (93). Plasma proges-
terone rises only aftcr ovulation is completed (221).
The rabbit is also a "reflex-' Ol'ulator. In animals
of this kind. mating is followed by rapid discharge of
20a-dihydroprogesterone from well-dilfercnliatcd
"interstilial glands" of the ovary. The progestogen
may conlribUle to the lI-I release that follows .
Nonst"ro ld". R"9ul"to.s o f Gonad o tro p In
Secretion
Folliculostalin is a peplide (or group of closely re-
lated ones) wilh biological properties similar to those
of inhibin (sec Cha pter 14). The question of chemi -
cal identi1y with hormones made by Serloli cells is
slill under investigation .
II eurrenl ly belicved that FSH promotes pro-
duction of folliculostatin (follicular Auid factor, FF)
by granulosa ..lis. Higher con.. ntrations or Ihe pep-
lide in non3lrclic than in deterilm.li ng
foil ides. and roles in folliculogenesis as well as in in-
hibition of FSH release have been proposed (lll).
The "second FSH surge" in rats docs not require
an increase in LR H secrelion. and it is unaffccted by
antibodies directed against the hypothalamic hOT_
mo"" (gO). It has been amibuted to a lihing of in-
hibin oontrol after the foll icles have undergone lu-
teinization . Exogenous FF can totally block the
su rge. Although low cone<:ntralions of FF preferen-
tially depress FSH synlhesis and release. large ones
presented al the appropriate times also block the
midcyde Ul surges in rats (l75). The mechan isms
involve dim inution of gonadolrope responsivity to
LRH.
Pineal gland hormones contribme to Ihc regula-
tion of ovarian cycles as well as to seasonal danges
in reproduc tive functions in at least some sjlC<'ies .

The LRH -like gonadocrinins affC\:1 'coth receptor
numbe ... and responses to gonadotropins ( 123).
CYCLICAL C HAN GES IN ACCESSORY
REPRODU CTIVE STRUCTURES
Since primales do not undergo behavioral estrus.
other mechanisms are necded to achievc optimal
liming of fertilization and the events that follow.
Glands 01 the Uterine Ce rylx
Doring the early follicolar phase. the cells of the
oterine are small. They release small quan·
lities of acidic fluids Ihat a re hostile to spermatozoa.
and muCoS production averages 60 mg per day. Es-
trogens secreted during thc mid- to late follicular
phase stimulate growth. proliferation, and secretory
activities. The cdl sizes and numbe ... peak shortly
before the gonadotropin surge. and mucus produc-
tion increases up to ten_fold. The fluids are then wa-
tery and voluminous but low in sialic acid and hy-
drogen ion oontent. They are rich in certain
electrolytes. and Ihey may additionally oontain fac-
10rs Ihat prolong survival of the spermat07.0a.
Parallel alignments of the glyooprotein filaments
facilitate rapid paS5llRe of motile spermatozoa to the
body of the uterus. and the direction of the ciliary
beat propels the mucus inward (161 J. However. the
spacings of the filaments may retard the entry of ab-
normal spermatozoa (e.g. Ihose with 11'10 heads Or
tails) and ones that have limited motility.
Cervical fluid taken at this time forms mucus
threads if it is stretched betW<'en two glass slides. It
is therefore said to display spinnbarHeil or fibrosily.
The Auid also displays crystal1i71!1ion
pattern. (ferning) if it is permilled to air-dry. The
observations are sometimes used to estimate the tim-
ing of ovarian cvcnts.
Estrogens may additionally increase the ability of
the to respond to relaxin. In at toast some spe-
ei •• they exert influences On lysyl oxidase and olher
enzymes involved in oollagen synthesis (150).
Stiffening of the cervical walls contributes to re-
tention of uterine fluids oondocive to upward migra-
tion and survival of that traverse the
cervix.
All of the preceding factors favor entry of sper-
matozoa shortly before and for a very brief time
after ovulation. Since they take time to develop. pre-
malure passage of spermatozoa that witt have time
to deteriorate as they await the ovulation is
discouraged.
Estrogens also induce progesterone rec<:pto....
When that hormone is r<:teased during the luteal
THE SYSTEM
phase. it invokeS changes that culminate in the for-
mation of small volumes of fluid that arc highly vis-
oous and hClStile 10 spe rmatoroa. Glyooprotein fila-
ments form networks Ihal impede sperm pas<agc.
and progesterone-invoked relaxation of the cervical
walls permits drainage of Auids from the uterine
cavity.
The progesterone influences decrease the chances
that spermatozoa will gain access to the fertiliz:lIion
si te after the oocytes have undergone some deterio-
ration but are still capable of accepting the gametes.
The Endo metrium, My ometri um, Bnd Uterine
Flui ds
Estrogens sec reted during the follicular phase pro-
mote growth and proliferation of the cells of the en-
dometrium a nd underlying stroma. elongalion of the
tobolar glands of the endometrium. and augmenta-
tion of uterine blOXld flow. They alo;o stimulate the
production of copious quantities of.n alkalino fluid
that contains proteins and othor macromolecules im-
plicated in supporting sperm survi .. al and capacita-
tion (6). The fluids distend the uterus and thereby
oontribute to stromal cell maturation (202). and
they stimulate uterine oonlraction.
Spermatoroa travel short distances in rodents. and
preovulatory "ballooning'" of the uterus seem. to be
especially important for the .wimming movement •.
In larger mammals, sperm movements are aided by
oontractions of the uteruS. Estrogens promote my-
ometrial cell growth and proliferation. they increase
the levels of PGf,. and other smooth musele con-
tractants. and they sharpen the sensitivities to stirn-
olants. In rabbit uterus, catecholamines and other
regulators limit the formation of ,,_adrenergic recep-
to ... (36). Estrogens increase the r<:ceptors, possibly
by antagoni1ing some catecholamine actions.
the time for ovulation approaches. the prelim-
inary preparations for implantation are completed.
HoW<'vcr. the endometrium is not yet receptive to
blastocysts. and uterine contractions can promote
of conceptuses that arrive prematurely.
During the luteal phase. progesterone aCtS only On
tissues that are estrogen primed (107). Progesterone
then terminates .,trogen influences on growth a nd
proliferation. It invokes changes that include glyco-
gen accumulation, inward migration of the nuclei.
coiling of the endometrial tubules. and further de-
velopment of the small blood (161). In many
species (e.g. rabbits) it "quie"" the uterus and
blocb organized contractions. This is accomplished
in part via membrane hyperpolarization. There a rc
controversies ooncerning whether progesterone di-
rectly relaxes primate myometrium. It may amago-
nizc the cffe<:ts of stimulanl$ such .Ii oxytocin and
reduce PGF,. biosynthesis;. Guinea pig mYOlI'\etrium
is not inhibited by progCJ;terone.
tn a nimal . ... ilh ytty iJIon OY;Irian cyclel, lhe ... is lim ·
ited "I.rine specializalion, 1I"",'.""r. hi"oIoCical chantu
CIo" be: dc_ral.d. a.d ... lIIut"" of the c..... i. permi ..
dr1Oi....,. oIlbe ulerine ftuids.
In humaros. the preparalions for implantalion
compleledaround a week afler lhe timeof ovulation.
If the oocyte is the zySOtc ckvelop' into.
blastoc)"Sl thai sl_1y lraycis d,oY.'" the oviduel lO ar·
rive in the now fully receptive uteru,. T he conceptus
then makes its own provisions fot rCllining the: en-
dometrial spc:cial;u.11ons (sec Chapter 16).
During nonfertik: the endometrium soon
underBOt' deterioration. may initiate
the PHICCM by reduci ng t1M: numbel$ of est'Olen and
progesterone receplors (107. 136). Soon .fle....."rd.
corpus luteum regrc::ssion cuts off the supply of Sle·
rQid horfl'>ON:5. The roiled arteries suppl)'ing blood
to the superficial la}'('1$ eonwict. and this leads to
hen>O$tasis in the aner;oles. capillaries. and v.nults,
The resulting ischemia and pH change wntribute to
cell necl'\l5is. 5<lmewhat later. the arteries and
blood escapes as the superficial endometrial cells
slough 01T. Blood 1005 usually 27-36 ml. but vol·
urnes of S-80 ml hayc Ocen reported for healthy
women (lg9) , The menses occupy something like
15%-20% of the ovarian cycle
Physiological sloughing results from the iiCqucnec
of \0 tstrogen and then prQiesteronc. fol·
lowed by ste roid withdrllVllll. If e'trogen alone is
given to ovariectomized females. the endometrium
unde'lOC$ growth and cell proliferation. but progts·
terone-dependent is oot s«n . With·
dfll ..... l of the estrogen is followed by some sloo,hing
of the superficial .:.::11s. If estrogen is Ii""n first. but
the progesterone administflltion is proIon&cd fa. be-
yond the usul limc. sloughing is; dela)-.:d: howeyc •.
ev.:ntuaUy occurs CV<:n if tile pro-
gesterone is still prCSCnl. P:tOSUterone alone cannot
promote substanlial endometrial buildup.
The Fallopian Tube.
EArogcns aCI on t1M: .:.::11$ linin, lumen to pr&
mote growlh. prolifention. and specitl)izations that
inelude eiliogenesis. They also regulate the aClivily
of t1M: smooth muscle (19). The ciliated epithelium
of fimbria directs the oocyte and surrounding cu-
mulus into the infundibulum and tlten downward tOo
ward the ampulla. In primates. cilia located inferi-
orly later ,uide the conceptus to the uterine cavity.
In many other species. smooth muscle contntctions
are more important.
Since ciliated coils have limited lif•• pans. dirTer."t
"""trot. ar. ne.ded by refte. oyulators. In rabbin. 20«·
hydro,)'prog.slerone i, a major "imulanl oIei1iosenesi.
(lS).
EstrogelHlominated luminal cells seuCtC fluids
that su pport sperm and oocyte su\'\';val. sperm ca-
pIlcitation. and fertiliu.tion. Contraetion of s mooth
m\!5Cle in the region of the ampul1ary-tslhmie junc-
tion IICOOmplish.. retention of germ; ... 1cells and 7.y.
gotcs in the upper pan of ,he fallopian luk
C .... nges in cstrogcn:progcsleronc: ratios can pro-
foundly affect the: smooth muscle fullC1ions in rats
"" laler. progesterone contributes 10 formation of.
lIu id that sU PfX'IU carly deYClopmcnt of the concep-
It is also belieV<:d to regulale mUKIe contrac-
lions a nd to thereby assure alTi..,.1 of Ihe blastoc)..
al the appropriate lime. Although estro-
ratios are imporlant. OIher regu'
lators arc involved in control of the Smooth mu..:le.
TIte cells havc tlll'O kinds of PG recepto($ and $Cvcral
forms of innervation. Vawa"ive int($t;",,1 is;
implicated as a neurotran:smiller or neu.ornodulator
that II'\edialcs relaxatkln of the It may
also the cervix, but it does not stimu late my·
ometrial pfep3ratioos in vitro (82).
Th .. V... gln ...
F.strogcn. stimulate growth and proliferation of the
vaginal mucosa, They also promote production of
acidic fluids that !(["\'C as lubricants. The low pH
providts prote<:lion against bacterial invasion. and
tstrogeM arc sometimes used 0011)' ror that pur·
pose: in children and in p<)St rnenopauS31 women.
In luinea pigs. the nginai membra .... undel'!o at .....
s.lHIepcr>dent opcAin& durin, tach .....rilln cycle. In
rail. <:Slrogcn is n«ded to a«omplisll the pcr""'..."t
openi", thaI pubeny.
lllc C)'('lical chall8ts in rats are 10'(:\1 eharaclcrized
(228). and vaginal smears are widely IUCd 10 c:sti-
--
IrQlte the timing of ovarian events ami the effects of
Figure 15020 prowides a rough indica tion of the
appearances of the smears during t1M: four Stages of
tlte rat C)'('le.
f'ROESTRUS: Grwp' of panially maMod ova.ion fol-
(16--22 hooI..) Iidcs ur>derco preparations for ".......
tion. Plasma <1t"" •• k:.cls • • e low .t
first. bOll they ,radually rise. TM utcru.
slo.'ly becomes h)'ll.rcmie and dil-
tended ,.ith ftuid. 1.$ !he endometrium
be,ins its spcc:iali .. tions for impb ...
'at;c,n.
Initially. lhe thin valina\ mucOlll por·
milS th. escapo of I.ukoxyt.s via diapo-

, ' '€?"
"
,,
' ",
o
...
@
•
Q large. flaltened cell remna." thaI ha.e
•
.... Pro- •• "", e.
, ®
• nified ceil, fall, and large. nucleated
• •
(V @ large n"mbe ... of quile .mall, nucleated
C. M eteWu$ O. Ditt.uu.
Fig. 15-20, "'ppea'af>Oe 01 • .,g;,ol ..,...... 01 "'" ,01 at
four pho . .. of !he e",r<l'" cycle.
desi$. A ,moa, la ken at \hl\ lime con-
lains many leu kocy!es and also
numerOUS .mall, rounded. "uolealed ep-
ithelial cell •. A> cmolleru pronwto cell
prolifera1ion, the vaginal woll gradu"lIy
lbicken •.
ESTRUS: Follicular ","lura1ion i. completed, and
(9-IS M>Il ..) Ihis is 1011"",0<1 by o"olalion. Hi&h eStro.
gen levels promote secretion of uterine
nuids and coomiction of lh. cc ... i • . wilh
con"'qucnt bollooning of the ul<ru$. To-
ward Ih. end of lhe phase. e'trogen ley·
el. dedine and SQme prog¢$lerone re-
loased . Co ..;o.1 rclantion Ihen permi ts
drainage <>f tho uterine ftu id. Soxua! n;-
ccpti.i,y d".lopS a' thiS limo_ h i•• t-
tribuled 10 em<lg.n Slimula!ioo.oo pro.
,,,,(erone facilitation. Howe.cr,
OltrOgell$ rromote prolactin seCreI;"".
and role. for this hormone ho'e re<:enlly
been dern<>n$traled (79A)_ M.. ing wilh
a fertile male u.ually lead. to OOI'I<eption
and Slimulali"" by an infertile ""e
bring. on p:<cudoprognancy_ In either
case (and also without mating). eM""ra
lutea form and secrete .mall.moun" of
progCSterone_
The .aginal rnuCQO.a i. ""w mull ilay_
ered, and il Ihe",fore bhxh leukocyte
escape. The cell. continue to srow. Since
R€PFIOOUCTIVE SYSTEM
the .uperficia l ones . re oot dose to blood
• ....1., they be.""", keratinize<! (corni-
fio<!). lose their nuclei, and soon . Iough
off. The .aginal sme.r i. crowded with
iIfegul.. outlines.
METESTRUS: Thi. phas< begin, soon ,f1el o,ulalion .
(10_14 h"",..) The ulel.' conlinu" preparation fM im-
plantalion. Sexual recepti.ity i. ler-
minated .
Proge .. erone prorTK>lcs mucification
of the thickened .aginal muc.,..., and Ihe
.me.r cont.in, mucus .hrod.. ,,>
.Ioughing continues, Ihe numbe" of cor-
on .. appea r a lonll with limited numbers
of leukocytes.
DIESTRUS: Th il ph... la>t. I,.., day, in 4-<I.y cy-
clers (and 3 in 5-<1.y cyclers) if concep-
tion dotl not occur. The ,mc.. contain,
epithelial cell., many leukocyte •. and
SOme muCu l .nd dobris .
MECHANISMS OF ESTROGEN ACTION
Much of the generalized discus.sioo of the me<:ha-
nisms of action of steroid hormones presented;n ear-
lier ehaptc," con be applied to thc ovarian hormone.,
The study of eslrogens presents a few special
problems.
I. Target organs such as c hic k o,iduct. mamma-
lian ulerus, a nd mammary gland COIltain more than
one kind of estrogen·responsive cell. It is difficult to
make quantitative measurements of the responses if
OIl ly one of the componenlS is invol.ed, if opposing
inAuences arc exerted, or if the time CO\Irses vary
with the cell types. The problems are not easily
>o1'ed by Out a single celltypc. The pro-
cedures in,oke injury. and they destroy normal cell-
to-cell interactions. Moreover. agcnls used to maKe
the separations can exert pharmacological effects.
2. Data obtained wilh one kind of preparation are
often not applicable to hormone functiollS in an-
mher. Chick oviduct ma kes very large quantities of
estrogen-induced proteins and it also displays growth
and proliferation responses. Utcrus undergoos differ-
ent kinds of specializalion, its proliferative responses
are unlike those of chick oviduct (206), and il makes
very little spedfic new prolein_ Kidney en?ymes are
affected by estrogens, but the cells neither grow nor
proliferate when the hormones act On Ihem.
3. The Same kinds of organs show speci es 'aria-
tiorn; in response to pharmacological agents. For n-
ample, tamoxifcn exerts mostly estrogen-like actions
when presenlw 10 mouse uterus. but it has anlics-
trogcn influences on rat uterus (140) .
 4. EslrogellS play impOrtant roles in regulalion of
Iheir own receptors and the receptors for other hor.
mones. These effe.:ts vary with the target cen type.
Ovary. uterus, vagina. and mammary gland are
among the orgal\S in which estrogen can increase its
own re<.:cptors and induce ones for progesterone. Pro-
gesterone tends to reduce the numbers of estrogen
and progesterone receptors in SOme of the cells. Only
some parts of the brain are affected by pretreatment
with steroids. In other regions, neither estrogen
(174) nor progesterone (136) receptor content is af·
fected by estrogcn "priming."' The infiucnces of ex·
tragonadal hormones on the receptors also va!)' with
the cen type. In some largets. the receptor numbers
even undergo diurnal variations (136).
In many studies, uterine preparations from im_
mature females Or from ovariectomized adults thaI
have undergone long-term hormone deprivation are
suddenty to fairly high concentrations of es-
lradkll-17p. The findings may not provide good in-
formatiQll on the roles of the steroid under more
physiological conditions. In the animal, the target
cells are gradually presented "'ith slowly rising hor-
mOne concentrations in the presence of many othcr
regulators. The rates of hormone uplake are affected
by plasma proteins. and the respOnses are modified
by such things as testosterone binding to cstrogen re-
ceptors and interaetklns.
5. A single hormone can exert a series of influ_
ences that 3re time-dependem . The earliest effeclS of
estradiol on the uterus of an intact female include
augmentation of blood flow. release of
and generation of cAMP. Some actions may be ex-
erted directly on surface receptors or on lysosomal
membrane, (159), and others can inV<lI\'C the gen-
eration of prostaglandins. Certain of the metabolic
effects have been linked with phosphorylations or
other mechanisms for activation of preexisting en-
zymes. whereas others the formation of new
proteins. Some delaycd actions depend on carly ones.
Others take time to devclop for different reasons.
Estrogen Binding Proteins
The target cells oontain macromole.:ules thaI bind
estrogen, wilh high affinity and specificity. The term
"receplor"' is applied to the ones directly implicated
in mediation of the responses. Although androgens
must undergo melabolic conversions before thcy can
act on some cells types. and many tissues melabohe
estrogen,. are good reasons to conclude that es-
tradiol. eSlronc. and estriol bind directly.
11 is widely assumed that all of the effect, on cell
growth and proliferation are preceded by the for-
mation of e$lrogen-receptor complexes that are sub-
sequently translocated in modified form to the nu-
elei. The no!k1n that the receptors are present in the
cytoplasm is supported by the rapid accumulation of
radioactive molecules in that compartment following
the presentation of tritium-labeled hormone, and by
the recovery of hormone-receptor complexes after
cell fractionation.
The molocular weights and sedimentation con-
stants (5 values) of the estrogen bindins proteins
(EBP!. eslrophils. estrophilillS) vary with the toch-
inques utili1.ed as well as the tissue sources. An im·
portant determinant is the concentration of inor.
ganic salIS used to stahilize the proteins.
RoCCpl"" for glue<><orl;<;<>id, ..em 10 r¢quire "'oct;va-
lion" before tbcy can bind to ,teroid, w;lh high affinity.
The f.cililalory of ATP. and "'her con-
sidcral;on •. oUPPOr! sugge.tions that the receptor mu'tl><:
phosphorylated. There arc eonlroversie. over ..-hether es_
Irogen receptors undergo activahon (or phosphoryl'lion)
undcr phy,iological condilions (76AJ.
A 4S (70.000-80.000 dalton) oomponent cx-
tracted from uteri in thc presence of 0.4 M KCi i,
stated by some to be made up of the "true" receptor
associaled wilh a Y protein that blocks receptor in-
leraction with nuclear "acceptor sites:' Jt is pro-
posed Ihat the constiluents must dissociate to permit
formation of an estrogen_receptor complex . Thc lat-
ter thcn undergoes a time and temperalure depen-
dent "transformation" that could inV<llve dimeri7,a_
tion, or association "'it h SOme other macromolecule
and/or changes in oonf.guration Or chemical ma ke-
up. The process culminates in production or a 5S
(I 140.000 dalton) derivative thaI (unlikc its
prccursor) binds with high affinilY to the chromatin
(145). The concept is consislent with
tbat the I""ddioactive marker shifts from C}'loplasm to
nucleus, and that tbe progressive reduction in cyu>-
plaimic 4S compOnent is associatcd with a parallel
rise in the nuclear 5S concentration.
Proponents of the lIOI;on that the 4S ESP is the
"truc" 1'Cceptor regard an 8S macromole.:ule that is
in thc of KCI as either a I'Olymer
of the 4S protein or as receptor loosely asSOCiated
with other cell compOnents. (The 8S form could .
thereforc, be an artifact produced during the extrac-
tion process.)
Different ideas have cmcrged from other labora-
tories (32) . It has been repOrted that when modcratc
concentrations of eSlroge!l$ are presented in vitro to
uterus and several other targets, half the hormone
binds to a "Type [" macromolecule to form a slowly
dissociating \IS steroid-protein complex. Since that
complex is translocated to the nudcusand this is fol-
lowed by changes in cell function that <:an be dircctly
related to Ihe horITlOlle 3ctions, it is concluded that
the 8S substancc is the "true" receptor. A rapidly
dissociating 4S complex forms when the steroid aI-
taches to a '"Type 11" cytosolic protein that binds

with spedficity but lower affinity and greater
capacity. Since it is IIOt Iranslocated to the nucieus,
it is proposed that the 4S complex serves to C<lncen·
trate the estrogen within the vicinity of the true re-
ceptor. The possibility that it resides in the extracel-
lular space has been considered.
Two different complexes haV<' addilionally been
identified in nuclei studied in vitro. The Type I nu·
clear compOnent is believed to be derived from the
Type I (85) eytosolie complex. It appears SOOn after
the steroid is presented to the cells. A Type II nu·
clear compicx docs !lOt appear until later. It is rwI
derived from the 4S substance (which does !lOt
undergo translocation) , The origin of the Type II
complex is not known. One possibility is that it is al·
ways present in the nudeus in a form that makes it
undetectable until after I(>ng·term nuclear residcnce
of the 8S complex leads to its "activation." Another
is thaI the Type [I component is derivc<! from the 8S
macromolecule . It has been demonstrated that a
" KCI resistant" material (one that can!lOt be ex·
tracted with KCI but requires the use of protcolytic
enzymes) can form from a "readily extractable"
precursor.
The Type I nudear compkx is implicated in me-
diation of hormone effects that are manifested in 6
hours Or less. whereas the Type II seems to be
nceded for ddayed stim ulation of cell growth and
proliferation.
Thc traditional conceptsof steroid hormone action
have been challenged on several grounds: (a) Since
extraction of unoccupied receptors (i.e .. ones not
bound to 'teroid) "'quires elaborate procedures, it
has been ,uggested that the receplors of unstimu.
lated cells arC sequestered, possibly in Iysosomes
(208. 2(9). and that Iysosomes participate in the
transport of complexes to nuclear sites. (b) Jt has
been pointed out that a 4S molecule may be more
suitable than a 5S for translocation, since it is
smaller (136). and the the 4S to 5S conversion pro-
ceeds morc rapidly in the presence of DNA (116).
(c) Early reports that unoccupied receptors are p",s-
ent in target cell nuclei (191) have been followed by
more recent ones indicating that mosl of the mole-
cules are. in fact. in the nuclei . and the cystolic 10-
cali7.ation is an extraction artifact (lOlA). It is now
suggested tbal rcceptors of unsti mulated cells are
loosely associated with nuclear compOnents, and the
steroid binding leads to tighter association (101 A).
Nuclear " Acc eptor Sites "
There are conllicting thoughts about the nalUre of
the "acceptor sites," Nonhistone ("acidic") proteins
differ from one cell type to another. and also in the
THE FEM/l.LE REPROOIJCTIVE SVSTEM
&lime cell undergoing changes in function. Nude<>-
somal "'gions are rich in proteins of this kind. and
they may be si tes of active transeription. It has
therefore been proposed that the protcins serve as
the acceptors.
In contrast. histones are remarkably similar
across the species. and oncs found in plants and in-
vertebrates are !lOt very different from mammalian
proteins. Therdore. there has been a tendency 10 re-
gard histones as "generalized" regulators of nucleic
acid function. However. it has been shown that es-
trogen receptors derived from rabbit uterus intcract
u/uliW'ly with histones of the H2B and H2A types
(95), DireCI binding of estrogen--receptor complexes
to Ihe DNA has also been suggested. It is possible
that hormone actioM invol", associations of the re-
ccplor complexes with multiple nuclear components.
Earl!f Co nsequences 01 Estrog en-Rec eptor
Comple)! Association within t he Nucleus
RNA pOlymerase II (B) activity rises rapidly and
peaks within one hour. This is associated with the
formation of DNA_like (p",messenger) RNA. It
may therefore be necessary for the cell 10 make
sman quantities of one or more specific mRNAs and
proteins that mediate the subseq uent events. Since
the changes in enzyme activity can be blocked with
«-3manitin but !lO1 wilh cycloheximide. the finding..
are consistent with "unmaskin8" of new initiation
sites but nol with V<'ry early induction of the poly.
merase, Small quantities of specifoc estrogen-in-
duced proteins ( IPs) can soon be detected, and they
are believed \0 be symhesi,ed on preformed ribo-
somes. The functions of the IPs arC not known. At
this stage. there is no gtltf'raliud increase in cell
RNA Or prolein content.
RNA polymerase I (A) is u-amanitin_insensitive.
Its acti_ity rises after the first hour, and high levels
a", attained within 4 hours after the hormone is pre_
sented. The RNA directs the formation of rRNA.
and its production in the target cdls is associated
with increases in the numbers of polysomes. There-
fore, this effect increases the efficiency of the pro-
tein-synthesi1.ing machinery.
Delayed Effects
The eSlradiol-t7.8 (E,) complex is retained within
the nueleus for many hours. The delayed conse-
quences include sustained elevation of RNA pOly-
merase I acti_ity and a secondary increase in RNA
polymerase II (33). Very small increments in DNA
synthesis can also be detected . but the cells do not at
this time p",pa'" for mitosis. More rapid DNA sy".
 thesis is Sten 18 or mOre hours after thc hormone has
been presented. and the f,rst signs of cell prolifem-
tion appear after 24 hours. The delayed responses in-
clude accelerated glucose uti1i1.ation and increased
activities of both DNA polymerase" and thymidine
kinase. Thoy a,. evidently dependent on the earlier
changes in RNA and protein synthesi •. since they
can be prevented with actinomycin D Or puromycin.
The increases in DNA polymerase and thymid ine ki·
nase activi(ies occur when these agents arc omitted
but inhibitors of DNA synthesis arc used. In the
presence of aminopterin (which imerferes with mi_
\osis), the cells undergo hypertrophy (206). Maosivc
doses of eStrogens can directly increase DNA poly_
merase activity in SOme eclltype •. but it is not known
if the actions a re purely pharmacologicaL
Estriol (E,l binds 10 the E, receptor. and the COm-
plex formed lranslocates 10 the nucleus. However.
the E, complex dissociates rapidly and E, soon re-
IUrnS 10 the cytoplasm. When a single dose of the
steroid is given to animals. only the ea rly estrogen
responses arc invoked , The RNA polymerase I ac_
tivity returnS 10 pretreatment levels within a few
hours, and there are no dcla)'ed effects On DNA 'yn-
thesis or cell proliferation. It seems, therefore. that
the late changes require long_term retenlion of the
steroid-receptor complex within the nucleus. The ac-
tions of E, Can be mimicked with frequently re-
peated dosages of E,.
Estrogen Influencell on E8irogen Reeeptor8
Receplor proteins are made by the target cells of
both immature and ovarieclomized animals. When
estrogen presentation leads to accu mulation of hor-
mone-receplor oomplexes in the nuclei. the cytosolic
conlent of the protein falls, and new synlhesis is ac-
celerated. Re<:eptor replenishmenl of this kind can
be blocked with protein synthesis inhibitors.
Stimulated cell$ ulilize two otber me<:hanisms for
n:ccptor n:plenishment. (a) When the hormone_pro-
lein oomplexes aeoomplish their missions within the
nucleus. the receplors dissociale from the steroids
and undergo changes that lower the affinity for the
hormone. Some of the "used" receptor is Ihen "re-
activated" via mecbanisms that do not involve new
protein synthesis. (h) A steroid-receptor complex
Can bind transiently to a low·affinity nuclear binding
site. When it leaves the nudeus. the complex disso-
ciales, and lhe receptor prolein undergoes direct"re-
cycling." Progesterone and pituilary hormones have
been shown to retard estrogen reeeplor replenish-
ment (136). Newly synthesized RNAs have been
implicated in release of the receptors (76A), and il
has recently been shown that RNAs can function as
catalysts (l14A).
Pharmacological agenls have been used to dem-
onstrate that the delayed actions of the cstrogens re-
quire reecptor replenishment and multiple cydes of
hormone-receptor allachments. Nafoxidine elicits
all of the early E, effects and also "one round" of
DNA ,ynthesis and cell division . Its subsequenl
"anti""trogcn" activity i, amihuted to failure 10
bring about receptor replenishment (33). Tamoxifcn
is more like E, in that it fails to sustain tbe RNA
polymerase I activity or invoke delayed responses.
However. the antagonism persi.ts in the presence of
E, and free receptOT. It has therefore been suggested
that tamoxifcn-reeeptor combinations ei ther block
the formation of the Type IJ nudear complex (im-
plicated in mediation of the delayed actions) or pro-
mOte production of an inhibitor of the effects exerted
on Ihe genome (140). The mechanisms could involve
binding 10 nuclear sitcs different from Ihe ones that
mediate estrogen stimulation.
Different pharmacological studies rai,e the possi-
bility Ihat some influences of E, do not involve at-
tachments of the hormone_receptor complexes to nu-
c lear components. binds
only to microsomal molecules, but it mimics E, in_
fluences on uterine groWlb without increaSing RNA
polymerase [activity (136).
Progesterone does nol bind 10 the unoccupied es-
trogen receptor or affe<:t the cstrogen binding allin-
ity. It may. however, interfere with estrogen uplake
or be convened to a metabolite that binds the EB P
(136). Its ability 10 rapidly and sele<:ti.cl y lower the
numbers of nuclear estrogen-receptor complexes is
dependent on new RNA and protein synthesis.
Thyroid hormones are e.idenlly addi tional modi-
fiers of estrogen actions. In deficiency states. the latc
(but not the carly) responses to estradiol are im-
paired (1M) ,
Anti-Mitotic Actions 01 E8trogens
Chick oviduct undergoes sustained proliferalive rc-
SPOIISCS to long_term E, admin istration. Pituitary
glands undergo marked hyperplasia. and they can
double in size during normal pregnaneies. Chronic
overdosage invokes tumor formalion. In cont rast,
'o'llgina, and cerlain other targets soon be-
come refractory to the milogenie actions. In some
forms of breast cancer, pharmacological dosages ini-
tially stimulate but subsequently arrest growth.
Delayed anli-rnitotic effec" may result from in_
duction of substances thaI block the entry of cell,
into the S (DNA replication) phase of Ihe cycle. or
of chalones (140,206). Anolher possibility is that
prolonged stim ulation depleles Ihe cells of constitu-
ents rt{[uired to sustain the proliferative responses.
Tissues that continue to divide rnay depend on estro-
gen.stimulated provision of other regulators. Growth
hormone. prolaelin. and prostaglandins accelerate
M.
of many c:elltypcs, El nlcas:lthcm. h
also induca EGF reaptors <,.·2).
e ,trOien Induction of Proieslerone
Recepto r'
The responus of Ulerus, uteri ne cervix, vagina. pi·
tuitary gland, alld some: olh., targets \0 progester.
0lIl: nquirc estrogen "priming.·· Estrogen ill(\ucl ion
of progCS\CI'OJIoC receptors is an early e\'enl t hal can
be &COCOfTiplisbc:d ..·jlh E)-
The bo:ncficial .FreelS of exogenous progesterone
in puienu "'jlh breast <:lInce. have been linked with
m()(iIIlalion of estrogen 5timuiaLiocI (57). However.
progeSterone probably eXC'1I estrogen-independent
elrects as well. h has been pointed OU1 thai steroid
em cdl proliferation can involve changes
in blood supply, cc!l'IO<CU inlcrnclions. rates of cell
destruction, and both production of and 1(1
immul\C faclDn (101).
PROGESTERONE RECEPTORS
On the basis of studies wjlh chid oviduct, the fol-
lowing OOllCC plS have been presen ted (216): The pro-
IICSt.ront is a heterodimer oomposed of a
3.65 subunil A wilh a w<=iaht of approxi·
malely 79.000 plus a 4.25 subuni t 8 with a weight
01' lI'ound 117.000. Each COITIpOIICnt pew...... an al·
Uochment sile for one molecule of procesleroroc.
Afler Ihe progcstcroncs bind 10 the dimer. lhe
complex underJOCS activalioo and lr.tnsloc;ues 10 Ihe
nucleus. The B COmponenl out" and 31·
tuhCli 10 Ihe appropriate site on Ihe g"lIOmc. possi.
bly by re.:ognizing nQIlhitlonc proteins.
The A subunil muS! from the romplex
before it binds to Ihe ae«ptOf si te. Th is may be ac·
complished via activation or release of a protease in
response 10 the inilial bindi", of the whole complex
10 lhe chromatin.
The A component (which holds Ollt 01' Ihe pr<.>gc:s-
terone molecules) then binds direct I)' 10 the DNA
sel'Mnllo which it is directed , It is believed Ihatlhe
ratc of R NA synthesis that follows re-
sult! from "unmasking" n\:W for RNA
merase a tlachment.
Ma ny aspects of progesterone me<:hanisms rc·
quire fu rlher inVeSliglltion. Targe t cells can metab-
olize progCSleronc to Sn- and 2Oa-rcduced metabo-
liles •• nd weh molecules are also pratnl in blood
plasma. The me\.abolitcsuen actio ... somcwhal dif·
ferenl from lhose of p1ogutcront. but only a few 01
the fu nctions are know n. The Clt.ly« sev·
enll reael ions. and some progCllteronc influences
THE FEI.IAlE lIEF iiIOC>VCTIVE SYSTEM
hive been anributed to oompclil ion with other
Mlbslratts.
In IIIe presence of proi<:UeS 01' the kinds found in
cells. receptor fragments thlt rClain progesterone
binding sites arc formed. The
fragmcnts may he physiologically relevant metabo-
liles or degradation products whOllC formation ron·
tributes to terminalion of the horlllOll<' actions.
(However. sil\Ce they have ba:n studied in vitro, the:
poMibility that they arc hu not been ruled
0111 1132].)
AI least some: actions 01' p1Q&<stcrone. for cum-
pie. ones utned on amphibiln oocytes (ISlA) may
00' involve inleraclions witb 'he classical kinds 0(
rC(;eplon.
GONADAL STEROID ACTI ONS ON OTHER
TISSUES
EstfOlCn .clions on hoM arc physiologicaLly impor·
lant bul not .. ell defined (sec PIon IV). Alihough no
eslroccn receptors bave been found. Ihe bormooc
can accelerate linear gTO'<O·th in jUVi:ni\C:S and pr0-
mote epiphyseal closure .flc.....ard . It also inHuc:1\CCS
vitamin D parathyroid hormone [1Inc-
lions. some Upeclll of ca lcium me tabolism !lOt di.
' '''' tty wi l h onrl form.
of behavior (e.g. food intake and tendency to engllge
in physical activity) thai indi'eclly affect 000c. Ad·
ditionany. il is an inhibitor 0( $Omalomedin produc-
tion ( 162).
Girls Sttreling u«:ssivelmounlS early in life may
be lall for age. but lhey underllO premature Clkifi.
calioo of ille Women OV3riectomi1.Cd duro
ing carly adulthood suffer rec!uctioo;n bone mw if
rcplacemenllllernpy is not provided. After the men-
Opause. reduced rates of estrogen production arc said
to acce lerate tlte bone loss litat accompanics normal
agina. Ilo,,'ever. Iher.:: are problems with lbe can-
Bone kt5s lhe menopause. Moreov<:r.
many women secrele sub5tantial qllantitics of adre-
nal andfOlCftS and CORVi:rt the steroids 10 estrogens.
Although e.<OgcOOU$ estrese", are reported to retard
bone loss in menopausal women. they evidently tan-
not re5lorc depicted tissues (13) (sec Part IV). The
Jleroids ore sometimes useful for acceleraling tile
hca ling of fractures in older women.
In the liver. estrogens stimula te sy nthesis of
seve ra l important plasma prote;lI$t hat incl \lde CBG.
TeBG. TBG . renin subslrate. and
some coagulation faclon. Under certain conditions.
lhe o;onccntrati ..... of lotal hoi " .....,es are adjusted so
thai the Ie,'cis of free (bioIogicIlly le' ;vc) steroid are
not changed. In ot hcrs, lhe: estrogens affe<:' tbe en-
docrine functions . In some women. negative feed·
back controls ()\Icr angiotensin production arC def:c·
tive. and high renin substrate concentrations invoke
hypertension during pregnancy or the use of onl
oontraceptives (99). Estrogens also alfect lipid me-
tabolism and the circulating levels of cholesterol and
triglycerides. They contribute to regulation of biliary
excretion. Although sexual dimorphism is invoked
mostly by different regulators (see Chap. 14). estro-
gens are major modulators of thc activities of en·
7.ymt-< involved in intermediate meta'oolism and ste·
roid hormone degradation. Hepatic re<:eptors for
are controlled by complex mechanisms
that invol"e growth hormone and glucocorticoids as
well as the ovarian steroids (44) . Progestogens
exert limited inAucnces on the glucocorticoid recep-
tor<, and they are also believed to alfect insulin
functions.
The have estrogen receptors, and re-
s!Xlnses to the hormone include changes in the activo
ities of ornithine dc¢ar'ooxylase and SOme other en·
zymes . However. most estrogen influences on renal
excretion are indirect. (For example. water retention
has been linked with production of renin subs trate;
th: chnges in calcium and phosphate excretion re-
sult mostly from effects exerted on calcium absorp-
tion and calciferol metabolism.)
Progesterone probably contributes to the water re-
tention experienced by many women during the laiC
luteal phase. Among other things. it is oonverted to
deoxycorticosterone in the kidney a nd at SOme other
siteS (225). The kidney is not known to contain pro-
gesterone receptors. When the cone<:ntTl\tions rela·
tive to aldosterone are very high, progesterone can
act like a mincralcorticoid by binding to aldosterone
receptors. Ho",·ever. since the ovarian hormone ha<
limited potency, its competition for aldosterone re·
ceptors can actually diminish water a nd salt
reabsorption.
ProgeSlogens are sometimes used to treat "pre·
menstrual syndrome." a oondition associated with
uterine cramps, edema. and often also anxiety or
depression. Limited numbers of patients respond
well to Ihe steroids. Others are either unaffected or
more troubled by the "sidIXffects" than the original
symptoms (207). It is likely that the benefits reali7.ed
result from loweri ng of prostaglandin levels and
from actions curtcd on the central nervOuS system.
(Ma ny clinicians report higher SucceSS rates with
prostagland in synthesis inhibitors.) Most of the ef·
feets on neurOnS are depressant. The drowsiness ex·
perienced by many women during early pregnancy.
and the psychic depression that accompanies the use
of oral oontraeeplives in some individuals, are attrib-
uted to progestogens. Pharmacological doses of a
rew synthetic agents mimic the actions of general
anesthetics . Progesterone can also act on body tem·
perature·regulating neurons . In 'lOme subjects. a
clearly defined small elevation of the rectal temper·
atu re can be detected around thc time when the cor·
pus lutcum begins to secl"<'tc progesterone.
Ovariectomized animals of ma ny slXX'ies gain
weight if they are not given estrogens. This is attrib-
uted to 'ooth reduction in physical activity and an in·
crease in food intake. It may involve inAuences e x·
erted On catccholamine mcta'oolism. Changes in food
preferences have also been described (112 ). In
women. estrogens can alleviate psychic depression
(A·3).
PUBERTY ONSET IN FEMALES
I n juveniles, thc hypothalamo-hY!Xlphysial system is
exquisitely sensitive to the inhibitory influences of
the small amounts of steroids released from the ova·
ries. The quantities of gonadotropins secreted are
then inadequate for promoting substantial matura·
tion of the gonad •.
The sensitivity is attributed at least in part to in·
fluences exerted by ex tra·hypothalamic neuroos. and
it probably involves the release of opioid peptides.
Precocious puberty occurs in children with some
kinds of brain tumors. and it can be invoked in ex·
perimental animals by placing lesions in certain
pam of the brain. Possible roles for the pineal gland
arc suggested by several observations. As diseussed
in Chapter 20. the activitie, of the pineal are regu·
lated by changes in envIronmental hgh\lng. ' r he
gland has estrogen receptors, and the melatonin it
seCreteS affects LRH release. Children ""ith pineal
tumOrs often suffer precocious or delayed pnbeny,
and blind girls tend to mature earlier than sigh ted
ones. Stalistical studies indicate that menarche (the
firsl menstrual cycle ) oc<:urs with highest frequency
in June in normal girls residing in the Northern
hemisphere. In healthy children. nocturnal blood
melatonin levels decline with advancing age. and low
!Xlints arc attaincd at the end of pUberty (1041\). In
rats. undernutrition delays reproductive system mat·
uration and pincalcctomy prevents this.
It has been widely stated that the age at menarche
rell steadily from something like 17 years during the
nineteenth century to around 12.5 years in the
! 950.. This hs been amibuted to higher levels of
"'I>:$ychosocial stimulation" (provided by television .
educational and recreational faci!ities, and SO forth) .
to "longer days" be<:ause of artificial lighting. and to
improved nutrition. The data have recently been
reexamined and found to be inaccurate. It now ap-
pears that th. mean age at menarche of 12.5 years
is not very different from the timing two centuries
ago (25). It has been pointed out that genetic factors
are major determinants . Although some girls
undergo pubertal changes at the age of 9, others st ill
do IIOt do so until after age 17.
."
The of nutrition has received a great
deal of allenliQ" in recem studies. II has been pro-
posed thai an adequate fat:lean body maSS ratio
must be attained bofor. the ovarian cydes can be
established and maintained (67.68), Acoording to
Ihis conC<'pl, neither age OOr height is of major im-
ponanC<'. fk,th "early" and "latc" maturing females
develop when they have 3C<juircd sufficient fat
SlorCS. Controls of this kind make "physiological
sense." When females acquire the ability \0 produce
fertilizable ova, they also require preparation for
pregnancy and lacl3lion. This includes slorage of
metabolic reserves. /I. poMible wont.ling link is lhe
high aromatasc activity of adipose ti ssue, and there-
fore Ihe buildup of higher estrogen levels in states of
adequate nutrition.
The fat:lean body ralio hypothesis is on sta-
tistical data for hUnlans, and on the effects of ad-
ministering diets with varying On fat ae-
cumu lation in experimental animals. It is
by observations that undernourished young
tend to develop laIC, that adolescents woo
restrict their caloric intakes can undergo
maturation or become amenorrheic if the
loss is postpubertal, and that anorexia nervOSa is as'
sociated with reversible lowering of gonadotropin
levels. Professional ballet dancers and athletes
have been koown to menstruating while Ihey
arc active, and 10 reestablish cycles when tbey
take vacations Ihal permil elevation of fat: muscle
ratio.
Some other observations said to su ppon thc find·
ings can be interpreted in different Rat pups
raised in very smalllillers grow rapidly, acquire sub-
stantial OOdy fat stores. and mature early. However.
it is obvious that they obtain more than a rich milk
supply. They are licked and stimulated frequently by
the mothe r, and they arc kept warm during the io-
tervals between feeding. They may a lso derive some-
thing from the milk that pups from large lillers lack
(since the mother easily satisfies her own nutritional
!"C<luirements).
Body llimulation and freedonl from SI,os< probably a{·
{cct pubeny limil\i. Pups that are .nd otherwise
gently handted malure earl i., than control. o{ the .. m.
strain and lill., ,ize. No, i"". Slimuli can delay the
development.
Not all of the nutritional studies support the "fat·
ness" concept. There are conditions under which di·
etary manipulation does not affect pUberty timing
(as determined by time of vaginal opening in ro-
This seerm; to be especially lrue for strains in
which controls malure late for genetic reasons.
There are others in which "late-maturing" underfed
THE FEMALE IlEPROOUCTtVE SYSTEM
animals undergo vaginal opening or f,rst estrus when
Ihe body weights and fat contents are lower than
those of well·fed controls. Growth rates, OOdy pro-
tein stores. caloric intake, and growth hormone lev.
cis ail affect the timing when the rat contcn t is con·
trolled (146). In one study of underfed male rats,
low plasma FSH was linked with the seerelion of
large quantities of inhibin (12). In mice,
arc major regulators Chapter I), Othcr
are markedly affectcd by the composition (other
than caloric content) of the diet and by enViTOnmen·
tal factors such as temperature and rainfa ll. The 01·
factory apparatus makes important contributions in
some animal types, and anosmia can delay puberty
in children .
In prepubescent boys. change. in Ihe central ncr·
vous system lead to accelerated LRH release, AI
first there are small nocturnal "surge'" and these
lead to corresponding LH pulses. In time, tbe pulses
become more frequcnt and they have grealer ampli·
tudes. The gonadotropins promote testicular matu-
ration and testosterone secretion. and bolh LRH and
LH receptor numbers increase, After a long series of
stepwise changes, the testes mature to the point
where they begin 10 suppon spermatogenesis.
In females, development of reproductive compe-
tence similar cycles. However. il is also nee-
essary to achieve positive feedback control •. In ad-
dition to gonadotropin stimulation of the gonads. this
requires ewogen participation in the formation of
FSH and LH receptors. The entire system =ms to
gradually advance to higher and higber states of de-
velopment until maturity is eventually attained
(163). Cyclical buildup and sloughi ng of the endo-
metrium precede the establishment of fertile cycles
( 146). It may lake time for thc hypothalamus and
pituitary gland 10 develop sufficient se nsitivity to
mount the midcycle gonadotropin surge. However.
observations on suggest that thc period of
adolescent sterility is more closely lin ked with the se-
cretion of estrogen in amounts tOO smail to fully
stimulate the system
(167).
Human females undergo changes in adrenocorti·
cal function ("'adreMrehe") during the peripubertal
period, and the adrenal androgens promote growth
of axillary and pubic hair. The steroids may contrib-
ute in other ways to puberty onset. (Adrenocortical
insufficiency delays pubeny, but it so profoundly af,
fects metabolic runctions that the roles in reproduc.
tive system maturation are difficult to define. Ste-
roid·secreting tumors can advance pubeny onset.)
Several indication. that prolactin plays important
roles in reproductive system physiology have been
cited, and estrogens stimulate prolactin secretion .
Estrogens also growth hormorK: secretion.
and growth hormone deficiency delays reproductive
system maturation.
MENOPAUSE
Aging females of most mammalian species show loss
of fertility and ullimate cessation of ovarian cycles.
In rats and $Orne animal types with short life
spans. the ova ries still CQntain substant ial numbers
of germinal cens and follicles when this occurs. Ova_
ries of older rats can continue to function if they are
implanted into young ovariectomi,_cd animals of thc
same slrain. The oormal dccline in reproductive
functions in these has been lin ked with changcs in
the areaatc nuclei and the associated ability to re-
lease sufficient quan tities of LRH. It ha. bc<;n pro-
posed that emogens playa role in hypothalamic
aging. since females gonadectomized $O(In after
achieving reproductive competence can support the
funclions of ovaries implantcd at a laler time.
whereas those permined to retain their OWn gonads
into "middle age" cannot do this (180)_
I n humans. cessation .of Ihe merul!rual cyclcs oc-
curs relatively early in the life span (usually $Orne
time between the ages of 48 and 52 but often $O(Iner
in women who may survive for 90 or mOre years). In
many, the ovaries are sevcrely depleted of germinal
cells as the time of menopause approaches, buI in
some, scattered fothctes wtth oocytcs can be found
decades later.
There have been sugges tions that the relatively
early loss of fertilily in women CQnfers three advan-
tages for the species. First, Ihe oocytes that are fi-
nally released entered the prophase of during
fetal life. There is probably an upper limit 10 th.
time they can remain in good condition. Therefore.
termination of ovulalion lessens the cnances that de-
Icriof1\lill8 oocytes will enter into the formation of
abnormal gametes_The concept finds some support
in Ihe observations that the incidence of birth defects
is greater for older than for younger mothers. A re-
lated concept is tbat the "recruitment" and "sclee-
lion" processes provide for maluration of only thc
healthiest of the germinal cells, and that the pool of
oocytes wilh normal characteristics faUs off sharply
with advancing age. Second. human infants and chilo
dren require extended periods of parental Care . It is
therefore advantageous for mothers 10 be healthy
and vigorous when the children are young. Third,
since humans haY(: highly developed mechanisms for
communication, older and more experienced females
can advise the women of childbearing age.
When follicles no longer mature, CQrpora lutea are
oot formed. The plasma estradiol ieY(:ls fall sharply
and progesterone concentrations are substanliall y
reduced. E51rone then becomes the primary est1"O-
gen. The plasma CQncentrations of both fSH and
LH risc and remain elevated. The hormonal chnges
are usually accompanied by a varie ty of bodily
changes. Ihe most prominent of whiCh is vasomotor
instability. The blood pressure can undergo wide
flucluations, a nd most womcn experiencc " hot
flushes" (or bol flashes), during which there is
marked vasodilation of the peripheral vessels supply.
ing the face and upper pans of the body_ An unoom·
fortable ..,n>alion of warmth i. characteristically fol·
lowed by sweating. the evaporation of which leads 10
feelings of CQld Or clamminess. Nocturnal sweating
is also common . The symptoms can be relieved by
estrogen adminislration.
Similar changes in card iovascular functions follow
ovariectomy in young women who are IIOt immedi_
ately given replaceme nt therapy. Therefore, they arc
nO! dire<:tly related to aging. The concept that they
are caused by elevalion of the plasma gonadotropin
levels is inconsistent with Ihe failure to find such
symptoms in hypogonadal individuals who have
neVer secreted large quantities of ovarian steroids
but maintain high plasma concentrations of FSH
and LH . Although temporal associations between
the Onset of the flushes and the release of "bursts"
of LRH hay. been described, it is unlikely that LRH
per so: is of the problems Agcnts that abol.
ish Ihe LRH pulses do 001 relieve the symptom... and
it has therefore been proposed that e.tradiol with-
drawal anects Ihe funcl10ns of estrogctl--SCnslI!ve
neurons within regions of the brain linked 10 si tcs for
regulation of both body temperature and LRH se-
cretion (29).
Other CQmrnon symptoms include fatigue. a sense
of muscle weakness, insomnia. difficulties maintain.
ing attention span. headache. weight gain. and
psychic depression. A widely perpetraled nOlion Ihal
such conditions are in origin seeks
support in Koowlcdge that women such
problems may be sim ultaneously undergoing poten-
tially distressing changes in lifestyle. Their children
may have reached ages at which they 00 longer re·
quire maternal nurturing. and much has been madc
of the "empty·nest syndrome." HU5bands of middle
age or beyond often become preoccupied with prob-
lems of career or aging thaI can add to the difficul-
ties. It has also been claimed that peri menopausal
women respond favorably 10 treatmen t with tran-
quilizers or placebo<!. The concepl.$ arc difficult to
reconcile with the appearance of symptoms of simi-
lar intensity in women busily engaged in work and
other activities. and with the failure of nu)SI to re-
spond to placebo<!. Tranquilizers that reduce the
overaetivity of $Orne neuron groups can also decrease
the mOli_ation 10 CQmplain or to seek out help.
Since estrogens Can alleviate suffering in some
subjects, there are clinicians who believe that the

'"
steroids should be prescribed for all women who de-
rive benefits. However, Ihe "side-cffccts" of estrogen
therapy can include nausea, "'-alor relemion, br<:ast
tenderness. and incr<:ased susceptibil ity 10 develop-
ment of liver tumors and endometrial canc<:rs. There
are claims that addition of progestogen! averts the
sequelae. Another point of view is thaI
estrogen withdrawal is physiological, and that natu-
ral adjustments should be permiued lQ proceed when
the problems can be managed without medication .
REFERENCES
I. Ackerman, G. E.. Smilh. M. E., Mendelson. C.
R.. MacDonald. P. C. and Simp$O/1. E. R. A",.
m.tization of Androstenedione by ilnman Adj_
po« TiMu. Stromal Cell. in Monol.yor Cullufe_
J. CUn. endocrinol. 5J: 4 12-1 7. 1981,
2. Adams. T. E .• Norman. R. l .. and Spie •• H. G.
Gon.dQ1ropin.Relcuing Hormor>< Rtoept<>r
Bioding and Pit"ilary Responsi.ene.. in E.ma-
diol.Primed Monkeys. 113: 1388-9(),
1981.
3, Adams. T. E .. and Spies. H. G. BindinB Char,c-
teri.ticSof Gonadotropin·Rele.Sing Hormone Re-
cepton throughout the Estrous Cycle of the Ham·
" " I'M","""", 1M· t9Rl.
4. Adam •. T. E., .nd Spies. H, G. GnRH·lnduced
Resul.tion of GnRtl Recept'" Concentration in
the Phel'>l)barbit"·Blocked Ham" ... Bioi.
prod. 15: 298-302.1981.
S. Ad.i,. J .• Richord •. J. S., and Ojeda, S. R. HI'·
perprol.ctinemia· lndueod Precocious Puberty:
Studi"OIl the Mechanism(s) by ",bicb Prol.ctin
Enhancc. O.arian Progc"erono R"lX'n'iven ...
tu Gonadotr<>pin' in Prepubertal R.!S, EIIIIIXri-
1Wi. 108: 1333_42. 1981.
6. Aitken. R. J, Uterine Protei",. Chap. 6. pp. 351-
82 of finn. C A .. ed, Oxford Revi...... of Rtp;o-
Biology. vol. I. O.ford Uni .... it)' Pr ....
7.
New y",k, 1979.
Amsterdam, A., Kneeht. M.. and Catt. K, J. H<>r·
mon. 1 Regulation of Cytoo ilferentiation .nd In·
t.rcellular Communkation in Cultured G,anu-
Ioso Prot:. Nail. Aead. Sci. USA 78: 30lI0-
4,1981.
8. Andre .. W. W .. ond Ojed •. S, R, Qu.ntitati ••
An.ly,is of tho Mat.ralion of Stcroid Negali.e
Feedbacks Controlling Gonadotropin Relo ... in
,h. f.m.l. Rat: The Inf.nlile·).,enil. Periods .
Transili"" from an Androgenic to a Predomi·
nantl)' Estrog.nic Control. Endoaiooi. 108:
1313-20. 19S1.
Arimura. A. Hypotha l.mic Gonadotropin-rele,,-
ina Hormone and Reproduction, Chap. I. pp. 1_
21 of Grcep, R. 0 .. cd. Phy,ioloty
II. Uni .... ity Park Pr .... Ilahimor •. 1977.
THE FEMALE REPFlOOUCTIVE SYSTEM
10. A.eh, R. H.. $iler·KhQdr. T. M.. Smith. C. G ..
and Scholly.A V, lut.olylie Effect of D·Tryp··
luteinizing Horm""".Rcleasil13 llolOlOne in the
RheSu$ Monkey ( Mac ••• mnl.1ta). J. Clin, 1;.'".
dIX,inc/, M£rab. 51: 565-71. 19SI.
I I. A.eh. R. H., Van Sickle, M" ReHori. V.. lIalma·
ceda. J. p .. Eddy. C. A.. Coy. D H.. and $chally.
A. V. Ahstnce of UI·RH Binding Sito, in Cor-
pora I.ulea from Rh .. u, Mon. ey. (M•••"". mu·
lOll.), J. 53: 215-17.
19S1.
12. Allardi. B. Faeililation . "d Inhibit ion of Estro-
s.n.lnduce<! luteinizins Hormone Surge in the
ROI by PrOBesl.rone: Err•• " on Cytoplasmic Ind
Nudea. Estrogen Receptor> in lhe H)"polhala·
Area. Pituilary and Ut.,U •. Endo-
"inc/, 108: 1487_96. 1981.
13. Aviolo. l.. V. Poslmenop.usal Qstcoporo<i$: Pre·
vention Versus Cure. Fed. P' IX. 40: 2418-22,
1981.
14. Bah •. J. M .. and El<n·Jonalh.n. N. Prto'UI.,O'y
D<pletion of O" ".n Calechol.mine. in lhe Rat.
1:IIIIIX';ool. 1M: lSI 1981.
IS. Baker. T. G. Oog.ne.i. and Ovorian D<vclop-
menl. Chap. 7. pp. 398--437 of Balin. l! .. and
Glaue •• S .. eds. BioJoty. bcerpta
M.dico, Amst.rdam. 1912.
16. S,"e', t. A .• nd G"rski. J. Prola.,in Synlh •• i.
in Bovi ... Pituita.y: No Evide""" r",
h}' Vi.., f·nd"ullVJl. 109:
1981.
17. Behrman. H. R. Prostaglandin. in Hypoth. 'amo-
Pituit.ry . nd Ovarian function . R<v. Ph}",
;01. 41: 6S5-700. 1979.
IS. Billiar. R. B .. Tal<aol<a. Y.. Reddy. P. S., H . ... D.
L.. Longcope. C , and Little, B. Spooifi. Ti$$u.
M.taboli,m of Progest.rone in Vi.o in the Anes·
lhcli.ed female Rhesus Monkey During lhe fol -
licula. and LUI.al Phases of the Men",,,,,1 Cy.le.
lOS: 1643-8. 1981.
19. Blandau, R. J.. Br.ctolt. B.. Br.nn.r. R, M.• BoI -
ins. J. L., Brode"",n. S. H .. Hamner. C ... nd
M."roionni, L.. Jr. The O.iduet. Chap. 13. pp,
,.
132-45 of Grew and Koblin, . y. ed... r.ference
20. Bloom. F. E. Nour()p"ptid ... $dtnli/ic Am". Uj:
148- 168.1981.
21. Bloom. W., . nd fa",ceU. D. W. A T,xrbook 0/
HiJrOioty, 9lh ed. Saunde ... Philadelphia. 1969.
22. Bom.. I·H.lmreich. 0 .. Goulle,,". A.. Thebaull,
A.. S.ltar.JJi. 0 .. Milgram. E., frydman. R .. "nd
Papi.rnik. E. Healthy and Atreric Human Folli·
cle. in lh. Preovulatory Ph."", Differences in
Evol.tion of Follicul.r Morphology and St.roid
Conlonl of the Fol lic.lar Fluid. J. Endor, i·
111)/, Mtlab. 4$: 686_94. 1979.
23. Br. illy. S .. GooIlC"", A.. Milgr()m. E.. Born.. l·
Helmrcich. 0 .. and Papi.rnik. E. Androgens and
Progestin. in the Human Ovarian Follicle: DiITer·
...... in the Evolution of Preo.ulalory. He.lthy
 Nonovul'lory and Follicles. J. Clin, E ...
do<,j/tOl. lII.tdb. 53: 128-34. 1981.
24, Bryant..(;rcenwood. G. D.• Niall. H, 0 .. and
Gre.nwwd. F. c., cd•. R. laxin. EIKvier Norlh·
Holland. Ne ... York. 1981.
15. Bullough. V. L Age at MeMrohe: A Misuoder·
stood;"!, Sri..... 213: 365-6. 1981.
26. Colaby, J. H .. and Tynd ale-Bisooc. C. fl .. ed •.
RtprodurtiQl! and Evolution. Auslral ian Acad·
emy of Sdence. Canberra Cily. 1977,
27. Carlson. J. C .. Buhr. M . M .. Gruber. M . Y .•• nd
Tooml"On. J. E .. Composilional .od Physical
Properties of Membrane lipids frOOl Reg .. ssi ng
Rat Corpora lUI •• , E"doc,iMI. 108: 2124-8.
1981.
28. Ca". D. B.• Reppel1. S. M.. Bullen. B.. S' rin".
G .. Beiti ... I.. Arnold. M .. Rosenblatt. M.. Mar·
tin. J. B.• and McArlhur. J, W. PI.sma Melatonin
InereaKS DurinS he,ei.., in Women, J. Clin, E...
do<,j""l. lII,wb. 53: 224- 5.1981.
29. C• • per. R. F .. and Yen. S . S. C. Me""p,u$al
FluSh",: Effect of Pituitary Gonadot,.,.,in I}w:n-
sit i,,atton by a Potent LUleini,ing Hormone-Re-
leasing Factor Agoni ... J. Clin. EmJoc,iool.
111mb. 53: 1056-8. 1981.
30. Channing. C. P .. Schaerf. F, W .. Anderson. L. D .•
and T .. friri. A. Ovari.n Follicular aOO LUleal
Phy.iology. Chap. 3. pr. 117-20 I <>f R. 0 ..
ed, RtproduCli .. Ph)-'Jiolof}' Ill. Uni,'crl it)" Par,
Pre ... Baltimore. 1980.
31. Chappel. S , C The Pr ... nc. of T"o Specie. <>f
H",,,,,,,,,, ... i,lIi"
Anter;or Pituilary Gland, a, Disclos.d by Coo·
cona.alin A Chromatography. t:mJoc,inci. 1fl9:
935-42.1981.
n Cl.. k. J. H .. Mark.ve,kh. 8 .. Upchurch . S .. Er-
ib""n. II.. lIardin. J. W.. and P.ck. E. J .. Jr, flel·
erogenielY of E$ltosen Rec¢pton and btro&cn
Bind ins Siles: Relation'hip \0 E'trogen-
Re.pon .... Rn:. P,og, /form, 16: 89_125.
1980.
n. Clark. J. H .. P.d, E. J .. JT .. Hardin. J , W.. and
Eriksson. fl. The B;"klU aod Pharm.cology <>f
EStrogen Rc<:eplor Binding: Relation'hip 10 Uler'
in. Gro ... th. Chap, I. pp. 1_31 of O'Mallc)' and
Birnb.umer. ed ... ref<renet 148.
34. Clay too. R, N .. and Calt. K. J . Gonadolropin-Re-
I.a.ing Hormone Rc<:eplors, Ch'T3Cleri,,atOon.
Ph)'siological Regulation, and Relation'hip 10 Re·
product; •• Funclion. t'ndoc,. Ri', }: 189_2fl9.
1981.
35. Conti. C. J .. Conner, E. Z .. Gimenc'.-Cooti. l. B..
Sil • .,be,g. S. G .. and Ger«:hcnson. L. E, Regu.
1.tOon of Ciliogenc,i, and ProIiferalion of Ut.rine
Epith.lium by
Administration and Wilhdrawal in Ovariocto-
mized Rabbits. 8iol. Reprod. 14: 903 - 11. 1981.
36. Corn.lI. L. E .• Goldfi.n. A.. aOO Robe"'. J. )..1 .
Tooie In Vivo InhibitOon of Rabbit Myornelri.i
Adrenersic R.ceptors, Nmuff 29]: 623- 5. 1981,
31. CriSl.r. E. S .. RUlledge . J. J .. and French. L. R,
Effe<:t of Indomethacin 011 lhe Int.r.Slrou. Inlcr-
.. I <>f !ntaCI and H)'$tercclomi7-"d Poeudopreg·
nant Mice. 8iol. Repmd. 24: 1000-5. 1981.
38, Cumming. 1. A., aod findlay. J. K. Evolution of
Ovarian Funclion in Sheep and Cank. pp.
B <>f Cal"by and Tyndale-Bi:ICOC ed... rcfer. nc¢
"
39. Da.id",,". B. J .. Gambone. J. C. La", .... L. D..
Cutaldo. T. W .. Hammond. G. L.. Siite,i. P. K ..
and Judd. H. L. Free E>tradiol in P""tmenopau .. 1
Women with and without Endom."ial Cancer. J.
EmJocrinci. Mttnb, 5]: 404_8. 1981.
40. Davi s. J. S" Fa""". R. V.. aOO Marsh. J. M.
Slimulalion of Phospholipid LIbeling and Ste·
roidogen",is by Luteinizing HOTmo"" in lsolaled
Bovine lUleal Cen., Endocrjnci. 109: 469_15.
1981
41 . O.v",,". 1-1" and M. B. Male Trophic Hor·
mo"". and the Ovarian Cycl. in the F.male.
Chap. 2. pp. 45_1 77 Or Inlmdu"ion ro
o.(Y. \'Ol. 5, Academic Press. New Y"'k. 1980.
42. Di7-troga. G , S .• and HOOgen. G, D, FoIli.uloge-
"",is in the Prim", Ovarian C)'eie. Endot:rint
Rtv. 2: 1981.
4J. DiUre&-,. G. S .. Lynch. A .. and Hodgcn, G. D,
I niliation of Asymme"ical O.a,i.n E>"adiol Se-
cretion in the Primale Ovarian Cycl •• flcr Lu-
t«ctomy. Endocrinol. 108: 1233-6. 1981.
44. DiZc,.ga. G. S .. Turne,. C. K .. Slouff,r. R. L..
And.rson. L. D.. Channing. C P.. 000 Ilodg.n.
G. D. Suppression of Follicle·Stimulat inS Hor·
mone·Depend.nt Follieulogene,i. Du,ing thc Pri·
m",' Ov .. "" (\<1<. . .1. ,Un. PmJ"","'" M""h
52: 451-6. 1981.
45. Doebler, J . A.. Wichcrlham. £. w .. and Anlhony.
A, Ut.rine PrO$t.&landin F,. Conlent and 20...-
tlydrox)'Steroid Dehydrogenase Activily of Indi-
vidual Ovarian Comp.rlmen" Du,ing Pscud.,.
preg"""cy in the R.t. 8iol. R,prod. }4:
1981.
46. Do,fman. R. I. Bi""ynthe.i, of Proge"ogens.
Chap. 23. Pl'. 537-% of G=p. ed .... ference 15.
47, Douington. J. H... OO Arm,,,'o n,. D. T. ElTec!.
of FSH on Gonadal FunOlion. R«. Prog. lI",m.
R.,h. 3j: 301-32. 1919.
48. Dorta. D. M.. Smi!n. E. R .. aOO Da. id""n. J, M,
Endoe'ine and El<h •• ioral Effect< of Continu,," ,
Exposur. of Mal. Rats to a P""nt LUleinizing
Hormone-Releasing Horm.;"", (LlIRH) Agoni";
Evidene. for Cen"al Ncr..,., Sy.t.m Actions of
LHR H. EmJoc,inci. 109: 729_35. 198 1.
49. B.. Shani. J.. Ra.id. R __ and Goldhaber.
G. Effect of AOO,ostanediol Sulfal" 011 Lu tein·
iling Hormone R.l .... in Q,'arLeclomi""d Rats.
Endoc,iMt.I08:500-S.1981.
SO. Eine,-J.nsen. N .. and McCrack.n. J . A. The
Tran.f.. of Progesterone in the Ov',ian Va .. ular
p.dicle of lhe She.p, E ndocYinoi. 109: 685-90.
1981.
51. Ekholm. C.. Hilkn,jO. T.. and lsa'''''''. O. Go-
n.dotropin Relea,ing Hormone Agonist' Slimu·
late Oocyte M<i""i. and Ovulation in Hypophy.
sectomi:ted Rats. Endoc,ino{. 108: 2022- 4.1981.
'"
52. Elfon!. D. A .. Rosko, J. P .• arK! Dimino, M. J. Cy.
[<>chemical Studies of Acid Phosph.lO •• , in Ov.,·
ian Follicles: A SUU"led Role rM Lysooomes in
Steroidogenesi,. Bi()/. 17: 787_95. 1977.
53. Elia,. K. A.. and Blake, C. A. A Delliled 1" Vitro
Charaeteri>.alion of the Basal Folliole.stimulat·
ing Hormone S«orelion Rates during the Rot
F(>uT-Day Est""'. Cycle . F.1Ui<xrinol. /Q9.- 708-
1),1981.
54 . Em.nuele, N .. Coo.iok. E .• Howell. T .• Ander·
wn. J., Hojval. S., G .. Souehek, J., KiT_
'leins, L.. alld Lowrence. A. M. Hypothalamic
Ilormonc ( LIl ): Ch ..... leri.lic. and
Response to Hypophy<cctQmy. Riol. )j;
321 - 6.1981.
55. Emmons. C. W.o.nd Gidley-Baird. A. A. hol.-
lion of the o..lru. Cycle. pp. 235-43 of Cal"by
and Tynd,le.Biscoe , ed •. , rderence 26.
56 . Engel. L. L. Th. Biosynthesi . of htrogons_ Ch.p.
20. pp. 467-83 of Gr«p. ed .• rcf... n.
57. £ngland. D. G .. Webb. R .. and Dahmer. M. K.
Follicular Sleroidog.... i. and Gonadouv pin
Binding to O'ine Follicles durin, the Emou,
Cyd • . Endoc,if.ol.IQ9.· 88 1-7, 19st
Eppii. J. J. Ovarian Glycosan,i""l!I)'cans: Evi·
dence for a Role in Regulating lhe Re,ponse of
the Oocyte·Cumulu, Cell Complex to FSH- En-
J"",inol. 10$: 1992_4. 1981.
Espey. l. l. Ovulalion as an Inftammalory Re·
Hypolhe. j•. 0101. n · 73_1 06,
1980.
60. Espey. L. Coon •. P. J.• Marsh. J. M. M.. and
leMaire. W. J. Effect of Indomethacin on Pre0-
vulatory Changa in the of Rabbit
Graafian Follicles, f,.·nJoc,irw/, 108: 1040-8.
1981.
61. Etgen.A. M. Est rog.n Re·
ceptors in Ihe Hypolha!amus of Male and Female
R." Which Diff.r in Their A bilily 10 Exhibit
Cyclic Gonadolropin Seerelion and Female Sex·
ual Behavior. Bioi. RrproJ. 15: 307_11, 1981.
62. E.. r<:Il, J. W., and Tyr.y. L. Comp ..ali •• Incre·
menIS in Circulating LUleinizina Hormone in
Ratl wilh I ncre31ing Dural ion of EI«tric. 1Slim.
ulation in Medial Prooplie or Medi.1 Ba.. 1 Tul>-
eral Sile,. Endoc'ino/. 1{)9: 691-6. 1981.
63. faiman, C" Winter. J, S. D., and Reya, F. I- En·
docrinology of Ihe Felal Testi s, Chap. 4. pp. 81-
105 of lIu'll'" H .. and De KreUcr. 0 .. eds,
Ra'en P..... New York. 1981.
M. Ferland. L., Marchetti. B.. SCguin, C .. Lefebvre.
F. A-, Rcc ..., J. J.. and La brie. F. Diuocialed
Changes of Piluitary LUleinizing Hormone·Re-
lta.ing Hormone (LHRH) ReceplO« and Re·
,pon,ivene.. 10 Ihe Neurohormone [nduced by
17ll-Estradiol and LHRH in Vivo in the Rat. f:n-
d"",;no/, 11)9: 87-93. 1981.
65, Fi,hman, J.. and Martucci. C. Absen<e of Mea·
sU ra]:)le 2.Hydroxye",one in Ihe Rat Brain: Evi_
dence for R.pid Tu'_er. I. EM"",iMI.
49: 940-2. 1979.
THE FEMALE REPAOOUCTIVE SYSTEM
66. Forcelledo. M. L.. Vera. R., and Croxallo. H. B-
Ovum Tran.porl in Pregnanl. Pseudopregnant
and Cyclic Rats and in R<lOlion.hip to Estradiol
and PTogmerone Blood L..'CI>. 8iol. U·
760-5.1981.
67 . Fri.ch, R. E. Pubeml AdipoSe Tissue : [, il Nec·
essary for Normal Se, ual MaI" ration? Evidence
from Ihc Ral and Human Fem.le. Proc. 19:
2395-2400. 1980.
68. FriS(;h, R. E., and MCArlhur. J. W. Menstrual
Cycles: Fatness a, a Determinant of Minimum
WeighIS for Height N=ry fot Iheir Mainle·
nance or On •• I. 185: 949-5 I . 1974.
69. Fujila. Y., Mori. T., Su"uki. A., Nihnobu. K., and
Nishimura, T. Funclional and Structural Reta·
tion,hips in SteroidOgenesis in Vil ro ]:)y Hum.n
Corpora LUlea During De"elopmenl and Regres-
.ion. I . Clin. Mt/ab. 5J: 744_51.
1981.
70. Gal, 0 .• MacDonald. P. C., and Simpsoo. E. R,
Cholesterol M.taboli,m in Human Cancer Cell.
in Monolayer Culiure. V. The Effect of Proges-
Ie","" on the Regnlalion of 3·Hydro' y-3· Mcth.
ylSI"loryl Coen,.yme A Re<lucII .. Aelivity by
Low Den'ity LipoprOtein . J . Clin, End"",ino/.
M e/ab, 53: 29-ll. 1981-
71, Giboti, G .. Ba.uray. R .• and McReynolds. D, Lu·
loolropic Rote of Ihe Decidu,l Tissue in Ihe Ral:
Dependenoyon Intraluleal Estradiol. /:;"nd""'ino/.
100. 2()(;(1-(1. 19$ 1.
n. G lass. A. R .. ond Swerdloff. R. S, Nutrilion. lln·
Auenca on Sexual Maluration in Ihe Ral.
P'IX, 39: 2360-4.1980.
13. G oldman. B.D .• and ZI,,,,,,. M, X. The Physi-
ology of Progeslin •. Chap. 24. pp. 547_72 of
Greep. e<l" reference 75.
14. L. T .• EssiS, M .• Sa""i. P., Beck. P ..
and Weiss. G . Hormone Secretion by Monolayer
Cultures of Human LUleal Cell •. J . C/in. Endl>-
eriMI. Mmb. 52: 890-2.
75. Greep. R. 0 .. ed. lIondbook of Hy.iololY. Sec.
7. vol. 2. American PhysiolOgical Society. Wa,h·
inglon. D.C, 1973.
76. Greep. R. 0 .. and Koblin,ky. M. A.. cd •. FFOI>-
/iu. in and Fmi/iry Com,oI. MI T
Press, Cambridge. Ma .... 1977.
7611 . Grody. W. W.. Schrader. W. T., and O·MaUey.
B. W .. ACli,ation. Tran,formalion. a nd Subunil
SI,"cture or Steroid Hormone Re«plors, Hndl>-
aiM. RfY. J: 141 - 61. 1982.
77 . Guillemin. R.. McCann. S. M., Sawyer, C H..
and Davidson. J, M. Seerelion of Gonadol",pin.,
Chap, 9. pp. 90-102 Gr«p and Koblin5ky. cd •.•
reference 76,
78. Haney. A, F.. and Schomberg. D. W. E.,rvgen
and Progesterone Production by Developing Por-
cine Follick:$ in Vilro: E,idcnce for Estrogen For_
mation by Theca. Endoc, ;/tOI. I{)9:971-7. 1981.
79. Han.el. W.. COlICannon. P. W.• and Luka_
,"cw.h. J. H. Corpora LUlU of Ih. Large D0-
me";' Anim.ls. Bioi. Reprod, 8: 222--45. 1971.
79A, Harl.n. R. E .• Shivers. 8. D,. and Pfalf. D. W,
Midb",in Microinfu.ion$ of Prolac,in I...,r<ue
Ihe Eslrogen·Dependenl Ren •• ior. Lordosi •. Sd-
219.- 1451_3. 1983,
80. H.,egaw •. Y.• MiyamQ1O. K.. Y.7.a1:i. C . and
19arishi. M, Regula\,on <>f Ih. Se<:ond Surge <>f
Follicle-Slimulating Hormone: Elfects of Antil.·
leini.ing Hormone·Rde. ,ing H(>rmone S.rum
and PenlobarbilaL t:ndortinoJ, 109: 130-5. 1981.
81. HeArn. J. P.• Short. R. V... nd Baird. D. T. Evo-
IUlion of Ihe LulOOlropnic Con,ro) of lhe Mon,·
malian Corpus Luleum. pp. 255- 63 of CII.by
and Tynda)e·Bioc<><;. cds .• rtferene< 26 .
82, lielm. G .• 011e.en. B.• Fanrenkru$. J .• Larsen. J.-
J" Owman. C .• N.-O .• Slolt>erg. B., Sun·
dler. F.. and Walles. B. V'<Oaelive Inle"iMI
Polypeplide(VIP) in the Human Female Repro-
ductive Traet: Dimibu,ion and Motor Elfec".
Bio/. 25: 227- 34. 1981,
83. Helmond. F. A.. Simoll$. P. A __ .nd Hcin. P. R.
Strength and Durolion Charlcle,iS1k. of 'he Fa-
cil.,ory .nd I nnibilory ElfeclS of Progestcrone on
,he Es,rogen. lnduced Gooadolropin Surge in ,he
Female Rnelu$ Monke)", £lIdrx';noJ. 1M: 1837-
42. 1981.
84. Hertig. A. T.. and Barton. D. R. Fioc Strue,ure
of Mammalian Oo<y,es and 0 ... Chap. 13. pp.
317_48 of Greep. ed .. referenee 75.
84A. Hess. D. L.. Schmid,. A. M.• Schmidl. M. J.
Reprodue,ive Cy<:le of 'he A,i.n Elephant (Ele.
ph.s maximu,) in Caplivil)". Bioi. 1$:
767-73.
8S , Hillenoj<!. T .. Magnu,""n. C. Svcn,,,,n. U.. and
Thelander. H. Effect of Lu'eini,ing H",mone . nd
Folliclo-S,imulaling Horomc on Progeslerone
Synlhesi, by Cultured Ra, Cumulu, Cello. t:n-
docrind, 108: 1920-4. 1981.
86. Hilli"d. J. Corpus Luleum Func,ion in Guine.
Pig', Hamsters. Rats, Mice and Rabbits. Bioi.
8: 203-2 I. 1973.
87. Hillier. S. G .• and Dc Zwart. F. A. Evidence lbal
Granul.,... Cell Aromatasc Induction/AC'i.. tion
by Follicle-$timulaling H",moll< i, an Andnlllen
Recepl<>r·Regula1ed Proce", in Vitro. f:lldrx,i""l .
109: 1303_S. 1981.
88, Holl. J. A.. Lorinc •. M. A.. and Ly11le. C. R. Es-
lrogen Receptor in R.bbil Ovaries and Elfoots of
Antiestrogen On Progesterone Production. £1Id0-
crinoJ. 108: 2308-15.1981.
89. Hsueh. A. J. W.. Welsh. T. H.,.nd Jone,. p, B.
C. Innibj';on of Ov. rian and Te"ieu'a, S'eroid·
ogene,i. by Epidermal Growlh Facl(>r. Ewdrx'i_
,.,1. 1M: 2002_4.1981.
90. Huhtaniemi. I. T .. and C.lI. K. J. Induction and
Mainlainance of Gonadolropin and Laelogen Re-
ceptors in Hypoprolactinemic Rat', l::ndrx'iltO/.
109: 483-90, 1981.
91. Jalfe. R. 8 .• and Mon,oe. S. E, Ho,mone Inter·
aClion .nd Regulation of lhe Me .... 'rual Cycle.
Fronl. 6: 219-47.1980.
92, Johnson, L. M.•• nd Gay. V. L. LU leinizing Hor·
mone in lhe Cat. [I. Maling·lnduced Secrelion .
EndOCtlnoJ. 109: 241_52. 1981.
93. lohnson. L.M .. and Gay. v.L. Luteinizing Hor·
mone in Ihe Cll. I. Tonic S.cr.tion, Elldrx' ;noJ.
109: 240---(,.1981.
94. Jordan. A. W. Elfecllof Pro."glandin F .. Trcal'
men, on LH and Dibulyryl cAMP-Slimulated
Proges1erooe Secrelion by lsolaled Ral Lu"al
Cell •. Bioi. R,p'od. n .' 327_31.1981.
95. K.lIos. J .. Fasy. T. M.. and Hollander. V. p, As·
$e$$lTIOnt of Estrogen Receplor.Hi SlOn< In,orae·
lion •. P'rx. Narl. A('Od, Sri. 78: 2874-8. 1981.
96. Kalra. S, P.• and Simpkins. J. W. Evidenoc for
Norad«ner8iC Medi .. ion of Opioid EffcClS on
Luleinizing Hormone Secrelion. l::!1drx, ;noi. 109:
776_782.1981.
97. Kalra. S. P.. Simpkin,. J, W.. and K.lr •. P. S,
Progesterone.lnduced Change> in Hypolh. llI mie
Lu,cinizing Hormon<;-Relea$ing Hormone and
Catecholamines: Dilferenli.1 ElfecISof Pon,obar-
bit.L Endrx,in{)l. 108; 1299_1304. 198 1.
98, Kawakami. M.. Kubo. K.. Ucmura. T.. Nag.se.
M.• and Ho)'ashi. R. Involvement of Ovarian In-
in Steroid Secrelion. £ndrx,iltO/, 109:
136--45.1981.
99, Ka)'c. A. M. The On'ogeny of ESlrogen Recep-
tors. Birxh,m, An Ho.m. 5: 149_201. 1978.
100, Ke,ner. J. S .. Convey. E, M.. and Anderson. C
R. Evidence th at E" ... diol Induces the Pre""ula·
,ory Surge in Cank by Increasing Pituitary Son·
,iti.it)·10 LHRH .nd then [ncre.oi ng LH RH Re-
lease. EnJoc,lnoi. 108: I 386_91. 198 I.
101. King. R. J. B. How Import.nl are S,eroid, in
Regu,.,ing ,he Grow,h of M.",m.ry TU",Qr<7
Birxhem. An lI{)Tm. 6,' 241_64.1979,
lOlA. King. W. J .. and Grecne, G. L. Moneelonal An-
libodie. Locali ... QcS1rogen Receplor in the Nu-
dei of Tatgct Cell$. J01 . 74S_7. 1984 .
102. Ki"",hita. F.. Nakai. Y.. Ka'akami. H.. Kato. Y.,
and Imu,a. H. Rol< of a'Adrenergic Mechanism
in Regulaling Tonic Luteini,.ing Hormone Re-
lea.e in Con,eiou! O.arieelomi.od R.". Endrx'i-
noJ. 108: 1272-5. 1981.
103. Kirehick. H. J .. and Birnbaumcr. L. p..,.,a8Ian.
din, Do NOI Appear 10 Play A Role in IICG -In-
duced Regression Of Dcsen.iti .... tion o>f Rabbil
Corpora LUle • . Bial. R,p'od. 14: 1006_1012.
1981.
104. Kirkland. J. L., Gardner, R, M .. MuHu. V. R ..
Akhlar. M.. and Stancel. G. M. H",monol Con·
lrol of Ulerine Growth: The Elfeclof llypolhy'
roidism On E"rogen-Stimula'cd Ctll Div ision.
Endrx';noJ, 108: 2346-51. 1981.
I()4A. Kolata . G. Put>erty My<lery Solved. Sci'TIff 22]:
272_3.1984.
105. Knobil. E, The Neurocnde<:rine Control of the
MenSlru.' Cyde , PtOt. I/o_m, Ruh. J6: 53-
88. 1980.
106. Konind,,,. P. R.. Heyn •. W.. Verhoeven. G .. Van
Baden. H .• Li$sens, W. D.. De Moor. P.. and Ilro-
sen,. l. Iliocbemieal Charae'eri.otion of Perito-
neal Fluid in W"",en During the Menstrual
Cycl •. J, Clin. Endrx'inoJ. Mtlab. 52: 1239-44.
1980.
107, Kreitma nn . 8 .• Bugat. R .. and Bayard. F. Eslro-
'"
gen and Proses!;n RcgulO!ion of Proge'terone Re-
ceptor Concentration in Hum.n Eodomcltium. J.
Clin. Endoc,j""l, 49: 1979.
103. bBarbcra, A. R .. and Ryan. R. J. Po",;n. Gran-
ulosa Cell. in Su.pension Cult .... I. Follicle_
Slim"lalinll Hormooc Induction of Human Cho-
rionic Gonadotropin.Binding Siles on Cells from
Smoll Follid... End"",;"",!. 108: lS61-70. 198!.
109. Laborde , N. P.• Wolf.. n. A, . R.. and Odel" W. D.
Sh<>n loop Feedback SY$lem for the Control of
Foliicic..slimul'ling Hormone in the Rabbil. E....
d/)C, in.>l. 108: 7l_7S, 1981.
110. Lach.lin, G. C.. Barnell. M.. Hopper. S. R..
Brink. G .. and Yen. S. S. C. Adrenal Function in
Normal Women and Women with Polycy.tic
Ovary Syndrome_ J. Clin. EniI""j1l()/. M.lab. 49:
882_98.1979.
III. Le •• V. W. K., Quigg, H., Findlay, J .. and Lo'"
... h•. l. o...;. n .nd Peripheral Blood I"hibi"
Concentratmn. Incre.se with Gonad<>lrQp;n
Treatment in Imma ture Rats. Endoeriool, 1M:
2403-5.1981.
112. Leshnu, A. l. An Introduction 10 S.hayjo;al En·
doe,illO/oty. Oxford Univ.rsily Pre ... Ncw Vork,
1978,
113. l eung, P. C K .• Arendash, G. W.. Whitmoyer.
D, I.. Gorski R, A.. and Sawyer. C. H, Eleclric.1
Slimulation of Mesencephalic Noradrenergic
Palhway: Effects on LUleini.i n& Hormone Lc ..I,
in Blood of O_ar;«tom;z.<:d and O•• ,;<clom;..,d.
Steroid.Primed Rau. End«rillO/, /(J9: 720- 8.
1981.
114. Lcuna, p, C. K .. and Armstrong. D. T. tnterae-
tion. of Sleroilb and Gonad<>lropins in the Co ...
trol of Sleroidogenes is in lhe Ovarian Fotlide.
A I1II. Rt>. Physfoi. 41: 71 - 82. 1980.
114A. lewin. R, Firsl True RNA Calyly5t Foo nd, Sri·
266_7.1984 ,
115, liebc,burg. I..• nd Mc(i wen, a. S. Steroid Hor·
Receptor> in the Central Nervous System,
8ioch, m. AN. Horm. 6: 41 S_59. 1979.
116, linke. D. M .. and Sii1eri. P. K. A Re-examination
of the tnteraction of Es"adiol wilh Target Ce ll
Receplo ... , J. S,m>id Biochtm. 9: 1011_8. 1978.
117, lipner. H , Mech.ni.m. of Mammalian Ovula'
tion . Chap. 18, pp, 409_31 of Greep. ed .• refcr·
ente 75.
118, lip«tl. M. B.. and R..... G. T. The Ovary. Chap,
4. pp. 119_34 of Ingbar. S. H .. ed. Conrtmporury
f.·ndoerillOiogy. vol I. Plenum. New Vork. 1979.
119. litwack. G .. ed. Bioch.miNI Aero'"", of I/or-
_ •. Academic Preu. New Vorl:. Vol. 5. 1978:
YoI, 6. 1979: Vol. 7. 1980.
121). 1..ool<en. M. R., Channing. C P.. D'Elctto, R.. and
We;". G. Slimulatory Elfect. of Her·
ltH)rle upon Rel ... in Socrelion by Cultu",d Pot·
cine Proo' ulatory Granul""" Ce ll$, Endoc, inhi.
111: 769- 71. 1983.
121. Lyne. A. G., and Holli •• D. E. Tho Early ])e,·cI·
opmen1 of Marsupi.ls. with Spe<:l.1 Refc",.ce 10
THE FE MALE REAAODUCTlVE SYSTEM
Bandicoots. pp. 293_302 of Calaby and Tyndale-
Biscoe. ed •. , ",fcren"" 26.
122. M.g<>ffin. D. A .• and Erickson. G. F. Mech.ni.m
by which I7p·Estradiol InhibilS Ov.rian Andro-
gen Production in the Rat. f.·MoerillOl. 108: %2_
9. 1981-
123. Mag<>ffin. D. A .. Reynold •. D. S .. and Erickson.
G. F. Direcl Inhibitory Effoc1 of Gn RH On An·
drogen Socretion by Ovarian C.II •.
HMOCrinol./09:UI_3.1981.
124. Marshall. J. C .• and Kcleh. R, P l ow Dose Pul·
satile Gonadotropin· Relea,ing HorltH)rle in An-
oroxia Ner""",: A Model of Human Pubcnal [)e.
velopment. J. Clin. lJmllXri/tOl. Melab. 49: 712_
18.1979.
12S. Martin. B.. ROltcn. D.. Joli,01. A .. and Gau'rlIy.
J. p, Bindi ng of Steroid. by Protein. in Follicular
Fluid of the Human Ovary. J. Clin, HndlXriool ,
Mmb. 51.' 443_7,1981.
126. McEwen. B. S. Binding . nd Meta bolism of So,
Sler<>ids by the Hypothalamic.Pit uita,y Unit;
PhysiolOgical I mplicatio"" Ann. N, v. Plty.iol.. 41:
97-110. 1980.
127. McNauy. K. P., A.. De Gra,'; •. C , Os·
alhanondh. R.. and R}'.n. K. J. Steroidogenesis
by Rewmbined Follicul., CeU, from the Hum.n
Ovary In Vi1ro. J. Clin. Endocrino/. M, ' ab. 51:
1286-92,1980.
128. McNally. K . P.• M. kris. A.. De Grni•. c., Os·
. th.nondh. R .. a nd Ryon. K. J . T he P","uct;Qn
of Progesterone. Androgen,. and Estrogens b)'
Granulosa Cell,. Thecal TiS$ue, and Slr"",.1 Ti ..
. ue from Human Ov.rie, in Yitro. J . Clin. Endo--
Mtt(Jb. <19: 687_99. 1979.
129. McNally. K. P.. Smilh. D. M.. Makri •. A.. Osa·
lhanondh. R.. and R)'an. K. J. The Microenviron·
ment of lhc Human Anlral Follicle: [nterrelation·
ships among lhe Sle,<>id levels in Antral Fluid.
,he Population of Granuio:<a Cells and the Stains
of the Oocyle in Vi,o and in Vitro, J, Cliw, E".
docrinhi. 49: 851-60. 1979.
130. MiChael. S .. Taguchi, 0 .. and Nishi,nlta. V,
Chang.. in Hypophyseal HorltH)rlcs A."",ialed
Wilh Accelerated Aging and Tumorigenesis of !he
O ..,i.. in Neonalally Th)"mect"",i:ted Micc. Elf-
docrlllOi. 108: 2375-80, 1981.
131. Mill ... 6, G., and Armstrong. D. T. Effoctiof a
Supe,ovulalory Dose of Pn:gnanl M.n: Sorum
Gonadotrophin on Ovarian Funclion , Scrum F.s-
1radiol. 3nd Prog"lero.. Le' el. and Early Em·
bryo Development in Immatu", R.". Bioi., II ...
prod. 15. 261_211. 1981.
132. Milkr. L. K. T hc M.,<>-reccptot.
Hor",. 7: 233-43.1980.
133. Miller. W. l .. and Wu. J. Es1rogen Reg ulation of
Follic1e.sl;mulating Hormone Produclion in
Vilro: Speci.. Varialion. Endue,lrIOl. 108: 673_9,
1981.
134. Mondschein, J. S .. and Schomberg. D. W.
Growlh F3Cl<)r$ Mod ulatc Gonadotropin Rocep-
 tor Ind uction in Granulou Cell Cultu ....
211 : I179_S0. 1981.
IH. Mossman. H. W.. and Duke. K. L. Some Com·
parative Aspects of the Mamm.lian Ov.ry. Chap.
16. pp, 389-4(}2 of Greep. cd .. reference n.
136. Muldoon. T, G. R.gul.t;on of St.,oid H",mone
Rec.ptor Activity. EndocriM Ri'>'. I: 339- 64.
1980.
In. N.lbandov. A, V. Control of l uteal Function in
M.mmal •. Ch.p. 8. pp, 153-67 of Grccp. cd,. ref·
er.nce 7S,
138. N ....... "'" M. B,. Horton. M. J,. Soego. C. M .•
)nd Seeler. B. J, Antibodies Against Estradiol·
Binding lysooomal lipoprot.ins Gain Acc ... to
the Nuclear Compartment of Preputi.1 Gland
Cells under onosen lnftuence . t;ndocrioo/., 101:/:
II 1981.
139. Nett. T . M .• Crowder. M. E.. M<)!.S. G, E.. and
Duelle. T . M. GnRH· Receptor lntc .. ction: V.
Down·R.gul .. ion of Pituitary Receptors for
GnRII in O.Ofie<:tomized Ewe> by In fu,ion of
flomologou. Ho,mone, Bioi. R. prod. 14: 114S _
55.1981.
140. Nichol$o n. R. L. and GrilT"",. K. The Bi""hem_
isny of Tamoxif.n Action. Adv. /form . Rsch,
f: 119_52.1980,
141. Nioole11i. I.. Filipponi. P., Fedeli. L. Palumbo.
R,. Santori. P.. Sant.usonio, F.. and B,un.tti. p,
PrtlgeSlerone Positive Feedback on Gonadotropin
Rei •• ,. in Estrtlgen-Primod Postme"".,.u ..1
Wom.n: Ctn"al Nt'"ou, Sy... m and Pituitary
Si,o< ANiM J Clin "'·nll"".-"", M"ni> 5].
IH-S. 19SI.
142. Niswender. G, 0 .. Sawyer. It. R .. Chen. T. T ..
and Endres. D. B. Actionof I.uteini,ing Hormone
at the C.llular lev.l. Ado. S.x Horm. RJrh. 4:
153_85.1980,
143. Nolin. J. Di\<:u"ion of RothChild. rderence 112-
hog. I/o,m, 37: 294. 19SI.
144. No"tcdt . G.. Wrange. 0 .. and G.' tafsson. J.•,I. .
Multihormone Regulation of the E$lrogcn Recep-
tOt in Rat Liv.,. Endoc'illOi. lOS: 1190-6. 1981.
145. Notidc<. A. C. Conformational forms of lho Es-
trogen Receptor. Chap. 2. pp. 33-61 ofO·M.lI.y
and Birn baum ... ed . .. reference 148.
146. Ojed •. S, R__ Andrews, W, W.. Advis. J. P.. and
Whit •• S. S. Rec.nt Advances in lht Endoc,inol·
ogy of Puberty. £ndocrltrt Ri'>'. I: 228_57. 1980,
147. Okulic ... W. C .. Evan •• R. W.. and Leavi tt. W. W.
Prtlg ... ertlne Regulation of the Occupied Form of
Nuclear Estrtlgen Receptor. 2/1.- I
1981.
148, O·Malley. B. W.. and Birnbaumer. L.. eds.
<tplor< and lIormDl1' A"1;Dl1I1. Academic Ptess.
New York. 1978.
149, Owen •. R, E.• Fleeger. J, L. . and Harms. p, G.
Evidence fo, Centrol Nervou. Syst.m (CNS) In·
vol •• ment in Inhibition of LUltinizing Hormone
(L H) Release by Do.,.mine ReceptOr Sl imula'
tion. EndfXl". Ruh, Commun, 7: 99-IOS. 1980,
IS(). 0 ..... II.. Tominaga. T.. Ni,himura. T .. atld
T.keda. T. L)'$yl O. ida\<: Acti.i,y in lhe Mouse
Uterine Cervi. ;s Ph)'$ioJOjIkally Regul.t.d by
E$tmgen , Endoc,;no/, IM:618_21 , 1981.
P.dmanabh.n. V .. and COn.ey. E. M. Progester-
one Inhibits the Ability of E$"adiol to Incre.se
8 ... 1 "nd Luteini,ing Hormon¢-Releasing Hor_
mone--lnduced Luteini,ing Hormone Rei ....
f,om Bovine Pituitary Cells in Cuhure. N.ith.r
PrtlgeStertlne nor Estradiol Alfoet, Follicle Slim_
ulaling Hormone Release. £ndocrillOi. 1M: 1091-
6,1981.
152. Pang. C. Y., and Behrman, H. R. Acute Effccts
of Prostaglandin Floon o.orion and luteal Blood
Flow. Luteal Gonadotropin Uptake in Vivo and
Gonadotropin Binding in Vitrtl. £/ldocrillOi. lOS:
2239- 44.1981.
153. r ardridge. W. M . T ... nsporl of P""ein-Bound
Hormone> intO Tissuc< in Vi..,. EndocriIW 2:
103_IB.19SI.
154. Paul. S. M .. Hoffman. A. R., and A.elrod. J. Ca-
techol Emogens: Synthesis .nd Met.bolism in
Br.in and OI.her Endocrine Tissues. Front.
6: 203_47 . 1980.
IS S. Paull. W. K.. Turkelson. C, :.1 .. Thom.s. C. R..
and Arim ..... A. lmmunocllemieal Demonstra·
lion of a TeStic ular Subotanee Related 10 Lutein-
izing Hormone·R.leasing Hormone. Sci."", 11):
1263-4.1981.
IS6. Pelleti«. G. Imm unohistochemical localization
of LHRH in Brain.t Both Light· and Electrtln·
Mieroocope Lcvel •. Ad•. S. "lIorm. Ruh. 4: 187_
211. 1980.
t51. P,I,,<6, J . J.. .nd F.nebnrl,ch.. l.,w""h . {'c. F",.
mation of O.arian Cym in I"egul.. ly Cy--
cling Rats. Bioi, R.prod. U ' 11S3- 90. 1981 .
158. Pieper. D. R.. RiChards, J. S... nd Ma"hall. j , C.
Ova,ian GonadOlropin-ReleOling Hor"""",
(GnRH) Rec.ptors: Char.et.rilatio •. Distribu·
tion. and Induction by GnRH . Endocrioo/.. 101:/:
1148_SS. 1981.
159. Piclra•. R. J .. and Soego. C. M. Binding
Site, for o.:slrOjlen the DtJlcr Surfaees of Iso-
lated Endom.trial Cells. 265: 69-82,
1977 .
160. Porte,. D. G. Rel .. in: Old Hormone. New PtO$-
peet. Oxford R.v. BioI. I: I- 57. 1979.
161 . Porter, D. G .. and Finn . C. A. The Biology oflhe
Ut.'u •. Chap. 13. pp. 146-56 of Greep .nd Kob-
lin.ky. ed, .. ref.rence 76.
161A . Rooow$l<y. C. Androgenic Modulation of Cyclic
Ad.nosine Monopbosph .. c (cAMP)-Dependenl
Meiotic Arre" , Bioi. R.prod. 28: 774- 81.1983.
162, R. isz. L G., and Krcam. B. E. Hormon.1 Control
of Skel.tal Growth. AM. R•• , Phy.;o/, fJ: 22S-
3S,1981.
163, Ramal.y. J. A. Biolog;cal Clock> and Puberty
Onset. Fd. Proc. 39: B5S - 9. 1980.
164, Ran;, C. S. $ ., Salhan ick. A. R.. and Armstrong.
D. T . Follicle-Stimulating Hormone I"ducl!on of
Luteinizing Hormon. Receptor in Cultured Rat
GranulO\.a Cell$: An Eumination oftlle N«d fot
Stertlid. in the Induction Endocrino!.
108.-1319_85.1981.
."
Rebar, R. W" and Ven. S. S. C. Endoc'ine
Rbythm, in Gonadotropin<.rId O .. ,i•• Sltr<>id.
with Refe",nce to Reproduc\i>. pp_
2>9_98 of Krieger, D. T.. ed. BndfX';M Rh)'lhms.
PTm. New York, 1979.
166. Reichert, L E.> Jr .. San"". M. "-. and Darga. N.
S . Studies OIl • Low Molecular Weight
Slim"lating Hormone Binding Inbibitor from
Hum.n Serum. J. I:ndlX';'IO/. Mttab. 49:
866_72,1979.
167, Resko. J. A.. Goy, R. W.o Robinson. J. ",-, and
N<>rman, R. L. The Pube,cenl Rhesu, Monkey;
Some Char.cteri";,,, of lhe Men",u ") Cycle.
8 ..01. Rtprod. 17"154-<iL 1982.
168. Reynolds. S. R. M. Blood and lymph Vascular
Sy".m< of lhe Ovary. Chap. 12. pp. 261_316 of
G rup. cd .. reference n.
169. ROOdin. J. A. G. IliJI01OV. Oxford University
Press. New York, 1974.
170. Richard., J. S. Honnonal Conlro! of Ovarian Fol_
licular De.t1<>pmenl: A 1918 Perspecti ve. Rtr.
Prot . HOI"m. RJ("h . 35: 343-68. 1979.
111. Rnpert. J. F .• Quigk}". M. E.. and Yon. S. S, C.
End08erlOUS Opiates Modulole Pul.. tile Lutein·
;z;ng Hormone Rele.se ;n lIumans. I. CliM.
dlX,llfO/, Me/ab. 51: 58). 1981.
In . RothChild. I. Th. Regul.tion of th. Mammalian
Corpu.luteum. Rtr. Prot. I/",m. Rsch. 37: 18 3-
283.1981.
17l. R",,'o. M, H .. lIi . ...""d. R. 8., Noym •• k. M. A ..
and Dimino. M. J . Synthesis of Mitochondrial
Protein. aftcr Stimulotion of O •• rian Follicles by
Luteinizing Hormone. EfldlXri1l(>/. IQ8: 127-32.
1981.
174. Roy. E. J., Wilson, M. A. Diurnal Rhylhm of
Cyt<>pl.,mic £$trogen Receptors in Rat Brain in
the Absence of Circulating Estrogeru.
IJJ: 1525. 1981.
17S, RUSh. M. E., Ashir •. O. A.. Lipner. H .. Willi.ms,
A. T .. MeRae. C" and Blake. C. A. The Actions
of Porcine Follicular Fluid and Estradi<>l.,. Per-
io,ulllOTy S<:cretion of Gonadotropic Hormone<
in Ral>. 108:2316-23, 1981.
176. Savard. K. The Biochemi'try of the Corpu, lu-
tcum. Bioi. Rtprod. 8: 183-2<12. 191).
177. Savion. F .. lui. a.·M" lah.rty. R .. and a",po-
darowicz. D. Factors Controlling Prolif.... tion
aod Pr¢gest.rone Pn)duelion by Bo,ine Granu·
Iosa Cells in S<:rum·F,ee Medium . EMdlXrillOl.
109: 409_20.1981.
178. SaV(ly·Moore, R. T .• and N, B. Dirr.,·
ent;,1 Control of FSII aod l H Se<:relion. Ch.p,
4. pp, 203_48 of Greep. R, 0 .. ed.
Phy.iol<>gy /II. Uni'ersily Pork Pross. Balt imQre.
1980.
179. Sch.tz, F., and Hochberg, R, B. Lipoidal Dcri,.
ative of E'tradiol: Tho Biosyn1hesis of a N.,.r><>Iar
£$u",.n Motabolit., EfldlXri""', 109: 697_703.
198 I.
THE SYSTEM
180, SchipP" •• H .. Brawer. J, R.. Nolson.J. F.. Felicio.
L S .. and Finch. C. E. Rolo of Ih. Gonad, in tho
Histologic Aging of the Arcu .. e
Nudeus , Bioi. 1('",00.15:413- 19. 1981.
181. Schoonma ker. J. N" Victory. W .. aoo Karsch. F,
J . A Receptive Period for Estradiol-looucod Lu·
le<llysis in Ihe Rhe<u, Monk.y EnJlX,11I(>/. /08:
1814-1.198 1.
ISlA. Schuetz. A. W. Control Mechanism. in Oocylc
Growlh and Matu,ation. I. S!troid BilXnn... II:
695-9.1919,
182. Schuet •• A. W.... d Dubin. N. H. Proge'teronc
and Prostaglandin Secretion by Ovulated Rat Cu-
mulus Ctll.Qocyte Complexes. Endor"""'. 108;
457_63.1981.
183. Schule., L A.. Toofl'. M. E .. and SlraU". J. F,
III. Regulalion of O"rian Chole'teroi MelOt»
li,m: Comol of )·H}'drox}'·3·methylglutaryl
A Redueta'e and Acyl Coenzyme A:
Cholesterol AcyI1ran"er • ..,. EndorrilfO/. 108:
1476_86.1981.
184. Schw.be. C. Sltine", B.. Wei". G .. Scgaioff, A..
McDonald. J , K.. O'Byrne. E.. HOChman. J" Car·
ri",c. B.. and Goldsmith. L Rel .. in. Prot.
1/01""1, Rsch 34: 123_99. 1978.
ISS. Schwartz. N. B. Mechanisms Conlrolling Ov.I.·
tion in Small Mamm.l •. Chap. 6. pp. of
Greep. ed .. referenco 75.
186. Schwartz. N. B. Novel Peptide. in Ovarian Fol·
lieul .. Fluid: Implic.lion. for Con'ta""p1i"" 0._
'elopment, R.rI,. Fromi, ,, in F,,,Wty
1: I_II. 1982.
187. Seplorr. A, Pharmacological R.cePlor Dotermi·
nation in Endocrine Therapy of B....t Cancer.
AMn, Ph'mmtcol. T(}J(iN>!. 20: 429- 39. 1980.
188. Seidel. G. E .• Jr. Superovulation and Embryo
Transfer in COllie. Sci'ltu 111: 351-8. 1981.
IS9. Shaw. S. T .. Jr" and Roche. p, C. Menstruation.
Ox/OI"d Rtv. R<prod. Bioi. 1: 41-96. 1980.
190, Sheme,h. M. E.modiol·17t1 Bios}'nthesis by the
Early Bovine Fetal Ovary During tho Aeti"" a nd
Refractory Ph ..... Bioi. RtprOO. 1J: 517- 82.
1980,
191. Sheridan. P. J.. Buchln.n. J. M" Anselmo, V. C .•
and Marlin, P. M. Unbouod Progesterone R.cep-
lors Are in Equilib.ium between the Nueleu. a nd
Cytoplasm in c.n, of lhe Ral Uteru •. EfldlXri1l(>/.
108· IB3_7,1981.
192. Sherman. B.. Wollac •. R.. Be.n, J .. and Sehla-
baugh. L. R.lationship of Body Weight to Men·
.",hoal and Menopausal Ag. : Implic"lion, for
Brelst Cancer Risk . J. Clin. EnJlX"rJOl. MtlQb.
51:488-93.1981.
193 , Sherwood. O. D., and Rutherford. J. E. Relaxin
Immunoaclivity le,-.I. in Ovarian Ew'.elS Ob--
lained from Rat' during Va';,,", Reproductive
St.tes .nd from Adult Cycling Pigs, t:fldorrinol.
108: 1171_7. 1981.
194. Shon, R. V. Speei.. Dill"er.",e,. Ch.p. I. pp. 1-
 33 of AU'lin. C. R.. and Shorl. R, V... d,.
dUel;", PO/Unu. Cambridg. ..... ily Pre ...
N.w York. 1972.
195. Siiteri. P. K... nd MacDonald. P. C. Rol • .,r Ex_
,ragland" lar f.$trQgen in Huma n Endocrinology
Chap. 28. pp. 615-29 of Greep. ed .. r.f.... nce 75.
196. Simpson. E. R .. Ackerman. G. E.. Smi'h. M. E..
,0<1 M.ndelwn. C. R. EmOgen Formation in
StrQm.1 C.II, of Adip<>5< Ti .. u. o>f Wooten: In·
duction by G luCOCOT1icoid,. Prvx. Nail. Acad, Sci.
USA 78: 5690-4. 1981.
197. Sippel!. W. G .. MUII.r.Hol". W.. DIlrr. H. G .•
Bidlingmaier. F.. and Knorr. D. Concentra lion. of
Aldost.rQ ... COrticosl.rone. 11.[)eo.yoortico-
$lorOne. PrQgmerQJle. 17·HydrQ,yprogClterQne.
11·[)eoxycortisoi. Corliwl, and COrli""", Deter·
mined Simultantou>i y in Hum.n Amniotic Flu id
t hrQUghout Gutation. J. £mloui""', Mttab.
52: 385 - 92. 1981.
198. S I.unwhile. W. R.. Jr .. Kird.ni. R. Y .. and S.nd-
bers. A, A. Metabolic Aspect< o>f Est rogen, in
M, n. (;hap. 21. pp. 485-52) of G .... P. ed,. ",f·
erenee 75.
199. Smith. M. A .. and Vale. W. W . Desen,ili""ion 10
Gonadotropi .... Rele .. ing Hormone Observed in
Superfused Piluilary C.lls on Cytodex BeadS. £n-
dat,inc/, 11)$: H2-9. 1981.
200. Smith. M. S. Role of !'rola.tin in Mammalian
Reprod uc,ion . Chap. 5. pp. 249_76 of Gre<:P. R.
0 .. ed. !II. Uni •• rsity
Park Press. Bal1imore. 1980.
lOt. M .. "8«<;. Y.. " .d Av;"". S. Molec-
ular Regulalion of Receplors: lnt.",ctiQn of Es·
,radiol and P'Ogute,one with the Muscarinic
S)"Stem, Prat, Nail. Acad. Sci, USA 78: 5554_8.
198 I.
202. Sorge,. T" and Soderwall. A. The Aging Ut.ru,
and th. Rol. of Ed.m. in Endometrial FunctK,..
Bioi. R, prod. 14: 1135_44, 1981
203, Sperolf. L.. GI .... R, Il .. and K.... N. G , Clinical
Gynuologic EndatrifIQ/agy and InfmililY. 2d 00.
Saund ..... Phil.delphia, 1979.
204. Stankik. S .. Dornfeld. L. P.. M'",well. M, II"
5, P... nd KGrenman. G. The Effe<:t of
Weight Los, on Reproducti" Hormones in Obe..
Men. J. Oin. Endat,;ool. M,'ab. 51.' )83-n.
1981.
205. St.inet,. B. G. Secr.ti"" and Functi"" of Ova rian
Estrogens. Chap. 19. pp. 4)9_66 of Gr«p. cd ..
",fe",nee 75.
206. S,orm$ha k. F.• Haffis. J. N.• and Gonki. J. Nu·
de .. E$t",gen ReceplOr and DNA Synt he$i"
Chap. 3. pp. 63_81 of O 'Malley and Birnbaum.
eds .• ,derence 148.
207. Symond$. E. M. Ten,ion. Oxford
Rev. R,,,,od, Bioi. J . 156-81. 1982.
208. S,ego. C. M, Lysosomal Fun<tiQn in Nucleocy.
toplasmic Communication. Chap. 14. pp. )85-
471 of Dingle. J. T .. and De. n. R. T" eds. Ly.o--
• on,". in Biology and Pa/holo:>, 4. EI ... i.r. New
York,19H.
209, Szego. C. 1'01, Parallel. in ,he Mod.. of Ac,ion of
Pep, id.. and S'erOid lI",mooos: Memb1ln.
Effects and Cellular Entry. Chop. 19. pp. 431_
72 o>f McKern<- K. W" cd . SlrurtUTt and FUn<-
lion of Ih, Gonadotropins, PI.num. Ne ... Yo,k.
1978.
210. Tagatz. G. E.. and Gutpide. E. Hormone Secro-
lion by 'he Normal O ..ry. Chap. 21. pp, 603-13
o>f Gre.p .• d" ",f.",nce 75.
211. Taya, K.. Terranova. P. r ..• od Gr«nw.ld. G , S,
Acute Effects of Exogenou. Prog."eron. "" Fol·
licular Steroidos.nui, in the C),clie Ral. £ndo--
crlnol. 108: 2n4-30. 1981.
212. Tcrasawa. E .. Rodtigue,.. Sie... . J, r .. Die"eh ke.
D. J .• Brid..,n. W. E .. and Goy. R. W, Positi ••
Fe.dback Effect of Prog.,t.rone "" Luteini.in,
lIormone (LH) Release in C)'clic Fem.1e Rhesu,
Mon keys: III Re.ponse Occu rs in T ..'o Pha""s. J,
C/ln, Endoc,'noI. M.rab. 51: 1245_50. 19&0.
213 . Tortor •. G, J.. 00<1 Anag[!Q$,akO$. N. P. p,j",;_
pi.. of AIIII/on,y ami rhy. iology, 31"<1 cd. Ilarper
'" Row. Ne". Yor • . 1981.
214. Tsang. B. K.. Arm<trong. D. T.. and Whi'field. J.
F. Steroid Biosynth.sis by holaled Human O.ar·
i.n Cell. in YitrQ. J. Oin. End(Jtriooi. M<lab. 51:
1407-11. 1980.
215. Tu'ge"". J. L.. and Waring. D. W. Aeu'e Prog ...
terone and 17/:1·Est .. di<>l Modulotion of lutein·
izing Hormon<: Secretion by Pit"it.. i.. of
Rats Superfused in Vi,ro. 108: 413-
19.1981.
lt6. • . W . V.. S<h ... d ... W . T., ond O· Malloy.
B, W. The Chick Oviduct P"".'t.rone Reeeptor.
Biath,,,,, Arr, /form. $: 322_12. 1978.
217. Veldhui$. J. L Kla.e. P. A" and Hammond . J,
M, Di ... ct Aelion, of 17# Es".diol on PrQgester.
one Produc,ion by H ighly Diffe ... ntiated Po,dne
Granulosa Ce lls in Vilro: H. R.sula,ory Int.rac·
tiQn. of Estradiol wi,h Lutcini,ing Hormone and
Cyclic Nucleotide" 109: 4)3-42.
1981.
218 . Veldhui•. J. D" Klase. P. A.. and Hammond. J.
M. Sex St.roids Mod ul ate Prol.elin Aeli"" in
Sponta neou,ly Luteinizing Porcin. Granulosa
Cells in Vilro, £ndatr;lIOI, 11)$: 1463-8. 1981,
219. R. A. Kono. S"Sauor. M.. UpseH. M.
B.. and lori.ux. D. L. Relative Bindins of Teo-
losterone and EstradiOl to TeS1O$terone·Em.di<>l·
Bindin8 Globulin. J. C/in. Mnab. 49.-
899-904.1919,
220, W.i ... L" .nd Greep. R. O. Hi.lO/ogy. 4th ed,
McGraw·Hili. New York. 1971.
220A Wel,hon". W. V.. liebc:,m.n. M. E.• and
J. Nuclea, localization of Unoc<:upied Oe'trogen
Reaptor,. NalUrt 307: 747_9. 1984.
22! Wildt. D. W" Chan. S. Y. W.. Seaaer. S. W, J ..
and Chakr.borty. P. K. Acti.i ,y, Circu·
la ting Hormone<- .nd Sexual Beha.iQr in the Cat.
I. Relalionships During Coitu .. lnduc'Cd Lut.al
Pha.. and lhe EstrQus Period Witboul Mating .
BioI. Rep'od. 15: 15-28. 1981.

'"'
222. Wildt, L, HI".I ... 1\.• Hutchison, J. S .. Mat_
shall. G .. and Knobi!. E. E.... diol as a Gonado-
tropin Rel ••• ing U<>rmone in the Rh",u, Mookey,
f;ndocrinol. 108: 2011_1 J. 1981.
223. Wildt, L. HI"510', I\" Marshll. G., Hutchinson.
J. S .. Planl. T. M .• Eklchelz, P. E.• arid Knobil. E.
Frequency and Ampli1ude or G<)IladotrQllin.Re-
le"!;n! HormQnc Slim"I'lion and Gooadotropin
S.cl"<',ion in the Rbe ... Monkey . Endocrinol. 11)9:
376- 85, \98l.
224. Wildt, L. HUIChi<On. J. S .. Marsh.II, G .• Pchl. C.
R .. and Koobi!. E. On tho Site of A.t;On of Pro-
gesterone in the Blocl<ado of Ih. Es"adiol-In-
GonadOtropin Di<chacg" in the Rltc<u.
Mookey. £ndocr;/IiJI. IfYI: I 293-4. 1981.
225. Winkel. C. A., ParK.r, C. R .. Jr .. Simpson. E. A..
and MacDonald, p, C. PrOOuction Rate of Dtoxy.
_ticostorcn. in Women During The Fo>Ilicular
and Luteal Ph •• e• ." ,he O.arian C)'cle: Tile
R<>Ie of Extr"-<l.drtn.l 21·H)'droxylation of Cirtu·
lating Progc.terone in De<.. ycOTliCQllterone Pro.
duction, J. J,Mor, ilWl. 51: IJS4-8,
1980
226. Wurtman. R. J . An Elfect of Luteini,ing Hor·
A·I . EppiS,J . J ..• nd Down •. S . M. Chemic,l Signal,
that Regulate Mammalian Ooc)'te Matur.t;on,
HioJ, X,,,,.oo. 30: I-II. 1984.
A·2. H. uch. A. J. W .. Ad •• hi. E. Y .. Jo"" .. P. 8. C ..
and Wd, h. T. H .. Jr. HQfmonal Regul.tion of the
I)irrcrtnti.,ion of Culturtd Ovari.n Granulosa
Ccll •. Hnd"". ,:
A· J. Klaiber. E. L.. Broverma". D. M .• Vogel. W.,
l HE FEMALE REPRODUCTIYE $YSlEM
mone on the Fr,ction.1 Perfu,ion of the Rat
O ... y. Hndor,ilWl. 75: 921-33. 1%4.
227. YUh. K.-C ..• nd Keye •• L EfTecuof Human Cho-
rionic Gon.dolropin in the R.bbit Corpu, Lu·
teum; Loss of Estrogen Receptor and
Steroidogenic Rcspon,e to Eslr.di<>l, £ndorrjMI,
108: 1321-1. 1981.
228, Zarrow. M . X .. YOChim. J. M .. and McCarthy. J.
L Endac,inoloty. Academic Pre",.
Ncw York. 1964.
229. Zekznik. A. J. Prema,ure EI... tion of Systemic
Estradiol Redu= Serum level. of Follicle-$tim·
nl.ting Hormone and Lengthen. lhe F<>Ilicular
Ph . .. of the Me ..,,".1 Cycle in Rhe.", Mon·
ke)',. t ·ndrx,illOi. 108: JS2-S. 1981
230. Zel",nik. A, J .. .Schuler. H. M .. and Reichert. L
E .• Jr. Gonadotropin. Binding Sites in the Rh .. u,
Monkey Ovary: Role of the Vasculatur. in the Se·
lective Dimibution of Human Chorionic Gona.
dolropin!O the Preovulalory Follicle. Endor,inol.
1(19: 3S6-62. 198 1.
231. Zor. U.. and Lamp=hl. S. A. M«:hani.m of
Prostaglandin Act",n in Endocrine Gl and ,.
BfrxMm, ACI. HOI'm. 4: 8S-133. 1977.
Kenncd)'. J. A.. and Nad.au. C. J. l. Estrogen.
and Ccntral I'."ou, Sy .. . m Function: Elec·
troenccphalograph)', Cognition. and Depression
Ch"p. 13. pp. 26 1- 89 of Friedman. R. C .• ed. il...
,It,
M" "lrual CJ'C/' . M."",I !)CUcr.
lne .. New Yor'. 1982.
A-4. Wei,,_ G. ReI ..in . Ann. PhyJioi. 46; 43_52.
)984,
 16
Conception, Contraception, Pregnancy, and Lactation
PREPARATIONS FOR FERTILIZATION
When spermatozoa enter lb. 1raCt. they Can
swim but they arc nO! yet capable of penetrating thc
prote<:!;". layers that surround the oocy1e. Their
head regions arc covered with glyooprOlcins provided
by the Icsticular and seminal Huids. and lhose mol-
ecules block further maluration as they confer sla-
bility (102) . Sialic acid-rich compounds increase Ihc
surface cha rge negativity and lesse n both suscepti-
bility to deSlrUctlon by phagocytic leukocytes and
the tendencies to agg'utina!e (lOS).
Capacitatio n
Further preparations for fertiliza tion. COIle<:livdy
known as capacitation. arC oomplctcd in thc female
trac\. These involve modifications of the head region
thaI will be nceded for interaction with thc oocyte,
and acqui.iti\m of the ability to engage in forceful
"thrusts" that facilitate passage through it. Sur-
rounding cells. The acrosomal membrane. enelose
protea,cs. phosphatases. phospholipase A. arylsul-
fatase. neuraminidase. and other en7.ymeS impli-
cated in fertili7.ation. Capacitation prepares at least
some of those proteins for activation or release . Con-
comitantly, the relatively hardy immature gametes,
pre"iously capable of wilhsta nding a period of Stor-
age in thc epididymis and of surviving the mechan-
ical punishments associated with ejaculation and
successive to seminal nuids and the female
tract cnvironments. are noW converted 10 delicate
gamctes wilh vcry limiled life spans.
Transmission electron microscopy does not di,
re<:tly r<:veal obvious morphological specializations
of the spermat01.Oa of primates. However. it Can be
used in conjunction with other techniques to dem-
onstrate changes in the densities and of
'"
surface glycoproteins and glycolipids. and in stain ing
properties. Alterations of the head r<:gion are also re-
ne<:ted in differences in electrophoretic mobility, an-
tibody binding . and agglutination reactions
Some of the proteins that arc re-
moved have been identified (62.67 ).
0'Y8cn uptake and glucose U1ili7.ation increase.
and thc cAMP that is generated contributes to the
ability to perform directed (40). (The
motility chanle< can b< elicited by prcscntin2 the
nUcicotide in combination with phosphodiesterase
inhibitors_) E'tracellular Ca h is needed, and one
function is support of adenylate cyclase activation.
Allempt. have been made to study the pbcnomena
under artificial conditions. Capacitation-like
cbanges can be accomplished by exposing cells to
media containing ,II-amylase. ,II-glucuronidase. neur-
aminidase. papain. tryp$in. eosinophil" or certain
viruses (lOS). It has bo.n proposed that the physio-
logical prOCCS$ involves a sequence of en7.ymc-con-
trolled event. which culminates in uposure of r«Cp"
tor .ites for molilily factors and other regulator!
(102).
Relationships between the changes occurrins in
vitro and the physiological have not
boen fully defined. The cstrogcn-<iom inalcd uterus
secretes copiou, quantities of fluids Ibal .upport ca-
pacitation. The fluid, contain glyeerylphosphoryl-
choline (GPC) diesterase that releases glycerol for
use by the 'perma to7.<la. a number of anticen, that
bind to tbe sperm head when the appropriale ,iles
are exposed. and several enzyme, implicated in the
capacitation (2). A neuraminidase removes sialic
acid groups (218). and the uterine ,8,gl ucuronidase
level correlates dir<:ctly with capacitating potency
(l02).
The maturation seems 10 require 7 hours in hu-
mans. 5-6 in rabbit'. 3- 4 in ferret' and cows. 2- 4

in sows, ralS, and hamsters, and less than I hour in
cal!; (39), It may procoxd mOSI rapidly when sper-
malozoa are brieAy to ulerine fluids and arc
Ihcn transferred to the oviduci.
DECAPACITATION AND RECAPACITATION
When capacitated sperm arc suspended in seminal
fluids, Ihey \(lSC thdr abjjjty to enter into the acro-
some reaction . This ha' been auributed to surface
binding of decapacitaliOll faclors (OF,) that origi-
nate in the Cowpds (bulbourethral) glands, seminal
vesicles, and epididymis. "Anti-fertility factors" in
seminal fluid include protooglycans and small pef>"
lides (62,184), but it has oot been establishcd that
Ihese arc Ihe subSlances removed during capacila_
lion. Spermat07.0a subsequently returned 10 Ihe utcr-
inc Huids 3r<: said 10 undergo "recapacitalion."
An Opposing concept is thai spermatozoa cannot
go through a secondary activation. Rather, il is the
cells which have not }'et undergone Ihe capacitation
Ihal malure when Ihc suspension is placed in the
uterus.
Ho rmonal Preparation of the Female Trac t
for Sperm Tran sport and C apacltallon
Spermatozoa deteriorale rapidly in Ihe femalc trac\.
They go Ihrough a phase in which they can still pen·
etrat. oocytes but are likely to enter into the for-
mation of abnormal zygotes. Aging oocytes also
transiently retain the ability to engage in ferlili7lt·
lion, but Ihey soon undergo surface modifications
that confer resistance to sperm entry (130). Since
primates mate during all phases of the ()\Iarian cy·
cles, moxhanisms are required to increase the prob-
ability thaI male and female gametes will meet at
optimum times. Some of the adaptations were dis-
cussed in Chapler 15.
FERTiLITY LI MITATION DURING NONOPTI MUM
TI MES
Unfenilizcd oocytes deteriorale during the luteal
phase. At that lime, the progestcrone-dominated
uterine ce .... ix secreteslimiled quantities of a highly
viscous muCuS that is hO$til. to spermalozoa and that
impedes Iheir passage through Ihe cervical canal.
(Similar Huid provides a barricr to th. entry of mi-
and spc:rmatozoa during pregnancy.)
Progesterone also acts on the uterus to create an
environment which disooul"ltges both capacitation
and sperm m(lvemcnts. It decreases Auid volume by
inhibiting the activily of Ihe glands that produce wa-
tcry secretions, by increasing endocylosis and thcre-
CONCEPTION AND PREGNANCY
fore reabsorplion, and by relaxing the cervix to per-
mit drainage (2). In some spe<:ics, relaxing effects on
thc myomctrium Further retard sperm passage 10 Ihe
oviducts.
In the oviducts, progesterone limits the ability of
spermatozoa to gain access to the fertilization site by
exerting innucnces On cil;ogenesis and Ihe COntrac-
tility of the smooth muscle. However, the cyclical
variations in nuid are insurr.·
cienl for blocking capacitation (39) .
During the early follicular phase, estrogen levels
are st;lIlow, and Ih. female traci is not yel prepared
for receplion and transport of the spermalozoa.
Therefore, the chances that the sameles will cnter
and undergo deterioration as they ""ait for ovulation
ar<: lessened.
Roles of the Cervix In Transpo rt of
Sps rmatozoa
In horses, ,-"bras, pigs, guinea piss, dogs, rats, mice
and SOme others, the spermatoloa ar<: catapulted di_
rectly into the uterine cavity. Humans.. monkeys,
rabbits, cows, and sheep are among the mammals in
which insemination is vaginal (21,238), and in these
the uterine ce .... ix performs several functions.
PREFERENTIAL DELIVERY OF HEALTHY
SPERM ATOZOA
During the estrogen-<lominated preovulatory pnase,
glycoprolein filaments within the ce",ical canal align
in parallel arrays. Well-Formed, vigorously motile
spermatozoa can pass between Ihe oolumll$ and
enter the uterine cavily. Since the swimming move·
menl!; are randomly dir<:cted, the filaments probably
orient Ihe migration (92). Few spermat07.Ga with
two heads, two tails, swollen heads, and other de-
formities are admilled. Degenerating and dead cells
are probably excluded because they seldom achieve
random pqsitioning of the head at the entry site and
canoot swim even if this occurs. The preFerential
barring of healthy spermal(71)a from other spe<:ics
may result from interactions between the surface
components and the cervical mucus.
ASSISTANCE IN THE UPWARD PASSAGE OF
SPERMATOZOA
The first part of Ine ejaeulale contains the largeSI
numbers of spermaI071)a. In and many other
spe<:ies, a coagulum is formed . Direci contaci be-
tween the coagulum and the mucus al the surface of
the cervical canal averts loss of spermatozoa to Ibc
walls of the vaginal cavity (2!),
 Contractions of the vagina and during coi·
tus. and of uterine and respiratory muscles. may fa·
cilitate sperm entry by creating positive prcssur<: on
the outside and a nega tive 00(: within 1he uterus.
However. although female traCt prostaglandins stim-
ulate smooth muscle (87). and spermatOl-Oa appear
in the utcrine cavities within 90---180 seconds after
vaginal inscmination (39). some in.'estigators ques·
tion the imporlan-x of such me<:hanisms in humans
(22).
RESERVOIR FUNCTION
Most of the spermatow.. arC detained in the -xrvix
for periods ranging from minutes to days. Their ten·
deneies to engage in reversible agglutination in·
crease the chances of entrapment within mucus-
lined crypts. Cervical fluid enzymes are believed to
subsequently promote of limited numbers of
trdnsicntly captured gametes. Although the ability
to fertihe is lost within 48 hours in many species
(39), (and full viabili ty may be retained for just half
that time in primates 192)). motile spermatozoa
have been recovered from human cervices as late as
six days aFter coitus. The reservoir function may
therefore be of gr<:ater physiological importance in
sheep and certain other species in whiCh the spero
matozoa are hardier,
ADVANTAGES OF STAGGERED ENTRY OF
SPER MATOZOA INTO THE UTERINE CAVITY
Pre,entation of limited numbers of gametes at a timc
SCems to confer several advantages: (a) The healthi.
est spermatozoa enter first and these ean complete
fertilization before the laggards arrive. (b) Protec-
tion may be CQnferred against polyspermy and fer·
tili7.ation of polar bodies. The surface properties of
tbe oocyte change soon after a spermat07-Oan enters.
The membrane then resists penetration by additional
gametes. The pr= nee of very large numbers of
spermatozoa increascs the chances that polyspermy
will OCCur before the reaction has been completed,
Morcover, although the first polar body usually de-
teriorates rapidly, there is 3 brief interval during
which it can be fertili7.ed: and (c) capacitation effi·
ciency is probably increased. since spermatozoa can
affect the composition of the microenvironmcnt and
compete for limited numbers of enzyme molecules.
Genetically determined properties of the cell sur·
faces. the volumes and compositions of the seminal
"uids, and the conditions within Ihe female tracts all
affect sperm longevity. Mammals with long estruS
periods generally present environments that prolong
survival. Motile spermatozoa ha'.. been recovered
4-6 days after mating in horses, at II days in dogs,
and after 156 days in bals (39), Som. nonmammal·
ian vertebmtes depend upon a singic insemination
for multiple succ<:ssive The oviducts of
birds store spcrmatoroa, and spcrmatoroa of """. of
the reptiles retain their functions for up 10 six years
Sperm Transport through the Uterus
The large volumes of fluid secreted by the estrogen.
dominated uterus distend the organ and provide a
medium for sperm migration, Observations on the
swimming pallerns and rates. the lenglhs of
the palhwa)'s. and the times required for arrival at
Ihe oviducts. indicale that the activities of the spero
mat().loa are of major importance in small mammals
such as the rabbi!. In cows, the spermatoz03 rapidly
travel long distance" Coitus leads 10 release of oxy·
tocin (92) and the U1eruS contracts in a mannCr con·
sistent "'ith roles in facilitation of the migration.
Moreover. uterine stimulants promote upward pas-
sage of inert particles.
The palhway is also long for humans. but the sper·
matozoa can arrive at the ferlili711tion site within S
minutes afte r inscmination (39). Estrogens promote
ovarian and uterine generation of PeF,. and pitu-
itary gland secretion of oxytocin. They a lso directly
stimulate the myometrium and increase the sensitiv·
ities to the otber regulators. Since healthy sperma·
t0700 tra"e! more rapidly than deteriorating ones.
spe rm surfaces may interact with uterine secretions
in a manner that eilher facilitates Iheir passage di·
re<:tlyor provides a myometrial stimulant (w he reas
degenerating sperm surfaces sc:cm to show greater
"stickiness"). PGs are also prescnt in seminal fluid.
but these are of the kinds that mostly inhibit uterine
motility. The magnitude of inhibition has been cor-
rclated wilh fertility (176 F).
Transportation to tha Fartllizatlon Slla
The uterotubal junction provides a mechanical im·
pediment. The lowermost end of th. oviduct iSlhmus
is dilated. but annular folds of Ihe uterine mucosa
form a sphincter.like Slruclur<: tnal guards th. open.
ing of the thread·like lumen (97). Locali,ed end<»-
metrial edema Can further delay spe rm entry. Me-
chanical factors may be especially important for
spe<:ies in Which insemination intraulerine. The
junction relaxes intermillcntly to release small num·
bers of Since the cilia lining the isth·
mus Can reverse the direction of beat . they probably
also play important roles (22). The me<:hanisms ao-
complish delivery of freshly prepared gametes to the
fertilization and provide prolection against the
accumulation of too many at anyone time (168).
Movements through the isthmus of the oviduct are

aided by perillaltie of the ovid uctal
musculalure and by fluid currenlS. The aClivily
undergoes cydic changn and is lI\0II1 villorous duro
inll thc periovulltory period (98). Estrogens incl'CI.lIe
lhe activity. the numbers of cilia. and thc numbers
of cNldrcnel'Jic reoeptors. Pro.l.IgJandins, Vll$Oactiv<:
inlC$lin.a1 peptide. a nd other rellulators conu ibute to
lhe complc.-. control muhaniSITI$ (sec also Chap.
IS).
Fertili1.lltioa usually occurs in the rellion jlUl
alxwc the ampullary-iSlhmic j unction (A U ). C0n-
striction in ,hi!; re&ion retenlion of lhe 00-
C)'tcsand their surroundi", cumulus. h is not known
whether an impediment is presented here fOf sper·
malozoal entry. II has b«n sp«ulatc:d that fQmC
product of OVIIlation (the oocyte, cumulus cells. fol-
licular nuid, steroids) provides a sigllllithal synchro-
nizes the arrivals of sperma tlm)l and oocyln (39).
Tre n e p o rt 01 Ooc ytee to the Am pu ll ery·
le lhmlc Ju nction
The tips of thc Ambriac at Ihc upper end of Ihe ovi.
duct direct newly released oocyles and thcir Sur·
rounding cumulus loward thc lumen. Cilia Ihat line
Ihe fImbriae and ampulla direCI Ihc cell masses
downward 10 tho AIJ. (Asen" that im!""r their
functions decrease fertilily or increa$!: the of
feniliunioo 100 hillh wilhin Ihe ovid ucl.) Glycoca.
lyccs al Ihe lipS of the cilia also form IooI.c "adhniv<:
bonds" wilh Ihe cumulus cell surfaces (160). In ad·
dition 10 providing more sitn fOf in leraction wilh lhe
cilia. Ihe cumulus cells enlarge the largel fOf sperm
approach. Spa= belwe<:n 1M C<llls orient spcr ......
IOZOO Ihal make COlItacI (161).
In ralS and mice. estqens secreled during the
periovulatOl)' period $limulatc lhe sphineter and
IlIcrcby promote relenlion dIlle OtXylcs above IIIe
AU 10 provide time for fertiliution. ( Moderate
am(Mlnl$ or exogenous hoIhKIIlC lnYOke utu ballot:k.
ing.") After rcniri7.ation. progesterone from the oor·
pus lu teum rclues the mUJele, dilates the lumen.
and llradually lowers tile resistanoc 10 downward
of lhe oonttplUIIeS (169).
Species diffen:nces are encountered (249). lilt-
mans .how limila r responses 10 nlroscns. and in
both primale$ and rodenls. pharamac:ological
amounts of wr<tgcns stimulate lhe Iongiludinal
muscle and promote eU,,"sion of oocylcs or conocp-
lUstS. In rabbits. eslr<tgCI'l$ constrict lhe AIJ moslly
by involtinll ,ur'acc ccll edema. In most of the mam-
mals. larlle doses of progesterone: reduce oviductal
muscle lone (249).
CONCEPTION AND PREGNANCV
The Ae roeome Reac t io n
When lhey enter the vicinily of fre$hiy ovulated 00>
c)'lcs and their layers, capacitaled 'per·
matoma undergo irrcV(:rsible morphological and
biochemical chanlles lhat are es..enlial for fertiliu·
lion. It is widely believOO thaI some factor pn:wi<kd
by the follicular cclls. the follicullr fluid, or lhe Willi
pellucida the aerosome reactiorl. and thaI
tal fluids iiUppor! the PI" =
lite high calcium contenl alld high pH of lile oriduo-
ProIeil'l$ rornmon to
blood 5crum and oviductal fluids may abo be
invoiV(:(j.
Tbc ehallJCS <:an be mimicked in vilro wilhout 00>
cytes when the ' permalOlOlll of some specicslre sus-
pended in calcium-rich mcdi:o with p Hs llreatcr Ihan
those found in the female InCI (1 10). The addilion
of llerum shorten> the lime required. Components of
scmilllli "uid. iocludinll sugars. are inhib;'
10f)'. (The sugars do not enler Ihe oviducl. bul lhey
may CQIllribule 10 SlabiliUlion of spe rm surfaces a t
lhe lime of ejaCUlation and passaiC inlO lhe ulerillC
lumen £1].)
The morphological ev<:nlS have been described in
detail (9). Before the reaction bellins. il is poiSible
10 identify a plasma membrane and both inner and
outer acrosomal membranes (Fill. 16-IA). Vesicle.
form when Ihe plasma and Ouler acrosomai mem_
branes fuse at scveral poinls (Fig. 16-18). En1.ymes
are released Illroullh the spaces between lhe vesicles.
along with inhibitors of different enzymes Ihal ad·
here 10 tnc head. uWhiplash" nagelllr movo-
ment, stir Ihe surrounding "uid, and these racilitate
both removal of Ihe discarded sperm CXlmponenlS
and interactions belween the gamelcs and lhe ovi.
ductal epithelium (II 8).
The _icles subsequently detach. and lhe now ex·
pooed inner acrosomal membrane fuJeS wilh what is
ldt of the original plasma membrane (Fie- 16- ID).
The inner membrane is belieV(:(j 10 play special role$
in penetralion of the spcnn bead. and 10 panicip:lle
in the first attachmenl 10 the oolemma (161) (Fia.
16-1E).
ACROSIN
The bolief lhal Ihis serine protease is essenlial for
fertilization is supported by observation< Ihal illCts
on lhe zona pellucida. Ihal activily ca n be detecled
in Ihe slil made by Ihe penetrati nll spe rm:Il<nOa n,
and by Ihe anti·ferti lity cffec" of in hibil,," (91). II
may CJltsl in "pool.... e3ch of which performs specia l
functions. Enzymes associaled wilh Ihe OUler memo
brane 3rc implicated in mediation or lhe acrosome
reaction. whereas the ones that transiently adhere to
the inner membl'llne probably contribute to the reo
lease of spermatozoal chromatin after penetration
has been accomplished (7).
A zymogen (proacrosin) is initially present The
sperm heads of the various species contain sut>.
stances that block the conversion. inhibit thc activity
of the acrosin that is formed, or both (17). Some
may be released to the surrounding fluids during ea·
pacitation or the acrosome reaction. The inhibitors
can dolay lhe acrosome reaction until the appropri·
ate time, and thcy may additionally prote<:t thc en·
zyme that adheres to the inner membrane.
The vast majority of spermatowa in the female
tract unde rgo deterioration. Dead and degenerating
cells can display a "false" acrosome reaction that in·
volves enzyme release but no 1C>ss of It.. plasma and
OlIter acrosomal membranes. The enzyme inhibitOl"S
may protect the female tract against proteolytic de-
struction (91). (Fructose and other seminal fluid
eomponents inhibit acrosin, but they never SCI 10 the
oviduct 17] .)
A role for hyaluronidase in depolymeri7.ation of
the cell matrix is consislent with observa·
tions that follicular cells disperse when 10
that enzyme, and that inhibitors impair fertilization
when the cumulus is present but not when Ihe oocyle
has been denuded (184). Enzyme reloased from ""V·

_ . '"::: oc!Osomat
; ",.mbr . ..
I........ '«050"'"
"'."'br .....

>,"_",_, "",mbrono

A. Bo!",. oc.ooome 8. Fuston 01 pI.. m.

,ooct_ . .nd ""to, . «000",.1
membr. ne l",m"io<>
0,-.,.:1-..

C. R...... of oc,,,,,,,m,, D. Det.ohme,." of ••• " ...

,rvO<.lgh ." . ... . nd "PO'U," of inner
bo,w..,n . .."', •• oc,osom" "'embr . ..

E. Contoc, of .".,"'"o«>On F fu."", of ><>«",010'0'''' during the aero_ ,.,actio<> ar.:1

.."h oofe mm. w,th.,..,m . w;,hthe_.

eral spermatozoa may be neroed to accomplish effi.
cient dispersion of the follicular (20).
Neuralninidase sialic acid, and it
reduce:! the ""ptivity 01 d><: charte , DilTcr.
ent hydrolytic enzymes rtmove gly«lllyl romponents
of zona pellucida glyooprotciM and al)'CCIUmiM-
alycaros. possi bly fOt tM PUrpo5C of uJl(l'ina ««=p-
tors invoh'Cd in sperm-oocytc binding (219).
FERTILIZATION
In spec:ic:s in whiel> boch the ew and sperm.re re-
Ic:ascd to an aqueous «tcrnal environment fOf fcrtil·
i•.ation., mechaniSITI$ may be mjuircd to attract t he
spem.luoz(ll. to the 081 «1I,.nd provide proieetion
against tbe joining of IM:tcroiocous gametes.
specit«: alywprotcins alied/mil/zlN are produced
and released from I he jelly eom of the (aasol some
animals. Can It chemotactic factors for
lhe sperm. and the: actual fort ili:ta.tion p'OCt;$$ seems
to begin with an antigclHntibody·likc combinallon
of the fertilizins wilh onl/fmllirlns on the su rface Qf
tile sperm head (11).
Mammal ian spe rm atOJOa move in random direc-
lions. but a few eventually achicve Ihe orientation
needed to penetrate the cumu lul. Ihey have
been observed to swim p.ast oocytes th" t thcy ap-
proach closely in vitro, it is unlikely that chemotaxis
is involved ( 125). However, once conlaCI is madc.
multiple "recognition si tes" or "r«cptors·· <;oo trib-
ute to the binding. (The proeess is imp.aiml by an-
tibodies directed against spe rm su rface mol"u les
[165] .) Penetralion of the zona pellucida 11 a sepa·
rable event. T he ZIlIU show¥ speeies v..iations in
comJl(l'ition (64).
It has bt:<:n pointed OOt that mam mals do not re-
qu ire protection alainsl M(I'OSS fettiliu tion. K $lnce
beharior.ll plltlerns pr«ludc: the entry 01 foreign
spcrmat01.OOl (199). bindi". I;:In be
!lctrK.lR$lral<:<i for jusl a few lpcCics (0:.1- mioe and
hanwers). II is not COIISistently (oIlowcd by
pcnc:lration.
Sanni". electron microscopy has K'U\cd that
protei ns .. ithin Ihc aCIOSOOlle Ire used to ntpidly as-
semble a 100, filamenl which makes 11M: fi"l «IntaCI
with tIM: oocyte by functior>ing as I MhlrpOOn"
(l91A).
ElItraccliula r eaf, is ""eded for sPClllHilI fu·
siOft. for the 1.ona reaction tllat follOW$, and [Of tile
subsequent swelling or the sperm llead that pn:cedes
formation oIlhe zygote. The eventl seem to be ini·
tiated by Cal. entry across tile cell membrane <>f I he
'perma tOJ;Oan, and the: reluse of H ' to the su r·
rcunding Auids. The spermlt07,OO.n Ihe n injecls ca l·
cium and .Ikaline eyloplum inlO the oocyle (197 A).
CONCEPTION AND PREGNANCY
The high K ' CQIIcentrations in both IlUlIe and fe·
IlUlIe reproducti"" trael Au id. can facil itate
lation and the acrosome reaction. However, they do
001 seem to be essen!ial for citller of the processes.
and excessive amoon" inhibit . In ((Intrast. K ' is ab-
solutely TC(juired for sperm-<:gg fusion. and uccssi""
a}ROCntolllions permit polyspermy to ooc:ur (188 ).
The Zona Reaction
When the sperm head attaches loosely to the micro
villi that protrude fn;m Ihe ookmma (9). SIIIlK 01 the
microvilli extend upward 10 clUj! the .... rm. The 0o-
cyte membnt"" immediately begi ... to bu lge in Ihat
.icinily. Clear cytoplasm moves in 10 form a Mfertil.
i,alion conc·· (illCOl poration coot) (161) that is usu·
ally e)'lindrical bul bas pseudopod·like projections in
',II"e sJ>I'<'ies (II). Cortkal granules are then ex·
pelled (limited numbe .. by human oocytes, bUI all in
se'"ral other animal types).
It was fortmrly belkvcd that 1M granule di$-
eharae and Ihe subsequent elaboration of a ··fertil.
izulion cn velopcM provide the blocks to polyspermy.
It now <cx:ms thai the changes in surrace charae are
more imp<:>rtant. (Enlry of new spermalOl.oa is af·
fected almQSt inslantaneously. wherel5 Ihe ot her
eve nts require a full minute to go to complelion ,)
n", .. iou>ly ci ....I<oncgali vc inle!;", I>o:c<;u"". .,0.-
ilivc with respect to the cxterior. and the ··fcrtili .,a·
lion pote ntia l'· is maintained for several minutes. AI·
lhot.tgh as.<;ociated movements of pola<$ium ions Ire
probably imponanl, a rapid inAux of Na' is held ro:-
spon!.iblc. Unfertilized eags exposed 10 e1cctrial
currentS do not permil sperm penetra tions ( I I).
h>OlStitidc pho<phorylalion (A-4) may precede d ·
evation of lhe cytosol C.l ' . M ost of the ion comes
flOm in tracellular S<:qucstration sites. The chan&CI
Ire believed to initialc the aranular discharge. Soon
arlerward. the qtosol Ca" returns 10 lhe initial
levels.
CytoplasmIc FUSion
The plasma membranes or the oolemma and fen il-
Will spermatOl:OllD fuse rapid ly .• nd tbe spe rm />cad
is drawn inward. The !.ail projccu.1 fi .. t into the
perivitclline space. In humans. it enters the forming
lylQle and soon deleriorates ( I 2S). but il is excluded
in many ot Mr mammals (9).
Oocyte " Activation"
In add ilion to <;OOlri buting its 'hare: of the aellClic
materia l. thc spermatozoon stimulates Ihe oocyte
(possibly by changing the nalure 01 or promoting ex·
lrusion of a ·' cytQSlatie faelor'" thai is also impli.
eated in a",:s\ing meiosis prior to fertilization). Cy-
IOplasm from fertilized eggs can rapidly "activate"
unferliliw:l ones Ihat are "ripe." the
reaction is oot essential. Activation occurs when fer-
tili,.cd <:><x:yteS are prevented from undergoing thc re-
action by exposure to NH'. and when unfenili"oo
ones a«: stimulated in sc"eral ways.
CytOSOlic Ca" elevation change:., the permeability
of the plasmalemma. Hydrogen ions arc extrudoo as
Na ' enters. and the consequent alkalinity is belicved
to provide a stimulus fOf protein synthesis. Ribo-
somes become organized into polysomcs. and there
is "unmasking" of pre-formed mRNA. In most spe·
cies. oxygen consumption increases (II).
Nuclear Fusio n
Soon after activation commences. the <:><x:yte com-
pletes meiosis II and becomes a "true" ovum. The
ehrumosomes rearrange to form a vesicular female
pronucleus that moves loward the Center of thc cell.
The ooplasm shrinks. and a clearly dema«:ated
space'ICpllMes thc oolemma from the zona. The 001-
ema may Iransiently contain thc second polar body.
The sperm head migrate> toward the female pro-
nucleus and the nuclear cap separates from the our_
face as small vesicle. form in the adjacem ooplasm.
The male pronucleus then undergoes "decondensa-
tion," increases 4-5 fold in volume (161). and SOOn
looks like its female counterpart. The tail detachcs
and degeneratcs, but the anterior cenlriole may give
rise to the centrioles of the 7.ygOte (125).
DNA replication proceeds in both of the pronu-
clei. pores form in the nuclear membranes. and fu-
sion occurs. The zygote then almost immediately
prepares for entry into mitosis.
If fertilization is delayed (because of an inade-
quate LH surge or when the oocyte «:mains too long
in the oviduct before the spermat07.03 arrive). the
<:><x:yle may fail to complele meiosis or to rapidly ac-
complish the changes in surface properlies. The con-
sequences can include polyspermy, incorporation of
polar body DNA inlO the lygote. or changes in the
zOna pc:ll ucida that block .perm entry (174). Both
lhe low fcrlility and the increased incidences of chro-
mosomal defects of aging females have been lin ked
with oocyte deterioralion.
Fertlllzalion al Olhar Silas
In eutherian mammals it is unusual for fertilization
10 occur at other sitcs. It is theoretically possible for
spermatozoa and <:><x:ytes to meet in Ihc abdominal
cavity, but the rare cases of abdominal pregnancy
are allributed to upward migration of conceptuses.
Ovarian pregnancies have been reported . but thosc.
too, probably result from implamation errors.
DEVELOPMENT TO THE BLASTOCYST
STAGE
Very young conceptuses of all cUlherian mammals
arc remarkably similar (138). The zygotes of hu-
mans. cows, and rabbits are identical in volume, and
there is only a two-fold variation aCross the entire
subelass of vertebrates. All of the zygotes attain the
2-.:ell stage within day. after fertilization.
They retain the zona pellucida, but soon free them-
selves of the cumulus cells and undcrgo successive
cleavages to form a clUSler of very small cell •. They
gradually make their way down the oviduct and ar-
ri,"C in the Ulerus by the end of thc 4th day (29). The
migration may involve special intcractions with the
luminal epithelium. since conceptuses can be trans-
ported when unfertili,ed <:><x:ytes 3«: retained (241).
At JO hour; postfertili7.ation. the human concep-
tus co.,.i,ts of twO Ullcqual"i"ed blaslOmeres. The
larger One divides first. and the smalter One within
hoors afterward. The G-I phases of the cell cyclcs
are extremely short, and a I0-12.;;ell morula is soon
formed (125) (Fig. 16-2).
Membrane permeability Ihen changes. and aero-
bic supports active uptake of inorganic
iono (15). As watcr enters. f1uid·filled spaces appear
between the surface and inner cells . and by 4-4)0
days the spaces join to form the blaS/(xo..le. The
conceptus is now a biastocysl containing /lO1 much
than 100 cell •. Mo<t of the cell' make up thc
surface Irophobiasl thai will become involved in im-
plamation. formalion of the placenta, and produc-
tion of hormones that act on thc maternal ovary.
Just a few (Ihe inner cell mass or pro-
vide the fo«:runncrs of the organs of the ncw
individual .
tn primates. many of the b1astocy,ts .how abnormali·
ties. Large number. doteriorate, and the , uTviVOt". often
have ""me malformed «11. (66) . It h.... been ."imated
that some uf YQuni en\br)·os die hef.,.,.. or.<OOfl after
implantation. and grossly defective coneeptu... have
heen recovered from the uteri of women who livo birth to
heatthy infan" (125).
Most of the componems of the morula are derived
from molecules that were presem in the zygote.
(These include nUCleic acids and proteins donated by
the sperm) . However, a hypoosmotic environmem
that supplies calcium. potassium, and small amounts
of phosphate and magnesium is required. Pyruvate
is used as the principle energy source during the first
1-2 days (138), and some is also used to
make glyoogen and alanine. When hexokinase and
other enzymes accumulate and the mitochondria as-
sume their metabolic functions. additional substra tes
are utilized . Oxygen and glucose consumption rise
dramatically by the 4-cell stage. and upta ke of RNA
precursors then begins to accelcrate. A second steep
 10: &
"re ·:.,
Blastome,,,

A, . Two-cel l stlge 8. Four-cel l Slag" C. M<>rul .

'""" ,,"" m,.. lembryoblaotl

, , "

TrophoblaSt
, cells

,
, "
Ilrophotlla.l)
E. Beginning of
D. Bl ulocyst
impt.ntati on

Fig. 16·2. EIolly <Ie'''iOp(rIeol of 'h. •.

(RaprO<!uOO<l with permission. ftom lAl'Igmlln. refor....,.
125.1

increment in metabolic activity oo;<:urs shortly before
implantation. when Ih. mn! pellucid. is shed. The
membrane is believed 10 contribute to the regulalion
of fluid uptake and to) protect the oonceptus against
premature implanta!ion in the oviduct.
Specie. difference. firs t become "bvi".,s 0' lh. bl.,,<>-
cyst .tag •. All conceptu... "' • • up water, bU'lhe
i. highly limited r", prim.Ie>. Rabbit embryos can in-
cr.... 4000-fold in volume during da)'14-7. Implanta_
lion occurs at day. in mice, 5- 6 in raj ••• ft., Sl>-6
days in humans. al day. 7_8 in rabbit<. bill only after 9_
I I day. in ,lie monkey and 17-18 in 'he d<>meSlic cal. In
CO"" >' associalion. wilh are made early.
bUI""e impiantalion i. unlil 30-55 day. (20).
PREPARATIONS FOR IMPLANTATION
Under normal conditions, implantation occurs only
in the uterus. It involves complex interactions be-
twecn the blastocyst and thc endometrium. and both
structures must achieve the required maturational
state.
Although a blulocyst can eventually "hatch" (i.e.
shcd its zona pellucida). cxpose its trophoblast cells,
and invade almo&l any kind of liMnC (even the tes-
tis), thc endometrium is believed to release enzymes
that accelerate the
Unlike other liMues. how;o,ver. the ulerus i. "*
«Plive" during only a very brief part of the ovarian
cycle. Shortly before lhal lime, il provides nutrients
and other subslances C<)nducive 10 survival of the
biastocysi. However. concepluses thai arrive during
lhe follicular phase Or too long after the corpus Ill-
teum is established . do not implant . It is believed
that Ihe cyclical changes in the endometrium protect
thc uterus against potential damage by the tropho-
blast, and that they also lessen the chances that a
C<)nteptus formed from oocytes that arc not fully
mature or that have had time to remain in the ovi_
duct long enough to deteriorate before fertili'.I\lion
will nol implant. (Trophoblastic cancer «II. are lhe
most invasive of all koown malignancies.)
Much of OUr koowlcdgc of the preparation of Ihe
endometrium is derived from st udies of species in
which pseudopregnancy can be accomplished (249).
Animals of this kind have been used because they
make it possible to study uterine respones when
there are no conceptuses. The cells evidently require
preliminary exposure to estrogens. subsequent pre-
sentation of progesterone, and then a S«Xlnd expo-
sure to CStrogCTlS. In rodents, blastocy.1S that have
attained the appropriate stage of maturity will im·
plant into the uteri of ovariectomir.cd females pre-
pared in this way (but not in uteri exposed to JUSt
one of the hormoflC$ or given thc regulators in thc
wrong sequence).
Ulerine mucosa comprises (pi/helium that in·
cludes both glands and luminal cells (which can be
stimulaled to enter into gland formation) and a sup-
porting that contains blood vessels. a mucoid
matrix, and both collagcnous and elastic fibers. Thc
dceper layers of Ihe stroma (the basallaycr or bas-
alis) remain permanently in contact with the myo-
metrium. The mor<: superficial layers"
(functionalis, d(Cidua/is) undergo eXlensive changes
during the ovarian cycle. The deciduali •• pecializes
mostly during the luteal phase. If conception does
OOt occur. it is cast ofT along with epithelial compo-
nemS. If the oocytes arc fertili1.ed, the dIXidualis de-
velops further 10 support the pregnancy, and it is dis-
carded during panurition.
At the beginning of the f()llicular phase, the entire
muc()Sa of the human adult i. only I mm thick . A
,i"ile layer <of cpit),elium h<>Tde ... I),C lumen .• n<!
simple. tubular glands extend downward toward the
stroma. Estrogens secreted by maturing follicles
stimulate glandular cell proliferation (48). a nd the
glands elongale. Meanwhile. aneries of the basalis
send up coiled branches to the top of Ihc .troma, and
the entire mucosa thickens 10 around 5 mm. The
uterine lumen becomes distended by alkaline fluids
released from the glands.
Activily of the hexose mollOphosphale palhway
acceleratcs. and the NADPH formed support. syn_
thesis of new macromolecules. However. the
NADP, NADPH ratio is low. and it i. believed that
this scrves to maintain high activity of the NAD-ki·
nase em.yme (needed to catalyze conversion to
NAD ' 10 NADP -) (248). An ewagen-induced pre-
tein (IP) possesses phosphoprotein phosphalase ac-
tivity. It probably acts on histone. (2) and in this
way facilitates gene transcription . Olher new pro-
teins include progesterone ree<=ptors.
The corpus luteum later sccretes substantial quan-
tities of progesterone. The hormone arrests the mi-
toses in Ihe glandular cclis (in part by lowering the
numbers of estrogen receplors). Under its innucnce.
the glands enlarge, and they become tortuous and
dilated. They make and release glycogen, several
proteins. and copious quantities of glycosaminogly_
cans (especially mucin). Some of the products pre-
vide nourishmen1 for the preimplantation blastocyst
and contribule to blastocyst expansion . whereas ()th-
ers may be needed f()r Ihe .ubsequent implantation.
NAD kinase activity in<:reases funher, and new ly-
sosomal en:<ymes are made (146).
The slromal arteries elongate . become highly
coiled, and send branches upward \() form an eXlen-
sive subendothelial capillary network. Fibroblast-
like cells within Ihe Siroma enlarge. and a mucoid
matrix accumulates. The Slroma takes up large
quantities of Auid, and the resulting edema aCCOUnts
for approximately 3 mm of the increment in endo-
metrial thickness, Ihe disporsion of Ihe IXlls, and the
bulging of the endometrium into the uterine cavily
so that tbe lumen is almost totally occluded (185).
Progesterone also nens innuences on estradiol me-
tabolism thai lead to lowering ()f Ihe level. of that
stcroid. (Excessive amounts of e.trogen at this time
result in very marked reductions in the numbers of
eslrogen receptors if progesterone i. also prescnt
[48]. ) Ahhoogh most actions of progesterone re-
quire estrogen "priming." progestemne is reported to
act indcpondcntly 10 accelerate proliferation and
speciali7.3tion of luminal cells (48).
Protein. iOOueed by P"'IIesterone inctude hhmoklnln
(ulcroglobin). This is made in large by rabbil
endometrium, and a comparable . ub.lanee ha. been de-
scribed for human, and olber .peeie,. It may be idenlical
wilb an ewogen.indueed "«me prole in" of the rabbil
u>iduC l an<! • pruldn ill tunll> an<! ulhor Ii»,,", lhal .r<
oot prog..teronc-<le.,.,ndent.
The rabbit bl.. tocy" take, up uleroglobin . Since lhe
protein binds proge.terone. one funclion eOlltd be pr<Wi,
sion of emadiol pn:cursor. i\lIOlber may be ,..,sulation or
the 8Cli.ili.. of uterine or trophoblastic prole.sc. (2).
i\ntibodie< direcled againsl uterogtobin impair imptan_
tation aOO cau.e embryo " .. tage.
i\ "purple protein" .. creted by pig endometrium can
f.cilil.le th. uptake of iron and olher inorg.nic , ul>-
Slanee •. Human endometrial fluid also contains consid·
.cable 4"onlitie. of protcins lh. t resembte tho<c fOllnd in
blood pl.. ma .nd of , mailer PfOIlesterone-inducod mole-
cut.s lbal may be unique 10 the uterus (227).
The progesterone-regulated phase requires al
least 48 hours. Toward the end of it. the endometrial
cells the hormone and convert il 10 prod-
ucts of lower potency (232). (On an equimolccular
basis, 20a-hydroxyprogesterone is only lIo as effec-
tive as its precursor in SOme tests on the uterus
[2S2].)
Finally. the second exposure to eslrogen completes
the preparations. The hormone is provided by the
corpus luteum of humans a nd many olhers. and by
maturing follicles in some species. On. of Ihe func_
tions is ()f lysosomal membranes to re-
lease protoolytie enzymes that will be u",d during
implantation. Aoother may be interference with the
formation of an implantation inhibitor. (The uterus
.00
Can be made receptive if actinomycin D is presented
instead of Ihe of [177).)
In ralS and mher animals with vcry shon ovarian
cycles, the endometrium undergoes changes compa -
rable to (hc ORCS described for (hc follicular pha'le in
primales. HoW<'vcr, very liule progesterone is se-
creted. and luteal phase spedalj'.8tions arc minimal
during !IOnfcrtile cycles. Such animals Illordore do
not "wa,(e their timo" making elaborate prepara-
tions for conc<=ptuses that never arrive. Ir oonception
oc<:urs. the corpus IUleum survives. undergoes devel-
opment. and provides (hc progesterone nceded (0
complete the endometrial preparation. Similar
changes occur if thc Ulerine cervix is stimulated dur-
ing the periovulalory period. Messages carried by
thc pelvic nerveS !,avd to the hypothalamus and
they invoke release of prolactin and possibly other
luteotropins (249). When progesterone secr<:lion is
in either way. the endomctrium incrcases
its oxygen use. accumulates glycogen, lipid. and al.
kaline phosphatase, accelerates DNA, RNA. and
protein synthesis, and shows higher ATPase and
acid cathepsin activities (180).
DECIDUAL REACTIO NS
The blutocy.t e'p"nd. and oontraet. a. it make<
physical contact with the reoxptive uterus. The en-
dometrial blood vessels then dilate, the capillaries
show incroased permeability, and the mucosal oxlls
soon undergo rapid proliferation.
Decidual responses can also be invoked by OOn-
specific stimuli such as pricking the surfaox with a
needle. superficial traumat;1.ation with a sharp knife,
or chemical irritation. Inserting thrcads, glass beads,
heparin, or air bubbles CQntaining high CO, will all
initiate elaboration of cdl CQnglomerations (deci-
duomata, placentomas) (252).
ROLES OF HISTAMINE. PROSTAGLANDINS.
AND ESTROGENS
The natural and artificial stimuh invoke histamine
release. Histamine alone Can start deciduali7.ation,
and some anlihiSiaminies block implantation. It has
therefore been proposed that the biochemical
changes supporting cel! growth. proliferation, and
s,.:cialization are seoondary to histaminc-dcpendcnt
changes in the blood vessels.
It is now that histamine interacts with
several mher regulatOl"!l. and that some of illl effects
take hours to develop (114). In many species. the
trophoblast steroids. oonvcrts pregnen-
olone to progesterone and estrone to estradiol (192.
CONCEPTION AND F'REGNANCY
214), and makes estradiol from progesterone (81).
In these. estradiol may be the initiating factor. r;.s-
tradiol promotes histamine rolease, and histamine
accelerates endometrial estradiol uptake.
Implantation can be hastened by exposing bias-
tocysts briefly to estrogen-rich environments and
then returning them to the uterus. Subthreshold
amOUntS of estrogen and histamine synergi>.e to in_
voke a response. The prc.",TIC<: of H,_type reoxptOl"!l
in the endometrium and of Hr type receptors in the
blastocyst suggests that tne amine functions at both
sites.
Ornithine decarboxylase (ODC) activity increases
just before ccll growth and proliferation begin in
many cell types. Histamine increases pr0<5taglandin
generation, the PG augments cAMP production.
and tne cAMP activates the OOC. (Activity of the
enzyme is high in the oonccptus during embryo-
genesis [741.)
Trauma and estrogens increase cAMP and PC ac-
cumulation (and PC ieyeis are highest at the sites of
injury rI 201). PC synthesis inhibitors delay implan-
tation. and their effects are antagoni7.cd by hista-
mine (114) or PG E (120). The same inhibitors im_
PIIir cAMP generation and oeD aClivati(lll (47). If
they are presented 8 hours after the initial stimulus.
they block d."iduo.li,ation (120). Cros<ly pharma_
cological dosages of estrogens are believed to inter-
fere with implantation by impairing responses to the
PG,.
Although roles for eStrogens in regulation of adc-
nylate cyclase and PG synthesis have been demon_
strated for many speeies (240). it has been observed
tnat rat blastocysts do not release estradiol (133).
Therefore. the initiation mechanisms probably vary
with the species.
When the blastocyst sheds the zona pellucida. ;t
"'allachment sites" and a negatively charged
surface that ;s attracted to the more positively
charged mueosa. Physiological '"hatching" seems to
be PG-dc,.:ndent (109) and to involve release of a
uterine enzyme. The denuded trophoblast also seems
to exchange different signals with the endometrium.
CO, may be a major one, since carbonic anhydrase
inhibitors block implantation.
Blastocysts preferentially implant at endometrial
sites with good blood How and high oxygen tension.
Estrogens, and histamine are all implicated in
their preparation (79) . In humans. implantation OOr-
mally oceurs along the posterior surface of the oor-
pus of the uteru s. When it is too close to the ee,....ical
os. the usual consequence is plaoxnta previa. a oon-
dition associated with hemorrhage during late preg_
nancy Or parturition. In animals with large lillers.
 conceptuses beCQme spa«d alon, the uteri""
borns. Redistribution oocurs I'lIpidJy if several blas-
tocyst, an: inserted into a small SoeJmC:nt ol one uter-
ine horn.
Delayed Implan tation
Although unfertilized oocytes deterioratc rapidly,
Iber<: are CQnditions under which blas tocysls arc
maintained in "dormant"' states ... i(hin the ulerine
tl"ity for nterlded time periods. late r develop
into normal o/fspring. Both (he enlry into dormancy
• rId the sub$cquent emergence from it In: controlled
by uterine fact'" and reproductive system
DELAY ASSOCIATED WITH LACTATION
Rat blaslocym implant days postfertilization if
the mother is not lactalin,. is arrested
durin, lhe Ihrce-...... gestalion period. but the fe-
male romes into cstrus ... ithin 48 hours afler partu.
rition. A. fenile maling at Ih31 time is followed by
the: formation of a new sel ol blastOtysu.. If the
mother is not suckling a liller an(\ she is well nour·
ished. implantation again takes plate 4-5 days polSt-
fertilization. If she is ca ring for I or 2 newborns. tbe
second implantation occurs at either the usual time
".. wi.hin ? rl.y<.
When lhe lilter is larger, the second sct of bias-
tocysu enters into a state of dormancy (diapau.llC),
tile duration of which is dircetly .elated to the num-
bers of p"p$ sutkled. 11 ean continue for up to 19
days when then: an: 8 or more PUp$. second sel
of lhen completes development. a nd the
)'00"1 are born around tbe lime that the older sib-
lin" are weaocd.
Diapause confers advantages on tlle molher. Ihe
nurslings, and the new conceplUSCS. t\ healthy rnl
pupp, from 4 a at birth to around 40 a by the time
ofweanin,. A 260-300 a mother may bcealled upon
to provide food arid nuids for up 10 19 young. AI·
thous.h she very markedly inereues her food alld
walt' inlake. ,he cannot simultllltOU$ly cope with
lhe metabolic demands of lactation llId I new
pre,naney.
Lactational diapause in ratS has been linked wilh
th811f1C$ in Ihe endocrine system thlt ;nelude fa ilure
to produce adequale amounts or cstro,cn to) support
implantation. and altered progesterone metabolism.
It may also in\lQlve transmiloSion 01 neuronal
saaC$ to the hypothalamus and inere.se4 setn:lion of
prolactin arid OlIytocin.
T he PUp$ initiate a suckli", reA" that leads 10 Ihe
releas-e 01 both OlI)"tocin and prolactin. Prolactin
presses lRH and LH release. and it probably mak...
an important contribution. However. ;t Cannot acl
.Ione. large doses are ineffective when they are
given to pn:fl!Qlnt mothers 0( their lillers
12151·
In • nonlacllli", mother. ,he _pOra formed
afte. o-ulalton and eslabli, hmenl or I p.eln'''''r are LH·
dc:po:nclent. Allhl. lim<. the <wary make' lxl'h P"'Ie'te.·
"ne a nd som< o.t"'len . Around r, •• dl)'s Ifter implan.
tation. the 0:0...,.. IUln shift their depo;ndc""y 10 a
plo«nlll lulea\ropin (228). The corpora IUlea are reo
tained well inlO Ihe lactal;""'1 po:.iod. If a .. cond prel·
nIO""Y occurs. a n.ew cmp of LH-okpo:ndc:nl CQrponl.l..
fot1ll$ Ind co..i$I$ ... ilh.he old.. ones.
PRL lell on tbe oIder .. t of eorpon lulea. Ind it ....
«lerales product"'" of 2On.h)'llro:.YP'"oeulemne. n..
or thaI "'e,<>id in lhe mlle.nal bkMxl .'" high '0<
Ihe 6_7 dlYS of lact.tloft. PR. L additionally atlS on
the ncwly forna<! corp"'" lUln. Incllhe.. make maotly
p,o,.steronc.
H the pu"" art ,. "", •• d during """Inatal day.
mlle'nll PRL falls. LH rises. Ind implanillion """,uro
... ;thin d hou ..... Implantalion .an Ilso be ba.tened in a
laclllin, _her by injcclin, atres.... It ;. dell)...:I b<:-
rand Ihe ull&llime by ovarieclomy (S6).
There art "'ber ..... mmal$ in which di.p...... is linked
";th Ihe '""I)" IarAc amooonu QI at_n. In
tM ... , proccsle..,..., lessens the eff(ct' •• "''' of the estre-
Aen. Impl.ntalion i. hlstened by either ...... ,ie.tomy or
Pffllc. lcrone injccti.,.,.
LACTATIONAL EFFECTS ON FERTILITY IN
WOMEN
Diapause ;. IlOl k"" ... n u) in humans. How·
ever. lactation can influence IVlllif),. especially in
women with just OOn:ly adequate nutrition wOO
nu. . chei. infants for extended time periods and do
DO\. offer other forms of food (2)7). Prolactin le"tls
a re hiah around the time of parturition. In women
who brelSt·feed. the concentrnt ion, ,how Substantial
further clnalions for periods of up 10 60-90 days
polSlpartum. The suckling rellcx arid the hiah PRl
both contribute to suppression 01 gooadotropin :Ie-
<:rct;o., by the piluitary aland. O ne c:onscqucnec is a
delay in follicle maturation and ovulation. AI11Iougb
PR l CQnOenlrations r,1I .flt. tllal I;me. tbe period
ol infertility is ntended if the infant is pennitted 10
nu . . at frequent intervals and is not given other
food. In wcll-noorished ...omen. the period of lacla·
lional inferti lity is usually brief. In monkeys. latla-
lional amenorrhea is allributed to a combination of
elevated prolactin leve ls and the secondary CQose-
quences of mammary gland stimulll;o., ( I%).
Sowt us..l1y SIlCkJe Ia"e liuCt$. and lhey 100 sIKrw
hi. h PRL low pldotropin Ie.. b. a"" IlOtSItuI duri",
lhe LacllliQot po:riotI. H""",ver. in Il\q& mammals. the ro-
lease of I.... of foJlinkiflltin (inhibin) Ind lhe
'"
consequent .UW'''';''" of FSH ",lease may b< of m;ljor
importance on).
LACTATIONAL OIAPAU$E IN MARSUPIALS
In these animals. the diapause is used in remarkable
ways 10 incr<:ase reproductive efficiency. The gesta-
lion pcrio<b arc shOrlcr than. equal to, or just .lightly
longer than Ihe ovarian They do not interfere
with oocyte maturation or ovulalion. The mother
comes into estruS!iOOn after giving birth.
The adult male red kangaroo stands 6 feel lall.
but it weighs just 0.8 g when it leaves the utcrus
(211 J. The nconale (joey) migrales to the pouch, al·
taches to a leat. and undergoes developmental stages
comparable 10 those of a eutherian fetus during the
nUl 7 [t Can then detach intermittently
from the nipple. but ;1 requires milk and Ihe protec-
lion of the pouch unlil il is 253 days old. After thai.
illeaves the pouch but it puts its head in for feedings
for an additional 130 days, In a seosc. thc first de.-
tachment from the nipple is like passage from fetal
to nursling status.
Two days after the first joey is born. the mother
conceivC$. and a new blastocyst develop:;. However.
the suckling st imulus and the associated secretion of
prolactin and oxytocin prcvent a new implantation
and they alSQ arrcst oocyte maturation, If the joey
continuC$ its aUaehmem to the tcat and suckles vig-
orously. the second blastocyst remains --dormant"'
for 204 days. (If the jocy dies or is forcibly removed.
the blastocyst soon implants.)
The lactational innuenoxs wane as the joey mao
tures. and implantation OCcurs around day 204. 33
days later (when the joey 00 longer n:quires perma-
nent attadment to the teat), the new neonate leaves
the uterus and makes its aswc.:iation with the unused
teat. It receives its Own private supply of protein-rich
milk as the older sibling is provided with nourish-
ment t hat is richer in fat and lower in protein con-
tent. Conditions prevailing around the time of thc
second implantation permit resumption of ovarian
activities. and the mother again comes into estrus
and matC$ when the younger joey is 2 days old. A
lhird conceptus oow develops to the blastocyst stage,
but it does not im plant for 204 days if the second
joey is healthy, The spacings of fertili:z.ations and im-
plantations make il possible to fully utilize the re-
productive capabilities of the mother.
Evidcntly. the entin: scheme rC<]uires special ad·
aptations of both the ovaries and the blastocysts, The
corpus luteum that cannot sustain implantation and
pregnancy during the first 204 days of the suckling
period is not totally inactive. If it is removed on the
CONCEPTION AND PREGNANCY
s ide whe re ovulation has occurred. ovulation reo
su mes in the con tralatera l ovary (211).
The marsupial blastocyst comprises a single la)'cr
of protoderm that endoses a sphcrical . Huid·filled
cavity. (There is 00 iMer cdl mass.) The protooerm
is surrounded by in a rona pellucida, a more super.
fieial mucoid COOt, and an OUter shen membrane
(209.210). The protective layers are shed before in·
timate contact is made with the endometrium ,
Different time scales for fertiliutiQn. lactatiQn. and
impla ntatiQn have been describe<! for OIhor kangaroo spe-
cies. There are some in whieh implantation is delay'"
during ecruin seasons. even when the pOuch i, empty,
Diapau,," I•• t, 83 days in the ..... rn gray kangaroo and
up to 365 days in the tama, wallaby (131), Some rna"
,upials rai", large lille" .nd do not undergo implantation
delays.
NONLACTATIONAL DIAPAUSE
Diapau:;e serve, different purposes in eutherian, that
can mate only during TCStricted times of the year.
have relatively short gestation periods. but must de.-
liver their young when climatic condillOns and the
availability of nutrients are optimal ,
Badgers are among thc mammalian groups that
undergo seasonal chan2C$ in reprodUctive system
functions. The European varicty becomC$ capable of
mating during January or February, bUI implanta·
tion is delayed until the following December and the
young are born in early wintcr. The American
badger has a different time sealc. Copulation occurs
in July Or August. and implantation in January or
February. Roe deer mate in July or early August.
but implantation is delayed until January. Bears
oonceive before going into the winter tOrpor and
delay implantation so that the young are born in the
spring. Bats mate before the hibernation period, but
implantation does not occur until shonly before the
awakening, The long list of other eutherians known
to have delayed implantations includes armadillos.
skunks. and shcep (46). In many cases.
changes in environmental lighting provide the sig-
nals for timing of the reproductive functions. It is
then ofltn possible to advance or delay implantation
by exposing the animals to artificial illumination.
Some species use di!fen:nt signals that can include
nutrilional status. changes in environmental temper-
ature or humidity, Or the presence in edible plants of
specific chemicals. There arc mammals living near
the equator in which diapause oc<:urs regularly.
The mechanisms for accomplishing diapause
probably vary with the species. In badgers. seasolllli
changes in thyroid gland functions may he of pri-
 mary importance (36). In the mink, the prolactin
levels are low, and PRL injections can rapidly bring
about implantation (149). The effects of PRL are
usually assumed to involw: stimulation of the COr-
pora lutea and augmentation of progesterone secre-
tion. However. although maternal progesterone lev-
els rise rapidly around the time of implantation in
mink. stoats. skunks. and EUropean badgers. neither
progesterone or estrogen given alone. nor a combi-
nation of the steroids. hastens implantation. It has
therefore been proposed that an additional stimulus
must be provided by the blastocyst (46).
The corpora lutea of roe de<:r maintain their se-
cretory functions throughout diapause. The blasto-
cysts undergo morphological specializatiom shortly
before the time of implantation. The embryo elon-
gates. and its surface microvilli be<:ome tran,formed
into interlocking ridges. Simultaneously. changes
take place in the endometrium (46). During Ihe dia-
pause. the uterus ae<:umulales large numbers of ves-
icles. but it releases litlle protein or earbohydrale.
Shortly before implantation. the glands begin to se-
crete copious quantities of a wMe. viscous nuid
(, ·uterine milk"') (2). The uterine naid then contains
suboitantial quantities of calcium, hexose sugars, al.
anine, and special proteins. In sponed skunks. pr<>-
gesterone has been shown to affect the quality and
quantity <>f th e protein. The incorporation of labeled
leucine Can be inhibited by giving estrogen along
with progesterone (46).
Mammals utilize me<:hanisms other than implan-
tational delay to assure that the young are born dur-
ing the optimal times of tbe y<:ar. Some undergo sea-
. ,·na\ ebanges in reproductiw: organ struc tures and
functions. and they become fertile during just lim-
ited intervals. In most cases, Ihe pineal picl:s up sig-
nals from the environment and mediates changes in
functions. Usually, variations in PRL levels can
be demonstrated during both involutional and recru-
descence phases . Some animals vary the gestation
periods after implantation hall occurred. (North
American spotted skunh living in the east mate in
"'pil and have a gestation period of 5(1-65 days.
Those living in the west mate in September. delay
implantation until April. and have a gestation period
of only 28-30 days [46 J.) Some of the bats mate just
before going into hibernation. but the females StOre
the spermatozoa and delay fertilization for several
months (193).
A single animal type can utilize more than one
Stralegy. [n mit<:. implantation occurs promptly
under ordinary conditions, but it is delayed during
lactation. The presence of an ·'alien" male, or of his
pheromone. can delay implantation. It ha. been sug-
gested that this provides protection again'l delivery
of young that may be killed by that male. Mice also
produce fewer and smaller litters if they are food·
deprived Or exposed to severe cold. (They are more
sensitive to low temperatures when the humidity is
also high [179J.)
FORMATION OF THE PLACENTA
The placenta is the site of chemical communication
between Ihe mother and the conceptus. [t provides
the embryo and fetus with nutrients and oxygen, re-
mow:, metabolic wa'tes, and secretes hormones. The
type of Slructure formed varies widely with the spe-
cies (159,238), and it is most elabora te in animals in
which implantation occurs early.
Placental Typesln Noneulher[an Mammala
Monotremes have 110 need for placentae. Endome-
trial glands secrete a ·'uterine milk·' that nourishes
the conceptus du ring tbe time whcn yol k-laden eggs
with albumin covuings and leathe ry Shells are
formed. After the eggs are laid. stored nutrients are
utilized. and gas e.changes occur across the shell
membranes. The young soon halch and they then at·
tach themselves to milk glands whkh arc. in some
species. contained wi thin pouches.
The duck-billed platypus produces two oocytes.
each 3 mm in diameter . After fert;!iution.
the eggs grow within the uterus umil they are 16-18
mm. The eggs arc la id in a and the mother
tends them for a lQ..day incubation period. When
the young hatch, they are like embryos (but they
breathe air). Spiny anteaters rear one cooe<:ptus at
a time in a temporary brood pouch (224.238).
Pregnancies as short as 12!> days have been de-
scribed for marsupials (131). and the marsupial cat
neonate weighs just 12 mg (211). Other members of
this group have gestation periods that last up to 35
days, but there are no direct relationships between
the dnr3tion and the kind of formed. Th.
bandicoot elaborates a quite comple. chorioallantoic
structure. whereas the American opossum gets along
without anything comparable to a eutherian organ
(131).
Eutherlan Placentas
All members of this subclass form a structure that
includes a conceptus-deriw:d chorion and endome-
trial components. One system of classification i.
based on the nature of the maternal component that
makos dire<:t comael with the trophoblastic surfat<:.
Pig, horse. and donkey conceptuses undergo ex·
tensive development before making permanent at·
.,.
to) the endometrium. Some of the tropho-
blastic cells become specialized for ingeslion of
hystrophc. a of secrelions and cellular debris
provided by the uterine glands. Eventually. the tro-
phoblast sends oul ribbon-like extensions that iiI into
grooves and depressions of the endometrial epithe-
lium and serv<: as sites for the exchanges of nu-
(rients. «'spiratol)' gases. and metabolic waslcs. T his
type ()f diffuse placenta is also
rornled in lemurs and whales.
Somewhat more elaborate (but still superficial)
Jyndesmrxhoria/ placentae arc found in sheep.
goalS, canle. and deer. Trophoblastic oolyIOOo"" in.
vade speciaii7.cd endornmial allachmcnt si les (ca-
runcles) and extend to the vicinity of the malernal
blood vessels. bUI ther<: is only minimal destruction
of uterine tissue. Sine<: the cotyledons retract
shortly before parturition, delivery of the young in-
volves neither uterine tearing nOr substantial blood
1=.
!n dogs, cats, fcrrets, elephants, beavers. and SOme
other species, trophoblastic invasion involves more
extensive destruction of the endometrium. The sur·
face cells make intimate contacts with the endothe-
lium of matcrnal capillaries. but the vessel walls
are preserved. Some shedding of the uterin. tissues
accompanies the parturition in species making this
intermcdiate-lypc endothdiochorial arrangement.
The Human Placenta
H umans, monkeys, and ratS are examples of animals
that form a hemochorial placenta. There is exte nsive
trophoblastic invasioo of the endome trium that in-
volvt.5 destruetion of endothelial as woll as stromal
cells . The surfaces of the embryonic membranes es-
tablish dire<:t contact with maternal
blood. and the maternal tissues ma ke subslantial
contributioll$ to placentation. During parlurition. all
of thc endometrial tissue above the basalis
torn away and bl(l(.ld vessels are brQI:.n. In a
woman deliveri ng a heallhy full-term infant, pow-
erful postpartum contractions of the uterine muscle
usually limit the blood loss to around half a liter.
TROPH08LAST SPECIALIZATION
Soon after shedding the rona pell ucida, the pari of
the trophoblast closest to the inner cell maSS estao.
lishes contact with an endomcuial site located close
to a bl(l(.ld capillary. Cells of both blastocyst and en·
dometrium Ihcn cooperate to form intimate interdi·
CONCEPTION AND PREGNANCY
gitatioru;. The trophoblastic cdls undergo rapid
growth. proliferatioo. and spccialil.ations. By the 9th
day after ferti1il.ation. it is possible to distingui sh a
cylwvphoblasl made up of a large. jXllyhwral. rap-
idly dividing mononuclcar cells. and a more periph-
eral syncytiotrophoblast that docs not show distinct
ccll boundaries.
New syncytiotrophoblastic cells derive from the
cytotrophoblast region, but some enlargement of the
layer is allributed to nuclear divisions .
protrusion. (cotyledons) burrow into the endome-
trium and penetrate the stroma, partially via cell
separations but al,;o as a result of ,;orne destruction.
The conceptus gradually sinks into the uterine mu·
cosa. and a fibrin clot seals the initial lesion site (Fig.
16-3A). The uterine epithelium then spreads and
proliferates until it totally endoses the conceptus
and separates it from what remains of the uterine
lumen.
The syncytiotrophoblast acquires numerous ribo-
somes and an extensive endoplasmic reticulum. It
begins to secrete chorionic gonadotropin (hCG)
while it is still differentiating.
FORMATION OF THE LACUNAE
Some of the stroma l cells enlarge. accumula te gly-
cogen and lipids, and secrete glycogen and mucin.
Others degenerate . and their remains arC incorpo-
rat.d into the syncytiotrophoblast. Plasminogen ac-
tivator and other substances made in the trophoblast
contributc to the cell destruction (and fibrinolytic in_
hibitors block implantation) (6J). However. decid-
ual cells may be "prograrnmw to self-destruct," and
they are believed to release stimulants to the invad·
ing trop hoblast. The invasion procC$.S shows similar-
ities to phagocytoois. However, it has also been
enw to cell fusion, since endometrial components
engul fed by the trophoblast maintain ,;orne struc-
tural integrity.
As the syncytiotrophoblast burrows deeper into
the endometrium. the maternal bl(l(.ld vessels dilate.
Spiral arte ries join up with endometrial veins. and
sinusoids de.elop at the sites of anastomoses. Sub--
released by the conceptus probably contrib-
ute to the processes (125).
Vacuoles appear in tbe rapidly c:<panding cyto-
plasmic mass of syncytiotrophoblast. and they fuse
to form la ke-like lacunae that fill with matemal
bl(l(.ld. Early in tho 3rd the lacunae mergc to
form an intercoonecting network. The labyrinthine
cavity is then called the intervillous space (sec Fig.
16-4) .
Primitivv ,0'"''"'-

"

Exl" -emb<yoo"
meSOde,m

Di.gr. mmo.'''' repreWu.,ion 01 ;"'plan,.,;on_

Fig . 11:\·3.
(Rep.-Od"""" wiln "..-miHion . "om La"9"'on . ...If,<""""
125. )
 CONCEPTION AND PREGNANCY

lacunar pofio(!- villous pcrOd

P""';""""
(9·13 days)
begnrw.g 01
elabQralion P8riod
(1 3-21 days)

Fig. 16-4. Oi.g<ommolic 'tj)I'eHrtlation ollhfl

_Iopmeot 01 the humon paac.ma 'rom the 9ttI day to the
21s1 day. (From Wi"'in. 241 . )

CHORIONIC VILLI lular layer closest to the endometrial stroma deteri-

Tongues of rapidly proliferating cytotrophoblast
push into the outer layers \0 form primary chorionic
villi that projc<:\ toward the uterine stroma. (Each
villus has a cylotrophoblastic COrC and a surrounding
region of syncytiallissuc.)
The cellular layer now gives rise In the cxtraem·
br),<:,",c mesoderm (mesoblast) Ihalgradually forms
a ring ""pa raling Ihe cytotrophoblast from the ex-
traembryonic celom (Ihe chorionic cavily, Fig. 16-
3B). Mesoderm invades the villi, and when Ihis i.
completed the structures 3re caUed secondary clur
rionic Villi. Close to Ihe embryonic pole, other cords
of mesoderm form the connecting Jlalk (body
that is the forerunner of the umbilical cord.
Terllary oil/I develop when blood vessels that form
in the mesoblast invade the proje<:tions. The term
chorirm (chorionic membrane) designates the ring of
mesoblast plus the oV<'rlying regions of cytOlropho-
blast and syncytiotrophoblast.
With continued proliferation, the cytotrophoblast
forms a "shell" that separates the "definitive sYlICy·
tium" front a ntorc peripheral la)'er that soon giV<'s
rise to a ji/;rillQid coating. By separating maternal
and fetal components. and perhaps bc:cause of ad.
sorption of substances made by the maternal im·
mune system. Ihe fibrinoid is belie,oed to oonfer pro-
Ie<:tion against rejection. The described changes are
oompleted by the end orthe 3rd week. later. the cel·
orates to expose the syncytium.
ESTABLISHMENT OF THE FETOPLACENTAL
CIRCULATION
rntravillous capillaries join capillaries Ihat appear in
the chorion and conne<:ting sta lk to form an ex·
traembryonic vascular system which is separated
from the maternal blood by the trophoblast. Func-
tional oommunicalion with the deVeloping fetal va:;.
cular system is gradually established. Eventually,
branches of the fetal internal iliac arteries giwo rise
to twO umbilical arle ries that carry fetal blood \0 the
placenta. The blood relurns to the fetus in a single
umb ilical vein.
Initially. the villi are found along the en tire Sur-
face of the chorion. Later. Ihe ones in the adem·
bryonic region degenerate. whereas those closer to
the body to form a
(Fig. The uterine ti:;sue in that region (de-
cidua capsularii) and it eventu·
ally deteriorates. As the fetus the small
cavity the capsularis and the decidua par·
ictalis disappears.
When fully formed, the human placenta is shaped
like a d isc . It is about 3 Cm thick and can have a
diameter of 15-25 em (125). Since the syncytiotro-
phoblast is close to the maternal blood. ils secretory

f ig. 16-5. Sch"""'t>c d, ... ing u.o.. itIg t!>ll ''''''tioo 01 trw.
1.,.1"*",>,.,,.,. and !he ... 1 oJlhe Ul ..... 0. .... Eoct 01 the
.ooond monlh. NotA thf yOlk .... e "' Ih/t <:ho<iOnic ca.ity
tIIIt",..., tr.t amnioo ,oct <:fIOhon. "'" '_yOnic pOlfI
trw. .illi ha • • d isoPJ>9.l.'.oI (""""iool ..... ). e. End oJ thf
products rapidly gain aocess to and can accumulate
in the mother's cireulation. Many kinds of rTlQlecules
pa» frum (he m,,(h« lU the tr"ph"blaSl and .ub..,.
quently enter the extra-embryonic capillaries or the
conceptus. Some penetrate the amniotic cavity and
are then taken into the fetal capillaries.
Early Deve lo p ment o f the Embryo and the
Associated Membranes
The inner cell mass form s an tmbryoni( di!c that
borders the part of the blastocoel most rerTIQvcd from
the implanting trophoblast. The struetur<: is said to
be bilaminar as soon as it becomes possible to distin-
guish a layer of small mlodermal cells bordering thc
blastocoel rrom the larger «Iooermal cells that arc
closer to thc cytotrophoblast (fig. 16-3).
Clefts then appear between the e<:toderm and thc
cytotrophoblast. and these to form thc am-
niOtic cavity. The amnioblasts are believed to be de·
rived from the cytotrophoblast and to secrete the
am niotic Huid. The cavity e nlarges rapidly, comC$
into contact with the developing chorion. and S<.>on
encloses the embryo (Fig. 16-5). Even tually. it
presses against and obliterates the cavity .
coV<'rs the conne<:ting stalk. and forms a componcnt
of the umbilical cord. The amniotic fluid bathes the
embryo, servC$ as a shock abwrbcr, provides useful
molecules. and collects embryonic wastes. Its
,
third month. The 0lMi0n and <:ho<ion /10 • • tusecj . "" I""
lIloril"le """"ty i. .... t!ld by lu.ioo ollh/t Ohorioo 18,"""
and the d&oidua lII" illotil. (F,om langman. ,et",,,,,,,,,
Jl'OISition is affected by that diffuse in both
directions aero:ss the placenta and the fetal skin.
When the feml orgam develop. the feIUs swallows
some of the Huid and it releases urine into it.
Thc blastocoel of the young conceptus is bordered
partially by entoderm while the remainder is en-
cklSed by 9totrophoblast. As the extra-embryonic
mesoderm gro .... , it compr=cs the cavity and a
la)'er of mesothelial cells from the cytOtrophoblast
joins with the "mod.rm to form 3 continuous ring.
What is left of the blastocoel is nOw called the prim-
ith'e yolk $0( (or extracoelomic cayity).
Extra-embryonic mesoderm continues to invade
the space between the cytotrophoblast and amnion-
ectoderm-primitive yolk sac region. SO that most of
the original blastocoel is obliterated. The entoderm
grows downward. and it soon completely lines a neW
cavity called the stcond(Jry, or dtfinitivr. yol k sac.
(It ii not defmitely known whether the secondary
yol k sac is a small remnant ofth. blastocoel or a new
cavity made within the mesoderm.) The pinched-<lif
lower portions of the r<:mainder of the blastocoel can
rersi'!t as one or more exocoelomie cysts. Spaces
then form in the mesoderm. coales<:e. and become
the extra-embryonic coelom (chorionic cavity).
The secondary yolk sac extends brieHy into the
cavity. It becomes vascularized. and the roof portion
contributes to the diifCr<:ntiation of the embryonic
gut. As the lauer grows. a constriction develops be·

'"
t ..... een
the embryo proper and the yolk sac. II clon-
gates into Ihe yolk stalk. which is incorporated into
the umbilical oord. The remainder of the sac
deteriorates.
The sac neVe, performs nut,ilh'c functions in
humans, bUI primitive germ cells first make their al'"
pe.rane<: within it. [t undergoes more extensive de-
velopment in species in which the fctuses project into
the uterine cavity. I n oviparous vertebrates (includ-
ing monotremes). it provides nutrients during the in-
cubation period.
The ol/(lntrXf begins as a small outpocketing of
the posterior end of the yol k sac. Although i1 receives
blood vessels and ;s brieHy associa ted with the de-
veloping urinary bladder. this membrane is probably
tolally ''eslisial in humans. lis remnants are inoor-
porated into the umbilical cord.
In oviparous vertebrates, the allantois spreads
over the inner surface of the shell. dcvelops a rich
capillary circulation, provide. the membrane for
change of gases. and 'iCrves as a reposi.
tory for urie acid waSlCS made by the embryo.
DERIVATIVES OF THE PRIMARY GERM
LAYERS
The ectoderm gives rise 10 the central and I"'ripheral
nervous systems and the adrenal medulla. parts of
the eyes (which grow out of the brain). the epithe-
liu m of the sense organs, the pituitary gland. the ep-
idermis of the skin, and the epi thelial linings of some
ot her organs. The caicitoni n-se<:reting cells of the
thyroid gland and some other endocrine oomponents
migrate wtward from the ""ural ectoderm.
The entoderm provides the major oomponcnts of
• //'
• r.PL /
"" //
,
10 20 30
WEEKS FROM LMP
CONCEPTION AND PREGNANCY
the digestive system and accessory structures that in-
clude Ihe liver and panc reas. the e pithelial lining of
the respiratory Iract. parts of the urogenital system.
and parts of the thymus. thyroid. and parathyroid
glands.
The embryonic mu odfrm that begins to form
during the third week aner ooncepti(lll is the source
of major components of the ciKulatory. skeletal,
muscula r. urina ry. and reproductive systems. the fi-
brous and fatty connective tissues and the blood
cells. and Ihe adrena l cortices.
CHORIONIC GONADOTROPINS
The trophoblas t begins to make heG almost u SOOn
as it forms. After the ditfertntiation into tWO layers.
the syncytiotrophoblast bcoomcs the primary SOurCC
of the hormone. Production rale peaks when the cy-
totrophoblast altains its maximum thickness (214).
but tbis is auributcd to release by those cells of a
synqtiotrophoblast stimulant (167). A chorionic lu-
teinizing release factor (hCl RF) in the cy-
totrophoblast seems to be chemically identical with
hypothalamic lRH (167) .
hCG Concentrations In the Conceptus and
Mother
heG is rapid ly ta ken up by the maternal blood ves-
sels. The plasma ooRCemra tions peak during weeks
10-11 ( 192) Or 13-14 (167 ) (wilh ditferen!:<'s re-
lated in part to whether day I is the first day of the
last menstrual perioo or the assumed dale of ovula·
tion). The lev.:ls then fall. and they remain low until
term (Fig. 16-6). The hormone is cleared slowly. and
--
Fig. 1&-&. Ma,,,,,,,,, Mrum
oone.ntr.,ion. 01 hCG ( 1
- 20 'lI) arM! hP\. . (-'<!oPled from Dr.
s. s . C. y"". wilh PMmi"""'.) (From
40 0"1""_ and Tu1<::!Mnsky ... I..""""
167.)
it Can be detccted for up to two postpartum
(233). Absolute .alues Can ..ar)" substantially. but
they are oonsistently higber in wOmen carrying more
than one conceptus (214) .
A seoondary eb·alion of the hCG levels that is
associated with resumption of eytoblastic prolifera-
tion has been known to occur when the mother is af-
meted with diabeles mellilUs Of lhe felUs is al\acked
by malernal Rh antibodies (214). The hormone lev_
cis in amniotic fluid "3ry in parallel with those of
maternal blood plasma. but they are only 1/100 to
1/40 as high. Tenfold yet lowe r concentrations arc
recorded for umbilical cord blood. The r,ndings sUI>"
port the belief that hCG is transferred from the rna·
ternal blood to the amniotic compartment (14).
Some of lhe amniOlic fiuid l1ormone enters Ihe fetal
circulation.
Chemistry snd Biosynthesis
The biosynthesis of glycoprotein hormones has al-
ready been discu<sed (Chap. IS). The alpha subunit
of hCG is almost identical with lhat of pituilary
FSH. LH. and TSH (Fig. 16·7A). The bela subunit
is similar to that of LH.but il oontains an additional
carboxy terminal amino acid S(<jucnce (fig. 16-7B).
Antibodies directed against thai se<juellCC can be
used to distinguish hCG from LH.
Both oubun it< a"" The car·
bohydrate prolongs lhe biological half.life. aCCOOnls
for much of the molecular heterogeneily. and may
affect hormonal functions.
Regulation of hCG Secreti on
Before implantation. heG secretion is controlled by
the cells that make it. Later. hCLRf assumes im_
portancc. Its aClions are probably partially mediated
via cAM P. (The nucleotide . its analogs. and phOS-
phodiesterase inhi bitors increase the secretion rates
when presented to cultured placental cxplants or
choriocarinoma cells. eGMP is inelfoxtive.) Epider·
mal growth factor and TRH can also stimulatc, but
hormones found to inelfective include insulin, oor_
tisol, and epinephrine (167,2 I4).
More alpha tha n beta subunits are made (75) . and
the ratio of free alpha: tOlal hCG rises sharply duro
ing late pregnancy. Production of the fJ oomp:.ment
is rate-limiting (167), and only this portion of the
hormone is alfected in a dose·related manner by lhe
hCLRF (213). There is no evidence for negalive
fcedback oontrol of hCLRf by hCG. Neither estro-
gens nor progesterone inhibi\. This is bener,cial.
since high ooneentrations of hCG and of both of the
steroids are needed during the early gestation period.
Death of the embryo is not consistently followed
by a rapid decline in maternal heG. Some placental
Or maternal factor may exert inhibitory in Aucnccs
during the seoond and third trimesters and thereby
account for the lower heG levels at that time. How-
evcr, reduction in trophoblast volume is probably of
grealer importance. Dopamine (214) and prosta-
glandins (167) can inhibit in vilro. but physiological
roles have not been eSlablished for either of them.
Func tio ns
hCG promotes oonversion of the ·'corpus lutcum of
ovulation·· to a ··corpus lutcum of pregnancy:· and
it supports the secretion of large <juantities of ovar-
ian hormones during the first 5-6 woxks of the ges-
tation period. Stimulation of oorpus luteum growth
has been linked with elcvation of the ornithine de-
carboxylase activity (175). Some evidence has been
presented for a pulsatile palleTn of release. and this
may explain the failure of the ovary to "down regu-
late'· its receptor numbers (170).
Later, heG accelerates placental production of
pregnenolone and progesterone from cholesterol and
the of CI9 steroids (167). II is prob-
ably needed 10 promote testOSlerone secretion by the
fetal lest is. and it additionally increases the forma-
tion of dchydrocpiandrostcronc by the fe tal adrenal
glands . Only some of the actions are believed to be
mediated via cAMP.
Although the effects exerted mo<tly I.H_like.
the trophoblastic hormone has some FSH-li ke p<>-
tency and it is also a weak stimulator of the thyroid
glands. It has been suggested that hYP"ll-Ccrction of
hCG accounts for lhe manifestations of hyperthy-
roidism in small numbers of womcn wlto show this
only during pregnancy. However. the TSH·like ae-
tivity is probably not important under physiological
conditions.
CHORIONIC GONADOTROPINS AND OTHER
FACTORS THAT REGULATE M ATERNAL
IMM UNE FUNCTIONS
Maternal immune sySlems function throughout
pregnancy. The mother resists infcetioM. reacts to
implanted tumors. responds to histooompalibility an-
ligens on sperm heads and paternally derived anti-
gens of conceptuses. and rejects skin grafts of em-
bryonic tissues. Examples can be ciled in which the
aClivities or product.'; of maternal cell. damage the
or prcmaturely terminate the pregnancy. Er-
thyroblastosis fetalis is of the disorders known to
result from fetal slimulation of the matcrnal system
and the subsequent deli"llry of maternal antibodies
that CrOSS the placenta. Substantial numbers of bo-
.inc and swine embryos have been shown to be killed
by immunologic attack (206).
Despite the potential for
 CONCEPTION AND PREGNANCY

.
,n "

.
, $
Nfl, .... - Pro "Asp - Val -Giro _A.p -CY' -l'to-GIoJ -Cys - 11.- -leu -G!o - Glu - Aop -

"
p,o _ -PIle -Scr - GIn -P,o - Gt/ - "" -1" 0 - lie -le u - GIn- Cys - Me ' - Giy -
35 '0 '5
Cys -<:ys -PIle-So>< - Arg - Ala - Ty' -Pro-TI.- -P,O-Leu - A'9 - Se, -L yo-l. ys-
.. 55 60
TItr -Me' -leu - V. ' - GIn-L ys - A"" - V01 - TI.- - Ser - GIoJ - Ser - Th, - Cy. -Cy.-
65 70 7.
V.. -Ala - L ys - Se< - T Y' -Asn - Atg -VaI- TI>r - Val - Met - Gly - Gly - Pho>-Lys -

30 "5 \10
Val -Olu- Asn - His - Ttv -Ala -Cys-H;s-Cys- Se, _ ll.- _ Cys _ TY' _ Tyr _Hi._

B ' • ,0
NH, - Se, -l yo - Olu - P'o-Leu - A'G - Pro - "'g -Cy. - Ar9 - Pro - 110> - Asn - Ala - TI.- -
2Q -;;-
lc>u -A" -Val - 01 u -L ys -Glu -Oly _ Cys _ PIO _ _ - lie - Thr - Vol_A .... -
35 '0 .,
lhr - Th' - lie - Cy. - AI, -Gly - T)'f' Cys - P'o -TOr -Me' - Trw - Atg - Val - l eu-
50 55 .0
Gin - - Vo: -le u -Pro - Ala-leu - Pro -Gin - V.,-V. 1- Cys -ASII - Ty' - Arg-
" '0 u
A,p -V.'- - Pt>e - Giu - Se, - U" -"'g -Leu -P,o -Giy-Cys - Pro- Atg - Gly -
I. \10
Ty,-Ala-Var-Ala -Lou-Ser -Cy. -Gln-Cys-
.. 100 105
Ala -le u -Cys - Atg - Atg - Se, - TI.- - -Asp-CY' - Oly - Giy- PIO - LY' - Asp-

FlO. 111_7. A. Lin&ar 01 amino a cid' In the " positions of the .... dillJl_ btidges flO"" no! yet _
so .....! of hCG. l la poSit""'. of ,he d;.ulso. bridge_ .. tablisheef. The _ . rod tn. lost 32
lave roo' Yl t been e.tobl;sher;l. lIMo 'hr" N·... mi"., ,-...os. w hiCh . r. roo! pre_t in hLH6 . • e<:oUn11or thO
"'sld\Je . .'" roo! pre ..... , in hUla, B. LIne.r ....... urooIOgic 01 1>CG6, (From O"U,,"nondh arod
01 .mlne _ _ In the 6 su"'-'"", 01 hCG. l he Tulchino.ky. re/oronc4l ' 67.)
can survive: until after the usual time of fertili7.ation,
and fetuses are permitted to complete their intra-
uterine development. 11 ;,; even to raise:
healthy CQlIC<'ptuse:s of cenain species within the
uteri of different OliOS.
It has been suggested that antigens expressed on
the surfaces of sperm heads do not often impose se·
rious problems because seminal plasma contains im·
munosuppressivesubstanccs that exert short-term ef·
fects. The possibility that progesterone provid«
additional prote<:tion has also been considered
(212A). Dilferent explanations are required for the
long·term retention of fetuses. especially in humans
and olhers with hemochorial placentae, since thc tro-
phoblast comes into fairly cl= comact with mater-
nal immunocompetent cells. Several hypotheses are
CQnsidered below. They are not mutually exclusive.
and more than one mechanism may be required
(l3A.212A).
I. The trophoblast surface c\oscslto the maternal
system does not usually accumulate high CQlIC<'ntra_
tions of fetal antigens. Thi s idea is not easily recon-
ciled with indications thaI the maternal system be-
comcs se:nsiti7.ed to paternal histocompatibility
antigens. How.:ver. the actual numbers of ant igens
presented are oot known.
2. The antigens are prescnt, but barriers are im-
posed between the fetal and male mal systems. A '·f,-
briooid lareety of "yp'ophan.rkh
sulfated glycoproteins is visible under high magnifi.
calion. It is usually cspecially wide when the preg_
nancy inVQlves CQnsiderable genetic differences be-
tween Ihe CQncepws and the mother. The fibrinoid
contains ,ialic and hyaluronic acids. and glycosidic
enzymes can under some conditions prematurely ter·
minate the pregnancy. However. Ihe layer is discon-
tinous. and indications that Ihe maternal
system is affected by the pregnancy sugg« t that no
really effective barrier is established. Other tissues
with glycocalyxcs do not deter the passage of anti-
bodies and of immunOCQmpetent cells. Moreover,
production of the fibrinoid seems to result from cel-
lular interactions between the trophoblast and the
endometrium. A related concept is that the antigens
do not come into close contact with immunocompe-
tem cells, because trophoblastic invasion does not es·
tablish direct connections with the maternal blood
vessels and trophoblaslic cells are said 10 shy away
from maternal lymphatic vessels and lymph nodes.
Progesterone is implicated as a regulator that pre-
vents fibroblastic penetration and establiShment of
dOlle associations with the materMI system (13A).
3. The Ulerus functions in other ways as an "im-
munologically privileged site." This idea is difficult
to r<:coneile with the ability of blastocyls to implant
and develop in many nonuterine tissucs.
4. Antigens are present on trophoblastic surfaces,
but they are "masked" and thereby rendered inca_
pable of initiating rejection reactions. The s ub-
statlCC$ implicated include transferrin, antipatcrnal
antibodies. a-fetoprotein, and hCG. Uteroglobin has
been said to coat the antigens. or 10 interfer<: with
their actions by cross-linking with e·2 microglobu-
lins . Deficiencies of transglutaminase (which cata·
Iyzes formation of the cross-links) have been associ-
ate<i with pregnancy failure in humans (2t2A).
S. Hormones exert speciftc influences on the ma-
ternal immune system during pregMncy. They may
invoke highly localized changes, Or responses specific
for the antigens presented by the conceptus. They
may synergize with other substances produced only
at that time. High molecular weight proteins sus-
pected of participation in such reactions include ones
named early pregnancy factors (EPFs) (247A).
Progesterone has received the most attention For
several reasons (2 12.212A). It could easily act
within the endometrium without exening serious
generalized jnHuenees on the maternal system. since
the placental concentrations are around 2000-5000
nll/ml whereas the plasma levels are in the rangc of
100- 1SO nslml. It has been demonstrated to act lo-
cally to decrease granuloma formation and prolong
the li ves of skin grafts. The high concemrations in
lhe uteri of pseudopregnant rabbits arc associated
with inerused s,.,ceptibility to infection. 'ho'
time. Progesterone is to inhibit T cell acti-
vation by plant \ectin5, transformations of lympho-
cytes to blast cells, thymidine incorporation. and
DNA synthesis; and progesterone receptor:! have re-
cently becn idemified in glands (InA). Pro-
gesterone may also alfeet macrophage Functions and
reduce leukocyte number:! within the uterus. and it
is known to induce proteins that affect the matcrnal
immune syste m (206). When injected syste mically
in combination with estrogens. it ean prolong skin
graft survival. II is additionally said to aCt On the
preimplantation endometrium to reduce the num-
ber:! of ciliated cells. One consequence could be a
change in immunological properties (13). since thc
nonciliated cells become involved in '·hybridiza-
tions" with trophoblastic cells.
Estrogens are also present in high concentrations
in the placenta. They have not been shown to
progesterone·like actions. but can retard stem cell
proliFeration in bone marrow, decrease the activities
of nalural killer (NK) cells (212A). and interact
with receptor:! in the thymus gland.
11 has been stated that hCG depresses maternal
immunoreactivity, invokes thymus gland involution.
and nxluces the w.:ight of the maternal spleen.
Neuraminidase renders the trophoblast immuno-
genic. and it has been reported thaI hCG counteraclS
'"
Ih. eifecls if;\ is presented before lhe tissue is eX-
posed to Ihe enzyme (24). However. oonlaminanlS of
impure beG preparalioll$ are now believed 10 ac-
OOUOI for Ihe immunosuppression (214) . beG is also
said to increase lhe n.galivilies of both trophoblastic
and lymphocytic surfaces and 10 thereby bring about
muw.1 repulsion. 11 can also accelerate progesterone
secretion (212).
6. Another point of view is that s)'nclio(rophobla'·
lie invasion invokes a delayed· hypersensitivity «'-
spons. that limits Ihe reactivity of malernal tissues.
The interaclions may contribute to oon1rol of re10;..
placental uni! development. since placental size cor-
rdates with Ihe magnitude of disparity between
mother and conceptus (13).
Pregnancy Teats
heG is excreted into malernal urine in a biologically
active form. Most of the oldcr t:sts were based On
the LH and FSH ·likc properties.
The Asebbeim.Zonde. (A.Z. mouse) leol developed in
t928 use-d the formation of bemorrha,ie foUid .. in the
ovaries of immalure mice a.< i.. endpoint . It can t>c pcr·
formed 3 or mor. we ... aher fertili 7A1rioo. and it i. said
to be 98% dependable. H""ever. il involve. repealed in·
jeetioJI$ of maternat urine and Ihe sacrifIce of 6 moder·
olely expen.i"" Inimal •. The resul" cannot be obla ined
before 96 lIoul"$. Since urinary hCG i. uJI$l.bte. a fresh
sample must be ta ken if the re. ul" are incondu.ivc and
the test must t>c repeated .
The Friedman modification use. fewer (bul mOre CJl·
pcnsive) rabbit'. bCG promotes ovulatioo in Ibosc '"in·
duced" ovulator. wi'hin 48 lIourS. A problem wi th this
te .. i"hat stre"ed rabbi .. can rel.ase pituitary lH a nd
therefore ,ive "fll«: positive" responses.
The Galli·Mainini "frog" tesl i. baud On tbe ability of
bCG to Slimulate spermiation in male f1"Ojls or loads. Tbe
o.imal. are chuper and e•• ie, to maintl in Ih.n mam·
mals. they can be used more than once. and tbe result.
Ire oblained within 2_4 hourS. The .. me ",inc specimen
can be u,ed if it i, "C<elSar)' to repeat the proc<:dure .
"False .egative·· re,ul1. are oflen obt.int<!. especially
during limes of Ih. ye., when tb. anima l. show low sen·
silivity to the hormone. T he Hogben t.. t involve. hCG
Slimulation of ovulilion in lhe fem.le Af,i.,n load. The
ew are rel.ased wilbin 8 hours after Ihe !Io,mone i. in·
jected. false negalive. are. problem ,,"'ilh lhis procedure
a, well.
Immunologic al Tea ta
I mmunological methods arc sensitive. do not require
direct of animals. and are quite specific. Detee·
tion of hCG can be accomplished rapidly.
Quantitative have been developed for
CONCEPTION A ND PREGNANCY
assay of moot hormone. and of a variely of other bi-
ological molecules. While SOme demand consider-
"ble skill and experience. the on which
they arc based are relatively simple.
hCG is collected from pregnancy urine. conecn·
trated and purified . When injected inlo a foreign
species (.-_g .. th. rabbil), il stimulates production of
,(>Ccific antibodies which are then reoovered from
the blood plasma ( Fig . 16-8A).
Purified hCG Can be lat>ckd with radioactive
markers. When bbckd hCG is added to anti·hCG
antibody. a reversible is formed ( Fig, 16-
7B). The radioaclivity of Ihe complex can be
measured,
If unlabeled hCG is then added to the complex,
some of the radioaclive hCG will be displaced by Ihe
unlabeled hormone (Fig. 16-8C). The greater Ihe
quantilY of unlabeled hormone, the greater the
displacement.
Tbe complex can be precipitated. and its radio-
activity measured . Standard curves are constructed
relating amount of unlabeled hCG added 10 loss of
radioactivity of Ihe wmplex (Fig, 16-8D). An alter·
nale procedure inVOlves measurement of the amount
of labeled hCG displaced from the complex; in Ihis
case. radioactivity of Ihe medium is measured after
removal of the antibody complex (Fia. 16-8F.).
Once the curve has been an esti male
can be made of the hCG content of a urine sample_
It will be appreciated that the outlined melbod·
ology requires facilities for purifieal;"n and labeling
of the hCG, obtaining and purifying the antibodies.
separation of tbe antibody and measure-
me nt of the radioactivity. (However. kits are avail-
able to test laboratories so that procedures there are
minimized.)
A logical extension of Ihe melhod is Ihe labeling
of the hCG with a dye that changes oolor ru; the bCG
i. displaced from its combination witb the antibody.
Dete<:tion of pregnancy would then involve purchase
of the dye-Iat>cled hCG-antibody and ob-
servation of color changes wben Ihe urine is
added. At the time of Ihis writing. an adequale dye-
labeled preparat;"n is nQl available.
"Home-use" kits based on aggl utination reactions
are, however. being sold.
AgglutinatiGtl-inhibitlon lost. are the most
oommonly used today. They are less sensitive than
the radio-immullOalSaYS . I'owever, they do nol re-
quire expensive equipment or advanced Ie>:hnical
training, and Ihe results Can bo obtained wilhin min_
utes (whereas Ihe radioimmullOalSays require 12-24
hours) (167).
"Scnsitized" erythrocytes or latex particles are
coaled with hCG . The cells or partieles agglutinate
 o ))) (clump) in the of anti·hCG antibody (Fig-

8
o
-o --m ure 16·9/\ and Bj. urine from nonpregnant subjects
docs not alTeet the agglutination. If the urine COn-
tains hCG. (he hormone binds 10 (he antibody and
thereby prevents (he clumping (Figure 16-9C). The
hCG "'lIi-heG aol;/>od .. s
u.ine-antibody combination can be added to a sl ide
A. Produc,,,,, of .... Iiboej". to hCG containing hCG-cooled particles, The test can also
,.bb;I blood pia"",")
.,.,
(oollected from
'00 perrormed by adding the components in a test

•• + » )
)
.,.)
tube and observing the accumulation of agglu tin ated
at the bottom. Some commercially availa·

••
> ble test'; involve the formation of "pr<'cipitation
<
"ngs."
) When pregnancy a sever<' threat to tlte
Lat>ele<l ""IH.CG Ubele<l hCG· mother. Or when the prcsence of a trophoblastic
"" ontit>oC-t complex
B. ReverSible lotmal;on of complex of laoeled
ncG with rabbil antitlOCy
tumor is suspected. methods that can pick up very
low heG concentrations in blood or urine may be
needed. The radi <>-reccptor assay (194) is 10 lime,;
o ., o_ .0 as sensitive as the asslutination-inhibition te.<t. and

0
o +_
o
_
_ - o.
_ 0
the results are obtained within an hour. The proce-
dure is difficult to perform. requires skill and special
equipment. and is expensive. It mili7.es purified hor-
mOne receptors. and a problem is tltat it docs no1 dis-
Unlabele<l her;· o;spiacement 01 IICG not ting uish between heG and L H. A cytochemical
flCG amibo<ty some I _1M <:<>mttinM bioassay 200 X more sensit ive than the radio-recep-
complex heO with tor assay is also available. but much more time is
un'abe1o<l !>CG
needed 10 obtain the responses (167).

hCG Inlluences on Oocyte Maturation and

i. Ovulation
;1 It is unusual for a scoond fertili7ation and implan·

H tation to procecd when a fetus is dcvdopinS in the

uterUS. The most widely accepted explanation is ste·
roid hormone suppression of gonadotropin release

" L::::::::,,"o-:-
Incre.sing quant"ie' 01
and oonsequent arresl of follicle maturation and ovu·
lation. heG sti mulales the ovaries. but it has lim iled
activity and it falls to low levels after th.
unlabeled hCG a<kled fIrst fcw weeks of the sestation period. It has hccn
reported that heG preparations contain contami·
D. Effect 01 """itkln of unlobeled hCG,., ,ad""",ivity
01 hCG-anliboc!-j oomple' nanlS Ihal inhibit oocyte maluration in rat< . AI·
lhough no physiolosical role has been established.
the potential uSe of suelt substa nces as contracep-
tives has been consider«! (58).

hCG-Like Hormones In Other Mammil is

E. Ehe<t of _ ilion of LlIlIef>eIed!>CG on radioactivity
<>11factkJ<l conlaining hCG F>:)t romt>ined antit:(Jdy
fig . 1W. Principr. 01 r.dioimmuoo ...... y prOC«!",. lor
Specie, difference, in chorionic sonadOlropin func-
lions have been linked with variations in dependence
on the corpora lutea for presnancy maintenance and
in the mechanisms for achievins CL survival.
In many animal types. there is a need to provide
I"<:sulators that suppress the seneratian or oppose the
actions of lutwlysins rcieased by the uterus. Btro-
sens stimu late, whereas prOSCSlerone inhibits the
formation of Ihe major lutwlys;n. PGF"". LH aug·
ment, progesterone accumulation by aeceleratins
formation of the precursor and by slowing conver·
 CONCI:PTION AND PREGNANCY

Appea'3nc<l on
A. Appea'_" 01 erythrocyoe. bol<>r8 addition 01 anl;-hCG an';oody

.'

.-...'., .."
,. . ...,.- .
...... ' ;.. .
.

lI, ... with U,j.. wit"

.mal' """""" '''90 """""n'
01hCG
""'" Fig. 1(1.9. AggI\l'it>o';o" ',"1 lor hCG_

of progesterone to 20a-hydroxyprogcsteronc
(121). Chorionic g<lnadOlropins si milar ac-
tions. walegies are employed by
SOme species. In sheep. PGEs and PGls may be Ihe
major luteolytic antagonisls (132). In mares, much
of Ihe PGFlo- is shunted away from the ovaries and
dire<:tcd toward the uterine lumen (240).
RalS, mice and some other species aecc1.ra.te LH
and prolactin seeretion soon aftcr ovulation. and
they Ihe luteotropic actions of tbose hor-
II'KIncs 10 establish and maintain a How-
ever, the depc:ndenc.:: shifts 10 chorionic gonadotro-
pins during Ihe later stages.
PLAC ENTAL LACTOGENS
Human plac.::mal lactogen (hPL. human chorionic
growth hormone prolactin, heGP. chorionic SOma-
tomammotropin. hCS. somatomammotropic hor-
II'KIne, hSMII) also synthesized by the syncytio-
trophobla,t. 11 is primarily to Ihe maternal
bloodstr.am. (The very small amounts foond in am-
niotic fluid probably gOI there via diffusion from the
maternal system ( 14).) Although il for
10% of total plaeental protein in torm preg-
nancy. hPL does 001 so:¢m to be tsscntial for fetal
(214).
The hormone can be first dcttcted 5-10 days after
implantat ion. Its conc.::ntrations in maternal blood
then rise in direct proportion to the placental mass,
and Ihey remain elevatcd until term (Fig 16-6).
There are controversies concerning whether compo.-
nents of placenta l extracts such as estriol, progester-
one. cortisol, :;omalOStalin, and
accelerate the synthesis. cAMP is effective
in the presence of extracellular Ca' · . Some glucose
is but high concentrations inhibit.
PG F,. depresses the if it is injected inlO
the amniotic Auid. and it may function as a physio-
logical r<:gulator. Catecholamincs also dccrease the
synthesis ( 167.214).
hPL is a linear protein dcvoid of
that closely resembles human prolactin. The most
abundant form has 191 amiw and shows 85%
homology with hOli. It, growth horll'Klne potency is
only .. that of the pituitary regulator. but enough
can be made 10 facilitato lipOlysis and nitrogen
retention.
hPL production is high in poorly nourished preg-
nant v.omen. It is ketogenic during fasting. bUI il
also stimulates insulin releaK u d Iowcn the blood
glueosc. hPL has been klKlWn to in..xe a tl'llnsient
diabetes-like syndrome: in women who have normal
glucose: tolcl'llllCC when thty a re not pregnant (214).
The anli.inwlin actions may be opposed by
Gluo;ose is a major fuel for the fetus. It has been
proposed that the lipolytic actions of h PL reduce
maternal UK of the sugar and ther<:by provide more
for thc fetus. The GH·like activity may promote mao
te rnal sloragc of nut rients that will subseq uently be
needed for lactation .
In the mammary glands. hPL can sync'1liu with
pituill.ry PR L to promocc cell specialiZiliOll. II
ens direct PRUikc effects in monkey$ given c:lcg-
CIlOU$ ovarian hormones (161). However. it is far less
potent than PRL foc stimulating milk production. It
hall tllerefore been suggested tJu.t by competing witb
PRL for receptor binding. hPL acts physiologically
to lactation. (M il k production is permitted to
proceed soon aflcr parturition. whe n the maternal
hPL levels f,lI . nd P RL secre tion increases !233J.)
Rodent placental laetogens can promote mammary
,land differentiation in animals.
However. the OOl"lnoncs arc luteotropic in these ani-
mals. and this may be IlIcir primary function (21 4).
I n mice. rdated hormones are anti-lutcolYlic (51).
Subnormal felal size is associated wilh low hPL
leve ls. Since the conccn tra tiOll$ of tnc hormone in
hum an plasma correlatc with placenlal siZ<'. it has
been proposed that they can be used to estimate Ihc
gC$tation stage (161). It has l iso been suggested that
dopamine tonil:ally dcpm.scs placental production of
hPL a nd fetal S)'nthesis of gfO'to'th hormone. How--
ever. tbe notion is inamsistent with Andings in other
sped.. (134).
The view has been exprclo$Cd that hPL is a 'TIl;"
tlal hormone for affluenl prelnant .... omen. since
fcta l fuel requ irements an: easily met by maternal
food intake. while hCG and pitui tary PRL preclude
the nc<d for the luteotropic and mamma tropic ao-
t ions. A suggested role of hPL in regulatioo of fetal
W3ter balance is inconsistent with the low levels in
tile amniotic Huid and the hi,h PRo L concentrations.
ADDITIONAL PEPTIDE-TYPE
TROPHOBLASTIC HORMONES
The n. me, chorionic <XlrtiCClropi n (hACTH).
hijman eborionic thry-'otropin (hCT). I nd human cho-
rionic follicle "imuil lin, I>ormono (hFSH) hive been Ip-
plied 10 pl.cental extract componenl$ poucssinl the bio-
Iclf]ical Ict;.ita of the cotU$pondi", Jbl>d
... ,ulllon. Endorphins ..... bo ptUCnt_."" they are be--
ti • ..,d 10 deri.., from pre.","",," that proride the IlACfH .
lillie It kI...... or possible functions or Iny or the
preCcdinl-
A humin placental uteNl"""" hormono( hPUTH ) h..
boeto identified in the blood 01 lI«'.... nt -.en. It can
1"00""te proliferation (boo, not hypcnlq>lly) of ute ....
Ind Nmmary Cia "" cells .. bcft tested in r"de.lI. (161).
A hi", "-"&ht prcCUI1Ol" 01 no"", ,rowtb
(NOf) yickh.n aClive ",sulltor or hi.h potency impli.
.Ited in diucting the _Iurl tion of 'he 'ympa,hc';'; sys-
tem Ind brain adrener,i. ncUtO/'lll of tIM: ret us. The pia_
ecntl h•• ucepton for $eYeral other Srowth fac,on tbat
mlY be mlde by the ,,,,!,bob!"'t. The cytotrophob! ..,
readily •• ehlnges molccule$ with the syncytiotropl>o-
blast. the Imoiot;.; fluid. and the fetal blood.. It makes
TRH-likc moIccule$ (in addition to lhe re,,,_
lator) .•I>d it cnpgts in Steroid hormone bioay.'bais and
moeutbolilm.
Ahbool.h the fetal bcsil>fto make PRL quile
earl,. the decidu is bclie<e<l,o be the pti_ry SOOrC<: of
amniotic (85,8.6),
MATERNAL AND FETOPLACENTAL
SYNTHESIS AND METABOLISM OF
STEROIDS
()¥arian steroids prepare Inc endomctrium for im-
plantation. facilitate formation of the pIa«-nta. and
play roles in maintenance 01 the blood supply tlla t
supports fetal growth. Estrogens do not promote
growth of the myometrium during oonfenik cycles.
but their effects during pregnancy aCCOUnt rar most
of the 10-foid increase in we igh! and SOO-fold in_
c rease in uterine volume. New musel. fibcrs are
made during thc first Irimester, and tile cells soon
acquire high RNA :DNA Tatios. The large quan-
tities 01 proteins synthesized include intracellular aO-
tomyosin and coIla,en ( 103). 1lle steroids di-
rectly ptOlllOle muscle contraction and tlley:scnsitiZ<'
tile m)'Ollletrium 10 otller stimu lanu. They acceler-
ate prostagland in generation. oxylocin a nd relaxin
secretion, and the induction of receptors for proges-
terone. oxytocin. and other hormones, Thc
permit the Ulerus to ae<:ommodate to tile growing
fetus .nd to later engage in the panurition. EstI'Q-
gelUi are also believed to play essential roles in the
development oI tnc fetal pituitary gland. cenlnll ner_
vous s)'Stem.liver. and other structures.
The functions of progesterone an: less ,"-ell do-
fined. Ind lhey show greater species variations. n.:
human placenta produces 250 or more mg per day
whe n there is a single fetus and up 10 800 mg/day
when there a rc multiple concep tuses (161), In
perilllental animals. removal of the sources of pro--
gcsterone leads rapidly to abonion, This ca n be
avened with cxosenoos pnlgCSterone butllOl with cs--
tJOgCIIS (192). In all species, progesterone contrib-
utes to the re,uiatlon 01 receptors for esttogcllS. pro-
g<:stote .... and other hormones. and .t afl"CCIS tbe
secretory activities of SoCw:ral end<xrine glands. In
rabbits, rats. and some other species. progesterone
hyperpolarizes myometrial cell membranes and in-
vokcs relaxation . The direct depressant clTcets are
prominent in humans and many other mam-
mals, but progesterone evidently blocks the contrac-
tion sylll:hronization and thereby protects against
premature expulsion of the fetuses. No influence on
uterine contractility ha5 been shown for the guinea
pig.
Role s 01 t he Corpus luteum
The human corpus luteum (Cl) is an essemial
source of Meroid hormones during the first 5-6
weeks after conceplion. Ovariectomy Or lutcectomy
is rapidly followed by abortion. The placenta grad·
uany acquires the ability 10 make progesterone and
to panieipatc in estrogen synthesis. Pregnancy Can
be maintained after Ihe end of the second month if
thc C L is removed . However. the structure normally
persists and se.:retes relaxin. The transition from CL
10 placental provision of steroids can be fOllowed by
measuring maternal 17a-hydroxyprogesterone lev.
els. The placenta docs not have a 17a-hydroxylase
(but the fetal adrenal later acquires one).
P roges tero ne Synthesis by t he Pla centa
Maternal blood supplies substantial quantities of
cholesterol. and the rate-limiting factor for ilS use
seems to be the numbers of high density lipoprotein
receptors on the surfaces of the placenta l cells. Small
amounts of plasma.ocrived pregnenolone may also
be taken up. The ability to synthesize cholesterol
from acetyl-«lCnzyme A is very limite<.! (214).
Side-<:nain cleavage and If;l·hydroxysteroid dehy·
drogenasejl-ketosteroid isomerase complexes simi·
lar to previQusly described catalyze conversion
of the precursors to progesterone. roles
for hCG have been both proposed and questioned
(214).
Some of the progeMerone is taken up by the ma-
ternal blood. and the levels arc maintained in the
120-180 ngjml range. (1n contrast. they are 8-17
ngjml durins thc midluteal phasc of the ovarian
cyclc.) Progesterone metabolism follows pathways
shown in Chap. 15. However. the steroid diffuses
more rapidly from the vascular compartment during
pregnancy (despite the high concentrations of
plasma proteins)_ Progesterone is believed to aug·
ment 5a-reductase activity when it is prescnt in high
and maternal blood 5a.oihydrop..,.
gesteron. is high. (h has been suSgcsled that that
metabolite provides some protection against the de-
velopment of hypertension during pl'<'gnancy. since
it lowers the sensitivity of vascular smooth muscle to
angiotensin II. However. progesterone also a pre-
Cursor of DOC ]96].)
Progesterone concentrations in amniotic fluid
reach 30-60 ngjml during weeks 10-20 (14). The
amnion and chorion 5a-red uctase and both
If:l· and 20f;1·hydroxysteroid oxidoreductase en·
'ymes. Fetuses take up substances from the amniotic
fluid by swallowing and via diffusion across the skin.
They send metabolites into that compartment when
they urinate. The fetal blood progesterone concen-
trations are 7·fo!d greater than those of the mother
(14)_ Fetal liver conjugates much of the steroid it
takes up with sulfate. glucuronMe. or both. Fetal
adrenal glands are at forst directly dependent on
plasma-derive<.! progesterone for their biosynthesis of
corticosteroids, but they latcr acquire the ability to
utilize choleslerol as well (55) . Placental enzymes
hydrolYle the sulfate conjugates. bUI they canTlOt act
on the glueurOllatcs.
Feto pl acenta l S ynthesis of Es tro g e n s
The human placenta cannot convert pregnenolone or
progesterone to androgens or estrogens. It utilizes
dehydroepiandrosteronc-sulfate (DHE AS) as the
major precursor of estrone a nd estradiol, and 160·
OH·UHt::AS to make est"ol (hg_ Approx·
imately 50-60 mg of estriol is produced each day.
but only 15-20 mg of estradiol.
In monkeys, and probably also in humans, estra·
diol is selectively transferred to the maternal system
(so tbat fetal levels are low). but estrone is more
equally distributed to fetus and mOlher. 11 been
proposed Ihal the syncytiot rophoblas t cantains a
protein Ihat spceificatty binds the e!\radiO! . while a
17f;1-hydroxystcroid on the felal side of the placenta
rapidly converts estradiol to estrone (242). Fetal
liver cantains a 15·hydroxylasc. and it provides the
placenta with the 15a-. t6a-dibydroxy-DH EAS pre-
cursot' of estetrol. Since that steroid is not made by
the maternal ovary. its levels have been used to
gauge liver function of the fetus. hCG accelerates
conversion of Cl9 steroids to estrogens Md it may
also serve as a tropic hormone for the fetal adrenal
(55) and teslis (Chaps. 13 and (4).
The Fetal Adrenal
This gland is very large when compared with either
the body weight at that time Or the absolute sev·
eral months afler birth. The weight decreases from
8 g at term to 5 g by Ihe end of the nrst postnatal
month. as the volume diminishes by 50%.
A "fe\al zone" that is believed to be the major (or
 MATERNA L CIRCULATION PlACENTA FETUS

to"" r-- Cholo"",01

I
, OHEAS

OHtA

AJ,O".""'doone
;=" E.., _ _
' - - (E. """" ESIr"""" . E,,,,,,,,,
16
,!, OH·OfIEAS
E,,,aOooI
, 6 " OH·OH!;A$
'6 .. OH· Ot<EA
'6 '. OH ·(o" """
Es1rlol ",.,;
--
Eo" ",
,I
I ,
15 t 6 d,·OH OHEAS_
( '" 6 "' ·0H·DH EAS

£"""01
1C''''''' P'''Il'''IC'''''''
i
• P'''Il''"cr"",, .

II
Fig. 16·10. PI.OM'" biOsynlhesiS of progo.....""".
eOlfone • • 'trodiol...trio!, a.o .

for .y",h",i. of DI·IEA$ ab<>o.u sui""" 1';8>. ACTH, il .1", ,timulalQ

SO% of Iho gland Qf Ihe noonate (216), wllile a
smaller "definitive zone" rontains the en •.yme,
nocded 10 make oonicosteroids, It was formerly be-
lieved that Ihe fetal zone ondergoes involution and
necrosis. as the definiti"e zone forms new cell, and
acquires delineated glomeruklSa, fasdculata. and re-
ticularis >-ones (55). A more recent concept is that
h
tile felal zone is "reroodcled inlQ tile 10na fascicu-
lata of the mature gland (207).
Cortirosleronc synthesis begins within 10 weeks
after ronception, and both pituitary hormone stim-
ulation and negative focdback control are estab-
soon afterward. 10---20 week-{)ld human fe-
tU!leS release cortisol. corticostcrQne, aldostorone,
and DOC imQ cu lture media. ACTH sti mulale. glu_
eoconiooid synthesis. It also accelerates low dellSi!y
lipoprotein degradation. and it may in this way pro-
vide large quantilies of DHEAS and eslriol precur-
so.. (171). I)cxamethasone inhibilion of ACTH and
glucOCQrticoid ,;ccrelion has been dell"lQn.strated in
monkeys. hut steroids other than gluoooorticoids are
implicaled in the negalive feedback oonlrol (207).
pi!U;lury glands comain ,...MSH. Cl..I P, and
,:!-endorphin, but it is not known if substantial quan-
tities an: released. ",-MSH can accelerate gluoooor-
tiroid production by fClal (but not adult) adrenal
slands of humans, monkeys, shocp. rabbits, rats. and
proliferalion.
GluCQCorticoids CI"Q:Sj; placenta in both direc-
tions. The felUS OOn!ributes to maternal cortisol, and
Ihe maternal s)'stem can supjKlrt gluCQCQrticoid
functions in anencephalic fetuses, The levels of free
are higher in the felus. sillC(; Ihe roncc ntra-
tions of CBG are 10,," (55), The maternal system
rapidly converts cortisone to cortisol, whereas the
fClal one preferontially oxidizes the cortisol \Q corli_
sone. CQngenital deficienciesQf 11/:i·hydroxylase and
21-hydroxylase enzymes impair the abili ty of the
felal adrenal to synthesize gluoocorlicQids. Large
UlI"IQunts of androgens arc then madc, and this leads
to emergence of the adretlOgeni/a/ .•yndrome (see
Chapler 13).
Lung matmat;"n includes lhe ProdUCliQn of large
quantilies of surfaclamS. These arC rompl.x mix-
lures of lipids (especially dipalmitolyl lecithin) and
proteins that lo,,"er surface tension and PI"<»
leet against collapse of lhe air sacs. GluCQCorticoid.
facilitale surfactant accumulalion (po:s.s ibly by aug·
mcming triiodothyronine synthcsi" [82]) and they
play addiliQnal roles in lung maturat;"n, Glucocor-
ticoids are also needed for malur31ion of liver,
intestine. pancreas. and some other organs (12). In
at least some species. Ihey promote accumulalion of
liver and cardiac glycogen, augmont insulin re-
 AND PREGNANCY

sponses to glucose, increase lhe activities of intes-
tinal disaccharidases. decrease the permeability of
gut mucosa 10 immunoglobulins and other maera-
molecules. and induce ,/kIdr<:nergic receplors in the
lungs. They induce the PNMT entyme (which cat·
aly1.es convcrsion of norepinephrine 10 epinephrine).
and their inAuences Qn thyroxin melabolism arc im·
plicaled in acquisilion of adaptations to cold environ·
ments (207). Influences on parturition are oonsid·
ercd later in this chapler.
MineralClCOrtieoids ar<: produced In large
amOUnl$. bm the cOntrol mechanisms are unknown.
The steroid, arc belie'-cd to regulate fetal sah and
waler balance. Angiotensin levels are high in fetal
blood. and the peptides can promote adrenal cell
proliferation. Additional hormones implicated in
regulation of the felal adrenal gland include fibro-
blast growlh faelor (which al'" aCl ive in Ihe adult)
and epidermal growth faclor (207).
DURATION OF THE GESTATION PERIOD
Genctic factors arc the major delerminant' of ges-
tation period length and Ihe associated malnrali","al
Slale of the newOOrn. Slrain differences within a spe:-
c ie, arc kllOwn. Large animals that develop one at a
time usually have the longest gestation perioos.
However, Illere arc no oonsistent relalionships 10 the
lengths of Ihe ovarian cydes. Sows ar<: among Ihc
mamrnal$ thaI have large lilters and moderately
long pregnancies (sec Table 16·1).
The maturation raleS can vary widely. Thus. kan·
garoos born after 35 days arc more like embryos
than hamsters deliver<:d afler 16 days. The guinea
pig born a liule ovcr 2 monlhs after conception can
survive wilham maternal care, whereas the puppy
wilh a comparable gestatiQn period is al fITS! blind
and helpless. Newborn whales of Ihe larger varielies
weigh mOre Ihan clephant neonates, but the gesta·
lion period is shorler for Ihe wh alcs.
Within a species. the nutrilional and endocrine
S\atus of both the mother and fetus and Ihe numbers
of ooncept uses have ",me influence On geslalion
time. Human twins lend to be born earlier than sin-
gle infants. and triplets earlier than Iwins. Pituitary
hormone deficiencies tend 10 delay parturition.
PARTU RITION
Tlte uterus can acoomplish powerful, organized oon-
traclions thaI expel the fetus long before the time of
parturition. The probability that il will manifest
such aClivily riscs during laic pregnancy. since Ihere
are progressive changes in lhe properties of thc mus·
cle a nd in the numbers of receptors for stimulanl$.
There is concomitant reduclion in the sensilivity 10
inhibilors and Ihis i, associaled in at least SOme spe-
cies with lowered rateS of secretion and/or .ceder·
ated rales of inactivation of myometrial depressants.
Slo""ly developing changes seem to be at leasl as im·
portant as rapid discharge of parturition "Iriggers"
(6.119).

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 The human uterus and uterine cervIX are
equipped with intrinsic neuronal '}'Stems tha t can
function indepondently of external 'timuli. and they
receive adrenergic input via the hypogastric pkx·
uses. The a·type re<;eptors mediate sti mulation and
e
the types depression. Since epinephrine interncts
with roth. its effe<:ts can vary (142). The cate<:hoi·
amines are more important in $OI11e species than in
others.
Roles of Relaxin
Relaxins (RLXs) arc species-specific peptide, witb
"",Iecular weights of just under 6000. They arc
made up of A and B amino acid chains oovalenlly
linked by disulfide ronds, 20 K·P'o-rela. ins with
long oonnecting (C) peptidcs and 3K signal se-
quences havc also been identified (80,153).
The hormones resemble insulin in tertiary
structure . and me<:hanism, of cleavage from tbe pri·
mary RNA transcripts (20 I). The "",Iecular config·
urations 3re also similar to those of insulin·like
growtb factors (somatomedins) and ncrve growth
factor (26),
It ha, been . peculated to.t an '"ancient" gene under·
went duplications and mooif1catlon' du,ing the course o>f
evoluti(H! to give ri.e 10 a "family" of related peptide reg·
ulators. The concept ha, been ,ecently challenged (200).
II M. betn pointed ou, tMt (a) tne memDcrs of tne hOr·
mone ll'ouP ' how limited amino acid 5equen"" homology:
(b) no .tepwise changes in the composition can be demo
onma'ed one ".scend$"' tbe scale from da$mobr3nch'
to human.: and (e) the hormone. di.play large dilfor·
enee< in biological properties and ,eocptor allinitie<. It i.
therefore possible th.t each of the peptide t)·pes dori"e,
from its own p,ecursor.
SITES OF BIOSYNTHESIS
In humans. the primary SOUrlX'S are Ihe corpora
IUlea of pregnancy. Malernal plasma conccmration$
fall precipitously if lute.ctom}· is performed (245).
Corpora lutea granulosal cens are also the primary
sour""s in SOws and in some other mammal •. Most
of the circuialing R LX of the pregnant rat mayorig·
inate in the ovary. but a placental factor (not present
in pseudopregnant animals or in ones bearing de-
cidua) seem. to be essential for secretion (88). In
several other species, the feto-placental unit makes
most of the Rl.X (223) . The endometrial gland. of
the pregnant guinea pig make substantial quantities.
and the peptide can be extracted from rabbit pia·
centa (72). decidua (18) and sheep placenta
contain tbe hormone. In ""'n ke}'" the placenta may
be the primary source. since the plasma concCntra·
tions do not rise to detectable levels until after the
3rd week of pregnancy (246). In mares. RLX ro-
mains low until arte r the corpus luteum regres<cs
and the placenta begins to make steroid •.
O varian follicle!! make small amount'l during thc
periovulatory pe riod . RLX is found in follicular
nuid. and it has been implicated in ovulation (33).
Moderately high levels in human peritoneal nuid
during the early to midlu(cal phases are aHributed
to cxuda(ion from the ovaries (230). Pcptidcs with
similar chemical and immunological properties have
been identified in human scminal plasma (68). and
these are implicated in regulation of sperm motility.
Rl.X is also evidently present in boar. armadillo. and
rooster tcstis. and it seems to be made in armadillo
prostate gland (34). The hormones bave been ex·
trac(ed from several nonmammalian ver(cbrates.
and shark R LX is biologically ro(ent in mammals
(124,201).
Re.son.bly good correlation, bet"'ocn immu"""... )·,
and bioa"'Y"'" obtained under ""me rondi.ion" How·
ever, it i. no •• Iway. possible to determine whether pep-
tid .. . howing immuOQreactivity art ""uc" RLXs. altd
the biologicol aCliviti", are often not predictable. " pcp-
tide from one specie. ma)' ,bow highe, .ct ivit)" whon
tCltcd on "'gel organ, of .nolher than when used in the
same animallype. 0"" form of RLX Can Ix potent at
ccrlOin site. but l0tally inactive when presented to cell ,
th.t respond to a chemicoll)' related peptide. The biolog·
ical ... ponse. are affccred by receptor "umb<rS (wbieh
can undergo large chonges) .nd .Iso bj' Ihe pre.e""e of
several other '.gul.tors. (It has Ixcn shown. fo, c. ample.
th.t $Orne cell type. become re.pen.ive onl)" aft.r exJ>O-
'u," to ."'<>gen,. and Ih. t ""TVe growth raCtor and in·
,ulin·li' e growth bo,mo"", compcte fo, binding (2211.)
Tissue, that make the RLX. al'" contain prot«Jiytic en·
,yme. that dcgrade the peptide<. They may male enough
hormone to act locally without contributing to ei'cul.ting
RLX. Othe, tissue, containing small amoonlS can have
r.ceptorS th .. bind Rl X. m,de clscwhere (8).
ROLES IN PREPARATION OF THE BIRTH
CANAL
Guinea pig fetuses are very large in comparison with
the sile of the mother. Delivery must be preceded by
chang.. in the symphysis pubi<. In other
mammals. the changes can be of much smaller mag·
nitude •• but in all $OI11e ",ftening and dilation of the
cervix is required. When the hormone was ftrst stud·
ied. the impression waS gained that it fUlICtions pri·
marily to prepare the binh for passage of term
fetuses. It is now recognized that RLXs have other
important elfects. For example. they act ()11 utcrine
muscle. and they may funclion in some specics to
bring about scparation of the placenta from the
uterus and weakening of the fetal membmncs (245).
Tbe earliest bioassa)'S were conducted on the
pregnam guinea pig. Thi, animal is stili a favorite
subject because tbe symphysis pubis is sclISitive to

'"
RLX and ;1 is possible \0 obtain ,<,producible data .
Sow ovaries the largest amounts of RLX of
all species tested (201), and porcine hormone i.
widely used as a standard against which other prep-
arations arc tesled.
When treated with porcine RLX. the symphysis
pubis of the guinea pig undergoes marked cbanges
in structure that culminate in conversion ()f a com·
paCI, cartilaginous ronneci;vc tissue imo a more nuid
Hcxiblc type and Ihe formation of a ligame nt be·
tween the pubic bones (201). There i. an associated
rearrangement of the collagenous filaments. ron...,r-
sion of some folaments 10 microfibril •. collagen digcs-
tion, and loss of "ground substance." Fibroblasts arc
probably the primary target cells. While individual
differences in the patterns of change of hormone lev.
els have been obscrvcd. there is consistent elevation
of plasma RLX prior to ligament formation (25).
The level's are high beginning at least 10 days before
parturition.
Pubic ligaments are formed in many other mam -
mals. In mice. RLX may synergize with estrogens to
additionally bring about selective erosion of the
pubic bones. (Estrogens exert dilTerent influences on
bone in other partS nf the body.) Tbe two hormones
interact 10 pramolc induction of specific lyS050mal
protcases that include cathepsin Band dipeptidyl
peptidase I (but not dipeplidyl peptidase II). Either
hormone aCling alone can bring aboutlimitcd induc_
tion (I 3?). It has noted in several contexts that
estrogens directly labilize lysosomal membranes.
and that thcy also promote generation of POs that
act on the membranes. RLXs additionally act slowly
in mice to bring about gradual "softening" and di-
lation of the
In women. "pelvic relaxation" u,ually entails
oomparativdy minor structural change.. However.
there are individual, in whom it can be exaggerated
to the point where it causes substantial pain and dis-
oomfort . Several findings are consistent with roles
for RLX in t' - processes_ but no consistent prepar-
tum changes in the con<xntrations have been found
(l81).
INFLUENCES ON THE MYOMETRIUM
In many of the mammals, RLX levels rise sharply
during the last few days of pregnancy. This is espe-
cially notable in sows, in which plasma val ues as
high as 150 pg/ml may be anained during a "pre-
pa rtum surge." In most . RLX declines rapidly
shonly before the uterine oontractions begin. This
suggests that RLX performs some other functions
that must be inhibited before parturition can be ae-
CONCEPTION ANO PREGNANCV
oomplishcd. Guinea pigs also show the laiC fall in
RLX levels. and pregnant animals of certain other
species become unresponsive to RLX very late in the
gestation period.
RLX is a myometrial depressant. In guinea pigs.
it is probablyth. most imponant agent that provides
protection against premature or the fetuses
(25). Unli ke the findings in rabbits and many other
species, guinea pig myometrium is tota lly insensitive
to the inhibitory influences of proge.teronc.
In the steroid-sensitive species, RLX probably
plays supporting roles. Its .ffects Can be distin-
guished from those of progestcronc . Exogenous RLX
acts within minutcs after presentation. and it aCCOm-
plishes its functions without influencing responsive-
no", to stimulants such as oxytocin or prostaglandins
(38) (ahhough uteri of QVQr;«Iomized ralS may
show some loss when presented with RLX [441>. It
is thcrefore possible for RLX to exert its inAuences
on thc birth canal very late during the gestation pe-
riod and to be by oxytocin and prosta-
glandins in ju,t the myometrium (245). In contrast.
progcsterorK: relaxation develops over thc course of
several hours and it is aeoompanicd by both loss of
sensit ivities to lhe stimulants (38) and inhibition of
their secretion (191) . Whereas progesterone in some
cases reduces muscle tone and brings about mem_
brane hyperpolarization, relaxill$ seem to mOStly di-
minish the amplitudes and frequerlCies of the con-
tractions. Roles of R LX in regulation of ccl1-to-cctl
oommunications have been proposed for rats, sows,
and some other mammals (6 1).
INFLUENCES ON THE ENDOMETRIUM
In primates, relaxin is implicated as a synergist wi th
estrogens and progestogens for preparation of the
endometrium for implantation. in placentation. and
in delivery of Ihc blood supply to the
(20 I). II also exerts insulin-like influences on glyoo-
gen and protein metabolism in rat utems (44). A rise
in plasma levels can be detccted soon after coneer>-
tion in women (182).
OTHER ACTIONS
In nonpregnant guinea pigs, the changes in cireulat-
ing RLX arc oonsistcnt with roles in lutcolysis and
in the regularly recurring opening of the vaginal
membrane during estrus (25). However, PO F,. is lu-
teolytie in sows. whereas RLX is not. Some obser,·-
crs find thaI POs are lutcolyticin guinea pig.' (IOn
but OIhcrs find no influences nf PO synthesis,inhibi-
tors on corpus luteum regression (25).
 Relaxin may contribute to stcroid-stimulated
growth and differentiation of the mamma ry glands
in primates and some other specie<. but it can reduce
milk production. atlea<t in rats and goot. (201) . Re-
lease or rdaxin into the maternal plasma has been
dCSl'ribcd for human,. and sows. and in all of
these. lactation can delay the reestablishment of
o"arian cycles. The guinea pig shows neither lacta·
tional delay nor relaxin release during nursing.
Rebxin docs no! bind with high affinity to insulin
receplors. and it docs not exert insulin-like actions
oulside Ihe ulerus. However. it acts on adipocytes of
estrogen-p rimed rats to increase the affinity of insu·
lin for its own r""eptor, No comparable elTeets ha"c
been found for adipoo:ytes of male or immature fe-
male animals or for other largets tesled. such a< Iym-
phocyles. It has been proposed Ihat the relaxi n se-
creled throughout much of human pregnane)'
provides most women with protection against Other
hormones that confer insulin resistance . Exogenoos
RLX may therofore f,nd some use in the trcatmem
of wOmen who develop a diabeles mellitus-like con-
dition during pregnancy (163).
MECHAN ISM OF ACTION
Some evidence has accumulated for the presence of
RLX receptors on the plasma membranes of the tar-
ee' ",,11.. l .i"le i. knnwn nf wh., h' rf"'.n< . f,c.-""rn
Sinee many of the influences involve changes in re,_
ponsitivity to olher hormones. RLX may alter the
membrane propeT1ies. Some elTeets may be me-
diated via cAMP,
REGULATION OF RELAXIN SYNTHESIS AND
SECRETION
The cell types implicated in RLX synthesis take
lime to develop the ab ilily 10 make Ihe hormone. It
is likely that Ihe)" musl acquire a certain malura-
tional state and Ihal the proccsSC!l arc dependenl on
other regulalors. Each cell Iype seems 10 have its
unique requirements. For reasons that have been
cited. changes in secretion rateS are not necessarily
associated with corresponding changes in blood or
tissue concenlralions.
Estrogens are implicaled in both stimulation of
the synthesis and in induclion of Ihe receptors.
Guinea pig uteri make their lar8",t amountS during
estrus when no conception OCcurs. The produclion
rate accelerates during pregnancy (although ovarian
levels fall). Exogenous estrogen (alone or in combi-
nation with progesterone) can inerease ulerinc RlX
production. raise the blood level s. and bring about
changes in Ihe symphysis pubis (\50). In IlOnpreg-
nant women, repeated injections of hCG augmenl
secretion (245)_ and the plasma RI.X changes par-
allel those for hCG during pregnancy , hCG does nol
increase plasm" RlX (201). In rals. Rl.X
increases along with placcnlall uleotropins. The con-
tributions of pilu;tary gland hormones are difflcull to
aSseSS. Both lH and prolactin may be involved in the
stimulation.
When ral corpora Imea are maintained in mono-
layer culture. neit her estrogen alone flOr eSlrogen
plus hCG is clTective. Howner. RI.X synlhes is is ac-
celeralcd when lhe cells are presented with certain
olhcr hormone oombinalions, for example. hCG.
prolactin (or hPL) and progesterone (89). Prolacti n
alone may nol be important in intact females. sin""
RI.X levels fall after parturition in women who
breast-feed their infants. Oxytocin has been impli_
cated in some species. and PGs are also effe<:live in
cerl"in OneS. It is possible Ihat e10ge1lOu< regulators
do nOI ael directly on the biosynthetic machinery.
The)" may instead maintain cell growlh and viabilily
and thercby permit the emergence of an "inherent"'
ability to make Ihe peplidcs.
The Progesterone Block Hypothesis for
Initiation of Labor
Progesterone -'lrQngly inhibits rabbit myometrium
throughout Ihe gestalion period. The steroid le,,,ls
ran sh"" ly befo,e the contractions begin. and
eoouS progesterone can dela)' parturition. It is be-
lieved thai Ihe birth process in Ihese anima ls is de-
pendent on Ihe fall in progeslerone levels (or on the
risc in the cstrogen: progestero"" ratio).
Progeslerone levels also fall sh<.lrdy before panu-
rition in sheep. goalS. pigs. and rats. and the con-
tractions can be delayed wilh cxogenous sleroid. In
these animals. the deeline in progesterone probably
makes a physiological contribution but it may not be
absolute ly essential.
There are controversies over the importance of
progesterone de<:line in primales, Somc investigators
report thai Ihc hormone levels decrease SOmewhal.
whereas others do not ( 191). The possibility Ihal
progesterone becomes less effecrive even when tne
ooocenlrations do not change has been considered
(52). Those favoring the concept tht a progesterone
block muSt be liftcd have suggested the foIlOl'o'ing
mechanisms (96): (a) "programmed" aging of thc
placenta leads 10 decrea$Cd progesterone synthesis;
(b) the blood supply to the uterus diminishes shortly
before parturition. and smaller amounts of choles-
tcrol substrate are presented to the cells: (c) a pro-
tein thai binds progesterone with high amnity and
thereby interfe res with sieroid-receptor interanions
is made laic in thc gestation period: and (d) the
numbers of progesterone receptors decline (38). An

earlier belief thut progesterone is more rapidly oon-
¥crted to inactive metabolites has not been substan_
tiated for However, the possibility that en-
dometrial oonccntralions fall as pla:sma levels are
maintained has not been ruled out.
ROle s 01 Estrogens
Estrogens act directly on the myometrium to aug-
ment contractile force and synchroni 7.e the activities
of fiber groups. They promote the release of oxytocin
and PG •. and (in at least SOme species). they addi-
tionally cbate the norepinephrine:epinephrinc rJ-
tios. The numbers of estrogen rcceptors can increase
during late gestation (4).
Large doses precipitate the onset of premature
labor in rats, mice. rabbits, cats, and other mam-
mals. Pharmacologica l dosages of synthetic estro-
gens have been used as "postooitul contraceptives"
in humans (144) . and it has becn reported that es-
trogens increase the sensitivities to endogcnous oxy-
tocin (113). and to PGs. On the other hand. whereas
injections of oxytocin and PGs baSlcn labor at term,
estrogens are ineffective.
Roles of Oxytocin
Oxytocin (OT) is a small peptide that is syn thesized
in the maternal hypothalamus. It is transponed to
the neural lobe for storage and subs«J uent release,
The peptide may addit ionally be made by the fetus.
since it is prcsc:nt in amniotiC Auid (14).
OT leve ls in mate rnal bl<X>d and endometrium
bavc been observ:d to rise abruptly short ly before
the onset of parturition in rats (4), rabbits (78).
and other species (145)_ Some authors re-
port a rise in amniotic Auid concentrations in
humans, but others do nOl r.nd this (1 4). Uterine
stre tching by an expand ing oonceptus approaching
term, and dilation of the cervix during the early
stages of labor provide pelent stimuli for hypotha-
lamic release of OT. Either estrogen alone Or a fall
in estrogen:progesterone ratios Can promote OT rc-
ceptor induction (4). and the receptor numbers in_
crease late in the gestation period. The changes ac-
count in part for the increa sing sensit ivity of the
uterus to the actions of the hormone. However.OT
is reported to promote PGF ... release. and PGs are
said to increase the responsiveness to OT (117).
When OT levels are low because of naturally oc-
curring e"entS or ex!'<'rimental intervention. partu_
rition is dela)'ed and prolonged, and this is aswciated
with fetal distress or mortality. In women thr.::atcncd
with premature labor. administration of ethyl ako-
hoi is believed to be beneficial at lea" in part be-
CauSe it inhibits OT release (78).
CONCEPTION AND PREGNANCY
All of the preceding findings are consistent with
the notion that OT "triggers" the onset of labor.
However,OT levels do not rise in all of the mam_
mals, and parturition can proceed in hypophysecto-
mized animals. In guinea pigs. OT increases a good
week before dc1ivt:ry. Therefore, the trigger coneept
could apply only if it is assumed that an inhibitor is
removed during the final few hours.
A more widely held belief is that OT functions to
hasten expulsion of the infant. to promote delivery of
the placenta, a nd to stimulate postpartum uterine
contractions that provide protection against exCeS-
sive bleeding, It may not be important for ;rririalion
of the contractions. (Roles in lactation arc described
later. OT has also been implicated in ovulation [5],)
Prostaglandlna
PGF ... and PGE l are extremely potent stimulants in
most mammals. Unlike they a re elfeetive at all
gestational stages. They have been used to induce
labor at term and to achieve first or second trimester
abortion. Lower dosages are actually required dur_
ing the early months (II 7).
Amniotic Auid concentrations ri,e a bruptly
'hortly before the onset and during the progress of
parturi tion , The suspccted sour.::es include myome-
trium. decidua and chorion, The fctal pituitary is in-
volved (since the rise is nOl seen in anencephalic con-
ceptuses) ( 14). Some observers fond that maternal
plasma PG also rises. Aspirin. indomethacin. and
other PG synthesis inhibitors delay or prolong par-
turition. However. each of the agents tested exens
additional innuences on the myometrium that arc
not antagoniled with exogenous PGs (6).
While there is evidence for PG contributions in
monkeys. rats. sheep, and other (38, 162), the
major meehanisms of action can vary with tbc spe-
cies. Luteolysis seems to be important in animals
that derive their progesterone from the ovaries. and
inhibition of placental production of the steroid has
been described for others. In women. dosagcs of
PGI, that do not affect the myometrium arc re-
jXlrted 10 bring about "cervical ripening" (176F).
Some elfeets arc probably exerted on lysosomal
membranes of both mother and fetus. In addition to
"song estrogen titers and falling estrC>-
gen;progestcronc ratios. roles for hPL in accelera-
tion of PG production have been proposed (38).
Roles of the Fetus
Fetal lambs a nd kids release substantial quantities of
gluC<lConiooids j ust before the onset of parturition.
In these, the steroid may "trigger" the uterine oon-
tractions (38. 128.129). In sheep. cortisol induces
 and it thereby lowm the levels of
placental proge$terone (207). The progesterone i5
rapidly converted to androgens and ultimately to ey
trogen!. The resulting rise in e!ltrogen:progcsterone
ratios may augment myometrial activity both di·
rectly and via PG generation. The thyroid system
matures very late. When it does. oxygen ronsump-
tion aOC<'lerates, and the anoxia that develops may
serve as a .timulus for thc release of ACTH . In
goots. the oortisol must act in diffe rent ways. The
ovaries supply the progesterone. and PG-associated
lutwlysis accounts for the fall in progesterone levels
(128.129).
In humans. amniotic fluid rortisol ooncentrations
rise somewhat just before parturition. The glucocor.
ticoid is not known to be e.'iSential for initiation of
labor, but there have been recent indications that it
makes a physiological cootributicn (216). Glucocor·
ticoid injections do not bring on premature oontrac-
tions in monkeys. and they have little effcct when
administered to women at term. Ho",·cver, they are
reported to be useful for induction of delayed labor
(191.225). and also for quieting a uterus that has
begun premature oontrnctions.
Anencephalic fetuses and OneS with brain damage
that impairs ACTH secreticn are ecmmonly born
either prema turely Or very late. Jt has therefore been
ronsidered that glucocorticoids play roles in fine con-
trol of birth As has been noted. the steroids
influence fetal growth and maturation. and they af·
fect the release of myometrial stimulants. However.
acoording to some observers, it is a steroid secretcd
in association with oortisol (possible DHEAS or an·
drostenedione [207]) that aSSume, impoortance in
primates.
A low molecular weight lipid that stimulates PG
symhesis has been identified in the urine of term fe·
tuses . Since urine i, into the amnictic fluid.
this substance may play roles in the initiation of par-
turition (224A).
In rats, the thyroid system matures after birth
(73). No roles for glucocortiooids in parturition ha.·e
been established.
CONTRACEPTION
Binh oomrol Can be achieved by (a) interfering with
gametogenesis, implantation . Or the progess of an cy
tablished pregnancy. Or (b) preventing contact be-
twecn mature spenn and oocytes.
Abstinence end Releted Methods
Tota l abstinence from se.ual intercourse is the most
obvious way to avoid pregnancy. It is the primary
method used in some societies, both before marriage
and for a proscribed interval after the birth of a child
(176£). For reasons. it is not considered aC-
ceptable by most couples.
CoilUs interruptus (withdrawal of the penis before
ejaculation) is regarded by some as a n10dified form
of abstine nce . It is probably the oldcst known
mcthod. and it is still widely practiced in SOme parts
of the world. One of the problems with it is the un·
avoidable escape of small quantities of sperm-rich
semen prior to the release of the obvious ejaculate.
Even whcn the withdrawal is accomplished. the es·
timated pregnancy rate for fertile women during a
year of use is 18% (10).
" Rhythm" Methods
All rhythm methods are modified forms of absti-
nence based on the following assumption.: (a) the
time of ovulation Can be predicted; (b) spermato1""
and oocytes remain func tional for .-ery limited time
periods; and therefore, (c) there are ·'safc periods··
during which ooitus will not lead to fenili7.ation.
The most widely used procedure involves deter·
mining the lengths of previous menstrual cycles . Pre·
sumably. ovulation occurs regularly a t midcycle, and
ooc)· tes remain in a fertilizable State for up to 48
hours afterward. Since spermat010a arc viable for 3
similar time period. the "fertile period·· exte nds from
two days before tc two days after the mideycle.
Some practitione .... abstain from ,exu.1 interoourse
for 3l!-4 days before through 3-4 days after the ay
sumed ovulation lime. More oonservative cnes ad-
vocate abstention for two or moT<: weeks of each
cycle "just to be sure."
It has been variously estimated that for every 100
women using the '·calendar'· method for one year. 24
(10). almost 29. (139). Or mOre (l76E) become
pregnant. There arc these wlto believe that thc
rhythm method "works" only for couples who are in-
fertile or nearly SO (226).
Although the interval from ovulation to onset of
the menses is fairly ronstant in healthy women, the
one: from menses to the next ovulation is not. Vari·
ations of up to eight day" are not nnCCmmon under
normal oonditions . Larger ones are seen when SOmC-
thing perturbs the hormonal balance. since stimula-
tion of the central nervous systcm can affe<:t LRH
release. Coitus·induced ··pamcyelic·' ovulation is
,,-ell documented in laboratory animals, and there
are good reasons to believe that it occurs in WOOlen
(95). The strCS5 associated with rape is believed to
account fOf the high incidence of conception that fol-
lows. The very abstinence can be the factor that
heightens sensitivity to vaginal or cervical stimula·
tion and thereby accelcratcs ovubticn. It is also p0s-
sible for spermatOzoa to be retained in an uncapa-
citated. viable oondition within the cervical crypts
for several days after insemination.

'"
Many couples obje<:\ to the close aswcialion be-
1ween sexual inlerCQursc and Ihe fear of pregnancy.
and \0 in\cf\'ais of abslincnC<llhal may coincide wilh
the period of lhc woman's mOS! intense sexual inler-
est. There arc temptations to "take chances,"
Women have also complained \0 fertility program
dir«:\Qrs in some locales lhal Iheir husbands rcfuse
to adhere 10 Ihc schedules. especially ancr drinking
alcohol (I 16E).
It is established in laboratory animals thai when
"overripe" gametes engage in fcrtihalion, large
numbers of abnormal '-ygOl •• arc formed. Although
some oOse ... rs doubt lhal Ihc incidences of birth de-
feelS arc greater in couples practicing lhc rhythm
method, others have presented impressive stalislics
to support tbc belief (I 76E).
Allempts ha<'c Ix:tO made \0 improve lhc rhythm
but there is no good evidence that modified
procedures lower thc failure rales, The "symplO-
thermal method" (STM) aSSumeS that ovulation Can
be prooicted from a progesterone-reiated elevation of
the body temperature, The woman is required to
mcaSure her rectal temperature each morning. to
keep records. and to refrain from intercourse from
Ihe time of onsel of the menses until the end of the
third day after the rise. (Usually, this means that
only around 10 days of Ihc cycle can be considered
"sa k") However, Ihe influences Ihal progesterone
exerts on lemperature·regulating neurons are oot di-
rectly linked with ovarian events , wOmen have
"textbook" pictures of tcmperature changes. and ex·
perts in reproduclive physiology cannot always pre-
dict ovulation times from the dala. The elevations
that do occur are only O.4-O.S · F. The neurons arc
inAuenced by many factors, and responses to mild
infections. psychological stress. or physical exertion
can invoke chanse of far greater magnitude.
The "cervical mucus" variation requires that the
woman examine her secretions each day and refrain
from intercourse during all but the ··dry" I"'riods.
The procedure is even less dependable than the
STM . Many women find the examination distaster ul
and soon abandon it. Others do nOI find large
changes in the mucus or are unable to interpret the
findings. (The subjcctive nature of Ihe interpreta·
tions may account for the higher pregnancy re·
porled by in which the husband in·
volved in the decisions.)
Yet anotber variation involves the uSC of exoge-
nOuS lo RH Or its analogs. It is assumed that if the
peptide is administered when follicles are mature,
thcn loH release and ovulation will OCcur. It there·
fore be<:omes "safe"' to indulge in scxual intercourse
from two to Ihree after the induced ovulation
until weli imo the next cyde (205). The method has
nol been extensivdy tested . It can be amicipated
ANO PREGNANCV
that loRH taken at the wrong times will disruPI Ihe
cycle. so Ihal the timing of Ihe next ovulation will be
totally unpredictable , The peptide may also invoke
discharge of immature oocytes thai can subse·
quently fail to undergo normal meiosis but retain the
ability to unile wilh spermato7.0a.
" Ba rrier" Metho d s
Proponents point QUl Ihat Ihe use of barriers d()Cs nOI
imerrcre with functions of the reproductive syslem
or with social interactions, The condom is the oldest
of the devices used and it can additionally providc
protection against transmission of venereal infec·
tions. The costs of distribution have limited ilS use in
some of the "developing" countries, Failure rales
have been estimatcd at 4%-10%.
Oiaphragms and cervical caps are used in con-
junction with spermicidal agents. When properly fu·
ted and inserted. thc ··,uccess" rate approaches Ihat
of the oral contraceptives. Acccptance rates dcclined
somewhat when the steroids beeame available. How·
ever. Ihe use is rising. since many women are now
concerned about the ··sidc-clTects·· and possible dan·
gers associatoo with oral contraceplives (139).
Foams, jellies, creams. suppositories, and oJther ve-
hicles containi"R spermicidal aRents offer uncertain
protection when used with()Ut the mechanical de-
vices. Human Semen coagulates immediately afler
ejaculation. and ;t thereby traps the spc:rmatozoa-
some in the immediate "icinity of the uterine cervix,
Some Chemicals that immobilize Or kill spc:rmat07.oa
in vitro do not penetrate the coagulum. When liq·
uefaction occurs. spermatozoa totally unaffected by
the surfaCtanlS Can enter the Ulerus. Transiently im-
mobilized spermato7.011 that retain Ihc ability to fcr_
tili,-" can also be transported . In .ivo slud-
ies on monkeys and women are mOre reliable for
screening agents of this kind than commonly per·
formed in vitro Sludies (25 I), bul not all of the prob-
lems have been solved , Sensitive individuals have de-
veloped irritations Or and there is concern
oVer possible systemic toxicity absorption
from Ihe vagina can oc<:ur) (I 76A). Adverse effects
on young animal embryos ha\'e also been described
(60). The methods are unsuitable for women who do
not have accesS to running water.
The active ingredients include nonoxynol·9 (Del·
foam. Onhoforms. Encare). Trilon X·IOO (Ortho-
gynol). Menfegol (Neosampoon). and OC!oxynol·9
(17M).
 A re.:ently introduced contraceptive sponge blocks
thc cervical opening and releases a spermicide, but
it is les. effective than the diaphragm (176A).
Spermicidal agcnts are incorpora ted into COmmer-
cially available douches_ However, they are quite in-
effective when used postco;tally. since some sper-
mat07.ol! gain access to the uterus wilhin a minute or
less after entering the vagina.
Slerll lutlon
The numbor of adults undergoing vasectomy or
tubal ligation increased rapidly until JUSt a few years
ago { I 39. I 76G). It has been estimated that 660.000
vasectomies arc performed annually in the United
States (60). and that 33 million couples in the
United States. United Kingdom. China. and India
use this form of conlraception (1768). In some lo-
cales, this has clearly led to reductions in the num-
bers of abortions and in improved condilions for
mothers.nd existing children. Objections have been
raised by religious groups. and by men who look
upon the result. as a threat to "masculinity."
Interruption of the vasa deferentia Can be aCCOm-
plishcd via the scrotal route in 1()'!5 minutes undcr
local anesthesia (60). Usually. no il l effc<:ts are ex-
perienced after Ihe discomfort during Ihe first two to
three postoperative days is overcome. In the over-
whelming majority of cases, permanenl sterilily is
achie"ed a rew weeks later (after spermatOlOO left
behind in the lTaCt have deteriorated). Alternate
procedures involve inserling valves imo the vasa. but
progress in accomplish ing reversible blockage has
been slow (32). Siliconc plugs that Can be easily in-
sertcd and removed have been lesled in laboratory
animals. and they hold neW promise. Nonsurgical
n,cthoos for accomplishing permanenl vas occlusion
are also being developed (176B). are now
being made to store spermatozoa for men who may
change Iheir minds aboot having children. but
human semen not easily preserved (243). and
there is corIC<'rn over the possibility that frozen.
thawed spumatozoa will form abnormal zygotes.
The incidence of infections and surgical compl i-
cations in men who do 00\ have access to med-
ical facilities is estimated at 1% (176G). There are
thooretieal grounds for concern over secondary ef-
fects on the immune system, but such problems arc
001 prevalent among humans (100.140).
Under normal conditions, the blood-testis barrier
protC<:tS the rest of the body against sperm antigens
that would be recogniw:l as "foreign" if Ihey entered
the bloodstream (71) . following vasectomy, sper-
matozoa trapped within the epididymis and proxi-
mal portions of the vas deferens deteriorate. The an·
ligens can then_ be released to the surrounding fluids
or be taken up by macrophages. Since the passage-
ways for testicular and epididymal Auids arc
blocked. pressure can build up within the testis and
damage Ihe barrier_ Anlibodies 10 spermalowa
been found in the blood of humans, monkeys, and
other mammals after vasectomy. Gencrali7.ed im·
pairment of immune functions has been observed to
increase the severity of atherosclerosis in baboons
and in cynomologous monkeys (3). while immun<)-
logical destruction of Ihe lestis has occurred in
guinea pigs. Some physicians are concerned ovcr
possible immunological anaeks against the intersti-
tial cells of the testi, ( 151). However, some men who
have not undergone sterilization ha.'e circulating
sperm antigens . Morever. long-term Sludies indicate
that vasectomy does not adversely affeel health
(1768).
For anatomical reasons, oviduct ligations are more
complicated and more ha7.ardous. Laparotomies are
best performed SOOn after parturition. New "mini·
laparotomy" and vaginal approaches promise to re·
duce Ihc dangers. but thc st ruclures arc difficult to
visualize (187). fiberoplic hysteroscopcs can in·
crease Ihe safely and compleleness of the procedures
(31). However, it is nOI yel possible to fuUy control
bleeding. injury to neighboring structures. adhe·
sions, and infc<:tions. Electrocautery . freezing, and
thc injection of sclerosing agents a rc used to mini-
mize the bleeding. There has been vel)' limited suc·
cess in the use of microsurgery to revcrse Ihc steril-
ization
The Estrogen-Progestogen "Pili"
It cstima ted that 50 million women use oral con·
a regular basis ( 148.1760). When Ihe
regimens arc followed. thc conception rate ap-
proaches lero. Usua11y one pi11 is taken for each of
20 or 21 consecutive days. Then, either no medica·
tion or a placebo is used for Ihe next 7 to 8 days. and
the cycle is repeated. Fertilization can occur if the
user omits two Or more successive dosages . In most
women. fertility is tota11y restorcd within 2- 3
months after the trealment is terminated.
CHE MISTRY
Only steroids are prescribed. si nce the nal-
urally occurring hormones are dcgra<kd by lhe live r
soon after they are absorbed. The agents are phar-
macological, both in their biological properties and
in the dosages requi red 10 achieve the results. Ethy-
nyl estradiol and mcstranol (Fig. 16-11) arc the
most commonly employed "estrogens." Most of the
"progestogens" (Fig. 16-1 2) have dirC<:t cslrogenic
or androgenic polency or ar<: metabolized to steroids
wilh such aClivities. Megestrol acetate has been
withdrawn because of observations that it promOlCS
development of breast nodules in beagle dogs (28).
Since there are individual differences in responses

"o
I
"..J..--C
o
I When introduced in 1960. it was assumed that the
B. EllYyny! estrad.,. (Progynon. f'Iove.sl<ol)
.1
"oL,
I "
C. MeSiraool
(EII'Iyny!·estradioi methyl ester)
Fill. 18- 11. Comparison 01 Slfuctur. ot ..
. SIr."",, will> . . 01 .ynt ..,,,, •• trog.". \>$..:I in .,...,
c<ln"8C&pli .....
to the various steroids. and there is COntern Over CS-
l!'(Igen toxicity. preparations Ihal vary widely in es-
trogcn:progC!logen ratios are available. Many con·
tain 0.05 mg of ethynyl plus a progestogen
(0.5 mg of norgeslrd in Ovrnl. 1 rng ethynodiol di·
acelale in IXmulcn, and I mg or norethindrone in
Ovicon-50) (148), Lo-Ovral (0.02 rng clhynyl estra-
diol plus 0.3 mg norgestrel) and Loc"';n 1/20 (0.02
rng clhynyl estradiol plus I mg norethindrone) arc
"Iow-.,strogcn" tyP"" Mestranol i. less potent than
cthynyl estradiol. Ovulen contains 0.10 mg along
with I rng of othyrnxliol diacetatc , has a
high total steroid COnlent (0.15 mg mestraool plus
9.g5 mg oorcthynodrel).
It was belicved for a soort timc that Ihe uSC of
eslrogen for 14-16 days fOllowed by an eSlrogen·
progeSlogen combination during the ensuing 5-6
CONCEPTION AND PREGNANCY
days rnore closely mimics Ihc "physiologieal" COn·
dition. However, highe r toxicity and rnore Irouble·
some sidc--clfects arC associaled with Ihe ·'sequen·
tial"' regimens. and the original preparations are no
longer used. '"Triphasic" medications containing rei·
atively low sleroid dosages are now being tested
(176D). The need to maintain artificial menstrual
cycles whose timing mimics the natural ones has
been questioned. and thcre are those who believe
thai extended periods of amenorrhea Can be benefi-
cial (60). Some dosage schedules are designed to
"",CH
bring about endometrial shedding only OnCe every
three months. A drawback is uncertainty concernill$
whethcr pregnancy has occurred.
MECHANISMS OF ACTION
oral contraceptives blocked fOllicular maturation
and ovu lation by inhibiting Ihe secretion of pituitary
gonadotropins. However. the very fact that concep-
lion often occurs when two or more pills are omitted
=CH
indicates thaI follicles can mature and Ihat thc pi-
tuitary g land retains respomivity. The concept that
the agents act moslly on the hypothalamus is consis-
lent with observalions Ihat womcn taking them re--
lease gonadotropins in response to LRH.
Moreover, brain levels of gamma aminobulyric acid
(GA6A) are el evated in laboratory animals given
comparable dosages, and plasma prolactin is usually
high in the animals and also in women using the pills
(2S). GABA is believed to depress gonadotropin reo
lease and to promote secretion of prolactin (which
,,,,.1Iy occurring secondarily impairs gonadOiropin release). !n
women. both FSH and LH are present in Ihe blood
plasma. but thc levels arc low. A major of Ihe
steroids is prevention of Ihc midcyele gOMdotropin
"surge" (43). Therefore. ovulation docs 001 ordinar·
ilyoccnr.
The contraceptives arc also believed 10 interfere
with preparations for implanlation. to affect {he
qualily of the cervical mucus. and to change the pat·
terRS of oviduct contraction. The ones with low stc-
roid contcnt may act mostly in Ihi' way, since they
do not consistently block ovulation. (Failure rates
are higher with these agcnts.)
··SIDE·EFFECTS··
Nausea, vomiting, malaise, breast tenderness and
pain, waler retention. body weight gain, somnolence,
faligue, headache. "ncrvousness:' psychological
depression . and loss or interest in sex are commonly
experienced not on!y by pill users, but also by sub-
Mantial numbers of women going through Ihe early
stages of pl"<'gnancy. A low incidence of chloasma
(irregularly shaped brown patches on the skin) is as-
sociated with both conditioll$. Some women using
low...,strogen preparations have "brea k·through··
blooding.
Although many women have few difficulties Or ex-
perience mild symptoms that disappear when they
continue to ingest the ste roids. othcrs a re distressed
to the point that thcy seek out other forms of COmra·
ception. Reduction in thc estrogen content may al ·
leviatc the breast and gastrointestinal disturbanccs.
while lowering of the progesterone contcnt ortcn re-
lieves the psychological dcpression and loss of libido.
One point of view is that the symptoms are
"harmless" and that measures can be taken to min-
imize the discomfon. (For example. nausea may not
be noticed if the pill is taken at bedtime.) Thel"<' are
those who belicve that the side...,ffects are mostly
psychogenic. It has been suggested thal depression is
mol"<' likely to occur in a woman who would really
like to becomc pregnant but avoids this because of
economic status or the wishes of her husband. Thc
notion is difficult to ree<mcile with the changes seen
when a pl"<'paration of diffel"<'nl composition is sub-
stituted. Few wOmen who hve experienced nausea
during pregnancy Or whilc taking the pill agree with
the idea that "it is all in the mind:'
A "cry differem concept is that the body is receiv-
ing a mes>agc that something is wrong.
TOXICITY
The term "toxicity" i, applied to the effeets that
bring about permanent da mage or thrC3ten health
and even life (254) . Fortunateiy_ the incidence is
low, and the pills can be less dangerous than closely
spaced pregnancies.
The liver has high-alfmity binding sitcs for estro-
gens. and the naturally occu rring hormones alfc<ot
receptor and entyme synthcsis (178).
They regulate the production of corticosteroid bind-
ing globulin, sex 'teroid binding globulin, cerula.
plasmin. renin substrate. some blood coagulation
factors. and other hepatic protein •. In Auences ex_
erted directly on the liver and on prolactin secretion
are implicated in the etiology of SOme kinds of liver
tumors (166).
The synthetic steroids travel directly from the gut
to th e liver via the hepatic portal vesscis. and they
are also present in the hepatic arteries . After com-
bining with l"<'eeptOTS. they can mimic the effocts of
high concentrations of ovarian hormones and addi-
tionally exert androgenic actions. Pill use is believed
to predispose to development of gall bladder disor-
ders and impairment of biliary Aow, along with ele-
vation of biliary cholesterol concentration, (2S,90J.
Small numbers of WOmen develop jaundice because
they canl10l efficiently dispose of hemoglobin degm-
dation products. Values rewrded for bromsulfa.
phthalein (BSP) excretion tests can be Ol.Itside the
normal mnge in women who do not ha", overt
symptoms.
Many women have small clcV3tioll$ of the sy,,"
tcmic blood pressure that are rapidly reversed when
the medication is stopped . In at least some. the ef'
feelS a re lin ked with production of too much I"<'nin
substrate, Or with impaircd formation of a naturally
occurring renin inhibitor (2g). More serious prob-
lems arise when estrogenic innuences on lipid metab-
olism (which include ele"ation of plasma trigly<:er-
ides) oontribute to blood vessel wall injury. Small
numbers of women de,'<:lop irreversible kidney dam-
age and malignant hypertension (28). A few acquire
estrogen-linked venous thrombosis, and emboli can
travel to the coronary and cerebml as well as the pul-
monary vessels. Unfortuna tely. Ihe thrombi can ap-
pear without "·aming. No rclationships to thc dura-
tion of steroid use have been found.
It has becn recogniledthat progestogen!
contribute to the development of myocardial isch-
emia and arterial stroke (30). The incidences of
m)'ocardial infarction and stroke are I"<'latively high
in women over 35 who smoke, and those individuals
should see k other forms of contraception ( 176D) .
Progestogens can also augment salt and water reten,
tion by interacting with mineralocorticoid receptors.
Fasting glucose concentrations are not orten af·
fected, but deterioration of "glucose tolerance" is
common, and diabetes mellitus is a proposed con-
traindication for pill usc. Progestogen! can alfeet
metabo1ilm and insulin secretion, "'hereas
estrogens mOre commonly increase the secretion of
growth hormone and other insulin antagoni'ts.
Estrogens a", mitotic stimulants. Diethylstilbes-
trol (DES) is believed to inerea,e the incidences of
endometrial and canCer if used for extended
time periods by postmeTl<.lpausal women. Children
born to mothers taking DES during pregnancy are
at risk for development of vaginal adenoses. some
rare forms of vaginal and testicular and ep-
ididyma l disorders. Estrogen, are dearly implicated
in some forms of bl"<'ast cancer. and there are con-
ditions unde r whiCh ovariectomy is Thel"<'
are indications that the steroids e.acerbate preexist-
ing breasl disorders. possibly by increasing prolactin
levels. (Estrogens Can impair vitamin B. melabolism
and therefore the synthcsis of dopamine . a physio-
logical suppressant of PR L secrction. High dClSCs of
the vitamin have been used with some success in spe-
cial cases [217J.) Some women with no cvidence of
pree xisting disease develop galatorrllea when they
use the pill.
Despite the preceding observations, many authors
have concluded that oral contracepti,·c usc does 1101
n. CONCEPTION AND PREi3 NA,NCY

,",
, ,",
,
c==o C""O
A A---
"
r "I

o? "
a.HydfoxyprO<,/e$[crl)(le caproate
(Oeialutini

A---,= A--"
r '"
r ,
o? o"
C. Norethin<;lrone D. Norethynodrel
lNorelhiste roM. "",ICIt;")

,C==Q
'",
A 0 k--

"I
,
o? ,, o
T
"
E. Me<lroxypr<>gest"""'" F. Mege5trol ace1al. (M<tgoce )
(Pro"" a)

FIg . 16· 12. Progesterone o<>d Iyn!l>ot;c

increase the incidence of brc:aSl and «,productive
system cancers in young women. and S<;Ime stale thaI
the steroids actually pro' ide protection (176 0) . On
the other hand. very recent work raises the possibi l-
ity that women who take Ihe pills at early ages and
cont inue the practice for many years increase their
risk of developing cancel'$. The p reparations with
high progeslogen content may be more da ngerous
than those with greater estrogcn:progcstogen ratios
(1 42A).
Estrogens are transferred 10 mil k. and nursing in-
fanls have Ixen known to develop reversible gyne-
comastia. Adverse effeets of administering estrogens
to mOthers have been reported for nursing rat pups,
but related studies On have yielded negative
data (156). Some clinici ans believe tht nursing
mothers should use other forms of contraception.
Progestogens alone are effective antifertility agents
at this time (In). Sincc the progestogens do not
enter the mil k in substantial quamities, use of a pro-
gestogen pm has been advocated (155).
Rarer conditions altributed to use of thc pill in·
clude isolated cases of pancreatitis. massh'C colonic
bleeding (whi ch in one instance was corl'(;cted soon
after discontinuing the steroid ingestion). ischemia
of the limbs, and thromboembolic destruction of the
 C<,
,
C"'O
J. - - C C>< k --

CH,cOO // o // //
G_ EthynodOoi diacct.,e
T
(Melfodiol)

>< ><
o o
k -C --' ---

// //
I. J. Norge"'"'
. ( L vnestrflnoi ) (Ov,e""1

><
, o
"'-
,
C<,

o o //
K Dyci<oge<;.eron<>
,
T
C<,
(Ge$ra"OIlI
l . O....tmte rone
(Se<;roo'c,,,,, I

retina (28). Some userS have found il necessary to
change the shpes of their lenses. but ther.
do not s«m to be any widespread deleterious influ-
ences On the eycs. frequencies and inten-
SPECIAL BENEFITS ATIRIBUTED TO PILL USE
sities of migraine headache have been reporled. Al-
though the steroids can bring about enla rgement of
the pituitary gland and tumor growth in rats. related
problems do !lOt S«m 10 be prevalcnt in women.
Small numbers of women have protracted periods
of amenorrhea when they discontinue uSC oflhe pill.
There are good reasons to believe that they ha,..,
medical problems unrelaled to the steroid ingeslioo.
However. use of the contraceptives by very young
teenagers may interfere with maturalion of the hy·
po! ha la mo-hypoph ysi al·gonada I SySle m.
In addition to providing an aesthetically
dependable form of oonlraceplion lhat e n-
joyment of from fear of pregnancy. and possible
protection against the development of some of
malignancy. some women the following
benefits (176D): (a) menslrual bleeding
(which can be associated with anemia) is oorrected;
(b) premenstrual tension and dysmenorrhea may be

'"
alleviated; (e) some protection against pelvic inAam-
malO,), disease is provided; and (d) the incidence of
rheumatoid art hritis is lower in pill users than in
oonlrol pOpulations.
" Mlnl" · Pllls
Proges!Ogen<>niy piUs were developed when it wa,
believed 1hat estrogens caused ITI()S\ of the health
problems. The major actions may be exerted on the
endometrium and uterine cervix. The sieroids "flal-
ten" bUI do not abolish miclcydc elevations of go-
nadotropin levels. Since ovulation sometimes oocurs.
the failure ralcs are substantially higher than the
ones with combination steroids.
ProgeslOgens can be more effective if adminis-
tered in different ways. Dep<)-medroxyproges!crollC
is a microcrystalline suspension thai can be
implanted under the skin for continuous release of
steroid 0"'" three- to six-month periods (141). Good
results ha,'e been described , but th. preparation has
not been approved for C<lntraceptiv( usc in tbe
United Stales. Progestogcns inC<lrporated into vagi-
nal rings and released can also prcvent C<lnception
for three or more months (204).
Nonoral routes assure that the medication will be
C<lntinuously available. and high concentrations do
nOI accumulate in Ihe liver. Some implants proteel
for 5 yea .. (A-7). Irregular bleeding pallerns. un-
toward effeclS On carbohydrale melabolism, rCCur-
rent headaches. weight gain. psycnic depression. loss
of libido. and long periods of amenorrhea wnen use
is discontinued can occur.
Post-coital Contraception and Interception
Very high doo.ages of estrogens can interfere with
fertilization by stimulating the secrelion of oviductal
and uterine nuids and promoting C<lntractions of th.
smooth muscle. They also act as imerceptives
(agents Ihat block development once fertilization has
occurre<l). rn rats. Ihey probably accomplish the sec-
ond effect by invoking premature expulsion of the
young conceptuses. The estrogens arc elTective in
women if they aN: administered before hCG levels
rise. An endometrial site of action is 1TI051 likely
(205). Blastotoxicity is another poo;ibility. The SIC-
roids .licit extremely unpleasant (e.g.
nausea. vomiting. and cramps). they have the poten.
tial for damaging young embryos that are not ex-
pelled. and it is suspected that repeated u<c ad-
versely affects the pituitary gland.
Estrogenic substances that have been used to in·
duce early abortion of pine needles.
subterranean dover. and the Mexican ,,aOp<ltle. All
CONCE:PTiON AND PREGN.o,NCY
(X)Se the dual problem. of systemic toxicity and in·
complete elTeetiven.,.. (205),
Prostag landlna
Since rG s stimulate uterine muscle during all stages
of gestation. it "'a. at one time iIoped that they could
be used routinely 10 accomplish fi .. t-trimester abor-
tion and poo;ibly be developed into agents for self·
medication. However, the other effoct. include
cramping. diarrhea. nausea, vomiting, and cardio-
vascular and respiratory problems. T he naturally 0c-
curring regulators are very rapidly metaboli:w.l and
must be given by C<lminuQUs infusion.
Analogs thai resist rapid degradation and silow
greatcr specificity for the reproductive tract (such as
invoke less pain and inflammation.
However. fetal may not be accomplished
for hours or even days. and evacuation of the pla-
centa is not always oomplete, Unfortunately. anal-
gesics. antiemetiC!. and anticholinergics do OOt COun-
teract the unpleasant sid.xffeets (176F). A reCCnt
approach to the problem shows promise. Single in·
tl"l\museular injections of one PG analog that aCls on
the utcrus. in combination with another that aCts on
the ovary. aN: reported to effectively interrupt very
early pregnancy in monkeys witiloUl invoking ob-
viou, disturbances in other body functions (2478).
Intrauterine Devices (IUDs)
legend has it that the earliest IUDs WCN: pebbles
inserted into the utcri of camels by Arabs and Turk!;
preparing for caravan trips , The objeels used today
vary widely in size, shape. and texture. They do not
block passage of spermatozoa. but a single insenion
can provide contraception for months or yea .., The
method is widely accepted in the People's Rcpublic
of China. in Korea. and in many Western countries.
Fifty 10 sixty million IUDs were reported to be in uSC
in 1979 (176Cj,
Unfortunately . theN: arc numerous drawback!;
(136). Many WOmen experience recurring or persis-
tent pain and uterine cramps afte r insertion. Men·
strual bleeding can be excessive. and the incidence
of pelvic inflammatory disease i. high. Cervical per-
foralions Can lead to hemorrhage and nccrOliis. and
uterine perforations have been followed by the for-
mation of adhesions and bowel oceulusions. The
chances of ovarian pregnancy appenr to be in·
creased. Several observers ha,'e reported high inci·
dences of tubal pregnancies. but it has been pointed
oul that some may be linked with olher factors
(I90), Unnoticed expulsions are said 10 account for
up 10 5 pregnancies per 100 wOmen per year. Uterine
pregnancies are infrequenl when Ihe device is re-
lained, However, when Ihey do occur, midlrimesler
septic abortion (XIS •• a danger even afler Ihe device
is removed.
The IUDs are believed to invoke sterile inAam-
malOry and consequent generalion of pros·
laglandins Ihat interfere with implantation. Thc PGs
also act on SmOOlb to promote expulsion of
oocyte,. rygotes. and young embryos. Report, thaI
beG levels frequcnlly rise transienlly are con.istent
wilh Ihe suggestion Ihal IUDs addilionally bring
about delerioralion of blastocysts just prior 10 or
vcry SOOn arter the initial slages of implanlalion
(195). Chronic use of salicylates. indomelhaein, Of
agems can decrease Ihe
PGs. histamine, and bep-
arin released from mast cells lbat accumulate. sub-
stances released by plalelel', and Olher small mole-
cules have been implicatcd as elevalors of menstrutal
blood volumes, Fibrioolysin aClivily is also elevaled
(19{I).
Recent advances includc the development of IUDs
wilh improvt:d shapes. better insertion procedures.
add ilion of Slrings Ihat eXlend inlO Ih. vaginal cavily
and indica le 10 Ihe user Ihal Ihe device is in place,
and incorporalion of progeSlogens. copper or zinc for
,low releaSt. The progestogens probably arreel
mostly glandular secrelions bul Ihcy may also
dampen myometrial contractions and Ihercby lessen
discomfort and Ihe probabilily of eApulsion. The
metals were inilially believoo 10 Ihcir primary
inAuen<:es on spermalozoa and on ulerine enzymes
involved in pr<:gnancy mainlenancc (229). Recent
studies indicate thaI copper inhibils PG degradalion
(119A). In experimenlal animals. il has been ob-
served 10 bring aboul blastocoel collapSe by
ing the tighl june lions belween n<:igbboring lrophec·
todermal cells (239). It is baclerioslatic in vitro. and
it may protecl against infection. Very high concen·
lralions inhibil OVulalion. bUI nol enough is released
from IUDs 10 acl in Ihis way.
Zinc is a weak inhibilor of enzymes Ihal degradc
PCs (119A). 11 can also reduce Ihc fertiliution rale
by inlerfering wilh Ibe acrosome reaclion (25 1).
Both metals may antagoni,.e PC stimulalion of uter·
inc muscle (239). Corrosion and breakage arc prob-
lems that a re said 10 be OverCOme wilh Ihe use of
silver COreS.
Newer Chemlcel Approaches
Ideally. we should have a conlracepli,.. that specifi·
cally affeclS one aspeCI of Ihe reproduclive process
wilhout disrupling Ihe endocrine sySlem, impairing
sexual performance Or enjoymenl. or incurring lOX·
icity. Agents curre ntly under investigalion include
an oocyle maturalion inhibitor (OMI) and an inhib-
ilOr of LH binding 10 corpus luteum (41) ,
Substances Ihal alter Ihc properties of Ihe oolemma
and Ihereby inlerfcre wilh sperm penetralion are
beingsoughl (204), but il will be necessary 10 assure
thaI Ihey do nol increase Ihe chances of polyspermy.
Use of fol\iculoslatin (inhibin) during Ihe follicu lar
phase has been considered. but a problem is thaI it
may dc1ay (ralher th an block) oocytc maturalion.
Something lhat increases the luleini7.alion inhibi-
tor:luteinization stimulant ratio may also be effro-
live (202) .
GnRH antagonists arc polenl of r<:pro-
duclive fUn<:lions. They cannot be given on a
regular basis. since they acl on Ihe gonads as well as
on the piluilary gland , [Among Olher Ihings, Ihey af-
fecI phosphalidylinositol melabolism in granulosa
cells (55A).] Early \rials in humans suggcsled Ihal
Ihe agents are 100 powerful for use as contraceptives
becausc they in"okc serious "side erreets" Ihal in-
clude inhibition of sleroidogenesis (77) and loss of
libido. Howe"er. since lhey arC rapidly degraded. Ihe
peptides may al some future time prove 10 be safer
Ihan Ihc synlhetic steroids. Allempls ar<: being made
10 give low dosages during Ihe follicular phase Ihal
do nol block OVulalion bUI lead 10 Ihe formalion of a
defeclive corpus luteum Ihal canOOI support implan-
lation (16A) , Aoolher (XISsibilily is Ihc administra-
lion of small quantities soon after conceplion for the
purpose of inhibiling hCG secrelion. since LRH ag-
onists can terminale pregnancy in rodents (16).
Several naturally occurring and inhibi-
10rs of spcrm enlyme, are under in,,,sligalion (70),
and some promise 10 provide proteelion against con·
ceplion withoul invoking unu<xcplablc 10Aicily
(251) . .'.1 0<1 are being considered for inlravaginal
presentalion, but a rew may be suilable for syslemic
administralion and for use hy males as well as fe_
maics. Some arreel sperm molilily and energy me·
tabolism , Hyaluronidase inlerfere with
sperm passage Ihrough Ihe cumulus layer. while.e-
rosin inhibilors are believed 10 acl al sevt:ral siles.
Some of Ihc planl derivalive< that have been used for
many ycars contain vinhlastine or vincristine . A rew
bring aboul irreversible 'Ierilily by exerting loxic ef·
fccls on Ihe gonads.
Reproductive phys iologists have been accused of
concenlrating Iheir errorlS on developing agcnts for
use by Ihe female because Ihey prefer 10 delegale Ihc
respon$ibiHtic.' 10 women, 10 leI Ihe women worry
abou llhe loxicilies, and 10 permil men 10 "relain full
masculinity.·' I,owever, Ihere are more logical rca_
son. for Ihe approach. It i, much easier 10 disruPI
Ihe delieale bormonal balance, r<:quired 10 support
Ihe formalion and funclions of a single oocyle than
10 interfere with thc production of billions of sper-
malOZoa while maintaining overall hormonal bal-
ances in Ihe male. Perhaps Ihis accounts for Ihe

greater diffICulty encountered by investigators at·
templing 10 obtain funding for ro&earch on the male.
One hormonal approach to fertility control in the
male is based on the koowledge that spermatogene·
sis and epididymal maturation rc<juire ooncentra·
tions of androgens higher than thooe in systemic
blood. Administration of synthetic androgens (alone
or in combination with progestogens) can maintain
oormal metabolic functions while suppre."ing lH
release and therefore testicular synthesis of the hor-
mones. Reversible infertility has been achieved after
several weels in humans. but SOme individuals are
evidently resistant to the treatment (53 ). The side-
effects ellOOUmered have ocen lin ked with influences
exerted by the sleroids on the liver. In studies thus
far C<lnducted with lRH agonists and antagonists.
the dosages fe<luired to arrest spermatogenesis in-
voke unacceptable suppression of testosterone pro-
duction and loss of libido. ($ce rI). p. 741.)
Ejaculated spermatoroa derive their energy from
glyC<llysis. Oral administration of enzyme inhibitors
has achieV<'d infertility without significant systemic
toxicity in ratS. Agcnts that compete with glucose: for
hexokinase arC effective when tes(ed against bovine
spermat01.Oa in vitro. No applications have as )'et
been made in humans (59) .
c,n,,.y pnl i<" rom""nent "f partially purifIed cot_
tonseed oils that have lx:<:n ingested by individuals
living in some parts of the Pcoplc's Republic of
China. Observations of the occurronces of amcnhor-
rhea and of male infertility in those regions led to
inve-tigation of po<sible uses of the compound for
contraception. Gossypol is also a component of the
root bark of some collon plants that have been used
in other parts of the world to induce abortion (253).
,eo " " anlibody 10 the antigen. Immunological stimulants
"0
° 1
:?
"-
"' CH, CH,
/ gens are shed during capacitation (140) or because
ce, ce, ce, ce,
GO$$ypol
It is a highly potent inhibitor of an iso1.yme of lac-
tate dehydrogenase that is found exelusively in testes
and spermatoZCI3. In primates. it se<:ms to act mostly
by damaging spermatoroa before they cnter the epi-
didymis. but it has variable elfects on gonadotropin
levels in other mammals (70) . The infertility is
CONCEPTION AND PRIO(lNAt/Cy
largely or totally rcV<'rsible (135 ). According to
some observers. its effectiveness approaches I()()')I,.
and there i. no indication that it increases the inci-
dences of birth defccts in children of former users.
The side-effects are disturbing in some individu-
als. They can include fatigue. gastrointestinal prob-
lems (especially diarrhea). skin rashes. somnolence.
hair diseoloration. defects that impair use
of dietary nutricnts. and circulatory di<orders that
may be aswciatcd with hypokalemia.
Chloroquine is used 10 troat malaria. SQme amebal
infections. and lupus erythematosus. It suppresses
spermatogenesis. but it is tOO toxic for regular use.
Antimitotic agents given to patients with neoplasms
similarly oombine unacceptable toxicity with
suppression of spermatogenesis.
,
C'o) H
HN - C -(CH,), - N _{C,,.,,»
,
ce,
ImmunOlogic al App rOaCl'tea
Certain practical problems must be solved before Ihe
high specificities of immunolOgical reactions can be
used to achieve safe and effective oonlrnceplion
(140). Most of the molecul.. against which it would
be desirable to obtain antibodies arc poor antigens.
Some aro chemically similar to physiological rogu-
lators that must be preserved. and cross-reactivity is
fre<[uently encountered. 11 is often difficult to get the
(and depressants) must be used with caution to avoid
interferonce with normal defense mechanisms and
the mounting of autoimmune attacks against
hcalthy cells.
Antibodies raised against seminal plasma compo-
0"
nentS can promote sperm agglutination. However.
some fail to bring about infertility because the anti_
the elfeets of the antibodies 3re antagoni1.ed by uter_
ine cervica l gland se<:retions. Ones directed against
enzymes of the inner membrane of the acrosome
may fail to gain access to the binding sites, There arc
concerns that agents capable of attacking testicular
spermatozoa will disrupt Sertoli cell j unctions and
bring about nonspecific damage to the immune sys-
tem or permanen t destruction of the gamete-produc-
ing machinery.
On the other hand . immune affecting
the spenn plasma membrane: componenlS may be ef-
feclive, and it i$ suspecled that naturally occurring
ones accounl for !KIme forms of hun'an sterility .
Spermatowa can also be recruited to carry sub-
.tance. that arc cytotoxic to oocytes.
Some animal studies indicate that development of
safe. effe<:tive immunological methods for contracep-
lion i. feasible. Anlibodies dire<:ted against LDH-
C •• a sperm-specinc lactale dehydrogenase iso1.yme
Ihat nrst appears in mid-pachytene spermatoC}'tes.
can inV<lke infertility by impairing energy mctabol-
oism and Iherefore sperm mobility. and by mcd ial-
ing both sperm agglutination and oomplcmcnt-de-
pendant cYloxicity. Female animals immunized
syslemically and then re<:<:iving intrauterine or in-
tr.toviductal anligcn build up anlibody lilers in Iheir
reproductive tracl nuids (86A) .
Thcoretically, anti -hCG antibodies should be usc-
ful, since Ihey acl on a hormone present during preg-
nancy. Some suCcess has been achie ..d in prepara-
lion of proteins Ihal bind 10 the C_lerminal 3mino
acid sequence which is not present in LH . When ad-
ministered in combination wilh adjuvants thaI in-
crease antibody produclion. they ha .. invokcd Iran-
sienl infertililY in monkeys (126) . It has been
pointed out . however. thaI damage 10 hCG-produc·
ing lrophoblastic tissue may lead seoondarily to the
release of substances thaI can iniliale immune-com-
plex di<eaies (35). p",btem< may "'" onC<Kln_
lered wilh antibodies directed against placental lac-
logens (which bave also proven \0 be efl"e<:li .. in
mon keyS) (205). It i. not yel known whether an ef-
fecti .. vaccine witt cau.e permanent damagc if it is
repea!C,dly injected. Monoclonal antibodies dire<:ted
against progesterone hn .. recently been demon-
straled to block the establiShment of pregnanc)' in
miee (247C).
MATERNAL ADJUSTMENTS DURING THE
POSTPARTUM PERIOD
Plasma ooncentrations of hPL. estrogens. progesler-
one. and certain "pregnancY-5pecif!c" prOleins fall
soon after separation of Ihe placenla. hCG and Olher
substances with long balf.lives may stitt be detecta-
ble al the end of Ihe seoond week (233).
The pitnitary gland is transienlly insensili,.. to
LRH, and LRH secretion is minimal. This probably
aewunts for Ihe postpartum infertilily Ihal persists
for around seven weeks in most (but 001 all) "'Omen
who do not breast_feed. Prolactin ooneentrations are
high for IWO weeks poslpartum. They undcrgo fur-
Iher substantial elevation in nursing molhers. and
the oonccntrations are mainlained well above the
prepregnancy le"els for up to Ihree months.
Cortioosleroid binding globulin (CBG) is high
during pregnancy. The production rate declines after
parturition. bUI individuals show widely varying free
glucoconiooid concentrations (83) . In mOSI cases, a
subslantial bUI transient devation is found. Accom_
modations must be made to deelines in SSBG and
associaled testosterone. and to changes in DHEAS
melabolism. Some WOmen seem 10 make large quan-
tities of Ihyroid hormones during pregnancy (ij4).
and all show a fall in plasma TBG . Parathyroid hor-
mone levels also falL The ovaries usually do not PUI
OUI much estrogen at firsl. but progesterone may be
secreled during Ihc first week.
POSTPARTU M DEPRESSION
Psychological depression is so common during the
firsl rew weeks thaI !KImc regard i\ as "normal" if
Ihe condilion i< mild and transient . It seems to be
more pronounced in women who report Ihat Ihey felt
especially well during the pregnancy. Most caseS arc
self-limiting. and olhers respond to various forms of
treatment. A few progress 10 "postpartum psy-
chosis:' There are conlro'.. rsies concerning whether
this happens only in women wilh pre..,xiSling !'Sy.
chological illne...
Proponents of the belief that Ihe depression is
"psyChogenic" point out that nighltime feedings and
other aspects of infam care impose fatigue. that
many women are adversely affected by being oon-
fined \0 the home and dep,ived of adull companion-
ship or pleasurable aClivities. and that a few reacl
Slrongly to the shifl of allcntion from them to the
infant.
However. the depression is also experienced by
WOmen who soon rClurn to work thaI they enjoy, and
by ones who can afford to relegatc household chores
to servants. 11 i5 wen recognized lhal changes in Ihc
of glucocorticoids. gonadal steroids, parathy-
roid, and thyroid hormones can all affect mood and
the "sense of well-beins.··
LACTATION
Laclation may ...... 11 be the most complex of all en-
doerine funclions. Several hormone oombinalion.
act sequentially to prepare Ihe mammary glands,
and different ones are required to maintain milk se-
crelion. Each of the regulalors aCIS at more Ihan onc
site.
Human mammary glands undergo con,iderablc
grOWlh and during fetal life in both
males and females. They regress during the first rew
weeks after birth and Ihen remain relatively quies-
cent until the lime of puberty. No further deYelop-
ment is =n in IlOrmal males. bUI in females a Slep-
wise maturation process oontinucs For several ycars.
The final anatomical p1'Cparations for lactation a1'C
made during pregnancy. and Irue milk fim appears

A. Portion 01 ma ..... a'Y
rOdge-7 WOOk$
C. LacidOfOUS ducts
1<:><ming-7 ...,."hs
Fig . 1ij-13. St'gM" _&Iopmenl 01 tho "..".....ry
glIJnds. A. F'o<1ion oj m. ....... r)' ,k;Ige_7 _
arod f>fIoginning
2-4 days aflcr parlurWon. In women who breast-
reed their infants. milk prod uction increases over lhe
6 montlts. It can b<' maintained 31 somewhat
lower Tales for many Y".rs if nursing continues. In
WOmen who do not breast-feed. and when lactalion
is terminated in the OIhers, Ihe glands rapidly revert
to the nonprcgnancy adult condition. Further rcgr<:s-
sion follows cessation of the ovarian cyclcs.
The term mamrnogenesis designates the differen-
1ialion, growth, and maturation of the mammary
glands. is Ihe production of milk. while
go/aropoeisis is lhe maintenance of lactation that
has become established. Milk rj« lion (rekase from
Ihe storagc sites within the glands) is a separate pro-
cess that dcpends on thc functions of wntractilc
components. GalactotThea is inappropriate secretion
of a milk-like substanox that can occur in both males
and females suffering certain hormone imbalanoxs.
Mammogen esls
The mammary glands arc derived from the epider-
mis and underlying eonnectiV<' tissues of the skin .
Differentiation begins with the formation of bilateral
epidermal bands just below the ventral skin surfaces
(Fig. 16-13A). In human embryos seven weeks old,
the band s (mammary rjdges) extend from the armpit
CONCEPTION AND PAl;:GN.o.N(;Y
..
. L""",n 01
,
O. L.oc1dorous """'. conr>ect
alveOli nippl&--po$tnatal
• . C. Lacti!<trous <luCls for .. ,ing 7 months . O.
so B . Bud lactil..,.ous cluel. e<>nn«:1 a Weoli nippla POSllllllal.
to the inguinal regions. Usually, all but small pec-
toral portions soon degenerate and disappear (12S).
The component On each side that persists sends a
single bud downward into Ihe underlying mesen-
chyme. but the superficial attachment is retained .
The bud grows until it assumes a globular form by
the end of the sewnd month. Development is then
arrested for several weeb.
During the fifth fctal month, each bud elongates
to form a solid cord of epithelium . The cord then
branches and gives rise to some 15-20 "sproots."
The sprouts cnlargc. penetrate more dC<'ply into
what has !lOw become skin dermis, acquire lumina,
and become the lactiferous duelS that will lalOr
transport milk if lactation is established. Mcan",·hile.
an visible pit gradually becomes
diseernible, and it marb the site for future forma-
tion of the nipple (Fig. 16-138 and C). Many lacti-
ferous ducts unite into galaerophores that to
thc s urface in the region of the pit.
When dense and adipose tissues grow
around each of the lactiferous ducls. the breast is di-
vided into 1000.r. The lower ends of the duets undergo
"arborization'" and give rise \0 secondary buds. The
laller become separated from each other by a highly
cellular connective tissue. and Ihere is subdivision
into lobults.
 The tips of the secondary buds grow and evaginate
10 bc<:ome rudimentary a/vroli (the future sites of
milk synthesis). There arc controv..rsies eonc..rning
the extent to which alveolarimtion progresses (23).
Late in fetal life. dermal papillae carrying blood
vessels and nerves invade the region of the epithelial
pit. The connective tiS5ye proliferates until it pro-
trudes above the surfa'X' . Pigmented epitltclium Ihen
covers the surface and forms the nipple. A secondary
pigmented region, the surrounds the central
parI. Just beneath it. each galactophore develops a
dilation (fart'luous $iI/us) as it passes toward the
cenler (Fig. !6-13D). Small glands of Montgcme'Y
(intermediate in structure belwct:n swcat and mam-
mary glands) grow into the pigmentcd arcolar re-
gion. and true swtat and se\la'X'ous glands develop
around the periphery.
Myoepilhelia/ cells differentiate from subcuta-
neous epithelial components that arc adjacent to
connective tissue. These contractile elements can be
distinguished by their fusiform s hape. small irregu-
lar nuclei, and cytoplasmic fibrils. They form basket-
like n.twor'" around the lobules.
The fetal mammary glands can differentiate to
the point where they elaboratc small quantities of se·
cretory and release a fcw drops of "witch's
milk" &oon aftcr birth. They thcn regress. In mal es.
the nipples are retained but moot of thc underlying
.m.l"I:(M''<
!Xvelopmenta! defects during fetal life occasion·
any permit development of supernumerary nipples
(polythelia. hypenheciism). excessive Or inadequate
growth of one of the glands. or. more rardy. poly·
mastia (growth of more Ihan IWO breasts). Nipplc
inversion ean begin prenatally or result from pres-
sure exerted later by tumors. Gynecomastia and
other bilateral disorders are usuall y linked with cn-
docrine imbalances.
MAMMOGENESIS IN OTHER SPECIES
Diffcn:n<e$ are encountered in the locati"", Qf the mam·
mary ridge •. the region. lhat undergo diffen:nliation. lhe
numbers. si,e<. and posilions <>f the adult gland •. and the
specioli''''ti''''' of lhe moot" (SO,S7). Tho ... oro stra;n ••
well ". 'peeie, difference, in lhe 'e<pen... ,,> Ioorm<)llCS
(23 1). GcoeraUy. est"'"' C)"cles aTe a."",i.led with
_ery limiled alveolarization. but further maluration oc·
ours if pseudopregnancy i, invo. od.
A linglt pair or m.mmary gland< form< in monkey$.
wholes. horses. goat •. ,heep. guinea pig •. and many oth..
'peeie<. Tlte struct."" are peetonlly located in thc _n·
key and elepbant. obd"",i",,1 in lho wh ale. and closer to
the inguinal region in the 00 ...... moot dQT$3 Uy 10-
eated gland' are round in tOe
Species th.l produce large litters usually have several
pairs of glands located on the ventral ,u,faoe,. but ox, en·
,ions to the b.d, of the .... seen ;n SOme of lhe
rodent •. Rus and mice have 3 pairs. and lhe parenchy.
maltiuue <)Coupies of the region below tho ventral
surface <>f the 'kin <>fthe Rabbits h.v.. 4 or S pa;rs,
cow, oan have .. many a. 9. Odd numbers arise in
marsup;.ls through fU$ions. The <>pOI$um has I] (12
ronged in a circle. with 1 in lhe cenler).
In goats and $h«p. the connective ti,",u, "'l!ani,e' an
that h""",,, 'ingle p.ir of d osely op"""ed gland$.
where .. ;n 00.... t"'·o pairs are incorponted. Udders store
quont;tics of milk and deli""r i, through teat.
differ in .truetu,e from primale nipple,. Olher '3rialion.
in nipple arc found among the mammalian spe-
ci... 1\ poueh prOtecl, teat< in $OIl\O ¢f loc marsupial,.
Monotreme, have milk.seeret;ng muclu"" devoid of nip-
ples that clO$e\y re$<mbk 'wea' gland,.
Regulation of Prenat al Mammogenea la
By thc t;me they can be identified and for
slndy. the anlage have already been eXpOSed to very
large numbers of hormones. and they have had time
to accumulate them. It is therefore difficult to deter·
mine the importance of specific regulators . Mesen-
chyme seems to be the primary sitc for reception of
early stimuli. and it plays essential roles in directing
the epithelial cell differentiation (52A). Combina-
tions of mesenchyme and epithelium taken from the
mammary regions of the cmbyro undergo mammary
.lifferentiation when cultured in
media. and when mmsplantcd under renal capsules
in micc (193A.231). Renal mesenchyme does not
support mammary epithelium dcvelopment. Salivary
mesenchyme stimulates growth but promotes Ihe
formalion of structureS that resemble salivary
gland •.
Although eJrly differentiation in females probably
docs not require stimulation by hormones formed
elsewhere in the body. rodcnt mammary and salivary
glonds androgcn-scnsitive during a critical
period known to begin around 13 days postcon'X'l'"
tion ;n micc. The mesenchyme evidently receive. the
testooterone signal (S2A). Postnatal maturation is
bormone-dependent. and the stroma (which devloops
from mesenchyme) plays essential roles. On the
other hand. cells transfer gl}'cosaminog-
Iycans and other moleculcs to the mesenchyme. and
these direct both morphologicial organiUltion and
acquisition of the charactcristie biochemical fca·
lUres. The salivary-Iype glands that form when sal-
ivary mc,cnchyme is cultured with mammary epi.
thelium retain the ability \0 make milk proteins
when the appropriate hormone combinations are
presented (231) .
dimorphism is seen in rodent, but not in
primate fetuses. In mice. teSlosterone delivered by
the fetal testes invokes regression. The connections

belween Ihe lactiferous duct pre<:ursors and the body
surfaces are 10:';\, no nipples form, and the subeuta-
neous tissue undergoes atrophy. Similar. but less ex-
tensive androgen-invoked changes are seen in nor-
mal XY rat fetuses (50.231). If the testes are
destroyed b}' X-irradiati011 before they have relea$Cd
substantial quantities of testosterone, males develop
female-type mammary glands. XX fetuses can re-
spond to exogenous androgens. but ovarie<:tOOly doos
not impair dilferentiation.
Postnatal Msturatlon
After the ovarian cycles arc established. the duct<
grow and acquire more branchcs. Ihe nipple and al-
veolar regions undergo some developmenl, and Iherc
is limiled alveolari1.ation. Adipose tissue accumu-
lates in all species, but it is Ibe most pronounc.::d for
humans. The breaSls are stimulated during Ihe laIc
follicular and early luteal phases. and Ihey show lim-
ited regression around the time of the menses, If con-
ception does nol occur sooner. maximal specializa-
lion is altained by the 20th year.
During pregnancy, most of Ihe connective tissue is
replaced by se<:retory epithelium. The limited e!l-
iargemenl of the breaSIll does IIOt fully refleellh e ex-
terudve 31veolari .... tion. A. term appl'Mehe •• • mall
quanlities of a watery tluid (colostrum) may be ex-
pressed, and much larger amounlll arc secreted soon
after parturilion, The breasts become engorged with
Irue milk 3-4 days later. even in mothers who do not
nurse their infant •.
An (}ld conCept that estrogens promote duct
growth and induction of progesterone receptors. that
acts on the eSlrogen-primed gland to
stimulale al.eolarizalion. and that prolactin can
then invoke milk 'ynthesis has the advantage of sim.
plicity. However. it is now that mam-
mogenesi. and lactogenesis have more complex r..
quircmenlS that vary widtly with the species.
Most of Ibe increases in size and weigbl of the er>-
ithelial componenls are accomplished via cell prolif-
eration (236). A relatively undifferentiated popula-
lion engages in the mitosis, and thcre are only
certain stages of the cell9'cle during which spox;ifie
changes in gene aetivitie. can be influenced by ex-
lernal regulators. T he more ,pox;ialized alveolar c.::lls
do not divide. Some as yet undefined "growth fac-
tor" is evidenlly needed to support the recurring
waves of DNA synthesis and mitosis. A heat-labile
protein of low mole<:ular weight present in serum is
implicated in SUpp<:>rl of processes when explants
arc grown in culture (236). Cells maintained in
serum_free "defined media" show somewhat dilfer-
CONCEPTION AND PREGNANCY
ent responses to the presentation of several
hormones.
Insulin elicits a single wave (}f cell division, eVen
when it is continuously present. DNA synlhesis in_
creases. peaks at around 24 hours. and then tmally
subsides by 96 hours Since supra physiological can-
cent rations arc needed. it is likely that the insulin
interacts with receptors for some other regulator. In-
growth factors (IGFs) and multiplication
stimulating activity (MSA) are among the pcptides
that can exert such activity (111) . The regulators
are present in blQOd and they are known to affecl
other aspects of fetal growth.
The mammary glands of virgin adu lt mice bind
insulin with high affmily, but they are resistant to illl
actions, They acquire sensitivity during normal
pregnancy. even when no hc:>rmone is presented.
(Mammary glands of diabetic mice and rabbits
underg(} dUel growlh when ovarian hormones are
given [231].) When lactalion is established. insulin
alfects carbohydrate metabolism .
Growth hormone accelerates progression from the
G, 10 the S phase of Ihe cell Onee this is ac-
complished. fo\l(}ws. The hormone is re-
quired 10 supp<:>rt duct growth in many species. Post·
natally. it may act mostly indireclly by stimulating
hepatic pr-oduetion of .om.. tomedin •. Although in_
ftuenees of grOwth hormone on several fetal
systems have been demonstrated (86). anencephalic
fetuses Can make substantial quantities of somato-
medins wilhout il. Insulin. prolactin, and pla""ntal
lactogens may be the major prenatal stimulants
(85).
In common with insulin. GH elkiujust a
wave of mitosis when it is presented in .itro (236).
It seems 10 be required for normal matU!'l\tion in pu-
bescent females (I 9JA). Prolactin exerts similar in-
fluences, but usually oot ellOUgh is seereled at that
time.
Epidermal growlh jaclor is a polent. insulin-like
mitotic stimulant Ihat is elfe<:tive when presentcd in
physiological concentrations (8 X 10- '0 M). Thus
far. it has been found in the plasma of only cerlain
species (e,g. mice. ralS, and rabbit.) (236), and in
these it can influences On cell. that do IIOt r..
spond to insu lin (231).
Prolactin concentrations rise somewhat during the
late follicular phases. and one function at such limes
may be induction of estrogen re<:eptors (197). It is
doubtful Ihal prolactin can acl alone to promote cell
proliferation d uring !l(}nfertile cycles (235), but it
probably makes contributions during pregnancy.
Estrogens secreted during the ovarian cycles seem
to be uniyersal stimulants of duet developmenl. Ex-
 ogC1l<lUS steroid attelerates cell proliferation in ovar-
ie<:tomi>.c:d females and also in males. Ahhough
mammary glands ha"e estrogen receptors. the ste-
roids are ineffe<:tivc in hypophysectomil.c:d anima ls
and in tiSllue culture studies in which no peptidc reg-
ul ators 3'" added. The functions in pubeseent ani-
mals probably include inAuen""s exerted on TSH.
PRL, and GH secretion and on induction of mam_
mary gland PRL re<:epton (231). The actions are
dose dependent and they can be triphasic. Prepuber_
tal plasma oonccntrations are around 4 X 10- " M.
and such levels inhibit cell proliferation in vitro.
Mid· to latc follicular phse levels (4 X 10- 1• M)
stimulate (236). Pharmaco logical doses inhibit.
Althoogh inAuen""s on ",,11 proliferation may be
"permiSlli""."thcy are physiologically important. In
hypoph)·sectomi1ed<lvarie<:tomi1.d animals of most
species. an estrogen·growth hormone combinatk>n is
required to stimulate growth. Estrogens act on the
neW cells to bring about tubuloalvoolar differentia·
tion. Progesteronc probably contributes under phys-
iological oonditions. but some differentiation can be
achieved with eSlrogen alone.
Glu(O(OI"/i(Qids act on newly formed cells to pro-
mote differentiation that includes claboralk>n of the
endoplasmic reticulum (IS7A ). Thcy induce re<:ep-
tors for other hormones and modify the actions of
other regulators. However. they arc rI\II mitotic stirn.
ulMU Some ductal growth be in
naleetornized animals. but full development requires
the glucocorticoids (231). Thp·Qjd h()l"mones are es-
sential for alveolar growth in somc species. and they
can also enhance the effccts of PRL. They scern to
be: absolutely rcq uired in dwarf mice. but they may
exert mostly actions in other animal •.
While adipost lissue is anolhu universal require-
menl. (Brown adipose tissue cannot substitute for
il.) In nonpregnant females. the epilhelium evidently
produce.sub'tances that restrict invasion of the adi.
pose tissue by mammary gland parenchyma. The
oonstraints are lifted during pregnancy.
ProgmerOfl(! is clearly needed by most species,
but littie is known of its mechanisms of actk>n . Its
effe<:ts arc enhanced by glucocortiooids. insulin. and
PRL. Only limited al""olari14tion occurs in non-
pregnant animals with short IUleal phases. Thc Ihy-
muS gland is not needed for duct growth. but Ihy_
me<:tomy is reponed to impair alveolar development
in mice (231).
Most mammals make plalYnlallactogf"lu during
pregnancy. Hormones of this kind have bc:cn identi·
fied in humans. monkeys. OOWS. shccp. goat,. rats,
mice. guinea and ham$ters, but not in rabbits.
dOg:!, Or pigs (197). Although they can stimulate
mammary sland growth, they are probably not
needed for thi, purpose in humans and others that
have high prolactin levds. The major effects may be
exerted on maternal glucose. lipid and protein me-
tabolism. on calcium metabolism. and On erythro-
poiesis (167). Since they can compete with PRL for
rc""ptors but are less potent than the pituitary hor·
manes. placental lactogens may aetually limi/ ac-
quisition of mil k_producing function and contribulc
to oolO$trum production, as they permit the mam·
mary gland to fully prepare for lactation. Milk pro-
ductk>n can then proceed postpanum when the
plasma hPL falls (2)3).
Lactogenesis
Wnen suitably prepared and then stimulated by
PRI.. the alveolar cells undergo regularly recurrins
changes in structure and function ( I 57,15S) . Durins
the '"active" phases of the cycles, the cells assume
oolumnar snapes with microvilli projecting into the
lumina. They have wc1l-developed Golgi regions and
endoplasmic reticula. mitochondria. and lipid drop-
lets. As Ihcy begin to release their products to the
lumen. that cavity dislends. The cclls change succes-
sively \0 cuboidal. flallened. and finally squamous
forms. and the luminal surfaces become smooth. As
soon as Ihc secretion. travel from the alveolar lu·
mina to the ductules the "quiescent" cells resume
elonsation.
COLOSTRU M
The first se<:relory prooucI is a yellowish, translucent
Auid rich in rome milk proteins, salts, immunoglob-
ulins. prolactin and other hQrmones. and substan""s
that stimulate the sastrointestinaltr3cts of the nur·
sling> (186). It oontains Band T lymphocytes.
mononuclear macrophages. and polymorphonuclear
neutrophils. T ne lipid content is low. and there is no
lactose. Small quantities of ool(l'ltrum arc often re·
during parturition. and mueh larger Ones du,,"
ing tnc first 1-2 da)'s postpartum.
MI LK COMPOSITION
True milk oontains caseins. lactalbumins, several
other proteins, lipids, lactose. hormones. and se veral
kinds of cells. The rolati"" quantities of the oompo-
nenlli change during the OOU!""!le of the day (112). In
women. the fat OOnlent rises between 6 and 10 A.M.
and falls during tne nighl. The milk first taken by
the infant is low in fal. The higher lipid conccntra·
tion of '"hind·milk"' is believed to oontributc 10 sa-
tiety. The frcquencyand inlensity of stimu lation by
the infant conlroltbe rales of production of some of
the constituents. The mother's diet affects the vol·
ume, protein , susar, and lotal fat content. but PRL

'"
induction of medium-chain acylthioester hydrolase
probably accounts for the predominance of fally
acids with 8- and l()..caroon chains (231). Extra-
neous factors. including psychological WC$S, also in_
nuence volume and composition.
Wdl-nourishe<! women produce up to 600 mllday
during the first month of lactation. The vC>lume grad-
ually increases to 1.50-1100 ml/day by the sixth
month. If lactation is continued long afterwards, the
quantities gradually decline. The caloric oontcnl can
range from 45 10 119 C Iday. and i1 averages 75
when the diet is adequate. (See (2) . p. 741.)
Human milk is almost 87% waler. and il conlains
approximately 1%, 3.8%, and 0.4% law,)se. fal, and
casein. respectively. In COntrast. fur .eal milk has
less than 35% waler and more than 35% fat. The
milk of dairy cows resembles thai of bumans in
water and fat content. but it oontains relatively more
protein. mOre sodium. and sugar (186). Al-
though it is rich in calcium. the somewhat low cal-
cium:phosphorus ratio and lower lactose are be-
lieved to contribute to thc tendencies for some
infants receiving it to develop hypocalcemia (I 98).
CYTOLOGICAL ASPECTS OF MILK
SYNTHESIS
Protei ns a re elaborated on polysome-rich endo-
plasmic reticula. Tbe molecules arc transportw to
the Goigi. in which concentration and packaging
into proceed (186). Lactose made in Golgi
lumina i< incorporated into prote in-wntaining vesi-
cles. and it osmotically draws watcr into those vesi-
cles so that the milk becomes isotonic witb the blood
plasma, Vesicle impermeability to both lactose (on
the inside) and sodium ions (outside) probably aC-
counts for the high sugar and low salt collttntrations
of human milk. (Parac<:llular sodium transport has
been described for some OIher species [172J.)
Fats ae<:umulate in droplets that are not mem_
brane-endosed. As the droplets travclto the ""II pcr-
ipheries. they cause the plasma membranes 10 pro-
trude. When the protrusions are pinched off. the
droplets, surroundw by SOme plasmalemma . enter
the lumina. They usually carry along bits of the cell
cytoplasm (186). Immunoglobulins a re believed to
be inoorporatcd into the droplets, but the concentra-
tions fan soon after lactation is established. Most of
the IgG and IgM seem 10 originate in the blood.
whereas [gA is probably synthesi7.ed locally. (Large
numbers of mesenteric Iymphoblasts commined to
IgA synthesis have been observed to migrate into rat
mammary glands during latc pregnancy and
throughout lactation.) T I)'mphocytes probably both
migrate from othcr region, and proliferate (203).
CONCEPTION "'1'10 PREGN ... NCY
HORMONAL CONTROL OF MILK PRODUCTION
Prolactin is :laid 10 be capable of acting alone in suit-
ably prepared rabbit glands (164.197). but it must
interact with other regulators in most species. Mke
and rats require gluoocortico;o;Is as well. and goots
additionally need growth hormone (164).
The content of specific milk proteins declines rap-
idly when mammary gland explants from midprcg·
nancy rats are supplied with just insulin and bydro-
oortisone in defined media. PRL can then increase
casein mRNAs within I hour and invoke a 7-fold
cbange by 24 hours. Evidently. PRL accelerates
transcription and also prolongs the life of the
mRNAs. (The actions are !lOt associated with gen-
eralized changes in nucleic acid metabolism [189].)
Hydrocortisone is ineffective alonc. but it p010n-
tiates PRL stimulation. The steroidal influences on
casein production arc altributc<:l to posltranserip-
tional changes and to a lesser extent on elaboration
of the endoplasmic reticulum (187A). Progestcrone
antagonittS PRL stimulation . The mechanisms may
include adcnylate q-dase activation and interference
with PRL induction of its own receptors. The steroid
inhibits only when it is presented along with the
PRL or soon afterward (189). Dibutyri cAMP and
eholera,oxin have oimila •• ffeet •. Th. dedine in pro-
gesterone influences after 4 hours may result either
from loss of progesterone receplOrs or diminishc<:l
coupling of receptor binding to cyclase activation
(231).
Thc observation that PRL is effective when it is
covalently bound to large sepharose heads has heen
cited in support of the cl)nceptthat tbe hormone in-
teraclS with receptors On the cell surfaces (235).
PRL does not affect adeny late cyclase synthesis or
cAMP generation, It may induce certain cAMP-<le-
pendent protein kinases and other cAMP-binding
proteins (236). but cAMP can antagonize the influ-
ences of the hormone on the synthesis of lactose.
fatty acids. RNA. and DNA (1 87A).
PRL binding to surface receptors leads to activa-
tion of phospholipase A, and the oonsequent gcner-
ation of prostaglandins. Both inhibitors of the phos-
pholip3l;e and indomethacin are PRL antagonislS,
whereas exogenous enzyme and PGs mimic some
PRL actions. Acoording to one hypothesis. PGs ac-
tivate guanylate cyclase. and the cGMP generated
then activates cAMP-<lependent phO$phodiesterases
(187A).
Spermidine can with tRNAs. and has
been implicated a, a stabilizer of mRNA that is
bound to ribosomes (189). [t probably contributes to
PRL actions. si nce all of the enzymes involved in its
biosynthesis arc activa ted by hormones that promote
 ,
'",
,
o '" ,
'",, ,
"'" ArQ"'aoe _

'", ,
,<"
, ,0 - 0 -

,0 -0
><C _ NH,

o"
o"
ARGININ E O RN ITHINE

,
'", ,
'"'
"'",,
Amno p",pyi I
_""""",,,,_,,,,-_"j" "'"
. ,
,
fiG H
S ol S, -ad""" yI)-3me1hyl-
"""cap'"",opyI .... "",
,
HC H
S _IS, -
me«:_"""lam"", -- -"'",
,
He H NH
, '",
,
HeH
ItC- NH,
IiCH
,
tiCH "'",,
" I
I
He-HI<, '",
H CH
" ,I
He-N..,
"
PUTRESCINE SPERMIDINE SPERMIN E

lactogenesis (Fig. 16-14). PRL is also said to acti- leinl· A·protein alone catalyzcs Following
vale Na +/ K· .ATPasc and (0 innuence Ca" reaction.
uptake.
During the "act;.-." phase of the sc:cretory cycle, U D P·galactO&e + N·acctylglucosamine _
Ibc cells internalize PR L and transport it to Ihe nU- N·acctyllaClosamine + UDP
cleus. The hormone is later transferred to the lumen
as the laueT fills with mil k and the cells HallOn. I n the presence of B·protein. glucose replaces the
N·l\cetylg\ucosamine. and lactose is made (164).
"Resting" (squamous) cells do nol contain PRL but
they have hormone receptors. The belief thaI PRL UP P·galactosc + gluwse '" lactose + UDP
exerts inAuences inside lhe cells is consistent with
observations Iha! it can aCI on isolated nudei in vitro It has Ixcn widely assume<l that progesterone se-
(158). and that dosages of estrogens suffititnt to im· creted during the gestation period inhibits prolactin
pair \atlogcnesis .Iso impede PRL intorp<:>ralion and induction of the ,,·lactalbumin. and that the rail in
dist ribution (1581 . PRL, in turn. oontributes to ste· progesterone concentrations aCCounts for the appcar-
roid ree<:plor regulation (147). ane<: of t he en7.yme S<XIn after parturi tion. Curiously,
however. progesterone is implicaled in bringing
about the differentiation that permits PRL \0 induce
LACTOSE BIOSYNTHESIS
the enzyme (1541. Changes in glucocofliooid <:on·
The IaClose synthelase s)'Slen, consists of gaiaclo&yl centratioo$ probably wntributc \0 the regulation
transferas. (A·prmein) plus ,,·Iactalbumin (S-pro- late in pregnancy and S<XIn afterward (164). 10- 1 M

'"
concentrations accelerate ".lactal bumin synthesis.
whereas higher ones (\ 0-' 10 10- ') innibit.
Each of Ihe I\Qrmoncs involved in mammogenesis
and laclalion performs other functions. PRl can
dampcn responses \0 stressful stimuli (106) and re-
duce gonadotropin socret;on. Adrenocortical steroids
play essential roles in maintaining walcr. electrolyte.
carbohydrate, and protein metabolism, while insulin
and growth hormone afTcc! appetite and food u1ili-
lation . Parathyroid hormone and calcitonin affect
milk wmposition, but the major eff...:!s arc exerted
outside the mammary glands.
The Suck ling Reflex
By stimulating nerve endings in the al'CQlar and nip.
pic regions. Ihc infam initiatcs a suckling The
messages \ravd along afferent ne ...'., 10 the mid-
brain and hypothalamus (127 .233). Oxytocin (OT)
from neurohypophysis is delivered by the
bloodstream to myoepithelial cells of the breast
and to ulerine muscle.
When the myoepilhelial cells CQntract, preformed
milk is discharged from Ihe mammary gland. The
is essential in humans. rats, rab-
bils, dogs, pigs, and SOme other mammals, but it is
of limiled importance in SOme of the ruminants
(197). It waS first olls<=rvcd by dairy farmers. and
OT is still sometimes referred 10 as "milk let-<lown
factor." Because of the anatomical arrangements.
contractions of ulerine muscle lessen the dangers of
postpartum hemorrhage. They also contribute to
physiological in''alution of uterus. Women who
do nol nuT$C their infants are routinely ergo-
novine (which exerts OT-like elfects on Ihe
myometrium).
After lactation is eslablished . OT release cootin-
ues to be important for some spe<:ies. In women. the
quantities se.:reted soon diminish (42), and then
breast stimulation can invoke milk release without it
(54). Suckling twins can double the volume (A· 4).
Proluctln Secretion
The suckling renex provides a strong slimulus for
prolactin secretion during the first few postpartum
weeks. The plasma PRL. concentrations rise stecply
within I minute. and the levels remain e1evatoo for
the next 20-30 minutes. They can exceoo 300 ng!
ml. (The average values for nonpregnant. nonlaetat-
ing women o[ the same age are around 10-20 ngl
mI.)
The "surges" gradually diminish. and after some
months there are times of the day when Ihe PRL.
concentrations fall to prepregnaney levels. However,
CONCEPTION ANO PRl:GNAN(:Y
small amounts of Ihe hormone are essential for
maintaining laclalion. Milk produclion Can Cease al-
most abruptly following the administration of agents
that block PR L. release (54). In rats and some other
small mammals. s uckling consistently promotes
PRL. secretion during the lactation period .
The dilferences are probably accounted for by the
early weaning (after 21 days in the rat), and by the
need 10 nourish large lille rs.
The predominant form of human PRL. is a protein
monomer devoid of carbohydrate that contains 199
amino acid moieties. It closely resembles the PRLs
of other mammals and ,hows 77% homology with
porcine PRL. Despite overlapping biological prop-
erties. the amino acid sequences have only 13% and
16% homology wilh hPL. and with human growth
hormone, respe<:tively ( I06). evidently
follows patterns described for Other secretory PI"(>-
and a prepl'Qlaetin 2000-3000 daltons heavier
than the 23.510 molecular weight of the mol>Qll1er
has been identified.
The cireulating hormone comes mostly (or tOially)
from the pituitary gland The small quantities found
in the brain may originate in part in nervoos tissue.
Molecules with PRL.·like activity released by some
tumor cells can have weighuof up to 100.000. Some
are belie"ed to be aAAre;:ales or polymers. The PRL
of fetal amniotic fluid is now believed 10 be made
mostly in the decidua (g5).
!..ong-Ierm eslrogen administration increases the
numbers of pituitary gland lactotropc!. This change
partially accounts for the higher rales of PRL SOCr.,..
tion. The cell numbers also increase during preg-
nancy and lactation. and they decreasc following
weaning. Sleep-associated circadian palleTns of hor-
mOne have been described for males and cy-
cling females, and some agents that inlerfer. with
REM sleep disrupt the rhythms. Although blood
concentralions during most of the day are in the 10-
20 nglml range, brief noclurnal and early morning
peaks of up to 45 ngfml are typical (76).
The .up .... chia.matic nuclei of the hypothalamus con-
tribute 10 the controls in rodent .. but their i.flueoce. in
primat.s hav. not been studi.d . Stimulation of the ut.r-
in. cervi< of a .... t in e. trus is followed by the app<a .... nc.
of nocturnal .urges that conlinu. for 12-14 The
tim ing can be n,ied by manipulating the environm.ntal
lighting. PRL promotes progC$terone secretion. and Ihe
51eroid. in turn. co"tributCl to th. PRL surges. H"".vcr.
ovariectomy. e>en wh.n CQmbin¢<! with ad renalectomy.
blu"" and shortens but doe. nol abolish the response •.
Hy.'ler""'omy protong> and augment< th.m ( (52).
In addition to increasing lactOlrope numbers, es·
trogens augment PR l ,ynthesi" increase the num-
bers of binding siles for TRH and other stimulants.
 and act On Ihc hypothalamus 10 decrease dopamine
contcn!. The estrogens certainly contribute 10 Ihe es·
trus-related PRL surges. but there are no simple re-
lationships belween the steroid levels and the aCliv-
ities of the hypothalamic neurons (1 S2).
As discussed elsewhere, PRL secretion in nonlac-
tating mammals is tonically inhibited by the hypo-
thalamus. Dopamine acts at hypotlla lamic and pi-
tuitary levels to decrease PRL secretion.
Dromocriptinc (a dopamine receptor agoni'l) and L-
DOPA affect REM sleep and reduce PRL secretion.
Although Ihe importance of dopaminergic neurons is
established. there arc ciear indications that it is not
the onl)' regulator. No simple dose-response relation-
ships are found, and even higllleveis of DA do not
totally inhibit ( IS2). Some observers believe tllat
DA promotes the release of a prola,tin inhibilOry
factor (P IF), which may be a peptide.
Gamma aminobutyric acid acts centrally 10 in-
hibit the activities of tuberoinfundibular DA neu-
rons and thereby accelerale PR L release. However.
studies wilh ethanolamine-O-sulfate (which pro-
long' the aClion, of GABA by inhibiting GABA
lransaminase). museimol (a GADA receplor agc>-
nist). and bicuculline (a receptor antagonist) indi_
cate thai GABA also exe rts opposing influcnces by
directly depressing lactotropc functions (31). Scrc>-
tonin stimulation of PRL release probably involves
inleractioru; with (;ARA at the hYJ'OIhaiomic level
Since PRL Icvels risc "ery rapidly following suck-
ling stimuli during early lactation. il is li kely thai Ihe
hypothalamus one or mOre prolactin releas-
ing factors (PRFs). In birds. hypotbalamic stimu_
lants the major controls.
The nature of the hypothetical mammalian PRF
is not known . TRH is a highly effective stimula nt
when il is presented in low concentT3tions (143). and
laclotrope sensilivity to TRH is high during early
lactation . DA concentratioru; affect lactotrope re-
sponses to T RH in vilro (69). PRL must undergo
two intracellular transformations before it Can be
discharged from the pituitary gland (see Chaptcr 8).
According to one hypothesis. DA suppresses the first
process. whereas augments the second. An-
other suggestion i$ thai a fall in DA levels leads to
"unmasking" of TRII receptors (69).
TSH levels do not rise in 10 Ihe suckling
stimulus. This has been cited as evidence aga;ru;t
TRH participation in the prolactin release. While
the argument may be valid. it is recognized that sev-
eral factors inAuencing prolactin secretion also affect
TSH release. Moreover. TSH secretion is eas-
ily inAuenced by changes in thyrotropc sensitivity
than hy variations in TR H levels.
Vasoocliw imminal peptide (VIP) is another hy_
pothalamic component Ihat has been proposed as a
physiological PRF. There arc controversies COncern·
ing whelher il aCIS directly on Ihe pituilary gland.
antagonizes the influences of DA. or functions in
both ways (152).
PR L can be releasod in response to Siress. Usu-
ally. Ihcre is simultaneous discharge of ACTH and
of fi-endorphin. Endorphiru; promote PRL release in
many species. In primates they may inhibit dopa-
minergic ncurons (244). whereas in rodents there is
some evidence for stimulation of Strtonincrgic ones
(183).
Glucocorticoid, act direclly on the lactotropes to
inhibit PRL hio:synthesis. When present for long
time periods. they lower sensilivily 10 TRH. They
may also synergize with dopamine. PRL is a regu-
lator of some adrenocortical enzymes. and il can ad-
ditionally decrease ACTH secretion (220).
PII. L release from deciduat tissue is controned in .ery
different way •. Neither TRH nor DA ..em, to be errec_
live. Moreove,. cAMP inhibits deciduot Steretion.
wherea, it 'Iimul.t.. pituitary Sl.nd relealC of PRL. Ar'
achidonic ac id and -lOme of its prec"rso ... inhibit the ' yn_
thesis of Ihe decidu,l hormone. HolVtver, neither tho
prost.glandin, tested ( POE .. PGE, .• nd PGF .. ) nor in-
hibit"" of Iheir biosynlhesi. from orachidortic .cid wore
found to exerl simila, .ctions ( tOt).
Terminat io n of Lactation
The aClivitie.. of the alvenlar cell. nf rhe
gland arc not synchronized . When milk aoxumulates
in some of Ihe lumina because Ihe infant does nOl
nurse, olher cdls continue making new milk. Pres-
SUrt rises within the breasl, and this eventually ini_
t;ates regressi"c changes. Some of the alvcoli rup-
ture. while others collapse. Proteolytic en,smes are
released. and many of the cells become necrotic.
Much of the debris is resorbed. In womcn. the
breasts become ,mailer. bu t some adipose tissue
builds up. Reversion to the nonpregnant state is usu-
ally accomplished within around 2 weeks. If lacta-
tion is terminated al. time when PRL secretion rate
is high. autophagic changes in the pituitary gland re-
duce the numbers of laetotropes.
HORMONES AND BREAS T CANCER
The factors associated wilh high incidences of breasl
Cancer in women include early menarehe, lale men-
opause. and obesity. A full term pregnancy com·
pleted before Ihe age of 20 markedly reduces the
probability thai breast cancer will develop. whereas
a first pregnaney begun after the age of 3S is asso-
cialed wilh higher risk than nulliparity (l75A).
Each of Ihe factors has been linked in
some way with prolonged eXjXlSure of the breast
to high levels of estrogeru; or high estr()-
gen:progestcrone ratios. but obesity additionally

augments insulin secretion. The tissues that give'
risc to the tumors initiaily (XISSCsses r(CeplOrs for eS-
Hogens. progesterone. probctin. and OIher hor-
mones. In many C3sel;. neoplasia is associated with
loss of sensitivity to one or more of the regulators.
The mechanisms whereby estrogens affect tumor
growth ar<: not known. Several authors have sug-
gested that the major effects result from stimu lation
of PR L secretion . However. SOme antiestrogens that
are used clinicaily for other purposes lillie Or
no influence on circulating PR L levels (173). and
agcnts that block PRL seerction have proven bene-
ficial in only very limited numbers of patients. More-
over. estrogen. arc known to exert at least some anti·
PRL acti(}n'l on mammary glands that can be reo
versed with anticstrogens (12JA).
Another concept is that cA MP protects against
tumOr growth . and that estrogens either oppose the
influences or lower the nucleotide levels (45). A dif-
fe rent idea that comes from studies of emogcn·re-
sistant human carcinomas is that bl<Xld ordinarily
contains different kinds of growth inhibitors "'hose
actions are opposed byestrogens.
In SOme patients with estrogen-<!ependent tissue.
ovarie.:tomyat least tra nsiently arrests growth oi the
tumors. and it can even invoke regression . Very large
d<><agc< of <ynthetic estroeen,
beneficial. Thi, has been widely altributed to inter_
ference with the replenishment of estrogen receptors,
However, pharmacological amountS of even natu-
rally occurring hormones can exert nonspecific ef·
fects on cells that do not po<.<e<.< high-affinity binding
sitcs. They can. for e xample, affect the properties of
cell membrane.< and the growth of small blood
vessels ,
Since progesterone antagonizes some cstrogen ac-
tions. it has been suggested that pregnancies during
early adulthood confer protection by elevating the
progesterone concentrations for several consecutive
months. If this is the case. it must be assumed that
progesterone cannot have similar e/fccts 00 breast
ti ss ue that has undergone long· term to es-
trogens during nonfertile cycles. The lo"'er inci.
denees of breast cancer in women ta king oral con·
traceptives have been linked with both the
simultallCOll, presentation of progestogens and eStro-
gens and the treatment regimes that include with-
drawal of thc steroids for one week of each month.
Limited numbers of patients "'ith tumors that can·
tain progcsterone receptors have bene fined from
progeSlagen therapy.
Psychological ,tre" is said to exaccrabatc the dis-
eaSe. The mechanisms could include aceel·
crated relea,., of prolactin. The elTeets of elevated
CONCEPTtON MiD PREGNANCY
glucocorticoid levels are diffteuh to assess. The stc·
roid, can have adverse effects on immune mecha·
ni,ms used to attack tumor cells. They often aug·
ment growth hormone secrction but lower the
prolactin levels. Stre.. is sometime, associated with
interference with thyroid gland functions, and hy-
pothyroidism may enhance sensitivity to proiactin ,
It is certain that both growth of hormone-<!epen·
dent tumors and responses to steroids are associated
with the presence of estrogen receptors, but the re-
lationships are oot clear, The pineal gland may in
some way contribute to physiological regu lation of
emogen receptor synthesis. a nd it has been reponed
that patients with estrogen receptor breast
cancer tend to ha.'c nocturnal melatonin levels that
are lower than those of both tumor·free cont rols and
patient' with estrogen receptor negative tumors
(228A). On the Other band, melatonin can invoke
dose-dependent augmentation of e'trogen receptor
numbers in human breast Cancer cells (5JAI.
It waS at One time belie"ed that the elTects of hor-
mone therapy often cannot be sustained beca use
poorly differentiated cells survive and proliferate as
the more speciali1.ed ones die off. The concept is not
easily reconciled with observations that a second
course of therap)' with a different hormone often in·
vo. "" '"mor "'e!"C«inn.
It is difficult to obtain experimental models for the
study of breast tumors. Thc numbers of mammary
gland cancers that arise spontaneously in laboratory
a nimals are small, and we have no assurance that the
pathological proccs,<cs arC ,imilar to the OneS that
occur in women. Most investigators use hormone Or
carcinogen invoked tumors. There have been several
indications that observations made on mice (104)
are mOTe usef ul than those obtained from rats (I 73).
In mice. ovariectomy is reported to either reduce
the numbers of tumors that form after carcinogens
ar<: administered or to delay their appearance. In
many cases. it can also arrest growth of established
tumors or invoke regression. There are conditions
under which further benefits arc derived from hy_
pophy,e.:tomy. Glucocorticoid injection. and proges-
terone-estrogen combinations may also provide pro-
tection. whereas estrogen alone or progcstcrone
alone can have opjXl5ing effects. Injections of prolac-
tin (123), growth hormone or insulin. administration
of agents that augment PRL se.:retion. and thyroid
hormone deprivation, are among the factors said to
increase tumor growth. Athym ie animal.. develop
more mammary tumors than animals with intact
thymus glands when no earcioosens are used. and in
these ovariectomy protects whereas estradiol and in_
sulin exacerbate the problems (20S). In rats given
carcinogens. melatonin injections have been reported
to inhibil lumor development whereas pincaleclomy
enhancos (53A),
REFERENCES
t. AdashL E. Y" and H,ueh. A. J. W. Direct Inhi-
bilion of Testieutor Androgen Biosynlhesi. Ro·
veating Anligonadal AClivity of NeurohYl'Oph}'-
sial Ilormones. Na,u" 293: 650-2. t 981 .
2. Ailken. R. J. Uteri"" Prol.in •. OxiCI'd Rn'. R ...
prod,8o'0I. I: HI_82. 1919.
3. AI ... nder. N. J .• and CI.,hon. T. B. Va<COlomy
Inc,.a= Ihe SO"«ily of Di.I·IOOuced Athe,...,.
..,lerQ:Ii. in Macaca 1Q1:
538-41. 1918.
4. Aleund,-,;w a. M .. and SoIolf. M, S. OX)'locin Re-
COP!""' and Parlu,ilion in lhe Guino. Pig. Bioi.
Rtprod, 21: I 106- 11. 1980,
5. Amico. J. A .. Seif. S. M., and Robin"",. A. G.
Elev.l;"" of Oxytocin and Oxylocin·Associate<!
Nouroph)"in in the Plasm. of Normal Women
During Midcycle, J. £milXrillOl. M"ab. 53:
1229_32, 1981.
6, Ando<$On. G. F.. K.wa •• T .. and Mar·
.hali. J, M. Elfecl "" Indomethacin and A'pirin
on Ut<ri"" AClivily in Pregnant Rats' Comp.,i·
<on of Circular and Longitudinal Mus<le. Bioi.
R,prod. U · 359-12. 1981.
7. AOO<r>oo. R. A.. Jr .. O,w. ld. C .. L<l<>. S" ond
Zanovold. L J. D. Inhibition of Hum.n AOrQ:Iin
by Frueu,.. and Olher Monosae<:haride •. Riol,
Rtprod.ll: 1079-82. 1980.
8. A,akaki. R. t·.• Kleinfeld . R. G .. and B'yan,.
Groonwood. G, D, Immunofluorescence Studio<
Using Anti,er" '0 Crude and '0 Purificd Porcin.
Relaxin. Bio/. Rtl"od. 23: 153-59. 1980,
9. AU5lin. C, R. F«lili7,3'i<)n. Cbap. 5. pp. 103-33
of AUSlin. C. R.. and Short. R. V.. ods ..
edt. and F,,,i/i,o,i<m. Cambridge University
Pro ... Now Yo ••. 1972.
10. A,o ... C. Bioloty of Sa, Wiley. No'" York.
1974.
II. Balin,ky. B. L An imroducli<m 10 Ernhr,"ology.
51h ed . Saunders. New York . 1981 .
12. Ballard. P. L. Glucocorlic";d, and Dilfcron lia-
lion. Chap. 26. PI'. 493_515 of Ba>ler. J. D.. and
Rou,,,,au. G, G.. cd ... Glucocol'lkoid HCI'rno'1l'
A,li<m, Springer.Veriag. Ne'" York. 1979.
13, Be ... A. E .. and Billingham. R. E. Tht immul1O-
hiology of Mammalian Rtpro<iucr;"", Prentice·
Han. Englcw<>Od Oilf•. N.J.. 1916.
I 3A. Bce,. A. E .. and Sio. J. 0. Placenla a, In I mmu-
noIogic.1 Barr ie'- Bioi. 26: 15-27. 1982.
14 , Boli,le. S .. and Tulchin,ky. D. AmniOlic Fluid
Hormon",. Chap. 10. pp. 169_95 of Tulchi n<k}'
and R)'an. cds .. r.rerence 234.
IS. Benos. D. Land Balaban. R. S . Energ)' Rcquire.
ment, of the [xveloping Mammalian Ol.slocyst
for Activo Ion Bioi. 11: 941_
7.1980.
16. Bex. F. J.. and Corbin. A. LUleinizi ng Hormone·
Relea.ing Hormone (LHRH) and LHRH Ag<>-
ni .. Terminalion of Pregnancy in Hypophy.eclo-
mi""d Rat&: F...trapi\Uitary Site of ACli<>n. End<>-
crlllOl. 108: 273-80.1981.
17. Bh'llacha'Yya. A, K.. Goodpa. lu,e. J. C .. aOO
Zaneveld. L. J. D, Acrosin of Mou", Sperm"lo-
7.oa . Am". J. Phy'ioi. ])7: GlO-E44. 1979.
18, BiBaui. M.. B,uin. P.. Nardi. E. Pmucd. F.. Pol·
lio inc. G .. F•• nchini. M .. SearSClli, G .. and Far·
nararo. M. Human Decidual ReI ..in, Ann. N.Y.
A""d, Sd, 380: 87_97. 1982.
19 , Billington. W, D, 0,gani7.. tioo. UI"a .. 'UClure
and HistOChemistry of Ihe PlacenlO: ImmunolOj;'
ieal Con,iderouion •. pp. 67_85 "" Edward, Cl aL •
cds .. roference 65.
20. Ellandau. R. J. Biolog)' of EW'o<I Impl.ntati<>n.
Chap. 14. pp, 797-8 82 of W. c.. ed .. S tx
ami In,,,,,,,1 S«miom. 3d ed. William. I< Wil·
kin •• Baltimore. 1961.
21. Blandau. R. J. Gamele T.ansport in Ihe Female
Mamm.l. Chap. 38. pp. I 53-63 Greep. Cd.,
roferonce 93.
22 . R. J .• Elradcll . B.• Brenne •. R. M .. BoI·
ing. J. L . Elrodo <$On. S. H .. Hamner. C .. and Ma·
lfoianni, L. Jr. Th O,iduet. Chap. 13. pp. 132_
45 of G,eep and Koolin.ky. ed, .. reforenc. 94.
23, Bloom. W .• and Fu.-celt. D . W., A Tu,l>ook of
IIiJloIogy. 91h ed. Saunders. Phil.dolphi •. 1968.
24. o",lo"d. R .. Y. W . . . ,0<1 Wil""". I). I",·
munological Privilege Resulti ng from Endocrine
AClivily of Trophoblast in Vi'o, pp. 151_64 of
Edwa,d'.l at.. ed •.• ,eferenee 65.
25. Boyd. S .. Kendall. J, Z.. Mento. N.. aOO B,yan l'
Grcenw<>Od. G. O. Relaxin Immunoaclivity in
Plasm. Du,ing the Reproductivo Cyde of the Fe·
malo Goi.e. PiB- Bioi. Rtprod. 14: 1981.
26. BradSh aw. R. A. and the In,ulin·Rctatc<l
Growth Foclors. pp. I 1_14 of B,y.nt.Greenwood
01 al. •• ds.. refe .. _ 33.
27. B,,,m·f·«t!lng Ihr Moth". Ciba Found"lion
Symposium 45 (new ",.ic.). EI""icr North·Hol·
land. N .... York. 1916,
28. Brigg •• M .. and B,igS" M. o.-al Conl,aupfi"'J.
Eden Press. Montreal. 1917.
29. Elri.Sler. R. L Nutrilion and Motaboli,m lhe
O,um. Zygote and BI.Slocyst. Chap, 39 . pp. IM-
85 of Greep. ed .. reference 93.
30. British Pill Studi.. SIre$> I mpomne<: of Rela,i¢n
Bel"'.. n Progestcrone Conlenl and Vascu lar Dis-
ease, Family Planning Jl: 262-4.
1980.
31, B,uesch.... E, E .. Fadel. H. E.. Maycrl>ofer. K..
s<;.ib.no. F. C .. "'chio. J. T .. Wilban ks. G. D..
and Zane,-.;Id. L J . D. T r,n<Oervioal Tubal 00·
du.i,," with. Sloerablc Hysteroscope, Impl anta·
li<>n of Devices inlo Extirpalc<l Human UICfi.
Am". J. Grn,(OJ. 117: liS-H. 1977.
12. Brue",hke. E. E .. Zaneveld. L J. D.. Kaleck ... R.
'"
A.• and Wingr.eld. J. R. Devcio;>pment of a R<>
vCl'$iblc Va. Deforen. Occlu.ivt Device. VI.
long-term Evaluation of Flexible Prosthetio Do-
• icos. Fm, & S""I. JI: 575-86,1979.
3). Bryant·G",.nwood, G. D .• Niall. H. D.. and
Bry.nt.G roenwood. F. c., ed., EI.,wier
North-Holland. New York. 1981.
34. Cam,ron. D. r .. Corlon. G . L.. and Larkin. L. I-I .
Rduin.l ike Antigenicily in (he Armadillo p."..
tate Gland. Ann. NY. Acad. Sri. 380: 231_40.
1982.
35. Canfield. R. E.,.nd DiTkon, S. H"lJ'Iln ClIorionic
GonadQtropin. PI'- 240--S I or rererence 49.
36. C. nivtne. R. Progestational AClivily in the
B.dg.r. pp. of Wol$!cnholme. G. E. W .•
and O'Connor. M .. ed, .. Egg Link.
Brown, Bo$lon. 1%6.
)7. C.","uc .. , F.. "pud. J.• Localelli V" Marlin.x-
CampO$. A.. C,valin c.. Racagni. G .. Coochi. D..
and MUlier. E. E. Mechanisms Sub.."ing th.
Stimulal<>ry and Inhibitory Components of ,,-
Aminobutyric Add .. ,gic Control of Prolactin Se-
crttion in the Rat . Endoalnoi. 1(}9: 567-75.
1981.
38 , Chal lis. J. R. G . Endocrinoiosy of Late Prtg-
nancy and Partu,ition, Chap. 6, pp. 277-324 of
Greep. R. 0 .. ed .. Rtproductivt Physiology 11/.
Uni..,,,it} Pa,. Press. Baltimort. 198().
39 , Chang. M. c.. Au"in. C. R .. Bedford. J. M..
Hrack.n, II.. G .. Hunt... K . H. f .. and YaMgi.
machi. R, Capacitation of Spermatozoa . nd Fe ...
tili'-"tlon in Mammal,. Chap. 36. pp, 434-51 of
G'e<:p .nd Koblin •• y. e<!1 .. ,.f..ene<: 94.
40. Chang. M. C .. and Hunter. R. H. F. C.pacitation
of Mammalian Sperm: 8i<>l"8ical and E.penmen_
tal Aspects. Chap. 16, pp. 339-51 of Hamilton
. nd G .. ep. cd ..... ference 99.
41. Chann inll. C. P. Follicular Malurallon and 0>"-
lation. pp. 147_57 of rtfertnce 9.
42. Cha,d. T. Rocent T'ends in Ihe of th.
Poslerio, Pituitary. Cu". T<Jpi,s Exp. Endocrinoi.
I: 81_120.1971.
43. Cha,lts, D.. and Rankin, J. S . Ano>ulalio. Sub-
sequent to St.roid.1 Antifertility Ag.nts. Chap.
19. pp. 303-25 of JO$imo>ich, cd .. ,derene<: 116.
44, Ch.ah. S. II .. and Sher"'ood. O. D. ElfeclSof Re-
luin on in .itro Uterine ContractiOll'i in Can.
sciou, and Vn .. mlin.d Est"'llen·T.. ated and
S .. roid·UnttUted Ovariec.omitcd Rat>. f::.wQ-
criMi. 109: 2076-83. 1981.
45. Ch<>-Ch"ng. Y. S .. Clair. T .. Bod",i •. T .. a.d
Ilc:rgllolfer, B. G'owth A rre!Jt and Morphological
Change of Human B.. a.. Cancer C.11s by Dibu-
tyryl Cyclic AMP and ,-,"Argini ne. Sci. ",. ]14:
77-9.1981.
46. Cla,.e. J. R. Ph),>io,,,,ic.' Problem. of Seasonal
Breeding in Eutherian Mammak Oxj(Nd R••.
Bioi 3: 244_31 2. 1981.
41 . Colla"'n. S. S .• Rankin. J. C .. Ledf<>r<l. B. 10 .. and
Bagg.tt. B. Ornithine Deca,boxylase Acti>i.y in
CONCEPTION AND PI*:GNANCY
the Artificially Stimulated Decidual Cell Reac·
tion in Ihe Mouu Bioi. R'f)rod. 14: 528-
33.1981.
48. Conti. C. J .. Gimenez·Conti. 1. B.. Zerbe, G. 0 ..
and l. E. Diffe.. ntial Effects of Es-
tradiol·Hll lnd P'oge$lc'on< On the Proliferation
of Glandular and Luminal Cells of Rabbil Uter·
ine Epithelium. Bioi. Norrod. 1f: 643- 8. 1981.
49. Sdtn«. and Appli<;o-
ri(HI. N.tional Research Council. WashinlltOn.
D.C .. 1979.
Cowi• • A. T, Lactation and i.. llormonal Control.
Chap. 5. pp. 106-43 of Austin. C. R.• and Short.
R, V .. cd, .. Hormone. in R. prOduC/i(HI. Cam·
bridge P..... 1'1 .... York. 1972.
51. Critser. E. S .. Rutledgo. j, J .. and F.. nCh. l. R-
Role of the Uteru, and th. C,,"e<:ptu, in Regulat.
ing Luteal Lifespan in the Moos<. Bioi. Rtprod,
23.- 558_63. 1980.
52 , CsalX'. A. L The Regulatory Interplay of Proges-
teron. and PrO$taglandin F.. in th. Control of the
P .. gnant Ute,u$, Chap. 15. pp. 221_$$ of Josi.
mo.ich. 0<1 .. referene<: 116.
52A. Cunha. G. R.. Chu ng. 1.. W. K .. Shannon. J, 101 ..
Taguchi. 0 .. and Fujii. H. lI<>rmone·lndueed
Mor phogcl\C<i, and Growlh: Rol. 0/ Mesenchy.
mal·Epith.lial InteraCt""". Rtf;. Pro: , HOfm.
. .w: 559_95.1983.
53. Cunningham. G, R., $il\'C,man. V. E.• TltQrnby.
J .. and Kohler. P. O. The Potential for an And,<>-
gen Male Conl,acepti ••. j , Clin. EndocrinoJ.
Mtlab, f 9:520-26. 1979.
53A. Danfo,th. D. N., Jr., Tam.,kin, l.. and Lippman.
M. E. Melatonin Inc ...ses Oeslrogen Receptor
Dinding Acti.ity of Hum,n Brea" Cancer Cell•.
JOj: 32)-j. 1983
54. Doughada)'. W. H. The AdeoohYJlOphysi" Chap.
1. pp. 73-166 of Will iams. R. H. ed .• of
Endocrin%ty. Saunde". Philadelphia. 1981.
55. Davies. l. J. The Fetal Adrenal , Chap, 13. pp.
242-51 of Tulehin,ky a.d Ryan. ed, .... fe .. nc.
234.
5M. Davi •• J. S .. F.rese. R. V .. and Clark. M, R. G<>-
nadotropin.Rel.asing H<>rmone (GnR H) Slimu_
lates PhO$phatidylinosilol Metaboli,m in Rat
Granulosa Cells: Mechanism of Aelion of G nRH ,
PrIX, Nail. A<:ad. Sd. USA 80: 2049-53.1983 ,
56. D..son. H.. and Segal. M. B. Inrr-oduNI(HI to
Phy.ioloty. vol. 5. Academic P,.... New York.
1980.
57. OeDlau. A. f .. and Martin. R. E, A of
Mamm%lY. 2d cd. Brown. Dubuque. 1981.
58. De La I.""•. M.. Arriagada, R., and ·nQng. Y.·
Y. Inhibition ofO>ulation in the Rat by GI)'co-
protein Fraetions Assooiated with Hum.n Ch<>-
rionie Gona<kltropin , Bioi. Rowod. U: 1112- 17.
1980.
59. Dill •. W. L.. J, .• Bell. l. $ .. and Onuma. E, K.
Inhibitory Elfec .. of Substrate An. 'o&, on lae·
tate P,<>duction from F,uclose and Glurooe in Do-
 vi .... Bioi. lj: 453-65,
1981.
6(). DjeT... i. C. Po/ilic. of COntMffplion. Frco·
monoSan Fr,,,d,,,,,, 1981.
61. DQwning, S, J., Brad,haw. J, M . C , and !'orter,
D. G. Rela,in Imp..,> •• the Coor<Iin.tion or Rat
Myometrial Actiyity in vivo. Bioi. 13:
899-903, 1980.
62. Dravland. E.. and Joshi. M. S. S!'<rm-Coating
Antigens Sec"ted by tbe Epididymi, and Semi·
nal Ve.kle of the Rat. Bio/. Rtprod. lj: 649- 58.
1981.
63 . Dubin, N. fL Cummings. D. B.. Blake. D, A..
and Ki"!. T. M. Effect or Epsilon Caproic ACid.
• FibrinolytiC Inhibitor, on Implantation ""d
Fetal Viability in the Rat. Bioi, Rtprod. 13: 553-
7,1980.
64, Dunbar. B. S .. and Raynor. B. D, Ch. r.cteri....
tion or Porcine Zon. P.lIucid. An,igen, . Bioi.
prod. J2: 941_54. 1980,
6S, Ed",·.rd,. R. G .. Ho ..·•. C W. S ..• nd Johnson. M,
H .. Immunohiology ()f rmphobla,/, Cam·
bridge Univcr>ily Pr.... York. 1915. In"<>-
duc,ion. pp. 1-3.
66. Ende .. . A. c.. Hendrick<. A. G .• and Binlord . P.
E. Abnormal De>elopment or Bla'tocy," and
Bla.tomeres in the Rhe,u, Monkey. Bioi. Rtprod,
16: 153_66. 1982,
67 . E,ben,h. de. K. l.. and Clegg. E. D. Surraee Pr...
tein. or Ejaculated Porcine Sperm and S!,<rm In·
cubat.d in the Uterus. B;<>I, R,prod. 21: 530-7.
68. 8$ig, M., Schoe nfeld. C .. D·Elel1o. R .. Amel.r.
R.. Dubin . l.. Steine1Z. B. G .. O·lIyrne. E. M..
and We i.. , G. Rel.xin in Human Seminal
Pla.ma. AIUI. N.Y. Ac()d, Sci, J8Q: 224- 29. 1982,
69. Fagin. K. D.. and Neill. J. The Effect of DQp.-
mine on Th}'rot ropin·Rol<a,ing Hormon .. l n·
duced P",lactin Secretion in Vi"o. I:;"mioc,inoi.
109: IS35_ 40, 1981-
70. Fa,,,,",'onh. N. R.. and Waller, D. P. Cu"en,
Sta,u. or Plan, Produc,. Rep:>r1ed to I"hibit
S!,<rm. •. in Pmil, 1: 1- 16. 1982.
71. Fawcel1, D. W. The Organ izatiQn of the Seminir.
erou' Epit helium .• nd it. Rde""ne. to fert ilily
Control. pp. 158-79 ofrefercnce 49.
72. Field •. p, A.. Pardo. R ... nd Larkin. L. H. Non·
Ovarian Source. of ReI ..in, pp. 180-2 of Bryant·
al.. ed . .. rere,e"ce 35.
7J , Fi,her. D. A., . nd Klein. A. H. The Ontogene. i.
of Thyroid Function and i" Rclati_hip to Neo-
natal The,mogonosi •. Cbap. 15, pp. 281-93 of
Tulchinsky and Ry. n. ed •., ",rerenee 234.
74. Fo,ard. J. R., P.rt, M ..l., Prnl:ash. N. J .• Gr""".
J., Sehech1tr, P. J" Sjoordsma, A.. and K<>< h·
W... r. J . L-Ornithinc An Essen·
lia1 Role in £arly M.mmali.n EmbryOgon<.i ..
SciOn« lO8: SOS-8, 1980.
75. Franchimool. P., Reu1tr, A... nd Gaspard, U. E..
topk ProdUO!ion of Human Chroionk G""adotro-
pin and il'" and P Subuni". e,m, Top. £xp. 1':,..
docdnol. 3: 202_16. 1978.
76. F,.ntz. A. G. Rhyt hm, in Pr",actin pp.
175-86 or Krci gcr. D, T., £ndOC'ine Rhylhm.,
Ra .. n f're ... New York. 1979.
76A. Fras." H. M. A New Class of Contracepti,'c.?
NaI",e 196: 391-2. 1982,
71. Fraser, H . M . Lu,<ini. ing Hormone-Relea,i"g
Hormone and Fertility Control. Oxf",d R'I!, Re-
prod. Bioi. 3: 1_48, 198 1.
78. Fueh •. A.·R .• and Fuch •. F. P""ib1e Mechani,m.
of Inhibition or Labor by Etha nol. Chap. 18. pp.
287-300 of J""imo>kh. cd .. rererence 116.
79. Go"i •. D. R.. and Whitehead. D. S. Uterine
Blood Flow and Timins or Blastoc),SI Impla",a·
tion in the Gui nea Pig. Am". J. Physi<>l, UI:
EI42_EI45, 1981.
80. Gast. M. J. SIudi .. on Luteal Gen<ratiQn .nd
Proce .. ill3 of the High Molecular Weiaht Rel .. in
Precur>Or. Ann. NY. Acad. Sci. )80: 11 1_21.
1982.
81. Georgo, F, W ., and Wilson. J, D. £<'rogen For.
mation in th. Early Rabbil Embryo. Sdel!<t 199:
200-- 1, 1978.
82. Gi.nnopoulos. G .. and Tulehin.k)', D. Tho Influ·
ence of Ilormone, on Fotal Lung Developmcnt.
Chap. 17, pp. 310-29 of Tulehinsk)' and Ryan.
cd •.. 234.
83. Gibson. M.• and Tulehinsky. D. The Maternal
Ad .. nal. Chap. 8, PI'· 129-43 of T ulehinsky " "d
Ryan. ed •., reference 234.
84. Gibson. M. , and T ulchinsky. 0 , The Matern,1
Th)'roid. Chap. 17. pp, IIS-128 or Tukhin,ky
II.Y". "rl • .• ,,,f,,,, ..,,,, 714
85 . Gluck man. P. D.. Gru mb.ch . M, M .. a"d Kapl.",
S, L. The Human Fetal Hypothalamu, and Pitu-
itary Gland: The Maturation o r Neurot"docrir>e
Mechani.m. Controlling Ihe Secretion of Fe tal
Pituitary Growth Hormone:, Prolattin, Gonad...
1ropi" ,00 Adrenocorticotropin·Related Peptide •.
Chap. 11 . pp. 196_ 212 of Tulchin,ky and Ryan.
"r..
cd •., enee 234.
86. Gluckman. P. D.• Grumbach. M. M .. a"d Kapl. n.
S. t. Tho Nour<><ndocrin. Regul.tion and Fun ..
tion of Growlh Hor mone and Prol.ctin in the
Mammalian Fe1u •. £ lIIloc' . 1: 363-95. 1981 .
861\ . GOldberg. E Current StalU' of Research OIl
Sperm Antigen>: Potenti.1 Application, a. Con-
traceptive Vaccine. R."h. F""" . in FmililF ReI!.
I-II . 1983.
87 . Goldberg. V. J .. "nd Ramwell. P. W, The R<>Ie or
Pr,,:I1.glandin, in Reproduction. Chap. 23, pp.
219_35 or Greep and Kobli nsky. ed, .. rererence
"
88 , Goldsmith. L. T .. Grob. H. S .. Sohe .. r. K.. Sur...
1\ .. Stcinctz. B. G ..• nd We iss. G, Placonl.1 Con-
t",1 of Ovari.n ImmUIlQ .. activ<
tion in the Pregnant Rat. f: mio(."Finoi. /{)9: 548-
52. 1981.
89. G<>Id.m;th, L. T.. Grob, H. S .. and Wei ... G. In
Vitro Indue lion of Reluin Secretion in Corpora
Lute. from Non'Pregnani Rats. AM. N.Y. Acad.
Sci. J8D: 60-71. 1982.
90. A.. and Salater, H. Pathology

of the Reprodueti.e Syst.m. Bre.st. and Liver in
Women During Horm""al Contraception . Chap.
21. pp. 343- 80 of JCtSimovieh. ed ,. reference I I6.
91. Goodpasture. J. c.. Reddy, J . M,. arid Zancveld.
L. J. D. Aerosin. Proacrosin. and Acrosin Inhibi-
tOr of Guin .. Pig Capacitated and
Acrooome·Reacted in vilro. /Jio/, lI.,pmd, 2:$: 44_
56. 1981.
92, Graham. C. E. FunCtional Microanatomy of the
Prima .. Uteri ne Cervix , Ch.p. 30. pp. 1_24 of
G,«P. «I.• reference 93.
9) , Greep. R. 0 ,. Handbook ofPhYJioiogy• .. c. 7. vol ,
2. pt . 2. American Ph)'$iolQgic.1 Society. Wa<h·
ington, D.C.. 1973.
94. Grcep. R. 0 .• "nd Koblinsky. M, A.. eds. hOlt-
lie" ReproduClimr ami F,"ilily Cmrlrol. MIT
Cambridge. M ..... 1977.
95. Guillemin, R.. McC.nn. S . M.. Sawyer. C. H..
and D.vid""n. J. M. Secretion of Gonadotropi ns.
Chap. 9, pp. 90-102 of Greep . nd Koblinsky.
eds .. rofe",nee 94.
96. G urpide. E.. and HOlinh. C. Pregnancy.Related
Chang .. in the Metabolism of Hormones, Chap.
3, pp. 45_n of Tulehinsky and Ryan .• d .. rtfer·
enco 234.
97. Hafe>. E, S. E. Anatomy and Physiology of the
Mammalian Uterot ubal Junction . Chap. 34. pp.
87-95 of Greep. ed .. referenco 93.
98 . Haf... E. S. E. Endocrine ContrOl of the Struo-
ture .rod uf the M."lIl1aliall
Ch.p. 35 . pp, 97_122 of Greep.cd.. referenee 93,
9'/ , Hamilton. D, W.. and Grcep. R. 0 .. cds. I/oml-
book of PhYJi%gy. sec. 7. vol. 5. American Ph)",
ioloBical Society. Washington. D.c.. 1915.
100. Han<ock. R. J. T. Immune Responses to Sperm.
Ox/",d R,prod. Bioi. J.- 182_208. 1981.
101. Harldwerger. S .. Barry. S .. Barre". J .. Markoff.
E.. Zeitler. P.. Cwikel. B.. and Siegel . M. Inhibi·
tion of the Synthesis and of D«idual Prolactin by
Ar.chidonic Acid. /:;"nd-xriool. 1(19: 2016-21.
1981.
102. Harrison. R. A. P. The Met . boIi,m of M.mma·
lian SpermatOl"-Ol, Chap, 32. pp. 379- 401 of
Gr.ep and Koblin,ky. eds .. ",fere""e 94 ,
103. Heap. R, B.. Perry. J, S .. and Cha lli •. J. R. G.
Tho Hormonal Maintenance of Pr.gnaney. Chap.
41 . PP, 217_bO of Greep. cd., refercnce 9 3.
104. Hilf. R. Modulation of Chemic.1 C.",inogenCiis
by Hormones. Ar.'''''' I/"'m. 6: 205_
45 . 1979.
lOS. Holt. W. V. Surface-Bound Sialic Acid on Ram
and Bull Sp<rmatozoa: Del'O"ition During Epid i·
dymal Tran,it and Stability Duri"3 Washing.
8oDl. !I.'prod. ]3:847_57. 1980.
106. Horrob in. D. F. Prolactin. vol, 6, Eden Pre .. .
Montre.l. 1918.
107. Honon. E. W .. and Poy .. r. N. L. Uterine lute<>-
lytic Hormone: A Physiologic.1 Role for Prosta·
gl.nd in F,.. PhysiDl. • . 56: S95-6SI. 1976.
CONCEPTN)N A NO PREGNANCY
lOS. HOSQi. Y., Niwa, K., Hatono ka. S .. and Irit.ni. A.
Fertilization in vitro of Rabbit Eggs by Epid idy·
mal Spermatoroa Capacitated in A Chem ically
Ikfined Medium . Bool. R.prod. 14: 637-42. 1981.
109, Hu"t. p, R.. and M.cFarl.... D. W . further Ef-
fee" of Non5leroid.1 Ant i·inflammatory Com·
poIInds on BI.stoC)'st Hatching in vitro and Im_
plantat ion Rates in the Mou ... Bioi. R,prod. 25:
777-84.1981.
110, Hyne, R, V .• and Ga rbe". D. L. Rcquircmcnt of
Serum Factors for Capacitation a rid the Acro-
oom<: Reaction of Guine. PiS Spermato,.oa, in
Buffered Medium Below pH 7.S. DiDl,
U :257 _66.1981,
Ill. Ja<Xlbs. S ..• rId Cu.trec.m. P. In,ul in Receptor:
Structure .nd Function. EmloC'ilU' R, •. 2: 1$1_
63.1981.
112. Jelliffe. E, F. P. Matern.1 Nutrition and lacta·
tion. pp. I I 9-30 of ",rerence 27.
1l3. Johanuon. E. D, 8.. and Holmdahl. T. H. My·
omet';.l. Contractions Relatcd to Endogenous
Pla,ma Emogcn, .nd Progesterone. Chap. 8, pp.
\29- 40 of Josimo'ich. ed .. refcrenee 116.
I 14. John""n. D. c., and Dey. S. K. Role of Himmir><:
in Implantation: o.xamethaiOne Inhibits Estr.·
diol· lnduced Implantation in thc Rat . Bial. R ..
prod. 22: 1136-41. 1980.
115. Johnson. p, M.. BTO"'n. P. J .. and Faul k. W. P.
ImmunobioloSical A'peCts of the Hum.n PI.·
,-enl •. R<pmd. S I,,/. 1: t-40. t980,
116. JOSimOVich. J . B.. ed. U..,iM CmrlTacri()l1. J,
Wile)'. New York. 1973.
117, Karim, S. M . M .• and Hillier. S. G. The Role of
Prostaglandin. in Myomeuial Contraction , Chap.
9. pp, 141_69 of Josimovieh. ed .. reference I 16,
liS . Kat:<- D. F., and Yan'Simachi, R. Movement
Characteri5lics of Hamster Spermatozoa Within
the Dvid uct. Bioi. R'wod. 11: 759-64, 1980.
119. Kaw.rabayashi. T .•• nd M.rsh. lI. J. M. F.etors
I nnucncing Circu lar Muscle Activity in the Preg'
nant Rat Uterus, Bioi. R. f"od. 14: 373-79. 1981.
119A. Kelly. R. W .. and Abel. M. H. Copper and Zinc
In"ibitthe Metaboli,m of Prostaglandin by the
Human Uterus , Bioi. Ref"od. 28: Sa3_9. 1983.
120. Kenncd}', T. G, EStrogen and Uterine Sen,itiza·
tiOll for the Decidual Cell Reaction: Role of Pros·
taglandin<. /Jlol. R. prod,)J 955-52. 1980.
121. Keyes, P. l.. Gibori. G .. Posslcy. R. M.. arid
Brown. J. M. Early Changes in Luteal Function
Associated "'ith the luteotropic Effect of Test.,..
terone in the Pregnant Rat. DiDl, R<prod. 11.-
1142_8.1980,
122, Kine!. F. A. Ikbate on the U.. of 1·larmonal Con·
tracepti"" During Lactation. Rsch. in R'prod.
/1: I. 1980.
123. King. R. J. B. How lmport.nt Arc Steroids in
Regulaling the Growth of Mammary Tumo ...?
/JI-xh'm. Ani"", /I"'m, 6: 247_64.1979.
123A. Kleinberg, D, L. Tcdd. Land B.bilSky. G, In·
 hibilion by Ellradi<>l of Ihe Laclogenic EffecI <>f
Prolactin in Primale Mammary Tissue , Roycc$ill
by Anlic$lrogens LY 156758 and
p"x, Nail. Acad, Sci. USA 80: 4144_8. 1983.
124. Koob. T. J.. and Callard. I. P. Rel.,in, Specula·
lionl On its Ph)'.i<>logk.1 Imporlance in Some
Nonmammalian Specie •. Ann. N.Y, AcaJ. Sei.
J80: 163-173. 1982.
125, Langman. J. Mdital t:",bryology. 2d od, Wi l·
liam. oS: Wil kin$, Baltimore. 1969.
126. Lau",nce. K. A. Reproductive ImmuoolOS)' .
Chap. 12. pp. 128-31 of G"",p and Koblin'Ic )' .
e<b .. reference 94 ,
127. Loako . R, D.. and Weit>:man, R. E. The r.ul·
Maternal Neuroh)'pophyseal System , Chap. 12,
pp, 233_41 of Tulchin.ky ond Ryan. cd ... ",fer·
ence 234,
I 28 , Linins. G. C Felal I nftue",.,. on Uterine Con·
lractil il)" Chap. 13. pp. 20,_21 of Jo>ilflO\'ich,
e<! .. ,.fc,ence 116.
129. Liggins. G. C .. fairclough, R. J .. Grie'." S , A..
Kendall, J . Z .. and Knox. B. S. The Mecb.ni.m
of Initiation of Parturition in the Ewe. R«. Prog.
Ho-m. Rsch, 29: III-50, 1973.
130. Lonso, F, J. Changes in lbe Zonae Pellueidac.nd
PI •• malemmae of Aging Moo", EU" Bio/, Ri'-
prod. U: 399- 41 L 1981.
131. L)'.. A. G .. and Holli •. D. E. Thc 1'...1), DcYel·
opmonl of M.,,"pial •. with Special Refe .. nce to
Bandicoot' , pp. 293- 302 of Calaby. J. It. and
T),ndalc.Bi<e«, C H .. cds ..
f.·m/"ri"". An " .. lia. Acadomy of S<io"" •. r:.n.
be"a City. 1977.
132. Marcu,. G. J. Prostaglandin Formation b), the
Shoep Embryo and Endometdum as an Indication
of Maternal Recognition of Pregnancy. Biol. Hi'-
"roJ.15: 56-64. 1981.
133. Martel, D" .nd Psycho)'"". A. E$trogen R=p-
10" in the Nidatory Silt. of the Ral Endolt\e"
trium, 14'4-5, 1981.
134. M.ni.Hcnnebers. C. P. D.. I.. ac,
R.. Kapl.n S . L , and Grumbach. M, M. Hor·
mone Ontogeny in the Ovine Fet us. XII, The 00-
p.minergic Regulation of G,owlh Hormone and
Chorionic Sommatomammotropin Rele'$<, /:".
JtJ<riooi. /()9: 135,-9. 1981.
13S, Maugh, T. Ii. II. Mole "Pill" Block. Sperm En.
>.yme. Sd."", 1/1.· 314.1981.
136. Mauldin. W. O. E'pedence ... ith Contraceplive
Method, in Dc"eloping CO""IT;". pp. 50-104 of
.. ference 49.
137. McDonald, J, K.. and Scbwabe. C . RoI.xin· l n·
duced El¢"alions of Cathepsin Il and l) ipeplid),1
Peplida,e I in the M"" .. Pubic Symphy,i., Wilb
Localiut ion b)' Fluot'<$CCnce En>:yme Hi'I'"
<bcmi.lry. Ann. N.Y. Arad. Sci. 180: 178-86.
1982,
138. McLar.n. A. The Embryo. Chap, I , pp, 1_42 of
Austin, C R" and Shorl. R. V.. cd .. embrJ<mk
and Flral Del'dapmml. Cambridgc Unil'e"ity
Press, New York, 1972.
\39, Monkon. J., Tru$$<lI. J., Ford. K" and Prall. W.
F. Experien<:e wilh Contraceptive Melhod. in De·
veloped Co"nlTi... pp. 24_44 of fOference 49.
14(), Mel', C B. Immuoologicallnhibition of Sperm
and Egg Funclion : ProspeCts for an Antifertility
V.ccine from Gamet.s, pp. 180--220 <>f refc,ence
".
14 1, Mi.hcll, D. R" Jr, Injectable Contraceptive Prep-
aration,. Chap. 21, pp, 209_13 of G .. op and Kob-
linsky. eds .. 94.
142, M...... ad. A, II. The Sympathelic Ne""". Sy".
tern ,nd tbe Ulerus. Chap. 4. pp. 65_79 of Josi·
lfIO\'ich,ed" .. f...... 116.
142A. More Wo,de. Aboulthe Pill . (Anonymous) Na·
",,.. 305: 749-50,1983,
14), Morley, J, E. Neu,oendocrine Control of Thyro-
tropin Secretion. enJocriM He". 1: 396-436.
1981.
144, Morri •• J. M. The Morning.After Pill: A Report
on Postcoila l Con1raceplion and Inlerception.
Cha p, 20. pp. 203-8 of ,,[c.. ne.: 49.
14S. Merd., M" SI<"On., S, W" ond Adams, M. R.
PI.,ma Oxytoc in During Presnan9 and U.Cla·
tiOn in the Cynomolgus Monkey. 9iol Rt",od. 23:
182- 1,1980.
146. Moulton. B. C .. and Ingle, C . B. Uterine L)'>OS<>-
mal Cathepsin D AC1ivil)" R.tc of Synthe,i,. and
Immunohi.tochemical Localizalion Following
Initialion of Deciduali1ation in Pseudopregnant
Rats. Bioi. 1J: 39)_8. 1981 .
14 7. Muldoon. T. G. Inlerplay betw.en utradiol and
Pmloc,in in rhe Reg\Jlarion of SIOfOirl
Receplor Level •. Natu re, and Functionalily in
),louse Mammary Ti .. ue. t:ndlXriooi /()9: 1339_
46,1981.
148. Murad, F" and Ha),n ••. R. C, Jr. Eotrogen, and
Prose.tin •. Chap, 61 , pp. 1420--47 of Gilman. A.
G.. Goodman. L. S .. and Gilman . A.. ods" Good·
man a",1 's TM Bosh oj
61h ed. M.emill.n. New York.
19K
149. Murphy, B. D" Concanoon. P. W" Travis. H. f "
and Han",l, W. Prolactin: The ft),poph)·sc.1 Fac·
\Of lhal Terminales EmbryOnic Diapau$< in
Mink. Bioi, R.",od. }j: 487- 91, 1981,
150. Napo. R.. a nd B'yanl·G .. cn •.-ood . G. I). Evi·
de",e for a Uteri .. Re laxi n in Ihc Guinea Pig. pp,
61-9 of Br)'ant--Grcenwood el ,I.. ed. __ Teference
"
lSI . Neave •• W. B. Leydig Cell" Chap. 29. pp. 321_
31 of Greep .nd Koblin,); y, e<!>. , .. fercnce 94.
152. Neill, J. D. Neuroendocrine Regul.tion <>f Prolac-
tin Sec""ion. Fro"'. NtUrlXndocrinol. 6: 129-S5.
1980.
153. Niall, ft., Hudson. P __ Haley. J., Cron);. M ., and
Shine. J . Rat P.. pror.lax;n: Complete Amino
Acid Sequence Dc ri Yed from eDNA An.ly.i •.
N. Y. A cad, Sci. 180: I 3-2 L 1982,
154, Nichol ... K. R" S.nlaran. L.. and ToppeT. y, J .
The Induclion of ,,-Lactalbumin in Rot Mam-
mary uplan" in the Absence of E.osenou, Pro-
n.
Ilelin, Elfects of Progesterone ar<! Estrogen. E ....
dOCTilt(Jl. 109: 918_80, 198 L
ISS. Nil,son, S" and Nygrcn. K.-G. Deb ... "" the Usc
of Contraceptive, Duri"3 Lactation. in N....
prod. I]: 1-12. 1980.
156. Ni1.ron, J .. and Nyg ... n, K.-G. T, ... r., of Con-
Steroid, 10 HurJ'l3n Mil k. R.ch. in Ht-
prod. II: 1-2, 1979.
\ 57. Nolin, J. M .. and Bogdaoov., E. M. Effects of Es-
t"'icn on Prolactin (PRL) Incorporation by lu-
tein and Milk Socrctory Cells and"" Pituitary
PRL Sec,..,,;o. in lh. PO$lpar1Um Ra1. 8ial. R ....
prod. 12: 393_416, 1980.
158. Nolin. J. Target Cell Prolact in. Chap. 7 of
McKern •. K. W.. cd., Strucwu aM of
GOniidoltopim. Plenum, New York. 1978.
159. N.".,;., D. O . V"'tbrolt t:lldom'"",ogy. Lea &
rebig.,. Philadelphi a, 1980.
160. N<>rWOOd, J. T. and Ande.-.on. R. G. W. Evidence
that Adhesive Site, "" the Tips of O.iduct Cilia
Membrancs Required for Ovum Pickup in
Situ , Bioi. ReprO<!. 23: 788-91, 1980.
161. Odell. W. 0 .. and Mo),or. D. L. Ph,'jiolo/O' of
Mosby. 51. Loo;., 1971.
162. O kauki. T .. Saga"o. N .• Bleudole. J. E.. O ki,a.
J. R.. MacDonald. 1', c., and JohnSlon. J. M. Ini·
,iot;"n of Hum.n Port.rition. XIII. Phospholi.
pase C. Phospholipase A,. and DiaCj'lglyccrol Li·
pase Acti.ities in Fetal Membranes and Decidua
Vo •• Ti .. ue. r",m Eo.ty u'e GeOta'i,,".
Bioi. RtprO<!. ]j: 103- 9. 1981.
163. Olefsky. J. M.. Saekow, M .• and Kroo. R. L. Po-
tentiation of h"ulin Binding and In.ulin Action
by P'IIrified Porcine Relnin. AM. NY. Acad, Sci.
380: 200-216.1982,
164. Ono. M.. and O k•. T. «-Lactalbumin.cosein I ....
duction in Virgin Mou .. Mammary Explant"
f>ose.D<pendcnt Diffcren,i.1 Ac,ion of Corlisol.
Scitnet 107: 1367-0. 1980.
165. O·Rand. M. G. Inhibition of Fertility and Sperm.
Zona Binding by Anli"",m to the Rabbi' Sperm
Membrane Autoanli,cn RSA·1. Bioi. ReprO<!.
]j:621 - 8.1981.
166, Ory, H, W. The Health Effects <>f FenHity Con·
t..,1. Chap. pp. I 10--21 of reference 49.
167. o..thanondb. R. . and Tulchi • • ky, D. Pla"".tal
Polypeptide Hormo .... Chap. 2. pp. 17_42 <>f
Tulchinsky and Ryan. cds .. reference 234.
168. O.el'm...,t, J. W.. Katz, D. F .. and Johnson. L. L.
MotililY <>f Rabbit SpermalOZO;> in ,he Sec rdi<)n<
of th. Oviduct. Bioi. Rtprod. 21: 1083- 8. 1980,
169. Overstrllm. E. W.. Bigsby. R. M.. and BlaC k. D.
L. f!ffccts of Physioiogic.1 Le •• l.of Es"adiol-17{J
and Progest.ron. on Oviduct Edema and Ovum
TranSpOrt in \he Rabbit. Bil)/. Rtp'OII. U: 107-
10,1980,
170. O .... ns. 0 , M .. Ryan. K. J ., and Tulchinsky, D,
Episodic Secretion <>f Human Chorionic Gonado-
tropin in Early Pregnancy. J. elin. Em/ocrinol.
M <Mh.51: 1307-9.1981.
CONCEPTION MI D PREGN... NCY
171. Parker, C, R., Jr,_ S impson. E. R., Bilheim.r, D,
W._ L.veno. K.. Carr. B. C .. and Macdonald. p,
C. In.. r$< Relation Iktwe.n Low_D<nsity lit»
prot.in.clloleste..,1 and Dehyd,oisoandrosterone
Sulfate in Human Fetal PIa,m •. Sci<net! ZO$.-
512-14.1980,
172. Peaker. M. Lactotion: Some Ca,diov.""ular and
Metabolic Consequen"" •. and th. Mcch.ni.m. of
Lactoseand Ion Secr.tion inlo Milk. pp, 81 - 97 of
r.r.rence 27.
172A, P.arce. P. T .. Khalid . B, A. K., and Fund.r. J. W,
Progesterone Receptof1; in Rat Thymu •. £ndocri-
rIOl. II): 1287-91. 1983.
173, Pc..-son. O. H.. and M" nni. A. Hormonal Con"ol
of Breast Growth in Women . nd R.ts.
eu". Top. t,·xp. Endocrilloi. 1: 7S_92. 1978 .
174, Peluso. J. J .. Engl. nd.charl •• worth, C., and
Hull. R. EffecI of Agc and <>f FoIlic"l.r Aging on
the Preovulatory OocY'e. Bioi. RrprO<!. 22: 999-
1005.1980.
17S. Piik, K .. Polo. H" and Jannc. J . Regulation of Or-
nithill¢ D<carboxyl."" Acti.ity in Rat O.arian
Cells in .i"o. Endocr, Commun. 6: 1()7_
121. 1979.
I75A. Pi ke. M. C. Krailo. M. D.• Hende...,n. B. E.• Ca ..
agrand., J, T., and Hoel. D. G. "Hormon.\"' Ri.k
Factors. "Breast Tissue ... ge:- " nd the "'gc,1""i,
dene. of Breast Cance,. Nmw,e )0): 767_70.
1983.
176. l'<>pulot;Qn R<IX"'" P"pul";<>n Inf",motion Pro-
gram. Johl"L'l Hopkin. Uni.ersity. Baltiml)fe.
A. IIofti.r Metbods. Se,ie, H. no. S. Septembe"
1979; 00. 7, January. 1984.
B, Female Stcrili •.•llion. Series C. no. 8. Septem·
ber. 1980. Mal. St.,ili,,ation. Series D. no, 4.
No'.mber.1983,
C. Intraut.rine De.ices. Series B. no, l. May.
1979.
D. Oral ConI ... cepli •••. Seri ...... no. 5. January.
1979. Oral Contracepti •• , in the 1980.. Seri ••
.... no. 6. May-Jun. 1982.
E, Periodic Abstinence. Seri.s I. no. 3. Sep'em-
ber. 1981.
F. Prostaglandin •. Series G. no. 8. March. 1980.
G, Special Topic Monograph., Dep\. Medical
and P'IIblic Affairs. George Washington Uni,
versity Med ical Centcr. WUh ington. D.C.;
M/F St.,ilization. #2. Mareh . 1978.
177. Portcr, D. G .. and Finn. C. A. The Biology of t hc
Ut.,u •. Chap, 14. I'p. 146--56 of Greep and Kob-
li.sky. eds .• reference 94.
178. Powell-Jones. W., Thompson. C .. Raeford. 5 .. and
Luci.r, G. W. Eff.ct of Gonadectomyon Ihe On-
t08eny of Estrogen-Binding Componen,. <>f Rat
Liv.r Cytosol. £m/oc, lno/. /09: 628_36. 1981 .
179. Pryor. S .• and B,onSQlt, f . H. Relative and Com-
bined Effec,.of Low T.mperatu,., Poor Di.,. and
Silort Dayl.nglh on the Productivity of Wild
House Mice. Bioi, ]j: 734-43, 1981.
180. Psychoy"". A. Endoc,in. Control of Egg I mplan_
 rarion. Chap. 40. pp. 182-21 S of Gre<:p. <;d .• ref·
trOnco 93.
181 . J.• Lusrig. D. S .• Steinett. B. G .• and
Wei... G. A'osc""e ofa Prelabor Relaxin Surge in
Women. Blo/. R,prod. 12: 202_4. 1980.
182. Q.'8Ii • .-.:1l0. J.. Sd.chtcr. N .. Steinett, B- G.,
Goldsmirh. L T .• and Wei ... G. Serial Rel .. in
Cootentrarions in Prcgnancy. Am. J. Db,,,,. G,-n.
135: 43_4, 1979.
183. Raga,.n. V. V.• and Franlz. G. Opioid Regula.
tion in Probetin Secretion; Evidence for. Specific
Role for Endorphin. EM«'lnoi. W9: 1769-71.
1981.
184. Reddy. J. M.. Slark. R. A. and Zaneveld. L J.
O. A High Moltoular Weight Antifertility Faclor
from Human Semi""1 Pla.ma. J. FtrI.
57: 437-46. 1979.
18S. Rhodin. J. A. G. }flsroloy. Oxford Univ."ity
Pre ... New York. 1974.
186. Rich.rd •. 11.. C. Milk Secrction; With Special
Reference 10 it< C<>nlenl of Hormone" En'),mes.
and ImmunoreaCli>e Component" Oxford, R",.
810/, I: 262_82.1979.
187. Richart, 11., M .. and Darabi. K. F. Female Sler-
ili'"lion. Chap. 18. pp, 178_87 of G,eep and Kol>-
linsky. cds .. r.ferenee 94.
1871\. Rillem •. J. I\. Meehani.m of Prolacrin Aerion.
Fd. P,oc, 39: 2593_8. 19KO.
188. Rog.", B. 1.. Ueno. M.. and Yonagimachi. R.
Fertili .. rion by Guine. Pig Sperm.tO,,,, Re·
qui"'" Pm.«ium 10'". Bioi. 15: 639-48.
Inl.
189. Rosen. J. M.. Matu.ik R .. Richard •. D. A..
Gup". P.. and Rodgers. J. R. Multill(lrm(HIal
Regulati(HI of Clsein Gene E.press;"" Ir Ih.
T ranscriplional and PO&!I .... n.. riptional Lt>el, in
tbe Mammary Gland. R«. Pro:, I/orm, R.ch. 36:
In-87.1980,
190. Rowe, P. J. Th. Intrauterine Device : A Reviewof
Recenr Advances and Controversies. Oxford
Rtp,od. 8101. J: 49_94. 1981.
191. Ryan, K. J . Mainten."". of Pregn,ncy and the
Iniriati(HI of Labor. Chap. 16. pp. 291- )09 of Tul·
chinskyand Ry.n. eds .. ,tferenco 2J4.
In. Ryan, K. J. PbcoOl.I Synthesis of Steroid Hor·
mone. , Chap. I. pp. 3- 16 of Tulchin,ky and
Ryan. ed.,. reforenco 234.
193. Sadlier, R. M. F. S, Cyclo. and Season,. Chap. 4.
pp. 85_102 of Ausrin. C. R..• nd Shorr. R. v ..
ed, .. G"", C, II, aM Frnil/zallOll. Cambridgt
Universily Pre". Ne", York. 1912.
1931\. Sakaku .... T.. and Ni,hi>."k •. Y. Mesenchyme--
Dependent Morphoilene,i. and Epithelium.Spe-
cific Cyrodifferentiation in Mouse Mammary
Gland. Sci,,,,, 194: 1439_ 41. 1976.
194. Sax.n •. B. B.. liasan, S. H.. Hao"r. F..• nd
Schrnidt·GoliwilT.t;rn M. Radiore«pto< Amy of
Human Chorionic Gonadotropin: Dereclion of
Earl y Pregnancy. 184: 793- 5. 1974.
195. Saxena, B. B.. lnd Landesman. R. l>oc$ Impla.·
!alion (kcur in rhe Pre,ence of.n Rsch. In
Rtp'od, 10: \_2. 1978
196. Schallenberger. E .. Richardson. D. W.. and Kno-
bil, E. Role of Prolactin in rhc Lactational Am ....
orrhea of the Rhou. Monkey (Macaca
Bioi. Rtprod, 1:1: 370--4. \981.
196A, $chally. A. V. Currenl Staw. of An .. g(HIi .. ic An·
alog. of LH·RH a. a Contraceptive Melhod in
lhe Female. Rts. f'tonr. Fmi/irJ Rtg.: 1_16.
1983.
191. Scham •. D. Hormonal Conlrol of uClalion. pp,
21_48 of refe,ence 27.
197A Schauen. G .. ond Schauen. H. The Energetic
Egg. TM S,I",«. 13(5): 28-34. 1983,
198 , $chcdcwie. H. K., and Fisher, D. A. Perinalal
Miner.1 Ilomoost ... i., Chap. 19. pp. 355_86 of
T .lchinsky and Ryan. eds .. referenee 234.
199. Schmell. E. 0 ., and Gulya .. B. J. Mammali.n
Sperm.Esg Recognilion and Binding in Virro. I.
Specificity of Sperm Inreracrion. with U'e and
Fixed EU' in Homologou. and !loterologou. In·
seminarions HamSler. Moo .. and Guin.a Pig
Oocyle •. Bioi, Rtprod, 21: 1015-85. 1980.
200. Schwabe. c.. Gowan. L.. and Reini,. J. W. he>
lution. Relaxin and In.ulin: A New Pers,,".ri>e.
Ann, N.Y. AN/d, S<i. .ffl0: 6-12. 1982.
201. SChwabe. c.. Sleine", B.. Wei$$. G .. Segaloff, A.
McDonald,J . K.. O'Byrne, E.. Ilochman. J .. Car-
riere. 8.. and Gold.milh. L. Rel ..in. R«:, Pro"
/f"'m, R,,,h.14: 123_99. 1918.
202. Schwartz. N. B. Novel Peplide. in Ovarian Fol-
licular Implicalion. for Contr.eeplive [)c.
•• Iopmenl. •. Fronr. Rtg. 2: 1-1\.
203 . Seeli g. L. L.. Jr. Dyn.mie$ of Leukocyte. in Rat
Mammary Epirhelium DUring Pregnancy and
Lactalion. 8101. R<prod. n: 1211_17. 1980.
204. Segal, S. J. M<lhod. of Fcrrility Regul .. ion in
Clinical Trial. pp. 13S -46 of reference 49.
205. Segal. S. J, Sy<ternic ContTllgcstational Agentl.
Chap. 17. pp. 110_7 of Gr ..p ,nd Koblinsky.
edo .. reference 94,
206. Segc<wn. E. c.. Jr. Immunosupprosive Effect of
O'ine Ur.rine Secrelo,y Prorein upon Lymplt<>
cyt.. in Vitro. Bioi. R.prod, 15: 77_84. 1981.
207. Serbl\·Perrt. M., and Jaffe. R, B. The Feral Adre--
n.1 Gland. Ann. R",. Pltyslo/, 4]: 141-162. 1981.
208, Shafie. S. M, 8trogen and 'he Growth of Brea ..
Cancer: New E>idence Suggests Indirecl Acrion ,
Srlmu 209: 101_2. 1980.
2{)\1. Sharman. G. B. of Viviparity in Mam·
mal •. Chap. 2. pp. 32-70 of Au"in. C. R .. and
Shorr. R. Y.. ed •.• 7"h< E:wlurjon of
,0'011. Cambridge Universiry Pr"", New Vork,
1976.
210. Sharman. G. B. Reproducrive Ph)-.io\ogy of Mar·
.u pial$, SdtnN 167: 1221_8. 1970,
211. Shorl. R. V. Species Differences. Chap. 1, pp. I-
n of AU'lin. C. R.. a nd Shorl. R, Y.. ed •.•
production in Mamm"!" Cambridge Unive"ily
Press. New York. 1972.
212. Siiteri, P. K.. Feb, ••• F" Clemens. L. E,. Chang,
R. J .. G(HIdoI.. B.. and Srires. D. Progest.rone and
Mai nlen...e of Pregnancy. I. Proge .. erono No-

'" lur.', immun","pprtSU0l1 Ann. N.Y. Arod. Sd.
286: 184_96. J 971.
212A. SHier;. P. K. and 5,ites, D. P. Immunologic and
Endocrine Interrel ationshipS in PrttM""Y. Bioi.
Rtprod. 26: 1-14, 1982.
213. Siler·Khod" T. M ., .nd Khoor. G. S. Daoe Re-
' PO"'" Analysi. of GnRH Slimul'lion of hCG
Rei .... from Human Term Plaoenta. Bioi. Rt-
",<XI. 15: lH-8. 1981.
214 . Simpson, E. R" and MacDonald. P. C. Endocrine
Physiology of the PI.cenla, Ann. Rty. PhYJi<>I. fJ:
163_88. \981.
215. Smith, M. S .• and Neill. J. D. Inhibi tion of Go-
nadolropin Secretion During L.ctalion in the
Rat; Relative Contribution of Suckling and Ovar-
ian S'eroid •. 8io/. R.prod. /7: 1917.
216. Sperling. M. A. N..... b<>rn Adaplat;"" , Ad",,,,,"
conic.l Hormone. and ACTH . Chap, 20. PI'.
387- 408 of Tulchin. ky.nd Ryan. "<h.oreference
2)4.
217. Spcrolf. l.. Olas<. R. H., and Kase, N. G.
GylltCoiogic /:.·/ldoc,jll(}iagy and In/trlilily. 2d .d .
William, &0 Wilkins. Baltimore. 1918.
218 . Sriv•• t.v•• P. N .. and f.rooq ui. A. A. Studies on
N.u .... minidase Activity oIth. Rabbit Endome·
trium. Bioi. U .. 858-63, 1980.
219. Sriv.... v., P. N., rarooqui. A. A.,a nd Goold. K .
G. Stud ie, on Enzyme. of Chimp.n·
Semen. 8101. 15: 363_9. 198 1.
220. SI_B.r. 1\. W .. Sii",mon. A . Y .• and A .. R. H .
Gluco<onicoid Suppression of Pituitary Prolactin
Releue in the Nonhuman Primate. J. C/in. En-
doc,jll(}i. 53: 161-10. 1981.
221. St.ine". (I. G. Spe<ificity and Reliability of Ra_
dioimmu"",ssays. Rad;orecepto, A.... ys. and
lIio>",,)", Ann, N.Y. ANU!. Sri. 380.- 51 _9.
1982.
222. Stevenson.J. S.• COle. N. M .• and 11';11. J. II. Rote
or the O.. ry in Controlling Luteiniling Hormone.
F<>Ilici. Stimulating lIormone. and Prolactin Se-
cret ion Duril13 the After Lac tation in PiS" Bioi.
U: 341-53. 1981.
223. Ste"'"'t. D. R .. and Stobenfeldt, G, Relaxin Ac-
tivity in the Pregnant Ma .. , Bioi. Reprod, 15: 81 _
289.1981.
224, Stoncl'louse, B. Introduction : Mamm.'. and their
Environment. Chap. I, pp. 1-/0 of Gilmore, D..
and Cook. B.. cds .. Ellv;ronrmlllal FIX"". in
Mammal Rq",>t/ucrjOtl. Univ""i.y Press.
Baltimor •. 1981.
224A. Strickland, D. M .• S•• ed. S. A., CalOy. M. L.,
and MitCh.lI, M. D. Stimulation of Pro.taBlandin
Biosynthesis by Urine or the Human Fetu. May
u a Trigger for Parturition. Sci,,,,,, nQ:
HI - 2.1983 .
225. S"·,,ab. D. F.. IIoor. G. J.• Boer. K.. Dose'trom.
J .. Van Loouwen. F, W.. and Vi ... r. M, Fe.al
Neuroendocrine Moo nani, m, in D<:vciorm.nt and
Partu,ition. Prot. /(sd.. 48: 271_89.
1978,
CONCEPTION ANO PREGNANCY
226. Swanson. H. D. Human R.production. Odord
University P.. ss. New York .
221 . Sylvan, P. E.. Maciaughlin. D. T .. Ri.hardson. G.
S., Scully, R. E., and Nik,u;, N . Hum.n Ute,ine
luminal Fluid Pro.eins A"""iated wilh Soc.. tory
Phase Endometrium, P'ogcstcrone-lnduood Pro-
BloJ. R.prod, 14: 423-9. 1981.
22S. Takahashi. M., Ided", M., and Suzuki. Y. Criti.
cal Period ror the Occurrence of ProIong.d Ges-
tation in Lacta.ing Pregnant Rat •. BioJ. lI.pt(}d,
U: 241-52,1980.
22SA, Ta markin. L. Danrorth. D.. Lichter,A .. D<: Moss.
E., Cohen, M., Chabn ... B. and Lippman . M . 0.:.
cr .... d Nocturnal Pluma MeI. tonin p.ak in Pa·
tienlS wjth E.trogen Receptor Posi.ive B.. a ..
Cancer. Sci...,;, 216: l003-S. 1982.
229, Tot"m. H, J. Intrauterine Contraception. Chap,
19. pp. 183-202 of G ..cp and Kot>li",ky. cd •..
.. ference 94.
2JO, Thoma., K.. loomaye. E .. and Donne,. J. 1m·
munore.ctive ReI.. in in the P.rito"".1 F1uid
Dudng SponlanOOlls M •• muol Cycles in
Women. Ann. N. Y. Acad. Sci, .J8O: 126_/50.
1982.
231. Toppe'. Y. J .. and Freeman. C. S, Multipl. Hor·
mone !nteraction! in the DevelOpmental Biology
of the Mammo,y Gland . Ph}'sioJ. R",. 60: 1049-
1106.1980.
232. Tsena. L Hormonal Regulat ion or St.r<>id M.t·
aboh. "".y ..... ;n 11"",." E"domc,,;"m. Adv.
StX HOI'm. R'cA. 4: 329-361. 1980.
233. Tulch in<ky. D. The Postpartum Period. Chap. 9.
pp. 144-66 of TulohirISky and Ryan. rofc .. n«
234.
234. TulohilUky, 0 .. and Ryan. K. J.. eds.
Foral £ndoc'inolo/lJ'. Saunde", Philadelphia.
IggO.
23S. Turkington. R. W. Molecular Biologi •• 1 Aspe<1S
of Prolactin. pp. 111-21. and Dis< u$$ion of pape'.
pp. 121-H of WOhtenholm<. G. E. W.. and
Knight. J.. (Ciba
Foundation Symposium), Churchill Livingston •.
London. 1912-
236. Tu rkington. R, W.. M.jumd.r. G. c.. " adohamo.
N.. Madndoe. J. H .. and Frant>. W. L. Itor·
monal Regulation of Gen. bp .... ion in Mam·
mary Cdls, 11«. Ptog. HOI''''. R><h.
1913.
B1. Tyson . J. E-. Freedman, R. S .. Pe .. z. A.. Zac""
H. A .. and Zan.,tu, S. Significance of tho $ecre-
tion of Human Prolactin and Gonadolropin for
Puerperal L.otational Infertility. pp. 49- 64 of
.. f...n« 27.
BS, V.nT ienhove". A. ReproduOivt f'Ay,;oJogy 0/
Vm.bta"$. Saunders, Philadelphia. 1968.
2J9 . Verdugo. P .. Latorre. R., Alva .. ,. 0 .. Med.l. M ..
and B• ..,.. D. EffeclS ofCopperand Zinc on Rat
Utorinc Muscle Contraction and Rabbit IIlasto-
cyst Fluid Aooumulation , Bioi. Rtp""', 15: S02-
10.1981.
 240, Verll(ln. M, W .. la.y. M, T .. Asquilh. R. L.,.nd
Sh.rp. D. C, Proslaglanidn F .. in Ihe Equine En-
dometrium: Steroid Modulation and !'roouelion
Capacilie. during 1M Estrou, Cycl. and Early
!'re8""O<Y' Bioi. R,.pro<t, ]5: 1981.
241. Vill.16n. M.. Ortiz. M. E.. Agu.yo. C .. J ..
• nd CrO>..llo. II, B. Differenli.1 Tran,port of Fer·
tili'cd and Unfertilized O.a in Ihe Ral . 8;01. R ...
prod, 16: 337 - 41, 1982.
242. Walsh. S . W .. and McCarth y. M. S. Sdeeti.o
PI.cenlal Secre,ion of Estrogon. into Fet.1 and
Maternal Circulation. Endoainol. 109: 2I S2_9.
1981.
243 . Walson, P. F. The PtesCT>alion of Semon ,n
Mammal•. Oxford RtY, R,.pr'Od. Bio/. I: 283-JSO.
1919,
244. Wehrenger8. W. B.. MoNie"'. D.. Wardl.w. S,
L.. Frantz. A. G .. and Ferin. M. Dopami .. rgic
and Serolonergic InY"'",menl in Opiat •. lnduced
PrOlaClin Rd •••• ;n Monkcy$. Emiouinol. 1Q9:
1981.
We;$>. G, Hum.n Relaxin, Source and Slimulu,.
pp. 167-8 of Bryant·G.eeowwd et 01.. ed •.. rd·
<:renee n .
246. Weiu. G .. Stcinoll. B. G .• Dicrtchke. O. I .• and
Frill. G. Relaxin Seeretion in the Rhe.u. Mon·
key, Bio/, R.prod.}4: 565-7.1981
247. Wilkin. P. G. Organogene.i, of Ihe Hum.n Pia·
centa. Ch.p. 30. pp. 743_69 of DeH.an. R. L..
and Ursprunll, B .. ed •.. IflgaMgtllnis, 1I01t. Ri-
nehart and Winston. New York.
A·1. Ander<on. G. II. The Effect of Prematurity on
Milk Composition .nd ilS Physiological Basi •.
PrIX. 43: 2438_42. 19S4.
A-2, Conn. p, M.. H,ueh. A. J. W .. and Cro"·le)". W,
L If. Gonad01ropi n-reic.sing Hormone, Molec·
ular and C.II Bi"'ogy. Physiol"llY. and Clinical
Application,. F.d. Pro". 43: 2351-61. 1984.
A-3, Coward, W. A.. Paul. A. A.. and Prentice. A, M.
The Impac, of M.lnu"ilion on Hum.n LaCI.lion:
Ob .." .tion, from Comm unity S,udie •. Fed,
Prtx. 4J.. 2432-7.1984.
A·4. Ilartmun. P. E ... nd Prosser. C. G. Phy.ioio&ical
I II T1I< i"hibilOr)" inHucnc." c, ".rre" or rev."", p«<OCiou.
pub<rl)' .nd in""" " ..,die.1 <.11 .. ,;.,."' in palieo" "",.
1OO<'I<..:t,pe ••;ko, '"""'" (A-2).
11 ] tocOnlplcle mal."I;"" of,o< m.m""'t)' m. )" "pl.in
th< high p""<i" and """. lipid.nd , upr ton,,", of mi l). pro-
247A. Wbyte, A. and Heap. R. B. Early Pregnancy foc-
!<>•• Nor.,.. 304: 121-2, 1983.
2478. Wilk$. J. W. Pregnancy Interception with a Com·
bination of Prostaglandins: Studi.. in Monke),,>.
Sritrw221: 1407_8. 1983,
247C, Wrigh t, L. J., Feinstein, A.. He.p. R, B.. S.un .
ders. J. C. Benneu. R. C. and W'''<l, M.· Y. Pr0-
geSterone Monoclonol Antibod)" Bloc ks Preg.
nancy in Mice. NalU,.. 295: 41 5- I 7. 1982,
248 . Yochim, J . M... nd Manoneo, R, C. Hormonal
Con,,'" or Pyridine Nucleotide Activily in the
Ute,us: A Model f<>r Progestation.l Differentia·
tion, Bioi. R. proO. 23: S95-t\Q5. 1980.
249, YO$hinaga. K . Hormonal Inl.rpl.y in the Estab-
li.hm.nt of Pregllaoc)", Chap, 6, pp. 201-23 of
Grecp. R. 0 .. ed .• RtproducU'" Physjoioty II.
Uni.ersity Park Pres.s, New York. 1977.
250. Young. I.. G .. and Goodman. S. A. Characte.i,a·
tion or Hum'n Sperm Cell Su,face Components.
Bioi. 1I..",od. 23: 826-H, 1980.
251. Zaneveld. I.. I. D. Sperm En,yme !nhibitorS for
Vagi".l .nd Other Co"t .. •. Front.
FmUi,y lI."g, 2: 1-14. 1982.
252. Zarro,.. M. x.. Y«him. J, M ., and McCarthy. J.
L. Exp"jrntllIQ/ End()(rj'f()/ogy. Academic P......
New York, 1964,
253 . Za,uchni. G. I.. and Osborn. C K, GO$,ypol: A
Pouiblo M.lo An'ifenility Agenl. RtJ. Fronl, jn
Rtg, 1(4): I -IS, 198 1.
154. Z.idcIl$IOin, G . The Nood for Now Con,,,,ccp-
ti •••. pp. 3-2J of ",f.rence 49.
Ba,i. of Longitud in.1 Changes in Hum"n Yield
.nd ComjXl$ilion . F.d. Pro.;. 43: 2448-53. 1984.
A·5. Qian. S·Z .. and Wang. Z·G. GO$Sypol: A Poten·
tial Antifertility Agonl fOT Males. Ann. R"".
Pharm. Pharmaroi. Toxicol. 14: 329-60.1984.
A-6. T urncr. p, ll... Shcctz. M. P .• and Jaffe, L A. Fo ...
tili'alion !ncrea,e, the PoiyphO$phoi11O:litide Con·
lent of Sea Urchin Egg •. Nmuff 310: 414_5.
In4.
A·1, Inv .. tiga'ors Manual fo. NORPLANT Subder·
mal Impl.n". The Popuialion Council. New
York,1983.
soon .fI" ,he IMrlh ol. prem.t"," infon, (A-I). flor-
changes pfObol>lr oe",,"", for the .ller«! """pooilion ,h.1
" ".... 1
foil"". of ...."''' ••1 erele. or pr<J,n'ncy (A""').
In poorly "",<fi.hed "ornen, dietary '.Wle"'"",, OOn " is< lOe
vitam,n !<vel., flQ"·e""r. lOe)' ore lOOI"e e!T«li .. r", 00«1e"""8
... ""bt;.h .... ol ol ferl;t ;ly Ih." for iocr• .,inl milk ),ield (A·J).
___ PART VI _ __

Hormones Affecting Body Size and

Composition
 17
Thyroid Hormones, Thyrotropin, and Thyrotropin-Releasing
Hormone
Genetic factors determine whether a 1.ygOiC can de-
velop into a small frog. a long-necked giraffe. or a 9·
banded armadillo. Nutrients permit realillllion of
the po\cnlial. since they provide both Ihe building
blocb and the energy souree:s- but diets deficient or
overabundant in one or more CQmpOnents can impair
de.cklpment and bring about imbalances in body
CQnst;tucnts. All of the hormones affcct nutrient use,
and many exert innucnces on nucleic acid functions.
The iodinated thyroid hormones arC major regula-
tors of metabolic raiC. food intake. and the dilTcr-
cntialion and mmuration of numerous cdl types .
THYROID G LAND S ANO THEIR HORMONES
The thyroid glands of healthy human adults weigh
20-40 g, and they lend to be larger in females than
in males. The right and left lobeS straddle the tra-
chea and extend upward from the 5th ring 10 the
sides of the thyroid eanilages. A thin isthmus joins
the lobcsanleriorly. and a small pyramidal lobe may
project above il.
The rich blood supply enlers mostly via the supe-
rior thyroid artery branches of the external carotids
and Ihe inferior thyroid vessels that originate in the
thy=rvical trunkli of the subclavians. The blood
drains from the superior and middle thyroid veins
into the jugulars. and from the inferior thyroid veins
into the brachiocephalics. The flow rate has been es-
timated at 4-6 ml/min/per gram of tissue. but it
can exceed 1 liter/min in seVere hypenhyroidism
(75) . The parathyroid glands are embedded within
the posterior portions of the thyroids. and they are
enclosed within the connective tissue sheath. They
receive blood from the inferior thyroid an.ri.s. An
extensi", lymphatic vessel network takes up $Orne of
the hormone •.
Postganglionic sympathetic fibers from the supe-
rior and middle ecf'ieal ganglia terminatc on both
blood vessels and glandular cells . Parasympathetic
fibers are supplied by the vagus nerves.
The glands collectively contain $Orne 3 million fol-
licles. cach made up of a single layer of epilhelium
that encloses a central lumen (Fig. 2-1). Follicular
diameters range from 50 jJ. or less to 500 jJ. (96). A
typical epithelial cell is columnar. with a height of
201'. but the shapcS vary from squamous to high c0-
lumnar (even within different follicles of thc same
gland). The ba>ophilic cytoplasm of an active cell
contains a woll-dcveloped endoplasmic reticulum
with numerous f')Iysomes. many mitochondria. Iy-
sosomcs. and inclusion droplets, but 110 "truc" secre-
tory granules. The large Galgi apparatus is near the
apex, while the also large nudeus is centrally 10-
ClUed. Stimulated ceU. extend microvilli and pseu-
dopod-like projections toward the lumen. A thin
lamina separates the basal surfaces of the cells from
th. blood and lymph capillaries. The small numbers
of parafollicular cells engaged in calcitonin synthesis
were described in Chap. 12.
Thryoid anlagen are present in 16-17-day-old
human embryo&. The enzymatic and structural C<)m-
ponents required to synthesiz<: thyroxine arc ac-
quired by day 14. The early differentiation, which
includes organiUtion of thc cells into follicles. can
proceed without pituitary hormone stimulation (5!).
Thyroid glands of rat', mice and many mher specie, .1..,
have right and left l<>bes joined by an i'thmus. Some
other mammals have a $ingie. ventrally located o,son,
and yet different anatomi",,] a"ansements have been do-
$Cribed (64). All vertebrate> have tccognitable
but they take tbe form of dilfu.. cell clumps in
cyelostomes.
Thyroid glands are among the largest of the en-
docrine Structures. and they po::;sess several unique
'"
fcaml'd. They produce a hormone that CQf1tains a
special dement (iodine) and \yrosyl moieties joined
in clher (rather than peptide) lin kage. Much of the
bi<lSynthesis is extracellular, and a precursor thai
can rapidly be converted to active horm()ne Slored
in the lumina in quantilies sufficient 10 support met-
abolic needs for many week!;. Bits of thyroid tissue
a. well as thyroid hormones can be administered
orally 10 correCt deficiencies. The superficial loca-
lions of tbe glands make it possible for untrained
observers \0 detect goiters (thyroid gland enlarge-
ments), and lhe beneficial eifc<;\s of fceding iodine-
rich seaweed have been recognized since antiquity.
A single, moderate sized dQ'ic of thyroxine exerts
metabolic effccts for 2 or mor. weds, and 4-6
weeks of continuous (...,almcnt may be required to
fully ,<,Slore the metabolic ratcs of thyroid..Jepleted
subjects. Many of the actions havc long latcnt pe-
riods. and Ihe elfecls of thyroidectomy develop
slowly. Thyroxinc cnters cells and &OITIe of ils
actions within the nucieus. but no cytoplasmic recep-
tor is required.
Although hormone deficien9 can profoundly af-
fe<;t rTI05t bodyccll types, lhere are those who believe
that thyroid hormoncs are not essential for survival.
cV<'n some of Ihe pioneers of thyroid phys·
iol02Y Questioned the notion (7). Hormone-like ac-
tivity has been detected in the livers of rats 4 months
after oomplete thyroidectomy (long after the hor-
mone has disappeared from the blood and thc ani-
mals have developed severe symptoms). At 6
months. the substance can no longer be found. and
most animals die (98).
OBVIOUS MANIFESTATIONS OF
HYPERTHYROIDISM
Palients secreting excessive quantities of thyroid
hormoncs are -restless. hyperactive. irritable. and
emotionally labile. They have shortened attention
spans. and they usually sulfer from insomnia. In cx-
treme cases. there are signs of psyeholosical disor-
ders. T he mO\lements are rapid. the reflexes are ex-
aggerated, and fine, involuntary tremors are
The hormones inerea,. the fOKe of myocardial
contraction. hastcn conduction, and may elevate Car-
diac output and systolic pressure . Howe,""r. Severc
can shorten diastole to the point where
filling is inadequate . while influences On the electri-
cal system can bring on atrial fibrillation .
The high metabolic rate elevates body tempera·
ture, despite cutaneous vasodilation and sweating.
The victim feels warm at environmental tempera·
tures judged to be comfonable by normal persons.
THYROID HORMONES. THYROTROPIN AND TRH
The increased oxygen needs, weakened respiratory
museles, and diversion of blood to oxygen·poor s kin
probably all OOntribute to the dyspnea that is often
manifested (75) .
Although appetite and food intake Can increase
dramatically. both dehydration and depletiOll of fat
stores tend to lower the body weight. Gastrointes-
tinal motility is stimulated. and some individuals de-
velop nausea and or experience boUIS of
diarrhea. Digestive system cn7.yme secretion can be
but stomach acidity tends to be low and
there is poor absorption of lipids. Hepatic glycogcn-
olysi. and rapid sugar absorption Can elevate the
blood glucose.
Skeletal muscle weakness is attributed to a com-
bination of accelerated protein degradation, defec·
tive creatine metabolism. and neuromuscular tranS-
mission impairment.
[.(lng-term oonsequences include disruptiOll of re-
producti ve systcm functions. (Amenorrhea is com-
mon.) The hair becomes excessively fine, the finger·
nails are brittle. and the skin may show patchy
pigmentation.
OBVIOUS MAN IFESTATIONS OF THYROID
HORMONE DEFICIENCY
Adults become apathetic, sluggish. and somnolent.
Hearing defects and other sensory impairments are
COmmOn. The term "myxedema madne .... has been
appl ied to the psychological symptoms that often de-
velop. Some patients hypoventilatc.
The heart tends 10 be Habby and dilated, the force
and rate of cardiac oontraction are depressed. the
blood volume is low, and both systolic and pulse
pressures are subnormal. T he diastolic pressure
often remains within the normal range.
An inade{juate metabolic rate lowers the body
temperature despite CUiallCOUS vasoconstriction and
decreased sweat gland activity. The skin feels cold to
the touch, and the patient cannot cOpe with oold en-
vironments. Depressed sebaceous gland activity dries
the surface while other influences on the ski n deriv·
atives account for the spam:. coarse facial and body
hair and the brilt1e fingernails. In se'-cre. chronic hy-
pothyroidism. hyaluronic acid and mucoprotcin s ac-
cumulate under the skin and bind water. The hands.
feet, face, and tOllgue become puffy. and specch may
be impaired. The term myxedema designates the
condition. [t i. associated with loss of the normal in.
hibitory inHueoces of thyroid hormones on glyoosa-
minogtycan accumulation (I 25) .
Gastrointestinal functions arc inadequate. Some
individuals eat more than Ihey can metabolize. but
many sulfer from appetite loss. Constipation is com-
 mono ReprQductive system can include
menSirual bleeding.
Crellnl.m
Ahhough the symptoms of adult thyroid d)'$fuoction
can be 100aily l"<'versed with appropriate hormone
suppkmcnts, thyroid deprivation thnt begins in fetal
life and eonti nues through infancy Icads to rrelinism.
The .micted individuals fail to undergo nervous,
skeletal. and reprQduclive s)"Slem maturation. and
they may not 211 feel in height if no treatment
is proo'ided. Delay«! administralion of th)"ro;d hor-
mones can heave dramatic elf«u 011 the bones and
reproductive organs. but the bnlin damage is
perlT\f;ncnt.
THE BIOSYNTHESIS OF THYRO ID
HORMONES
The follicular OI:lIs iodide. iTl<Xlrporale
the ions into high molecular w<:ighl gl)"COproteins.
and store hormone precursors ",jlh in the lumen. "The
pr«:' sses arc inlerdependenl. and Ihey occur simul-
laneously. but il is convenient to discuss lhem as so:p-
arale cven15.
Uptakl and Concentration ollodlna
Allhough the clcmenl is avidly con§crved. the supply
must be rcncwed from dietary $O<IICCS. Human
aduhSlolcrate intakes lhat range from 0.5 to several
milligrams daily (75). and they can withstand ic>-
dine-frw diets for brief periods.
I is rapidly and efficienlly absorbed from lbe:
small ;ntesline and trarosponed 10 Ihe th)·raid. Ex-
tlmcellul ar nuid concentrations are in the range of
1.0-1.5 !'I/d). BI<xxI plasma 31$(/ cOlllains 3.5-8.0
I'a/dl of iod ine Ihal is incorporated inlO organic
eom.,aunds. buI such molecules canOOl be directly
utiliw:l.
When the diet is adequate a nd er.docrine func-
lions are normal. folli<:ular 01:1 1$ aOl:um ulate the ion
and aChieve th)"roid:plasma (T/ ft) or lliyroid:serum
(TIS) ralios of 20 or 25:1. In iodine deficiency
Sla le$. T / P o;an CJlC«d 300: I.
wi.h bu. lw impress; •• lbi]i.i<;$ to
inor"" nic iodide include ,,$lrk mucosa. in_
.es.il"lC. Illi •• r)" and mammary , lands.• kin. hli r. eryth_
rocytes. choroid pl.,u •. cil.,y bodie,. and pl acen,.. They
COlI"ilaote to iodine COtISCrv.liod by dellyin, loss into 'l>c
urine (S). (The u.se 0( Ki lO "Iooocn" a dry COIIlh depends
"pool tcC1Imulll ion 0( ion I nd the . uo.:iated ,"at,,, "p"
lI te by purynsul m _.) Uowe ..... . he 'hyl"Oid
,I.nd,an: in tha. d••y . ,.. in hilltoer 1- """""""
1'"lioN.. ..... the ions '0 make borrnorccs. Ind ha", uptake
r..".".,ive ' 0 thyrotlOll"in and some other
"imulanll.
Ihe acinar are rich in iodide and are
electronc,ative wilh rcspecllO lhe interslitial fluids,
Ihe ioros must traverse the basal pI.sma membranes
a8lil"dl bot h concenlflliion and eleclriQlISflldients..
Olycol)'$is can provide some of lhe A TP energy lhal
IUppol"lS lhe prooesses, but alenl' such as amylal,
IOICIIOIlC . an limycin. and oI ilomycin (",hich aCt on
mi tOChondria 10 impair A TP formalion). uncouplers
or phosphorylation. and all imerfel"<'
"'ith iodide accumu lalion and use.
I - e••f}' probably in ..... vcs N.' <>O-.rllllSjlOt1. low n.
tra«llular N.- depc l", ,h. uptake (14). AgenlS 'MI
.poIlriu may iocTeaK it by .. 1'01. ' en, ry_
n. """ibillty Itt.a, ]- is .""""tlP l<lf HPO'- lw; also
betn consi.rcd (lS). Roles l<lf plasma .... mb"'M-aDO-
cilled N. '/ K '-ATPa.. are W1ltn»emal. DIIaboi. de_
preson bu' docs 001 '01.1Uy block iodide accumul'lion
(lOI. hs elfects .re r.versed b)" hi,h e"'.. cellula r K '.
Extr. c.llul . r Mg" i. no. absolut. ly r.quir«! in .cut<
Iludies. bU .lh. cell may "or•• """Ih aft hat ion.o main-
lain .he 1\ TPI.. aClivily
The tran.port evidently invol"es. "l"'c;i!\c iodide car-
rier. I, .... y be. lecithia.
COftOCtI,ra,iono . ilhin ,he lumea .xcoed .hose
blood pl.$frUI. bul Ih.y .... 'han ,,- ";,hitl lhe
cells. It hI$ bet. "'""'tcd lhal 1- dilfuscs
clown. _ntralion .radi.n, lrom c.II,o I..... n. lIow-
... ilh perehlora.e I nd some ot her ag.n .. ,ha,
atr.et iodine metabolism suuest Ihatt h. uehange. be-
""0<:. cell, and lumen a re ca rrier-m.dialed and
regUlated .
The thyroid ,land. tonilin some 9()';\ of totll body io-
di ... """'". mostly in orpnic: molecules. Oeiodic\aSC$lib-
erat. small amounu.. and free ion CIt" "leak" to tM l ur-
roundi", lIuids.. Studies "" hypOphyscctomi.cd .....
"'won lhe i• • IMI there is """ pwI ••i.... from bko>d
plasma IIIaI .«011"'" or
f<lf 4'1. Lht "orcs .nd hI$ •• ur...
over rot. of 8 days. A sccond larger .nd sto-I)" .e....... bl.
pool i, linked with lhe d.indina,>ons
The rll.s of lransfer from blood 10 e.II."" from cell
'0 lumen arc affec •• d by Ih. relaliv. ptrrncabHitk. of .h.
bas"land .pical m.mbra ..... M extracellular and in. ",_
cellular co ..... ntr. 'ion$ of several ions. and .he .c.i.itk.
01 ....ymcl'hat tatl lyz;c I- il\COfpoution into and r...
lea .. from <><pn;" motccules. A,en" 'M' reduo; boAl
.... mbra ... permeability tan r:aisc: ,he in.",cellular iodine
by relordin, "", .... rd leakaI"C ( 30). Bitar_,. iono are
belic..d LO compete ";th iodide f<lf membn"" tbn ... b.
and <:arbonic .nh)"d ..... inhibi.ors may ineru.. lumi ....1
and d«n:ase cellulor I by Iow.rina Lhe inlracellul ••
HCO, . h i. fIOI k"""n if.he requiremenl lor e ..",ce\-
lul>l C. " i. rel •• ed ' 0 en'ymt ICl ivotion. m.intenance
or .h•• I«.rical potential •. <If both.
8r -, AI - . perchlorate (CIO; ), pertechnela,e
(T<:O i), and nilrile (NO; ) arc among the mooo-
valenl anions that Ql n be con«nlraled in Ihyroid
aland,. They promote release 0( inorpnic iodidc. in
pi" because lhey compele for tmnspon. At least
some additionally interfere wilh iodine incot"pO<lltion
into proteins.
'"
Circulating 1- is freely filtered by the renal glc>-
meTal; . While much oflhe ion is reabsorbed. urinary
excretion usually parallels dietary intake and ac-
oounts for most of the iodine loss_ Minute Quantities
of iodine: leave the body via the expired air and
sweat. Larger ones 31"¢ 5(:nl into the milk during lac-
tation. The feces remove around 12 "8 of iodine per
day, almost all of it in organic form.
Blo8ynthesls of Thyrog lo bu lin.
Thyroglobulins aTC spe.;ies-spccific giyroprotcins
with molecular weights of 650,000-670,000 that
contain 8%-10% carbohydrate. Microheterogenci-
lies, even within a single gland (42), are attribute<:!
\0 variations in carbohydrate and iodine conlent and
to the numbers of cr<)SS-iinkages. Human glycopro-
leins have molecular weights of aroond 660,000.
With rew exceptions (e,g. guinea pigs. which a lso
make unusual insulin!. growlh hormorn:s. and Olher
proleins). Ihe amino acid sequences art remarkably
similar across Ihe speeies.
Biosynlhesis begins wilh poIypeplide ehain assem·
bly. Allhough "gianl" polysomcs have been de-
scribed (140), each of the subunils seems to be made
on its own organelle. labeled 125 proteillS can be
identified soon after the cells are presenled with la-
beled amino acids. These evidently combine to form
175 "prethyroglobulins" (75). Protein synthesis in·
hibitors block formation of the 125 nt()\ecuies but
not the associations into larger ones (140).
Galacto:;c is rapidly incorporated when the wm-
pleted amino acid chains enter the cisternae of the
endoplasmic reticulum. Mannese and fucose are
added as the protein traverses the Golgi region. The
"core" oligosaccharide undergoes processing, and
sialie acid is then added.
The glycosylation seems to be essential for secre-
tion of thyroglobulin into the lumen. II may addi·
tionally be required for a&.soeiation with
idase, a glycosylaled enzyme that i$ described later
(4SA).
175-185 forms recovered from the cell$ contain
many exposed tyrosyl moieties. Iodine attaches to
them and increases the molecular weights when the
protein reaches the apical membrane-luminal border
interface (75). Or possibly just after the molecules
enter the lumen (69), Within the lumen. the iodi-
nate<:l glycoprotcins undergo "maturat ion" that in·
volves peptide chain folding and the formation of di-
sulfide bonds. ( Iodinated glycoproteins are the major
constituents of the "colloid" within the lumen.)
''True thyroglobulins" contain 4 polypeplide
chains. At first they are 195 proteins with approxi.
mately 120 tyrosyl moieties. As they mamre, they
incrcase in weight to 27S (and sometimes 325). as
THvROtD THYROTROPIN A ND
thcy acquire additional iodine and become increas-
ingly resista nt to hydrolysis. Only some 70% of the
tyrosyls can be iodinaled because of the folding.
Un:a and Olher denaturing agents facilitate addi-
tional iodine attachment,
Incorporation of Iodide Into Thyroglo bullna
The 1- must first be oxidized. The form of the ac _ n
t;vate<:l" intermediate i. not known. It has variously
been prol'O"d to be elemental iodine. iodinium (['),
hypoiodile (01 - ). Or a free radical, but a rguments
against the first of these have been presented ( 137),
The o,idali,," i. associated with the generation of hy.
drogen peroxide (H,o,) from molecu lar 0, plus h)'dr'"
gen. donated by pyridine nuciCQtides. The cells
have a heme<ontaining peroxidase which probably par·
ticipates in iodine incorpor.tion as well as H,O, gener.·
lion. The enzyme acts in vitTO to ellalyze pero.ide-de·
peodent iodinali,," of a wide variety of proteins, Agents
lhat with H,o, generation block thyroglobulin
iod in3tion . and 000$ used 10 block iod ide organification
retard iodide o.idalion_ The I"'ro. idasc been 1«.1·
i,cd to tbe .pic.1 (luminal) membrane. and. ring of ra·
dioactivity apl""r$ thtre when labeled iodin< i, p=nted
10 the follicles (150).
It has been propo$<d that the pentooe pathway provide'
NADPH. Ind lhal a flavi n'<'Onlainine NADPH.."idase
Catalyles the transfer. A vitamin K, cof.ctor may react
directly witb molecular oxygen to form frec radical.
(137). Ascorbic acid. reduced glutathione, and othe r rc·
duct"nt. within the folliCular etn eytoplll$m art impli.
caled a. physiological inhibilOr$ that .ct on either the io-
dine intermedi.te or the hydrogen peroxide (75).
The iodine combines wilh tyrosyl moieties of the
thyroglobulin to form mostly 3-monoiodo and 3,5-
diiodo derivatives. The glands contain small quan·
tities of monoiodotyrosine (MID and diiodotyrosinc
(Oln. but these are formed when the iodinated pro.
teins are hydrolyzed , Iodine does not attach 10 free
amino acids. and no iodinaled amino acids arc in-
eorporate<:l into Ihe thyroglobulin _
Couplin g ReacUons and Fo rmat ion of
lodothyro nlnes
While still attached to the glycoprotein. thc iodi·
nated moieties interaCI 10 form elher linkages, Thc
reaclions culminate in Ihe production of the pr«ur-
501'$ of thyroxine (tetraiodothyronine, T. ) and T,
(triiodothyronine). The molecular mechanisms have
not been defined.
One hypothesis for the coupling reaction Ihat
leads to the formation of Ihe T. precursor prOpOSes
that peroxid(ll;c catalyzes generation of diiodytyrosyl
free radicals. which combine to form a quinol ether
intermediate that is subsequently hydrolyzed.
 Splining of the quinol ether intermed iate would The peroxidase may Ihen catalyze o.<idalion of
then yield ei ther a serine or dehydroolaninc ",sidue DIHPPA to DIHPPA-hydropcroxide, and i( is pr\l-
at the site formerly occupied by one diiodotyrosyl posed that the latter combines
moiely. wilh a diiodolyrosyl moiety of thyroglobulin 10 yield
a lhyroxyl residue. By-products of the reaction
I II would then be ammonia (inoorpor3ted into other
amino acid,) and pyruvate.
" I
I (:= 0

o , C1l
I
'-
, II I
' C_
""
, O
Formation of T, presumably follows a similar
pathway, but different amino acid ..,quences are in_
volved in tlte coupling reactions (A-I) .
Very small amQunts of DIHPPA (and of its mQn_
oiodinated analog, MIHPPA) have been detected in
thyroid tissue.
11 is unlikely that thyronine formation evCr pre-
cedes iodination. since no uniodiMted thyronine has
ever been found in the gland.
When the iodine supply is abundant. mostly diio.
dotYl"QSyl and tetraiodothyronyl moieties are fornled.
'I"".' " ...,
,,"" ",,<I,... In deficiency states, the quantities of mQnoiodOlyro-
syl and triiodothyronyl components increase.
The Fnllnwing "'luMinn< <hnw , . I.. inn<hil'" ht,_
, tween M IT. DIT. and the thyroid hormone precur-
, "
::':11 sors. They do not, however. depict reactions that aC-

"""
C _ II c _ (; tually take place within the gland .
"0 I According to some estimates. the T.:T, ratio is
", " " ", " 10: I in iodide-replete states Small amounts of diio.
dothyronyl moieities may also be formed.
",." I " , .h., I,.h"," I " ,.h.,
An alternate hypothesis is thaI a diiodotyrosyl res-
idue is first deaminated to yield 4-hydro.y·3,5-<1iio- Proteol ysis and the Release 01 Free
dophenyl pyruvate (DIHPPA) which is then ta UI<>- Hormones
mcrized \0 Ihc enol form. Although some thyroglobulin seems to be taken up
I );H, 0 by the major mechanism is macro.
pinocytosis, Thyroid stim ulating hormQne prOmQtcs
"
, II 1/ the formation of til(, pseudopod!; that from
the apical surface, of the follicular cells into the lu-
mina. The pseudopods engulf small quantities of wl-
'"' laid, and "oolloid SOOn appear in the cyt<>-
plasm. The fUM: with Iysosomes to form
"phagolysosomes" oomaining cathepsin D a nd other
hydrolytic enzymes. Microtubules and mierofila-
ments direct particle translocations, After disulfide
.. ,,' UUI,'I'A
and peptide bonds are broken. free T •. some free T"
jT."'"....." and smal! quantities of iodinated peplide$ are "'-
lea..,d to the extracellular Auids for uptake by the
blood capillaries.
Newly synthesized and newly iodinated thyro-
globulins form rings that border the peripheries of
the lumina. with the poorly iodinated components
IllIll'l'A ,001 r,.", closest to the mcmbrane-col!oid interface. Because

'"'
of the location and Ihe presence of fewer disulfide
bonds, recemly synthesized 195 thyroglobulin is
"preferentially" up. Since the pseudopods ex-
tend several microns beyond the luminal border,
they bypass the region that contains uniodinated
molecules {48A). Intracellular deiodinascs conV<'rt
minute quantities of T. 10 T, (and to traces of re.
verse T,. which is described laler). However, the en-
zymes function primarily 10 recover iodine from bi-
ologically inactive mokeul.,..
Small quanlili .. of poorly iodinated thyroglobulin of
10... mQl«:uiar weight are present in the blood. They a,.
belie.ed 10 get there via direct pa ..... ge from the COUS10
lit<: lymph v....,ls without prior entry in10 lhe lumen (13).
Thyroid glands ,ynthe,;ze lhyralbumin (which rOSem-
THYROID HORMONES. THYROTROPIN "'NO TRH
bl.. pla.ma albumin) and SOme Othor ;odin. ted prOt.ios.
No functinns for the,e ,ubstance, ha •• been establi.hed
(and the iodination may be: fortuitous). SUrgical manip.
ulations of the gland •. infection •• and ",me pharmacolog.
ical agenu .ccelerat. lhe r.I .... of ,u.h prot.i ... Som.
are bclieve<lto initiate aulo-immune r.action. ,
Thyroid Hormones In t ile Blood Plas ma
Normal human adull blood contains around 8(l()O
(4000-11.000) ngldl of T. and 120 (SO-I 80) ng/dl
ofT) (75). Since it binds wilh high affinily to plasma
proteins. only some 2 ngldl (0,03%) of Ihe T. is pres·
enl in Ihe "free" or "aclive" form. T, associates
more loosely wilh the proteins, and 0.4 ngldl (0.3%)
is readily available for ew)' into the cells.

, , , ,
I O\J---{! "II hX)lt + 1 1 0
II :>.'11, 11 "II ,

, ""
_t'
, ""
C_ (· - C()(JII

"'9 "-0 " " ",''0'''"' .T"

( '- ('

A I,",",

IlO
0, "" "
• ('

"._",.. ""
",
"U, + III

9 ""..
__
- C
H
"H
('- looll
V 9-"'",
" ,_ _()_. _ Irii- COOII
Tn .... .. ' " " .. "" .,," . A I. . ,,,.

The plasma proteins perform "reservoir" and
"buffer" functions. protect the hormones again't ex·
cessively rapid degradation and excretion. contribute
to control of the targct cell uptake. and may also fa-
cilitate normone transport through the bloodstream.
Some extrathyoidaltis.sues produce substances that
impair the binding. There are pathological condi-
tions under which they arc released in large amounts
(28).
THYRONINE BINDING GLOBULIN (TBG)
15-77% of the circulating T, is associated with neu·
raminic acid-rich a-glycoprotcins with molecular
weights of around 60.000. (Relatoo molecules
"'eighing 58.000-63.000 and contain ins 15%--22%
carbohydrate have been identified in IIOnhuman spe-
cies 131ll. The proteins were 3t collectively
known as thyroxine binding glohulins. hut the name
was changed when it was dcmonstrated that there is
interaction with T, and with some other T, metab-
olites. Each molecule bears One hormone attachment
site. but u,ually there is only 30% occupancy. The
total TBG concentration is 1.5-2.0 mgfdl. Although
the functions 3rC regardoo as important, they are ev-
idently IIOt essential. Humans with genetic defects
that block synthesi' of the proteins can be euthyroid
(110).
The proteins are made in the liver. Physiological
amounts of thyroid homoncs are needed to maintain
normal concentrations in the blood. but toxic OneS
lower the levds ( II 0). Stress. glueocorticoids. acro-
megaly. and some debilitating illnesses lower the
production rates. and salicylates are among the
pharmacological agents that decrease thc binding af·
finities. TBG is higher in children than in adults.
Since estrogens accelerate the production in humans
and monkeys. the plasma concentrations are high
following the ingestion of oral contraceptives and
during normal pregnancy. Androgens lower the lev-
els. but men and women have similar concentrations
of unbound hormone.
Control systems differ in other mammals_ Estro-
gens do not affect the levels in rats. The protein' do
1101 bind thyroid hormones with high affinity in most
IIOnmammalian vertebratcs (149).
THYROXINE BINDING PREALBUMINS (TBPAs)
These are I.tramerie proteins with molecular
weights of around 54,000 that bind an additional
15% of primate T. but have liltle affinity for T,. The
tW<l binding sites differ from other, and kinetic
studies are consistent with m:gati'e cooperativity
(I I 0). Usually more than 99% of the T,
sites remain (31). Plasma
al"<' around 30 ngjd!.
Seriou. ilt n..... depreu TBPA prodUCI;OO (\ 49) . • nd
salicylales. ba rbilurates . • nd penicillin are among Iht
agenlolhat decrea .. lhe binding to T. (75). .....
trogen, d""rea .. while androgens Slimulatc proouetion.
and the levels arc low in thildren.
TB PA. may perf.".m other funetiooo. R.tinol bindinll
proteino (R BP.) h.I'<' molecular _ightS of 31.000 00<1
single attachment .ite, for vitamin A. Each TBPA mol·
""ule complcxes wilh 4 of RBP. Retinol stabilius lhe
<Xlmpiexeo. whereas T, is wi tbout influe""e .
PLASM A ALBUMINS
These prote ins bind with low affinity but high capac-
ity. Each molecule has $everal altaehment siles for
T" one wilh much higher affinity than the oth.rs
(31). The prop.. ties of the prolein facili tate rapid
aSSOCialion with Ihe hormone when T,levcls ri.e. but
also rapid transfer to thc la rget cells. AlbumillS have
molecu lar weighls of around 69.000 and thcy arc
prescn t in 3500-5500 I'gjml concentrations. Usu·
ally thcy bind around 8% of the circulating T,.
Ma la bo ll , m or Thy ro )(ln.
Normal human thyroid glands $ectete approxi.
mately 90 I'g of hormone dai ly, most of it as T,.
Small amounts of T, a re also .. lealed . and minUle
qua ntities of other iooi nated thyronincs and of M IT
and D IT arc present in Ihe venouS em uent.
gO% of the secreled T, undergoes sequential de·
iOOinations Ihal in the forma lion of the
metabolites shown in Fig. 17-1 (7 5). 35% of the IOtal
is converted to T, a nd around 40% to '·reverse T,··
(rT,). The liver is Ihe major site for
and il releases substanlial quantities of Ihe products
10 the bl<X>dstream. Kidneys have lower
activity. bUI they. too. CQnlribUle to the plasma T,
levels. Hypothyroidism lowen; Ihc ,clivilies (A·2).
Most observers that T, is thc primary (and
po:ssibly Ihe only important) iodinated thyroid hor·
monc. Targel cens that take up T, contain dciodi-
nases. and also proteins Ihat bind T, with high
affini ty.
rT, is widely regarded as a degradation product.
Its forma tion may provide proteclion against hyper·
thyroidism. since the T, used in Ihe rellctions is no
longer available for T, production. Food deprivation.
carbohydrate rest riction, and febrile illnesses lower
plasma T" in,rease rT" and elevate the rT ,:T, ratio.
It ha. therefore been suggested thai se lecl ive deio-
dina\ion pcrmia CQn$ervation of metabolic reserves
when Ihey are in short supply. However. the concepl
that that there is "d iversion'· from the T, 1(1 the rT,
pathway under Ihose cond ilions has been discarded.
The rT, ie,els rise moslly because fasling slow. Ihc
melabolic clearance of Ihal metabotile (47).
rT,lack. calorigenic pOtcncy. It hO$ be. n cla imed Ih ..
rT, enhances erythropoielin-f.cilitated erythr"""ie,i. in
mice. ' limul..., a minQ acid uptake by thymoeYI<1. pro-
moleo growlh hormone "«<lion. incr..... T,·.mi..,.
tran.ferase acti,ity in liver. and in hibitS phosphodiester-
ases or ral <.Ivari •. Howev.r. lhc t!fcc" Seen only
when very high concentration, are u..d (27).
The deiodin .... require solubl. <Xlf)eIOr< th. 1 include
reduced glutathione (GSH). According to one hypothe·
sis. an S f! group on Ihe reaelS directly wi lh lhe
iodothyrooine. The II i. exchanged for the iodine atom.
and lb. <n,yme lransit nlly be." a 'ulfcnyl·iodide ( - SI)
llrouP. Tbe en,_}·me then inte raCIO ,,"ilh Ihe GSII. and l-
is liberaled (i5) _ The dccre.std ...... of T, proouctioo
during fasting.". carbohydra1e r." riclion has been .ar-
iously allributed to GSH deplelion. decrea ..d .)·nlhesis
of lhe cn.yme. Or lcssened stcretion of lhe T, ,uhl"..e
(5). Glucose can a<celerate deiodin.st induclion il
is pr.sen l<d to hepatocyte! eilher in viyo", in ,itro (even
when GSH levelo are low). Protein fe.ding io less effeclive
lh.n glucose for promoting enz)"me induction. bUI it can
to some exlenl augmenl deiooinase aClivily (57).
food deprivation. earbohydale rest riclion.
and pharmacological agents such as propylthioura-
cil, salieylalc" lOO""""lale, and diamidc .Iow all of
\he deiod inasc in liver. ;\ has been sug-
gesled that a single kind of en'.yme is involved and
that microen'ironmental faClors such as pH affecl
the various substrate utili,.ation ra les (29,1)2).
However. th.re are indications for Ihe existence of
several enzymes. each with its d ist ri-
bution. Some act on phenol derivativel; (A-4).
In ralS. eel"<'brocorlical 5'-<leiodina.. promoles rapid
<Xl"verSion of T. to T ,. Thyroidectomy i. followed wilhin
24 bout""$ by 2-4·fold tlev'lion of lhe aClivily. bUI lhe
same operation retards 5-<l.iooination. Such ... Iective
variation. in en,yme aCli . ily would be .Xpecled 10 def.nd
cerebrocortkal T, I..·els when Ihere are .ub>lanlial
Chang.. in the Circula ting T, (g7). In immalure .. imal.,
the activities of hypolh.lamic deiodinases do nOI folio,,"
,imilar pallerns (80).
Both T, and rT , undergo successive dciodinations
Ihal lead to the formation of diiOOo and monoiOOo
thyroninel; and ult imalely 10 Ihyronine (To). Small
amountS of T, and ils melabolites undergo deami-
nations and (see Fig. 17·2).
T RI AC binds to Ihe nuclear receptors for T) and it
can therefore hormone-li ke However.
it has low in vivo potency because of both tight bi nd·
ing to Ihe plasma proteins and rapid degradation.
Sulfation pree<:des and ae<:eterales diiodolhyronine
deiOOination (A-6).
 THYROID IiORMONES. THYROTROPIN AND TAH

"
" "'
C-C-COOH

,, ,, " "

H NH,
C-C-COOH

" "

o
-0-
'/
-
" "\""
" "
C-C-COOH

o
-0-
-
I" "\"",
" "
C-C-COOH

F ig. 17- 1. o.;omnotO<l me1aboH!. . Of thyrox ... _

 , ,
__

Tcl,ac (lelr.ioOolhy,oacctic acid)

T, ·amine (',;ioOOlhyroanW>e)

COO"
"

0' ,

__
II H
° ,
"
Fig . 11 -2 . Ihyr<>id fl<)r""""" mma bol;u,. ,otrMd "' IivOf
.1'>(1 _ Olht< ' ;SS"H ,
,,.
T. -Sulla'"
, T. -Amine
T, ·SulI310
Fig. 11·3. UltCls ollhytOidee1omy .od Idmi" . t,ation
ItI"c>id rIOrmonel on ba ..1metebolOo rat••
All of the metabolites citoo can be: conjugated
with glucuron3lC and to a lesser extent "'jlh sulfate
(142) (Fig. 17·3). The products and small amOONS
of free hormone arc secreted into the bile_ Some of
the molecules arc los! !<l the feces (eilher dire<:tly or
after modification by bacterial enzymes). However.
conjugates can be: hydrolyzed by intestinal enzymes.
and there is substantial reabsorption via the "cntero-
hepatic circuit." T, enlers the bile some 20 times as
rapidly as T,. bUI it is also more completely
re<:laimed.
Intestinal motility and dietary oonstilucnls .(fOXl
the ",wrption rales. Fecal less increases when the
tOial food intake and the COntem of unabsorbablc
residue are high. and it decreases in iodine deficiency
states (142).
CALORIGENIC ACTIONS OF THYROID
HORMONES
The basal metabolic rate falls after thyroidectomy,
and it can be raised in dosc-.dependcnt fashion with
THYROID HORMONES. THYROTROPIN "NO TRH
3'5' · T,
oj
T. or T,. There was a time when many
investigalors believed that all Olhcr actions of the
hormones could be linked wilh such and
when metabolic rate meMurements were the only
lools available for clinical assessment of thyroid hor·
mone funClions. We can now determine the plasma
conc.:ntrations of thyroid hormones and thyrotropin
the rates of iodinc upta ke by thyroid glands.
and the response to injected TSH and TRH. Meta-
bolic rates are, however. used to a limited extent in
conjunction wi lh other diagnostic aids .
Measurements of Basal MetaboliC Rate
(BMR )
The BMR of a whole organism is the quantity of
heat produced pcr unit time under standardized con·
ditions that are designed to minimize energy needs.
tt is usually expressed in Calories (kilocalories) pcr
hour per square meIer of body surface.
Ta avoid the variable incremems in heal produc-
tion 3!SQ1;iaied wil h the ingeslion. digestion. absorp'
\ion, and utilization of foods. the subject is studied
in the pDSlabsorpliw SiGle. For humans, this meanS
that food is withheld for at least 12 hours before the
test is performed. It is then assumed that an endog-
enous mixture of ploteins, carbohydrates. and lipids
of predictable composition is use<:! to support vital
functions such as circulation and respiration .
Exogenous nutrients raise the metabolic rate, even
when they are administered via a catheter place<:l in
a large vein and presemed to subjects unaware of the
timing of tbe injections. The terms $(HXific dynamic
acrion af foods (SOA). si'U.jic dynamic
(SDE). and dielary-induu d Ihermagerwsis desig-
nate tbe changes thai are unrelaled to ingestion.
digestion. Or imestinal absorption. Some observers
find greater responses 10 amino acids and proteins
than toother nutrients and allributc this to heat pro-
duction associated with deamination, urea forma-
tion. and related reactions . However. carbohydrates
and lipids are also effe<:tive. and the changes associ-
ated with the amino acids arc blunted by simulta-
ncous presentation of sugars.
Since fasting depresses. whereas feeding aug,
ments cate<:holamine release (157), some of the SDE
is allributed 10 stimulatory influence. exerted on
adipose tissue (61) . Thyroid hormones do not bring
about substantial acute increases in metabolic rale.
but they support the actions of catecholamincs in a
"""rmi<-,ive" (t L'I). The Sr>F. VMie.< widely
from individual to individual.
Skelctal muscle contraction is associated with pro-
duction of largc amounts of heat. Exercise addition-
ally stimulates Ihe sympathetic nef\'OUS system. and
it demands increased activitics of the respiratory
C. H,,o, + 6 0 , - 6 CO, + 6 H, O
C " H"COO II + 260, - 18 CO, + 18 H,O
It has been determined that, under standard con-
ditions, 4.825 Cal are released per liter of oxygen
consumed when RQ .. 0.82. (The Caloric equiva-
lents for RQ .. I and RQ .. 0.7 are 5.047 and
4.680, respectively [411.)
Asdomonstrated in Table 17,1, BMRs for many
mammals are similar if the dala are corrected for
body surface arca (but no! for body weight). Since
heat loss varics with body surface, and sinc<: adipose
tissue metabolism differs from that of "lean body
mass," spuriously low values are obtained for obese
subjects when the data are expressed in terms of
body weight. Charts rel.ting height. weight, and
surface arCa are available for humans.
It has been assumed that a healthy wOman 30-40
years of age gives off around 36 Cal/hour per square
meter of body surface. while a healthy man pro-
duces closer to 39.5 Cal / h/m .l Deviations of
- 20% or greater have been ta ken as indications of
museles along witb augmentation of cardiac output.
Adjustments to cold Or hot environments and emO-
tional stress also elevate the metabolic The sub-
ject is therefore required to remain at rest in a quiet
room maintained at approximately 20 · C and is pro-
vided with a light blanket. Theoretically, it could be
preferable to do tbe measurements when the subject
is asleep; however, few individuals can attain such
status "on command."
RELATIONSHIPS BETWEEN HEAT
PRODUCTION AND OXYGEN CONSUMPTION
It is poSSible to meaSu", heat production directly,
and this has been done. However. it is easier and
more convenient to look at oxygen consumption .
When appropriate corrections 3'" made for environ-
mental temperatures and atmospheric pressures. the
amount of consumed is quantilat ively related
to the numbers of Calories released.
Whon a fuel is burned, the heat release<:! per gram
is 1101 affected by the chemical pathway. (Each gram
of sugar converted to CO, + H,O releases 4 Calo-
ries when the ",action occurs in vivo or in a calorim_
eter.) However. the oxygen equivalent of a Calorie
varies with the respiratory quotient (ratio of CO,
produced to 0, consumed.) The following equation.
demonstrate that the burning of pure glucose is as-
sociated with a re<pi"tory quotient (RQ) or t.
the burning of pure stearic acid with an RQ of close
to 0.7. The quotient rises above unity when sugar is
madc into fa\. It is assumed that a previouslyade-
quately nourished subject burns a mctabolic mixture
with an RQ of 0.82 in the postab!Orptive state.
+ 4 Cal/g CO, :o , = 1.0
+ 9 Calls CO, :O, - 0.692
hypothyroidism and ones <>vcr + 20% as signs of hy_
perthyroidism. Howevcr, factors as cmotional
stress, anemia, cardiac decompcllSation, and some
endocrine disorders unrelated to the thyroid gland
can elevate the BMR, whereas malnutrition and
adrenocortical insufficiency lower it.
Latent Periods Assoe lated with Thyroid
Hormone Regulation
When the thyroid glands are excised and no hor-
mones are administered, the BMR can remain at
presurgical le_els for two or more "'Ceks. The term
absolute latent period designates the time inIO"'al.
During the "relative latenl period" thaI follows, thc
BMR declines slowly and finally stabilizes at somc
35%- 40% below the initial values (Fig. 17-4). The
slow rates of change are only partially allri butable
to the long plasma half-lives of the hormone •.
,. THYROID HORMONES. THYROTROPIN AND TRH

Tab .. 17-1 MoI_ Rate M.... ·.......,ts Rec><>rted by Variouo .t.utnors ''''
Ma..-wnals ' - - - . . . Conditions
BOO)' C.Iorie< 1><' Color"'/ .. Cak>ri<.,m >
A";m.al

Sh ......
(k,)
Q.004_tHXJ5
'"
M
per day pcrday

800-1000
M_ O.Olg-O.025 180-210 1W-! SO
",
Go;"". piS
O.2SO_IUOO
0 .4$-0.\\
23_30
7()...80
100-300
860-1000

,,,
R.blO,
,.,
1.8_2. 3
". 65-10
g00-9SO

M<>nkC)' J.O-J.J 6»-100

""
Shoop
lI um"
6.S_24

"
65-70
"00
I :roo-1700
25- 26
18-2S
1000-1200

9QO-IOSO
8_11
"" 1200-1800
Co.
"-
EI.ph. n,
,.
lloOO--J800
»00
11_14
12-6
14-16 ".-
""

A single large dose of hormone very transiently in-
creases the metabolic rale. However,;1 Can take 6-
8 weeks of treatment to normalize the values in
myxedematous patients.
T issues Involved In the Calorigenic
Responses
The oxygen consumption of the whole anima l nec-
essarily n:fleCIS the oxygen consumptions of al leaSI
some of its component pans. Skeletal muscle gen_
erally 3CC(1unts for around 40% of body maSS of ac-
tively metabolizing tissue. and it is not Sur-
prlsmg that samples taken from animab
thyroideCtomized long before the lests show low
rales of oxygen consumption when studied in vitro.
Liver, kidney, and hean weigh less. but they utilize
large amounts of oxygen. and these. 100. show re-
duced rales of uptake in vitro. Skin epidermis. pan-
creas. salivary gland, and gaslric mucosa arc among
the additional body components thaI respond in (his
way. All but epidermis show supernormal rales of
oxygen utiliation when they are 1aken from
chronically overoosed with the thyroid hormones.
In contrast, adu lt brain, lung, thym us, spleen, der_
mis and male and female reproductive orgaru; are af,
rected by thyroid hormones but they do not show re-
lated changes in oxygen consumption. The
adellOhyJ)Ophysis its metabolic rate in thy-
roid hormone deficiency "ateS (7) (See Table 17-2).

Influences of Thyroid Hormones o n

Mltochondrls
Weeks 01 STudy
ThyroO:l More than 90% of Ql;ygen consumption can be di-
reclly linked with the functions of these organelles
aM'Iin iStc,e<l (71). The ea rliest studies oonducted on them were
fig, 17·4. J>r()\lOMd po.II1WAy' for /ormation ollh.,.,.,
performed before it was recognized that "free" thy.
h<>fmonemtllll>01ites. (ft) _ S"I; (b) - 51; (0) roid hormone levels in the blood arC low. that
(d) - 31; ( I ) _ f'.jH,: (t) _ NH,. +0; ( g) -00,: T, is oonverted to T) before it oombines with most
(h) + glucuronatl ; (I) +",,""1&. r.:.:epten, and that thyroid hormones bind to "lIOn-
physiological" sites when they are presented in
grossly pnarmaooiogical concentrations.
"UNCOUPLING" OF OXIOATIVE
PHOSPHORYLATION
Under normal conditions. some of thc energy re-
leased from the transfer of hydrogen (provided by
redueed pyridine nuc\eotides) to mole.:ular oxygen is
trapped for the synthesis of ATP rrom ADP + Pi.
The P:O ratio (numbers of ADP molecules phospho-
rylated for each 0 used) can auain a maximum
valuc of 3. The overall "coupling" of oxidation to
phosphorylation can be summarized as follows. (The
chemical bond energy released thaI does nO! go inlO
A T P symh",i, is lost as heaL)

NADH ' H"

.,

3 ATP

Very high ooncentralions of T. can "unoouple ox- rates of heat production, nutrient utilization. and
idative phosphorylation" when they are presented to body weight loss of severely hYl"'rthyroid patients.
liver mitochondria preparations. NADH oxidation. and possibly al", the skeletal muscle weakness.
oxygen consumption. and water formation continue.
Stud i•• ",ilh dinitroph.nol (DNP) w.r. cited in .up..
but some of the energy that would otherwise be di-
pOf!. DNP is widely used as a I.boratory '00)1. 'incc il
verted to ATP synthesis is dissipaled as heat. There' "unoouplcs" both in vi_o and in v;lro. h. t"", inc' .....
fore. the P:O ratio ralls. as the heat loss per mole of hea, production and metabolic ra,.(71).
0, consumed rises.
When the ftndings were first made. it was sug, H 2,4,Dinitrophenol (DNP)
gested that such "uncoupling" explains the high
° NO,
T.".. 17· 2 E.--, '" Th"""""",,,,,,," ond Thyro ....
lrlo<:IionS on Oxygen Conoo..ml>trn I
Pcr Cenl e,",nle Pfodu«d by
Ti" ., Thy'oOlo<'''''Y Thy'O<''''
..,
li"'"
Di.p' ..
KOlo<y
,m
Soli •• ry «I."<l
-"'"
-"
-n
...
."

."
The agent wa. admini'tered briefly f'" the Ire.tmOnt
of obesity. However. it was <00" found lhat DNP can .1,
eVate body temperature abo •• 106' F. damage th. liver
f'aoc",.. - ro ", and kidney •. and invoke cotaract formation.
Ilea"
Epi<l.,m"
-"
.,
-H ,
+ 132 We now recognize that tb. unooupling achieved
with T. has liule connection with thyroid hormone
lunl
-, .,., runctions (45.135). Grossly pharmacological 00""

.,-,
S .. in
Spk<"
.., centrations are needed '0 achieve the effect. and sub-
stances chemically related to T. but unable to mimic
T .. ,i,
Somio,l "".,01, -,
-, 0 its biological actions (including the D i",mer of thc

-, -,
...,
Pro,,"" H natural hormone) can be equally potent. Moreover.
0,,"
U..,., -, T. does not unoouple when tested on Skeletal musele
Thymu,
lymph nod,
-,
-,
0

H
mitochondria .
Mitochondria taken from animals gTO$Sly o_er_
G.mic • ..,."h mo",,1<
[)e,mi,
Adenohypophr>"

Soor«o FK>II'I /b,ko, ... T...... 1.

...
H
0 ,
-"
dosed with thyroid hormones retain the ability to
synthesize ATP. In fact, the hormones actually ac,
eelerale ADP uptake and ATP symhesis in vivo
without impairing the coupling (129). Alrno:st all of
the physiological actions are associated with prOtein
r ...... "h. f. - 'o!' " leu, on< """"h [>0", io
r'" t.y""'" "",. 0" "",",'''''' _ d.&y alt" t....,... h ""',,..., . . . synthesis (a process that would be blunted by ATP
,", 'Iy ;.i«t,,- of '_1 ....... of ,b,.,...; ... depletion). Even the catabolic effects or overdosage
• 1<,. ...1«1 011,h"" .... _ . 001 •• 1<.;,11" .p;d<,m;" _ do,"", depend on production of larger quantities or prote<>-
I""" ioj«l<d
_pt.>e.
,,,><, ,,'... h ,..,_ • ' ''''''' rOo. ____ , "'n<"
lytic enzymes (63).

'"
"LOOSE COUPLING"
Altllough mito<,:bQndria can rominue \0 engage in
oxidative activities under ronditlons that preclude
ATP biolynlbesis. the fUllClions a rc usually
Laced r'l ightLy controlled ") by the availability or
ADP. conc:cnll'luioll$ or T. (Iow<:r
than the ann 11K<! 10 "uowupk") ma.y brina about
"Iooseni"," of the conllob. Then. lhe rales of sub-
strale ulili7.lllion 'e«kratt. bul lhe a bility 10 make
ATP is The whercb)' this is
l«Omplished. and the physioloa;inl relevance: of lhe
findings. have been holly debated.
"«Ordinalo observeI'$, the bioloaical effectS
or thyroid t..." ,IVnc:s in<:l udo: I very rapid. lra",,;'n!
stimulation of OJtYSC" QOtI$U.mption thai can be
tinked. wilh Ihe "loosening" in hepalOCYIts. Much
later, very different mechanisms account for the sus-
Uline<! increases in mygcn oo'1!u mption by skeletal
mU$CIe ... ..-ell u liver (71).
MITOCHONDRIAL SWELLING
Mitochondria undergo regularly recurring variations
in water contem. Ph armacological o;(lncenlratlons of
T. pmmote mitochondrial swelling tht is aSS<lC iatod
with ehanllts in oxidative phosphoryla tion, ae<:cler-
ated "leakage" of pyridine nucleotides and proteins
from the organelles, and reductions of the
NA DH :NAD' raliOS, '::x<lI!cI\<)u$ NAD ' and cyto-
chr<l111e C are to n<)rmali7.c the respiration (71).
Hyperthyroidi sm is rep<)rtcd to decrease milo-
chondrial l:()IICentratlons <If NAO" NAOH,
NA DP·. and NADPH, 10 decrease the ratios <If rc-
duccd:<lJIidiud f<)fm! of Ihe pyridine nucleoridC$, \0
tighten the binding belwcen redU«d pyridir>e nu_
elc:olidC$ and dehydrogenase enzymes. and 10 in-
crease hepalic ftavukinasc aClivity, Ni<Xllinamide
fteding aon elevate Ihe hepal ic NAO·.
il is doubted Ih,u T.';nduccd mito-
chondrial swcllin, upla;'" lhe h<lrmone actions.
Pharma<:Olot!;,;;,1oonCCntratiOlll are required. and fI<)
positive c;orrcllti<)ns Ire f(lllnd when effecls of T. an-
alogs on s".. lIin& are compared wilh lhe lbilities to
mimic T , biologieol Ictions. Inorganic iodide op-
posc1 some effects of thyroid h<lrmones, bUI il pro-
mot.,. mitochondrial swelling, M<lrC<M:r, T, antA,-
oni7.<:S lhe inHl>C11CCS of DNP on lhe wlter uptake,
and thcre are coodilions under which the hormone
brings about milochondrial coolraclion ( I JJ).
RELATIONSHIPS TO Na ' I K '-ATPase,
Plasma membranc-associaled Na '/ K '-ATPascs
are used locxtrude N a', facililate K ' uplake.
thereby maintain oplimal cytosolic concentrations of
THYROID HORMONES. THYRQTIlOPIN "NO lAH
the ions. Some cells additionally employ the enzyme
to aC<:OOlplish net transport of $Odium iom from one
fluid comparlmenl to aoother.
The activil ies of the A T Pases arc linked in scvera l
ways wilh <lJIygen consumplion. phosphor-
ylalion. thermogenesis. and the funclions of scvera l
mitochondrial enzymes thaI are not components of
the electron lransport chain. M ilochondrial synt l!c-
sis of ATP is coupled 10 the transfer of protons and
elCCtrons 10 molecular <lJI)'gen, a nd heal is liberaled
during both ATP synlhesis aM ATP lIyd'oI)'Sil.
delivel)' of ATP can be rale-limiting for todium
transport. and the ADP rO' lhed by Ihe pump 00II-
lributts 10 the regulation of the phosph<lr.
ylalion. When protons and elect rons a re obtained
rrom cytosolic substrates, the quamities of mito-
chondrial no-glyccrDfihosphatc dehydrogclU.sc (no-
G PO) can affect the Talts of ATP production.
Cytosolic NADH does not eros< tlte m'l""bond".1
membra ....... bul ,I can uoed 10 reduce ,Iyccrophol·
phate in a , •• etion by a cy'opl:l$mic ,,-<;jDP:
Glycorophospha,. + NADH + H ' -
Dib},dro,pCC10...... + NAD '
Afte, en'o"n, tho m,t""Iiond,ion, the dihydro,yaco.
,one'phospho,. i. oxidi""d by mi1<xhOlldri.l""OPD:
DihydroxyacelOnC'phosphate + "AD -
Glycoroploosph a'. + FADIl ,
TIM: hydroten :I$<Oeialed ,"'ilh Ihe "ov"l',OI.in cnle"
Ihe electron IranspOrt chain. and the ,Iycoropbosphale
returns to th. There/OTe, the",.rc conditions
uock. which induction of mitochondrial ""(;PD til" be
linked ",;th accelerated ATP 'rnthe.is _not sodium
Irall$p<)<I.
Ou.abain inhibits lhe plasma mo;:mbotno: No '/ K ' "
A TPascs, bUI il has little or fI<) influence on many
other enzyme SyslemS (1 2"). It has been used 10 . .
scss the incremo;:nts in <lJIYJC"n c;onsumption directly
attribulable to sodium traQ:SP}l1 when celli are Slim·
ulated with TJo calccholami..... and other agents.
According to some .... plasma membrane-
associaled ATPucs account for vel)' substanlial
fractions of the '"basaI heal production. and calor·
M
igenic responses 10 Ihyroid hormones Ire mediated
primarily induction of nc .... sodium pumps (124).
T ile ();)nclus.ions lire based lar&ely on Sludies of lis-
sues laken from adult hypothyroid and eUlhyroid
adult Tats. but measurements have also been ffillde
00 cultured hepatocylts and on perfuscd livers. II i,
rcp<)rtcd that OIIabain-scnsit;'.. respil"1lt,on
for much of the increased 0 , production by livcr,
skeletal muscle. and kidney Ihat follOWll ,,·ho1.,...ni.
mal pretreatment wilh Ihyroid and Ihat
Ihere is an associated increase in skeletal mu sele
 Na+j l< +-ATPase activity when !lQ ouabain is ad-
ministered. Increments in ouabain ..... ",itive me tab-
olism have add itionally be<: n found for jejunal epi-
thelium . but not for brain tissue.
In newborn animals of ma ny mammalian spc<:ies,
cold eXp05ure accelerates oxygcn use. thermogene-
sis. and the Na ' II< ' -ATPase activity of brown adi-
pose tissue (BAT). The responses are attributed to
sympathetic nervous system stimulation and the re-
lease of .atecholamines. and cxogenous oorepincph-
rin<: (NE) can directly increase the oxygen con·
sumption. Involvement of thyroid hormones is
suggested by observations that deficiencies blunt or
abolish, and T) administration restores, the sensitiv.
ities to both cold and NE in young rats.
The coneepttha t the calorigcnic actions of thyroid
honnones arc di rectly linked with ATPase induction
is not universally ae<:epled (129). Many investip-
tors believe that the plasma membrane ATPases ac-
count for only a small fraction of cellular oxygen
consumption and heat production. Some of the mea-
Surements cited above were made on tissuc slices,
and it hs been suggested that sodium leakage into
injured cells located along the cut end, artifactually
augmented AT Pase acti vity. It has also been ob-
scrved tha I thyroid hormones Can rapidly change
ATPase activity in kidney via mechanisms that are
not affected by protcin synthesis inhibitor.;.
There arC conditions under which Ihyroid hor-
increase oxygen consumption without mark·
ed ly affecting Na ' IK +·ATPase activity. and others
in which ATPase-linked incrcases in usc arc
unaffe<:ted by thyroid hormone injections. In new-
born rabbits. T) pretreatment markedly augments
"basal" oxygen consumption and ....oPD activity of
BAT. but ouabain does not affect Ihe oxygen con_
sumption in either control Or T)-exposed lissues. NE
accelerates the oxygen consumplion in BAT from
both control and T)·treated rabbits. and Ibe changes
arc markedly diminished by ouabain. However, T,
does not alter the responses to either NE alone or
NE presented in combination with ouabain. More-
over, although T , accelerates Na - / K --ATPase ac-
tivity in th. livers of neonatal rabbits. il doe.. not in_
crease the oxygen consumplion in those organs (SI).
The influences of thyroid hormones On non.hiver·
ing thermogcnesis invoked by eXp05ure to cold cnvi-
ronments have been attributed to effects exerted on
the rC';ponsivencss to beta adrenergic stimulation
(53). Thyroid hormones may additionally play "pcr-
missive"' rol"", that are essential for normal function
of the Na ' / K+-ATPascs.
MITOCHONDRIAL RECEPTORS
Specific. high·affinity receptors for T, have been de-
scribed for the inner mitochondrial membranes of
cell types implicated in thc calorigenic actiOn! of thc
hormones (e.g. liver. kidncy. myocardium. and skel·
etal muscle). but not for on<:s that fail to display the
changes in oxygen consumption (adult brain. spleen,
or testis) (130). It has also been reported that phys-
iological concentrations of T, rapi dly aceelerate 0'_
idative phosphorylation by mitochoodrial vesicles
obtained from hypothyroid rats (I 29). However, the
concept that the mitochondrial components thai
bind thyroid hormones are true receplOrs involved in
the mediation of biological responses has been qu ....
tioncd (116).
INFLUENCES ON PROT EI N SYNTHESIS
When thyroid hormones invoke slowly developing.
sustained elevation of basal metabolic rates. they si.
multaneously increase the mitochondrial conccotra-
tio", of enzymes and cofactOr!; involved in oxidalive
phosphoryla tion (114). Some of the effects arc at·
tributed to induction of new mRNAs that direct the
assembly of proteins on cytoplasmic ribosomes. It
has been proposed that the hormones additionally
promote the release of a mitochondrial "translation
acceleration factor" that travels to and acts on the
ribosomes (126). Actinomycin D and puromycin
rn<)Oit of the delayed calorigenesis.
A problem with puromycin studies is that the an-
tibiotic aCtS centrally to invoke hypothcrmia. Its ef·
fecls arc blunted when the body temperatures arc
maintained within the normal rangc (129). The fmd-
ings may be related to observations made on eeto-
therms. T hyroid hormones elcvate the mctabolic
rates of those animals when the environmental tem-
peratures are very high. but not when more ordinary
conditions are provided.
Thyroid hormones may additionally accelerale
mjlochondrial DNA and protein synthesis (134).
Long-range effects on cell maturation in homce-
therms. and on amphibian metamorphosis. evidently
require the formation of wholc new populatio!15 of
cell organ<:lIes. The mi tochond ria Ihat appear after
several days of trealment are larger and more nu-
merou. Ihan Iheir predec"",sors, the endoplasmic re-
liculum is more elaborate. and the polysomes more
efliciently support amino acid chain assembly (136) .
II should be pointed out, however, that some of thc
changes in mitochondrial components arc CO<l'C-
qilM{"(>,< rather than mediators of the increases in
ygcn consumption. The ubiquinone conlent rises fol.
lowing lhe administration of DNP (which docs nol
stimulate protein synthesis).
THYROID HORMONE RECEPTORS
Although T, probably interacts dircctly with other
cell components (129). there is universal agreement
that high-amnity. low-<:apa.cily receptors within the
nuclei mediate most of the hormone actions.

Charac teristics of the Nuc lear Recepto rs
PrOleins with molecular weights of 50,000-60,000
have ocen identified in liver, kidney, heart, lung, pi,
tuitary gland, brain, circulating leukocytes, and
other The properties are similar (and pos.
sibly identical) in all of the tissues. The numbers
of protein molecule. are reduced in SOme (86) (but
I'IOt all 123]) patients .howing target organ insensi·
tivity. No mch substances have ocen found in inver·
tebrate cells that are to thyroid hor.
mOne •.
When presented in 10- " M concentrations. T, is
avidly taken up by Ihe molecules. T •• some other
lhyronines, and several T, analogs attach with I=r
amnities. The lightness of binding and the biological
potcncic. are closely correlated in vitro. When fae.
10rs such as the associations with plasma proteins
and the degradation rates are considered. there are
also high in vivo correlations. Certain analogs that
lack halogen interact with the receptors. 3.5-
Dimethyl·3'·isopropy)·lhyronine is one of the most
potent and 3. 5-dii()\lo.3'·isopropyl-thyronine is bio-
)ogical1y more active than T,) (54A),
When rcsJXInses of a single cell Iype arc examine<!.
the sensilivity 10 lhe hormone is direclly relaled 10
the numbers of nuclear .ite. for T,. and the
magnitude of thc ""ponse varies wilh the numbers
of T. molecules bound. These and other ob$crvation.
ar. consistent with the concept that the nuclear pnr
teins arc true hormone receptors (45.103). T) also
altaches to the nuclear membra ne whcn the COncen-
trations are high. However. Ihis association is re-
garded as nonspecific and unrelated to hormone: ae.
tions (86).
Evidently, the nuclear receptors are acidic (non·
histone) protein$ implicated in the regulation of gene
transcription (10,45,I02). They a", made by eut hy_
roid. hyperthyroid, and thyroid hormono-deprived
• ubjects. It has been stated that . the numbers are I'IOt
closely regulated by hormonal statU.<. However,
some effects of thyroidectomy, hypophysectomy, and
glucagon and insulin deficiency have been found
(3S). Morever. T, induction of thyroid hormone re-
HO o }-C-C-COOH
THYROID HORMONES, THYROTROPIN AND YAH
eeplOTS has been demonstrated for amphibian
(55A. 93A).
Apparently. the functioning molecules (holoreccp.
tors) comprise (a) rore subunits Ihat directly bind
the iooothyronines, and (b) regulatory components
(probably his tones) that modify the binding affinitics
of lhe corc subunit',
The core protein, a", asscmbled in the cytoplasm,
and they may aCt there to concentrate T. for subse·
quent tra nslocation to the nuclei. When present
without the regulatory component', they bind T.
more tightly than T" and they display other ",.em·
blances to TB PA. Unbound COre proteins enter the
nudeus even when no hormone is present. They sui>-
sequcntly cntcr into the formalion of holoenzymes
that have much higher affinilies for T" (T. is biolog-
ically active only when presented in very high COn-
cenITations [1 OJ J.]
The regulatory COTnJXIncnts are separately lrans·
located. They arc implicated in directing the holo-
protein-hormone complnes to the appropriate DNA
segment'.
Cal> and Mg l - may play roles in maintaining the
colIC<'ntralions of hormone·frec receplors within the
nucleoplasm (111). They augment holoreceptor·
chromatin binding, but they decrease holoreccptor·
Transport of Thyroid Hormone s to Nue lear
Aec eptor Sites
T. and T) rapidly enter cell •• traverse the cyto-
plasmic compartment. and penetrate the nucleus.
Phannacologieal agents that impair the functions of
microfilaments or Iysosomes, or interfere with enoo.
cytosis. relard uptake across the plasma membrane
but do not affecl translocation of internali7.<:d hor·
mOIl<' 10 the nuclear compartment (67). The plasma
membrane is one of the cell ,ite. inVQlved in COIlver_
sion ofT. to T) .
The binding of thyroid hormones to cytosolic pro-
lei"" does nOt accelerate tran.location to the
(86). (In fact, T) binds more rapidly to c hromatin
when it is presented to isolated nuclei than to intaci
Dimelhylisopropyl1 hyron ine
H
H H
cells.) Holorcceptor attachment is brief under phys--
iological oonditions. a nd labeled T , easily «,places
unlabeled hormone. (In One study, 50'% of the la-
beled T ) returned to the cytoplasm within 15 min-
utes 11021.) The released T) may be either re<:ycled
or extruded across the plasma membrane. Some cdl
types deiodinate (and thereby inactivate) T,. but
many do not .
RelationS hips Between Nuclear Rec eptor
Occupancy and Biological Res ponsa
In euthyroid subjects. most ta rget cells have some
10%-15% of the total T) altached to nuclear recep-
tOr sites. However. only around 3% of tcsticular cell
T) is found in thc nucleus. whe«'as the value can ex·
cced 50% in adcnohypophysial somatotropes.
The numbers of total and occupicd nuclear recep-
tors vary widely. A typical neuron nucleus contains
half as many receptors a$ a kidney or liver ccll nu·
cleus, a nd a tcsticular cell only around 1/25 that
amount. The percentage occupancies have been rCo-
poned as 35. 39. 44. 47, 50. and 90% for kidney,
brain. hean. liver, and testis. «'spectively (103).
No evidence has been obtained for the existence
of "sparc" receptors or for "down regulation" of re-
ceptor numbers. Chronic elevation of the plasma
hormone levels leads to increased receptor occu·
pancy and exaggerated responses to the hormone .
There are cell types in which close to 100% occu-
pancy can be achieved. Chronic, severe hypothyroid-
ism drastically lowers the pereentages.
Certain cell types have mechanisms for "defend-
ing" their T J level, (87). When brain i$ presented
with too much T•. it convens most of it \0 rT J. When
plasma T. is low. conversion to T J is accelerated. The
protection is. however. limited . Ultimately, T, dep-
rivation or excess impairs the functions. In pituitary
soma totropes. hypothyroidism has liltle inHuence on
the «,ceptor numbers, but toxic doses of TJ slow re-
ceptor replenishment (86). The somatotropes seem
to have two pools of receptors that differ from each
other in locali7.ation and turnover rates but not in
chemical makeup. T, Can lower the numbeT$ byap-
proximately 50% by acting on the OneS with rapid
(2\ hour) turnover rates (1 16).
Some forms of malnutrition slow T. entry into thc
cytoplasm, and they thereby red uce nuclear occu·
pancy (100). The adjustmentS can contribute to the
conservation of nutrients.
Consaquaneas 01 ExeaSSlye Oceupaney 01
Nuetear Raeeplors
Under normal oonditions. thyroid hormones e'crt
greate r inAuences on some en>.ymes than on others.
They thereby accomplish metabolic balances that
se"e the needs of the organism as a wholc. Toxic
d<Ji!.ages disrupt the balances. In some cases. they
augment the activities of protoolytic enzymcs that
CQIInteract the usual anabolic elTects (4). They de·
plete skeletal muscle and hepatic protei"" (63), and
Iltey aceelerate Cholesterol degradation in the liver.
Physiological concentrations of T) facilitate glyco-
gen storagc in brain and myocardium, whereas toxic
levels invokc depiction.
liver cells can resist changes when the hormone
levels rise somewhat above the physiological range.
They thcn show very limitcd increases in the I'dtes of
,,-GPD and malic en'yme synthesis. Howcver.
grossly pharmacological concentrations overpower
the control mechanisms, and "amplification" of Ihe
effcct, occurs when critical level, are at·
tained (103). In contrast. somatotropes di'play al·
most linear «,sponses (116). They ma ke excced ingly
large quant ities of GH as nuclear receptor occu-
pancyapproaches 100%.
DeYelopmental Changes In Racaptor
Numbers
Thyroid hormoncs a«, essential for supporting the
maturation of brain. lung, heart, and intestine dur_
ing late fetal and early post natal life. of skeletal
structUI"C$ mOSt obviously during juvenile stages, and
of reproductive structul"C$ afterward.
In thc lungs. T, contributes to the regulation of
fally acid synthesis and the production of surfactant.
The receptor numbers are highest when the felU' is
preparing for air breathing, and they fall after birth .
In liver. maturation is associated with a steady in·
crease in receptor numbers.
fetal and neonatal brains have more T, receptors
than thc adult organs. and the qua litatiye «,'ponses
\0 tlte hormonc change with age. There is an early
stage during which effects on oxygen consumption
can be demonstrated . Many of the influences on the
brain muSt be exerted during time-limited "critical"
pericxls. and the hormones must also tlten be prcsent
in the right concentrations. Thyroid-deprived human
fetuses and infants suffer impairment of brain mal-
ura tion that is unresponsive to hormones adminis-
tered later.
Under ph)lSiological condition', T, panicipatcs in
regulation of ce«,bellar neuron proliferation, synap-
tagenesis. and the accumulation of muscarinic re-
ceptors (13). It elevates the nerve growth factor and
levels and lowers substance P concentrations
(43) . It also affo:cts catecholamine metabolism and
may be involved in determination of the numbers of
«,coptors for the amines. Influences on the "SC t-
points" for pituitary-thyroid feedback have also been
described (107). Excessi" T , during the critical
stages invokes special kinds of defccts. Although de-

'"
YclQpmen\ can be precocious. learning ability is
impaired.
Mechanisms of Action 01 T. within the
Nucleus
Information in this arca is limited, in part because
the respollSe$ vary wilh the cclllYpe and there are
interactions with other regulators. It is proposed by
some Iha1 T) binds \0 very restricted transcription-
ally active siles (79), whereas others suggest wide
distributions of chromatin aoccplors (86).
T) seems to be absolutely essential for induction
of growth hormone mRNA. It excrts d-.rc1ated
inftuen= OIl G H production without bringing about
generalized increases in pfO!ein synthesis. It also aC-
celerates GH rclea.e and affects target C<'II responses
to Ihe hormone (45). T J additiona ll y suppresses pro--
loain synthesis in cells that make both hormones
(116). and it regu latcs hepatocyte upta ke of pro lac-
lin (44).
The dose-response Curves for induction of GH
mRNA paralellthose for acceleration of glucose and
nucleoside upta ke and glucose oxidation. They are
affected by glucocorticoids. The steroids cannot act
alone to promote GH biosynthesis, but they amplify
the effect. of T, How.ve" et"cocorlimirl<
nizc GH actions on target ce lls, and they decrease
thyroid hormone secretion.
GH levels rise within I hr and pea k after several
hrs. Liver enzyme induction follows longorlatent pe-
riods. but T) affects some mR NA precursors 10 min
afler it is presemed (A-S). Liver eellsar<: &aid to "re-
member' that they have been previously exposed to
T,. They cannot make the enzymes when protein
symhesis inhibitors are administered along with the
T). but the clfects of the thyroid hormone are man-
ifested if the inhibitors ar<: subsequen tly removed
(103). It is likely, therefore. that the treated cells
contain long-lived mRNAs.
In some cell types. thyroid hormones augment the
activities of RNA polymerase! I and II (75, I03) . aCt
on phosphokinases to increase nuclear prOiei n phos-
phoryialiOll$, a nd accelerate the use of orotic acid for
RNA synthesis. The possibility that T) lifts inhibi-
tions OVer gene transcription otherwise by
unoccu pied recep tors has been both considered and
questioned (116).
Some rapidly developing responses have bee n
linked with innuences on Ihe processing of pre·
formed nucleic acids-possibly via production of
sP«' ial forn-u; of R N A that serve as regulators within
the (60). Responses with the latent
periods are associated with the appearaoce of la rger
THYROID THYROTROPIN ",N D TAH
a nd more numerous mitochond ria. whole new p0p-
ulations of ribosomes and other organelles, along
with marked changes in the structures and comp<>-
sitions of intracellular membranes (I 36).
Actions Outslds the Nucleus
Most observers belie .. that at least .orne of the ae-
tions are extranuclear (129). The possible e xistence
of mitochond rial recepton was earlier. High
concentrations of the hormones accelerate glucose
and a mino acid uptake by certain cell types. and
they rapidly augment plasma membrane Na+ / K '-
ATPase activity. Accelerated passive K ' efflux (A-
3) may indirectly invoke enzyme induction.
T, can rapidly activate Ca"-ATPases. and the
targcts include fully differentiated (nonnucleated)
erythrocytC$ (37). Both membrane and cytosolic
proteins bind T). and the hormone may eXert some
influences on mmslation. However, binding to he-
moglobin can s.crve the purpose of removing exces-
sive amounts of T 1 from the blood (156).
The direCt incorporation of thyroid hormones into
proteins (40) may have funetional significance. In
the brain. cytosolic proteins that bind T) differ from
ones fou nd in other edl types. The regional distri-
butions of the proteins. and the developmental
changes in the levels. suggest potential roles in me-
diation of some specia l functions (58). Neurotrans-
mitter or neuromodulator roles for thyroid hormones
have also been considered (39).
THYROTROPIN REGULATION OF THYROID
HORMONE SECRETION
Thyrotropin (thyroid stimulaling hormone. TS H)
stimulates growth of the follicular cells and it ac.:eI-
erates both synthesis and release of the thyroid
hormones.
[t is probably needed during fetal life 10 assure
that the thyroid glands attain optimum si?.e and s.c-
crete sufficient hormone 10 support maturation of the
lungs and other structures (45) . It can be detected
in the blood by 10 weeks pOStconception in humans.
but the levels do not rise sharply until weeks 18-22.
Thyroid gland are reported 10 increase from
251 mg during days 145-165 to 1430 mg at term
(51). Amniotic fluid TSH leyds do not show such
time-related variation. Concentrations of O.15-1.1
I' M/m! and 0.15..{).S5 pM/ml have been found 3l
16-19 weeks and during the 3rd trimester. respC<:-
tively (82). hCG has been said to exert some TSH-
like activity. but the phenol used for its extraction
may account for Ihe effects ( IA).
Sec retory P atte rn s In Ad ults
Normal pituitary glands release some 100-165 mU
daily. The pattern is pulsatile. and diurnal variations
permit the blOCld concentrations to range from 20 to
300 mUjdl. The levels peak during th.late evening
(127). and a "no<;:turnal surge" can precede slcep
onset. The lowes1 values are found during daylight
hours. but they can rise if naps are taken . Some au-
thors reporl lTIQre pronounced rhythms for men than
for women, while others find 4-6 A.M. peaks only in
women (111). Estrogens increase the numbers of
TRH receptors. and this may acrou nt for the larger
quantities released during periovulatory than during
luteal phases of tbe menstrual cyde ( 149). Rats
(which are nocturnal) have their highest concentra-
tions during daylight hours. No diurnal variations or
sle<: p-associated elevations have ocen found in rhesus
monkeys (59). The plasma half-lifc is around 54
minutes. T. rhythms do not follow those of TSH.
Humans usually show nocturnal T. declines (117).
and monkeys have similar patterns (59) .
Che mis try end Biosynthesis
The subunit structure and thc biosynthetic pathways
are similar to the ones described for FSH and LH
(Chap. 14). The mosl commonly fou nd TSHs have
molecular weights of 28.000-30.000 and they con-
tain 7%-8% carbohydate. "Big TSI U' tht wdgh
up to 200.000 have also been identified in normal in-
dividuals. and some are biologically active (36).
They may be aggregates of hormones or their sub-
units. or TSHs with other molecules. Mi-
are attributed to .ariations in car_
bohydrate content." and (J subunit precursors with
weights of 14.000 and 17.000. respectively. have
been obtained in studies utilizing mRNA. derived
from mouse tUlTlQrs (25) .
There are species differences in the amino acid
makeups. However." subunits oonsistcntly comain
five disulfide bonds a nd the (J subunits six. Prepara-
tions from one animal type are biologically active in
another, but native hormones can show differences
in potencies a nd clicit responses t!tat have different
time courses (149).
The rate at which Ihe (J oomponcnt is made is
probably rate limiting. a nd sepa rate controls may be
exerted o_"(:r not only production of each of tile sub-
units but also their combination. Under I10rmal con-
ditions. both the gland and the pituitary venous ef-
Huent contain some frc<: alpha (but 110 free (J ).
Severe hypothy roidism can be associated with up to
51).fold increases in total plasma TSH, and doubling
of the free alpha levels. The appearance of small
amounts of free \lela (149) is attributed to produc-
tion of a TSH with low biological activity (49A).
Physlolog le el Actions
In untreated, hypoph)1'eetomizcrl animals. the follic-
ular bewme flattened. and the apical surfaces
are smooth. The lumina are distended "'ith colloid
tbat contains tbyroglobulin of bigb molecular weight
and iodine coment. Within 5 minutes after TSH is
injecled. the apical membranes eXlOnd microvilli and
pseudopodia toward the lumen. Within 10 minutes.
the follicular cell cytoplasm fills with colloid droplets
and phagolysosomes form. as plasma T. begins to
rise. The and durations of Ihe responses
arc dose related (138). Intense and prolonged stim-
ulation raises t!te T): T. ratio of the emuent. This is
atlributed to uptake and proteolysis of newly formed
thyroglobulin that is low in iodine content.
TSH also augments incorporation of iodine into
proteins, oxygen consumplion. and NADPH oxida-
tion. probably via activation of the peroxidase. Blood
How to the gland improves, and usually this is ac-
companied by accelerated glucose uptake and use
via glycolytic and hexose monophosphate pathways.
However. alternate fuels can be used. (Glucose--de-
prived cells with minimal glycogen storage respond
\0 TSH.)
Nuclear volume increases after 2 hours. and SOme
new mRNAs arc made. The first new proteins are
enl.ymes used for hormone biosynthesis. Total cel-
lular RNA not rise substantially until after one
day. and rapid incorporation of am;,1Q acids into thy-
roglobulin can then be demonstrated. TSH seems to
affect the chemical oomposition of the thyroglobulin
a5 well as the quantity produced (66). It also pref-
erentially induces the RNA in volved in thyroglobu-
lin (118).
later. ornithine decarboxylase acti.ity increases
(109), and the cells grow and accumulate nomhy_
roglobulin proteins. Some augmentation of
dine incorporation into DNA can be detectcrl at 24
hours. but rapid DNA symhesis and entry of the
cells into mitosis require two days of stimulation.
As dis.:uSI;e<! earliu. hormones that promote cell
specialization do I10t ael directly as mitotic stimu-
lants. Pituitary preparations rich in TSH probably
contain growth factor "contaminants:' TSH may
also induce substances that accelerate endQlhelial
cell DNA synthesis and the formation of new capil-
laries ( 146 ).
MECHANISM OF TSH ACTION
Thyroid gland cells have low-affinity TSH binding
sites believed to concentrate the hormone in the vi-
cinity of smaller numbers of high-affinity receptors.
Binding to the high-affini(y receptors is rapidly fol-
lowed by dose-related activation of cyclase
and an increase in cAMP-<lependent protein kinase
'"
function (55). Exogenous cAMP and its analogs
mimic several actions of TSH. and phosphodiester-
ase inhibitors enhance the effectiveness of both the
hormone and lhe nuclcotidcs. Epinephrine and tI-ad-
renergic agonists 1ha\ promote cAMP gcncMion
also increase thyroid hormone :;ccrelion. All of the
preceding observatioru; are consiSlen! with Ihc con·
cepl lhat cAMP serves a. a second messenger.
TSH PrQhably accelerate, the interaction of the regu_
1.lOry prole;n of lh. adenyl.te cyclO$c system wi1h GTP.
However (although such effect. II ••,. betn described f<)r
other cell types). GTP doe. not oeem 10 ;nHuence the
binding of TSH to its ,e""ptc ... (115).
Membra"" gangliOSide, lIa .. been implkated in lh.
hormone-receptor binding mech.ni,ms. According 10 one
concept OM, is a compo""nl of the receptor, wile ....
other ganglioside< inl.rf.... with hormone-receptor int.r·
action$ A mod.1 hu been pre$.n ted in whi.h the (J
subunit <>I" th. TSII allach .. directly to a gly<:<>protein
C<lmponent of the receptor. The ganglioside then bring.
about C<lnf",mational cha!lj!e. in the", subunit. after
which the" component penet ,.... Ihe plasm. membrane
to >clivatethe ad.nyl". cydasc. It has been pointed OIIt.
ho ..... er, that .11 .vid.nce for 0 M, in.olvemont has bee"
obtained uockr """phy,iolog;.;.1 condition •. In rat thy.
roid celb, neuraminidase, al1.r structure of the OM,.
yet lhey inc ... ase the cAMP ""pon« 1o TSH. Mor.ovcr.
the interact with lo,...,.ffinity .itO$. T hey
do not .cem to alfe<t cAMP ilene ration or cell sc"";ti,,-
tion in wheJe.ce1l preparation, (12).
TSH probably acts at ,,<,v.rallnei. Low C<lncc:nlra·
tions can accderate T. secretion wilhoul aff«:ting
organificalion of iodine. There ar<: indicalion, Ihal
cAMP accumula tes in distinct "pools,'· each in·
volved in m.dialion of specific responses. The glands
also contain cAMP·independent protcin kinases Ihal
arc activated by TSH.
Stimulated cdls make prostaglandins. and those
of the E type are implicated in both augmentation of
cAMP produclion and acceleration of blood How to
Ihe gland. Pes may additionally aClivate ornithine
(109). However. TSH can still stirn·
ulale in the presence of indomethacin. (Salkylates
decrease responses 10 TSH (149) . butlhey may
act via mechanisms olher than inlerference with PG
generalion.)
Thyroid function is often poor in palie.IS wilh unC<ln-
trolled diabeles mellitus. In insulin-defici.nt mice. hor·
mone secrelion il impaired de,pile Ihe gencra1ion of large
.mounIS <>I" cAMP. The defecl con be C<lrre<:t.d witb in·
suli n (3).
T he thyroid glands of humans, micc. and some
other speci es arc richly supplied with adrenergic fi·
bers and they rossess at =epwrs. In these. norepi·
nephrine and other "'t agonists can anlagonize some
THYROtO HORMONES. THYROTROPiN AND TRH
TSH aClions without interfering with cAMP gener·
ation (95). The effects can be exaggerated wilh fl·
receptor antagonists. There arc other species in
which ,,·adrenergic agonisls decrease cAMP pro-
duction (119). In calf and mouse thyroids. they an·
tagonize TSH-slimulaled secretion of T. but acoxl·
crate organification of Ihe iodine (90).
TS H doe. nolseem todi ... ctly affect eithercGMP for-
mat;on or the fUnClKUl$ of cGMP-deperKIent protein ki·
However, il may int.",ct with .celylcheli". and
Dlher regul>!o .. Ibat affect the ,ua nyl .. e cyctue. Guan·
ooine is laid to acl on a cAM P·i"dependent protein kin • ..,
10 antagonize the effeclS of TSH on ornitbin< decarbox·
ylasc (55).
TSH REGULATION OF IODINE UPTAKE
W hen TSH is first presented to thyroid glands prt:)-
viously deprived of the hormone, T , sceretion accc!·
crates, small amounts of MIT and DIT leak from
Ihe cells. and Ihe plasma membrane danges facili·
tate Ot.Ilward diffus;on of iodide ions. Therefore, hoth
the organic and inorganic iodine content fall.
Physiologically impOrtanl aeceleralion of iodide
uplake and accumulation requireS 2 or more hours
Qf stimulaliQn, and maximal T:S ralios a ... allained
at around 30 hou ... Chang.. detected during the la·
tenl period include accelerated inoorjlO .. tion of la·
beled phosphate into phospholipids and RNAs. and
increases in Na ·/ K· ·A TPase content. One of the
new phospholipids may be a lecithin iodide carrier.
TSH INFLUENCES ON TSH RECEPTORS
Chronically high TSH levels eventually bring about
down regulation of the TS H receptors. Substantial
reductions in binding capacity (but not affinity) are
apparent at 24 hours. The sensitivily 10 TSH stirn·
ulation can d«:linc before this happens. probably be-
cause of effects relaled 10 rec<:plor occupancy (148).
Acti.",ion of the .d.nylat. C)"cla.., is :wooi.tcd with
clustering of the surface receptors. Very early changes
cannot be detecled by el.ctron microscopy. but ··patche,··
that are e.,ily visualized develop wilh time. High ""neen-
t ... tions of cA MP are proposed 10 .xert a form of ··neg.
Iti.e feedback C<lntrol·· that lowe .. sen.it;.i1y to TSH
involves some inftu.nce< on the clust.ring (21. Inter·
n.lilation of the hotmone·receptor clusters undoub1edly
contribute. to thc down rcgulation. II may «rYe olher
function •. since TSl-! binds with bigh affinity to cytO-
plasmic components. TSII facHiI.tes ADP·ribosyla1ion
of scveral pla.m. memb ... ne components, and the hor·
roone itself beC<lmes ribosyl.ted. Th • .., rClclion. m.y be
retated to ··de..,n,itilation·' (t 43).
THYROTROPIN RELEASING HORMONE
Thyrotropin releasing hormone (TRH. thyroliberin)
needed to maimain the Structures and secretory
function. of the thyrotropes. Antibodies directed
against the hypothalamic hormone reduce basal
TSH secretion. and they impair the responses to oold
environments and other stimuli (149). Exogenous
TRH can tlieit prompt rclease of TSH when testcd
in vivo or in vitro. However, there are only 10000e re.-
lationships between TRtI and TSH levels in intact
MOOit thyrotrope regulators affect the .cn-
sitivitiC!l of thc cells to TRH (rather than the TRH
conC(:n trations.).
ONTOGENY
TRH is present in developing human brain at 4)1
weeks postconception. The hypothalamo>-hypophy.
sial portal system does not bc<:ome functional until
after 11 week!; . but it has been suggested that TRH
exerts "paracrine" control in very young
fetuses.
TRH concentrations rise rapidly during week!;
16-20, a nd TRH·like activity is present in the am·
niotie nuid (62). It should be pointed out. however.
that the TRI'I may perform functions other than
stimulation of the tnyrotropes. It can, for example.
promote prolactin secretion.
In rats, the portal blood vessels complete their de·
velopment after birth . The thyrotrope$ of
and «,lease TSH, bear TRII r«,eptors.
and respond to the negative feedbadc inAuenees of
thyroid hormones. At this stage. they do not «,quire
hypothalamic stimulation to maintain their func·
tions. but they are exquisitely sensitive to exogenous
TRH (131).
Chemistry. Biosynthesis, and Metebollsm
TRH was the first of the hypothalamic releasing
hormones to be characterized and synthesized. It is
a pyroglutamyl-histidyl-prolinamide
(Fig, 3·5A). Since the bonds resistant allack by
system enzymes. TRH is effective when it
is administered orally.
Some c(mtroversies Over the biooynthetic path-
ways (94) are difficult to «,solve. The neurons that
secrete the hormone a«' not organized into morpho>-
logically ident ifiable duners, only minute amOunts
of the peptide arc synthesized. and both intracellular
and cireulating enzymes cleave the bonds. The tri-
peptide sequence is a component of proteins that do
not «,gulate TSH secretion. and it is difficult to sep-
arale TRH from some of those substances.
It has been suggested that cytoplasmic en',ymes
assemble the peptide directly from amino acids. A
pathway of this kind has been C!ltablishoo for gluta-
thionc and a few other small molecules. It been
reported that labeled glutamine and glutamic acid
are incorporated into TRH at rates that parallclthe
TRH synthesis. and that neither cyclohexim ide r.or
puromycin retards the reactions (108). Labeled pro-
line is also said to be incorporated into TRH in the
presence of either cycloheximide or chlorampheni-
col, but this process can be blocked with ribonucle.-
ase A. One intcrp«'tation is that an aminoocyl·
tRNA p«'cursor is utilized but ribosomes are not re·
quire<! (93), Different invC!lligators find that proline
is into TRH but the other two amino acids arc
not (9).
Studies have been conducted on cell-free systems
containing bacitracin or peptides Ihal prevent rapid
TRH degradation. In these, labeled proline was in-
corporated into a variety of small molecules, SOme of
which comigrated with TRH On chromatographic
columns , Certain of thc findings are regarded as con·
sistent with the belief thaI TRH ;5 cleaved from a
larger pre<::ursor. However. it has been pointed out
Ihat hypothalamic tissue contains at least 11 differ_
em peptides that include the TRH ,equence. More.
over. the fact that TRH Can be released from them
does not prove that the pcptides are physiological
TRH precursors (93) ,
SECRETORY PATTERNS
In common with other hypothalamic regulators.
TRH is released in pulsatile fashion. and the most
recently synthesized molecules are preferentially se-
creted (93). Neurotransmitters and other regu la tors
affect Ihe liming and magnitudes of release.
In heallhy human adults. the plasma COnCentra·
tions rangc from 0.5 to 20 ng/dl. Some of the cir·
eulating hormone comes from extra-hypothala mic
site •. TR H i. present in extra·hypothalamic brain.
spinal cord, pineal gland, panc«'as, reproducti.'e or-
gans. lactating mammary glands. the gastrointes-
tinal tracI, and elscwhe«, (94). It has been estimated
that of plasma TRH of newborn rats originates;n
the pancreas. (In SOme amphibians. the poison
glands of thc skin are the major sources of the eir-
culatory peptide [77).)
The half·life in human blood is around 6.2 min·
but it is affeetoo by several hormones. IXgra·
dation occurs ;n plasma as well as in cells. IXam;·
da5C$ removal of the NH, group of
prolinamide to yield "acid TRH" (Fig. 17-5). The
product (pyroglutamyl-histidyl-proline) lacks thyro-
trope-stimulating potency, but it is a. effe<::tive as
TR H for eliciting behavioral e/fe<ot' in rats referre<!
to as "wet dog shakes."
A pyroglutamyl peptidase eataly1.es separation of
thc pyroglutamyl moiety and the formation of hi!-
".
" SU)1c -PROI.IN£
OO<E
FI;. 17-5 .
ridyl-proli/UlQmide. The laneT can either undergo cy-
di7.3.tion to histidyl-prolinc dikc\opipcru7.inc (eyelo.
His-Pro). or be acted a histidyl prolinearnide
imidopcptidase that deavcs the molecule in10 free
histidine plus f= prolinamide.
Since is biologically active. TRH
can be classified as a prohormone as well as a hor-
mone. The derivative decreases PRL secretion and it
lowers lhe activities of gU\ 3_hydroxy-J.mclhylglu_
\3ryl cocnl.ymc A reductase and brain Na' / K' -
ATPase. It anlagon;?.<:! pharmacological depres·
sants and analgesics, and j{ may play role, in ther-
moregulation and aPl"'ptilc suppression (94).
TRH Regulation of Thyrotropes
Soon after binding to high-affinity receptors of the
plasma membranes. TRH invokes Ca" uptake and
TSH release. The hypothalamic horm<lne is believed
to elevate cytosol Ca" . to interact with calmodulins.
and to bring about intmcellular redistribution of the
calcium ions. Calcium emux accelerates soon after
the hormone is presented.
TRH cannot prom<lte TSH secretion if the pitu-
THYROID HORMONES. THYROTROPI N AND TRH
.... iOINE
OM'...,"" •• " •
, . p.
'''' I AAOI.H:A" Q[ I
01 TRH .
itary cells are bathed in eakium-<:ieflcient media
(26). When the ion is supplied. calcium ionophore •.
ouabain. and depolarizing concentrations of K + all
promote Ca l + uptake and TSH secrelion in the at>--
;ocoee of TRH. D600 and phenytoin act in diffcrent
ways to block Ca 1+ uptake. and they antagonize the
effects of bolh TRH and K+.
Some investigators implicate cAMP as a second
messenger (117) and report that physiological con-
centrations of TRH generate smali quantities of the
nucleotide (75.84). Howe'"Cr. TRH has not t>een
shown to directly aClivate adcnylatc c}"Clase (117).
Others sec Ihc cieyations only when pharmacological
amounts arC presented. and they find flO increased
cAMP binding to protein kinases. Actinomycin D.
cycioheximide. and puromycin are among the agents
that can raise the cAMP levels without promoting
TSH secretion (94).
On Ihe Olher hand, cholera toxin. some cAM Pan-
alogs, and some phosphodiesterase inhibitors do ac-
celerate TSH secrelion. It is therefore JlOS$ible (hI
there are conditions under which high TRH levels
act via eAMP to enhance other actions of the hor-
mOne . Tritluopcrazine d<xs not lessen the effects of
g·Br-<:AMP (52). although it interferes with depo-
larization-mediated Ca" upta ke. calmodulin func-
tions. and both T RH and K· stimulation.
PGEs enhance the effects ofTRH. but Ihey prob-
ably do not act via cAMP. augment
cAMP production in many cell types. but thcy d(l
not promote TSH release. PGI stimulation has been
attributed to direct actions on the thyrotropes (152)
as well as to vasodilation.
It is poosible thaI TSH release and new synthesis
are lin ked under physiological CQndition •• and one
suggesti(ln is that lowering of the intracellular T RH
in some way promotes production of new hormone.
TR I1. calciu m ionophores. and depolariling COnCen-
trations of K· accelerate TSH synthesis as well as
release (49). However. removal of extracellular
Ca" affects mostly release. whereas protein synthe-
sis inhibi tors selectively block the synthesis.
It is important to reoognize that CI and p subunits
can combine 10 increase IOlal intracellular TSH con-
tcnt even when no new peptide chain assembly oc-
curs (92). and that glycosylation Can affect the (:(lm-
binations and thc hormone release rates. Species
differences in Ihe relatiV<' quantit ies of the CI SU\>-
unit" fJ subunits. and TSH have been found (26). It
has been reported that TRH accelerates TSH gly-
cooyla tion but run proline incorporation when it is
presented to rat pituitary cells in culture. Mon.min
(which interrupts transit of vesicles from Ihe Golgi
...,gioo to the plasma membrane and terminal gly-
cooylation buI not protein synthcsis) antagonir.cs
TRH effects on both labeled glucosaminc incorpo-
t'Jtion and TSH relcase. Tunicamycin. which aITccts
the OOre glycosylatioolhat OCcurs at the (ime of pro-
tein synthesis. decreases the inCQrporation of labeled
glucosamine into intracellular TSH but it docs not
antagooize the TRH effects ( 104A). TRH docs not
stimula te thyrotrope prolife ration in (92).
T RH is slowly internalized by thyrotropes (94).
High-affinity binding sitcs haV<' been identined in
nudear and microoomal fractions, but most observ-
ers belieV<' the internali'.3tion is linhd with receplor
down '<'gula(ion .
TRH ACTIONS ON OTHER CELL TYPES
TRH acls on laclOtropes to accelerate production of
the mRNA that codes for PRL precursor (105). it
is equipotent for stimuiatioo of PRL and TSH re-
lease. but the effects on the laclotropes occur more
rapidly (94). T he question of whc(her TR H is a
physiological prolac(in ...,leasing h(lrmone was
cussed in Chap. 16.
TRH promotes growth hormone secretion in pa-
tients with acromegaly, but it i, nol belicV<'d to be
an important regulator of G li sec...,tion under nor_
mal (:(lnditions. It does perform this function in birds
(77). and possibly also in callIe. Nonspecific stimu-
lants of TSH release have been observed to increase
Ihe formation and release of gonadotropin subunits.
but TS H is not known to exert important influences
on gonadotropes.
Centrel Nervous System TRH
In rats. 75% of brain TR H is oulside the hypothal-
amuS. The content is not affected by hypothalamic
deafferentation (24.46). Substantial amounts arc in
the ce rebral cortex and brain stem. and smaller ones
OCCur in the cerebellum . Thc peptide is also present
in the ce rebrospinal flu id. Related distributions nave
been described for othcr mammals.
INFLUE NCES ON BODY T EMPERATURE
TRH-secrcting neurons are located close to the an-
terior hypothalamic neuron$ tht ,<,gulate body tern_
pct'J ture. When TRH is injected into the region. it
elevates the body tempera ture in rats and rabbits
(22) and in several other species. 11 also counteracts
the temperature·lowering influences of a variety of
agents.
Rats a nd human neonates increase their T RH re-
lease when eXjXIScd to cold envi rooments. Thyroid
hormone activity inc reases in goalS in response to
hypothalamic cooling (91). jXlSsibly because larger
amounts ofT RH are secreted. In many of the mam-
mals. adaptations to CQld environments are blunted
following the administra tion of antibodies directcd
agains( TRH (I 17). Callie a lso secre(e more thyroid
hormone when exposed to cold. but adaptation. can
be made without this (1 4 7). Humans depend heavily
on behavioral responses to avoid body cooling. Most
observers report ,mall acute increases in TRH re-
lease. but others do not (1 4 3A).
TRH interactions with temperawre-regulating
neurons are CQmplex. The hormone is implicated in
accomplishing arousal from winler hibernation and
the associated elevation of body temperature in
ground squirrels. However. exogenous TRH lowers
the temperatures of ground squir...,ls that a rc fully
awake. and it is mOre effective in animals that are
behaviorally active than in ones that arc resting
(128) . In calS. TR H lowers the body temperature,
presumably because it acts on Ihe medullary respi-
ratory neurons to increase panting (22).
The effects of TRI-l on "arousal" are probably
linked with the ones on body temperature. The gen-
eralized slimulatory influences on (he central ner_
vous system arc accompanied by changes in electro-
encephalographic patterns (94). The hormone can
invoke some forms of behavior (such as body sha k-
,..
ing), augment Ihe cffcet$ 0( mythn' .... and other
stimulants. antagoniZll: ,he .<:tions 0( dt.p.. BanIS
w<:h as blrbitur:ues and Opiates, and interfere with
$Ie<:p. On tile other hanel. TRH uer\s "quieting" in·
00 behaviorally aClive ground squirrels
(128).
OTHER EFFECTS
When injtttod into the bfain. TR II ;"...xes pupil·
lary coosuic\ion. and it c:oIonic motility
and the secretion of gasnic acid.
«lis ""idely dimibulcd to pe.-
ripheralorgam. II was al one time believed INII 11M:
cells originate in the embryonic neural cmt$. How.
ever, they appear so early in the C(IU= of deve lop-
ment thaI diffcrcnaat;on from endodermal compo-
nenl$ of the gut and from other cell types ""ems
more: li kely (104). Some or the peripheral effects 0p.-
pose the cenlral ones. Systemic administration or
TRH decreucs gastric He l. depresses pancreatic
enzyme secretion. and de«eucs JUtroinleslina l mo-
tililY and &iuoose absorption. lIowever. it increases
glucagon ('14). When inj«ted intra-;e-
nously, TRH can also cardiovascular fune-
tions in o::unscious rats subjected to or hcm-
oflha,ic .hock (72).
PHVLOGENETIC CONSIDERATIONS
The wide dill ribution ofTRH in species in which no
inft uen<;CS a.n be derllOrl$tl"lllcd on Ihe pituitary
alarld (and even in ones that lack such a Slructure)
underlies tM: con<:cpllhal TRH is an "aDCK:nt" m0l-
ecule Ihat was "'oo-optcd" only late in evolutionary
deve lopme nt for use as the ""suialor of thyrotropes
(77).
TR H is PfCS"nt in hi,h concentrations in Ihe pi-
nalgllnds of 'lOme of tM: venebrate$. and the levels
are I fI"e<:tcd by environmcntallighting. (The lripep-
tide his also been found in tl>c reli nas of the eyes.)
In some amphi bians. TRli Sttms to fu nction as a
releasing hormone for "MSH (mela nocyte stimulat-
ins bormoru:J, and it al$(! promotes PR L release.
Bolh MS H and prolactin have been implicated in
the ""gulation of wa ter and electrolyte baiJnce .
NEUAOENDOCAINE CO NTROL OF THE TRH-
TSH-THYROID SYSTEM
Sevel"lll hypolula m ic pcplides and aminco act on
TRII ne urons. thyrotTOpc$. or both.
Soma loltatin ( SS )
SS leIS dir«tly on lhe pituitary gland 10 decrease
basal TS H secrelion and to dampo:n the responses to
TRII. II probably mediates lIrt1s·,ssodated inhibi-
tl<m efTS11 release (117). In humaM, 55 infusions
aboliSh the nocturnal "surges" and they lower
thc plasma TSH in hypot hyroid patienls (94). The
receptors differ from tbe ones that bind TRH (84).
In ralS. thyrotropc I"CI'ponsivellCSS to SS appears
earlier than TRH depcndenec (101). The median
emilK'llCC eoncentr.l1ions are as hi,h as the ones
nudcd 10 act in vitr(l on piluilary cells.. l esions of
the pcriventricula r nucki lower SS levels in the
brain and they invoke 10000·term elevation of the
plasma TSH. Antibodies directed against SS al$O el-
evate the TS H . and they cxaggerate the responses 10
cold en_iron mentallcmpcratures (9 4).
SS-iCcreting cells within the thyroid glands a re
implicated in Ioca.lited inbibitory o::untroi over thy·
roid hormone secretion (149).
nervous 5y$tem 55 antagonizes several
central actions 0( TRH . It enbaRCC$ lhe effectiveness
of barbiturates a nd other deprcssanu. It inhibiu
growth hormone secretion, and it blunu 50rtlC influ·
ences on the gul. Ho,,·cver. belh TRH and SS op-
p06C the hypothermia invoked by carbachol . neuro-
or .s..,ndorphin in raU
FEEDeACK CONTROL OF SS SECRET10N
Both TRH and TJ seem to be in wolvcd in negative
f«dbilck conlrol or lhe SS secretin, ncunlJlS.. Acute
Up05ure TRH his been reported 10 in·
creasc, and chronic treatment to decrease, IIIe num·
bers ef SS receptors on the thyrocropes. Hypotha·
SS is subnormal in hypothyroidism a nd
cle_ated following Tl admi nistra tion (94).
Oplold, and Other Peptide,
Endogenous opioid pcplidcs probably exert Ionic
stimulalory control (111). Mel-<:nkep/lalin all<llogs
augment TS H secretion in eUlhyroid humans, and
naloxone depresses it in hypothyroid patients. AI-
lhough il has been assumed tballhey aCI exclusively
on the hypolhalamus, di,..,ct stimulation of dispersed
pituitary cells and supo:rfused pituitary fragmenu
his been shown for leu--cnkephalin,
and ./kndorphin (18A). On the hand, opiates
imp*ir TS H responses 10 cold environmenl$. p<.>SSibly
by acting on dopaminergic neurons (94). Lcu-<:n-
kephalin ha$ abo been reponed 10 diminish TSH re-
sponses to TRH via moxhanisms unaf-
foxted by naloxone (117).
Neurotensin. cholecyslokinin, and calcitonin arc
addilionalpeptides implicated in 11>< control of TSH
secrelion or effecliven.... However, since the sitcs of
administration and the conditions of Ihe teSt subjects
alfect both the direclions and magnitudes of Ihe re-
sponses. the roles have not b«n defined (94).
Dopam ine ( DA)
DA is believed to exert tonic inhibitory controls over
TSH secrelion in humans and other species. and to
be involved in regulation of the diurnal rhythms
(121). It probably acts mostly On the Ihyrotropes.
The cells have DA receptors, and DA concentrations
in the median eminence and portal blood arc nigh.
When given systemically. DA does nolpenetrate the
blood-brain barrier. but it d<:>es decrease Ihe release
ofTSH and its subunilS. Receptor agonists mimic ilS
.rrects (94). Anlagonists are more elfective in hy_
pothyroid than in euthyroid subjects (111).
Some influences are additionally excrted on the
hypothalamus. L·DOPA (which does penelrale) can
elevate hypothalamic TRH and lower plasma TSH.
Opiates are believed to dampen the TSH n::sponses
to cold environments by accelerating DA rdease.
Some stimulatory innuences of norepinephrine arc
linked with inhibition of DA release.
The greater responses 01 women than men to
TRH administration. and Ihe increased sensilivity to
TRH during the preovulalory phase of the men_
Slrual cyde. have been lin ked with influences exerted
by over brain DA turnover.
There are complex interactions wilh prolactin. As
waS noted earlier. TRH promotes prolaclin secre-
tion, DA inhibits it. Hyperprolaetinemia ex-
aggerates DA-medialed inhibition of TS H release,
and it antagonizes se,-eral peripheral actions ofT).
No repinephrine end Epinephrine
NE increases TRH se<:rction when it binds directly
10 <>, receptors in the hypothalamus or inhibits tne
DA ""urons. It can. however. decrease T RH release
by interacling with <>, receptors (83).
Peripherally. NE tends to decrease T. secretion.
since the thyroid gland also hu <>, rc<:<:ptOl'$. Epi_
""phrine opposes this by binding to /I-type receplors
and promoting cAMP generation. The calechol -
amines also act at postn::ccptor sites to exaggerate
Ihe elfeclS of cAMP (7S). One mechanism seems 10
be lowering of ph05phodiesterase activity (54). Thy-
roid hormones modu late Ihe elfecls. They augment
the numbers of {J receptors and may reduce the num-
bers of Ihe '" type.
large doses of catecholamincs invoke several of
the symptoms of hyperthyroidism. including tachy-
cardia. hypermetabolism. rapid lipolysis. and also el-
evation of Ihe plasma rcnin activity (I S). Dosages
easily 10lerated by euthyroid animals can be fatal to
hyperthyroid ones.
Effects of Cold Enviro nmental Tem perature s
Catecllolamines play major roles ;n both acute and
Iong-Ierm responses to cold exposure (70). It has
been proposed thal lhe elfectivenessof Ihe regulators
is enhanced by concomitant activation of the
TRH-thyroid sySlem. Hypothyroidism is associated
with low metabolic rate. low body temperature.
poor resislance to acute cold exposure. and impaired
ability 10 acdimatile.lt can lotally abolish thermo-
genic responses 10 catecholamines. and restoration
is accomplished within 3 hours after T, injection
(20). In some spedes. TRH secrelion increases
if the hypothalamus is cooled bUI Ihere are
no generali7.cd changes in body tempcrature (95).
It has been reported that cold-expose<l rats have
high thyroid hormone and prolein-bound iodine
le'-els (154). and that larger quantities of the hor-
mone are present in free form when catecholamine.
elevale the plasma free rally acid concentrations
(53).
However. other f,ndings arc more co",istent wilh
the bet,ef that phySlOloglcat concentra\tons of thy_
roid hormones exert "pcrmissive" innuences, and
that no rise in thyroid hormone levels is required .
These include the following: (a) TRH are not
consistently elevated during cold c<posurc (II 7): (b)
theelfeets of hypothalamic coolinS may not be phys-
iologically relevant. since stimulation of cold recep-
tors on body surfaces soon leads to Ihermogenesis
and heat conservalion that avert cooling of the brain:
(c) TRH can act centrally to raise the body tcmper-
ature without inereasing TSH secretion; (d) if TRH
release dae5 lead to increased Ihyroid hormone se-
er'lion. T. SOOn decreases thyrotrope sensitivity to
TRH: (e) ahhouSh thyroid hormones alfect Ihe
basal metabolic rate in Ihe brown adipose lissue of
young rabbits. levels do not en-
hance eateeholaminc-5timulated thermogenesis
(81): (f) thyroid hormone levels in the blood do not
consistently rise in rats exposed to eOld in the labo-
ratory (53). and cows cope with cold environments
without incn::asing the socrelion (147): and (g) ani_
mals that aeclimatize under natural conditions tend.
if anything. to lower Iheir eirculaling Ihyroid hor_
mone conccntralions as they aequin:: more efficient
control over heat conservation. They respond to nu_
mcroU'l stimuli provided by the winter environment.
including shortening of Ihc photoperioo. Many grow

heavier fur COOlS and acquire thick insulating depos·
its of subcutaneous fat (154).
M05t commer<:ial rat laboraIQry chows are high in
fiber content and they often contain thyro.ine. Since
cold-exposed ralS cat more. and fiber bil.
iary excretion. T. lurnoV<'r and fecal excretion ac-
celerate. When rats are fed diets lower in fiber and
devoid of T •• they cope ""'" efficiently with the cold
but they do not raise their plasma thyroid hormone
levds. Cold Stress is usually associated with accel·
crated release of glucOOJrticoids that contribu te to
the adaptations. However. glucocorticoids act in sev·
eral ways to depress thyroid hormone functions.
These and other findings are consistent wilh the be-
lief that hyperthyroidism impoir$ Ihe responses 10
cold (154).
Serotonin
The addition of small quamities of serOlonin to suo
perfused rat hypothalamic fragments Can ac<:derate
TRU secretion via mechanisms that are blocked
with 'pecific receptor antagonists (24). Earlier stud·
ies indicating that the amine fails to affect or that il
decreases TRH release may have involved the ac-
cumulatic>n of so much TRH in thc media that out·
ward diffusion of additional hormonc from Ihe neu·
rons was blocked . tn al leasl some SpeCIes. serotonIn
dirc<:tly stimulates the Ihyroid gland. and the T. reo
leased se<:ondarily brings about TRH in hibition.
Serotonin may additionally act on thermoregulatory
neuron. and oppose the eWcclS exe'ted by r-.:E (16). The
on pitui tary glands, but i1 probably
dcoes 001 affcct1hc thyro1ropes (78).
Pineal glands make large quamities of .. rotonin.
They convert much of it to melatonin. especially duro
ing the nigh\. Both mdalonin injections and pine·
alcclomy have been reported to affecI Ihc thyroid
gland directly. to innuence TSH sccrelion via T RH·
independcnt mechanisms. and to modulate Ihe fune·
of neurons involved in regulating TRH release.
The physiological implications are not clear. since
the pineal makes several other regulators, its a,tivily
chang.,. wilh the season of Ihe year. and Ihere arc
marked speci.,. variations in the responses,
Hi stamine
The hypolhalamus is in histamine. and thc cells
have both H, and HI recepton. The amine i5 a pro-
posed ,egulator of thermogenesis (89). Exogenous
histamine can promote TRH release from incubated
hypothalamic fragments and TSH release from pi.
tuitary glands (94). II has been observed to elevate
THYAOtD HORMONES. THYAOT1'IOPIN AND TRH
plasma TSH (although it does not penetrate the
blood·bra in barrier). but the findings are not consis-
tent. Histamine also interacts with thyroid gland 11,
receptors. and il promoles cAMP generation ((49).
It may additionally increase responsiveness to TSH
by improving the blood now 10 the gland.
Gamma-Amlnobutyrlc Acid (GABA)
Some studies with GABA. agents affecling its me-
tabolism. and agents affecting its receptors. suggest
thaI this regulator acts On dopaminergic neurons to
bring about lowering of TS li. Howevcr. observations
that bieueulline alone has no effect (although it an·
tagoniles the action. of exogenous GABA ) are con·
sistent with suggestions that GABA participales in
a negative feedback control that in_olves TRH neu·
ron collateral •.
INFLUENCES OF STEROID HORMONES
Estrogens decrease TSH secrelion. probably
by affecting DA turnover. "&cape" from the inhi·
bit;on that occur.j within 1- 2 da)'s is amibulcd tt>
induction of new TRH receptOr$ in the pituitary
gland (75). Estrogens also accelerate production of
the thyron ine binding globulins. and they are rCo
ported to slow T:)H (as well as T.) dcgF.;dation in
mon keys (149) , The higher incidence of goiter in
women than in men may be related to the findings.
but estrt>gens also promote the secrelion of growth
(38) t I , ( In rats.t
lillie
i have been used In conjunction
with other agenls 10 alleviate the symptoms of hy·
perthyroidism. While some effects may involV<' the
immune system, the 'Ieroids decrease thyrotropc
scnnivities to TRH and to SOme other stim ul ants.
and they thereby 10"'cr the circulating TSH and T,.
They are also reported to lower plasma T) and ele·
vate rTJ in adults (143A). to decrease circulating
TBG but elevate the TBPA. and to diminish thyroid
hormone binding in the liver (75). Howe_cr. the SIC,
roids accderate th e T. - T) convenion in human
infants.
The antipyretic aClions of glucocorticoids. and
similar effecls of ACTH in adrenale,tomi7.ed ani.
mals. have not been .hown tt> be mediated via the
TRI-I·thyroid .)'Stem (88).
EFFECTS OF STRESS
Glucocorticoids exert "permi.sive" innuen..s Over a
wide variety of hormonal functions. The blood levels
rise in res""nse to cold uposure. food depriva tion.
forced exereise, a nd other forms of stress, and there
arc good reasons to believe that the steroids then
participate in the adaptations that must be made . In
contrast, pharmacological dos.ages of the hormones
impair thc res""nses.
During fasting and thc anti·insulin
effects of the glucocorticoids contribute to thc ability
to mobilize and utilize fuel reserves. However. food
deprivation and insulin deficiency can act in other
ways to diminish thyrotrope sensitivity to TRH (3).
Glucocorticoid inhibition of T. conV<'rsion to T ,. and
of TSH secretion. facilitate conservation of meta-
bolic reserves when they are limited. These inAu-
ences arc usefu l during fasting. but they may OOt be
following cold exjX)Surc.
It is not known whether the effects of forced ex-
ercise on thyroid system functions arc mediated via
glucocorticoid s. Women voluntarily submitting to
"end",""nce training'" that depletes thc fat reserves
despite food inta kes that maintain body weight. have
been (}b:o;crV<'d to show augmented thyrotrol'" re-
spon""s to TRH.lowering of the plasma T,. and low-
ering of the circulating T,: rT, ratios (19).
The clinical literature contailt!' numerous sugges-
tions that hyperthyroidism makes its appearance
500n after an individual subjected to seve re stress is
relieved of the stimulus. (The earliest symptom!
have been observed. for example. in patients heavily
burdened w'th the care of a n invalid parent soon
after the death of the parent) It is jX)Ssible that the
thyroid syste m becomes disrupted as a result of pro-
longed glucocorticoid-mediated inhibition and the
subsequent lifting of the inhibition. It is also known
that glucocorticoid! suppress immune functions. and
that hyperthyroidism is frcquently associated with
autoimmune disorders. Catecholamines release thy-
roid gland amines and affect T. production (A·7).
They also elevate body temperature. On the other
hand. many clinicians do nQt believe that stress is an
important factor.
TRH-TSH-THYROID H ORMONE
INTERAC TION S
T, directly depresses Ihyrotrope function •. Although
some inAue""",s on unstimulated cells have been
demon"'ated. physiological inhibition involves
mostly lowering of the sensitivity to TRH. Within
30-60 minutes after T, binds to its receptors. the
thyrotrope.s release less TSH. and they become in·
sensitive to TRH and certain other stimulants. TSH
synthesis declines after some time. and the numbers
of TRH receptors fall markedly within 6_12 hours.
Since the .ffects of T, are blunted by protein syn-
thesis inhibitors. it is likely that the thyroid hormone
exuts its innucnces via induction of either a labile
protein thaI directly inhibit.s or an enzyme that re-
moves a physiological stimulant (56).
Under ordinary conditions, thyrotropes take up T.
from the bloodstream and rapidly convert half of it
to T). When plasma T. concentrations fall, less T, i.
made in the pituitary. Thyroid gland. seCrete mostly
T •• and small changes in the aelivities of the follic-
ular cell, affect plasma T. {but not T, ) cOncentra-
tions . Therefore. thyrotrope.s readily detect changes
in thyroid gland functions.
In contrast . most other target cells take up T) as
well as T •. They can maintain their functions when
T. levels fall transiently. since T) tends to remain
within the normal range for a much longer time pe-
riod. Some important differcnces between thyro-
tropes and other thyroid hormone target cells can be
demonstrated with pharmacological agents that af·
feet total thyroid hormone secretion and T. cOnver-
sion to T,.
Propytthi(>Uraeit is widely used in 'he laoo..,ory to de-
crcase thyroid hormone function •• and il has also be.n
given to patie n" with cenoin fOTms of hyperthyroidism.
It .ct. <>II Ihe thyroid gland to block thyroid hormone .yo-
th"i'. and i, atso ae" periphefOlly '0 slow eonve,..,;on of
T. to When given alo .. for extended time period •. it
invokos hypothyroidi,m (.ince it Iow.rs cir_
culating T. and T,). Th)'rolropes ",nse the fall in T. a nd
,hey $Cerete more TSH . Although the thyroid gland can·
nol make much hormone under such conditions. cdl
g",""h i. ""',kcdly "im.l.'o<! by ,h. high TSH levet,.
Propylthiouracil doe. 1101. !)ov,'e""r, .ffoelthe aelivily
of tb: pi,uitary gland d.iodin .... Th<refore. if T. is iliven
along with the drug. the thyrolrOpe$ lake up lhe T" COn·
.ert it to T,. ond reduce their TSH secre tion. At the same
I;mo. periph.ral cell, dependenl on btood sour= of T, Or
on intracellular T. to T, conve",ion. affected by the pro--
p)'lthiouracil continue to show the effects of hor mone
depriv.,ion.
By contr.. t. iopanoic acid impairs dc;ooina, ion ,..ilhin
,he pituit.ry ,land as ""ell as in the liver. When it is given
in combina'ion wilh T. '0 th)'roidee,omi,cd .nim.t$. the
T. fail. to suppress TSIl ..erclion (99). Very h;llh can-
contration. of T, can 'hen '0 some ."en, inhibit the
thyrotr<>pts.
topanoic ac id (tetopaque) is a radiopaque substance
that i. used in diagnostic procedu"," such as
eholecySlovophy.
CH, -CH,
" ,
HC-C-COOH
, ? "
,
Thyroidectomy leads. in time. to elevation of both
plasma a nd pituitary TSH . Continuous infusion of

T, mosl of Ihc peripheral efTe<:ls of thyroid
hormone dcfLciency. However, since liuk T ) is di-
rectly laken up by Ihe thyrotropcs when the CQncen-
tralions are low 10 moderate. Ihe TSH levels remain
high (32). Continuous infusion of T. is somewhat
less for oorrecling Ihe peripheral deficiency
(since the T, 10 T) oon.ersion is suboormal in somc
of the targels). However. it inhibits the thyrotropcs.
Despile these fioding$. thel'<' '1'<' limiled numbers of po'
tient< who "'I'<'le lorac amount< of TSH when thc cir·
culating T. co"ccnu.lion. are high. It i. $u$pccled that
Ihoy suffcr e;lber receplor defeels Ih.1 ""'or Ibo .0ns;li ...
ily to T, made in!racellalafiy, Or thatl.ey ha •• impairod
abilily 10 con.. " T. 10 T, within Ihe piluitary gland. In
.uch ca.... very lorge dose. of T, can have b<neflcial ef-
feoIS(12).
TSH and Thyroid Hormone Influences on
TRH Secretion
Thel"<' is no <.:Onvincing evide""" thaI the concentra-
tions of TSH within the sySlemic blood. piluitary
gland, portal system, or hypothalamus have impor_
lant dil"<'cl influences on TRH secretion. (The cir-
culating le..ls can bring aoout small changes in
TRH by on the thyroid glands.)
Small quanlilies of T) to required 10
maintain normal hypolhalamic functions. A mOder_
ale. transient increase in TR I-I Out",,1 may follow
the administralion of low dosages to previously de-
prived animals. When very large amounts of Ihyroid
honnones are given 10 euthyroid subjects. th e TRH
Ic..ls fall somcwhat. II has becn reported that nor-
mal individuals have only minute quantities of TRH
in Ihe blood. thaI Ihe le..ls be<.:Ome undetectable in
hyperthyroidism. and that Severe hypothyroidism el·
evales the plasma TRH (75).
UIUllshort Feedback Control 01 the ThyroId
Gland Activities
Following prolonged stimulalion by high levels of
TSH. and whcn exogenous thyroid hormones are ad-
ministered. Ihc follicular ",,11$ become refractory to
snbsequent presentation of TSH. The responscs of
the adenylate cyclase. protein kinase, phospholipid
synthesizing, and glucose oxidation systems can be
blunted without significant impairment of TSH
binding to its l"<'eeplQrs (149). Evidently. Ihc accu-
mulalion of iodinated proteim brings about irrever_
sible changes in the catalytic component of Ihe ad-
onylate cyclase thai can be corrected only by new
protein synlhesis. The cell. Ihen become insensitive
10 other agents that affect cAM P generation. In oon-
traSl. TSH desensitization can affecI receptor num'
THYAOIO HORMO NES. HIYAOTROPIN .... ND TRH
bers and Ihe funclions of Ihe regula/ory components
of Ihc aden)'laIC cyclase system. Methimazaole
(which blocks organificalion of iodine) prevents i0-
dine, but nol TS H desensitizalion (50A) .
EFFECTS OF IODINE DEFICIENCY AND
EXCESS
Humans can main tain endocrine balance when the
daily iodine intake ranges from 100 I<g 10 20 mg.
Some pans of the world al"<' called "goiter belts" be-
Cause the soil. vegetables. and livestock contain only
minute quanlities of Ihe clement and locally availa-
ble foods do oot supply enough iodine to meel the
minimum requiremenlS. There was a time when
most adulls living in those I'<'gio"s developed en_
larged thyroid glands (simple. iodine-dcficiency, or
endemic goiters). The <.:Ondilion i. less prevalent
today. because KI is usually added 10 lable sail. Io-
dine deficiency is sometimes seen in patients On salt-
restricled diets. and in ones wilh renal and hepatic
diseases thai aecelerale iodill<' 1<M via the urine Or
Fc"" •.
It is eslimaled Ihal persons residing in the Uniled
Stales ingesl 240-740 "g of iodine daily. This
greally exceeds the requirements. bUI it is well tol-
erated . In some coastal regions. Ihe soil is exceed-
mgly nch in iexline a nd it is Ihe custom to eat large
quantities of seafoods. A different kind of goiter can
develop under such condition •. It is rare among oth-
erwise healthy populations. but the high intake
causes problems when it is associated with genelic
defects thai impair thyroid gland iodine melaoolism
(149). Iexline toxicity also occurs in SOme patients
taking certain medications for asthma and other re-
spiratory ailments (97).
Direct Effects 01 Iodine on the Thyroid
Gland: Autoregulation
Normal Ihyroid glands COOlain only small amounts
of inorganic iodide. Soon after 1- enters thc
lar cells. it is oxidized and incorporaled into thyro-
globulin. Some of Ihe iodine rel=ed by deiodinase
reaclions is "I"<'cycled"-i.e. used 10 make Il<'W
thyroglobulin.
If the exlracellular iodide concentralion rises. the
levels also rise transiently. T, se<:l"<'tion
can then accelerate for a very brief period. However,
the rale of iodide uptake soon diminishes. and 1- ex-
trusion incl"<'asts. "Auto-I"<'gulation" can be demon_
stnned in hypophyseclomized animals tOlally de_
prived of TSH, and in animals given <.:Onstanl TSH
dosages as the iodi ne levds are varied. It is believed
Ihal high intracellular 1- leads 10 the production of
a transporl inhibitor. Since agents that interfere
with iodine incorporation into organic molecules im·
pair the autoregulatory mechanism. the inhibitor
may be an organic iodine compound dilTerent from
thyroglobulin (106).
In iodine-defieicney states. the follicular cells in·
crease their rates of iodide uptake. The iodide is rap-
idly incorporated into thyroglobulin. and iodide re-
leased during thyroglobulin hydrolysis is avidly
conserved.
Effects 01 lodlns Excess In Intact Organisms
Chronically elevated iodine levels reduce follicular
cdl sensitivity to TSIi. Even when TSH binding
continues at a normal rate. less cAMP is generated
(139). The cells then make smaller amounts of thy·
roglobulin , and they incorporate iodine into other
protcins. The thyroglobulin that is made is retained
for longer times within the lumen. and it become
heavily iodinated. The rates of endocytosis and thy·
roglobulin hydrolysis decline. and most of the hor·
mone that is released is T•.
As was discussed earlier. thyrotropes take up
mostly T •• and they convert about half of it to T,.
When thc plasma T. is high, the T, formed inhibits
TSH release. In time, the follicular cells undergo
atrophy (but the lumina become distended with col·
Ioid). The reduction in cdl size is anributed in part
to decl"<'ased nudeic acid synthesis. However. SOme
of the regression may be rdated to lessencd produe-
tion of acid metabolites that invoke vasodilation
(149). In rats. repeated administration of large doses
of iodine lowers thyroidal ATP and pyridine nuclo»
tide content (97).
In patients with goiters that make exte$Sive quan-
tities of thyroid hormones, shon courses of treatment
with Lugors solution (KI + I,) often rclicye some
of the they lower the plasma
T, and T,. The carliest effccls arc linked with less·
ened sensitivity to stimulants. Endocytosis and hor-
mone secretion decline. In some cases, the goiters
al.o regress.
Chronic presentation of I'harmacologica\ dosages
of iodine can invoke different responscs. The glands
sometimes become hyperplastic but lose their ability
to make thyroid hormones. "Iodide has
been known to develop in patients ta king iodine·rich
medications and in individuals with genetic defects
thai permit the glands to accumulate very high 1-
concentrations because the iodide is 110\ incorporated
into proteins at the usual rateS. It occurs in pans of
Japan in which $C3weed $Oup (which contains 80-
200 mg of iodide per bowl) is a regular component
of the diet. In addition 10 disturbances in iodine me-
tabolism invoked by chronic consumption of large
quantities of the element, the diets may contribute
to thyroid gland dysfunction by ad"crsely affecting
the irnmune system (92A).
Effects of Chronic Iodine Deficiency
At first. the autoregulation accelerates iodide uptake
and accumulation, and the iodide i, rapidly incor-
poratcd into thyroglobulin. The T :S ratios Can rise
above 250-300: 1. The glands become highly sensi·
live to TSH. Thyroglobulin is taken up by the follie-
ular cells and it is hydroly'.cd 500rt after it is synt he-
sized. Therefore. the colloid within the lumen is
depleted, but the plasma hormone levels are main·
tained for several weeks. The T,:T. ratio of the ef-
nuent rises. Since many peripheral cells utilized T,
directly. nearly normal thyroid functions arc main.
tained for an even longer lime .
The thyrotropcs sense the fall in plasma T •. and
eventually more TSH is secreted. The follicular cell,
grow. and they become more efficient at synthesizing
the thyroid hormones as the capillaries in their vicino
ity proliferate. Increases in gland size arc limited
during the early stages. since the lumina arC
shrunkcn.
With continued iodinc deprivation and TSH hy-
persecretion, the follicular cells proliferatc (38), and
a thyroid-{!cficiency goiter develOpS. In $Orne individ·
uals. lhe compensatory changes Stave off hypothy·
roidism for many months. In others, thyroid bor-
mOne dcfieiency develops rapidly. (AS has be<=n
discussed, TSH is probably not a direct mitotic
sli mulant.)
When first formed. the goiters are easily treated
with iodide salts. However. the cells eventually
undergo degenerative changes that include nccr05is
and cyst formation. The glands become nodular and
resistant to iodine replacement therapy. (In limited
numbers of indiyiduals. some of the nodules enlarge
and ma ke thyroid hormone but become TSH
insensitive.)
GOITROGENS
This term is used loosely to encompass all agents
that interfer<: ,,'ith thyroid hormone synthesis, sec-
ondarily asumenl TSH secretion. and ultimately
bring about thyroid gland enlargement. It is some-
times restricted to the ones that impair iodine organ_
ification, the coupling reactions, or both.
Small Ions
Thiocyanates inhibit iodide upta ke and promote dis-
charge of 1- from the cells. They are too toxic for
clinical use, but they are widely emplo)"d as labo-
ratory tools.
Vegetables of the cabbage family conta in small
,,.
of thiocyanates, and several OIher plam!
have cyanogenic glycosides. Diets rich in casava
meal have been known 10 cau,," problems (149), bUI
most Olher edible plams arC wen wlerated when
laken in moderate alllQUnlS , (The food. can. how-
ever, aggravate Ih. elf of iodine deficiency.) Cig.
arctte smoke conlains enough nitrile 10 elevale blood
and urinary eNS - .
Perchlorate. (C10 ;). perrh.nate (ReO.). and
pertechnetate (TeO;) interlere wilh organifiC31ion
as well 35 uptake. and they can CQmpelo wilh thyroid
hormones for plasma prOlein binding siles (155). Ni.
ITate exerts sim ilar. bul less polent influe nces. and
cobalt may act in the same ways. II is 001 known
whether Hlhium ions decrease thryoid functions pri·
marily via inh ibition of ad.nyblt cydase.
Agents Affecting Iodine Exc retion
rkh in fiber and other that
late bile flow accelerate loss of iodine to the fe<:cs.
The goiters that develop in infants given soy mil k
formulas, a nd in la boratory given large
quantities of walnuts. have been all ributed to this.
However. soy products also contain component.s that
bind intestinal iodine and thereby block absorption.
They may additiona lly have goitrogcru; that affe<:t
the thyroid gland (92A). The cfie<:tsof the foods arc
exaggerated when iodine is inadequate.
Agents that bind T. can also limit the usefulness of
trea tment with the hormone.
Naturally Occurring "Gol trogens"
Cabbage, kale, kohl rabi. rutabaga. cauliflower, and
mustard contain pregoilrin. A plant enzyme
(myrosinase) catalyzes its cor.... ersion to goitrin (l·S·
vinyl·2·thiooxa wlidine). Intestinal bacteria contain
enough ofthe enzymc to liberate goitrin from cooked
foods (see Fig. IHi). Rabbits fed cabbage diets de·
velop goiters and thyroid hormone deficiencies. On-
ions contain several s ub.tanccs. the mOSt importan t
of which may be n· propyldisulfide. There are locales
in which the preva lence of goiter has bttn linked
with consumption of very large quantities of that
vegetable. Goitrogen! are also present in
and pine nut.s (92A).
Pharmacological Agents
Thionamides inhibit peroxidase activity. and thereby
iodine organification and iodOthyronillC synthesis
(48). Some additionally impair conversion of T, to
T). Thiourea is less effectivc than the thiouracils.
whereas methylmercaptimidnole (methimazole,
THYROID HORMONES, THYROTROPIN AND TRH
Tapa'.ole. MMI ) and carbimazole (which is COn·
verted to MMI) are highly potent. In humans, 6-n·
propylthiouracil (PTU) bas greater effec15 Ihan
thiouracil . but the i5 true for ra15.
PTU , methylthiouracil. MMI, and carbima7.ole
are used to alleviate human hyperthyroidism. When
given alone, they increase the sizes and vascularity
of goiters. This ean be advantagrous if the patient is
being for treatment with rad ioactive io-
d ine. However. the agent.s are usually administered
a long with iodides to decrease the sensitivity to TSll
and other stimulants. PTU is more effective in hy·
pcrthyroid than in euthyroid sybje<:ts (34). Goitre-
also affcct the immune system (A·7).
In some cases, the goitrogens control the hormone
problems for weeks or montbs at a time. In Others.
tbey arc used for temporary suppression of the car·
diovascular eifects of thyrotoxicosis. so that the pa-
tient Can beller withstand thyroid gland surgery.
The side effects indude nausea and loss of appe tite.
rarely, influences exerted on the bone ma rrow
lead to agranulocytosis.
It ha, been .ugge'ted Ihat MMI i. more poIontthan
PTU bec.ousc i\ inhibit' bolh oxida lion of iod ido and us<
of the "octive form" fo< iodolhyronine synthe,i,. wberea.
PTU . !fCClS mostly lhe formation of iodolyrosyl moielie.
of the thvTORlobulin. Howo.or. PTU btocu ""'iphoral
conversion ofT, to T" wherea, MM I do.. 001 (751.
It is therefore ;nte""ti"g that Oragrafin (I he sodiu m
sail of ipodale) i, on. of the most elfeet;ve of all agents
for short·term U-.:alment. It is mort polentth" PTU for
blocking T, form.lion (t53), and ;t markedly elevate, the
rT, le.el •. (It has been .ugge"ed lhalthe SlI me en7.yme
ealaly,•• eonverSion of T, to Tr• and of rT, 10 3.3'·T,
[l43A1.)
!pod"le
Goitrogens are often used to make laboratory a n·
imals hypothyroid. Dosages can be adjusted \0
achieve the desired 'uppression of thyroid hormone
function. and the animals can also be siudied during
the recovery period that follows withdrawal of the
agent. The stress and trauma as.wciated with ,urgi.
cal thyroidectomy a re avoided, a nd parathyroid
functions are maintained .
Figure 17·7 shows the Structures of some agents
that affect thyroid functions when they arc used for
other purposes.
 N -OSO,· ,
>=s
H,-C-N

I "
H"c=C-S-C.H"o,
I
, ,,
""C=C- C-H
-. H, C= C-C- O
" ,
, B. 00<"" (5 ·V"",'·2·
IhlOOxazoli<looe)
JI" P"'OO'l"o
,
N-C =O
'".
""-0
/ S=C/ "CH
S=C
/'
"
C. H,;o",ea
,",
",

s=< N-CH

N-OI
I
I
,",

F,
(mothyl;m;oa:rolc· 2.1hioI,
rneth;,y,azole. MMI. Ta"..""'.
,, m(!lcaplQltl.omlo I

C- OC, H,
I
N-CH

N-CH
I
I
,",

Fig. IT·e, S!IUCIvI.' o! 01 some

"''''''''_ goillogen' .

11,); - 0 (;0011

""
0",...
"'"
0 11
FIg. 17·7 . Arom.!C C<)mI)OI.'I>dI W;'"
anWhyroid 'C'''ity.

HUM AN THYROID SYSTEM DY SF UNCTI ONS
Thyroid system diseases are among the commonesl
of the endocrine diwrders. In most cases, Ihc pro\).
lems a", linked wilh malfnnclionl of Ihe immune
'}"tem (11), bUI nine major inherited biochemical
disorders have been identified (S1A).
Less common cau,e, o>f d)'sfuncti"" in<ludelhe fnllow-
int: (a) fai lure of Ihe thyroid glands to undergo diffeT'
enliation; (b) inadequate production o>f the e.'yme, thot
cataly,," thynlid hormone biosynthesis; (c) gcnetie de·
fec .. that impair plasma membrane iodine lTanoport; (d)
[Grmation of abllQTn\l1 type. of thyro&lobulin; (e) pTo-
duction of TSH that is biologically ineffectiv. but dc-
tected in radioimmuooassay. (151); (f) receplor defect.
thot Tender T, Gr TSH ineffective; (1) Tele.se of thyroid
.timulant. fTom tropllobla.tic tumors and fnlm some
types of lung cancer cell, (120); and (h) ..eretion of th)".
roid hormone, by tumor cells that bewrn. independent of
TSIl. Some patient' mako excessive quantitie, of pro-
tein. that bind cireulating lhynlid MTmone,. However.
compe... toty inc rea ... in TSH and T...crction u,ually
then maintain
The term Gr(lV<S' distllst is applied when a dif_
fuse-type goiter is associated wilh hyperthyroidism
and exophthalmos (bulging of the eyes), bUI ;1 is also
u$Cd to de. ignate condition. in whichju.ttwO of the
features are obvious_i.e. diffuse soiler with exoph-
Ihalmos but euthyroidism. Or diffuse goiter with hy-
perthyroidism buI no exophlhalmos. Thyroid gland
growtb and hyperfunction arc allribuled 10 the pro-
duction of anlibodies directed against the TSH re·
ceptors_ The anlibodies mimic Ihe actions of Ihe pi_
tuitary hormone, butlheir synthesis is not dep"'ssed
by high concentrations of thyroid hormones_
Thyroiditis (inAamrnation of Ihe gland) is associ_
ated with the formation of differenl kinds of anti-
bodies and Ihe mounling of aUloimmune allaeks
againsl glandular lissue. The consequences can in·
dude eilher goitrous or alrophic changes. Thyroid
hormone s,,""'lion is often impaired in advanced
cases. but in some patientlthe plasma T. remains
within the normal range.
The lWO diseases can coexisl. PalienlS wilh
Graves' disease and Ihyroid gland inOammation
have been known 10 progress spontaneously from hy_
perthyroid to hypothYnlid Stales. or 10 develOp severe
hormone deficiencies following Ihe administration of
goilrogens which lransienlly control Ihe clinical
symploms. Thyroiditis with impaired produclion of
Ihyroid hormones can be followed by the appearance
of TSH·independenl nodules Ihal secrete excessi,e
quantities of T._
The links between exophthalmos and thyroid
gland dysfunctions arc only dimly understood. The
THYROID HOAMONES. THYROTROf'tN AND TRH
eye condition can develop before. ak>ng with. Or long
after changes in thyroid hormone se<:retion be<:ome
Obvious. and il has even been known 10 appear after
Ihe symptoms of hyperthyroidism have been amelio-
rated by treatment . It can improve or worsen when
the circulaling T. levels arc OOfmalizcd. Since hy-
perthyroidism is associated wilh sensi-
livity to <:alccholamines, norepinephrine may COn-
Iribule 10 lid retraClion. However, the innammation
and proliferation of rctro-orbital lissue. Ihe lympho-
cytic infiltralion, the fal aceumulalion. the hyperlro-
phy of the exlrinsic musdes of Ihe eye. and Ihe
buildup of osmotically aClive hyaluronic acid. arc all
allribuled 10 autoimmune distinel from
Ihe ones Ihal invoke hyperthyroidism (99A).
It was alone lime believed that when pituilary
glands arc stimulaled 1<> make excessive amounts of
TSH, the celli also release an exophthalmos produc-
ing suh5lanee (EPS). Howevcr, oh5ervalions Ihat
palients' sera affect Harderian glands (but not ocu-
lar muscle) and thaI TSH digests invoke exophlhal-
mons in animals are not related to the clinical di,_
orders. TSH secrelion is usually stnlngly inhibited in
palients with Graves' disease (A· 7).
Hu m o ra l Anllb o d les
Several techniques are used 10 daraclerize Ihe cir-
culatins anlibodiel found in patients. In SOme cases.
proteins known under diffe",m nameS have similar
or idenlical chemical properties.
LONG-ACTING THYROID STIMULATOR
(LATS)
Circulaling antibodies of the IgG dass thaI stimu-
laIC suitably prepared mouse or guinea pig Ihyroid
glands were among the firsltO be discovered . Unlike
1"$1 [, Ihey manifest thei r effects after long lalenl pe-
riods, and their 'Iimulation conlinues for hours. The
proleins a", fonnd in suh5lanlial quanlities in af'"
proximately half the palients wilh Graves' disease.
It has been Slated thaI eUlhyroid clo5e relatives of
Ihe patients also often have the LATS. bul this has
been recently queslioned (6). In other palients, an·
libodies thaI stimulate human (but nol moose Or
glands have been delectcd . It has been
with aClive Graves' disease
r I I It.
i act On Ihyroid gland ",cePlOrs
in SOme cases interfere with Ihe bioassays (99A).
Since half the patients do not have lATS thai
aets on rodent thyroid glands, and no correlations
belween Ihe tilers and the severities of Ihe diseases
have been found in patients with positive sera. most
observers doubt that the proteins invoke Ihc
thryoid gland dysfunctions. The antibodies can.
however. serve as markers for immune system
disorders.
LAT$-PROTECTOR (LAT8-P)
When serum IS preincubated with
loses its ability to subse-
It is believed Ihat
receptors during the
of LA TS-posilivc
subsequently incubated with same human Ihy-
roid tissue also fails to stimulate. presumably be-
cause the TSH are Ihen occupied by Ihe
LATS previously presented . However. Ihe second
serum retains the ability to aCI on rodent glands.
When LATS_n.gative serum is incubatcd with
the human thyroid tissue. a positive serum subse-
quentlyadded to the incubate continues to be active
in rodent assays. The negative serum is sa id 10 con-
lain LATS-P. an immunoglobulin different from
LATS that binds LATS. However. there are some
disagr«'ments over this interpretation. Some 90% of
the sera taken from patients with Graves' disease are
said to contain LAT$-P.
TSH-DISPLACING IMMUNOGL08ULlN::> (TOIS)
Sera taken from almost all hyperthyroid patients
contain components that TSH from thyroid
gland membrane preparations. Some of the antibod_
ies aclivate just human thyroid celts. others addition-
ally stimulate mouse celts. and yet different ones dis-
place TSH but do not mimic its actions. Antibodies
that mimic TSH but do not displace the hormone
have also been described.
The that Ihe immunoglobulins
made by one patient can be different from Ihose
made by anolher. even when the endocrine abnor_
malities arc similar. Evidently, SOme proleins alter
the affinity for TSH by binding to non-receptor sites
on the membrane. Others se<:m to affC<;t mClSlly POSI-
receptor evenlS.
THYFIOGLOBULlN$ AND ANTI-
THYFIOGLOBULI NS
It was at one time believed that were
totally sequestered by normal glands. and that im_
mune attacks againsl the thyroid were initiated by
release: of the proteill$ to the bloodstream when the
gland becomes inflamed. It is now recognized Ihat
normal human serum contains SOme thyroglobulin
(I-ITg). and thaI the levds are high in fetuses. There
are data indicaling that all with hypcrthy-
roidism have elevated plasma HTg before they re-
ceive Ireatment. When the endocrine condition can
be corrected in Gravcs' patients who retain
high IITg lilers are the ones most likely to sulfe r re-
lapses (I40A).
In IlashilYlQlo's thyroiditis. lymphocytes infiltrate
and Can deSlroy thyroid tissue. It is common for Ihe
gland to enlarge but lose ilS abilily to maKe thyroid
hormones. The sera of most palienlS ha.,.e high anti-
thyroglobulin liters. and Ihe B lymphocytes ca n be
stimulated \0 produce Ihe antibody in vitro (11). II
is. ho,,'Cver. unlikely Inal the antibodies arc a pri_
mary cause of the thyroid gland disorders. For O!1e
thing_ B-cell-medialed destruction usuatly inVOlves
activation of the complement system. and anti-thy-
roglobulin is a poor activator. Most patients have an-
limicrosomal antibodies and T cell Or immune net-
,",ork imbalances (A-7).
OTHER KINOS OF ANTITHYROID ANTIBODIES
Immunoglobulins thaI bind to non-receptor compo-
nenl. of lhe Ihyroid ccll membranes. 10 lipoprolein,
of the Golgi and endoplasmic reticulum. and to non-
iooinc<ontaining components of the colloid have
been in various laboratories. Some patients
also maKe proleins tllat interact with the thyroid
hormones. The latter do 001 necessarily impair hor-
monal function •.• inee eomp<>n.atory inerea.e. in
TSH secretion can accelerate T, and T. synthesis.
The coexistence of euthyroidism and supranormal
thyroid hormone levels is probably explained on this
basi •. Hypothyroidism in patients with hyperplastic
glands ha. been 311ributed to the production of im-
munoglobulins with growth-promoting but no TSH-
like activity. or 10 postreceptor defects.
ANTI-PITUITARY ANTIBODIE$
Anlibodies directed against the Ihyrolropcs can de-
press TSH secretion. However. Ihe effects will not be
obvious in patients producing antibodies thaI di_
rectly stimulate Ihe Ihryoid glands.
T an d K Celt Contributio ns to Thyroid
Disease
Birds are often used to study immune functiO!1s be-
cause neonatal bursectomy permanently impairs the
humoral immunity syslem without seriously affect-
ing ""lIular immunity. whereas noonalal thymec_
tomy cripples the ""nular immunity mechanisms.
Obese (OS) chickens have genetic defect. that pre-
dispose to tbe development of a form of thyroidilis
that closely resembles the human discase. Since neo-
natal burseclomy prevents the disease, links with the
production of circulating antibodies are suggested.

Howe.er, neonatal thymectomy accelerates the
onset of the thyroid gland disorder. Moreo...er. bursal
cells from either healthy Or OS chickens Can inV<lke
the disease in OS birds. but the cells do not do th is
when injected into healthy birds. In contrast. healthy
chickens irradiated to deplete T lymphocytes dc-
velop thyroiditis when they are injected with T lym-
phocytes from the genetically defective birds. These
and other observations ha •• led investigator.; to con_
clude that spontaneously developing thyroiditi, in
OS chickens can be .xpres.scd only in the presence
of functioning B eens_ but that the genetic defect in-
volves inadequate suppressor T cell fUll<:tions_ a thy-
roid gland abnormality, and certain major histocom-
patibility characteristics (123B). Nwnalal
thyme<:tomy has also been shown to predispose to
the de.elopment of thyroidits in beagle dog.., mar_
mosets. and Buffalo rats. A somewhat differenltype
of thyroiditis that develops in rabbits. guinea pigs.
and mice is linked with ove ractive helper-type T
cens.
The relationships betwecn T lymphocytes and K
(natural killer, NK) cells are just beginning to be
appl"<:ciated. The K cells may be determinants of
thyroid hormone production in patients with anti-
bodies affe<:ting the thyroid glands. K cell activity i.
n;ported to be dcp""""d in paticnlO with thyrotoxi-
cosis associated witlt either Grave.' or Hashimoto's
disease. within the normal range in the patients that
al"<: euthyroid despite the presence of thyroid gland
abnomalities. and elevated in the hypothyroid pa-
tiems(I).
ADDITI ONAL REAS ONS FOR IMPLICATING
THE IMMUNE SYS T EM
Indirect evidence includes the following. (a) Rheu-
matoid arthritis, myasthenia gravis. pernicious an ...
mia, diabetes mellitus, and adrenocortica l insuffi-
ciency can all be caused by immune system
dysfunctions. The incidences of those disorders are
high in patients with thyroid disease. and in their eu-
thyroid close relative •. Hashimoto's thyroiditis can
OCCur in One identical twin and Graves' disease in the
other. (b) -'Immune remiss ions'· invol ving Iower;ng
of antibody titers have been observed to follow cor_
rection of thyroid gland problem with surgery, ra-
diooctive iodine, or goitrogen •. (c) The thyroid
glands of patients are usually extensively infiltrated
with lymphocytes. Many patients ha...e lymphade-
nopathy. enlarged spleens. or enlarged thymus
glands. Some have absolute lymphocytosis or normal
total white blood cell numbers with relative granu-
THYROtO THVROTROPIN AND TRH
locytopcnia . Patients with Hashimoto·s disease com-
monly have hypergammaglobulinemia. (d) Cyclo-
phosphamide. an immune suppressa nt. sometime,
corrects the thyroid dysfunction (76). The beneficial
effects of glucocorticoids are also attributed in part
to influences excrted on T lymphocytes. (e) Circu-
lating lymphocytes taken from patients with Graves·
disease havc been observed to bind to TSH I"<:ceptors
(145).
HeredltarV Factors
The major histocompatibility ( MIIC) lo-
cated on human chromosome 6 dire<:ts the formation
of cell surface antigens and some components of the
complement system (144). It contains genes thaI
",gulate immune responscs and also immune
suppression (50). Four separate loc i (each with nu-
merOuS alleles) determine the natul"<: of the antigens
(HLAs) that appear on Ihe cells. These a re usua lly
transmitted together as halotypes. Statistical studies
have revealed that certain HLA combinations al"<:
associated with a high prevalence of thyroid gland
dysfunctions. The hereditary factOT$ can affect ma-
crophage. T, and B cell activities, and they probably
impair the responses to uteraal factOT$ such as viral
infections. Differences in the patterns lin ked with the
disease, arc found when Caucasians are compared
with Orientals. or wben individuals of one type ;n a
certain geographical locale are compared with simi_
lar persons living elsewhere.
Some investigatOr1 find that when studies are re-
stricted to a uniform popula tion. the balotype pro-
vides information on the susceptibili ty to develop-
ment of Grnve·s disease (141). report that
kllOwledge of both the halotypc and the TSH-I"<:cep-
tor antibody titer.; at the time of d;seontinuation of
drug thernpy permits them to predict the chances
that a patient will suffer relapse.
A whole new dimclISion has recently been added
to our concepts of endocrine-immune s)"'tem inter-
actions. It has been demonstrated that mitogen-
stimulated lymphocyte< a glycoprotein that
appears to be chemically an d immunologically iden-
tical with TS H (123A). The st imuli differ from the
kind. that cause lymphocytes to make an ACTH_
like peptide. Phagocytic leukocytes cleave T. ether
bonds and act on iodotyrosines (A-2). iodine re-
leased is bactcricidal. Morcover. T, is reported to en-
hance K cell activity. The auto-immune thyroid
gland disordcrs may therefore result from defecti.e
regulation of normal leukocytic functions Ihat arc
directl)" lin ked with the endocr;nc secretions.
REFERENCES
I. Amino. N.. Mori, H., 1,...,lni, Y., Asari. 5 .•
l"'mil\lC:hi, Y alld Miyoi, K. Pcripho;"" K I.ym-
pboc)'lts in Au,oimmu nc Thyroid Disease: De-
era.. in G",,,,,,' DiKa .. Ind Inc.ea .. in
IIIOIO'S Imc_. J. j 4:
S87_91.1982.
IA. Ami •. S. M.• Mul ........ N. J .•• nd Inaba •. S. H..
Phenol. A POlent Slimul aw of Adenylal. Cy·
d.", in Human Thyroid Mcm b.. nes. t·""""'.
RJ(k. C"",,,,un. H: 8l_9S. 1981.
I . A.i.i. A.. T""l">OIlUlIlO. D., Ambesi. lmpiombiOto.
f . 5.. and SChlessi...... J. Ade_i ... 3'.S'·Mono-
pholphalc Modullt .. Thyrocropin Re«p'... C .....
t.ri ... alld Thyro"opin Act;";.)" in Cult.",. S ......
,.... 114: 1911.
1. ealohi. N .• Brown, T. R., Shi"" .... B.. LuCH. S ..
and Mack. R. E. Deer.aS« Thyroidal Respon ..
to Thyrotropin in Diabetic Mi.e. £nJlXrinoi. 1119:
1428-32.1981.
liallord. f . J. H"rn""",1 Cont rol of Prot.i" 0.1'
.odolion in Li""r and IsoIat.d C.lls. A<"-
.;0tU HOt",.,. 7: 92-1 17. 198(l.
5. BaISlm. A.. Seu..... F... nd [nlba •. S. H. The: I...
ftuonee of FUli ... and ,he Thyroid SUl' O on l he
Ac' i";' )" of Thyn u ill< 5'· MOfIOdc:ioidi ..... in Ita,
U... r: A Kinetic A... ,y ... 0( Micl"OSOIn>.l Forma·
,.". 0( Triioclotk)"fOItinc frotrl Thyro.inc , £!Id".
mnol. 1()8: 412-7.1981.
6. a.no.... K.. Zakl.ijl. M.. McKen,i •. J. M ..
Wille. A .. a nd M. Absence of Thyroid.
$llm.'at;n8 AntibOdy ond l.onS·AelinA l -hyrOi d
Stimulator in 1I..ll1i l'e$ of Grovos' Di..,.... Pa·
• ien ... J. CIi". E"lkKrlMl. Mna!>. JJ: 651-3.
191 1.
1. Barker, S . B. Phys;oq:ieal Ac, i.ity of TIt)·roid
lIormones and Ana"". cs. Cloap. 10. pp. 199-236
of Pill·Ri"" .... R ....... Troct ••. W. R.. M .. TM
nyr(Jid Gland. vol, I. BUIIC"'-Of.h. London.
''''
8. Baslonuky. C. H, Thy.oid Iodide Tron'pOrt .
C hap. 6. pp. 81 - 99 of Or«' and Solomon. ed ...
relerence 6S.
9. Baucr. K.• and lippm.n. F. Altemp," Toward
Biosyn thesis 0( !he Th)'rocropin· R.leasin, Hor.
mone: a nd S,udi<;$ on i .. Brcakdo"'11 ie H)1lOIha·
Iom;c Ti..... Prepa""ions. t ·>ld«riMi. 91': 230-
1976.
10. Bauer. J. D . Eberluird •• N. L . J. W.•
Jolt........ L K.• [ .... ric. R. D.. $(luie1< •. B. S ..
Monis. J. A.. Sccbu ... P. Ii .. GoodTltln. H_ M..
l.atluim, K. R .• PoII .. ky, J. R .. and Martial J. A.
Thyroid Hormone R<<<pt<)ru nd R.. .,.,...... R«.
Prot. lI«m. Rsck. 1j: 91_147. 1919.
I I. Beall. G. N. Production of Huml " Anlilhy"'l\o!).
"lin in Vitro. S.imulalion by Antigen . I .
£ItdacriMi. Mttoh. .H : 1-5. 1912.
11. Beck..... S. K.. Brady. R. 0 .. and F.. hrru. ... P. H.
0( ,he Rok 0( G,nslio.ides in the
Bindin. and Aaion of Thy.OIropin. h «. /10'" ,1.
An>d. Sri. USA 18: 4848-52, 1911.
13. Ben. Baruch. G .. E,,,, •. Y.. KIooj, Y.. M.. hiach.
S... nd Sokolcwsl:y, M. Alteud o..t"l"""';' or
MUloClrini<: Re«ptor in Mouse B",in: Elfec, o( L-
Thyroxine a nd BcUlIIIC,h,V." 1:1tdom1tOl. 109:
1lS_9. 1981.
Berkowitz, M.. Oauah. rida" 0 .. I IId Sherwin. J.
R. Au'oregulation 01 Thyroid 1000i<k Tro".porI:
!'ooibl. Modiali"" by Moclifteation in Sodium
Cottan. pon. Am.,. J. PhYJloI. UO: El1-E4 2,
1981.
I S. Birnbaum... L. • • nd O'M.lley. B. W... d•. R ...
rrprOt"J ond ilOt""KJM 14(1/01111/. Aca<kmic Pr.ss.
N.... York. 1918.
16. BIllie... C. M. Hy,.,.hallmic S .bw.o..:cs in the
Control 0( Body T.mpe",t.u: C. ... ",I Cba ",..
lerinics. Frd. f>r-or. .fIl' 1981.
ll, BliUlt rd. R. B. Au'oimmu";,y and Endocrine
Di...... Chip. 26. pp. I 115-24 of Williams. R.
II... d., Tur/icok 0/ Elld«rl/fOJOf)'. 6th cd, Sau ...
de I'S, Philadolphio. 1981.
18. Bouhnik, J .. Gol.n. F.. X. , CI,u scr. E .. M.nard.
J .. and CotVOI. P. Thc Renin·An,iotc ..;n Sy... m
in Thyroide<:tomiud Rail. £Nl«,;noI. 1M: 646-
59.1981.
19. 1Ioy<I.... T . W .. Pamente •• R. W .. SlInfooh. P ..
ROikis. T .• Ind Wil..-.. J. H. Ii.. i<k_ for M ild
Th)TOicbI [mpain n'''t in W omen Undergo;na
Endu",_ T",inins. J . f:ltdorri>tOl. 53_
6. 1982.
20. Btay. G. A.. and Jacobs, H, S. Thyroid ACli.ity
. nd Other Endocrine G lands. Chap. 24. pp. 413_
II of Q •••• and Solo", ..... d ... ,.r... 6S.
21. Bro,..n. M. R. Bombc.in. SomOlon.tin. and Re·
I..cd Peplide$' Aaions on Tbcrmor.guillion .
v.
Proc. 40: 216S-8, 1981.
11. B"""n. M ....... Y. Hypotholamic Pcp"
lida: C.m",] Nt"""" Syst.m Conuol 0(
oeral f".""" ions. Proc. lO: 2S6S.9. 1981.
n. Chail, A .. Kan" '. R.• Gre. n. W.. and Kenlt)'. M.
Oc:fccti""Th)"loid Hormone ACtion in Fibroblasts
C ultured from Subj.cts ,..i, h thoe Syndrome or Re--
.ist, nce to Thyroid Ilo.O\OIlu. J. C/;n. Endrx,;'
>tOI. 54: 167_ n, 1982.
14. Ch.n. V. F .. and V. O. Scroconin Slim'
.lata Thyrotropi ... Rclcasin. Hormone; R.I ....
from SuperftaSed Rli H ypothalami. E..d0l:T;1tOI.
108: 2lS9-66. 1981.
lS. Clli ... W. W.. Kronenbera. H. M .. Dec. P. c..
Maloof. F .. alld Habcner, J. F. Nuclcol i<k: s..
q ... ncc 01 .... mRNA lillOOdi", Ihc Pre-st.!).
uni, or MOll .. Thyrocropin. " roc. Ao1d. &1.
US A 78: S329- 33, 1981.
26. Chin. W. W.. MalOQf, r .. "brtarl""" . M. A ..
Pierce. J. G .. and Ridgway. E, C. Production and
R. I.... of Thyrotropin and ;If S ubun;1S by Mo-
nolayer Culture. Cont.in;n, Bovine Anter"" Pi,
tuillry Col .... EnJ«,,>tOI. 108: .3"-94. 198 1.
21. Chopr,o. L L Soiorn<:M. D. II.. Chopn.. U.. Wu.
5. Y.. Fishe •. D. A.. alld Nabmuta. Y. Pa1hwars
of M.tlboIi<m or Thyroid Hormones.. R«. PrOf.
NOt",.,. R.d. 14: 521-56, 197'.

'" 28, Chopra, I. J.. Sol<HnOn. O. H.. Tcoo, G. N. C .. and
Eioc .berg, J. B. An Inhibitor of the Binding of
Thyroid H<>rmonc. to Se,um Proteins i. Pr ... nt
in Extr. thyroidal Tis.ucs_ 115: 407_9,
1982.
29. Ch<>pra, I, J .• and Teo>. G. N. C. Cha..
of Inner Ring (3 Q< Mooodeiodinali"" of
Oii<>dothyronine in Rat Li'er: E.id .... Suggest.
ing Marked Simiiori'i", 01 Inner and Outer Ring
Deiodin.,e. for lodolhyronincs. t::ndocrillOl. 110:
89_91,1982.
30. Chow, W. Y., Yen.(:how, Y. c.. and Woodbury.
D. M. EIf.eli o>f Thyrolropin. Acetaznlamide.
4·1\00" midO-(' .llOIh;<><y' nosl i lbe ..,.2. 2' .0;," I·
rooie Acid, Perchl<>ra'., and Ouabain on the Dis-
ltUblion of Iodide roo in Cells aOO l uminal Fluid
of the Turtle Thyroid. Endoc,im;>l, 110: 121-5,
1982.
31. Cody. v. Thyroid /lnrmone In,.,• • tions: Mole.:_
"lor Conform., i"". Protein Binding, and lIor_
mone AClion . lindo(r. H.". I: 140-66. 1980.
32. Con .or>, J. M., lnd Hedge, G. i\. Effcol of Con·
linuou. Thyro, i"" Adminimalion on Thyr<>lropin
Scorelion in Ral' . Emloerinol.
[(II:/: 2098-2102. 1981.
33. Connon. J. M .• and H.dge. G.A. Feedb.ck Reg.
ulalion of Thyrotropin by ThY"",i". under Phy ..
ioIoj:ical Conditions. Am". J . Ph)"siiA. UO:
EJOS-E3!3.1981.
34. Cooper. D . 5 .. S .... V. c.. Meskell. M.. Maloof.
F .. and Ridgway. E. C. Acut. Effccti of Propyl.
thiouracil (PTU) on Thyroid.1 Iodide Org.nift·
cation and p.riph.ral lodothyronin. Deiodin.·
tion, CorrelOlion with Serum PTU Level.
Me.sured by Radioimmunoass. y. J. Clin. Endo-
"'Inol. jl: 101 - 7. 1982.
35. D.., D. K., and Gangul)". M. Diabetes. Hn"'phy.
seclomy. or Thyroid.Clomy Nuclear L·
Triiodolhyronine-Binding Capacity of Rat Lung.
Endoc,int>J. /09: 2%-300. 1981.
36. D.ughaday. W. H. Anl.rior Piluilary . Chap. 2.
pp. 21_76 of Ingbor, refe..,nce 74.
37. D"i •. F. B.. Kite. J . 11 .• Jr .. Davi .. P. J .• and
BI ... S . D. Thyroid Hormon. Stimulation in
Vitro of Red Blood Cell Ca' · ·ATPase Activity:
Int .... pecics Vari.lion. EndoerillOi. 110: 297_8.
1982
38. De .. f. J .• F .• Haumont. 5 .• CorOClte, C .. and
Beck .... , C. Correlated Functional and Morpho-
m.tric Study of Thyroid Hyperplasia I nduccd by
Iodin. Defici.""y. Endoe'inol. /08: 2352-8.
1981.
39. Dratman. M . B.. F\ltaesa ku , Y .. Crutchfield. F.
L . Berm.n. N .• Payne. 8.. S.r. M.. and Siumpf.
W. E. lodine-125-Labeled Triiodothyronine in
R., Brain' E.idencc for Locali"'tion in Di",ret.
N.ur.1 System •. 21$: 309- 12. 1982.
40. Dralman. M. B.• Richter. M. E:.. and Lyncb , H.
A. Intorporalion of Thyro,in Carbon in Ptolein
Frlclion. of Ran>. Catesbiana Tadpol. N.",oo.
THYROID HORMONES. THYROTROPIN AND YAH
SysICm. Li.er and Tail. Hnd""t1no1. 86: 217-24.
1970.
41. Dunean. G. C. of 2d cd.
S.und ..... Philadelphia. 1947.
42. Dunn. J . T .. and Ray. S. C. Variation, in
StruClure of ThyroglobuliN from Normal Ind
Goitrou. Human Thyroid,. J . Clin. EM"",i""'.
Mml!>. 47: 861 - 9. 1978.
43 . Dupont. 1\.. Du ..... ull. ).·It.. Rooleau. D.. Di
Paolo. T.. Coulombe. P .. G.gne. B.• Meland. V..
Moore. S .. Ind Bard.n. N. Eff.ct of Neonatal
Thyroid on Ih. Catcchol.mirt<. Su\).
'tance P. and Thyrotropin·Rel... ing Hormoo.
Contents of Diserete Rat Brain Nucl.i. J::nd"",i·
Il0l.108: 2039-45.1981-
44. Du ran.(ia,da. S .. Obregon. M. J .. Morreale d.
E.cobar. G .. Ind E>eobar del Rey. F. Diff• ..,nlial
Effecls of Hypothyroid i.m on the Spedfte Upta ke
of Growth Hormone and Proiaelin b)" lhe Rat
U_er. Endoe,;IfI)/. 108: 2054_9.1981-
45. Eberhardl. N. 1... Aprilelli. J . W .• and B.. ter. J .
D. The Moleeul. r Biology of Thyroid Hormone
AClion. Biochr m. ActiQlt.! Harm. 7: 312_94, 1980.
451\. Euo. M. C .• nd Burrow. G . N. Glycosylalion of
Thyroslobulin-It. Role in Seeretion. lodinat;on.
and Stabil ity. End"",ilfl)/. IIJ: 1655-63. 1983.
46. Eiden. L. E., and Brownltein, M. J. Ext rahypo-
Ihalamic Dimibutions and Function. of Hypo-
thalamic Ptp1ide Hormonel. FM. f'nK.10: 2553-
9.1981.
47 . Eisenst.in. Z .• Hags. S .• Vagena ki•• A. G .• Fang.
S. 1... Ranlil, B .• Burger. A .• Bal<am. A.. Bray..
erman. I.. E .. and l1\8bar. S. H. Effe<:t of St.rva·
tion on ProduCIion and p."ipheral M.tabo-
lism of 3.3'.5'·Triiodorhyronioc in EUlhyroid
Obese SUbjects. J. Clin. End""t1nol. Mt Mb. n:
889_93. 1978.
48. Engler. H .• Taurog. A.. and Dorri .. M. I.. Pr.f·
erenlial Inhibit iM of Th yro.in< and l.S.3' ·Trii<>-
d<>lhyronine Form.tion by PIOI'yilhiouracil and
Met hylmcrcaptoimida>ol. in Thyroid P.""'id ...·
Catalyzed Iod ination of Thyroglobulin. /:.·M"",;-
nol. 110: 190-7. 1982.
48A. EriC$On. L E.. Ring. K. M.. and or.erholm. T.
Scleclive Macropin<:>cytosi> of Thyroglobulin in
R;tl Thyroid Follicl ••. /:.·Moc,lnol. I iJ: 1746-53.
1983.
49. Eto. 5 ..• nd FI.i.cher. N. Resulilion of Thyrotr<>-
pin (TS Il ) Rei .... ond Production in Monolayer
Cuilur.s of Tran,plantable TSH.Producing
Moose Tumors. Etw""rillOl. 98: 11 4-22. ! 916.
49A. Foglia. G .. Beck·Pc<xm. P., Ballabio. ,\1 .• and
N.va. C. Exce .. of Il.subunit of Thyr<>lropin
(TSI1) in PlIientS wilh Idiopathic C.n"al 1Iy--
polhyroidi.m Due to Ihe Secr.tion of TSH with
Reduced Biological Acti_ity. J . C/in. EMoalnol.
Mnab. 56: 908-14, 1983.
50. Farid. N. R .• and Bear. J . C. The lIuman lI i$t<>-
compalibility Complex and Endocrine 0; ......
Endoe;. R.". ; . 51)-86. 1981.
 Fileti. S. and R.poport. B. thAI Org.nic
Iodine Anenu .... the Ade.".in. 3',S'· ),1 <>1\Ophos·
Re.porue to ThYf<)tropin SlimulMiM in
Thyroid Tissue by an Aelion" or neor Ihe Ade-
nylat. Cyclase Calalytic Unit. IIJ:
1609_15.1983.
5 I. Fi,her, D, A.. and Du ... ul1. J. H, Development of
the M.mm.,i.n Thyroid GI.nd. Ch.p. 3. pp. 21_
38 of Greer and $olomon, eds .. refe rence 65.
52. Fleckm_n. A.. Ehrlichm_n, J .• Schubarl. U. K..
and N. EIf"", ofTrifiuopc,",ine. 0600.
and Phen),lOin on Dc""lari'Allion· and ThYf<)lro.
pin.Rele.. ing Hormone·1 nducod Thyrolfopin Re-
Ie... from Rat Pituitary Tissue. 108:
1072_7.198t.
53. Fregly. M. J . The Role of Hormones in the Re-
s""n, •• <>I' lIom.otherm. to Cold, pp. 159-68 of
Undcr •.-ood. L. S., Tic,,",,". L L . Callah.n. A. B__
and Fold. G. E.. cd ... M«hanisms
ofCo/J AJur/ollon. Academic Pr..s. Ne"
1979.
54, hegly. M, J.. Field. F. P.. Kalovich. M . J .. and
Barney. C. C. Catecholamine-Thyroid Hormone
Interaction in Cold·Acclimated Rats. Fw, Pro<.
J8.- 2162-9. 1979.
54"- Frieden, E, lodi"" an<! Thyroid ]-lormone,.
Trends Blochmr. Sri. 6: 50-3. 1981.
55. Friedm.n. Y.. l evasseur. S .. Crowdl. D... nd
Burk •. G. [IfCClS of Adenosine and Guanosine on
Thyroid., Ornithine Decarbo.<yla,",. PrOtein Ki·
na... and tho Adcnosi""
C)'cl.", S)'<1om in Mn"",.
ui"m. /09. 113-19. 1981.
Galton. V. "-!'utative Nucle.,Triiooothyr""in.
Receptors in Tadpolc Erythrocyte" Regul.lion of
Receptor Numbers by Thyroid Harm""". E ...
/ /4: 735-42. 1984,
56. Gard. T. G.. Bern"ein. II .. and LarSOn. P. R.
Studies OIl Ihe Mechani,m of 3.5.3'·TriiOOothy·
ronine·lnduced Supp.-es.ion of Seoretagogue-In.
ducod Thyrotropin Reka .. in Vitro. HnJOCTIIIOi.
108: 2046-53. 1981.
57. Gavin. L A.. McMahon. F. A.. and Moeller, M.
Carbohydrate in Contra.t to Protdn Feeding In·
cre""'.th. H.patic Cootent of Acti,. Thyroxine.
5' .(kiodinase in thc Ra .. EndlX'irroi. 109: 5)0-6.
198 \.
5S. Ged.S, E .. Gontlll ... L. and Timin •. P. S. Prop-
erlie. of Triiodothyronine Binding Sito. in Cere-
bnl COrlical CYlosoL EndIXT. Commun, 8.-
I_S.1981.
Gianella·Ncto. D.. Quabbe. H.·J .. and Will. I.
PoUe,n of Thyf<)tropin and Thyro,ine Plasma
Concenlr01ion. During the H·Hour Sleep-Wake
Cycle in th. Mal. Rhe.us Monkey.
109: 1981.
60. Gibson. K. D.. Ben-Porath. £ .. 0011 ... H. J ., and
Segen, B. J . InAucnce of Thy.oid Hormones on
Growlh and Growth Related P"",.sscs. PP, 101 _
10 <>I' Ko",up. K. W .. and J. H .. ed •.
Growrh F(}<;I(>I'S. Pre ... New Y""k.
1978.
6L Glick, Z .. Teague, R, J .. an<! Bray. G. A. Brown
Adipose Ti"u., Thermic R.,pon .. Increa .. d by
• low Pf<)tein. High Carbohydr .. e Meal.
Sci. flU 21 J: II H - 27. 1981.
62. GlUCkman. p, D.. Grumbaoh. M, M., and Kaplan.
S. l. The Neuroendoerine Regulation and Fun¢-
tion of Growth H<>rmon. and Prolactin in tbe
Mam malian Endocr. RI:>'. 2: 363-95 . 1981.
63. Goldberg. A. L. Ti,chl.r. M.. DcM ."ino, G ..
and Griffin. G, lIormon.' Regulation of Protein
Degradation and Synth.. is in Skeletal Mu..:le.
FM, PtOC, 31 - 6. 1980.
64 . Gorbrnan. A.. and II<rn. H. A. A Turbook of
Compatolivt EnJoctlnology. Wil.y. N.w Y""k.
1962
Greer. M. A.. and Solomon. D. H .. cds, lIolld·
book ofPhYJioloty. sec. 7. vol. 3. American Ph)"<-
iological Society. Woshington, D. C" 1974.
66. H•• berli, A.. Kneubuehl. F.. and Studer. H.
Change. in Ih. Polypeptide A.. embly of Guin.a
Pia Th)'roilobulin Induced by Thyrolropin.Res·
ul .. cd Thyroid Aeti"ity. EnJocrino/, 109: 523_9.
1981.
67. Halpern. J.. and Hin kl•. p, M. [,idenee for an
Active Step in Thyroid Hormone Transport to
Nuclei: Drug Inhibilion of L-"'t·Triiodothyr",
nine Binding tu Rec.pt"". in Rat Pitu·
itary C.lIs, EndlXTiltOl. 110: 1070-2. 1982.
68. H.rt. J. S. Roden ... Ch.p. I. pp. 1_ 149 of Wbit·
lOW, G. C.. ed .. Compotorive Phy,;ology of Th'T-
'01. 2: Mamm.ls. Acadomic PreM.
New v ..... tQll
69. Hild.brandt, J. D.. and H.lmi. N. S. Intral hy-
roid.lly Generated Iod ide; The Role of T ran.port
in in Utilization. £ndoctiMi. 108' 842-9, 1981.
70. Himmo-Has.n. J . Role oflhe Adrena! Medull. in
AdaptatiM 10 Cold. Chap. 38. pp. 637-65 of
Blaschko. H .. Saye ... G.. and Smith. A. D.. eds ..
/londlx>ok of PhySiology. .. etion 7. '01 , 6. Amer·
icon Ph)',iological Society. Washingt"", D.C ..
1975.
71. Hoch, f. l, Melabolic Elf.. " of Thyroid Hor·
mon••. Chap, 23, pp. 391-4]) of Gteerand Sol·
omon. cd, .. refctenco 65.
n. Holaday. J. W" D' Amato, R. J .. and Faden, A. I.
ThyfOlropin.Releasins H<>rmone Improve, Car-
Funotion in Experime ntal EndotO'ic
and H.morrh.sic Shock. Scim« 213: 216-18.
1981.
13. Ik. kubo. K.. Ki'hihara. M.. SanderS. J .• IUllon.
J .. and Schncidcr. A. B. Dilferenc.. Bet"'.. n Cir·
culating and Ti .. uc Thyroglobulin in Rats. t:n-
dOCf;no/. 1fJ9: 427-32, 1981.
74. Inabor. S. H .. ed, COtU'",porOTY EnJocTillOiogy.
vol. I. Plenum. New y""k, 1979.
75. logbar. S, H.. and Wocber. K. A. The Thyroid
Gland . Chap. 4. pp. \17_247 of William,. R. H..
ed .. Ttxrlx>ok of ElldlXtlMiogy. 6th ed. Saun-
ders. Pb iladelph ia, 19St.
76. lI'ine, W. J. Autoimmunity in Endocrino Di,.
ease. R«. Prot. Horm. Rsd , J6: 509_56, 1980.
77. Jackson. I. M. 0, Evolutionary Signific.n<e of tbe

Phylogenttic Distributions and Funotion, of Hy-
pothalamic I'cptide Hormones. rN. PfO<. 40:
2S53_9.1981.
78. Johns. M. A .• A.mitl. E. C. and Krieger. D. T.
Specific in Vitro Uptake of SerOlonin by Cell. in
the Anterior PituitaI)' of the Ra1. Endo<:,;IIQ/.
/10:754-60.1982.
781\. J"dd, A. M .00 Hedge. G. A. Direct Pi tuitary
Stimulation of Thyrotropin S«oretiQn by Opioid
Peptides. Endo<:,llk>l. 11 J: 706-1 O. 1983.
79. Jump. D. B., and Oppenheimer. J. H. Thyroid
I!ormone Receptor-Containing Fragment Re·
le.tw! from C hromatin by [)eO>.yribonuek • .., I
and Mkro<occal Nuel""..,. So/met 109: 811-13.
1980.
80. Kaplan. M. M., and n$lQ:lki. K. A. Eff«:ts of
Congenital Hypothyroidi.m and Partial and
Complete Food Depri •• tion 00 Phenolic and Ty-
rooyl Ring lodothyronine Deiodination in Rat
Bt"lin. EMo<:';OO/. 110:761-1. 1982.
81. Klein, A. H., Jenkins, J. J .. A .. and
Fi'her. D. A. Thyroid Hormone-Sen,iti"" Brown
Adipose TiMue Respiration in the Newborn Rab-
bit. J. Phys/Q!. 241: E449-E4S3. 1981.
82. Kouride,. I. A .. Heath. C v..• oo Ginsberg.ren.
nero F. Mea,urement of Thyroid-Stimulating
Hormone in I'[uman AmniOlk Flud. J . Uin. f:n-
do.:,ilk>l. MtMb. 54: 635_7. 1982.
83. Kruiich. L. Mayfteld. M. A.. Steele. M. K..
McMill. n. B. A .• McCan". S. M .•• nd K<>cn'e. I .
I. Effeots of Pharmacologic,1 Manip-
ulations of Central a,· and "r Adrenergic Rocepo
tnrs on the Secretion of Thyrotropin and Growth
Hormone in Mal. Rots. EMoa/ON>! 110: 796-
804,1982.
84 . Labrie. F.. Borgeat. P.. Barden. 1'1 .• Godboot. M.•
llea"lieu. M ., Ferland. L., and l»oie. M . Mech·
anism of Action of lIypothalamic Hormone, in
the Anterior Pi t uitary. Chap. 22. pp. 235_51 of
B.er. R. f .. Jr .• and B... ett. E. G .. eds ..
1/0"'IOM'. Rayen New York. 1980.
85. Lar$en. P. R.. Silya.J. E .. and Kaplan. M. M . Re-
l.tion,hipS Between Circul.ting ,nd Intracell.lar
Thyroid Hormones: Phy.iological and Clinical
Implie.tt ion,. Endo<, . Rt'. 1: 87-102. 1981 .
86. Latham. K. R.. M.cLood. K. M.. Papayosiliou. S.
S .. Marti.I, J. A.. Seeburg. P. H.. Goodman. H.
M.. and Baxter. J. D. Regul.tion ofGo.e E.pr($-
.ion by Thyroid Hormone,. Chap. 3. pp. 75-100
of Birnbauner and O'Malley, c<h __ reference 15.
87. Leonard. J . L.. Kaplan. M. M.. Visser. T. J .•
Sil... J. E.. and I.a .... n. P. R. C<rebral Corte.
Ro.pond, Rapidly to Thyroid Hormones.
]14: 571 - 3.1981.
87A. I.<yer. E. G .• Medeiros-Neto, G. A .. ar>d D<.
Groot. L. J . Inherited Disorders of Thyroid Me-
t'boIi,m . End""" . R . v. 4: 21J_39. 1983.
88. lipton, J. M.. Glyn. J. R.. and'Zimmer. J. A.
ACTH and ,,-Melanotropin in Central Tempera-
t ure COntroL FN. Proc. 40: 2760-64.1981.
Tf.lYRQID f-IORMONES. THYROTROPIN AND TRIi
89. Lomax. P.• and Green. M. D. HiMaminergic Neu,
ron' in the Hypothalamic
Pathway:>. Fd Proc. 2741 _5,1981.
90. Maayan. M. L.. Volpen. E. M.. and From. A.
Norepinephrine 000 Thyrotropin Elfee" on the
Thyroid in Vitro: Stimulation of Io-
dide O'ianifioation and Antagoni,m of Thyroxine
Release. End"""irJ()/. 109: 930-4. 1981.
91. Marques. P. R.• lllner, P.. W illiam •. D. D..
Green. W. L.. Keodall. J. W., D..i•. S. 1.., John.
son. D. G .. and Gale. C C. Hypothalamic Control
of EOOocrine Thermogen.. i•. Am"'. J. Phy.lm.
241: E4 20-E42T. 1981.
92. Marshall. M. C .• Jr .. Williams. D.. and Wein-
traub, B. Regulation of de No>o Bios)'nthesis of
Thyrotropin in Norm,l. Hypcrpla"ic. and Neo-
pl.stic Thyrotrophs. t·ndO<tlno/. HiS: 908_1 5.
1981.
92A. Mot""inovic. J. Endemic Goiter and Cretini,m at
the Dawn of the Third Millenium. Ann.
Nur,. J: 341-412.1983.
93. Me Kel,y. J. F.• and Epelbaum. J. Bios)'nth.. is.
P,ckaging. TranspOrt. aM Reko.., of Brain Pep-
tide<. pp. 195_211 of Reichlin. S., B.ld ..... rini.
R. 1-. .nd Martin. J . B.. ed,., Hypolhalamus.
Raven New York. 1978.
93A . Moriya. T., Thomas. C. R.• and Frieden. E. In-
in 3.5Y·Triiodothyronine (T,)- Binding
Site; in Tadpole N"clei during Spontaneous .nd
114.-
1984 .
94 . Morley, I. E. Control of Th y",.
trapin Secretion. EMO<:F. 3%-436. 1981.
95. Mu,.li. 1'.. Uzumaki. 11 .• Nak.datc. T .. 000
Kato. R. In.olvoment of ",.Adre nergic Receptors
in the I nhibitory Effect of Catechol.mines on the
Th),rotropin.lnduced Release of Thyro,ine by the
Mouse Thyroid. EM"";",,,. /IQ: 51-4. 1982.
96. Nadler. N. J. Anatomical Foatures. Chap. 4. pp.
39-54 of Gucr and Sokomon. ed,., .. 65.
9 7. N.gato ki. S. EfTect of b .." Qu" ntities of Io-
dide. Chap. 19. pp. 329_44 of and Solomon,
reforcnce 65.
98. Obreg6n. M. J.• M.l lol. ) .. Escobar del Rcy. f.
and Morrc,le de E,cobar. G. Presence of L-Thy-
ro.i"" ,nd 3.5.3'·Triiodo-l·'hyron ine in Ti"ue;
f,om Thyroidectomized Rats. EndOCfillOl. 109:
908-13. 1981.
99. M. J .. P.",u,l, A.. Mallo!. J .. MO"eale
de EscoM r. G., and Eocobar del Rey. F. EviderlCe
Against' Major Role of L·Thyro,ine at the Pi·
tuita'y l.c>el, Stud ie, in Rats Treated ,,'ith lo>pa-
notc Acid (Telep.qucl. End"",,;no/. 106: 1827_
36.1980.
99A. O'[lQnncli. J .. TrOkoudes. K.. Sil>crherg. J .. Row.
V.. and Volpi:. R. Thyrotropin Displ.""rncnt Ac·
ti"ity of Serum Immunoglobulin from Patients
with Grave<' Dj"".., . J. Clin. EndocrirJ()/. Mnab.
770--11 .1978.
100. O kamura. K.. TautOil. A.. and DiStefano. J. J.
 111. Elcvaled Serum Levels of T, Wilhoul Mela·
boIie Effecl in NUlrilionally Deflcit nt Ral$. AI'
tribulablt to Re<Juced Cellular Up..... of T ,. Ell-
docri/lOI.I09:61J- 5.1981.
101. Oliver. C., Gira ud. P., Li»hky. J. c.. COle. J ..
Boudou'CSQue. F,. Gillio •. P.. and Conle.Devol.,
B. lnHuence of En<iogt<IOU' 8omatOSlalin on
GrOWl" Hormone and Thyr<>l,,,.,in Secrelion in
Neonalal Rau. Endocri/lOI.liO; 1018_22. 1981.
102. Oppenheimer. J. H. Thyroid Hormone Aelien al
Ihe Cellular Level. &Itna 2M: 971 _9. 1919.
101 , Oppenheimer. J. H .. and Dillman, W. H. Nuclear
Re«plOrs f<>l" Tri;odolhyroninc: A Physiologio.l
Perspt<:live. Chap. I. pp. 1-33 of Bi rnbaum., and
O' Malley; ed ... refer.nce 15 ,
104. P....... A. G. E .. and Ta k01' T. k<H". T. Embryol·
ogy of tho Diffuse Nturoendocdnc Sy"em .nd ilS
Relalion.hip 10 Ih. Common P.plide<. Ft"d. Prot:.
3$: 2288_94. 1979.
II)4A . Pon. in. G. and Mornex. M. Conlro! of Thyrolro.
pin Glycosyl' lion in N01'mai Rat Pituilary Cell,
in Culture: EffecI of Thyrotropin·Rele .. ing 1I0r·
mone. EndoerillOl. 113: 549_556. 198).
105. POller, E .• Ni""laisen. A. K .. Ong. E, S .. Evan •.
R. M.. and Rosenfeld. M, G . Thyrotropin.Rolea •.
iog Hormon. Exerts Ra pid Nuolo.r EifC(:\$IO In·
Crea.. Producl ion of Ihe Primary Prolaclin
mRNA TranKript. Proe. Nail. ANJd. Sci. USA
18. 6662_6, 1981.
106. R.poporl . B.. West. M. N .• and l ogbar. S. H . On
Ihe Mechan ism of Inhibilion by lodineoflhe Ad·
""yl... Cyd ... Ro.pe ... 10 H()j"_
mono. t.·ndtKrirI(Jl. 99: \ 1-22. \976.
101. Rekhlin, S. Neuroend<>crinology. Chap. \ l. pp.
of William •. R, H __ ed .. T.xlbook Q!t::"..
d<>crilfQiogy. 61h ed, Saunders. Philad.lphia.
1981.
108. Roiohli n. S ..• nd M ilnick, M. Biosynlhe<i. of Hy·
pothalamic Hypophy.iolrOpie Facl"", Fronl.
3: 61_88, 1973.
109. Richman. R.• Park. S .. A kba,. M.• Yu. S .• and
!lurk<. G. R.gulation of Thyro id Ornilh ine [)c.
oarbo.. ylase (ODe) by ThyrolrOp;n . I. T he Rat.
t::ndrxdrIGl. 96: 140) - 12. 1915.
110. Robbin,. J .. Cbeng. S.·Y .. Gcrsh<ngorn. M. C.
Glinocr. I). • Ca hnmann. H. J .. and Edolnoch, H .
Thyroxine Transport PrOltin, of PI.,ma. Molec-
ular P, opert ies a nd R«. Prog,
Harm. Rsch. 3#: 4 I 7. 1918.
Il l . Rodgrigu ... Peh. A.. ond Bernal. J. Effect of Di-
valenl Calio", on lhe Binding of 3.5.)'.Triiode>
Ihyronine 10 Isola led Ral Livcr Nuclei. EndtKri·
n<>/ 110:246-5).1982.
112 , R(Ioler. A.• Litvin. Y.. Hage. c.. Gro». L and
Cer.$i. E. familial Hypcr1hyroidi.m due to In·
appropriate Thyrotropin SecIClion Suoc..,fully
Trcalcd wit h T,;io<:!ol hyron;ne. J, Clin, £lIdo<:,;-
n<>/. Me/ab. 5f : 76- 81. 1982.
113. Rot h"'tll. N. J., a nd Sloc k. M. J, Regulalion of
Energy B.I.nco, AM. RfY. I: 235_56.
1981.
114. Ruzicka. F. J .•• nd Rose. D. P. The InHuenec of
T hyroidal SlalUs on Ral Hepatic Mitochondria!
NADH D" ",,!uinone R.duo",... Endo<:rin<>/,
/09: 664-6.1981.
115. Sahiel. A. R.. Powell-J one •. C. H. J., Thom.$. C.
G .. J r.. aod Nayfeh, S . N . ReBul alion of T hyroid
Adenylale Cyeta..: Gu.nyl N ucleotid. Mod ula·
lion of Thyrotropin RecepI<H".Ade nylaIC C)-clasc
Funolion. t::nd<>cril1Oi. 109: 1578-89. 198 1.
116. S.muel •. H. H. In Vitro S iud ics on Thyroid Hor·
mQno Re«plor., Chap. 2. pp. 15-14 or Birnbau-
mer and O·Malley. ed . .. ,erer.nce 15.
1\7. $can lon. M. F., Lewi •. M. , Wcighlman. D. R ..
Chan. V.• and fbll. R. The Neurores"lation of
Human Thy10lmpi n SecrClioo. Front.
dQCrin{)/.. 6: ))1-80. 1980,
118. Sche,b<rg, N. H., ..t. G .. Lecocq. R .. Du·
monl. J .. and Reretoff. S. Modulation of Thy,.,.
glQbulin Memnger RNA Aocumulalion in Ih.
Ral Thyroid. Endoainoi. 1a9: 1650_6. 1981.
119, Sh.rwin. J. R .. and Mill •. A. Epiocphrine Inhibit.
T hyrolropin,Slimulale<i Ado"",ine l'.5'.Mono.
phosphate Accumulation in Car Thyroid Ti«uc.
Endocri/lOl, 106: 28-34, 1980.
120. L 101, EClopic H<H"mooc Syndrome>.
Chop. 10. pp. 34 1_86 of Ingb.,. cd .. refere"".
121. " J, E .. and Larsen. p, R. Pituilary Nuckar
1.5.1'_T'iiodOlhyronino and Thyrotropin Seere·
lion: An Explanalion for Ihe Effecl of Thy"",in.,
198: 61 ;-20. 1917.
122. J .. Ind Volpe. R. AUIOimmunily and
Thy,oid Oi........ Chap, II. pp. l45 _i6 of l oSb.t.
S. tI ...d .. Tht in EndQCrinoi<>gy 1977.
Plonum. New York. 1978.
123. Simon. c.. and Basl i.ni. 1', The Follicular Iodide
Pool as a Two-Compa"menl Sy.t.m:
fmm Ihe UnS\;mulaled Thyroid GI.nd. EIldQCr,
Rsc-h. Commun. 6: 149-S8. 19;9.
12)A. Smirh, ". M. Human Lymphocyte Produolionof
Immu"",ea'li"" Thyrolropin. Prot:. NOli. Ac-od.
Sci. (lS A 80: 601 0- 13. 198) ,
12)S, Smilh. H. R .. and Sieinb<rg. A , D, AU loimmu-
nily-A Po"pccli ••. A nn. R",. Immunoi. I: 1;5_
210. 1983.
124. Smith. T. J .. and Edelman. L S. The Role of $Q.
d ium T .. n.pon in Thyroid Thermogtn",i •. Ft"d.
PrtK. 38: 21 1979,
125. Smith. T. J .. Horwitz. A. 1... and Refoloff. S. The
Effect of Thymid Hor mone on (ilyoO$llminogl)'
can Accumulal ion in Human S kin FibroblaslS.
EndQCrillOl. /Q8:2391_9.1981.
126, Sokoloff. L. Francis. C. M.• and Campb<ll. P. L
Th)'ro,in' Stimulation of Amino Acid Incorpo-
ralion into Prolcin Independe nl of Any Aelion On
Messenger RNA Synl he.i., hoc. Nail , Acad. Sci.
USA 52: 128-36. 1964,
127. $ower<. J. R.. Catania. R. A.. and Hor<hman. J ,
M. Evident<' fo, DopaminerSic Conl",1 of Circ ••
dian V.. i.tion. in T hyrotropin SecICI;on , J. Clin,
t::ndQCr;no/. M.",b. 5f.- 673-5. 1982.
128. Slanton. T. L. Beckman. A. L. and Wi"",""u"
A. Thyrol,opin-Relea.ing Hormon. Effects in Iho
".
C.n' ....1 Ne,vous System: Dependence <HI At""",,1
Stat._ Sdtn« lU; 678-8 1, 1981,
129. St.rling, K. Thyroid Il<>rmonc AClion .,the Cell
L•• el. Eng. J. M.d. 300: I I 7_11 .nd 113_7.
1979.
UO. Sterlins. K.. La,.aru., J. H .. Milch. P.O.. Saku"
rod •• T.. and Brenner, M. A. Mitochondrial Thy.
roid Hormone Roc.pt.".: Localization .nd Phys_
iologi",, 1 11)1.- 1126_9. 1978_
131. Slrbak, V" and Qr •• r. M. Thyrotropin Secretory
RCSpOnse 10 Thyrotropin.Re leasing Harm"". in
the Hypothyroid Perin.tal Ral: Funher EviMnce
of Thyrotroph Independence of the Ilypolnal •.
mU$ during Early Ontogene,i •. Emltxrint)/. IQlJ:
14m -6.1981.
In. Tan.ka. K .• In.d., M .• hhli. H .. Nailo. K .• N i_
shikawa, M .• MMhio. Y" and Imura. H. Inner
Ring M<>tIOd.iodinalion of Thyro<ino and 1,5,3'_
L·Tr iiOOolhyronio< in Rat Brai n. HNI"",itwl.
109: 1619-24. 1981.
133. To". J. R. Biologic.1 Activity of Thyroid Ho,·
mone, at the Ceilu'ar and Molecula, Level •.
Chap. 2. pp. of Litwack. G .. and Krilch·
e .. ky. D.. cd • .• ActiON oj IIOF"''''''' 011 MaJer,,'
la' Wile)'. !'<c'" York. 1964.
134. nta, J. R. Di",uss;on of Pa!l<'- Gen. of Compa'.
Endoc,'1!OI, S"ppl. J: U6. 1912.
US. TOll . J. R. Growth and D<:w:lopmental AOlion of
Th)',oid Hormone> 01 lhe Ceilular Level, Chap.
26. pp.
e,en", 65.
of G=r dnd Solom,,", cd •.. ref·
136. Tal •. J, R. The Aelion of Thyroid Horm""",.
&". " Compa', Emiocri1!Ol. $uppl. 1: 385-97.
1969.
137 . Taurog, A. BiO$ynthe,i, of IOO""mino Acid •.
Chap. 7. pp. 101-33 ofG,«r and Soloman. cd, ..
refererlCe 65.
138. Tong, W. AClions of Thyroid Slimul"ing Ho..
mone. Chap. 16. pp, 25S-83 of Greer and Solo-
mOn, cds., refererICe
139. Uehimura, H .. Amir, S. M .. and Ingbar, S, H,
!'ailure of Orpnic Iodine Enrichmenl 10 lnAu·
enoe the Binding of Bovine Thyr01rnp;n to Ral
Thyroid Ti .. ue. £ndlXriOftOI. 1M: 1201_10,
1919.
140, Ui. N. Synlhe>i, and Chemistry of lodopr01o.ins.
Chap. 5. pp. of Greer and &>lomon, <;ds.,
refe,ence 6S .
1401\. Uller. R. P .. and Van HOtle, A. J. EIf«1 of Ther·
apy on Serum Thyroglobulin Leve l. in Patient.
,,·ith Gra\'e>' Dise..c. J . Clin. Emioeri1!Ol. Mrrob,
46: 747-55.1978.
141. Uno. II .. Sa •• zuki. T .. Tarnai, II .. and Matsu·
mOto. H. Two Major Gene., linked 10 HlA
Gm. Control Su,ceptibilily 10 Graves' Di ......
Nalu" ]9}: 768-10. 1981.
142. Middlcswol\h, l. Melaboli,m and Excretion
of Thyroid Hormone •. Chap. 14. pp, 215_31 of
Greer and Solomon, <:<1$" refercnce 65.
143. Vini. p" Dc Wolf, M, J. S .. Acquaviva.A. M ..
Additional references
THYROID THYROTRoPtN A ND TRH
Epstein. M .. and Kohn. L D. ThyrOtropin Stirn.
ulation of the ADP.ribosyltrarufe,""" AClivityof
Bovine Thyroid Membran ... P,oe. Nml. Acad,
Sci. US A 79: 1525-9. 1982.
143A. Warlof.ky. L and Burman, K. D. Alteration, in
Thyroid Funclion, in PatienlS wilh Systemic Ill ·
... ss: The "Euthyroid Sick Synd'OO'te." Endoe"
Rtv. J: 164-217, 1982.
144. Wel,h, K. HLA Gene •. Immunoglobulin Ge ... ,
and Human Di ..... , Nalur< 192.- 673_4.1981.
145. Wenzel. B" Wenzel. K, W.. K01UI I•. P.. and
Schleusencr. H. Binding of SoIubili.ed Human
TSH-Recep\Qr Prolein by Peripheral Blood l.ym·
ptlocytc, of PatienlS with Graves' Dise.se. J. t·".
d<x';noJ. InvtJI. 4: 161-6, 1981.
146. Westctm.rk. B.. K.,I,,,,,n. F. A ...nd Walinde"
O. Thy rOlropin i. Not a Growth f.clor for
Human Thyroid Ceil' in Cultu",. Proc. NaIl.
Acad. Sci. USA 76: 2022_6.1919.
147. Whinow. G, C. UngulatCi. Chap, 3. pp, 192-281
of Whinew. G. c.. ed .. Compo'ati'" PhF#oiogy
of Th.,morqulal;on. "",- 2. Academic Press.
New York. 1971.
148. Wi"e, A. and McKenzie. J, M, Regulation of the
Rat Thyrolropin Receptor in Vitro. Endocri""/.
108.-305_9.1981.
149. Woebct. K. A.. and Braverman. L. E. The Thy·
roid. Chap. J. pp. 77_117 of I ngba" 0<1 .. reference
"
Wollman. S. It .. and Ekholm. R. Site of k>din.-
lion in Hyperpl ... ie ThyrOid Glands Deduced
from AUlOradiograph" Hndoc"1!OI, lOS: 2082_5.
1981.
151. Wotlh. G. K.. Ret.llack. R, W" and Gutleridge.
D. H. Abnormal Thyroid Stimulating H<>rmone
Followi"3 Piluilary Surgery. J. Endoe,i1!Ol, I".
I'w. 4: 233-6. 1981.
152. Wright. K- c., and Hedge, G. A. ElfeclS of Var·
io", J>rostanoid. on Thyrotropin Secrelion by Suo
perfused Anlerior Piluitary Cell •. t·ndoeri1!Ol.
109: 637-43.1981.
153. S.·Y .• Sbyh. T,.P .. Chop .... I. J.. Solomon.
D. H.. Huang. H.·W" and Chu. P,-C. Com p.ri.
son of Sodium lopodate (Oraarafin) and Prnpyl·
lhiour.cil in Early Treatmcnt of Hyperthyroid.
i,m. J. Cfin. ElldoeriMl, Mnab. 54: 630-4. 1982.
154. Wunder, B. A. H<>rmonal Mtohani<m •. Chap. 5.
pp. 143 -58 of Underwood. L. S" Tieszen, l. L.,
Callahan, A. B.. ond Fold. G, E. ed ... Compa,a-
rive M«hani.m. of Cold AdaploliOll. Academic
P..... New York, 1979,
155. Yamada. T .. Kajihafl. A .• nkemuU. Y. , and
Onaya. T . Antithyroid Compound,. Chap. 20. pp.
345-57 o f Gr.er and Solomon, eds .. ref.",noe 65.
I S6. YO$hida, K .. and Davi,. P. J. Binding of ThYloid
H<>rmone by Human Erythrocyt. Cyt0501 Pro-
lei ns. I,:ndoc'. Commun. 7: 171-88, 1980.
IS7 . Young. J. B.. Ind land,berg, L. Suppression of
SympathetiC Nervous Sy"em During Faning.
SrI,,,,,, 196: 1473_5. 1977.
in proof will be fo und On page 894.
 18
Growth Hormones and Somatomedins
The mOM obvious effects of growth hormone (GH.
somatotropin, STH) are exerted on the long bones of
j u""niles. Fetuses unable to make the hormone a re
usually of normal length at term. and they are often
above average in weight. Infants Ihrive for a time.
but young children totally deprived of Ihe hormone
soon lag behind their contemporaries. They ,''<'OIU'
ally devclop into miniature adults, some of woom
never altain heights of more than 2\1, fC<'1. If the en·
docrine system is otherwise healthy, pU!>.rly is de_
layed but reproductive system maturation is
achieved and full intellectual potential can be real·
ized. Normal a dul ts se>:relC substantial quantities of
GH. but no serious problems have been linked with
deficiencies that begin late in life (15).
The connecl;ve tissues develop thcir highest sen-
$iti. ity to GH during the preadolescent )'cars, and
most hormone-<leprivcd juveniles respond well to re-
placement therapy at that time. When too much GH
is se<:rcted during ehildh()(:Oj, the obvious conse-
quence is giganlism. One man is known to have at-
tained a height of 8 feet . ! I inches (41).
Since gonadal steroids promote calcification of the
epiphyses of the long bones of humans and most
other mamma ls, li near growth ceases during early
adulth()(:Oj. However, many eelltypes continue t(} re-
spond to GH $tim ulation. Too much hormone then
invokes acromegaly. The victims sufTer thickening
(and deformities) of the jaws. !l{)l;e, orbital ridges.
fingers, elbows, a nd knees. The changes a re usually
associated with a rthralgia, foot ailments. and de-
creased ability to perform tasks requiring fine move-
me nts of the fi ngers. Hyaluronates accumulate
under the skin . phosphate is retained. interstitial
edcma devclops. and the ribs elongate. In'''ard
growth of the cranium can pressure on the
brain and cause headaches and visual disturba nces.
These problems are often eucerbated by pitui tary
'"
gland enlargement. Coarsening of the hair.
sweat and sebaceous gla nd activities. growth of the
larynx. and cardiac enlargement are additiona l char-
acteristic findings (41). The metaoolic derange-
ments include hyperglycemia and insulin resistance.
Preacromcgalic symptoms are occasionall y encoun-
tered in very tall juveniles.
Rats a1"<' among thc speCies that grow during
adulthood. Their long oones cominue 10 respond to
GH. but the sensitivity declines with advancing age,
THE COMPLEX NATURE OF SOMATIC
GROWTH
Clearly. a hormone that promotes growth of the
skeleton must affect virtually every other aspect of
lxldy function. Larger. Slrongcr muscles are nceded
to maintain attachments to the bones and to function
as efTectivc levers. The1"<' must be enough skin and
underlying connective tissue to covcr lxldy strue-
tures. Accelerated erythryopoeisis. cardiac hypertro-
phy. roore extensive development of the respiratory
and an expanded capillary network are all
needed to provide and and to carry
away metabolic wastes and heat. More f()(:Oj is eaten.
the IraCt. liver and aSSOCiated organs
enlarge. and thc kidney weight adjuSts to the greater
exc rctory demands. Although brain size is not much
affccted.the high GH levels influence the functions.
Moreover. periphcral extensions of the central ncr-
v(}uS system must elongate to reach their targets.
GH increases the appetite. elevates metabolic
rate. plays roles in maintaining the immune system
functions. and interacts with other hormones to reg-
ulate carOOhyd rate. protein. lipid. nucleic acid.
Water. and electrolyte metaoolism . I "ftuence!) are
erted on plasma membranes, ribosomes. mitochon_
dria . nuclear components. and other cellular struc-

'"
tures. The targets include not only bone and
cartilage. but al!:O bone marrow, liver. kidney . heart.
endocrine pancl'Uli, mammary glands, ovaries,
\C!l\CS, gland, adipose tissue, and hypOthala·
mns (80,124).
Each cell type undergoes its u nique forms of 5pe-
cialiuuion (160), and Ihis must be CQnsidcred in as-
sessing the dTe.:ts of stimulation. The brain acquires
;1$ major characteristics early in life and attains full
during childhood. Differentiated neurons cannot
proliferate. but they retain some ability to repair
themselves and to vary Ihe connections with other
celis, the sensitivities to regulators. and Ihe quan.
tilies of ncurotransminers «,leased. Skeletal muscle
fiber numbers arc also established early, but the cells
can at any lime afterward undergo •• vcrsible
changes in size and conlractile propertics. The long
'oonc& of large mammals grow through(>Ut the juve-
nile period. Linear growth is tcrminated when the
epiph}'5cs calcify, but 'oone cdl populations are rll-
ne"'<'d throughout life, and the borlC$ undergo
ehangcs in shape, thickness. and mineral oontenl.
The liver maintains a fairly oonstant size in healthy.
welt·nourished adults. but it does so by regularly re-
placing cells. Thc organ shrink.s during starvation
and enlarges when certain k.ind s of stimuli are pre-
sented. If a portion is removed or seve rely damaged.
repairs that rccstablish functions can usually be
made. T he kidncys also maintain constant sizes
under usual oonditio1l$, but one of the organs will
undcrgo "oompensatory hype rtrophy" if the other i$
removed. In this ea,"", much of the growlh results
from ctll elongation. Epidermis, gastrointestinal mu-
cosa. and hemopoietic tissues provide examples of
structures Ihat engage in oontinuous ctll renewal
Ihroughout lik Reproduclive organs completc a
preliminary form of differentia tion duri ng certain
time-limited, "critical " periods o f embryonic and
fetal life. They then enter a "dormant'· phase and
resume maturation only when pres.:nted with the ap"
propriate hormonal milieu. Precocious or delayed
maturation of the associated endocrine glands af-
fects many other cell types.
Slle s lor Biosynthesis
Somalotropes are Ihe TIIO!il numerous of the adeno-
hypophysial cells. and they are the major SOurceS of
GH. A Iypical human adult pit uitary gland contains
around 8 mg of the hormone, and the protein ac-
counts for up 10 10% of the dry weight of the gland .
(lflOWTM HORMONESANO SOMATOMEOINS
In contrast, only microgram quantitics of the other
major hormoncs are found (92).
Somatotropes and l.ctotNpes are d . .. ified a. acido-
ph ils. Morphologieal characteri.tic. haYe been used to
distinguish the two cell type. (>eo Chaps. 2 and 19). but
rat ""m'MtN1"" can conlain prolaclin (along with addi·
tioo.1 .ubsl, nen of biologieat int<fest 'hat i"duM met-
en"ph.lin and protein. th.t bind .nti·renin antibodies
[SS)). 5Qme pituitary lumor eetl. make both PRL
GH when first cultured, and others initially secrete on<
of the regulaton but later .cquire Ihe .bility 10 m.ke ,he
other.
Pcplides Ihat share immunological properties with
adenohypophysial GH have been identified in the
neurohypophysis and in several "'<'Il-defined 1"<'gions
of the brain. Sinox TRH is distributed 10 the same
region •. it has been suggested thai the two horm(H1cs
a1"<' cleaved from a common precursor Ihat plays
roles in neurotransmission and ncuromodulation
(87). The observation Ihal brain GH concenlrations
fall after deStruction of the paravemrieular or peri·
ventricular nudei (but no! after hypophysec tomy) is
consistent with the belief that al leas! SOme of the
molecu les a re synthesized by hypothalam ic neurons
(88). Fibroblasts make a PR L·like factor (A-8).
GH·like p'nt.ins are present in higher cone.nlr.tio..
in live,. lung. kidney. a nd SOme other li$$uCSthan in blood
pl",ma . Allhough the possibility thai Ihe peripheral cell.
.. idly accumulale Itormone relea..,d by the pitui tory
gland has not heen ruled OUI. il is believed likely that the
regulator. are made by nonpituil3ry cells (8S ). 5Qme
lung careinom", rele • .., very large quonlities of relate<!
moteeul ...
Chemi stry and Blosynthasls
GHs are species-specific globulin-like proteins de-
void of carbohydrate. Monomeric forms iSOlated
from seve ral species have molecular we ighls of
19,500--22,000 (170). The "apparent molecular
weight" can vary with the molecular configuration
and measurement lechnique. as well as witb the
amino acid content.
It is now recognized that "purified" preparations
conlain C<Jmplex mixtures of related molecules
(SO.92) . The best known human hormone (oflen re-
felTCd to as "Iinle hGH") is a singlc.. haincd prOlein
wilh a weight of 21.500 that contains 191 amino
acids and bonds connecling the cysteine
moieties at positions 53 to 165 and 183 to 189 (Fig.
IS-I) .
Three components of extracls from human glands
that have electrophoretic mobilities different from
those of the major type have been caUed "slow-slow-
 Fig. la·l . Amino oCd $8QUMCe of ""';0. h""",n grOWlh
GH:' "slow-GH:' and '·fasl-GH." All are linear
peptide:s with two S.S bonds per molecule and
weights close 1021,000. Ddelion of amino acids in
134_150 po<ilion< ",<u il. in "opening" of the
peptide to yield a IWo-<:hain derivative Ihat has been
ealled 24K GH because of the altered physicochem·
ieal properties. (The modifiealions have been likened
to the removal of the proinsulin conne<:ting peptide.)
Although 24K GH is found in pituitary gland 110-
mogenates. it is not known whelher the protein is
presenl in inlact glands or in the circulation.
A "20K varianl" lacking amino acid moielies 32-
46 accounlS for SQme 15%-20% of Ihe GH in Ihe
normal human pituitary. and Ihis form is seereled.
A chemically unrelated "diabetogenic fac tor"
prcscnl as a separable contaminant in Ihe
In addition. the pituitary makes and releases
growth-promoting substances of different kinds.
Proteolytic enzymes within the piIU;lar}" and pe.
ri phery cleave Ihe peptides at specific siles. The orig-
inal molox:ules and Iheir dcrivalives ma kc noncova·
lem al1ac hmcnlS to olhcr prOieins. Endogenous and
injected GHs alSQ undergo dimerizations and aggre-
gat ions. a nd il is believed that some of the high mO-
lecular weight "big GHs" are formed in this way.
The changes OCCu r rapidly. and they are associatcd
with loss of im munoreactivity (45) (although SQme
growth·promoting aclivily may be retained). Com-
with weights of 160.000 ha''C becn described
for humans, and ones ranging from 70,000 to
200,000 for rats. 5<.>me of Ihc arc slable,
whereas others are casily converted to smaller
wmponenlS.
In common with other proteins prod uced for
port,"' the GH. are initiall)· .ynthe.ized a< "pre-pro-
tcins:' and a 26·amino acid "signal sequence" with
a weight of 4500 has been identified for humans
(15). The molecules travd through the cisternae of
Ihc endoplasmic reticulum 10 the GoIg; region, The
hormones are Ihen packaged into secretory granules
for slorage and subscqucnl release.
Human growth hormone: genes contain at least 3
intervening sequences. One: Q<X:urs belween the seg-
ments that direclthe inse .. ions ot amino acid moio-
ties 31 and 32. Since Ihc 20 K hormone lacks amino
acids 32-46 of the 22 K form. one possibilily is that
a si ngle primary transeript is processed in different
ways to direct production of the IWO major GHs
(50). However, although most observcrs believe that
a single gene codes for both thc 22 K and 20 K GHs
(113). others suggesl that an hGH t gene directs Ihe
synthesis of the 22 K whereas an hGII, promotes
production of Ihe 20 K variant (120).
The growth hormones are regarded as members of
a "family" of chemically and biologically related
proleins. At lnst 7 different human DNA sequences
thai code for produclion of th. mRNAs have been
identified . Human chorionic somatomammotropin
(hCS I-I. human place nlal laclogen) has 191 amino
acids. 85% of which arc sbared with the most com-
mon form of hGH. Its mRNA shows 92% homology
with the hGH messenger (113), Human prolactin

1= dosely ""sembles hGH, but tht PRl gene is bI:.
lieved to bI: situated dose thc one for GH (144). A
growth hormone·like gene (GHl). and the DNA se·
quences directing production of hGH and hCSH
have all been localized to chromosome 17 (117) .
Multiple genes bave also been iden tified for sev·
eral other mammals. Although each species
its own kind of GH proteins. th."" hal; bl:en "strong
evoluti onary conservation" of the primary structure.
11 has therefo"" been suggestcd that all vertebrate
genes coding for the production of growth hormone-
like mole<:ules derive from a common ancestral
DNA (13). However, the concept that sUC<:essive
mutations we"" made and "passed up tht evolution·
ary scale" is not easily ""conciled with observations
that thc GHs of cartilaginous fishes more closely reo
semblc the mammalia n counterparts than the regu·
lators found in teleosts.
[t hal; bl:en stated that rats possess a single GH
gene, but 3n additional protein that closely resem·
hies hGH is present in rat brain (S8). Thc differ·
ences in chemical makeup are not of the kinds that
can be related to alternate mechanisms for process·
ing a common mRNA. According to some observers,
the production of two different forms of a hormol!<'
within the same individual can be auributed to the
presence of dissimilar alleles on homologous chro-
mosomes. This would ""quire that the mutations
leading to the appearance of human and rat GH
mR NAs oc<:ur""d bl:fore the species followed diver·
genl evolutionary palhways. Rats could then possess
both alleles but express only one of them in their pi·
tuitary glands.
However. many other hormones appear in multi.
pie forms within the same individual. Alternate in-
tcrpretations been offe""d, and tbey may be
mo"" appropriate when (a) one molecular species is
produced in much larger quantities than the other;
(b) the twO kinds of mole.:ules arc distributed to dif·
ferent parts of the body: and (c) the variations in
chemical makeup a"" associated with dissimilarities
in binding affinities for receptors. The following se-
quence hal; been proposed.. The ancestral gene du-
pHcatcs. The newly formed genes separate . Muta-
tion of one or both leads to the production of similar
but nonidentical proteins. Each gene is CQnserved
and maintained, although only One may control the
synthesis of the active hormone (133).
Biological methods are still used to determine 0 H
concentralions in human subjects. since thc various
mole.:ular types differ from each other in immu_
noassay:bioassay ratios. and values obtained with
receptor techniques parallel those of the immunoas-
says (SO). DNA recombination studies used in coo'
junction with such measu""ments have provided in-
GROWTH HORMONES ANO SOMA TOM€OINS
sights into the natu""s of thc disorders that affect
some children displaying growth retardation (121).
Those with immunoassayable GH levels in the IIOr·
mal range may secrete proteins that cannot interact
effectively with the re<:eptors (137). They arc be-
lieved to possess a defective hGH·N gel!<' (which
otherwise codes for 12K hGH) along with an hGH·
V genc tbat directs the synthesis of the 20K variant.
In onc study, all family members homozygous for
the DNA irregularity we"" short, whereas the het·
crozygotcs had normal stature.
Since the normal 20K variant i. made in substan-
lial amounts and is known to possess growth-pro-
moting potency (50), Ihe child""n may additionally
suffer a second genetic defect that alters th. amino
acid composition of the 20K prolein. the Structu""s
of the receplOrs. or the cell components involv.d in
post""ceptor events. However, other possibilitics
have """n considered. For example, mixtu""s of two
or mo"" different GHs may be ""qui""d to achieve
normal growth. 20K does not raise serum glucose or
fally acids (A·9), and there a"" dear indications
that 20K and 22K binding affinities to ""ccptors dif·
fer (71). Failure to respond could also result from
the production of antibodies directed against the en·
dogcnous proteins. In laboratory animals, different
kinds of tenetic dcfects can impair production or
processing of mRNAs or block the development of
somalmrope cells (29).
Posttranslational processing begins in Ihe pitu-
itary gland. but it is probably completed after the
hormone is released to the bl<X>dstream. Enzymes
that clcave the molecules at specific sites a"" present
in plasma membranes, and GH may function in part
al; a prohormone (A-6). Glutathione and other sui-
fur.containing molecules are implicated in the pro-
cessing (95), a nd dithiOlhreitol promotes lhe for·
mation of some of the derivatives in vitro. Th."" a""
probably some children with retarded growth who
make GH but canoot process it properly (I 37).
Although most of the protein found in "purified"
pttunary gland extracts has a hioassay:
immunoassay ratio of close 10 unity. the circulating
proleins include C<lmponents with ratios ranging
from 50 10 lOOO. Antisera that totally block the bi·
ological actions of injecttd GHs may have little or
no effect on the potencies of endogenous hormones.
Thcre is a 4·fold greater incidence of GH defl·
ciency in boys than in girls. This may be related to
thc roles of othcr hormones affe<:ting Gil synthesis
and release. Glucocorticoids and thyroid bormol!<'s
act in diffe""m ways to accelerate the mRNA tran·
scription (48) and affect the biological half·lives of
secreted GHI. low concentrations of
tend to increase. whereas high ones de¢rease GH so-
cretion (8). Estrogens also antagoni,.c rome of the
peripheral effects. Testosterone with GH
10 promote linear growth. However. although it ac·
cclerates growth in gonade.:tomized rats, it ii incf·
fe.:tive in gonade.:tomized·hypophyse.:tomized ones,
even if some G H is given (74).
Tumor cells that «,lease large quantities of GH
usually show atypical «,sponses to regulators. Al-
though responses to the major regulalOrs (somato-
statin and growth hormone «,leasing hormone) are
predictable (168), glucoconicoids and thyroid hor-
mones Can exert inhibitory innuenees (3).
Secretory Patterns
GH is released episodically. The lowest ('"basal")
plasma concentrations of 3 ng/ml or less have been
recorded just before breakfast in well-rested human
adults that have not )'<'t begun daytime activity (41).
Typically, there are small spi kes 2- 4 hours after
meal ingestion, and these: tend to be more pn>-
nounced when the food is rich in protein . Intra ve-
nQUs injection of arginine (and also {}[ glucagon,
which is released in response to protein feeding)
stimulates G H relcase. Muimal values approaching
40 og/ml gencrally OCCur soon after the OnSCt of
deep (slow.wave) sleep. even when day·night envi·
roomental light pallerns are artificially altered Or
when subjects voluntarily shift the timings of meals
and physicat aCtivities. Daytime naps al"<' also asso-
ciated with high rates of GH I"<'lease. The link with
sleep can be established as early as the first postnatal
year, and it persists throughout life. It is also ob-
served in blind individuals (lIS). However, the
neural mechanisms that control the slow-wave sleep
dilfer from the ones that alfect secretion. and
the two pbenomena are dissociable (I (II). Studies on
humans subjectw to Hjet lag'" or sleep deprivation
point to negative correlations with tbe amounts of
rapid eye movement (REM) sleep (54).
In well·nourished adults, the peaks are believed to
contribute to tissue repair. In healthy children. they
come at times when glucocorticoid levels are low.
and they would therdore be expected to be impor-
tant for growth stimulation . In GH-dcficient ehil-
dren, treatments administered at bedtime are far
more effeetive than the same dosages presented in
the morning. On the other hand. G H levels risc duro
ing times of food or prolein deprivation. As discussed
later, the hormone then quite diffcl"<'nt ac-
tions, and it is believed to play roles in the mainte-
nance {}[ the blood glYCOlie levels.
Age-Related Change8 In Secretory Patterns
GH has been identified in humans as early as 7(1
days postconception. The coneentrations in fetal
serum rise to exceedingly high levels between the
20th and 24th w..:'-'. Pea ks of 132 ng/ml are com·
mc)n. but normal fetuses can have 250 ng/ml. The
hormone evidently orisinates in the fetus. Maternal
plasma GH rarely exceeds S ngl ml during preg-
nancy, and there is good evidence that the hormone
does not cross the placenta (6).
It is difficul! to ."e.. G H funetions in fety.., with long
gest.tion periods fo, $Cverat rea$Qns. M OSt of the proce·
dures introduce e,tranwus fact"'" (37). No method for
setectively de51foying somatotropos has been devised. tn·
jection, of regulators or inhibitors into eitber the fetus or
the ttt(lther invoke poorly defined dysfurlClions in both.".·
ganisms. Fetal hYIX'PhY$C(;\Omy il not <uity performed
without interrupting the p«,gn.ncy. and some invest;ga·
tors the,efore reson to fetal decapilalion. Some inf.".·
mati"" can be obtained from subjects with defects that
btock GH productto. . Stud ie, of progrc"ive chang", in
infant rodent. can provide in.ights. since the animal. are
very immature at tbe time of birth. Measurements have
also been made of GH 'elease by pituita,y gtand$ <>b-
tained from rat fetuses killed at various ages. and of hy·
GRIl·tike ,eti"il i.,.
It has been demonstraled that high GH levels
maintained during the late prenatal and early post-
natal periods in rats. a nd that the hypethalamus ex-
erts stimulatory control evcn before the hypothal·
amo-hypophysial portal system matul"<'s (70). The
glands respond to the hypothalamic factor. and the
brain contains very liute somatostatin at that time.
The need for high GH levels SO early in life is not
known . Since fetuses unable to GH Can be of
normal length at the time of birth (52). it is possible
that tbe hormone is used for purposes other than
skeletal system Srowth. For example. it may be
needed for induction of the brain growth factors de-
scribed below. for neuronal maturation. or for regu·
lation of glycogen .ynthesis and adrenal steruidogen·
Cl;;S (?9). However, it is also possible that fetuses
normally depend on the growth-stimulating actions
but possess the ability to accomplish ··compensa·
tory" synthesis of other stimulants when they are
GH-dcprived. Fetal fibroblasts display PR L as well
as GH receptors. and they produce media tors ofG H
actions whtn exposed to either of the hormones
(liS).
It has been observed that when fetal rat paws are
transplanted to older hos ts, growth and differentia·
tion can proceed even when host growth is severely
retarded by hypophysectomy. W hen small amounts
of GH are injectcd . the fetal tissues show gl"<'at sen·
sitivity to the hormone (37). They may therefol"<' be
capable of responding to ext remely ,mall amounts.
A problem with the interpretations is that the hosts
do not supply the environments normally uperi·
enced by the immature cells.
I n prepUbertal and pubertal boys. the "basal"' (i.e.

early morning) levd. are DOl very differenl from
those of adul!$. However, Ihere are mOre peaks
Ihroughoullhe day, and Ihe IIOCturnal ones during
Ihe latter tWO-Ihirds of the sleep phase are generally
much greater than those of men. Growth responses
in juveniles and peri pubertal individuals may depend
On greater stnsirMly to the hormone as well as the
allainment of high and more frequent peah. Aging
is said 10 be associated wilh wme decline in bolh "".
cretion and sensitivity (58).
The abilily to respond to sleep, exercise. and other
Sl imuli is, h<.>wever, relained in older individuals.
Generally. changes in nutrition fail to disturb the re-
lationships between sleep and hormone release
(118). They modify (but do nOi initiate) Ih. daylime
rhythms (102) and they infiuence the peripheral
responses.
Species Differences In Rel e a s e Patterns
Rats display 3.1, ( 118) or 4.hour (102) periodicities
Ihat are synchronized with photoperiods hUI are nOI
obviously linked witb sleep/wake cyclcs. The
··bursts'· of GH release appear to be independent of
fluctuations in corticosterone. PR L. TSH. insulin. or
glucose levels.
Rhesus monkeys hve patterns Ihat superficially
resemble the ones desenbed for humans. However.
these 100 seem to be synchronized wilh changcs in
environ menIal lighting ralher Ihan with sleep, and
they are affected by the feeding cycles (I 23). In con-
lnlSt, "chair_trained" baboons behave mOl"<' like
humans.
II has been suggested thai rats. dogs. and other
mammals do not show sleep-rdated release because
such animals remain fully alert for only a few hours
at a time. Dogs subjected to prolonged periods of
forced wakefulness release large amounts of GH
whcn they are finally permitted to Fall asleep (I 54).
Abno rmal GH Secratlon Petterna In Humens
Some acromegalic adulu; have plasma GH levol.
only slightly above the normal range ng/ml)
when le.ted under "basal" condilions. bUI tbey sbow
greater and sometimes also more frequent Jl"aks.
Othcrs bave anained conccnlration. of up to 1000
ng/ml (41). The severity of the symploms correlates
poorly wilh values measured by immunoassay. pos-
sibly because altered pathwa)'1 for posllransiJtional
processing affect Ihe active sites. GH-sccreting tu-
mors are known to show atypical=ponscs to phar-
macological agents and to ph)'1iological regulators
(103,128). Some children said to have "conslilu-
GROWTH HOI1MONES ... NO SOM ... TOMEDINS
tional tall Slature" show "paradoxical" increases in
GH sccrelion in response 10 glucose loading and
TRH (47) .
Re lease Mecha nisms
Bolh cAM P and Ca" may serve as mediators.
Those regulators are known to affecl mierofilament
and microtubular S}"Stems and to act in olher wa)'1
to stimulale (xncytosis in mauy cell types. Dibutyryl
cAMP and M IX are polent Slimulanu. When PGE,
functions as a secrctagogue, it raises the cAMP le ..-
ds. The nucleotide Can elevale Ihe cytosol Ca" by
accderating ion uptake from the environmenl and
ion release from Ihe mitochondria. It is ineffective
when presented 10 cells bathed in ealcium-deficient
media. A23187 (a calcium ionophore) promotes GH
release when Ca'· i. pre""nt, evidently without ele-
vating Ihe cAMP levels. It may acl in part via innu-
enc.::s exerted on mitochondrial membranes (83).
Very high extracdlular K' stimulation is atlributcd
to plasma membrane depolarization and consequent
augmentation ofCa'· i"nux.
Me te b o llsm
The plasma half_life in humans is around 20-25
m,nUles for both ,nJected and endogenous U H. Jt is
OOt known 10 be affected by age. sex. or acromegaly.
but i\ is changed in hypothyroidism and in other con-
dilion, that affect the aClivilies of hepatic enzymes.
The liver is Ihe major sile for cleavage. Some of Ihe
peptides produced are biologically aClive, and they
may perform special functions. The kidney also de-
grades GH. Only minute amounts of Ihe hormone
appear in normal urine (15.41). but multiple molec-
ular forms have been identified there (4) .
HYPOTHALAMIC REGULATION OF GH
SECRETION
The prodUClion of a growlh h<.>rmone release faclor
was ,u'pecled long before sub:stances such
activity were isolated from Ibe hypothalamus
(22,114). Pituilary glands deprived of tbeir usual
COntaCI with ponal blood put OUI only minUle quan-
litiesofGH, and Ihey can be stimulated bolh in vivo
and in vitro by components of hypothalamic
tracts. Hypothalamic injury has been known to
cause growth retardation in childrcn. to interfere
with sleep-related GH ··surges." and to blunt the se-
crelory responses to hypoglycemia, argininc and
DOPA. Electrical stimulation of the vcntromedial
nuclei augments GH secretion in rats. Lcsions in the
 same region impair grow(h and lower (he plasma
GH levels(lOIJ.
Growth Hormone-Releallng Hormona
(GRH)
Difficulties were encountered in altemp(S 10 isolate
and characterize the GRH. in part because only
minute quantilies of the regulalOr are present in hy-
polhalamic ntracts.
A decapeptide with tbe fo]lQwing $" uCtu", wos pr<>-
posed to be the regulator. bUI il ,"'as subsequently found
to be identicat ",ith the N_ttrminat fragmcnt of porci ...
hemoslobin jl..,hain and i"dr.ctive for SOmat01rope
OIimul.tion.
Val-Hi,-Leu-Ser-Al.-Glu-Glu-Lys--Glu-Ala
Additional ,uMtanc",ull8e,ted inetud. the 1ripeptide
p-Glu&r-Gly-NH, (S9),
Interestingly, progress was advanced by the iso-
lation. identification, and subsequent <ynthesis and
lesting of peptides found in the extracts of pan_
erea(ic and careinoid tumor cells. hGRH (A-7),
which is idenlieal to a tumor pep(ide isolated from a
patient wilh acromegaly has the following amino
acid scque!l(e (60):
H-Tyr-Ala-Asp-Ala- Ile-Phe-Thr-Asn-Ser-Tyr-Arg-
Ly._ Val_Lcu_Gly-G In_Lcu_Ser_Ala_Arg_Ly •. Lcu_
Lc u-G In-Asp-II e- Met -Ser -Arg-G In-G In-G ly-G Iu-
Ser-Asn·Gln-Glu-i\rg-G Iy-Ala-i\rg-Ala-i\rg-Leu-N 1,1,
Concentration. as Iowa. 3 X 10-" M can pro-
mOle release of GH from pituitary cell s maintained
in monola}'er cullure, and One. of 5 X 10- 11 M in-
crease GH rclease into perfusates wilhin less than 30
seconds. The peptide has been shown to prom<ote GH
secretion in eonsdous ralS and dogs. and in rats with
icsion, of Ihe ventromedial nuclei. It shows struc-
tural homology with Ihe ",cretin.glucagon "family."
and is chemically even more closely rela(ed to a
newly discovered porcine intestinal peptide given the
name PHI-27 (155), High doses release PRL (A_I).
Low Ones alTect exocyloois and generation of cAMP.
They arc specific for G H (91).
In addilion 10 the 44-amino acid peptide (human
pancreatic growth hormone releasing hormone,
hpGRF-44). smaller peptides with similar activit ies
but lower po(encies have been idefilified. These in-
clude hpGRF-40 and hpGRF-J7.
hpGRF-40 is a stronger stimulanl of pa!l(reatic
acini (A-IO). but after comparisons with a compo-
nent of hypolhalamic extracts and studying other
properties tha t include anlagonism of the aetioos by
somatostatin, it was concluded Iha( the hpGRF-44
i. Ihe "true" phy,;iological stimulant, whereas Ihe
smaller peplides are derivatives. Thc name
crinin waS then proposed (24).
In other studies, it waS found Ihat a peptide con-
taining the first 40 amino acids of the hpGR F is
highly potent for .. leasing GRH, Ihat ilS actions
parallellhose of dibutyryl CAMP. and tha( all of (he
biological activity is contained within the 1_29
amino terminus "'gment (130).
Anti"'ra direcled against synthetic hpGRH_40
bind tn the nerve fibers of Ihe median emi nence re-
gion and the areuate nuclei of humans and monkeys.
Limited binding In the ventromcdial nuclei nf ma-
caques and monkeys has also been detected.
The distribulion of imm unoreactive sitcs dilTers from
that of somatos(atin. LRH. and corticotropin (19).
Other investigators have found (hat peptides ob-
tained from abdominal carcinoid tumors exert
highly polent, Ca" -dependent, cAMP.like slimula_
lion of GI-l release (hat differs from the clTec(s of
hypothalamic--derived stimulators. The careinoid
peplides also stimulate human GH-stcreting pitu-
ilary adenoma cells (168) .
Roles 01 Catecholamlnes
Although subsets of alpha adrenergic receptors Were
initially defined on the basis of their sitcs of action.
they are now dislinguished by their affinities for ag-
o"i,,, and antaeonists (Chap. 8)
NE is believed (0 promo(e GH releasc.
conlribu(e to the hormone secre(ion rhYlhms. and
mediate the influences of other physiological regu-
lators by interacting with pos(synaplic receptors of
(he a, type on eilher GRH-secrcl;ng neurons or on
cells that synapse with them, Generaliled alpha ad-
renergic blocking agents such as phentolam ine blunt
the stimulatory effcets of hypoglycemia. exe rcise. va-
sopressin. and several forms of noMpceifie stress in
humans (128). Yohimbine. whkh preferen tially
binds to (he "" reeeptors. decreases basal GH levels
in rats and blocks the surges (84). How.,'cr. it has
been proposed that NE additionally exerts less im-
portant inhibilory inAnenees by interacting with at
reccptors.
The roles of dopamine (OA) are difftcult to define
because (a) DA is converted 10 NE; (b) therc 3rC at
least twO different kinds of OA rec<:ptors in the
brain: (c ) DA is believed to act on both hypotha-
lamic neurOnS a nd adenohypophysial cells: and (d)
OA promotes the release of somatostatin (a major
inhihitor of G H ",cretion).
Systemically administered DA travels to the me-
dian eminence and pituitary gland but it does nOI
readily cross thc blood-brain barrier. Although il
usually augments GI-l secretion. it is less effective
than L-JX) PA (which enters Ihe brain and serves as
'"
a OA precurwr). Carbidopa inhibits Ibe peripheral.
but not the central. DOPA decarboxylase. increases
the production of DA wilhin Ihe brain, and
the effectiveness of systemica lly administered I.-
OOPA. It has been concluded from observa-
tions tltal DA is a more polent c.nlmllhan p<:riph-
eral sti mulant (11). However. lite central actions
may include conversion of DA to NE (128). since
neither pirnozide (a DA receplor antagonist) nQr
apomorphine (a DA agonist) substantially alters the
magnitude of DOPA stimulation {I 14).
Apomorphine does not affect NE production.
Small doses injected into lite cerebral ventricles in-
crease secrelion. The proposed mechanisms in_
clude binding \0 presynpalic OA neUI"QIIS, wilh con_
sequent inhibition of Ihe firing and blunting of the
elfe<:ls exerted over somatostatin release (114). High
doses can dircctly release somato:;talin.
Acromegaly is often caused by GH-secreting IU-
rnors that have receptors ditTerent from the ones
found on normal somalOtropes (100). l-DOPA low-
ers plasma GH in mosl of Ihe pal;en($, and DA d;·
re<:tly inhibits GH release when it is presemed to
cultured lumor celis (ll). TRH stimulates GH se-
crelion by tumor cdls. and il has comparable effec($
in some of the patients. Bromocripline (a DA ago-
niot) bloc ... Ihe TRH ",muiat ion (159).
Epinephrine (E) may interact with p·typc adre-
nergic receptors to inhibit GH release. Isoproterenol
(a P agonist) depresses GH secretion, whereas pro-
pranolol (a P block.er) enhanees the responses to glu·
cagon, vasopressin. and L-DOPA (1). However, the
findings are difficult to reconcile with the effects of
PNMT inhibitors. These agents lbe conversion
of NE to E. but they intene'" with both the episodic
release of GH and the stim ulatory effe<:ts of mor_
phine (38).
GABA is believed to stimulate GH secretion by
promOling DA rcleas<:. The effe<:t$ are anlagonized
by bicuculline (a GABA ",ceplOT On the
other hand, GABA can di",ctly accelerale somato-
stalin ",lease.
Serotonin
The slcep-associa tcd GH surges have been attrib-
uted to s<:rtonin (5-HD rciease (28). Oral admin·
istration of tryptophan OT 5·0H·tryplophan (sero-
tonin precursors) smail elevations of the GH
levels in humans and monkeys (10 I). However. s tud·
ies with 5·HT blockers such as cyproheptadine have
yielded conflicting data. The relationships to cate·
cholamines have not been defined. The pharmaco-
logical effects of S-HT include displacement of NE
from secretory granules (114), but d06agC!l of ph.en-
GROWlH HORMONES AND SOMATOMEDmS
lolanline thaI oppose hypoglycemic, vasopressin or
l-DOPA stimulation do I10t affect sleep-",Ialed GH
surges (102).
Opiold Pe ptldes
p-endorphin is rclcas<:d during stress. and it may
contribute to GH elevation at such times in humans
and other primates. The effects a rc believed to be
exened on the hypothalamus. since P-endorphin
does not seem to directly slimulale the somalotropcs
(26). However. a lthough they a", blocked wilh na-
loxone, they may involve inftucllC<'S on GABA lur".
over. The stimulation thaI follows the administration
of a synthetic me\-enkephalin analOg is antagonized
by bieuculline and picrOloxin (18). The opioid recep-
tors differ from the ones that mediate PRL rcleas<:
(151).
II has be.n .uggested Ihal Gil U regulaled by choli".
ergic mechani,m. and Ihal Ihe opioids exerl fine eonlrol.
Over them. Melilooeopolamine affecl' moslly muscarinic
Iype recepton.. and il decrea$C$ the mo",il.de. of Ihe
slecp4ssocialed .urges. Piperidine is a nicotinic rec<:pl<>r
aiOnist us<:d os. pharmacological 1",,1, bU I $Orne is made
in Ihe brain. It I>J>POSCs Ihe influence. of ..Iicholinergic
agenls (108). Auopi .. ean affect oolh musc.r;nic and ni·
colinic receptors when pres<:nt in hilh concentraiions. It
blunt> =ponsUl0 opioid"
HUlamine mediation of opioid aCI;on. is another po>-
sibilily. Diphenbydram;ne i. an H, an,ogoni'l thalexerl,
some influences on cholinergic neurons. while demOSline
blo<:ks jusl the H, reeeptors. Both blunt the opioid effects.
eim.tidi"" (an H, blo<ker) is wilhout effect.
other Ho rm ones
TRH decreases GH release when presented in vitro
to fetal or adull pituitary cells, and it is implicated
as a physiological regulator. As noted earlier, it die-
its "paradoxical" GH secretion from tumor celb.
When vasoactive imestinal peptide (VIP) stimula·
tion was first demonslraled for tumor cells. it wM
suspected Ihat Ihe actions purely phannOC<lI·
ogical (31). However, VIP is present in the hypo-
thalamus and portal blood. Moreover. its potent in-
fluences On the adenylate cyelas<: activity of
somatotropes are antagonized by somatos tat in (43).
Vasopressin, ACTH, and ",· MSH a", all released
in response to stress. and all incrcas<: GH secretion
when present in high concentrations. Glucagon Ie"-
cis a'" elevated during and "'hen blood glu·
cose levels faU. Although that hormone may directly
stimulate somatOlrOpes. the fact Ihal its effect.s are
potentiated by p·adrenergic receptor blockers has
been cited as evidence for an aClion on monoami.
nergic neurons (101).
 Melatonin (MLT) is made from serotonin. and pi-
neal gland production of that amine increases during
thc night. According to some authors. MLT contrib-
utes to the nocturnal GH eie_ation and is involved in
the rapid growth of children. According to others. it
competes with serotonin for receptor sites and by
thereby inhibiting GH secretion accounts for the
growth retardation commonly seen in blind children
(40).
PGE, cie_atC!) pituitary cAMP and it may
act in this way to promote GH secretion. [t has also
been suggested that PGE , facilitates GRH re[ease
(105).
Nutr[ents
Arginine is commonly used to assess the ability of
the pituitary gland to release G H. It invokes greatcr
elevations in women than in men. and its effects can
be enhanced with estrogens (41). Leucine, lysine.
and phenylalanine similar actions . GH secre-
tion following the ingestion of protein·rich foods
Ala-G Iy..c ys-L'fS'"A sn-Phe- Phe-T rp- Lys-Th r_Ph e-Th r·Ser-C ys
A more recently recogniz.,d member of the group
is an octocosapeptidc. SS-28 (3 . IK SU). [t has a
Ser_Ala_Asn_Scr_Asn_Pro-Ala_Met_Ala_Pro-Arg-Glu_Arg_Lys-
SS-2g was initially called prosomatostatin (140).
It is cleaved in vivo 10 yicld SS-14. and it probably
serves as the SS-14 precursor in many cell types
(73) . Howe_cr. Iherc arc good reasons to believe thai
it acts directly at olher sites. Morwver. the lime
courses for appearances of labeled large proteins,
SS-28, and SS-14 following the presentalion of la-
beled amino acids. arc consistcnt wilh Ihe concept
thaI a large precursor is processed in alternate ways
10 yield several small. biologically active forms of s0-
matostatin (163).
Aocording to some reports. SS-28 binds with
3.2X greater affinity to receptors involved in the
control of GH =relion. and it acts there without
prior cleavage to the smaller molecule (I 53). In one
study, it was found to be equipotent with SS-14 for
inhibiting GH secretion. but 10 times as effeclive for
blocking insulin ll'lease (110). [n others, il proved to
be 400 times as potent as SS-14 for arresting insulin
secretion and lOX as effective as SS-14 for blocking
bombcsin-invoked hyperglycemia (73).
Peptides that share immunological propenies with
SS (SUs) are widely distributed. Among other
things. they inhibit the secretions of glucagon. insu-
lin. TSII. thyroid hormones, cakilOnin. gastrin. cho-
lecystokinin. pepsin. gastric acid. and pancreatic bi-
carbonatc (140). SS also de<:reascs the aClivity of
gastrointesti nal muscle. antagonizes the effccts of
probably contributes to growth in children and to tis_
sue repair.
Somatostatlns
The names growth hormone inhibitory factor (G [F),
somatotropin release inhibitory factor (SRIF), and
growth hormone inhibiting hormone (GI F) ...ere ini_
tially given to a hypothetical component of hypotha-
lamic extracts that decreases GH sccretion. A tetra-
decapeptide ... ith a molecular weight of 1638 was
latcr isolated. and called somatostatin
(SS). The same peptide is now more commonly re-
ferred to as SS-14, since longer pcptides with related
biological propenies have been found. Substances
that display somatostatin-like immunoreactivity and
SCem to be of similar size are known as 1.6 SUs.
Native SS-14 hal a disulfide bond; the termS cyclic
and midiUlI arc applied to this form . Thc reduced
(lincar. sulfhydryl) derivalivc is also biologically
potent .
molecular weight of 3145. and the following amino
acids attached to thc NH, end of S$-[4.
ADH on toad bladdcr (49). and is implicated in thc
regulation of renin release. Interactions with calcl-
ferols in the modulation of bone function s have been
suggested (146). Some actions ha .. been linked with
PG generation. but olhers ha_c not (94).
The highest SU concentrations are found in the
hypothalamus and median eminence. Neurons con-
laining the peptides are present in the ventromooial,
arcuate. para .. ntricular. and suprachiasmatic nudd
and in components of thc limbic systcm (amygdala.
hippocampus, nucleus accumbens, and olfactory tu_
bercle). Substantial amounts have been found in the
OVLT (organum vasculosum of the lamina termin-
alis) (106). and smaller ones in lhe preoptic a;<:3,
cerebral cortcx. cerebellum. brain stem. spinal cord.
and pineal gland (10 I). as well as in the neural ret·
ina. sciatic nerve, pancreas. stomach, duodenum. je-
junum. ileum. and colon (1 19) and in the thyroid
glands.
The SS-14 of the hypothalamus and pancreas of
mosl vertebrates seems to be replaced by a n-amino
acid form (2.6K SU) in teleost fishes. In rats, 14K.
3.1 K. and 1.6K molecules are all present in hepatic
portal blood. whereas the 14K form predominates
peripherally (119).
Receplors thaI prcfell'ntially bind one of the types
have also been described. Evidently. SS-14 is of
greater potency Ihan SS-28 for cenlral nervous sys-

tern effects (153). and Kveral $OI1Iatostatins are
made by cultured forebrain .:.:l1s (131).
PreprOiorrnuostatins and tIM: genes coding for
them have also been identified (I 56). and one gene
component is known 10 code for an l&-emino add
"leader sequenec:" (H). The pos5ibililY that 11M: very
large molecules give rise 10 bioloaically active peP"
tides allM:r than SS h" b«n considered.
MECHANISMS OF ACTION
SomatOlUtins evidenlly lei at multiple $ites to i...
hibil boIh basal mild stimula ted GH w:retion ... ith·
OIIt alfcaina GH They are efl'caive
boIh in vivo and in vitro. and they opp;ISC tIM: stim-
ulation by GRH. VIP. dibulyryl cAM P. MIX .
PGE .. AllIS1. DOPA. arginine. illWlin-inYOked
hypogtyocmia. barbiturates. exercise. and electrical
slimulalion or tIM: ventromedial nuclei or dorsal
amygdala (lg.43.IOS). The rcsponses are dose-rc-
lated. Although Ihe SS is rapidly dearaded (83).
continllOlls presentation of the peplide sustains the
actions.
The inHuenees on baSllI G H secretion have been
altributed to depression of cytosol C." levels and
interference ... ith exocytosis. T hey may involve in·
hibition of both C.1o uptake from extracellular
lIuids and lransfers of ions from milochondrial to cy-
toplasmic compartments. The changes in calcium
metabolism contributc to the ability to antagonize
tIM: actions of sevcralsccreta801uC$,
GR H. VI P. MIX. and 5Cver'll1 other stimulants in·
voke rapid. sustained elevation of tile Intracellular
cAM P levels. and some: actions of PGE, may be ac-
complished in Ihis WIly. SS is a potent inhibitor of
cAM P generation. aoo it may additionally acaler·
ale cAMP efflu:t. However, altlo:)u,h. major c0m-
ponent of SS anlapism involves Io>vering of 1M
nueleOlide oon<;Cntnnlons. SS does not fully return
tM cAM P to biisallcvcls ... hen it i$ in dosages
tha t 10001ly block GH secretion. Tbcrefore. some: ef·
fe<:ts mUSI be on 10 the nucleotide.
It has been SU&&csted Ihal cAMP performs !lIher
funclions thai include 51imul.tiol'l of GH synthesis.
and lhat these a rc unaffected by $OI1Ilt(ll$tatins..
Synlh.. i<: .... Jots thai dil'CClty
pituilary Oe\l$lnd )\f')/IIOte Ihe ",leu< of Gft wilhoul ar·
f"'lin, the KeretionJ III TS II. ACTH. PR L 01' I\W'do-
In)pi", III"" bc<:n 10 $Iu dy .dditional interre,lal""
ships bctw«n GRllind 5Ss. It hll bc<:n proposed tllll
GRH must as.oo<:i.lc with t ... o \>indin. $>to< OIl the..,.
mnOl.ropes. Ind Ihlt SS bind. 1(1 one of them. It i$ P'l'-
sible thai SS .els alone 10 sl")fI.lerm in hibi·
lion. but ilS continued occupation 01' Ihe r«eptOl'
interferes ..,ith GRH bindina for Ioo,er lime periods
(22).
GROWTH HORMONES AND SOMAr OMEOIN$
RELEASE OF HYPOTHALAMIC SS
SS is the major physiological inhibitor of GH re-
[ea!.C. Antibodies directed against the peplide elevate
the basal GH levels and they blunt the resp0nsc5 10
stimuli (151). The inhibitory effects of melalonin
and of bombcsin on G H ",Icue are a\tributed 10 SS
discharge (1). and DA s«ms to blunt the response
to hypogtyocmia in Ihis WIly (1 I). When serotonin
increases GH scetction. this is associated ... ilh l0w-
ering of tM SS levels (129).
The release is episodic. In ralS, I>OIIrly pulses
under basal condilions deliver 1-3 pa/min inlO the
median eminellOC. Slress and the adminislration of
pharmacologkal stimulanu increase the amounts.
Catecholamine injections !'\lOse il to 10 p&!mln,
while e1carical stimulation of tM median ptOOp1ie
region can ctkit rales of up 10 30 PI/min ( \(i).
G H CJCens ncgalive feedback conlrol its "",'n
or
w:retion. and it limits the masniludes the !l()Ctur·
nal surges (107). The mechanisms clearly include el.
evation of tM S5 levels. (Portal blood SS rises
promptly when GH is injected into thc 3rd ecrebral
ventricles of ralS [30J. and it falls aflcr hypOphysec-
{161.) However. Gil also promolCf Ihe acncr.
ation of somatomedins. and l!Iofe peplides d«rUK
G H release when they are into thc ve""kles
(2). by 'Clint on bolh br.in .Mr>i11tha ry (A-4)
CHANGES IN NUMBERS OF SS RECEPTORS
Glucocorticoids have been observed to "do... n reau·
late·· the 5S rectpton of GH<sccrctina tumor «l1f.
but to illCrease the numbers of TRH receptors. Some
of the effects on Gil secrelion may de-
pend upon such mechanisms. The aluooconicoid in-
fluences on the rettplOl'S arc not blunted by
TR H also down regulates SS re<:cplo", but ilS ac-
lions can be blocked ,,·ith cycloheximide. It is Ihere-
fore surprising that Ihe effects of gluoocorliooids and
T RH are 001 addilive (141). GH-sccretin, oclls also
have aldosterone receptors. but Iheir roles are not
known (86).
Brain Reglon l lnvolved In Contro1tlng GH
Secretlon (102 )
Most of the GRH thai reaches the ponal blood it
believed 10 Griainate in ventromedial (VM) and
arcuate {A) nuclei of the "The major
studies of GH release have been performed in !'lUS.
bUI similar p3 th"'ays !item 10 in the other
mammals.
V M stimulation is followed by accelerated G H re·
lea!.C .... hereas bilatera l destruclion of the nuclei )0 ... •
crs plasma GH in young animals and relards
growlh. When connections between the hypothala·
mus and other regions of tbe brain are severed. the
pulsatile patlun for GH release is maintained. The
plasma GH and the growth rates of the animals tend
to increase. but responses to several regulators are
blunted or lost.
Axons from hippocampal neurons travel through
the medial corticothalamic tracts to the VM-A com·
plc x. Stimulation of the neurons accelerates GH re-
lease. Excitatory neurons also arise in the basolateral
amygdala . whereas inhibitory pathways originating
in thc corticomedial amygdala and passing through
the stria terminalis have been found. Plasma GH
rises when the inhibitory pathways are disrupted.
55 coexists with GRH activity in thc VM·A re-
gion and amygdala. Therefore, stimulation can pro.
mote the discbarge of both stimulants and depres·
sants. It is not unusual 10 find that stintu lants
become effective aftcr a lalent period-probably be-
cause SS is firsl discharged and the GH secretion
involves a '·rebound·' phenomenon. When agents
promote GH release more directly. there can also be
"oompensatory'· discharge of the SS. Further oom-
plications arise because the VM-i\ region of the hy-
pothalamus contributes to tbe regulation of insulin
se<:retion and to food intake.
Although primates. sheep. and many other species
increase their GH secretion when stressed. rats and
some other rodcnts do not. In rats. there are high
concentrations of SS in the prcoptic regions of the
brain. Lesions at such sites remove the blocks to
stress·associated GH release.
SLI is widely distributed to other brain regions
that include the cerebral cortex (148) . No links wilh
peptides in those areas and GH secretion have been
established. liowever. it is now well known that
··psychosocial deprivation·· impairs growth in chil_
dr<:n who are offered well·balanced diets and arc
otherwise maintained in good health (28).
Glucocorticoid and Estrogen RegulatIon of
the GRH-GH System
In addition to directly promoting the synthesis of
mRNAs that code for GH. glucocorticoids enhance
somatotropc responsiveness to G RH (169). and they
decrease the sensitivity to somatostatins (152). The
catabolic effects of high levels are allributed to in_
terference with (a) GH release in response to other
stimuli; (b) somatomedin functions; (e) calcium me-
tabolism; and (d) protein synthesis in the target or-
gans. Estrogens can 3ceelerate GH synthesis and
augment thc pituitary hormone content. They also
incr<:ase somatotrope sensitivity to certain stimu-
lants. However, some effects are blunted in the pres-
ence of gl ucocorticoids, and roles for estrogens III
Gil release ar<: controversial (166).
SOME SPECIAL PROBLEMS INVOLVED IN
THE STUDY OF GH PHYSIOLOGY
1. 11 Is DiffIc ult to Achieve GH Deficienc Ies
and Excesses
There is no technique available for selectively de-
stroying the soma tot ropes without disrupting all
other adenohypophysial functions. Antibodies di·
reeted against GH bave th us far proven to be more
effective against injected than endogenous hormone.
There is no target gland that stores and secretes a
specific negative feedbaCk regulator Although 55
depresses GH sccretion. it also affects many other
endoxrine funClions. Spontaneously occurring GH
deficiencies in laboratory animals arc almost invari·
ably accompanied by othcr defects. ISOlated GH de-
ficiency is rare in humans. When it is diagllO$-Cd, rc·
placement therapy is usually promptly instituted.
More information regarding the molecular nature
of GHs is required before injections of the hormone
Can be used to fully define the effccts of overdosage.
Most of the preparations ·now available come from
animals with large pituitary glands that are slaugh·
tered for food. Since the glands oontain limited
amounts of hormone. the studies are usually per.
formed on small laboratory animals. GH seems to
pose more problems of species specificity than olhcr
regulators. Implantations of multiple pituitary
glands into other animals of the !an,c species have
been tried, but the structures arc removed from hy-
pothalamic sources of GRH. They usually secr<: te
more PRL than GH. Autonomous GH-seereting tu-
mors have limited usefulness. since many release
products that differ from the nat ural hormonc. along
with othcr agents that oomplica te interprctations of
the cffeets. Proteins thus far obtained from micro-
organisms also differ from the natural GHs (166).
2. Many Factors Affect the Res ponses to GH
Age. sex. nutritional status. endocrine balance. past
endocrine hi$tory, and time of day arc among the
factors that affoct the responses to the administra-
tion of a specified dose of GH. Spee ies differences
are encountered in the chemical makeup of the hor-
mones. the usual plasma eoncentratioru. the sensi tiv·
ities to exogenous preparations. and the reactions \0
agents that inHuencc GH secretion.
3. Many 01 the Responses Cannot be
StudIed In Vllro
Many GH actions arc secn aftcr long latent perioos.
and some require the release of secondary mediators.
There is only limited information on the events that
proceed during the lalen( periods. In most cases. it
is neeessary to administer the hormones to whole an-
imals and to then remove the tissues for in vitro stud-
".
Since preparations from intact animals are often
insensilive. it is common \0 C<lmparc tissues of GH-
treated hypophysectomized an ima ls wilh oneS
tained from untreated operated controb. The \iSliuCS
have been deprived of regulators Olber than GH.
4 . Blphsslc Actions
The dr.cts SCen soon after presentation of GH can
be oppOSite in direction to the ones observed 31 a
later lime. This is especially li kely to occur if the lar·
gels are obtained from hypophysectomized animals.
5. Disc repancies Between Bloasseys and
Immuno888ays
Bioassay, are often difficult \0 perform, dependenl
on subjective judgments, and limited in reproduci-
bility. Most of lhe lest systems require the presence
of regulators other than GH to dicit responses. and
olhers wnlsin nonspecific inhibitors (50). The esti-
mated potency of a preparation differs from target
type to target type.
Radioimmunoassays are generally more sensitive,
mOre easily standardized. and more reproducible .
They have been widely used for diagnosing GH de-
ficiencies and excesses in patients. However. they
measure antibody-combining sites that may be t(»
tally unrelated to interaction s with CH receptors.
Some preparations have high "growth_promoting,"
"insulin-like," and "diabetogenic" activities but low
affinities for the antibodks. Some give high values on
the antibody tesll; but have lil1le influence On intact
animals .
THE SOMATOMEDIN HYPOTHESIS
AI least some of the influences of GH on the skeletal
syslem seem to require the intermediary production
of peptides that are collectively known as
oomatomedins.
History of the Hypothesis
During early attempts to elucidate the meChanisms
of CI·t actions, it was observed that (a) sera from
intact animals stim ulate growth of cartilage ex-
pla nts. whereas sera from untrea ted hypophyseet(»
miled ani mals are ineffective; (b) GH does not re-
stOre the activity when it is added in vitro 10
hypophysectomy sera; and (c) the sera of hypophy-
sectomized animals pretreated with GH stimulate
cartilage growth .
The term fac/or (SF) was given to the
serum component that ae<:elcrated lSSO. incorpora-
GROWTH HORMONES ... ND SOM ... TOMEDtNS
lion into cartilage proteoglycans. and the term thy-
midiilt factor (TF) was used to designate the sub-
stance that stimulated DNA synthesis. It was soon
recognized that the tWQ kinds of activity oou ld not
be sepa rated . and that the same serum oomponents
additionally act on bone, promote the $ynthesis of
oollagen and other proteins, exen insul in_li ke effects
on adipose tissue and skelctal muscle. and support
thc proliferation of several kinds of cultured ceils .
The term somalomeriin (SM) was then introduced
to designate GH4ependem peptides possessing all
of the a Clivities (40).
Observatlona ConSistent with SM Mediation
01 GH Actions on the Skeleton
Hypophyscctomi7.cd animals have undctectable lev-
els of circulating S Ms. The peptide concentrations
are low in most cbildren of short stature with low
plasma CH. and they rise when there are good re_
sponses to hormene re placement therapy. Dramatic
elevations acoompany the "STOWth spurt"" in normal
adolescents (97). The concentrations arc high in
most acromegalies. and they fall following treat-
ments that lower the G H (40).
Animals infested with cat tapeworm la rvae gTOW
rapidly and display metabolic changes similar to the
ones elicited wit h exogenous G H. The effects arc as-
sociated with elevaled SM levels. but with low cir-
culating growth hormone. The terms "WQrm factor"'
and ple,ocercoirl g,owth fac"" (PGF) have been
given to the component thai stimulates SM
genera tion.
The liver is believed to be the major site for syn-
thesis of the circulating SMs. and liver ext raelS can
st imulate growth (165). Concentrated plasma de-
rived from nonnal rats acts en tibial cartilage in
vitro, even when an tibodies directed against G H are
added (81) . Few stud ies of purified peptides have
been conducted. since il ;s difficult 10 obtain ade-
quate quantities of the hormones. (No organ is
known to concentrate SMs. and only minute quan-
tities can be: extracted from large volumes of blood.)
It has recently been reported that purified prepara-
tions administered via infusion pumps accelerate the
grow th of young hypophysectomi'.cd rats (142).
Proponents of the SM hypothesis have offered sev-
eral explanations for tbe failures to demonstrate di-
rect effects of the peptidcs in tbe early studies: (I)
the amounts presented were inadequate; (b) impure
preparations oontain proteins tbat ma.k the rece!"
lor-combining sites of the SMs; (c) exogenous SMs
are rapidly degraded; and (d) the test systems oon-
tain factors thai interfere with Ihe responses to the
peplides.
Some Clinical Applicatio ns
by the hypothesis, some children of
stature low Ie"ds of both GH and
and the inCI'<'3SC when =cive and
respond to GH. Others have immunoas-
sayable GH within the normal range but low SMs.
Tho ones in this group who show SM ele\llltions and
growth respOnses to replacoment therapy are be-
lieved to make a defectiveGH that does not interact
in a normal manner with GH I'<'eeptors. Their prob-
lems are, however, difficult to define. The 20K GH
variant is made in large amounts by wme of the
short child ren, and that protein Can promote SM
generatinn in hypOphysectomized rats (149).
In a different Form of dwarfism. circulating GH is
high. SM. arc tow, and the patients arc reFractory to
GH. The amietcd individuals arc believed
to have either defective Of-! receptors Of some other
abnormality that interferes with SM generation.
Some Problems with t he Hypothes is
I. The faci Ihal Gil can elnau the drculming
SM dOt!s IlOl prove Ihal SMs medime Ihe efffiCts of
Gil on the skeleton, It has been suggested by some
that the rise in plasma SM is hut OnC manifestation
of a generalized stimulatioo nf protein synthesis
(50,8 1).
2. GIf m(1), p/tWn{1 .<OM by ml!Chanr.m .•
Olher Ih{1n Slimulaling SM genfr{1l1on. SMs have
Inng circulating half·lives, bc<:ause they travel
through the bloodstream as components of macro-
molecular oomplexes (21). Under normal conditions,
most of the SM associates with a 150K BP that dis·
appears from the ""rum of patients.
The binding protein is restored by hormone replace·
ment therapy, and il is therefore believed to be in·
duced by Gli (33). [nj«:teci SM, rapidly leave the
blood of hypOphysectomized ralS.
Human blood plasma d,.... however, C(lntain a 40K BP
that bind. SM. with high .ffinily, It i. u.ually mootly un·
.. turalcd. In GH deficieney>latcs. Ihe affinity or lh. 40K
for SM. increase., and il is normalized by GH replace-
ment (34.61) , (The small., protein may provide 1«. d·
feeti"e protection agaiMt SM degradation Of in some way
r.cilitate more rapid tran.rer or the SM. to their
,«:<:ptOT$.)
J. are no direct quantitative relationships
/)elwun plasma SM concentratiQIlS and linear
growth raleS. Between birth and 2 years, the mean
values for pl3.'l ma SMs are only 0.4-0.5 Ujml in
normal humans. Aduilleveis of 1.2_1.5 Ujml arc
attained during the 10th-11th year. In both very
)'<lung and older children, G H deficiency causcs
growth retardation, while hormonc usu·
ally accelerates the growth , However, a lthough the
piluitary hormone markedly elevates plasma S Ms in
older juveniles, il is minimally effcctive for this pur·
pose in youngsters 5 years of age (132).
Several kinds of for the discrepancies
have been offered. The most important of them may
be the production of "embryonic somatomedin,"
which stimulates growth during the fetal period and
is proposed to continue to exert influences postna·
talty. The levels are high in fetuses, but they fall soon
aftcr birth in huma ns. They do not crOSS"react in
bioassays for adult SMs. Birth weighls correlate pos.
itively with the [evels of the fetal peptide (138).
Fetal lungs evidently and usc S Ms (A·3).
AnOlner possibility is that infants and ve ry you ng
children arc more scnsitive than older One!; to the
adult forms of SMs induced by GH arter bi rth.
Bioassays For the SMs are routinely conduc ted On
pl'<'parations obtained from fetal and neonatal ani·
mals because the responses are mOre reproducible
and of greater Other explanations or·
fered indude the rollowing : (a) It has been suggested
that SMs are ntade dose to the target but that
lillie of the regulator i. released into the blood·
stream; (b) qualitative Or quan titative differences in
plasma SM·binding proteins may shonen the half·
lives of the peptides in the circulation; (c) clinical
laboratories routinely take their blood samples in the
early morning. Although some investigators do not
find diurnal variations, others repOrt higher SM lev·
el> in the arternoon. Ihan in the morninp , The con·
centrations may be higher yet al night in actively
growing young children: (d) glucocorticoid and S M
plasma levels arc inversely rciated , The venipuncture
and other clinical procedures can invoke stress and
the releasc of sufficient quantities of the steroid 10
transiently lower the SM concentrations; and (c)
other than OH and SMs play important
roles in the stimulation of growth, ".MSH h3.'l such
effects in rats, and there are indications thaI it also
acts in human fetuses (1 58). TS H and thyroid hor·
mones stim ulate in young hypophyseclomized ratS
(51). Clinically elfeetive preparations may contain
"contaminants" tbat act via SM·independent
mechanisms.
4. GN {1nd S M in Ihe blood do IlOl rise and
fall in par{1llel. The possibility that changes in the
plasma proteins that alfect S M plasma half·lives ao-
count for some of the d ifferences has already been
mentioned. It has also been observed thaI heparin
and some other substances made under physiologica l
condition' Facilitate the releasc of S Ms from high
molecular complexes (33), and the plasma
levels can vary over wide ranges. Several other ex·
planations for the failure to find parallel changes in
GH and S M concentrations have been offered; (a)
Regul.tors ol her than GH affect SM production.
Prolactin has received the most a ttention , bUI insulin

and nutrients are koown to be important (65). Food·
dcprived children make liule Or no SM. despite high
GH levels. Their retarded growth can be corrected
by refeeding alone. and Ihe GH level$ then fall.
Obese children oflen show accelerated growth and
high SM levels, bUI Ihey have low circulating G H,
They are usually hyperinsulinemic. (b) The", is
good c.. ideocc that SM, exert negative feedback
conlrol over the secretory functions of the somato-
lropes (2). The high GH in food-deprived juveniles
with low SMs is attributed at least in pari to loss of
this function. (c> Hormones other Ihan GH alfect
skeletal system growth. Child",n often resumc bonc
elongation when craniopharyngiomas are surgically
removed, although the plasma may not contain de·
tectahle amounts of GH. (d) Factors other than GH
determine the effectiveness of the SMs. 1nsulin can
prolong the plasma half·lives of the SMs by compet-
ing with them for protcolytic enzyme, in the kidney
(164). In somc cell types. insulin enhanoX' the bind·
ing of Ihe SMs to Iheir ",ceptors (75). The pan·
creatic hormone also seemS to decrease production
of SM inhibitors. Streptozotocin·lr\:ated rats have
higher inhibitor levels than healthy controls (64).
5. GH probably exuts SOme direct aCliom On shl-
eral structure growth. Some of the early studies in·
dicating that GH cannot act directly may not have
4WlOp,i4tdy ,J""i,ncd. T he lar,et prepara-
tioM could have contained inhibitors of the responses
to G H. Morcover, if tbe GH molecules require some
form of metabolic before they can stimu-
late tbe cells. this step is bypassed by the in vitro
techniques (81). It has been pointed OIIt that the
demonstrated effecls ofSMs may be too small to ac.
count for the in vivo effecls of GH on the skeleton.
When GH was administered locally to cartilagc
growlh plates of hypophysectomized rats. longitudi·
nal growlh fOllowed On the presented side but not in
the contralateral limh (72). it has also been demo
onstrated that GH binds with high affinity a nd spec·
ificity to canilage cells (44). and that it stimu lates
DNA synthesis when added to cartilage cultured in
defined media (99). However. although no similar cr-
feets of prolacti n are obtained. the need to preincu-
hate the tissue and to avoid frequent changes of the
media are consistent with the possibility that the
cells produoX their own S Ms.
CHEMICAL NATURE OF THE
SOMATOMEDINS
Several growth-promoling peptides whose synthesis
is directed by G H have been identified in the blood
of various mammalian speci es. We still do not know
how many SMs are made. and we are just beginning
GIlOWTH ANO $OMATOM EOINS
to understand some of the interactions and species
variations in functions.
Nonsuppresslble Insulin-Lik e Activity
( NSILA )
Long befwe any of the SMs was characterized. it
was recognized that blood scrum contains ··insulin·
like" components whose actioities are ··not sup-
pressed·' by antibodies that totally block the
of exogenous insulin. The substances can be ex-
tracted with cold acid ethanol and separated into sol·
uble (NS l LAs) and precipitable (NS llAp) frac_
tions. Different tcchniques have been used to
separate growth factor I (IGf.l) from
insulin·like growth factor II (IGf-II ). both of which
may be components of NSILAs.
Iluman spinal nDid contains a peptide resembling
the blood [Gf·1 1. It also has another pcptide with a
IIlQlecular weight of around 9000 with similar bio-
logical activity known as ··hig IGf·II," but no IGf·
[ (62).
Somet o medin Cs
Human somatomcdin C (hSM-C) is a pcptide found
in sera that is indistingui sha blc on the basis of im·
munological and rlAOeplor binding propert ies from
IGf_1 (136). It has 10 amino acid, and an alkaline
isoc lectric point. The molecular configuration resem·
bles that of proinsulin. There are amino acid se·
quences similar to Ihe ones found in insulin A and B
chaim;, but the connecting peplide is different , A
similar subslance (rSM-C) is present in rat blood.
The tertiary structures permit binding 10 insulin re_
ceptors, but not to antibodies directed against insulin
(20). The peptides have high sulfation activity. Pro-
duction is strongly GH-dependcnt. The prohormone
has a long c·terminal peptide.
Somatomedln As
These peptides are similar in size to the SM-Cs. but
they differ in immunological properties and have
more neutral isoclcctric points. HUman SM-A may
be identical with IGF·IL The la tter is a 67 amino
acid peptide with a connecting peptidc quite differ.
ent from the one found in the SM:'C. (66). (Antisera
directed against that component do not crQS'Heact
with biologically relaled peptides f(HInd in the blood
of juocnile and adult rats.)
The insulin-like potencies are greater than those
described for the SM-Cs, but th. sulfation activities
ar<: lower. Although SOme GH is needed to maintain
normal blood concentration •. high levels of the pi·
luita')' hormone do IIOt further elevate tbe
trations (66).
Studies in botb bumans (21) and rats (42) support
tbe concept that SM·As may play special roles in thc
regula tion of fetal growth. whereas the SM-O; as-
sume greater importance aftcr birth. Tight as.'IOCis-
lions to carrier proteins usually block in vivo inllu-
on the blood glucose concentrations (20).
Multiplication-Stimulating Activity (MSA)
Calf serum has bttn widely used to supjXlrt thc pro-
liferation of culturW cells. Mixtures of peptides pos.
sessing IIOt only such capabilities, but also Sf and
TF potencies and insulin-like activities. arc collce--
lively called MSAs. The components seem to range
between 7tXX1 and l3,tXXI in molecular wcights.
Since the levels found in Ihe sera are related to th=
of GH. thc peptidcs are properly claS$ified as SM •.
One componcnt d=ly resembles (and could be
identical with) SM-A.
"Conditioned media" in which rat hepatocytes
have been grown contain peptides known as condi.
tioned rat liver MSAs (CRL-MSAs). The peptide,
are biologically similar to the serum-derivcd MSAs.
Although it differs in molecular weight. biological
potency. and immunoreaclivity. rat SMA is believed
to be Ihe physiologi<;:al counterpart of human IGF-
II . i, i, (V a. rlO F_1I. TI"
level, are high in fetal serum. They fall after birth
as the rlGF· 1 conce ntrat ions rise.
Some rat fetus fibroblasts release substantial
quantities of Ihe rlGF·]] into culture media, but
v<:ry li\1le rIGF· 1. Placental lactogen increases pro-
duction of just tne 101'-11. whereas OH is without
effect. Fibroblasts from oldcr rats make large
amOunlS of IGF-I but lillie IGF- 11. In adult cells.
both placental lactogen and GH induce the IGF·I
(4).
Human Skeletal Growth Factors
A protein with a mOlecular weight of 83.tXXI that
stimulates the growth of both human and chick em-
b')'o bonc cells has been isolated from human bones
and named human skeletal gro,,·th factor (hSGF). It
is known that bone resorption is coupled under nor·
mal conditions to new bone synthesis. and it is p0s-
sible that hSGF is the coupling factor. Paget's di5-
ease is linked with ex..ssively accelerated new bone
formation. and thc levels are high in the bones of the
patients. The protein acts On bone when it is pre-
senled in very low concentrations, and among other
thing •• it acceleratcs DNA synthesis and cell prolif·
eration. It ha' lillie effec t on othe r cell types that
have becn tested. Related factors with lower nlOlee-
ular weights have been isolated from cultured em_
bryonic rat bone. The 25 K component rosembles
pla telet-derived growth factor. and it stimulatcs
DNA syn thesis. A 10K peptide that promotes col-
lagen synthesis is simi lar 10 SMs described above.
Yet a different, 17K regulator has been called bone
morphogenetic protein (BMP) sin.. it persuades
mesenchymal etlls to differentiate into bone cells
(104).
Brain Growth-Promoting Activity (BGA)
Growth of the fetal brain appears to be regulated by
a peptide (BGA) that resembles SM -As. and the
levels rise in response to GH. BOA is a potent mi_
togen for rat and human neuroblasts, and the num-
bers of binding sites rise rapidly around the time
when much of the brain shows its rapid fetal growth
phase (wcek, 16-19 aftcr conception in humans and
around day 20 in the mt) . NGF cannot substi tute for
BGA in the affected cells (139). A motor neuron
growth faClOr has also been identined (A-II).
Growth-Promoting Peptides That Are Not
Classified As 5Ms
Blood contains several substances that supporl the
proliferation of various kinds of cultured cells and
somc that promote differentiation. Certain of them
exert broad.spectrum actions. while the domains of
others are very limited. The peptidcs arc not claS$i·
lied as SMs bttause they lack certain biological
eharacteristies as Gil dependency, insulin_like
potency. Of sulfation a"ivity . Ho,,·evcr. thcy contrib-
ute to GH functions. Thc ones that accelerate thy·
midine incorporation into DNA do not necessarily
comparable changes in mitotic rates (25).
"SO MATOMED IN B"
Tbe peptid.. of ,hi. group ate .imilar in oi1.• to the
"truo'· SM., butthcy have more aoidie i$OCleelIie pOints.
They are inappropriatel)· named .• illte they do oot .tim·
ulate cartila," grow,h or ero.....eact ", ith SM·C. or SM-
A. in immunotOjlic.1 .tudie •. Moreover. their produC'ion
is 00' .. ro",l), Git dependent. They were orisinally cited
for the ir "imu\ati"" of the proliferation of glial cell •. The
mitosenie activity has been recently attributed to c<>n·
.ami.ation "ith epide,malsro""th facto, (6l). The IG F-
II of e.rebMpinal nuid is no"" belie.ed to be a major reg·
ulator of gli.1 cell proliferation (62). A differen, peptide
""ith an apparent molecular weight of ]1.000 that "im·
ulates Sch""an" een proliferation has been given ,h.
name glia/ g",,,,,h f(J(:'or (GGF) (89).
NSILP
Proteins with molecular weijlht> of amurt<! 90,000 that
exerl >orne imulin·li\;O action. bu,lock o.lfation potency
arc pre.ent in human sera. They may be SM' comptexcd
with prot.ill$ tha' mali: ,h. Nld or
.,.be, ...a)'l 10 inl.,f...... ith lbe obilily 10 .. imula,.
ca'tila,•.
EPIDERMAL GROWTH FACTORS (EGFS)
EGFs are fOllnd in high conttntration, in rnl)U$Csal.
ivaI')' glands. is augmenled wilh both en-
dogenous and androcens. and the levels
are mueh hijher in normal .... Ies than in IIOmIaI fe.>-
males. InteUSling:]y, hI).."CVCr. lhe " , _ JocIn5 to
be controlled primarily via adrenergic te«pu:..... nd
there a .. 110 sex diff... n«S in the of
mollSC EG F in Ihe blood plasma . It has b«n
ported lhal hG H inC1U$eS lIN: releuc _lid lluit EGF
stimulates SM production by eultured fibroblasts
(SO). Iluman urine rotItlins • related SUb$tlntt
(h EGF) ..... hieh may be similar to or idenlical w,th
,6-uroga<tron< (an inhibitor of gastrin secretion).
EGFs promote epidermal growth. keratinizati"".
and differentiation. When sivcn 10 ,nfant rodents,
thcy acC(:lcrate open'ng of the eyelids and eruption
of the teeth. At earlier SIIg<:S of development. they
exert inRuencos on Ihe formation of the hard palate
and on the epithelia of Ih. moulh, esophagus, and
cornea. They a re 1 1$0 said to promote the formation
of lung .u,f•• lant. ",1301"' h•• be.n found to ae«l·
craIe proliferation of chick embryo skin a nd mam-
malian mammary gland epithelium. hEGF acts on
human fibroblas\.S. on rat and rabbit kidney cells,
and On rabbit epidermal eell,."The e!Teets seem to be
organ (bul 1101. species) .pecifu;:. I nfluenecs have also
demonslrated for bovine granulosal eell. and
for human lun,. btlt not for adrenocxmical or v....
cular endothelial cclls (2S). The erfects of EGF and
of scv<:ral other growth faelon have been linked with
activa tion cJ protein k'lII$<:$ lluit atlllyzc phospho-
I')'lations cJ tyrosyl moietic$ of specifIC proteins
(147). The .ubstrates ma,y include plasma, mem-
brane components that undergo eonformatlornol
NIICC tlN:re is very rapid aecderation of
Na ' /H ' ueha",cs. wilh consequent elevation of
cytosolic pH . The alkllinity may. in lum. a ffect aJ)'"
oolytie cnq'mcs (especially p!tosphofructo/r;inase).
synthQis, Ind eytOiokelet.a1 reorpni1.atiolt
(1 12). In fibrobllStJ. insulin docs not di'"tly
affe<:t tIN: eell pH. btlt it potentiatcs lhe effeelS of
EGF.
EGF syn.ramm w,th growth hormone may be
linked with activation of a proIein kinase that cata·
lyzes phoilphorylalion of 12K The 20 K variant
lacks the reaion affecled by the en1.ym •• and the fail·
ure of the 20K form to display early insulin· like ao-
tions may be related to Io$s of the phosphorylati""
sile (10).
When presented to culture<:! rat pituitary (O H, )
cells. EGF al$O aClivales cyclic nuclCOl'do-indepen.
proIein kinascs. However. although the reccp-
tOf'S resemble ones found in nc)rma,]lissues. the hor·
mone inhibits cell prOIiferalion as il oecdenltes
PR L production and inhibilS O H secrellon (6 1).
EO F stimulatcs 0 II secte\ioIt by nannal cells (A·S).
NERVE GROWTH FACTORS (NGF)
Structural homologies "" ith proinsulin. and influ·
.nca on lhe survival and matu ration olsympathetic
ne,""""" system ncurom (l4S) were discussed in
Chaps. 1 and 8. The funoction cannoc be mimicked
wilh BGA (and NGF substitu te for EGA in
the suppon of brain growth).
cate that NGF does not aff«t the survinl cJ para.
sympathetic neurons. but it does promote neurite
outgrowth in the ciliary g'lIfIlia (36). Androgens
alld thyroid hormones are major regulatOfS of NGf
production .
FIBROBlAST GROWTH FACTORS (FGFs)
Pituitary gland FG!'s arc basic proteins with appar.
ent moleeulM "'eight< of 13.400. belief thol
FGF serves as the major stimulant for the prolifer.
ation of adrenoc<Jrtical cells was discussed in Chap.
7. However. it was also noted Ihal the innervalion to
the remaining gland contribules 10 the compensalory
hyperplasia thaI follows unilateral adrenalectomy.
Reoc:nt findings raise the pos!libilily Ihat FGF t ync ...
gius with .,.her facton released from the hypOthal.
amus. lhe pituitary gland. Or both. Peptides located
at the N-terminal reg:ioo of proopiomclanoeortin ev·
idently accelerate DNA, but not R NA synthesis.
They are to be secreted in a n inacti ... form.
along wilb ACTH, a nd to undergo
cleavage (96).
FGFs also stimulate vascular endothelial eell.,
.nd they additionally act on myoblasts and on am-
niotic libroblam. Roles in wound heali/li and rege.
eration ha ... been proposed. The funoctions require
the presence of other stim ulants thai SMs
(128). Brain FG!'t d iffer chemically from the pitu-
itary gland hormones.
PLATELET·DERIVED GROWTH FACTORS
(POGFs)
Serum supports the growth of connective tissue eeili.
,s
btlt plasma does IIOt. This tlIplained by th. release
of several PDGFs from platelets when the blood
clots. Two hc:al-Slable pcplides. PDG F· I and POG ".
 J J, .... ith molec ... lar "'eights of BPI'f<lxima!ely 32,000
and lS,OOO, lUpec1ively, have: b«n identified for h ... ·
mans. (9). In common with seven,l other (VOWIh
stimulanu.. the molecules Qontain polypeptide chains
linked by disulfide bonds.. In a dd ition to promoting
lrowth of fibroblasls. anerial smooth musele cells,
and Ilial cells. PDGFs nim ... la!c cell migration,
amill() acid tl'"dnspor!. art<! Ihe synthesis of chol.,..
lerol, pTOStacyclin and proteins. They also affect Ihe
receptors for low dcnsilY lipoprOleins. serotonin,
EGF, somatomedin. and IUlein;,jlll hormone.
PDG Ps have: been shown to affect several endocrine
func!ion$. and i! is suspected Ihat the peptidcs con·
tribute !o some of the PIIthoiosical consequences of
blood vCS$Cl injury. In rommon with EGFs. they ae-
tivate pluma membrane Na o/ H uehangc. but the
0
POOF effeclS are seen after a longer talcnt period
(21),
PDGFs have been classified as "competence fac·
lors·' which "Iriggor"' (he enlry of Go-G, cens into
lhe S phase and prevenl cyelinl cell, from entering
lhe Go phase. They evidenlly induce proteins lhat a!l-
S<Xiate wilh nuclear COffipoMnlS a nd render lhe cells
. esponsive to MprogrtsSion (116). !'GF is
abo classified as a competence factor, whereas EG!'
and insulin are included in the prOiression factor
group. Cerlain actions of PDGF may require the re-
kase of different kinds of mediators. It has been pro-
posed, for exantple, Ihal the innuences on bone re-
sorption Ire medialed by proslaglandins.
OTHER PEPnoes INVOLVEO IN THE SUPPORT
OF GROWTH ANO PROUFERA TION
T1Ioe trythropomin isollned rrom hu ....n .ri"" is U
acidic 'illopr9lein .. i,h a molecular "ei,hl of 39.000.
The hormone is believed 10 • .,. On bone marrow '0 p,o-
mote both "em cdt prQlifer>lion and Ihole'mi""1 waves
of mil(lf.i, lhal Iud 10 Ihe rormation of
The levell rise during hypo>i. (e.l. when Ini mllo . ..
kep' II hi.k .lli 'udes, ,ubjec,ed '0 h. """"hale . or in
od .. r WIYS I'«",,"ttd from (..""portinl'iM: ...al <lUI ....
tilies of 0, in lhe blood). Additioluol f.ctOTs in'-'Olvul in
Ih...,ulation hue ..ec.;ntty been deKribotl. Gil ..
....... "'mula'''''' direClly...... its powoh-promoIi", at.
.iOftJ inc",... Ihe needs fen o:<Y&en , (160). The po _ _
of IGF '''«plOTs on YOU"' (bul no! 011 'Ii".) erythro-
cyles ,",,",IS Iha, IGF, a>ntribule to "is C(Ift-
lrol (122).
Co/Of!)' Srirnulaling FarrO', a,e I lycoprOicin. wjlh mo-
tcoul. , ",.iahls of a'(lUnd 10.000 lhal promote 'he pr<>lif.
e .. 'ion of ,ranuJoe)"e. and of mc)I\()Ilu"lear phagocy'es.
Inlaconi •.e ,he effcots or erylhropoietin on bone
"'"'row. The ftI«f'OPMf:t """'·.Aj«.O', ....y be
eIIl "';th lhem. bu, .My loa •• been detected in diffe .....1
I... t)"ll..ms. The aclivilles I .. hiJ;h It si,.. of inlla ....
"'"'ory ","elions.
o...rlan G,"""",A F«IOI" is ..id 10 be a carbo-
hy<i ..,e-f,.. buic polypeptide with I maIec.la. "';Ahl of
to.oOO-1 3.000 produeed by piluilary ,lands. It proIorIJS
'0
,he li"",of lOn>C ..... rian celt. """ .... y be ..,laled FGF.
GH is needed fOf _ ....1 development of the immullC
system; and Ih)"lIlOltq>ic propenia I\a"" been dcKribed
(1't). S."" ...1 pepticlcs produced by Ihe Ih),mll' pa"
IU , d'ect various a.peets of ma,oralion,
proliferation. Ind func.ions h.a"" been iden'ified A,
leu, IIOme peplldel 'r<: imp]i.ated in
more rcSulalion or cell,row,h and ,cptici'
'ion, In,crleukin II (m.de by T Iymphocy,es) and inler.
Ie"kin J .. d from "'""fO!'>bl iCl) arc lmong the leu·
kotillCl kr.own 10 conlrol the proliferation of celli
ia'-'Olved in responses.. fI«1t proliferation ""rae-
torr U"" .tso been i<kIWitied ('9).
T_j(}<"tinl """,d j«•.", (TGFt) Irc acidic, h... t·
... bl. pep,idcs ,h.at induce
'ro.... h in ",,""nocopllSlic .""horaa«!cpc!>dcnt cells.
Some ;n,er.el ...·ilh EGf •. • nd these contribute '0
""",nd h•• linK (IJ t i\),
SM Blolynthe sil and Met. boUl m
are reasons for believing thaI lhe liver
is 1M major sile for GH-stimulated SM synlhesis
(1&5). HepllocytC$ h3ve G H n:ceptors. a nd SM ae-
tivity has been found in both dos li,cr "<:00IlS d·
"ucnts and media in which hcpatoxytes havc been
cu ltured. The quantities of and SM binding
proteins that are into perfusates or can be
cxtracted from rat liver arC increased by G H pre-
lreatment. They are decreased by puromycin. and
they are undetectable afler hypOphysectomy. The
blood SMs fall following partial hepatectomy. and
lbey rise as the li""r regenen,tC$. Palients with se-
vere liver diseases have low circulating S Ms. Some
ea rty UR$Uccessful altemP!S to demonslf'ltle SM ac-
tivity in liver an: ,lIrib\lled to tM presence of ... b-
stances thai inlerf.re with Ihe bioaMay •.
SM"r<: presenl in extf'l!CIS of hearl. pancreas. pi-
,uitary gland, and brain. Howevcr, since all of Ihese
contain SM receptors cireulating peptidcs may
be laken up and c:oncenlrDled. Although thc possi·
bility that the cells make SMs (or Io<:a! USC has not
been ruled OUI. il has IlOl been dCmons!f'l!ted that
any of th06C SifUC1ures contribute to blood SM .
Kidocys abo contain SMs. but suggestions that
' hI;)' synthesize and secrete the peptides are dillkuh
1(1 rtCOncik: with obiServatiOllS lhat ""illter renal di!l-
0 3$ nor n<:prhrectomy consistently affecls Ihe
pluma (164). On Ih. olher hand, Ihe
kidney affecu SM functions, a nd i! is probably Ihe
major si le for degradation. An as.$(lCialed
.... il h renal plasma membn,nes shows high specificily
for SM-c.. aDd. C",10s0lic enzyme thai acu mostly
on insu lin .nd glucagon also anlcls S M! ( 164). The:
SM. ca n lherefon: retnrd insulin degradation. IGF·
II is more potent lhan IGF·I ( I l l ), Since uremic pa.
lien!1 of!tn have high immUnoa.5S;l)'able but low
."
bioassayabl. levels of SM.A.. it is thaI Ihe
kidneys make SM inhibitors. Children with renal
disease have been known \0 resume growth when the
kidney problems are corrected. even if the SMs do
not return to oorrnal values. The orlh. kidneys
arC difficult \0 define for reasons. Renal in-
sufficiency is associated with elevated plasma sulfa te
levels, metabolic acidosis and impaired appetite. Nu-
trilional deficiencies decrease SM production. aci-
dosis afrom binding. and sulfate interferes with SF
bioassays.
No organ that cone<:nlrates SM. has be<:n identi-
fied. However. it has been observed that V<'ry large
amourns of MSAs bind 10 vaSl'ular endothelium (al
least in heifers and steers) (12), and tile cells per-
form "reservoir" run.lions. Targe! organs through-
out the body take up and internalize SM" Most COn·
tain lyS050lllal enzymes that degrade the peplides .
Prolactin sc.eral GH-likc actions. and it
probably contributcs 10 SM production. The oormal
SM levels in fetuses unable to make GH are allrib-
uttd 10 the presence of PR L and placentallactogcns.
Liver is richly supplied with PRL rec<:ptors. but thc
hormone may also aCI at e1lra-hepatic sites. [nsulin
is implicated as a I'<'gu[aw of bolh SM and SM-
inhibitor concentrations. When given in combination
with protein-rich diets to nutritionally deprived sub-
jects, it can restol'<' SM levels without stimulating
GH secretion.
SOMATOMEDIN A CTIONS
Very large numbers of SM I'<'c<:ptors are distributed
throughOUlthe body, and links with oncogenes haye
been suggcsted (A-2). The physical and immunolog-
ical properties vary from one tissue to the next
within the same individual (127). Certain of the tar-
gets conlain mulliple componenls, each of which
hinds with specificity to one of Ihe peptidcs. Others
have a si ngle form of I'<'c<:plor capable of inleracting
with twO or mOl'<' different regulators (77)_ Many of
the cells additionally have insulin I'<'CCptors.
In contrast, insulin receptors appear 10 be of a si n-
gle type within a specics. and there are OII[y small
species variations among mOSt mammalian groups.
Both resemblances 10 and dilferences from IGF re-
have becn found ([7). There are targets s uch
as human fibroblasts in which insulin and IGFs com-
pete wilh each other for binding siles and others (e.g.
adipocytes) in which insulin increases SM binding
(75).
A "type I growth faclor receptor" with a molec-
ular weight of around 350.000 Ihal closely I'<'sembles
the insulin receptor in si1.e and subunit SlruClure has
been identified in skeletal muscle, but nOI in adipo.
GROWTH HORMONES AND SOMATOM£OINS
cytes or liver. [t IG F-[ wilh high affinily. has
a [ower affinity for IGF_I I, and associates only
weakly with insulin. A smaller I'<'c<:ptor of dilferent
configuration that docs OOt have disulfide bridges is
pr=nl in rat liver and adipocytes_ [I displays high
affinity for tGF-t I, $Omewhat lower affinity for IGF-
I, and no tendency to bind insulin . It dilfers from thc
receptors for NGF, EGF. TGF. and PDGF (which
are al$O believed to lack the S-S bridges). It has been
observed that tissues containing the receptor for
[GF-II invariably also have receptors for either in-
sulin or IGF-I. and that insulin augments IGF·II
binding affinity (39), bUI insu lin and [GF-I lower
IGF·[ receptor numbers. [t has also been demon-
strated that an IGF-I stimulated protein kinase cal-
aly"es phosphorylations of the p-subunits of both the
IGF-I and the i!!.!ulin receptors ([35).
SM Stlmulatlon o f Ca rtlla g e G ro wth
[I has been proposed thaI SMs initiate a series of
interrelated cascading •• ents ([ 64). The peptides in·
voke prompt, K' ..::lependenl acceleration of amino
acid uptake. When they arc preyemed from doing
this. e.g . by presenting the cells with ouabain or de-
priving them of eilher K' Or Na', the subsequent
influenccs on sulfation arc blocked. SMs also aocel-
crate amino acid incorporation into proteins. Puro-
mycin acts at this sile to abolish the SM e/focts on
sulfate incorporalion into cartilage protcoglycans.
Delayed, sustained inAuences require new RNA
synthesis. Actinomycin promptly retard, uridinc in-
corporation into RNA. Lalcr, it brings about paral·
101 inhibition of leucine use for protein synthesis and
of sulfate incorporation inlO the proteoglycans.
Thyroid hormones and SOme other (as yet uniden-
tified) Serum components are needed to suppan the
in .ilro actions of SM in some cartilage bioassay sys-
tems. Canilage is believed to lack insulin receptors,
and thaI hormone has not been shown to substan-
tially contribute to the SM stimulation.
enzymes evidently cO!llribute to
growth of Ihe tissues. GH increases the activities of
calhepsin D and of acid phosphatase. and its actions
Ihcre may be mediated .ia thc SM •. Thc activities
are higher in young, rapidly growing rats than in
older animals (70). (The GH stimulation is specific.
No influences have been found on canilage cathep-
sin B Or on hepatic acid hydrolases.)
Infl uences on Bone
The mechanisms whereby SMs sti mulate bone
growth are not known. Some effeclSon collagen syn-
thesis have been found. The peptidcs also a<xelera te
the oonversion of 25-OH·vitamin D to 1.25-dihy.
droxyvitamin D in the kidncys of hypophysecto-
mized rats ( 150). They may thereby increase Ca'"
availahility.
Insulln·Llke Actions
While the described influences of SMs on amtllQ
acid uptake and protein synthesis in cartilage are
reminiscent of insulin actions on SOme other targets,
insulin does not mimic SM when it is presented to
cartilage.
Both hormones act on skeletal muscle and adipose
tissue to accelerate glucose and amino acid uptake,
glucose and the synthesis of glycogen.
fats. and Each acoomplishes this after bind·
ing to its own, specific receptors. There are reasons
to believe that certain responses invoked by very
high concentrations of insulin presented for long
time periods involve insulin binding 10 SM receptors
(75).
Other Aellons of GH That May Be Medialed
Via SMs
GH is belieoed to play physiological roles in repro-
ductive system maturation. Children with GH defi·
cieney and retarded growth typically undergo de·
layed puberty. Whcn Gil is implanted into the
median eminence. the negative feedback inhibition
of GH sccretion is associated with delayed ovarian
maturation in young rats (5). The gonadal defect
can beovercome with a cal tapewerm facior that de·
creases GH secret ion but invokes S M generation
(126).
GH exerts long·range influences on sevcral other
cell types. It reStores gastrointestinal muCOSa that
has undergone post·hypophysectomy atrophy. in-
c reases the sizes and weights of spleen and thymus
gland and the mass of lympha tic tissue (mostly by
increasing cell proliferation). and accelerates pro-
duction of red blood cells (125). G H is also a potent
stimulant for liver growth. It can enlarge the organ
in intact animals and accelerate regeneration aher
partial hepatectomy. In skeletal musele. the delayed
elfeets on growth involve stimulation of RNA syn·
thesis. Since most of the preceding effccts are first
scen afte r GH has had sufficient time to elevate thc
SM SM mediation has been suggested.
GROWTH HORMONE ACTIONS THAT HAVE
NOT BEEN LINKEO WITH SMs
The plasma membranes of many cell types havc
high·affinity receptors for GH that are distinct from
SM binding sites. (A sialoglycoprotein with a melec·
ular weight of 300,000 comprising foor nonidentical
subunilS has been described for the rabbit.) Some ef·
feclS nf GH are seen after very brief latent periods.
In vitro responses are obtained when cells are bathed
in media that arc serum·free or oontain serum from
untreated hypophysectomized anima ls. In many
cases. they can be blocked with antibodies directed
against GH butllQ\ SMs. it is unlikely that the ac·
tions are mediated via locally produced S Ms. but it
is difficult to test this.
Since only a brief in vitro exp<.>:mre to G I1 is re-
quired and washing the tissue soon afterward does
not impair the responses. GH may "trigger" early
changes in the membranes or promote rapid gener·
ation of second mess.::ngers. No specific mediators
have been found. but interrelationships with Ca"
and with cAMP are described later. &:veral of the
promptly invoked responses are insulin-like. and this
raises the possibility that GH utilizes mechanisms
similar to the ones proposed for insulin (68). The
pancreatic hormonc interacts directly with plasma
membranes. and it has recently been .hown that the
insulin receptor possesses protein kinase activity
(I 34). MClSt of the delayed responses oppose those of
insulin.
Carbohydrate And Lipid MetabOlism
Within minutes after Gil is injected into in tact an·
imals. glucose release from the liver diminishes. and
the blOCld sugar concentration falls (98). Although
G H affects the secretions of insulin and pancreatic
polypeptide (172). no acute elevations of the insulin
Ie"el s are associated with the hypogl)'ccmic reo
sponse. On the oth.r hand . some prior exposure to
insulin is required (7). Within half a n hour. the
blOCld glucose returns to Or exceeds the IIQnnal
range. This is attributed in parI to compensatory reo
lease of hyperglycemic hormones.
When G H is presented in vitro to skeletal muscle
taken from hypophyscctomized animals. glucose up-
take accelerates within 20 minutes. However, al·
though muscle upta\.:e of glucose accounts for most
of the early hypoglycemic effects of insulin. it prob-
ably ma\.:es lillie oontribution to tnc blood sugar
changes that rapidly follow G H injection into intact
animals. The stimulation not seen when tissues are
taken from either intact or GH.pretreated hypoph·
ysectomi7.cd animals. Moreover. hypophysectomy
tissues develop refractoriness to the stimulation
within an hour. and they then ta\.:e up glucose at
lower rates than tissues nOt presented with the
hormone.
GH probably participates in glucose homeostasis
under normal conditions. Hypophysectomized ani·
mals and GH-deftcienl humans tend to become hy·
poglycemic when fasted. and antibodies directed
against Gil Can lower the sugar of inlact sub-

jects. Most acromegalies display mild hypergly-
cemia and at least limited insulin resistance. Mod-
dosages of GH decrease glu= tolerance
within 2 hours in healthy humans. Chronic o.erdas-
age in\'Okes sustained hyperglycemia in laboratory
ani mals. The delayed effects involve increased secre-
tion of insulin. changes in hormone receptor num-
bers and and post-rece ptor defects (23).
Older animals of some species addili<mally su ffer
islet cell "exhaustion". II is agreed Ihal young ani-
mals rarely develop sustair.cd diabeles mellituS-like
syndromes, but there are controversies over the rea-
sons (7).
GH tends \0 increase glyoogcn storage in s keletal
muscle when it is gioen moderate amounts. Studies
on fat cell. indicate that it can augment glycogen
synthase aelioity and antagonize the glycogcnolylic
effects of other regu lators (68) via mechanisms that
differ from the ones attributed 10 insulin secrelion.
It may elert similar effecu on muscle cell,.
When the hormone is administered to food-de-
prived hypophysectomi1.ed animals, the animals
have higher blood glu= leve ls tha n untreated con-
trols. They also lose moTe fal but display bener pro-
lein oonservation. Sine. OH is lipolytic (56), it has
been suggested that high free fatty acid ooncentra-
lions in the blood pla$ma retard glucose uptake by
skeletal muscle cells. However, moderate dosages of
GH do not substa ntially elevate the fatty acid COn-
centrat ions (23). As noted earlier, certain effects of
GH preparations on carbohydrate and lipid metab-
olism a re altributed to lhe presence of a "diabeto-
genic" contaminant that is lipolytic and also keto-
genic (92).
Some e.idence for early, transient stimulation of
gluoosc uptake by adipocytes of hypophysectomio<cd
animals has been presented (68). Howe.er, whcn
ra ts are chronically of Oli, the transport
rates become maxi mal and they cannot be further
st imulaled by insulin. OH admi nistration normalizes
the "basal" rate of glucose uptake, and it also re-
SloreS insulin seru;ilivit y. It has therefore been pro-
posed thai GH induces (or activates) a factor that
limi ts gluoosc uplake under physiological conditions
(141).
The relalionships to cAMP au; comple._ In.ulin
augments the acti.ity of • 10", Km phosphodiesterase:
(POE) in .dip<>:« tissue (46), and it lowers the cA MP.
h s effeel$ on t lue= uptake are by paraUel
change. in the POE. GJ[ inhibit, the POE,an<! il' abmty
to antagonize in.ulin effects on glucose traruport are
probably relaled to this mechanism. In chronic GH-defi-
eieney $IlOlts POE activity i, maximal and unaffected by
in,ulin. GH treatment relu,,,, the POE activity to basal
levelland r.,tOfU rC$poMi .. ncu to in,ulin. Taken alone.
GROWTH HOFtl.40NES AND SOMATOMEDtNS
the observatioMluggtst that cAMP inhibit' gluCQ!.C up"
take. and Ihat the effect' <>f both 'Mulin admini.trati¢n
and GH-deficiency are linked with cAMP dcstructOon.
1I",,·ever. Ihc conc lu,i<;Hl$ arC in<:QMisten, ",ith ",hcr
find ings.
Cha"3c, in cAMP do nOt dirc:<:tly affcct the glucose
traruporl. Moderate amount. of 8-bromo-cAMP do oot
affect glucose uptake rat<>, and epincphri .. can acceler_
ate Ihe tran'port when il arlivar .. adenyllte cycla ...
In,ulin 'Iimulati¢n of gluCO$C uptake i< calcium-depcn_
dent. The hormone i< believed to rai .. cytosolic C.'- by
inhibiling a plasma membrane u"u<ion pump. Its influ_
ence, on the PDE moy be .econdary,.ince high cytvSolic
c;,.'- alone affeel< the enzyme. The PDE may then aug-
ment the insulin dfecls by further "'evating Ihe calcium
Io>cl •. (1'0£ inhibitOr$ are known to promote calcium
extru,ion.)
C."
It is likely that cytosolic i, high in GH-depdved
cell •. GIt may rC'(ore glutos. ratC$ and ;Mulin
.. nsitivity by a.lin8 on the PDE to cause .econdary
depression of the el leium le>cls.
Some of the elfects of GH on fat stores are prob-
ably linked with inhibition of glucose uptake. How-
Cl'er, there are rcasons to believe that the hormone
additionally accele rates lipolysis. The concept is con-
sistent with obsero8tions that children who respond
well to GH replacement therapy "Iose thei r pudgi-
ness" even when the growth is associated with body
weight gain and increased food intake.
Whc n G H is prtsenled in vitro to adipose tissue
freshly isolaled from young adult rats, it accelera tes
lipolysis after a lalent period of 1-2 hours. T he ef-
fects can be potentiatcd with glucocorticoids and
with thcophylline_ Preparations from weanlings dis-
play qualitatively simlla r rtsponses. bUI they are
more senS;live. The latent periods are shorter, and
lipolysis is also easily invoked with epincphrine (5S).
In contrast, tissues taken from GH-<leprivcd ani-
mals display insulin-li ke responses to exogenous hor-
mone t hat include antagonism of epinephri nc-stim-
ulaled lipolysis. The effects subside after some hours
of exposure to OH, and lipolytic responses can then
be demonstrated in the presence of potentiators.
Adipose tissuc taken from intact animals tha t is
preincubatcd in a GH-free environment for 2-3
hours behaves like tissue from untreated hypophy-
sectomitcd rats.
It can be argued that the insulin-like effects arc
nol important under normal condilioll$> since OH is
secreted and il invokes However>
stress LlSua\ly inhibits OH secretion in rats. and lis-
SUts from inlaCt. stressed rats display the antilipol-
ytic response (35). The changes can be rapidly in_
.oked in intact anima ls, and they are eMily blochd
with nalOlone. Moreover, since OH is released epi-
sodically under nQrmal conditions, there are times of
the day when the levcls low. The amilipoly,is
may therefore represent a physiologically relevant
reaction wl\Qsc importance remains to be defined.
Influence s on Protein Metebolis m
The physiological effccts in well· nourished juveniles
inelude lowering of the plasma amino acid levels. ae·
celerated amino acid incorporation into proteins, el.
evation of the body protein: fat ratio. nitrogen n:ten-
tion. reduction of urea production, and lowering of
the plasma and urinary nonprotein nitrogen concen-
trations. True growth also requires delayed slimu-
lation of RNA production and aC<:umu lation. In ad-
dition, GH sharpell$ the appetile ($2).
W hen presented in vitro to skoletal muscle prep.
arations from hypophyseetomi,-"d animals. GH aC-
celerates the uptake of certain dietary amioo acids,
and it also affects some artificial ones that "r" OOt
metabolized. The selectivity differs from that ob-
served for insulin (7). Thc latent periods and dura-
tions of responses resemble those for glucose uptake.
but the mechanisms are different. Amino adds an:
transported against concentration gradients. Protein
synthesis inhibitors block the 5Iimulatory effects of
GH. It is therefore possible that the hormone pro-
motes the formation of labile proteins rC<Juired for
transport via mechanism, involving utili7.ation of
long_lived mRNAs. Alterna!ively. the inhibitors in-
terfere with an ongoing pT"<ICCSS of protein synthesis
that is to support amino acid uptake.
Glu= deprivation and RNA synthesis inhibitors
prolong the stimulation . They may interfere with the
production of trarulport inhibitors. Another possibil-
ity is that they slow the synthesis of en7-ymes that
degrade transport proteirul.
Gil additionally accelerates the rate of amino
acid il\COrporation into proteins via mechanisms dis-
sociable from the ones on transport. The
small (4OS) subunits of the ribosomes may be the
primary sites of action. Organelles taken from GH-
deprived rats the amino acids at suhnor-
mal rates. GH pretreatment of the animals II<)rmal-
iles the function, and the hormone also some
effects in vitro after a latent period of approximately
half an h(lur. Once begun. the effects persi,t for 24
hours or longer. Repeated injections of GH into hy-
pophysectomized animals bring about increases in
the quantities and activities of RNA polymerases
and in cellular RNA content . In very immature an-
imals, GH a lso accelerates DNA synthesis and cell
proliferation, but in older ones all of the growth re-
sults from cell hypertrophy.
Cardiac muscle behaves differently. The protein
content is subnormal in chronic hormone deficiency
states. GH accelcrates amino acid uptake and re-
stores the protein in deprived animals. but it has lit_
tie effcct on hormone-replete rats. The changes in ri-
bosome activities deseribed for skeletal musele are
nOi observed (82).
In liver. G H induces SMs and some other special
proteins. It is also said to increase the numbers of
GH receptors, although the h(lrmone "down regu-
lates"' in other target organs. Chronically elevated
GH levels an: aswciated with enlargement of the
organ, and GH is believed to play essential roles in
regeneration following hepatic injury or partial
removal.
NUTRITION-RELATED CHANGES IN GROWTH
HORMONE FUNCTIONS
In \V01I·nourished children. GH levels peak and glu_
cocorticoid concentrations fall around the time of
slcep onset. [t is probable that G H then exertS its
major, SM-mediatcd stimulation of body growth.
During times of food or protein deprivation. mct-
abolic reserves are limited. It then becomes physio-
logically appropriate to divert the available resources
into pathways that support vital functions and to
temporarily arrest growth. The elfects ofGH on SM
generation are allenuated during fasting (32), and
the IGF-l (which exerts the most prominent effccts
on bone elongat ion ) is more affected than thc IGF_
II (109). fasting also leads to the production of in_
hibitors of SM actiom;. and this probably contributes
further to the arrest of skeletal growth (162).
The GH secretion is accelerated, an elTect attrib-
uted in part to loss of the negative feedback inllu-
eocesof SM. on the somatotropes. Then. GH seems
to facilitate maintenance of the blood glucose con-
centrations. increased use of lipid fuels, and the
"sparing" of body protein.
SM I <"",ation "nd SM I''''''''!'''' d<pr<SKd.
$.\1 ... I",med
SUPPOfl of •.
lipid o.<Hl ......... "" ptOl<io
'pa ri08
REFERENCES
I. Abe. H ., Cjoja .... K.• Minamitani. N .• Iwasaki, J.,
Chiba. T .• Mat,ukufa. S .. and Fujii •. T. Slimu,
la!ion by Bombc<in of ImmunorOlC!;'C Somalo-
,tatin Relea .. ;nlo Rat Hypophy>ial Portal Blood.
End«r;no/. 1()9.- 229_234.1981.
2. Abe. H., Moli!ch. M. E.• Van Wyk, J. J..and Un-
der"'<l<>d. L. E. Human Growth lIormone and So-

m'lOmedin C Supp,ess Ihe Sponlaneou. Rele •••
of Growt h Hormone in Unanesthetized R .... E,..
dor,/noJ. II): 1319-24. 1983.
3. Adam•. E. F .• Braj kovich.l. C, . rId Mashiter, K .
Gf"OI" t h Hormooe and Prolaclion Secretion by
Disperted Cell Cultures of Hum.n Pitui tary Ad·
enom." Long Term Elfe<:l&of Hydrocortisone. E..
tr.diol. In,ulin. J.$.3·.Triiodolhyronine and Thy·
ro,;"". J . CI;n. endor, llfOi. M"ab. 53: 381-6,
1981.
4. Adam •. S . 0 .. Nissley. S. P.. Handw< ' ger, 5 .. a nd
Rechler. M. M. De>elopment.1 Pauerns of In.u·
lin-Li ke Growth Fac'or'] and ·11 Syn,he'i. and
Regulation in Rat Fibrobl.. lS. 102: 150-
3. 1983.
5, Ad>i$. J. P .. White. S. S .. and Ojeda. S, R, Acti·
v.tion of Growth liormone Short Loop Fecdbaek
Delays Puberty in tlte Female Rat. EndOt:F;nol.
108: 1343- 52. 1981.
6, Albrecht. B, H. n. Malern.1 Adenohypophysis.
Chap. 6. pp. 97_114 of Tulchin,ky. Do> and Ryan.
K. J .•• d•.• EndorrifJOlog)", Saun·
ders, Philodclp hi•. 1980.
7. AIt"uler. N. AClion, of Gro"th Hormone On
Carboh}'drate Mctabo! i,m. Chap. 31. pp, 233-H
of Koobi! and S."y<r. ed.,. referen<e 80.
8. Amara. J. F .. and Dannie,. P. S. 17Q·Eotr.d iol
H••• Biph .. ic Effect on Growth Hormone Cell
Growth. EnJor, llIO/, 1/): 1141_3. 1983.
9. Anlionada. H. N.. • nd WHliam •. I.. T. I'[uman
PlaICICI·Derived G,owth F.etor: S"ueture and
Function, Pror. 42:2631)-4. 1983.
10. Boldwin. G. 5 .. Grego. B.. Uearn. M. T. W.. Ken·
KI. J. A., Morgan. F. J., and S impSon. R. J. Pho.-
phoryJation of Human Growth Hormone by th e
Epiderm.1 Growth Faclor·Stimul31oo Tyrp;sine
Ki n.",. Pror. NaIl. A<od. Sd. USA 8(): 5276-80.
1983.
I I- BalUal. S. A,. Lce. L. fl .. and Woolf. P. D. Do-
pamine'llic Stimulation and f nhibition of Growlh
Hormone 5ecrClion in Nor mal Man: S tudie. of
th. Pharm.eolog;c Spedrodly. J. C/in. Em/or'/'
001, M",ab. jj: I 273 - 7. I-
12. Bar. R. S.. Gold,mith. J. C .. R«hlcr. M. M ..
Peakcock. M, 1... and Ni .. ley. S , P. Inte,"ction.
of Muitiplic3lion-Stimulali ng Activi'y with So-
>ine Epilhelium: Comparative Stud ies in Pri -
m.,y. P...... ged. and Cloned Cultu, o< from the
Pulmonary a nd S)'stemic Cireulat"""-. Endoa/·
1fOi. I/O. 990-6. 1981.
13. Bartka. A. . ·R ichard,. R. I.. Ba,t<r. J. D,. and
Shine. J. Prima,y Structure and Evolut ion of Rat
Growth Hormone Gene. Pror. Noli. Acod. Sci.
USA 78: 4867-7 1.1981.
14 , Baum.nn. G ..• nd Ab",mson. E. C. Uri nary
Growth Ilormone in Man: Evidence fo, Multiple
Moleeul., Form., J, Clln, EnJorriooi. M<lab. 56:
305-11.1983.
IS. !kntley. p, J. Cam-
b ridge Univcrsit),. Pre .. , New Y¢rk. 1980,
GROWTH HORMONES ANO SOMA TOMEOINS
16. Berelo"il>. M,. Fire<lone. S. L. artd Frohman, L.
A. Effect. of Growth Hormone Exee .. and Defi·
ciency on lIypothalamic Somal.,.t.ti n CMte"t
and Re loaK and On TiS$u. SomatO:lt'lin Dimi·
bution. Elllior'/MI. 11)9: 714_19.1981.
17. Bhaumie\:. B.. B.I •. R. 101 .• and Hollenberg. M,
D. Somatomedin Re<:eptor of Hum.n Placenta,
SoIubiliution. Photolat>eling. Partial Purification
and Comparison with In,ulin Reoeplor, Pmc.
Na'i. Acad. Sri, USA 78.- 4279_83. 1981 .
18. Bilc1.ikjian. L. M .• and Vale, W. W. Stimulation
of Adenosine 3'.5' -Manop""'phate Production by
Growth Honnone.Rde.. Factor "nd It. lohi-
bitioo by Somatostatin and Pituitary
Cell.;n Vilro. I/J: 1726_31. 1983.
19. Bloch. 8.. Brazeau. P .. LiItB, N,. BlIhlen. 1'.• 8eh.
F .• Wehrcnberg. W. B.• 8<rIOit. R,. Bloom. F. , and
Guilkmin. R. Imm"noh i$lOChcmic.1 DctectiOl1of
Growth llormone·Rele • • ing Faetor in Brain. Na-
19SJ.
20, Blundell. T. L.. Bedarkar. S,. and Humbel. R. E.
Tertia ry Structures. Receptor Binding, and An·
tigen;dty of In,ulinli ke Growth Factors, Fd.
Proc. 4): 2592_7. 1983,
21, Do"i. L.. Roscnfeld, R. G .. Liu. F.. and Hinl1.. R.
I.. Som3lomooin P.plide Di",ibu t ton and Soma·
tomedin.Binding Protein Content in Cord
PI .. ma: Comparison to Normal and li}'popitui.
tary PI.. ma. J. Clin. Hnd"",IIfOi. Mt/ab. 5#: 223-
8.1982 ,
22. 8o" ·e... C. Y., ReynOld •. G. A.. C h,ng, D.. Hoog.
A.. Ch.ng. K ,. and Momany. F. A Study 00 lbe
Regulation of Grow,b Hormone Release from the
Pit";'arie. of Rats In Vitro. Elllioc';nol. 108:
1071 - 80.1981.
23. Bratu""h·.\ larrain. P. R .• Smith. D,. and De-
Fronro, R, A, The Effecl of Gro",'th Hormone on
GI"COiIe Metabolism aOO Ini ulin S<x:retion in
Man. J. C/;n. Endor';ooI. M",ah. H: 973 _82.
1982.
24. Brazeau. P.. Ling. N ., BOhlen. P., E""h. F .. Ying.
S. -Y, . arid Guilkmin. R, Growth Hormone Re·
lea,ing F.ctor. $omateeri" in Relea"'$ Pituiury
Growth Hormo"" in Vitro, Pmc. Na'i. Acad. Sri.
USA 79: 7909_13. 1982,
25, Carpentcr. G.• and Cohe n. S, Epidcrmal Growth
Factors. AN;V'" Horm. 5.- 203 -47.
1978
26, Ca,aneuva. F,. Belli. R.. Cocchi. D.. Chidi. T.,
Manteg"'-'.... P .. and Millier. E. E. Proof for Hi ..
taminergic but not for fldrene'llic In>ol" ement in
Hormone.Releasin8 Effectofan Enkcph-
alin Analog in the Dog. Elllior';IfOi. 108: 157- 63.
198 I.
27. C..""II. D. Rothenberg. P .. Zh"ang. Y·X .. Deuel.
T. F..• nd GI.ser. I.. Piatelet·De,ived GrOWth
Foeto, St;m"late. N.· IH' E.chango and In-
duce' Cytoplasmic Alkalillltion in N R6 Cell •.
P'oc. Na,l, Arod. Sci. USA 80: 6224-8, 1983.
28. Chec k. D. B.. and Hill, D. E, Effect of Gro"'th
 Hormooe on Cell and SomatiC Gro ... th. Chap. 28.
1'1'.159-185 <>I' Knobil and Sa ... yer. ed ... refer·
enCe 80.
29. Cheng. T. C .. Beamer. W. G .. Phillips.J. A .. IlL
Banke. A.. Mallonee. R. L. and Dowlin,. C
EtioiOllY of Grov.'th Hormone in Un lc.
Arne" and Snell D... arf Mice, Endocrinol. II):
1669-78.1983,
30. Chihara. K.. Minamilani. N .. Arimura. A.. and
Fujita. T. Intravenlricularly Injected Growth
Ho<rnone Stimulate, Somatostatin Release into
Rot Hn,ophy.i,,1 Port"l Blood, Endoerinol, 1{)9:
2279-81. 1981.
31. Chih .... K.. l...."' ki. J .. Min.mitani . N .• Kaji.
H.. M.t.uku,a. S .• Tama;;i. N.. Ma"umoto. S ..
a nd Fuji ... T, Effect of Va"",c,i.e Inte"in.1
Polypeptide on Gmwth Hormone Socretion in
Perifused A""",egalie Pituitary Adenoma Ti"
• uc,. J. Clin End"",i",,/. MNab. 54: 773_9. 1982,
32, Clemrnon,. D. R .. Kliban' ki. A.. Underv.'ood. L.
E.. McArthur. J. W __ Ridg .... y. E. C. Beiten •. I.
Z .. and Van W)'k. J. 1, Reduc,iQr, of Pla.ma 1m·
munoreacti" Somatomedin C During Fa.ting in
Human,. J, Clin, Endocrinol. MNab. 53: 1247_
50. 1981.
)), Clemmons. D. R .. U nderwood. L E.. Chordain.
P. G ... nd Van Wyk. J, J. Ubewion of Somat.,.
medi ... C from its Binding ?to,ei., by Proteolyt;"
r: nz)'mes and Heparin, J, Clin. EndocrilOOJ,
56: 384_9.1983.
34. Cohen. D. A.. and Blethen. S. L Somawm«lin
Binding Prorein' in GH · Defieient Children wi,h
Normal Plasma Som.lOmedin le"I" J. Clin. E"..
douinol. M"abi. 56: 461_6.1983.
35. Coiro. V.. Grichtinl\. G .. and Goodman . H. M. In·
duetion <>I' ' n;ulin·like Response, to Growth Hor·
mone by Slrm. f.·ndo.:rino/ . 109: 2213-19. 198 L
36. Collins. F... nd Da"'son. A. An r:ffect of Nerve
G'o"lh Factor on Paro.ymp.uhetic Neu,ite Out·
gm"'th , Proc. Natl. Acad. Sri. USA 80: 2091-4.
19H
37. Cooke. P. S .. Ru,sell. S. M .. and Niooll. C S. A
T",n;pl.nt Sy"em for Sludyin, Hormono l Coo·
,,,,I of Gmw,h of Fetal Rat Tillue", EIf""I' of
H}'poph)'scctomy. Growth Hormone. Pml.ctin.
and Thyroxine. f:ndocrinol. 111: 806_12. 1983,
38. Cm,,'ley. W. R.• Terry. L. C .. and Johnson. M, D.
Evidcnedor 'he I n>ol.cmcnl of Central Epineph.
,ine S),'I<m> in the Regul.,ion of luteinizin,
Horm<)nc. Prolactin. and Growth Hormooe Re·
lease in Fem.le Rats, End""i""l. 110: 1102-7.
1982.
39. C,ech. M. P .. Oppenheimer. C l.. and Mo·
ssagul:. J, lnlerrelalion.hips Among Recep,or
Structure, for In.ulio and Peptide G,owth Fa<>-
to,"" F"I. Proe, f2: 2598-2601. 1983.
40. Daughad.y. W. H. Anttriot Pituitary. Chap. 2.
PI', 21_76 of Ingbar. S. H.. cd .. CO/1umporo'}'
M "O/>o/i,m . >01. L Pleoum. New Yor • . 19')9.
41 . Daughaday. W. II .. Th. Ad<nohypophy.i •. Chap.
3. PI'. 73_1 16 of William$ .• d .. Reference 171,
42. Daughaday. W. II.. Par'er. K. A .. Borowsky. S ..
Trivedi. B.. and Kapadia. M. Mta$urcment of So-
malonlOdin-Related Pcplides in Fetal. Neonatal.
and Maternal Rat Strum by In.ulin·li" Growth
Fact'" ( IG F) I Radioimmunoa ...,y. IGF· II Ra·
dio,"e."tor Assay (RRA). and Mu!tiplie. tion.
Stimulating Activit), RRA aftcr Acid· Ethanol
Extraction. EndocrilOOJ 110: 575-81. 1982.
43 . L J.. and 5<honbrunn. A. Somato-
statin Inhibits Basal and Vasoaeti" Intest inal
Peptid<.Stimula!ed lIormone Rekase by Diffe ..
enl Mechani,m. in G H Pituitary Cell •. Endoc,j-
IOOJ. IIJ: ISSI-8. 1983.
44, Eden. S.. 1"<$<On. O. G. P.. M.d,en. K.. and Fri·
ber3. U, Specific Binding <>f Growth Hormone to
Isolated Chrondrocyle' from Rabbit Ear and Epi-
physeal Plate, t:ndoerjno/. Ill; 1121_9. 1983,
45. EIIi •. S .. Vodian. M. A.• and Grindol.nd. R. E.
Studies on the Bioo.ssayable Gm"'lh Hormone:·
Like Activity of PI.. ma . R«. Prog. Ht)Tm. .
J4: 2U-34. 1978.
46. Engfeldt. P.. Arner. P.. Bolinde,. J .• and o.tman.
J. Pho<ph(KiiCltcrase Aeti.ity in H uman Sub<u-
tane"". Adipose Tissue in In,ulin_ and Nonin,u·
lin· Dependent Di.bet", Melli!u$. J. C/iw. End",
"i""l. Me/ob. 55: 983_8. 1982.
47 . Evain.Brion. D.. Garnier. P., SChimpf!". R. M ..
O •• u,,,,in. 1. I. ... nd J<>b. J. C Gmwth Ilo,mone
Respon.eto Thyrolropin.Relca.ing H<>r_ .nd
Oral Glu""""to.ding In Tall Children and Ad·
l>leseents. j, Clin, Endocrinol. M,.,,,bl, 56: 429_
32.198).
48. Evan •. R. M .. Bircnberg. N. C .. and [{"""nfeld.
M. G. Glucocorticoid .nd Thymid Hormon ..
Transcriptionall}' Regulate Growth Hormone
Gene E.p"".ion . Proc. NIJI/. Acad. Sri. USA 79:
7659-63. 1982.
49. r ",reSl. J, N .. Jr.. Reichlin. S .• and Goodman. D.
B. p, Som.lostatin: An Endogenous Peplide in the
Toad Urinar)' BI .d der Inhibi" Vasopre" in.Stim.
ul.1O<1 Water Flow. Proc. Na'i. Acad. Sci, USA
77:4984_7. 1980.
SO, Friesen. H. G. Raben I.«lur. 1980: A Tole of
Stature, IindocrilOOJ. R, •. /: 309_18.1980.
51. GI."coc<. G. r .. ond Nicoll. C. S . I!",monal
Control of Gmwlh in the lnfaOl Rat. t:ndoaino/,
/09: 176-84. 1981.
52. Gluckm.n. P. D.. Grumb.ch. M. M .. and Kaplan,
S. L Th< Hum.n Fetal Hypothalamu . aod Pitu·
itar)' Gland: Tho Malu'ation of Neuro<ndocrin<
Meeh.ni.m. Controllina the Secretion of Fetal
Pituitary Growth 11",,,,,,,,,,. P,<>i.ction. Gonad.,.
tropin. and Adre""""rlie<>tropin.Related Pcp-
tide. , Chap. II. Pl'. 1%-232 of Tukhin.<)'. D.•
and Ryan. K. J .. ed ... Mal.mal-Fe/al t:ndoc,j-
IOOJOV'. Saunder •. Philade lphi •. 1980.
53 . Goldstein. A. L .. Low. T. L. K.. Thurman. G. B..
Zall. M. M .. Hall. K. Chen. J.. Hu. S. ·K .. 1".)'.
lor. P. B.. and McClure. 1. E, Current Slatu. of
Thymosin and O,he' Hormone' of 'ho Thymu,
Gland, R«. Prog. l/t)Tm. lUck. J7: 369-412.
1981.
54 . Goldstein J .. Van Caute,. E. V.. Dbir. D.. Noel.

P .• Spire. J. _P., Refet""', S .. and Copil'l>hci. G.
EffcClS of "Jet Log" on Hormonal Palt.rn •. IV.
T ime Shifts Increase Growth Hormone Release.
J. Clin. Endocrinoi. 56: 4JJ-440. 1983.
SS. Goodm.n. H. M .. and Coiro. V. EffeeuofGrol<'th
Hormone on Adil><'" Tissue of Weanli ng R.t>.
Endocrino/, 109: 2046- 53. 1981.
56. Goodm.n. H. M.•• nd C,itohing,G. Growth Hor-
mone and Lipolysis: 1\ Ree'aluation, t:ndocrino/.
113: 1696_1702, 1983,
57. Goodman. R. Il .. Jacob,. J. W.. Chin. W. W..
Lund. P. K" Dee, P. c.. ond Ilobener. J. f. Nu_
cleotide Sequence of • Cloned
Cooing fo r a Pr<:eursor of Pancre.tic Somoto--
".t in. Proc. Nml. Arod. Sci. USA 77: 5869-73.
1980.
58. Gregerm. n. R. I" and Bierm.n. E. L Aging and
Hor""",,,,. Chap. 29. pp, 1192-1 217 of William •.
ed., referen« I 71.
59. G "illeman. R. Hypothalamie Peptide. Regulating
tho Secr<:tion of Growth Ilormooe : Growth Hor_
Jl10Ile Relea.ing faCtor, pp. 139-143 of Raiti. ed ..
referenoc 124.
60. Guillomin. R .. Brueau. P.. BOhlen. p .. Esch. F..
Lina , N ... nd Wehrenberg. W. B. Growth Hor-
mone- Releasing Facto, from a Human
Tu""" that Ca u,od Acromegaly. Sci,'W 218.-
58S_7.1982 .
61. Hapgood. J .. Libermann. T. A.. Lax. I.. y."kn,
V .. Schr<:iber, A, B., Naor, Z .. and Schl.ssill!ter.
J. MOr>O<lonai Antibodies Against Epidermal
Growth Faotor Receptor Induoc Prolaetin Syn-
the,i , in Cultured Pituitary Cell, (Gil,). Pro<.
Na!l. ANJd. Sri. USA 80: 6451 - 55. 1983.
62. HUdbooher. G, .• nd Humbel, R., Evidonce for
Two Species of In,ulin-li ke Growth Faotor II
(IGF II .nd "Big" IGF II) in Human Spinal
Fluid. t:ndo",ill()i. 110: 1824-32. 1982.
61. Heldin . C.·H .. Waste...".. A. Fryklynd, L. and
Westermark. B. $omatomedin B: Mitosenk Ac.-
tivity Deri.ed from Contaminant Epidermal
GrOWth Factor. ]13: 1122-3. 1981.
64. Herington. A. C.. and KnlTer. A. D. Identi fication
of a Specific Inhibitor of Non<upp""'ible In<ul in-
Like Aeti'ity in • Parti.lly Purified Human
Serum Frootion, Hndl)<:rino/. 109:1634-40. 1981.
65. Hill, D. 1-. Pouer, J . M .. Cullen. D. R .. Ind Mil·
net. R. D. G. Rapid Changes in $omatomedin
Aotivity during In,ulin- Induced Hypoglycemia:
Possible Relea.., of an Inhibitory Factor. J. Clin,
Endl)<:,ino/. 53: 4)9-42. 1981.
66. Itinl>. R. L., and Li u, F. A Radioimmunoa ..... y
for In.ulin-Li ke Growth Faotor I I Specifio for the
C-Peptide Region . J. Clin. Endl)<:,iNJi. 5#:
442-6. 1982.
67 , lIin". R. L. Liu. F. RO$Cnfcld. R. G .. atKl
Kemp. S . F. Plu ma Somatomedin·Binding Pro-
leins In Hypopit"itari.m: Ch.nges during Growth
Hormone ne .. py. J, Clin, t:ndlX' ;noi. MnQb.
53: 100----4. 1981.
GFIOWTrI rlORMONES AND SOMATOIA EOINS
68. Honeym.n. T. W.. and Goodman. II . M, Effects
of Gro,... h Hormone On Glycogen in
Adirose Tissue of Itypophy..,ctomize<l Rats.
Am". J. 238.- £ JS9_E394, 1980.
69. Howard. M ... nd Paul. W, E. Regulation of B·
Cell Growth and Differentiation by Solu ble F.c_
tors. Ann . Rev. Immunol. I: 307-33. 1983.
70. Hubbard. J. R., and Liberti. J. P. Regulation of
Cartilage I\cid Hydrol .. e. by Growth Hormone.
t·nd(J(rino/. 110: 1483. 1982.
71. lIughe •. J . P .. Tokuh iro. E.. Simp$On. J. S. 1\ ..
and Friesen. H, G. 20K is Bound with lIi,gh Amn-
ity by On. Rat and One of T",'o Rabbit Growth
Hormone Receptors. Endocri""l, 113: 1904- 6.
1983-
72. lsa kuen. 0 , G. P.. Janue". J ,-O .. and Gause. I.
A. M. Growth Hormone Stimul.t.. l.ongitudin.1
Bone Growth Directly. SdmN 116: 1237-9.
1982.
73. [lVanaga, T., Ito. S" Yamad • . Y.. and Fujita, T.
Cytochemioal Demonmalion of Somatostatin 28_
(1-14)-Like in the Rat Hy!»
thal.mu, .nd Gastero-Entero-Pancreatic End()-
crincSy"em . EndocrinoL 113: IS39_1844.1983.
74. Jansson. J, -0 .. Eden. S .. and Isak...,n.O. Sites
of Action of TC$tosterone and I'.otradiol on u.n-
giludinal Bone Growth . Am". J. Phy. i"', 244:
!;1J5- EI40, 1983 .
75. Klhn . C. R .. Baird . K. L.. J . S ..
C .. Harmon. J, T .. H.rri...".. I.. c._Karl...,n. F.
A.. Ka,us •. M .. King. G, l .. Lang. U, C. Pod-
, kalny. J, M,. and Van Obberghen . E, In,ulin Re_
ceptors. Receptor Antibodie .. and tile Mochani'm
of Aetion of 11IS"lin. Prot. lIorm, 37:
477-533. 1981.
16. Kasting, N. W.. M.rIin. J . B.. and Arnold, M. A.
Pulsatile $om.tO$t.tin Release from the Medi.n
Emincnce of the Unane.lhetized Rat and ito Re·
lationship to PI.sma Growth Hotmone u,ei •.
t:ndlXrillOl, 109: 1739-44. 1981.
77. K",u83.. M .. Van Obber,ghen, E.. Nissley, S, P.,
.nd Roehlet. M. M. Structure of th. In,ulin-Like
Growth Fae,or Receptor in Chicken Embryo Fi_
brobl ..... Proc, Noll. Acod, Sd USA 79: 1864-8,
1992.
78. Katakami. H.. Kato. Y ., M.tsushita, N .. Shi_
m.tsu. A., and Imura. II, Posoible lnwl'ement of
'Y'Aminobutyrk Aoid in Growth Hormone Re-
le.se Induced by • Met' -Enkephalin An.1og in
Conscious Rat., t"ndO(rino/. 109: 10]3-6. 1981.
79. Khorr.m. 0., DePaI.tis. L R._ and McC.nn. S.
M. Development of Hypothalamic Control of
Gro"'th Hormone Secmion in the Rat. £ndoc, j-
Il0l.111: 720-8, 1983.
SO. Koobi!. E.. and Sawyer. W. B.. edo. Handbook 0/
Physiology. ,.C. 7. vol. 4. part 2. American Phys-
iologic.l Society. W.. hington. D. c.. 1974.
81. K"'tYQ. J, L.. and 1.... eson, O. Growth Ilormone
and 'he Regulation of $omatic Growth. 1m""",.
R,., Physiol. JJ: 255- 74. 1977.
82, Kostyo. J. 1... aOO Nutting, D, F, Growtb Hor·
mone and PrOtein Metabolism. Chap, 29. pp.
187-2 10 of Koobil and Sawyer. ed, .. reference
83. "'
Kraieer. J ... nd Spence. J. W. Rei .... of Growth
H<>rmon< from Purir.ed Somatotroph" Uk of
High K ' and tile lonopllore A23187 to Elucidat.
Interrelation,hips Among C. ·· . Ad.nosin. l'S·
Mooopbosphate and SornOlOStalin. Endoc,inoi.
108:651-7.1981.
84. Krulich. L. Mayfield. M. A.. Steel •. M. K.•
McMill.n. B. A.. McCann. S, N .. and Koenig. J.
I. Differenti.l ElfeclSof Pharmacological Manip.-
ul.tion, of Cen"al " I ' .00 a,· Adrenergic Reo.p-
tOr$ on tbe Secrel;on of Th}'r<;>lropin and Growth
lIormono in Malc R.... t::nd(X,inoi. 110: 796_
804.1982.
85, Kyle. C. V .. E.. n•. M . C .. and Odell. W. D.
Growlh Hormone·l.i ke Malorial in Normal
flnman Ti l'u",. J. Clio. t::nd(X,;noi. Me/ab, j3;
1138- 44.198 1.
86. Lan. N. C .. Matulich . D. T. Mord •. J . A.. and
B"'ter. J. D. Mineralocorticoid Receptor.Like
Aldosterone· Binding Prolein in Cell Cuhure. E,..
doc,inoi. /09: 1%3-70. 1980.
87. Loch.n. R, M .. M<>Iitch. M. E.• • nd Jackson. L
M. D. Di'tribution of Immuoor.acth'. Human
Gro"'th Hormone-Like Maleri ol and Thyrolro-
pin.Relea.ing Hormone in the Rat Central Ncr-
'00' System: E.idcnc. f<>r their Coexistence in
Ihe Same Ncuron •. End(X,inoi. Ill: 877_84.
1983.
88. Lechan. R. M.. t'c<tler. J. 1... and Mol ilch, M. E,
Identification of a Novel
Substance with Human Growth Hormone-Like
Immunoreactivity in Rat Brain. 109:
1950-62.198 1.
89, l.emke. G. E.. ond Brockes. J. p, Gli.1 Growlh
Factor: A MitOjlenic Pol}'p<i>1ide of the Brain .nd
Piluitar),. rtd, Pn>c. 42: 2627_9. 1983.
90. Lepp<fl. P .. Guillory. V. J .. Rosso. I.. J .. and
Moore. W . V, In Vi"o Effect of Hum.n Gmw,h
Hormone on Hep"ic Adenyl.,c Cycl • .., Activity.
109: 990---5.1981.
91. Lewin. M, J. M.. Rcyl.Oc.maf$. F.. and Ling. N.
Somatocrinin Rcceptor Coupled wilh cAMP-De·
pendon, Prolein Kina .. on Anltrior Piluilary
Gr,nules. Proc. Nail. Acad. Sri. USA 80: 6538-
41. 1983,
92. Lewis. U. J.. Singh, R. N . P.• Tutwilcl. G. F..
Sigel. M. B.. Vander Laan. E. F.. and Vander
Laan. W. P. Human Growlh Hormone: A Com·
pl.' <:>f PTOtei"'. R«. Prog. lI",m. Rsrh. 36: 477_
504. 1980.
93. Li. C. H. in the Chemical Bi-
<>108,1-' of lIormon ... Puspt<:ri,", Bi<:>. Mtd. II:
49g. 1968.
94. Ligum,ky. M.. GOto. V .. Deb.,. H .. aOO Yamada,
T. P,ost.glaOOin$ Mediale InhibitK1n of Ga$lric
Acid Secr.,,,," b)' Somalosmin in th. Rat. Sri·
tI.tt 1/9: 101 _3. 1983.
95. Loren,,>n. M. V. and Jacobs. l. S, Thiol Regul.-
lion of Prot.in. Growth Hormone. and Prolactin
Rde'k from Isolated Adeoohypophysial Secre-
lory Granul.,. /;,'ndoc';noi, I/O: I 164-72. 1982.
Lowry. P. J.. Sila •. L.. McLean, c.. Linton, E. A..
96.
• nd F.$,iv.. i,. E. E. Pro----r-Melanocyte-$timul ...
ing H<>rmone Cleavage in Adrenal Gland
Undergoing Compen<alory Hypertrophy. Naturt
306: 70-3. 1983.
97. Luna. A, M.. Wilson. D, M .. Wibbol.man. C. 1..
Brown. R. C .. Naga,him •. R. J .• Hintz. R, L.
and Rosenfcld. R. G, Somatomedins in Adole ..
cenCe: A CrQ<s.sectional Study of the Elfect of
Pubefl),on Pla,ma In,ulin-Like Growth Factor!
and [I Level •. J. Clin. Endocrine!. Metab. 57:
268-271. 1983.
98. M,cG<>rman, L R .. RizZll. R. A.. and GeriCh. J .
E, Ph)',iological Concentration, of Growth Hor·
monc bon In,ulin-Like and I n,ulin Anl'gonistic
Elfec" on Both flepalie and Extra·hepatie Ti ..
,uc. in Man, J. C/in, I::ndoc'illOl. Mtlab, 51: 556-
9.1981.
99. Mad""n, K.. Friberg. U.. Roo<. $ .. Ed';n. S. and
I"'''<on. O. Growth H<>rmonc Slimulate, lbe
Prolif.rat;on 01" Cuil.red Ch<:>ndrocyto. from
R.bbit Ear and Rat Rib Growth Cartilage. Na-
ture 304: 545-7. ln3.
100. Marcovi!>. S .. Goodyer. C. G .. Guyda. H .. Gar-
diner. R. J .. and Hardy. J . Comparative Study of
Hum.n Fet.l. Normal Adult. and Somalotropic
Adenom. Pituitary Function in Ti,sue Culture. J,
I:"ndoc,illOl. Mnab 54: 6-16. 1982.
tOI. M8fl;.-.. J, 8 . 8m;.-. R<gulot;on of Crowth Hor
mone Secretion. F",,,,iers 4:
129_68.1976,
102. Martin. J. B.. llrazc.u. P.. Tannenbaum. G. S ..
Willoughby, J. 0 .. Epelbaum J .. Terry. L. C .. and
Durand. D. Ncur<>cndC)Crine Or8aniulion of
Growth Hormone Regulation. pp. 329-55 of
Reichlin. S .. Bald«<atini. R, J .. and Martin. J.
B.. ed ... Hypolholomu•. R..en Pre .., New
York. 1978.
103. Matsu lhi... /01 .. Kato. V .. Kalakami. H.• Shi·
n,."u. A.. Vana ihara. N... nd lmu ... H. Stimu·
lation of Growth Hormone Rde .se by Vasoactive
lnto5lin.1 P<:>iypcpt ide from !luman Pituit.ry Ad·
eoomos in Vitro. 1. M.tab. 53:
1297_1300.1981.
104. M.ugh. T. It II. Human Skeletal Growth Faetor
I<olated . Sci,,,u 117: 819.1982.
105. McCann. S. M. Physiology and Pharmacology of
I.HRfl .nd Somalostalin. Ann, Rtv, PhuTmarol,
T()Xic<:>l. 12: 491_515.1982.
106. McCann. S. M .. Krulick. 1... OJ.d •. S. R .. N.gr""
Vii ... A .. and Vij.)ean. E. Neurotransmitters in
the Control of Ant.rior Pituitary Function. pp.
329_47 of Fu,c. K.. 1l0kfell. T .• and Luft. R.•
cds .. CtnlTa/ of Ihe I:"ndOC'iM S,S/em.
Plenum Pro ... New York. 1979.
107. Mendelson. W. B.• Jacobs, L. S .. and Gillin. J. C.
Negali.e Feedback Supp...."'" of Slccp-Related
Growth H<>rmonc Sc<:rction. J. elin. EndtXTinoi.
Mtlub. 56:486--8, 1983.
'"
108. Mendo]",". W. B.• Lantigaa, R. A.. Wyall, R. J..
Gillin. J. C, and joC<)b •• L. S. Pipcridinc F.n·
ha""., SI""p-RcI'lcd and l!I$ulin_ lodu<;¢d
Hermon< Secretion : FUrlhe, Evidence for
o ChaliFICTgi. Secretory M•• h3ni.m. J. Clin. /::".
dlX"ooI. /IIt/ab. 51:409-15, 1981.
109. Mcrimoc. T. J .• Zapr. J.• and Froesoh. E. R. In·
su lin-li ke Growlh ract"'" in the red and Fa'ted
Stale •. J. Hnd(}(YiMi, MtlQb. 55: 999_1002.
1982.
I 10. Me),e.., C. fl. .• MUrphy. W, fl. .• Redding. T .• Coy.
D . H .•• nd Schall)" A . V, Synlhe.isand B;ologic.,
A.lion. of Prosomaloo1alin. Pro<:. NOli. A«(ld. Sci.
USA 77:6171 - 4. 1980.
111. M i,bin. R. t, Almi .... E. C. DudwQrlh, W. C ..
and Mehl. T. D. Inhibilion of [n,uTin o.,••
dolion
by r ",ulin·li ke GrOWlh FaCtor,. End<>erinoi. 11):
ISIS-IS27.198).
112. MooI ••• "., W . H .. T"en, R. Y..• an dc r Sao&- P.
T .• and de la.t. S. W. No' / H - b oh.ngo and
C)"t<>plasm;c pH in the Act;"" of Growth Factors
in Human Fibroblast,. Nature 304: 645-8.1983.
113. Moo< •• D. D.• Walker. M. D.• Diamond. D. J.•
Con kl ing. M. A. and Goodman. n M . Struct ure.
Exp,ossion. and Evolut iOn of Growth Hormone
Gene •. Prot. I/orm. Rsch . 38: 191_222.
1982.
\ \ 4. E. E.. Cocchi. D.• locatelli. V.. Parati. E-
A.. and Mantc,""" P. Ncurotran,mia.r Con·
lrol of Growth and Prolaclin Soe,.tion.
pp. 417_56 of Fuxc. R.• HoHch. T .• and lufl. R.
od, .. Cmuol of tho l:.·ndtXriM Syst"'l.
Plenum. Ne ... York. 1979.
115. Murphy. I.. J .. Vrhov,d. E. a nd la'",ru •• l.
Characterization of Specific Gro,,·th Horm""e
Binding $it« in MOIl« Fibrobla .... Endocri""'.
1\3: 750-7. 1983.
11 6. Ol .. ltaw. N. E. and Pledger. W. J . As.<oci3tionof
Platelet·Derived Growth F.et.,...l nducod Protein
wilh Nuclear Material. Nat ure J06: 212_4. 1983.
117. O w.rl>ach. D.• Ruaer. W. J.. Martial. J. A.. and
Sh",,· •. T. B. Gene, for Growth Hormone. Cho-
rionic Som.tomammo<ropin. a nd Growlh HOf·
mone·Like G ene"" Chromosome 17 in Human •.
109: 2g9_92. 1990.
118. Parker. D. C .. Rossm.n. I.. G .• Kripke. D. F .•
Gib",n. W .. and Wi l"'n. K. Rhythmieiti« in
Hum.n Growlh Hormone Concentration. in
Plasm •. pp. 14 3-73 of Krlogc • . D. T .. ed .• t:"da-
rriM Rh,.,hms. Raven Pr.". New Y or\:. 1979.
119. Patel. Y. C .• Wheatley. T .• arid Ning. C. Multiple
Form. of Immunoreactive Somat""l.,in: Com·
pari",n of OiSlribution in Neura l arid Nonneural
Ti .. ue, arid Portal Pla<ma of lbc Rat. ffnlitX'inoi.
109: 1943_9. 1981.
120. Pavlaki,. G. V.. Hi,u k•. t>: •• Gorden. 0 .. Stobur,.
R. and Hamer. D. H. Exp, ... ion or Two Human
Growth G.ne. in Mon ke)" Cell, In·
fected by Simian Vi ru, 40 Recomb in."". P,tX.
Nail. A{",Jd. Sci. 78- 7398-7402. 1981.
GROWTH HORMONES ... NO SOM ...TOMEOIN$
121. Phillip,. J. A.. II I.. Hjell •• 8 . 1... Soebu " , P. H.•
>nd Zac hm.nn. M. Molecular 8..i. ror Familial
lsolatod G rowth IJormon< Deficiency. PrO<:. N'lTl.
Acad. Sci. USA 78: 6372-5. 1981.
122. Pol)"ehronakoo. c., Guyd •. H. J.• and Posner. B.
I. ReccptofS for In,ulin·like Growth Factors on
Human Erylhrocyte. J. Clin. EndtX,i"f)/.
1983.
123. Quabbc. H. .J.. Gregor. M .. Buml.,.Vogt. C ..
Eckhor. A .•• nd Witt. I. T,,·.nty·Four·Hour Pat·
lorn of G rowlh Horrnonc &':retion in the Rho, u,
Monkey, Studies Including Alteration. of the
Sleep/Wa ke and Sloop Stage Cycles. t:nd"",jnol.
109:513-22.1981.
124. Raiti. S. cd. Ad,wlNs In I/uman Gm..·th 1101'-
mOM DHEW Publication {NIH} #74·
612. Wa.hington. D.C.. 1974.
125. Raiti. S. Clinical Studies with Human Som.totro-
pin. pp. 309-19 of Bec ... R. F.• Jr .. • rId B....U.
O. H .. cd, .. l/omWNs. Pres ••
New York. 19813.
126. Ramaley. J. A.. arid Phares. C. K. Delay of Pu·
berty Onsel in Females d ue to Suppression of
Growth Hormone. t.·natX, in<>l. 106: 1989-93.
1980.
127. Rcch1cr. M. M .. 7..l1pf.J .• Ni,,1cy. P.. Froeseh. E.
R.. M""es. A. c.. Pod,kal ny. J. M .• Sohilling. E.
E.. and Humbel. R. E. Inleraclion, of In,ulin'
Like Growth Fact"" I and II. nd Mulliplication·
Sl;mul. l;ng ..... Cl;v;ly w;lh Reccpto .. and So<um
Carrkr Prot<in •. end"",.iMl. 107: 1451-9. 1980.
128. Reiohlin. S. Neuro<ndocrioology. Chap. II. pp.
588-645. Willi. m•• ed .. reference 111.
119. Riohard"'n. S. B.. Hollarlder. C. S .. Prasad. J . .......
and Hirooka. Y. Somat"",.. in Relea", from Rat
Hypoth.l.mu. in Vitro: Effect. of Melatonin arid
Serotonin. endocrinol. 109: 1102-6. 1981.
1313. Rivier. J .• Spi .... J .. Thorner. M .. and V.Io. W .
Choraet eriMtion of • Growth Hormone·Releas·
ing Faotor from • Hum.n p.n<:rcal ic 1, Iet Tu-
moor. 300: 276-8. 1982.
131 . Robbin •. R. J .• and Reichlin.S. SomatOStati n Bio-
,ynthesis by .. 1 in Monolayer
Culture . EndocriMi. 111: S74_81. 198].
13 1A. Roben,. A. B.. C. A .. An,,,,no. M. A.. and
Sporn. M. B. Transforming Growth Factors from
Neoplastic and Nonneoplastic Tin ue<. F,d. PrO<.".
41:2621-6.1983.
1)2. Rosenfeld. R. G .. Kemp. S. F.• and Hin!>.. R. L.
C""'laney of Somatomed;n R.. pon", 10 Growth
Hormone T reatment of HypopituilO IY Ow.rfi,m.
and of Correlat ion wilh Growtb Ralc. J.
C/in. £nd""rinoi. jJ: 61 1- 17. 1991.
IH. Rosen7.wo;g. J. 1... le Roilh. D.. lesn;. k, M........
Mae lnt)·re. I.. Sa"·)"cr. W. B .. and Roth. J. Two
Di,ti nCtive In,,,lin. in the Guinea Pig: The Broad
Rekv.ncc of The .. Firlding, to Evol" lion of
Peptide Hormones. Fd PrO<:. 4]: 2608_14,
1983.
134. Roth. R. A.. and Cassell. D. J. [nsul in Receptor:
 EvidenceThat It Is a Protein Kinase , 119.-
199_301.1983.
135. Rubin. J. B.. Shia. M, A .. and PiTch. F, P. Stirn-
ul"ion of Tym<ine-Spoeifie Phosph<>rylatioo ,n
vitro by Insulin·Lik. Growth Foetor I.
J05. 438-40. 1983.
136. Rubin. J. 5 .. Mari •. l.,Jaeob$. J, W.. Daughaday.
W. 11 .. and Brad,ha"'. R, A Isolation and Partial
Seque""e Analysi, of Ral Ba.ic Basic Somal<>-
medin , EndoNinoi, 110: 734- 40. 1982,
137. Rudner. D .. Kutner. M, H .• GOldsmith. M. A..
Kenny. J,. Jenn;ngo. H.. and Bain. R. P. Fullher
Obsc,vations On Four Subgroups of Normal Var;·
ant Short Stature. J. Clin. Endom·/IOI. 51:
137S_84.1980.
138. Sa ra. v. R.• H.11. K.• Rodetk. C. fl.. and WeI'
te,berg. l.. Human Embryonic Som.tomedin.
Pm< Nail. Acad. Sri. USA 78: 317S-9. 1981.
139. Sora. V. R.. Hall. K.. and Welterberg. L.. ed ...
Growlh Ho,mo"" Dependenl Polypepl ides and
Ihe 8 .. in, pp. 63-72 of de Wied. 0 .. and .an
Keep. p, A .. edo.. lIoml(""s arrd Brain. Uni·
verSi ly Park P",.". 1Iallimore. 1980.
140, Schally. A. V.. Hu.ng. W._Y .. Chang. R. C. C .
Arimuro. A .. R",1ding. T. W .• Millar. R. p .. Hun·
kapi lkr. M. W.. and Hood. L. E, lsolalion and
Struclure of Pro-Somal<>olatin: A l'uI.,iye $0-
mal",,,,in P,ocu""r from Pig Hypolh.l.mus.
Pf"()('. Nail. Arad, Sri. USA 77: 4489_93. 1980,
141. Schoonl • . E.. 7.apf. J.. and FToe.ch. E. R. In Vivo
Control.,.. In,ulinoSen';I,'e Ph<>ophodiestora", in
Ral Adipocy'e. b)' Grow'h Hot"""",.nd h. Po<.
• lIeli.m 10 Glucose Tran,port . t::ndO<",lnoi. 109:
561-6.1981.
142. Sohoonlo. E.• 2.pr. J.• H umbel. R. E .. and
F"""d. E. R, 1",.l in·Like Growlh Faclot I
Stimulate. GrOWlh in Ral>,
196: 252-3. 1982.
143. Schoob,unn. A.• GIUC<lCOrlicoid, o",,·n.RC8.lato
Somatostatin Receplorson Pituilary Cell' in Cul-
lure. t·ndO<",;/IOI. 110; I 147_54. 1982,
144. ScebUTg. P. H . S"uc'.ro and Regulation of Pi-
lu i'ar)" Hormone Ge"",. Chap. S. Pl'. 19-3 1 of
Boo .... R. F.. Jr. .• nd Bassen. D. H.. .. Poly-
I"Plid. HOI"mMl", Ra"on Pre". New York. 1980.
145, Shoote,. E. M.. Han k""r. B. A .• Landrelh. G. E..
and SUller. A. Oiosynlhe,i, and Meehani,m of
AClion of Nerve Growlh Fact"'. R«. Prog.
IIfNm. 37.- 41 7-37. 1981.
146. Silvc. c.. Lieberh .... M,. Garabedian. M .. Guil·
101.0, J .. 0""",", 11. . Tbil. C. Land Bal.. n, S . So-
m'IO$ta\in and Vitamin OJ Motaboliles in Ral
C.I'a,ium : In Vitro Evidence fot Physioloflioal
Inleraolion . t::m/""rinoi. 109: 14S4-62. 198 1.
147. Soderquist. A, M.. and Carponto,. G, Develop-
ments in Ihe Mechani,ms of GTOWlh F.clOT Ac·
lion: Activ.tion of Protein Kina", by Epidermal
GTo"lh Faolot. hd. PrO<". 41: 261S-20. 1983.
148. Seren",". K. V.. Christensen. S. E .. II . n",n. A,
1'.. Inao ... lo)'. J .. Pede"",", E .. and O... ko,.IL The
Origin of Ce rebrospinal Fluid Somat"'latin,
HYpolhalamk or Disperse Central No,"ous
System Secreti",,? N'''fMm/O<",iltOl. Jl; 13S-8.
1981.
149. Sp<ncor. E, M .. le"';,. L. J,.and lewi$. U. J. So-
malomedin Genorating AOI;,i'y of 'he 20.000--
Dalton V.rianl of Human Growlh H",mone. E"..
dO<"rlnoi. 109: 1301_2. 1981.
ISO. Sp<ocer. E. M ... nd Tobi.sscn. 0, The Mecha-
nism of Iho Action of Growth H",mone on Vi,.·
min D Metabolism in 'he Rat. ENi"",;noi, lOS:
1064-70.1981.
151. Spiegel, K.. Koorideo. 1. A .. and Pasternak. G, W,
Prolaclin and GTowlh Hormone Rele..., by Mo,-
phine in lhe Rat: Different Rocepl'" Mechani.m•.
IH. Spiess. J .. Rivicr. J .• and Vale. W. Charooleri,,,,,·
lion of Ral Hypothalamic Growth Hormone-Re-
lo •• ing Fact"', 303: 532-S. 1983.
I H . Srikant. C. B" and Patel. Y. C. Re«plor Binding
of Somatostatin·28 i. Tissue Sp<cifie, l'U:
259- 60, 198 I.
I S4. Tabha'hi. Y.. Ebihar •. 5 .. Nakamu,a. Y.. and
T.k.ha •• i. K. A Model of Human Sleep-Relaled
Gro .... lh Hormooe $<;<:r<tion in Effects of 3.
6. and 12 Hoo ... of Foreod Wakefulne .. 00
Plasm. U",monc . Cortisol. and Sleep
Stage •. t::nd",,';noi. 109: 261-72. 1981.
ISS. Tate",,"'o. K.. and Mult . V. ISOl1lioo and Char·
acteTi>atioo of the I nte .. i.al Peptide Po,cine PH I
(PIII·27). a New Member of the Glue.gon·Se·
cretin Family. P"x. Nail, Mdd. Sci. USA 78:
6603_7.1981.
T'j'lor. W . L . Collie •• K. J .• o..eh<nn. R . J .•
Weith. fI, 1... and Dixon. J . E. Sequence Analysis
of. eDNA Coding for. PancTeatio Procursor to
Somatoslalin, P,O<", Nail. Arod, Sci, USA 78:
6694-8. InL
157. Terry. L. C..and Marlin. J . B. The Effemof lat-
eral tlypothalamic--Modial Fo",brain Slim"l.,i""
and &>",aloslatin Anli.trum on Pul .. tilo Growth
U",mono Sec,etion in Fleely 8cha'ing Ra ..: Ev.
idence for Dual Regulalory Meohani'm. Endor,;·
Il0l.109:622-7.1981.
15K -rhody. A. J . MSH Peplid-.. Academic PTe».
New York. 1980.
159. T,ai. J. S .• and Pasqua!. A. Effecl of Bromocrip-
tine on Th)"oid Hormone Induced G rowlh Hor·
mone Production in Cultured GH , Cells. t ·ru/o-
c,lnol. 109: 1306_8. 1981.
lbO. Underwood. L. £.. and Van Wyk. J. J. Hormones
in Normal and Aberrant Growlh . Ch .p. 28. Pl'.
I 149_91 of William<. cd .. r.forence 171.
161. Van Arsdel. P. P.. J,. Allerg),. Immunol<>gy and
Hormone •. Chap. 7S. pp. 1108_14 of William •.
ed .. ",reronee 17 I.
162. Van don Brande. J. L. and Du C.ju. M. V. L.
Pla,,,," Somalomodin Activil)' in Child"," "'ith
Growlh Di".rbanoc;. PI', 98-115 of Raili. ed ..
referenee 124.
163. Van Ital!i., C. M.. and forn'trom. J. D. In Vi",
Studies of SO",",<>ot31in·14 and Somatos'atin·28
Bi",)'nlhesi. in Rat Hypothalamus, t-ndlX'inoi.
10: 1210-17. 1983.
."
164. Van Wyk. J. 1.. .nd Underwood, L E. The So-
matom<din. and nei, "elions. B/(}(htm, AU/oil.<
1/",,,,,5: 101-48.
165. V... ilopoulou.sellin. R ... 00 Phillips. l. S. E. ·
traction of $om.tom.din Activity from Rat Li •• r.
EndlX' (If()/. 110: 582-9. 1982
166. Walli •. M. Molecular Ba.i, of Growth Hormone
Defidc"0'. 296: 112-111. 19&2.
167. Webb. C. B.• Szabo. M.. and Frohmann. l. A.
Ectopic Growth Hormone-Releuina Foctor and
Dibutyryl Cy<:lic Adc_ioe Monophosphale-
Slimuiotcd a", ... ,h I!ofmone Rel.a •• in Vitro: Ef·
rect. of COfliCQ$lerone and Es\ , adi<>l. I::""ocrinoJ.
111: 1191_6. 1983.
168. Webb, C, 8., Thorni ..!. J. L. and Frohma n. L.
A. Ectopic Growth Hormone Releasing Factor
A·I . G.13to, M. C, P."ovil •. O. 1\ .• Cas.sorla. F.. Lor·
iau • . D. L.. and Merri.m, G. R. DMe_Re.pon.e
Relal;on.hips for lh. EIf.clsor Growth Hormone-
Rcle •• ing fac\or.(I..j4)-NH, in Yoong Aduh
M.n and Women. J. Clin. Ende><, ilt()l. M"ab. 59:
19 7_201. 1984.
A·2 . S,i.s.nden. 1. E., Ullrieh, A .. and Fro ncl;c. U.
!luman Chromosomal Mappin, of Gene, f<>t In-
,uln·Like Growth Factors I and II and Epidermal
Growth Factor. Na/u" 310: 781-4 1984.
A_). Hill. D. J .• Wa'"",. R,. and Mil""" R. D. G . 30-
matomedin ACtivity in Traeheal Fluid from Ihe
Newborn Infanl. J, Clin. £ndoailt()l. 59:
231 _4,1984.
A..j, Goody ... C. G .. de Stephan<>. Lai. W. H .. Guyda.
H, J ., and Poonu, B. I. Cbarae.eri :tation of I",u·
lin-Like Growlh Facl'" Receplors in Rat Ante·
rior Pituitary. Hyp>pthalamu,. and Brain. I::nd<>-
<rilt()l. 1/4: 1187-95, 1984.
A-S, Ikeda. II .. Mit.uha,hi. T .• Kubat •. K.. Ku,"Y".
N .. and Uehi mura, H. Epidermal Growth Factor
Stimulat •• Growlh H"""one Secretion from Su-
p<,fu<Cd Rat Adenohyp::>phy.ial Fragments. En-
dor,;It()I. 115: 556-8, 1984,
GROWTH HORMONES ... NO SOM ... TOMEOINS
Stimulat.. Growlh Hormone Role.", from
Human Som.totroph Adenoma. in Vilto, J. C/in.
!::ndor,inoJ. Mtlab. 56: 41 7_19. 1983.
169. Wehrenberg. W. B.• Baird. A.. and ling. N. P<>-
ton, Interaction Bt,w.. n Glucocorticoid. and
Growlh Hormone-ReleMin, Fael'" in vivo. Sd-
mU ]]/.- H6_8. 1983.
110. Wilhelmi. A. E Chemi<try of Growth Hor"",ne.
Chap. 23. pp. 59- 18 of Knobil and Sawyer. ed •..
r.fo",n« 80.
I?!. William'. R. H.. ed. Tnr/xXlk 0/ Ende><rinoJOV
6,h cd . Saunde ... Phil.delphi •. 1981.
In. Zipf, W . 8.. Kelch, R, P" Floyd. J. C. and HOp-
""'ood. N. J. Gro,,"'th Hormone Suppr ... ion of
Pancrea,ic Polypeptide Secre,ion. J. CIi•. Enda-
M./aM. 52: 574-9.1981.
A·6. Lewi •• U. J, Variant. of Growth Hormone and
Prolactin and .heir Pos",-,lIl$lationol
I;on •. R..,. PltyJiol. 46: 33-4Z. 1984 .
A·], Ling. N.. Esch. F.. Bohlen. P.. Bra,eau, p, j.
Wehr<:nber,. W , B.. and Guillemin, R, Isolation.
Primary Structu .... and Synlhe," of Hum,n H)'_
path.l.mie Samotocrin;n: Grow,h H<>tmone·Re.
l...i", Factor. Pro<, No/I, Sd. USA 81:
4302-6.1984.
A-S. I.;n,. r. D. L H.. and Nathan •. D. NuclOOlide lie.
que""e of . Gw .. ,h·R<la'ed ",RNA E olC<;J<li"K'
Member of th. Ptoloctin-Growth Hormone Fam·
ily. PtO<, NMI. AN/d. &i. USA 81.- 1984.
A_9. Miller. W. L.. ond Eberhan:lt. N. L. StruClure
and Evolution of the Growth Hnrmone Gcne
F.mily. Emiort. 4: 97-00. 1983.
A-I O. P.ndol, S. J.. Seiferl, II .. Thorn ••• M. W.. Rivie,.
J .. a nd V.le. W. Growth Hormone.RelcaS;",
faCtOr Stimulal.. Pancreal ic En7.Ymc Secretion ,
ScI.n« 215. 326--8. 1984.
A_I \ , Sanes. J. R. MOT. N.rv. Grow,h Facto .. ? No/ute
307: 500. 1984.
_ _ PART VII _ _

The Hypothalamus, Hypophysis,

and Thymus Glands
 19
Hypothalamus and Hypophysis
The pituitary gland (hypophysis) barely half
a gram in Ihe human adult male (23) and 10-1 2 mg
in a 400., aduh male rat Despite the small this
organ exertS major influences over carbohydrate,
prOiein, lipid. and nucleic acid metabolism. waler
and electrolyte balance, cdl differentiation. body
growth and maturation. metabolic rate and body
temperature. waler and electrolyte balance. cardi".
vascular functions. reproduction and lactation,
pigmentation, mood and behavior, and Ihe rc.. iSl311C1'
1<, 51re.. and infection.
Sin« ils hormones tonically stimulate the thy-
roids, adrenals. gonads. and other components of the
endocrine system. the pituitary hM been referred \0
as Ihe "master gland." However, it would be dillkui(
to find a more rtguiOled organ. The morphology and
secretory activities are alfected by androgens . estr<r
gem. progestogens. glucocorlicoids. thyroid hor-
mones, somatomedins. melatonin. insulin, glucagon.
and calciferols; by substances obtained from the diet
that include gluoose. amino acids, and minerals; and
by the very products that the pituitary produces. The
celis also respond to hypothalamic ··releasing hor-
mones,'· to somatostatin. dopamine. norepinephrine,
serotonin, gamma-aminobutyric acid, and to other
neuroactive molecules. The functions vary with the
nutritional state. sex, and age of the subject, and
with the time of day and the ",ason of the year.
Adenohypophysial celis begin to synthe>;ize hor.
mones during early fetal life. and the regulators play
roles in prenatal development, If the pituitary glands
are excised during the early juvenile stages, the an-
imals remain permanently delicate. stunted, and im_
mature. Animals hypophysectomized after attaining
adulthood can survive in protected environments.
but they are ever poiscd on the brink of disaster.
They cannot withstand even brief periods of food or
water deprivation, sudden or sustained exposure to
'"
heat or cold, or the presentation of the kind, of nox-
ious stimuli that are easily tolerated by intact or
sham-<>pcrated controls. The roproductiveorgans in-
volute, the ability to engage in demanding muscular
activity is severely impaired. and there is high sus-
ceptibility to infc<;tion .
The hypothalamus of a healthy man weights 4 g.
oc<:upies 5-6 em' and accounts for around of the
brain mass (3). Yet, as will be discussed. it is vir-
tually impossible to cite a bodily function that is not
controlled by thi. part of the brain. The neu",n. "'t;-
ulate the secretions of all of the pituitary gland hor-
mones (89), and they synthesize chemically related
substances. They receive inputs from gus-
tatory, pootic. thermc-, osmc-. and prcsso-
receptors, and they thereby link the endocrine sys-
tem with both the outside world and the autonomic
ner.ous system. They also information
with other parts of the brain and with the spinal cord
and somatic ncrves. Some of the cells respond di-
rectly to changes in blood temperature and compo-
sition. while others are "protected" by the blood-
brain barrier. Every known hormone, neurotrall.'i-
miner, and neuromodulator seems to alfect the hy-
pothalamus. and mQj;t nutrients have some effects. A
partial list of the regulators made in the region in-
cludes (a) hormones that ,timulate adenoh)"pophy-
sial cells (e,g. TRH , CRH, LRH, GRH. and PRF);
(b) hormones that inhihit the adenohypophysis (s0-
matostatin. dopamine, and others); (e) hormones
that directly enter the s}'stemie blood (oxytocin and
vasoprcs5in); (d) the better known ncurotransmillers
(norepinephrine. dopamine. serotonin, acetylcho-
line); (el substances usually classi fied as ncuromo-
dulators (GABA, substanC<' p , enkephalins, endor-
phins. histamine, angiotensin. prQj;taglandins.
neurotensin, melatonin, and several amino acids);
and m molecules related to MSH, ACTH. GH,
B1S AND HYPOPHYSIS

Sub<livi.ion> P:a .. di",Ii> Modi.n .mi ... nce

Pan i.t.rmedi • Infundibulo. "em
.,.,. tube,.h, 1' ...., lobe
Embr)dOli<" ",iei" Rl1h);.', pOOoh N...., <Ot<>k,m
Mojor «II types P... di",'i. coo,.i", thyNlrop<., Blood ",,,,,I. ".,,1 th""",h m«Ii,"
""ticotr(If><J, """. '''' r(If><J, emincnc., ....... e "0011 throogh
IoOt.trop<' JOI'IO<IOIropeo. ond i.fundibul.r mm
"'_"'*'""
P.,.. i."rm.dto. con,.i .. m.lo_ropes
Nou ral lobe ha ... on ,ndings .nd
,",.i'Y'"
ond .,"'" 1<rmi",,10
C.vit"" R.. i<!u."'''''' (hypophy.iol "eft) lol\ondibul.< (,,"trio.to.,) oIo1'!
Major . rr,,,", blood .....1. "",ori« or supcrior hypophy.i.1 ' ''ori.. P",,,ri« or inr,rior bypophy.i,I .r1.rieo
M,jor hormoo><. P... di".Ii. .ynlh ..i" ond ,<0,<1. N.ural lobe «<,i, .. , ,,<>US, o.d
TSH, i\CTH, Endofphi ... ...-MSH., "I..... V......... in.nd O. )100:i.
GH, PR L , F$I!, LH, and some th .. ori! in01' in the hypolhalomuo
I ,,"'th /o.t""
M,I.oooy'" ,y",h«ito.nd ... , ...
MSH and ",,,",, .m.1I pcpt;"",

TSH, CCK-PZ. and other "peripheral" hormoncs.
The classification is artificial, since a singlc molecu-
lar species can function as a hormone, neurotrans-
miller or oeuromodulator_ and a hypotha lamic fac-
tor that inhibits one cell type can stimulate another.
Certain neuron groups have been impl icated in
the control of appetite and food intake; the storage
and l"<'cruilmenl of fuels; Ihe l"<'guialion of cardio-
vascular, respiratory, and digcslive syslem funclions;
Ihe generalion of circadian rhythms; arousal, slcep-
wake cycles, and Ihe levels of molar aClivity: body
lemperature; l"<'productive behavior: the physical
e>:prcssion of emotion and the associatcd
with suack and territorial defense: and thc appre.:i-
ation of both l"<'ward and punishment
An overview of the anatomical and function fea-
tures of the hypothalamo-hypophysial system was
presented in Chap_ 2, and thc chemistrics_ bio-
syntheses, and functiO!l$ of the various hormones
have been described in several sections of thc text
The subdivisions of thc hypophysis al"<' summa-
rized in Table 19-1.
DEVELOPMENTAL ANATOMY
Mammalian pituitary glands show marke<:l specics
variatiO!l$ in slructure, but they possess common fca-
tures (33,37,96). The developmental stagcs for a
"typical" hypophysis are summarized diagrammat-
ically in Fig. 19-1.
At around six weeks postconception in humans
(and at a comparable stage in other mammals), the
ectoderm of the roof of the mouth (buccal, stoma-
deal ectoderm) grows upward and evaginales to
form pOuch. The pouch soon dcvelops inlO
a vesicle that gives rise to the adenohypophysis. It
transiently retains attachment to the pharynx, as the
anterior walls thicken more thn the posterior ones
and both acquire the ability to makc pars distalis
hormones.
Thc neural ectoderm along Ihe noor of tbe 3rd
ventricle of the embryonic brain grows downward as
the sacculus infundibulus. The saccus elongates into
a funne!-<lltapcd infundibulum that cstablishes inti-
mate oontact with the vesicle. It is widely believed
that the honnone-se<:l"<'ting cells of Ihe adenohy-
pophysi s belong to Ihe APUD system, and neuronal
elements may wander in at this time.
The neuroectoderm evidently releases an inducer
that slimu lates diffel"<'ntiation of oontiguous portions
of the vesicle inlo a specia li zed ring of tissue, the
paFS inltFmedia (PI). (No PI forms in birds, or in
whales, porpoiscs, and other mammals in which the
oonlact is not made. Artificial barriers to the passage
of Ihe l"<'gulator can block PI fonnation in othcr
spec ics.)
As the pars distalis oontinucs to enlarge, the orig-
inal cavity of t he vesiele persists in some species, and
it is then known as the residual lumen or hypophy-
sial cleft. In humans and olhers, Rathke's cysts form
 _en'",1e
S3<;(;uluS

Ratrlko"'
A. Nev,.l lbla ;") anti bo.Jtcal
Irnouthlll'Cl(>derm S. For"",'"", o j
Rathke's poocn

,
C. FOtmalioo 01 oC$icle
Pars ' t
,
." " ''¢l:

rl '""e ••

, , I i
Fig. 1\1· 1. Oio ...... mmat;c
i Ii , repre ....,lalion 01
.... erl\;' lion.

and they partially or totally occlude the space. Con-
comitantly, the pars inlermwia undergoes atrophy ,
The sphenoid bone grows whil e the pituitary gland
develops. and eventually the hypophysis of humans
and some others QCcupie$ a dep,es,sion within it
known a$ the sella lureica. The connection with the
pharynx i. broken. but SOme glandular tiSliue may
oc<:upy the pharyngeal side.
The d istal portion of the neural ectoderm becomes
bulbous. The expanded region is then called the /,..
j um/ibuiar proctJS or Murallobt. Someau thors pre-
fer lhe terms posrer/Oi' or pars l!el'WJSa; how-
ever, others use posterior lobe to mean both
infundibular pI'<J<XS/i and pars jnt.Tmedia. and pars
nervosa 10 designate tile enlire neurohypophysis (sec
also Chap. 2).
wilh cell bodies in hypothalamus
send long axons into Ihe neural lobe.
travel in bundles. th. hypolhalamrrhypophysial
nerw Iracts. which in perivascular spaces.
lobe also contains specialized neuroglial
oomponents. Ihe piluicylts.
The Hoor of Ihe brain located between the optic
chiasma and lhe mammilla/)' bodies 101m! an extel'
nal1y visible, longitudinally directed bulge, the Mitr
cille'eum. As Ihe blood vessels develop, the posteliol
exlension thickens most obviously in humans.
whereas the anterior region becomcs more promi.
nent in ralS. The term median of Ihe tuber
cinereum (M E) is applied 10 the thickened portion.
The M E has been defined as the zone of the infun·
dibulum exclusive of Ihe infundibular stem and in·
fundibular process that conlains Ihe prima/)' eapil·
laries of Ihe hypolhalamrrhypophysial portal vessel
Syslem. [I is a compone nt of bolh Ihe hypothalamus
and the neurohypophysis. In Ihis conleXI, the tenn
stem (neural Slem. nerve slem) refers
10 the lissue thaI joins the infundibular process with
Ihe ME (77).
Sma ll laleral projeclions of the wall of Ihe pitu·
'" HYPOTHALAMUS _NO HYPOPHYSIS

111-2 o.lII j lioo'sO! T_ 0 " .iDOng eo""".,ts01

Abo"llobe of R.,hke'. pOUch
"'",eriOl' pi'.i" ,),
C.ph. lic . <><1 ".d.1 lobe.
Cone of Wul,.en
Embryonic """,(un: ,hat Ji= ri>< to of """', p;'.;" 'Y Ilan<l .. ,I>< , ..d,1
lobe of _ . an<! ,he """""""""'ypophysi. of fi'l>cs.
(Som<tj""" 01«1 .)'",",y""""ly ... j,h pa .. d;".lis.) I. 110001. "'toinint ,h. hYMhy,i.1
ddt. tho: aRterior pit.;,.,y ''" be .."" .... ,ed r""" the pooto' iot p;'oi"I)'. C.,.,,,;,,, . 11
of po" di".li. and pons of pon ,ube .. l;"
Sub<!;,;,ioo>$ of ,he po" diM';, ;n '1>«'""
in ..-hi<h 'he embryonk oral lob< 1><";''' '0
form the «ph,lie pori"" (I)'pical of 1h,,1<). In moo' mamm.'" ..,If 111< ."""'1
lob<
de""Iop< 0.0 i< JJ\On: oIO$<ly ,dOled I. 1he "" udol lobe.
Co-'''''pod mw of <p«;.Ii<ed «II. de,;.«1 ftOtO p><l<nor wa ll of Roth);,', pouch. May
be in COIl'''''' ,.ith pars i.torrr.<di. but dilf... in «11uI.,
few .. hOI ' 1>«;", bu , noI in Il10>, •• im. I•.
"'.<1.""
SU_ in .k«p I n<! •

Hypophysi.1 cl.ft R.. idutl l."",.: l><lw •• n po" di".li, . ocI PO" in'cr"",dl." ",mnan' of tu""," of R.H.ke",
pouch.
Hypoph)"i., rue .. infundibular or """,,;,,ul,, rec< .. ,
1.("<><I ibul" process US«! by "'h<r ,.,hor;
10 des.i, .. « ,he b,lbou. ,n<! of 'he r><urohypoph)"is. " hOch "om<
on<! ..., ...... pepMe 1\0,0'>00'<0, This ., "'",,, i. "ro,,,d '" • • ,he ne,rol lob< i. ,hi,
"Xl,
E"e •• ion of ,he "",i 'y of ,he ,hi,d ""."lele i.,o ,II< os s."'"
hypoph)";., """"'-
N.,ral 'i ..... from ,he ,.bo,
c i.. ",m
to ,he ",.rallob<. s."", •• "0",1 ",m
.n<! no"","'m.
I.fuooibut.m Uoed he" .)'nonymousiy wi'h infun<!ibular "em. "'I"".oed ' 0 d",iJlU" ,he fu.", ... h.ped
,",i,y of ,he i.fundibul., ,,, .. of.1te pi"i""
CI.. ,ly "'m.. relion of >okoollypophpis 'hat ...,,,... MS I!. or,," ust<I
'y_y""",. ly " i'h po" i.."",o.H. ,
Medi .. emi""",,, ('p.ood<d upp"' .• upo'("'" po<1ioo of pi',i"" . ..11 , C....i .. blood .....1. of ,he pott.1
'y"''''
U"d her< '" desi""", .1 1of ,he hYP<lllhysis dori....! from ,be ..,,.1 «""'"., I n<! ,ho:
ouooi.. ed blood ,....,,, tho: medi. n emi"' .... 1""I.des ,he neu ..11ob< . nd
i.lunditlou l. m. Som, , ., """ ,nc'UO, J>l'"(II ' . . . ypoth.l.mus ,." 'Y""""':
n•• ro/Iorrnorres.
Bul""" . ..... , "po "'ion of ,he ncurohypophys;. 'ho' .krrU .nd "I..... ne'rohypophpiol
pop'id«· """, ", I"d inf,<><Iibul., ]><0<:e$0. Sorn, .uthors i.<:I. do ,ho: , .. i"
no. rohYJ>OI'h)"i •.
No"'.I .... lk S11"o,",e ktdill£ f,om tube, d", .. ,m '0 neu,,' lobe; incl.d.....",1 ",... <><1 _ion
,.,i,..,nco. M.y eon,.i. i.f,odibolo, ,"',"" """",i"", ust<I 'y_y""",.ly "i'h
i.f.<><Ii tIou I. m.
No ..,' ",m N,ur, 1 , ..... e",<><Iin, from .. t.:, eineroum '0 infuooitloulor ?"""'" ( ......1 lobe).
N<u ral (i",m. l) component of ne. 1I1 .ulk.
1',.. oi"",rncdi." ..be St"'''''' lor .... d by f.,ion of pt" i.te,modi, " i'h neurohypophysis. Typic. 1of
. mphibi . ... urd ("ho<,
Or.I ..be A'IO,ior po<1ion of ",,"oh 'ho' dol'""""" i. ""'"' ..imolo: in OIh'" i, Ii'''''
ri .. '0 ,Ire cop"'Oc '" ..,.",1 lobe. ""'. lUbe",'''' or l'fOO""oohypoph)'>is.
Po" .n,.,"" Som<1i.,.. usod '1",,"ym<lll$ly .. i'h p.>t$ dist.l i.. """.,i,lIy i" 'PO""" i. .. hOch Iocotkrlt is
'0
,"'i"ly .."rior ' he neurohypophysi •. O::cu .... Uy .,..d me . . . . '0 ",lor pi" i,,'Y,
Pa" di".li. LorS"'. "",,<><led .,.".'ion of ."'ooIIYJ'Oilhyoi" ",,,,,.. . 11 of ,he es' ablished
. d,,..,h)'J>OI'hys;.l hot""""" "cop! M$Il , 01"", ,.. '0
t< desi, .. " , ",,,io< pilUi"rr is
booi., di,."niod. ("'",o,io< pi"'''')' .1", i.dud" pan. of ,Ire "",,',be,'li")
Pars i.f.<><Iib."ri. U.. d he" . n<! el .."",,, '0 deoiJ.rg." 'h, J>l" of ,II< J>l","boo", li. (,,,,, .. ) ..-ithi. ,Ire
mod;" ,miner.<:< •• d "1<<><Ii', lor 0 '"'Yin& di"."e . i<>n.J! 'he ,uboor cine""m. Uoed
by 01""" '0 d""n"e ''''' PO" i"'"m.," •.
Pa .. i.termedi. OlIO. ooed .y,"",y""",.ly w;'h inl.rm«li ... lobe. M.y 10< used '" dooif .." M$H ·
...,,,li nl cell. ''''' • ..-h.. no ... ,... i<.lIy i." ,medi ... lob< i. pre .. n\.
Po" of ,Ire pi,"i",),.
Pa" "",,,,•• Used by """' . Ulhors '0 d"";,",,, ,he <n1,re lIC.rohYJlOPhy.i. 000 by ",Ire" '0 de'i. ""
t ho n<urollol><,
De,i, .,i" <1 1.".-.1 porlion. of R.. hk, pOU'h: co"i.. blood " ....1. of 1'Ol",,1 ')'OllO",.
Also ",10<1 pa"
P;a" IUbe"l;, "',,.. The I."" po<1ion of 'he par. ,."'roli. ,ha,carri .. ,10< 1'Ol"'" blood ' .... is. I. moot
oolr ,he "',,•• pr=nt ••• d tho: ,,,,,, i• • oed ' 1",,"y""""'r with p.>"
,uberol'"
T.ble o.Intionsoi Termo 0" ';t>io'll A_ypoptr,......... Neo.rohyp<lphyo

"" .. ,.be.,I" in .. ' .... 1\ .,• • lIy .m.lI. "., ..1 p. " of ,h. ,.be..li. p",,"" in ' p"ci ...
>Om<

Pi, ,,i"'y En,ire "'.".re by ...·hieh ,iI< 11<.""

lobe i•• ,,,,,,,ookd Irom ,he ,.1><,cine",,,m. inel"din,
,he i.I"""io.l., "'m. ,iI< med"," eminence. ,..s or ,he ,."",,.Ii.,
Sam< ..
.,."ral ",I •.
S,,,.d. of cell. &<O<>mpo.yi", ,he ,.."..,. lrom ,he ... ,,,be.. li. c• .., ... to 'he
POtto,ube ..1 "oc'
poT> ,.""'",Ii. in4<r .. , Secn ""'""y in . " ·Ioyi,,, .... mm ... , bird •• • rod rep'iles. in ",hieh
,he po,. ,.beroli, e'''''' <10<.1>01 I<.d dir..,.ly 10 'he po,. di".h.,
f'>.t1 01 hypophy>;' """ ",main. wll<. ,ho ".n'.,io< pit.i ...ry" i. "''''''''t<!. ,.,.Iud .. ""u,.1
lobe. po ... i., .. m«!i ••• "" po'" of PO" ,."", .. Ii •.
p,.,.. me..,.. met,· S"Wi.i,.",. 01 ,ho 'ypie.ol 01 I"he,. Til< ....".d.""hypOph)1io sc.m, 'Q
• dcooh ypofOh)"i' "'" """" c,,,,<ly ",I.'ed '0 ,ho po ... di,,,ti. or .... m""," Of to ,ho e.ud.l 10"'" (...
.bovc). ,iI< '0'he eeph.,i. lobe •• "" ,tto met . ...dcoohypOphy>i. '0
'he i.'ermed"'" lobe.
K.. h);e·, pouch Embr)'''''ic "'"".'" form«! lrom roof or phory', ,h .. Ii ... risc '0 ,II< oclcoohypophy,i •.
R=s>" hH'Ophl'''' ' tlyf>OPh)·,iol Q< inl.""i,,,,., "'<eo<.
R"id.,"u"",n lIYf>OPhy.iol cl<n,
inl.OOi"",., (.. 0<., C.-ity formed .. "".,,1 .."oderm 01 embryo from Roor of ,hirO
inl""" ib" i,,.) ve""i,l<. 1.>10' becomeo hypophy-li.1 'eceS>,
So",," lu, .,.<.Iou. (.,,,,e", 1""'«""
Folded. >'> scul .. i",d "'u"u'" in Roor 01 ,hi,d ..,."",1. or fi,h ...
\'uc" I",",)
T.Io<,<;nc".", Tl>c PO" of ,tto Roor 01 ,h. 'h;,d ..,."",1< ,h" .n,." in,o 1"'.... ';0" of 'he inl.""i .... l..
".m. It ,,"00, lrom ,ho op'ic ehios ..... to ,to< mammillary"""....
V•• "oll_ A "',,"UJ< """",Ii'l lorw.rO lrom ,tto "''' di".Ii, or d»rnobfOn<h" bd;."", '0 be
lormed lrom ,he 1"" ,,,Io< .. li,.
A defined. 0""'''' por,;"n 01 ,II< PO" di".Ii, <)1 ....... "imol,. beli •• ed '" "i.. r,om the
"",11_ of R.. hk.·, pouch. Abo co lted """.1 ,,,",,, ....... " i. h.mo",. l i,..If... " ....
ete.

itary 'csiclc ,,"iV<' risc to Ihe par< /,dxrali.< (which
carries blood In many specics. Ihe proje<:-
lions grow and fuse to form a oollar around
Ihe saccus infundibulus. The pars lUbcralis can
eilher extend over rncrs\ of Ihe tuber cincreum or tor·
minale more ventrally. In humans. it appears as a
thick cloa k around the anterior ,urface of the neural
stalk (23). The term infundibularis is used by
some to the pars tubcralis. but by others
10 mean the inlermediate lobe of the adenohypoph.
ysis (par> imermedia).
In :lOme of the vertebra,. •• orol 00<1 Q/xH-al di,i,ion< 01
pouch de'elep in,o rostral (<<ph.lie) .nd clud.1
region, 01 Ih. pars distalis, respecli"el),. whi!c 'hc proj"'"
lion, ,ha' form 'ho pars tuberali. ar ise 'hem. In
<>thers. 'he oral component i, ve"igiol or roduoed 10 a
,man remnant. as ,h. major pari of 'ho pa .. di".li, de--
rive, from 'he aboral COmponenl.
The term pi/uilary stalk often sign ifies Ihe infun·
dibulum and ils associated ne!,\'e5 and blood vessels.
However. it is also used synonymously wilh infun·
dibular $ICm.
Usually. the entire nourohypophysis is said 10 be
made up of the infundibular process. the infundibu·
lar and the median eminence.
Table 19-2 lists the various definitions lhal have
been given for oornponents of the hYf"JPhysis.
BLOOD SUPPLY
Recent studies have demonstrated that the vascula-
tu re is highly complex (Fig. 19-2). A simplified sum·
mary is presenled firs!.
The imtn",1 carotid arteries give olf branches
known as and inferior hnlOph,'sial arlelies
in upright creatures and as ameriQr and p<JSurior
counlerpartS in olhors. The superior (anlerior) ves·
sels lead inlo capillary beds wilhin the hypothala-
muS. In addition to supplying oxygen and nutrienlS
and carrying away wastes. they take up .. leasing
hormones made by the hypothalamic neurons. The
blood is into wmponents of the hy-
po/halam£rhypophysial porlal syslem. and il enlers
a sewnd set of in pars distal;'. Thus.
the pituitary cdl, rec<:i ve most of thcir blood supply
indirectly. There are unresolved oontrove",ies oon-
cerning whether small amountS of arterial blood pass
directly to the pars distalis in at least somc specics
(73). The posterior hypophysial arteries go directly
to the neurohypophysis.
In humans. ""silar ar/t,i.. lormed by the union 01 vcr·
tebral branches of Ihe $"bdavian . r.eriC$. divide into
'iShl and lcfl pM/trior e.ch of which
kad, in,o a communicating 'hat COnnect<
up wi,h II>< internal carotid on that ' ide . The in'er •• 1ca·
rmids give off onterior ctrt'bral ar/erits Ihat are joined by
"'" HYPOTHAlAMUS A ND HYPOPHYSIS

Anler.o< commu,,;caling
aMry

hypophysial

,
,
",.m.'
ca,c>tOd
anery - - POM"""" eommuniea,inS
MeO)'

ce'et>fal
Mery

- \_ _ _ Basilar artery

FIg. 111·2. Diag.....mmalio ,,,,,,_.uon 01 ""perior.

_ . I nd ;m",io/ hypophysial arterie_ ( ...... <Sood) 1 00
,,;rei. 01 Willi •. (Only ,"- ......... ,6Iev.nt 10 tile disouo.aion
. r. ohown.)

,h. uterior communicatin, . nery. The of Willi,
tbu. formed permits the mixing of arlcrial blood. from
different $OUr=. The $upcrior hYPQph)'Sial aner;es lin'
'he oi,d. of Willi, .... ilh the infundibulum. while Ihe in-
rerior hypophysi. ' arteries go 10 the infundibular proc ....
The .mall middle IIypopkysial ar/eries are probably iden-
,ical with th. /"'0/ (l,abee"lar) "'.ries said 10 b .... nch
from the superior hypophysial vessels (l I). They supply
bloOO (0 the lower portion of the infundibular $Iem. Nu-
m.roII. anaOlOJfKl$C$ klw •• n ,h. hypophysial arteries
have been described .
Simi lac haY<' been found i. mam·
mils. The infundibular and peduncular arteries of raol.
an: the counterparts. ""'pec'i'ely.orlhe ".'erior and pos-
'erior hypophysial arten .. of other speeit$.
The arterioles of the superior (anlerior) hypophy-
sial arteries lead inlO a thin OUter capillary shell. the
txlertllli (superficial. mantle) of Ihe median
eminence. Some of the blood flows from Ihere 10 the
imertllli (deep) pltxu. Ihat toward the tan-
cytCS that border the 3rd ventricle. Capillary coil.
and Olher formations variously known as vascular
lufts. vascular spikes, and gomiloli. consisting of
shQrt. muscular arte riolcs surrounded by
 finely ;nneNated capillary networks. are present COMPARATIVE MORPHOLOGY O F THE
within the decp pIe.1.us. Blood from the two plexuses HYPOPHYSIS
is roIlcaed into long that u ;avel moslly
10 the uppcr and anlerior pans 01 the pan distalis. Pituiu,ry &land Structures vary widely, I'lOl only
Blood from lower paTU of the in fundibu lum enters amana the species. but often strik;ngly belween
s/w,r pOrltll that su pply the lower and more stnoins .nd individuals of the s.me strain. The fol-
posterior !'t,ions. Capillary networks ""ithin the pars lowing information is drawn from studies of large
tubera1is provideadditional connections between Ihe numbers 0( tat.!, rabbits, ca lS. doss. cows. frogs.
hypothalamus and adenohypophysis. The vessels monkeys, and other readily available animal Iypes.
that lcad inlo the secondary capillary bed within the and from very limite<:! examinations of thc more ex-
pan dillalis are often called port.1 veins. [t has been otic forms (33,37,46.99).
pointed OUt that this is inappropriate br:causeof the
fenestrated (o:apillary-like) endothelium (II).
Pars distalis eelk receive a very nch blood supply.
The Pan Inte rmedla
The capillaries have a discontinuous. fenestraled ep- This re,;on it ... ly defined in """,t ' .ndw..,. r<1 ........
itl>clium •• conti nuous buemcnl membrane. and a in humans. ",tilbs. and cbimpanlCCS, il ""d-
perivascular connective tii\llue space . The fealures ually muJU ,,;th the ""ur.lllobe, Ind only $Cluer«! •• 111.
are consistent with the belief Ihat the prolein and pel'lill a fterwl rd (Fi" 19.1A). I" tome other m.amm.I.,
,tyooprotein hormones Can easily gain to the po.rt int.rmedil·type cell. "'e found moolly in 11K PO'"
blood. T he earlier li lerature wnllins numeruus ,ef- disllli,. In f."is .• Iumob .... ""h f,shes, and many of th.
erences to "sinusoids." However, electron micrQo r.ptiles. lhe port inte.medil ruses ""ilb Ih. "" .....1 lobe,
,raphs support the concept that those highly dilated
0't$S(1$ arc lrue capilarics (27).
It ....s assumed for many ye'l$ thaI the blood
from the pars d istalis is collected by lateral veins
that drain into the cavernous sinus. lIowever. such
veins have not been found in rccenl tludics. The
blood evidenlly pai.SCS first to the neural lobe, or it
drains inlO adcnohypophysial branches of Y-shtlpW
veins Ihal also pick up blood from thc capUlaries of
the neural lobe. Small amounu 0( blood llso se<:m 10
be transferred from lhe neural lobe \0 the

The inferior bypopbysial arteries lnovel directly 10

lhe neural lobe. Therefore, this pin 0( the piluitary
"and rc<:eives some blood thaI has not first entered
the hypocllalamus.
The operation of "shon feedback loops" requires 0, O.
that blood leaving th. pituitary gland rel urn to the C. Wild cal
hypothalamus. The details of the pathway have not
been fully defined, bul it has been e5lablished that
blood tan !low from the median emincnoc: to the
uppcr inrundibula, stcm (68). In at Jcast iOIIlC spe-
cies, it may feed a subepcndymal o:apillary nct""'lfk
and provide a possagc"'lIY for communication be-
IWttn the capillaries and the ocrebrospinal ftuid.
, ... _ _ PI .. '-tenT.cIio
IlthOllgh $OInC of the Madcnohypophysial"
1;;;",0<,'1 • "'-'''OI'YPOPhy''''
hormones within Ihe brain originate in the hypoph·
ysis. others are synthesized by bllin neurons tllat do o . lutl</ralis
not directly make COIIlaCI with palhways fed by Ihe Para O;lIaJ4
hypophytis. When Ihe pituitary gland is removed,
lhe hormone concentrations in tho5c brain regiorus do
not diminiSh.
In contrast 10 other componcnlS 0( tbe hypopbysis. O. lOn
the pars intennedia is mostly avasc:ular. The cens de-
' 19. lIN!. Di....'.'.lic r... " .... _01
pend heavily on diffusion for their supply of nu· _ .... p' pl morp/.-g, 01 ....
trients and removal 0( wasle and ("-,=",,,,,, ..1\h 1*" '3" "" f<otn _Item. .....,. 28_)
 HYPOTHALAMUS AND HYPOPHYSIS

Hypotl\alarnlJ. Ju,laOfl",al
1<IlI<I,ali. ,;
"""OfInco
I'acl r - Ne",ol1ob<l

, ,
,
par. dlslali.
,
,, - i I
A. Sperm whale
- _ Pars di'lali,

A, Goose
Pars lube'all,
j I I

8 . Cpo • .....,

Fig. HI·5. Sornoo unusual m.,.,...".lion piluitl ry gll _,

(Redrawn permission !rom Hlma1f¢m. ""ortnOll 29, )

6 . Spa'row
Median
RooII.1
po.rs __
(cephalic) , inlc ,,,,,,di• . On the olher hand. (a) many bird. c.n with_
, "and ""'ale, deprivalion , (b) alt hough whal •• and por-
Fig. 19-4. Diagr.""""1ic "'1>' .... 0111;0" 01 IIOnII
nonma""'alian pilulla'y Qlarod • . (_.wn w11l> perml_
110m W;"gs" . rMI. 'elorenoo 99 [pan. A and 8). arMI T",,,",,
100 Bagn.,•. ,ej .."""" 7T (part. C arMI 0) . )
and a 10M i, thu, formed (Fig. 19·
4C).
The pars intermedia (PI) ;, very 'ma ll in Ihe baboon.
gibbon. Hying [emur. a nd opossum (Fig. 19.58). II scem,
10 be lotally aboenl in Ihe pangolin and nine-banded ar-
madillo. There i. re ..on 10 bel ie'. Ihat il ne,e r uodergox:;
enn preliminary for malion in porpoi,e. and whale, (Fi! ,
19.5A). •ince the adenohypophy.i. and "". rohypophy.i,
ore separaled by connec1i>e li"ue. However. bormone.
a..odated with the region are preoent in those mammals.
No distinct , t",ol.", has been ;de.lifted in bird> (Figs.
19·4A and H). but scamred cell' wilh cha,acleri"ic
S1aining propertie •• ,e p'esenl •• ithin the pi tui13ry gl. od .
In conlra". Ihi. pall of Ih •• denohypophysi, i. e.p"·
eially "'ell.de,eloped in the camel and llama. in each of
which it can occupya full orth. gland 19_
) 8), It i. also la rge in the rabbit . • hrew. rat, and mou ..
(Fig, 19·JF). and in mQ$t of the replile•.
The , i,e of the P[ Kem. 10 be closely linked with the
abilily 10 w;lh.und O l>soroations con-
. i"cnt " ilh the concept include Ihe re.,ark.blt adapta-
tion. of camel. and llama< to aTid cnvirQn ment>. the abil·
iti.. of ,nake. 10 go for Iolli periods without drinking. and
the ,.lali.ely pcoor tolcr ..lCc, of most prim.,.. '0 w" "
,hortages , MSH i, implicaled .. a regulalor of w.ter and
electrolyte balance . and it i. kIlO"'" Ihal ..,me fibe rs of
the ' " p,"opliro-hypophysia[ traets lermin"e on the pars
poi... arc su rrounded by Wale r. thai water i.loaded wi th
salt.; (e) hormones other Ihan intermedin. play ;mpor·
t.nt Tole. in Ihc regulalion of water and eleclro[yle bal ·
ance; and (d) MSH perfOfms other funct ions. Ihe be"
k"""n of wh ich i, .,i mulatOon of Ihe pigment cells,
The .hape and loc.tion of the P[ can
,he oi>e (37), II
'"r)'"
much
caudally and do .... tly 10 com·
a,
p[ele[y encircle Ihe neural lobe in dogs. wol.e •. poIa,
bea". OjXISSUTnS. ealS. giraffes. and horu, (Fig. 19·)C
and II ha, rosu.[ fold. in lb. dog. while the polar
bea r PI extend. een column. inlo Ihe ""ural lobe. There
i, a dO .... lly located lumen withi n ,he PI of the .,olf.
mink. 3nd 1"'1«31. The d"""'Slic COl. wild gray cal, mier-
cal •• od molliOOK all h."" a cauda lly ioealed double
layer of li"ue that parlially enci,d.. the hypophysial
den (Fill. 19·3C). [n 10110;1« .nd salamanden. Ihi. pan
of the pituitary B[and i. thickened laterally ,
[n mosl .pec ie •. Ihe PI i, separaled from the pa" dis-
talis by the hypophysial clefl . In ..,me, the «II, spread
o"er bolh surfaces. In addilion 10 the u, ual compone nt •.
tbe PI can contain C)',a li ..d wilb ciliated epilhelium
and .treaks of colloid.1 malle ..
The"""" 0/ Wulzm is. deriY"liye of the posterior ,,'.11
of Rathke', pOuch tht i, found in .h.ep. ""en. and a few
otber 'pccie, (Fiji. 19.3D), II e.tend, for"'ard from tbe
PI to th. di,tali •. bu' its cell. are of 1he pan di,tali,
type. No 'pecial funclion ha. been .ssijlnro to il.
The Pars Tuberalls
Tb. "typical" pars luberali. ari .., from laleral proje<-
tion. of Rathke', pouch Ihal grow do ... lly and caudaUy
10 form I coll.r around the infundibulum bUI mainlain
conlaCI with the pars dillali., In $Ome of the mammal •.
lhe pars tuberali. (PT) is conlinuous wilb Ihe PI, bUI il
differs from that pari in ",uctu ,e.
Th. colla, can .'Iend I . far •• lhe optic chiasma (in
fe"els), eomplctely C<We, nol only Ihe en,ire infundibu·
Ium but much of the lube, cinereum (in giralfes). Or ap-
pear 10 be totally mi .. ing (in .IOlbs) ,
In .U·loying mammals ('piny anlealers. plalypu ..s).
"'me marsupial. (includina Ibe wallaby), in lhe domeslic
cal. all known birds. and mosl of the reptiles (but oot
,na'e.). the PT consist. of a chief pari Or pars luberali.
extern., which resembles th. pars tube .. lis of other
mammal•. and an addil ional pars tuberali. inte,na that
lend, to grow r(l$lrolly to fuse with Ihe anlerior pars dis-
tali. a, a solid strand or a. i",lated nonvaseular cell. that
accompany lhe por,.1 ...,I.
y• and form. fIC"OIub,,/aT
!TIKI (Fii. 19·4A).
The PT Ihe n'IO<' hiahly d•• eloped in in whiCh
i, may con,i" of • l"beraH. in'erna dooely
wilh 1he pars di, I.li •. a ju'taneural pori ion .'Iending
.klna Ihe tuber doereum. and. connecting porloluberal
lraOI (Fig. 19·4A). A prominent pof1()1 uberallract i, aloo
widely found among reptiles.
In those mammab (OpO$$um. airalfe, 0', .nd man) in
which there is . hislologically dislinguishable '''''lral re-
gion of lhe pars di.tali. kno",-n .s the ron, luberali., the
tuber,li, iOlema .'IOnd. inlO lhe region. Some .ulhors
belieyelhat Ihe zona tube,ali. derives from the luberali.
inlcrn •. bUI mO$I trace ill to Ihe .nl.rior pari of
Rathke', pouch, The pars luber.li. may conl.in a lumen
0' C)-'I$ linro wilh eilialed cells.
In eU lhe rian ant.alers. I'1ngolin •. I"ngr..he •. and bony
fi.hes. Ih. PT i. well definro du,ing deyclopmenl, bul il
disappears with malurity , It probably ne"e, appears in
..akes. I n the etOlmQb"n<h fishes. ventr.lgTOwlh of 'he
,egion I.ad, 10 formalion of Ihe yentrallobe of the ade-
nohypophy,i. (Fig. 19-4[»). a '''uClure identifiro only in
this "oup of """ebrotes.
The Pars Olstatis ( PO )
This c<>mponenl aCCOUnl. for 9&% of the piluilary gland
weighl in wl"lcs (Fig, I9-SA) and f<>r close 10 80% in
mO!1 other spoeies_ However. il i. "'lual in si"" to the
ncural lobe in Ihe rhinoceros. In loads, 'he .. urointer_
mediate lobe i, larger th.n the PO_
The PO can be re.triOlro to Ihe roslral ,egion of Ihe
hypophysis"$ in tigc". lion •. and camels (Fig, 19·3G).
or .xt.nd. ribbon.like. in a hoti,.ont,1 pl ... 10 thec,udal
end of the neurohypophy.i. (Fia. 19.3F) in ral" hros<:-
bogs . •loth., shrews, and mice. It grow. dorsally 10 pa,-
tially <>r completely .urround the neuIlII lobe in dogs,
be.o.rs, seal lion" borm, and gi,alfes.• nd I .imilar a,'
rangemenl i. d=ribed for Ihe opossum (fia. 19_5B). In
amphibial1$. the PD ()C<:upies a mO$ll)" Cltud.1 posilion
(Fig. 19-4C),
In ,nake. Ibe hypOphysis is asymmetric. ",ith Ihe pa rs
di,lali. on <>ne .ide and lhe neuroinle,medi.t" lobe on thc
OIher. Both left- and righHidc 1<><:81io", of Ihe p.rs di.·
tali. have been found.
Cepla.lic (rostral) . nd caudal (prOJ;.imal) lobe. or Ihe
pars di"ali. Ire clearly di,cernible in the more primiliv.
mammal. and in bird,.nd reptile •. The .ubdiyi.i<>n Of Ihe
pors di.lalis is highly developed in OpO$$um (Fig. 19·
58).
The zona luberali. in Ihe roslral pari of the pars di.-
tali. of Ihe human, bovine, and airalfe pituilary i. be-
10 be embryologic.lly reJalro 10 lhe cephalic klbe.
taking il> oriain from the oro l lobe of Rathke', pouch.
I nd;vidual. of many .pecies relain • con.eclion belween
lhe hypophy.i. and the pharyu, e>lending ", a rem"".,
of Ihe o,allobe. The ,emnanl may later .. pa .. te from Ih.
pars di,tali. and persi.1 as a pharyngeal hypophy'i'.
In Oyei<:l5lOO1es and fi.he •• pnr. mm>-, and mt/a-.de-
""hYpOphysial TOaion, can be di'lingui,hed. The meta
poriion i. embl)'Ologicallyand [" notionally 'elaled 10 the
pars inte,media of olher vertebrates. The mesoadenohy_
Or prOXimal pars di$t.li. ",sembles Ihe pars dis-
talis of higher mammal. and the caudal pari of that
,l'uClure in reptiles and bird>. MO$I associale the
pr""denohypophy,;. (also known a. 'he """,.1 P<01'> di. ·
lali') wilh Ihe cephalic region of bi,d. and reptil.s, .J.
Ihouah a homology with Ihe pa" luberali. has aloo betn
proposed.
The pars distalis of many rlShes and of cyclostome, i.
a dilfuse 'Iruetu re Ih.1 in' ordigilatc.s wilh Ih. neurohY·
pophysis and may .. ceive axon. from hypothalamic nu-
ciei, (The,efoTO. funclional in,errelation,hip< amona
pm. of Ihe hYpOphysis and belwe.n the hypophysis and
hypothalamus differ f'om Ihose of tClrapod •. ) T he .de-
n<>hypophY'is of eyciO$I"",e, deyelops in dose associ'lion
wilh Ihe <>Ifaclory organ. and an epitheli.1 'talk continu·
ou . ..-ith 'he proadenohypophy,is pe"i.".
Th a Infundibulum
T fle infundibulum is long. Ihin. and hollow with a T·
shaped Cayil)' in "..,.1 replile •. bird •. and egg· laying
mammal, (Fill , I9-4B). It is al"" long in ",me eutherian
mammal •.• uch a, the lion (Fig, 19.)G). bu, in <>tho"
(camel. deer. manal •• ). il and difficult
10 define. In ",me ;1 i, compact fo, T1'IO$I of il> length (pia.
,abbit. dee,. IIlma ....1. walrus. badger). bUI in oth ....
Ihe hypophysial clefl i. "'ell deyeloped (a. in Ihe pOl.,
be ... anlcater, cal. liger. lion. and ,Iolh).
The mammalian infund ibulum i. typically .u rrounded
by Ihe pars luberali.; bUI the ayian pars distali. is scpa'
r.tro from lhe neurohypophysis by • clefl bridged only
by the porloluberoll.. <I .• nd the pa" tuberali, may .x·
tend far oUI,ide the mroian eminence ,
Sn.ke. bave a medi,n eminence bUI no tuberolis,
."
An ""differentiate:<! portion of the infundibulum. the pars
orali. tuber; •• separa,es the median eminen<. or oome
rept iles ud birds from th. third v<:mricle.
In fish •• the medi.n eminen« develop< along the "en·
tral w. 1l of the .. cculu, infund ibulu •. but a $Irucluno pe-
culiar 10 fi'hes. lhe ..""ulu. >uculosu, (fit. 19.40).
forms from the dorsal ",an. The lalter reloins ""ural COn-
nection, 10 O1her parI> of lhe bro;n.
T ile NeuraLLobe
The ne.mllohe of most ve'tebrates contain. p;luicytes
(which are modified neuroslial cells). and U<H\S that
brin, in .. cretory granul.. f,om neuron cell bodi.. of the
In cyclostome<. however. the enlir. neu-
rohypophysis is nothing mOfe than a $Iighllhickening of
Ihe floo r of tbe thi rd "."lfiel •. Secretion. moy be poured
directly into lh. vent ride. The of fish""
i. diffu$C, It iolerdigi!'les with Ihe adenohypophysis. into
which i\ sends neurosecretioM. and i. ,hares, blood Sllp'
ply wi !b the pa .. intermedi •.
The neural lobe of ler,",1I'",1 vertebralC$ il more highly
de .. l<>ped lhan Ihal of aqualic form" In mammals. il
may be ,urrounded by the pa .. inle rmedia, and some-
limes parlially or complet.ly surrounded by Ihe pa .. di. ·
\3li, . , well (as in d08$, be .... lions, and giraffes). It can
e.. n be deeply embedded within the pa .. distalis (Fig.
19·58). bUllhe blood supply;' largely independenl of , he
one 80;n8 to the pars di". lio. In r.pt;le< and in <omo of
the more primitive mammals (e.g. ante. te,,), Ihe neural
lobe is .imple and hollow; and • similar arrangement is
secn in lhe ,Iotll (Fig. 19-310). II may be completely sep'
araled from. or intimately associated wilh the
. denohypophy$il.
The axi. can be horiwntll (Fig. 19·3n vertical (Fig,
19-3G), Qr bent (Fig. 19·38 and C). II may s!ant in ei ther
an anterior Of posterior direclion,
The Ph ary ngeal Hy pophyais
A remna n, of Rath ke', pouch often develop' into I small
.Intcture witbin Ihe .ubmuOOlJl of the posterior pharyn.
geal roof bellind Ihe nasal septum. Thi, epithelial sta lk
remn.nt becomes .nalomically separated from Ihe hy.
polhal.mm by the sph.""id 'oo"e, but extcll$ioru of the
portal btood vessels can penetrate the bone. The strueture
i. quite consistently found in humans, butlher. are few
reports of it. presence in OIher .pecie•. Both GH and
PRL have been fou nd there in human eadaver1,and GH·
",ereling tumO" can developal Ih.1 .ito.
Size of the Hypop hysis
The of the gland ranges from 0.1 mg in the
shrew to more than 50 g in the whale. h is usuany
arou nd 10-12 mg in the rat and 450-500 mg in
adult men. Wome n have oomewhat he:!'ier glands.
and enlargement to I g Of more is common during
HYPOTHALAMUS ANa HYPOPHYSIS
norma l pregnancies, Estrogens a re among the best
known of the growth Ilimulants.
MICROSCOPIC ANATO MY OF THE PARS
DISTAUS
The various cell types identified by lighl and electron
micrO!;copy (43) and by other lechniques are sum·
mariz.,d in Table 2·2. h was initially assumed Ihat
each morphologically distinguishable entity Ihat
COIltains granules synthesizes and releases a single
kind of hormone. The OOnCep! "'as bascd on severa l
kinds of observations, Labeled antibodies directed
agai nst specific hormone types were found to b ind to
certa in ccll types but not to olhe!'$. In large animals,
cells with common structural feature, cluster within
restricted regions of the pituitary gland. It has been
demonstrated thai the gran ules collected from Cer·
tain zones contai n rdatively high conc<:ntra tions of
l H whereas tho:se oblained from other sites contain
different hormones. Thyroidectomy leads to the for·
mation of enlarged thyrotropes (thyroidectomy
cells). and thyroid hormone administration can pre-
vent Ihi•. Gonadectomy is followed by the emer·
g<'nce of "signet ring" (gonadectomy) cell,. and
early lac talion i, associated with the presence of
large number< of laelolrope<, Somalolro!"'. are
mi.sing or scaree in ani mals wi th congenital
dwa rfism.
It is now recognir.cd tha t Ihe "one cell_'m c hor·
mooe·· hypothesis is invalid. ACTH. lipolropins, en·
dorphins. and MSHs are all cleaved from a large
precursor. and a single cell can release two or more
of lhose regulators. FSH and LH /l·subunits are
made on d itTeren t ribosomes. bUI some gonadotropes
Itercte both of the glycoproteins. Cens that make
ACTH as well as gonadotropins ha.e also been
identified ,
Pitu i!ary cells probably undergo fu nct ional
changes when their microenvi ronments are varied,
Tumors initially secreting large amounts of j ust G H
or just PRL often eventually acquire Ihe ability to
make both of the proteiru;. Moreo.er, GH is One of
several regulato!'$ known to OCCu r in mu hiple molec-
ula r Wben normal pituitary gla nds are re-
moved from Ihei, associations with the hypothal·
arrlO'hypophysial porta l system and a re implanted
inw anot her site within the same an imal, they usu·
ally secrete large amOU nts of PRL bul little of the
other hormones. In time. they "learn" to make some
of the othe r adenophypophysial products.
h has re« ntly been shown that gonadotropes
exert pa raerine controls over the lac tot ropes (25).
and il has long been recognized that thyroid hor·
mones, glucocortiooids. estrogens, and other regula·
tOrs alTeet the secretion of growlh hormone. More-
over, each of Ihe hypothalamic peptidcs alTecu more
than One kind of pituilary gland cdl. Th us, thryOlro-
pin releasing hormone Can sti mu lale the lactOlropcs.
and somatostatin alTccts the Ihyrotropes.
Light Microsco py and Olfferentlal Staining
Much of the early work on adenohypophysial cens
(80. 81) was canducted with Ihe light microscope.
The te<:hniques are still used for some purposes.
Eleclron microsc<Jpy provides much more in forma-
tion on the sizes and shapes of Ihe cells. on Iheir in·
terrelationships with other piluitary gland campo:>-
nenlS, and on the changes in appearance of Ihe
organelks under varying condilion s. HoweY<'r, a
major disadvantage is Ihat only a liny fraclion of Ihe
population can be studied. Moreover, electron mi-
croscopy re<juires special skills and elaborale e<juip-
ment. It is timc-c<lnsuming and expensive.
ACIDOPHI L$
When sections of adenohypophysis are stained with
any of several mi xtures of acidic and basic dyes
under specified candi tions, Ihe granules of cerlain of
the cell types preferentially take up Ihc acidic cam-
ponents. Those cells are known as acidophils. eosin-
ophils, Or oxyph ils. The granules are large. and they
Call lJe by dilfcrential and grad icnt cen-
trifugation and Ihe uSC of milliporc membranes (94).
Stareh and polyacrylamide gel electrophoresis have
proven useful for separation of the granule proteins,
and il is known that the grnnules contain GH and
PRL.
Two me>rphe>logically distinguishable acidophil
subgroups have been identified. One Iype is missing
in individuals with congenital dwarfism and unde-
tectable plasma GH but present in large numbers in
those with high GH le.·els and symptoms of acro-
megaly. II is therefore evident ly Ihe somate>trope.
The OIher type (laelotrope) assumes prominence
during laIC pregnancy and early laelal;on. The cells
undergo degenerative changes in lactating females if
the pups are laken away.
Attempts have been made te> disti ngu ish the tWo
Iypes by means of differential staining. Cells con-
laining granules that preferentially bind e>rangc-G
and take on an e>range or golden cale>r ha.e been
called ()I"(Ingtophils or Quranlopnils. whereas Ihe
ones whose granules preferentially lake up 3ZOCar·
mine and appear red are known as CQrmjrwphiis.
The ability to in this way somatotrOpes from
la<t01ropes is limited. The technique in.l>lves ' 1.;ni"3
wilb on. preparalion. _ntersl.ining wi,h the other. and
observing Ih •• xte ntlo which Ihe second dye can r.place
,he firsl. Since the order of prt$Cntati(HI offccl$ the end
reprod ucibility is achicved only wh.n Ihere i.
strict adh.r.nce to a specified proc.dure. The orangeo-
phils of e>ne lab<>ratory Can be the carminophil. of an·
other. Ther. are speci •• in which the distinction. eantJOl
he made. Nonpregnant ewes seerete large quanlities of
PRI. ond they bave larg. numbers of cells ident ified in
other "a)·s as lactatropos. When differen,i. 1 Staining i.
usod , I(}m. granul.s are said to appear ""'ng.·.. d and
others red""",nge. It h.s also been claimt<l 'hat
ereting cell. take up both of the .cidicdy.type•.
The manner in which the data are usod to cla$$ify cell.
also varies from labon,ory 10 lah<>r.lOry. Some investi_
gat"" apply the term «-«II (or ·'ordinary "ciclopb ir·) 10
,,/I somatot'ope$. Oth ... uSC carminophil 10 designate
.ny cell that binds Ihe o<sociated dye, ,egardlt$s of its
hormonal produet . There are those who laclotrope,
of nonpregnant mammals < cells. and rtoe've tbe desig.
nation cell) fo, the acidOphil' that appear
during pregnancy and lactation. Othe" use < cell to mean
any lactOltope. and yet diffe,ent authors ha.e adop,ed
the term cell. In some laM. tori., .• 11 orangeophils
arc. cells.
BASOPHIL$
Cells wilh smaller grannIes that bind basic dyes are
known calleelively basophils. The periodic acid·
Schiff stain ( PAS) has been used 10 distinguish the
mucoprOleinoCOmaining granules Ibat SIOre FSH,
LH, Or TSH from the seroprouin-comaining gran·
uie. that hold Mnglycosyiatcd itor""""" such a.
MSH. (The slides must be pretrealed with carbo-
hydrases, since PAS reacts with glycogcn .)
In SOme species, tenain e>f the basophilic gran ules
take up aldehyde fuchsin (AF) under speeified con-
ditions. and the cells containing them are said to be
AF- , AF I. or {J cens. Changes in Ihe sizes and num·
bers are e>bserved following thyroidectomy and the
administration e>f thyroid he>rmones. For these and
other reawns, Ihe cells are beHeved to be thyro-
tropes. Cells oonlaining barophilic granules thaI do
nollake up Ihe AF are known as AF- , AF 2, or 0
cells. and these seem to be gonadotropcs.
Although thyrotrOpes and gonadotropes are diSlin·
in tbis way in mOISt mammals. exceptie>n> are
encountered. Thus. ham.ter thyrotrope • • re evidently
AF- , "hereas hamster gonad01ropes are AF · .
The species in which AF can he used 10 separa'e th.
cell Iypes haY<' heen called ·'fave>rable.·· H""eY<'r, even in
lh .... the condilions under which the reactio", are car·
ried out must he rigidly controlled. It has been .how. lhal
a highly concentrated preparati(}n of AF SI.ins ,,/I
chromophil. (i ncluding the PAS·negative .cidophil.). A
somewhat les' concentr"ed solulioo stain> In basophils
inctuding the one • .."reling MSH. but no acidOphil ..
With fu"her di lution, Ihe dye is ta ken up by juStlhyro-
trOpe' Ind MSH cells (but not by gooadotrope.j. A rei·
.t iY<'ly weak AF preparation stains ju>! Ex_
tremely dilute dye is not bound by Iny of the granules.

Several flCt(>r$ aff.ct th. dye affiniti••. p ... t ... alm.nt
of Ihe cells ... ith chromate roduce •. wher... pn:t ... atment
... ith pennanganate enhances the binding.
In human. and other .""ci<:$ in which MSH-sec"'ling
cell' are found in Ih. pan dist.lis. all c.lls oontaining
granule< that stain with t!le second-high." AF concen·
tration but ""t the Ihird ..... called l' cell •. Th..., arc pre-
sum.d 10 be mela""trope!l. but ol h. .. use the urn. Gr •• k
leller to designal' "neutrophils" or "ch romophobes"
that. at I. ... t in some <:a$C$. appeu to be oortiCOlrope •.
Human celis ,h., .. ain wilh the 'hird conctntration a,
w.ll .... called fJ cell' by $(Ime authors. bUI <>Ihen use the
leller to designate just thyrolropc •.
DIFFERENTIAL STAINING OF GONADQTROPES
It is casicr to distinguish between gonad(}\ropcs as a
group versus other basophilic types than to identify
sped Oc gonadotrope type,. T hi, is not , urprising,
since some cells are known to make both FSH and
LH. and thcre are indications thaI a ,ingle cell can
vary thc qualitative as well a, quantitative nature of
the secretory products.
In the bat. adva nlage i. taken of seasonal changes in
... productive c)·de •. of lXInation. and of dilfeT<ntial stain-
ing re.ction. , It has been possible to subdiv ide th. baS<).
phil' "" the ba.i. of amnity for the d)'e Alei.n blue (AI
H) T hy""'"!"" •• k. up ,h. dye """,t .vidly ond
called AI 8 1 cell, (or cya"""hil. ,i nce Ihey appear blue) .
AI 82 cell. or amphophil. with intermediate affinity ap-
pear purple. Thcy arC believed to be since
lhey seem to be most acti.. when ripe follicle. ar. p...sen t
in the ovary. They di»ppc., arter OVulalion. AI B3 cell.
with the ,,' •• ke't affi nity for the dye appear brick-red
whcn dye miuuro< are are most evid.nl during
p"'g"ancy. and .... bel ieved to be interstitiotrope •.
Simil" till<:toria! reIIction$ have been de.c.ibed for the
dog pars dist.li •• but e,·id.nce . upporti", relation,hips
between .",ining and hormone function is I... ",,"vincing.
Cat gonadotNpcs respOnding "rongly to tho PAS pro-
oeduT< h... been d ... ifi.d as GI <ell. and .... believed
'0 be folliculotrope •. The m.genta-eolored g,"nule. of G I
cell. ean be distinguished fNm the purpl. one. of G2
cell. , The laller re'pOnd only wea kly '0 the PAS and
seem to be interstitiotropcs .
.;.cell. a ... ea.ily found in the hypOph)'SC1of ad ult hu-
m.ns but are infrequ. nlly seen in child ... n, They ha ..
been cl.arly a$SOCia ted with gonadotropin .. cretion. but
no def,niti". separat ion into folli<ulotrope. and inlersti-
ti<>lrope' has becn accomplishod .
In the rat . 11 g""adotrope. of the m.l. and ""npreg-
nan' female .imilar staining propertiC$. For rca-
SOIl. cil.d below centrally located gonad<>lropes are be-
lieved by wme to be in.erstitiotrope •. ",h.rea. mOre
peripheral cell. m.y be folliculotrope., The lIranulation
of the inte rstitiotrope i. described a. fine, and more
",'e nly distributed within the <ytopl.,m. Th«e . ... sug-
gcsl;ons th.t ",Ivents can be used to pr.f.T<nti.lly rc_
HYf'OTHALAMI.!S AND HYPOPHYStS
move one of the lonadotropin. and .ff.ct a»ociated
ch.nse. in the appearance of one type of gonadotropc
whil. lea ving the othc r type and its ho,mone ""nlenl rd-
Oliv.ly in tact.
Some investigatot1O have reported ' uccess with 'peeial
'Iaining method. based on the ... Iotively more intense
PAS ... action of Ihc ""ntral gonadOtNpcs. Th u., with a
oombination of PAS and methyle .. blue. thc c.ntral cell.
.. in red and ,h. peripheral 0.... pu.ple. With PAS and
... kian Blue at pH 2. the interstitiolrope. are sa id to .tain
red .nd the folliculolrop<S violtt. while at pH 3 the ccll.
appea, green and violet. respectiv.ly.
Cu,r.tion l•• ds to hyperl rophy of the gonadotropc.
and an early rise in both ,be FSH.nd LH Contenl of the
hypOphy.i •. T he term has been appli.d to
all enlarged gon.dotrope. regardlcu of location witbin
the gland. Some of the cell. a""um"late 0 hyalin • • "b-
. Iance and ... um. an appe.ranct which has led to the
designation sig"'" Ting According to certain authors.
allllonadodotNpe. can .how Ih. arrangel1'l< nt . but <>Ihe"
"ate that only folliculotropesdo so, Distinction. have also
been made btt ..... n ",ruc" ,ign.t ring c.II •. peripherally
located and pre.umabl)' foll kul<>lrope,. in which granule<
a... coarse a nd confi ..d to ,h. cell edges. Yersu' "filigre'"
I)'pe co.trati"" cells that are centra lly .ituated a nd con-
toin more uniformly di.l ributed. f,ncr gran ulation ,
The tendency to form .j gnet ring cell. i. far greater in
SQm. , peci.. than in olh .... Such c.llure f roqu.ntly en-
countered in pituitary gland, of castrated rats. but thcy
hovt . 1"" he.en r""nd in in. oCl •. or. ""t._
.ioOlllly seen in human 'peCime .. but . ... rare;n 'he ca$-
"ated mouse.
When di$\inctio", be,ween the two gonadotrope' .rc
not e•• ity made in intact anim.I•. the diff.... nce •• r. said
to be accen tuated by castration. Soon after the 'urgery in
r.ts. both the FSH and LH ""ntentof lhe pituitary gland
increase, La,or. LH may be mOT< abundant than FSH.
and this can be assoc i. ted with the appeara nce of .n-
I'rged. ce nt rally I<xated gonadotrOpes.
IIo"'"e r. c.,(ration alfects the .i .... and weights of the
ad... n.1 gland. of moot opeci.. and augments ACTH $<_
.... tion, Estrogen level • • fftet not only corti"""Ope', but
al.., I. ctotropes.
Gonadotropel are inHuenced by nutritional deficien-
cies. chronic illn .... and cha nges in thyroid function.
while pregnancy aff.cts the entire erni<x,ine 'yilem.
Th. centrally I<xat.d gonadotNpe. betQmt prominent
before th. onset of . exual mat uration in the rat.
and Ihey a re rapidly degranul.ted ju" befo ... ovulation.
They allO ,how evidence of increased activity du,inll
pregnancy and .ft.r .strogen injeclion. All of the prcced_
ing fi ndings arc co",i .. ent wit h tbe view th .. cent ra lly 10-
c.. cd gon.d<.>trOpe' are inlerSlitiot.ope., Further evi.
dcn<. i. obtoined from injcction of female rats w;th
to"ostcrOne p,opionate. Thi, i, followed by prompt cle-
".Iion of the FSII oont.nt and ;n< ...... d granul.t ion <>f
tftc pe riphcral gon.dotrope., . 'ong ",·it h lo,,·cring of tOe
Ltl content and degranulation 01 the centr.1
gon.dolrope<.
AccQrding 10 some authors. ,h. findings , uPpOrt the
c:onC.pl lhal Ihere arc. in facl. Iw<> .. parale Ind di"inCI
Iypeo of gonadolrope in Ihe ....1. buI Ihal diff.rences be·
Iween Ihem Ire <HII .a.ily d.monmaled wilh differenli,l
Slaining Ie<:hniqucs in normal mIle. or in nonprellnanl fe·
mal ••. Olhers fa.or Ihc .iew Ihal Ih.re i. jU'1 on. kind of
gonadotrope th.t .. ri •• il' function. when the mieroen-
• ironm.nt chang...
E.idenee fOT the exi.tence of a singl. type of ganado-
trope i. convincing for som. of Ihe fi.hcs_ Otber fi.h",
sc.m 10 have tW<> type<. Diff.... nc •• betw.en follie"IO)-
tropes and inl'''litiolrope' have been d'$CTibed f'" ....
.....1of th. r.ptiles and amphibians.
Attempt. to Identif y Co rtlcotrope. By light
Mi croscopy
Corticolropes were the most difficult of adenohypo-
physial cells to identify by light microsoop)' and re-
lated techniques. Early suggestions that they are
chrQnJophobes derive from observalions that (aJ pa-
tients with Cushing', disoase and high ACTH levels
often have chromophobic adenomata, or large, clear.
hyalinized "'Crooke's cells"'. (b) Chromophobe sizes
and numbers inereaso afler Ihe administration of
amphenone in cats. and afler adrenalectomy in rats.
Thc chang.s ean be reversed with glucooortiooid but
not thyroid hormone administralion. (c) Some non·
granular tumor cells release ACTH-like substances.
(d) ACTH·like activity has bcen found in the ··mi·
crosomal". but nOl In Ihe acidophil or basophil gran·
ule fractions of pituitary glands taken from normal
animals. Howe.er. it is now recognilCd that thc clear
Crooke's cells do not take up antibodies directed
against ACHI, that they form following chronic eX-
p:;tiure to elevated glucocorlicoid levels, and Ihat
very small granules are nol visible under the lighl
mtcroscope.
Indications that ACTH is made by b(1sopho/ic
cells include {aJ of basophilic dumps
in some of Ihe Crookc's celts; (b) Ihe presence of
highly vacuolaled cells with basophilic granules in
Ihe glands of dogs; (c) baso-
philic lumors in Ihe piluilary glands of SOme palienls
with Cushing's disease; (d) some reports Ihat the ba-
soph ilic zones within the anterior portions of the pars
distalis of a few species contain ACTH-like activity.
and that Ihe cells bind anti·ACTH antibodies.
AI! of the observations arc difficult to interpret.
ACTH is leached from cells during preparalive pro-
cedures. and this raises questions concerning the
origins of the substances that lake up antibodies di·
rected against the hormone. ACTH shares a 13-
amino acid sequence with ",·MSH (which is found
in basophils). and some antibodies bind to both hor-
moncs . Adrenalectomy and stress have been used 10
artificially stimulate the corticotropes. but the ad-
ministration of saline and nutrients Ihe
changes in adcnohypophysial morphology. More-
over, glucocorticoids exert negative feedback con-
trols over melanotropes as well as corticotropes. In
at least some species, Slress affects the functions of
melaoolropes (69.70) and also of laClotropes, soma-
totropes. and Ihyrotropes .
A y-cell Ihal in SOme ways resembles chromo-
phobes bUI contains PAS ' vesicles has been de-
scribed for human pituilary glands. The numbers
and si1.cs increase after adrenalcetomy. and they de-
crease after long· term administration of gluco-
corticoids.
In dog •• cells c.lled lKulrophii. may corlicolrope.o;.
Ho.... ver. the neutrophil. of Other 'p<eie$ SCem to be
idenlieal with Ih. r..,ell •. tn diff.... n1 •• rt.b .... Ie •. ACTH
activity can be d.lected in barophitie cells of the par.; tub-
eraH •. In 1.leosl fi.he •. th. "X" cell. wilh;n Ih. "",Iro-
medial r'gions of the adenohypophysis have been impli,
•• Ied in ACTH ..eretion.
Melanotropes
When it is prescnt as a clearly demarcated structure.
the pars in(ermedia is the major sour<;e of
Endorphins and some ACTH are also made. It is
usually poiSSible 10 distinguish type I (light) cells
from Iyp< II (dark) celis w;lhin Ihe cen(ral region.
However, although the dark cells arc said to
more ACTH, Ihe IwO Iypes may be members or a
OOmmOn populalion Ihal undergoes reversiblc
changes in form and Nongranulated chr<>-
mophobes within the cenlral region may be relaled
to the mc1anotropcs. Cells quile different in appear-
ance border the hypophysial cleft. Some are ciliated.
There are several reasons for suggesting Ihat the
intermedia docs not function like a ··Iypical"
endocrine gland. The secrelory cells of Ihe pars dis-
talis are grouped into cluslers Or follicles. and lhey
are richly supplicd by capillaries. The rew nerve end-
ings in that parI of tbe pituitary seem (0 terminate
cxclusi"clyon blood veoscls. In contrast. pars intcr-
media cells occur in layers. Thc blood supply is
sparse, but the thcre are many n.rlle endings. Neu-
rosecretory subslances of origin
accumulale in Ihe pars inlermedia eclls_
In humans and olher mammals Ihal do not have
a dislinet pars intermedia. r-cells have been found in
Ihe neurohypophysis as well as in the pars distal is.
The funclions are not known . Human blood plasma
evidenlly docs not oontain MSHs of the kinds se-
creted by animals with inlermediate lobes. It is sus-
pected thai some cleavage product of the large pro-
lein thal gives risc to ACTH and related PCPlides
(possibly a -y-MSH) stimulates the mclanocyles.
Perhaps the t-cells sccrete ACTH, while the -y-cclis
(corticotropes) release a pigment-regulating hor-
."
II1Qne. Reversible hypcrpiament3ti(}n or the skin is a
C<,lmmon finding in Addison's disease. and glucoco,-
tiooids correct the condition. Human brain contains
MSH·li):e pc:plides. but ;\ has not been demon-
strated that Illey originate in Ihe pituitary gland.
In birds (wilh "" pars i"termedia). lh. MSH. are con-
centrated in lhe ,oslra J zone of the pars distal i., ",hieh
oomain, orangoophil" thy'01ropc$. and ",<>bably c<>ni·
cotropes. Auempts to define a <-<ell (or molanolrope dif·
fe",nt from l "V" celL or coniOO1fOpe) ha •• b«n made
in the duck.
Aleia" blu" has been used., different pH. 10 "'1''''''.
out basophil type,. One technique i"\'(llon prior oxidation
",ilh "",formic acid 00<1 dusification c.r ba"'pbils inlo R
(performi. acid r.,istanl) .nd S cells (wilh cyst.;"" . ul·
fUHoot"ining 8ranules). Aldehyde Ihioni"" has .1..,
b«n used becauselhe numbers of granules th.1 Slain in·
cr.... progressively with the amount of preoxidation.
1\ lermin(>iogy oom .. imes used Ih.t is .. with
the one described abovo de,ignate< follicuiotropes a. It·
cell'. ;ntCtStit;OIrope, a. ,)"«:11., and thyrotropes as ..
cells.
ELECTRON MICROSCOPY OF THE PARS
OISTALIS
Electron miel"\lSC()Jly, in combination with a utora·
diography and immunological tcehniqudJ, has pro--
vided insights into Ihe StruCtureS and funclions of
par distalis Cl:lls that cannot be obtained with Ihe
light microscope. (5,20.35.46,100) In many cases
the findings have confirmed and extended the ideas
obtained from the earlier work. The structures of
several of th. cell types are shown in Figs. 2-D
through 2-17.
When it first became posIlible to determine the di·
ameters of the secretory granules, it was hoped that
the measurementS could be directly linxed with Ihe
horlllQne chemistry. However, considerable overlap
in hormone COnlen! was found when the granules
were separaled On the basis of size. More(lver, im·
ma ture granules arC smaller than mature ones, and
up to 4·fold variations in diameter bave been de--
scribed for a single cell type (26,42.67).
So matotropet
These cells are the most numerous oflbe found
in the pars distalis and Ihe most resistant 10 post_
mOrtem deterioration. In the glands of healthy non·
pregnant . oonlactating adults, fully half the secre-
lOry cells arc somatotropes. Although they arc more
concentrated near the peripheries. the cells can be
found in all of the pars distalis with the excep-
HYPOTHALAM US AND HYPOPHYSIS
tion of the region bordering the pars intermedia
(whcn this component ;s present). Typically. clusters
of three. four. or five occupy regions around the
blood "sinusoids"
Somatotropes are usually medium_sized. They
can be rounded, oval. or polygonal. The nuclei are
eccentric. and round or nearly round elcctron-dense
granules of fairly uniform ,iz. are scallered
Ihroughout th. cytoplasm. (Most observers report
diameters of 300-350 ml<, but ones ranging from
100 10450 lllI' have been described.) The endo-
plasmic ret iculum often forms a narrow band, but it
is well developed and shows characteristic parallel
arrays. Some of the ct:lIs may be ciliated.
The changes in appearance: that follow thyroid-
ectomy. castration. and adrenalectomy support con-
elusions drawn from light-microscopy studies. No
somatotropes have been found in the pituitaries of a
strain of dwarf mice, whereas hypertrophic cells
abound in a strain of diabetic mice known to ,eerete
large quantities of G H. SomatOlropes rC5pO!ld to hy_
polhalamic extracts rich in GRH, and they are af·
fected by food deprivation and other forms of StreSS.
The population remain.! stable throughout reproduc-
tive cycles. All of the preceding are consistent with
the concept lhat somatotropes are morphologically
distilllluishable from lactotropes.
Lactotropel
Cells ela.. ified as lactotropes are large and numer-
ous in pregnant and lactating animals. but only
small numbers are seen in other females. Even fewer
ce lls of this kind are found in males.
The cells are considerably larger than the soma-
They have oval or irregularly shaped gran-
ules that are most abundant along the peripheries.
Although granule diameters are often reported to
average 100 mp (range 400-9(0), immature organ-
elles as small as 2SO mil can also be found. The en·
doplasmic reticulum is broad, and it bas the kinds of
para llel arrays seen in the somatotropes. Even when
numerous, the lactotropes tend to OCCur singly. seat-
tered Ihrougbout the pars distali •. Many either bor-
der the capillaries Or extend cytoplasmic projections
toward them. Tumors that release large quantities of
PRL, and PRL-se<:reting pituitary explants, contain
,ubstantial numbers of such cells. Thc lactotropes
respond to estrogen administration and to compo-
nents of hypothalamic e xtracts. Crinophagy (lyso-
somal destruction of the granules) has been de-
scribed for the glands of lactating ralS deprived of
their pups (26).
Thyrotrope8
Except for laetotropes in males, th= arc the least
abundant of the pars distalis Stcretory cells. They
congregate in the oxntral regiOll$, and they arC al·
most always located dose to capillaries. Thyrotropes
ean vary in size. but all are relatively small and an·
gular. with spars<: cyloplasm. Most of the gmnules
ha,-e diameters of just 100-200 m)<, and some can
be as small as 40 mI'. In animals subjected to thy-
roidectomy or the administration of propylthioura-
cil. the cells become degranulated and can attain
siles 2-10 times those of normal controls.
Gonadotropes (27,30)
These cells are rounded Or oval and almost invaria-
bly associated with the capillaries. The granules are
less dectron4ense than the ones of somatotropcs Or
lactotropcs and intermediate in sizt. Most have di·
ameters of 150-250 mI'. but a few are considerably
smaller (around 75 m)<). Much variation in both size
and dcnsity is observed within a single cell. The mi-
tochondria are elongated, and chains of vesicles can
usually be identified in the Golgi region . Structures
related to the signet ring cells found under light mi-
croscopy appear in gonadeclomi,.cd animals. Gona-
dOlrop<:s are also affected by conditions such as per-
sistent estrus and Ihe administration of gonadal
steroids. CyClical changes foUow the ovarian cycles.
According to some repans, folliculOtropes can be
distinguished from interstitiotropes. The former are
said to have prominent endoplasmic reticular vesi-
des that contain a substana that appears lighl gray
in the photographs. They have pale nuclei and evenly
distributed granules 150-200 m" in diameter. [nter_
stitiotropes. in contrasI. have smaller electron_lucid
cisternae. granuks with diameters of 200-250 ffij.I
aggregated into clumps. and a sparse. ftoc.:ulent pre-
cipitate within the cytoplasm. The cells are said to
have a "filigree·· appearance. The lilerature also
contains descriptions of cells intermedialC in type
that cannot be dall5ified as either folliculotropes Or
inte rslil iot ropes.
Cortlco1ropes
Electron microsoopy has provided some
for the difficulties encountered in allempts 10 iden-
tify the ACTH·secreting ceil,. Conicotropes have
highly irregular contours that can range from Stel-
late to U-shaped. Many send out long processes that
extend toward the capillaries, and $Orne of the pro-
jections totally encirde neighboring cell,. The nuclei
are often located at some distance from the ends of
the processes. The granule diameters Can range from
SO to 200 mI'. but most arc very small. Some authors
state that they are surrounded by dear regions
("halos··). but others believe that the formations are
artifacts that arise when the ce lls arc prepared for
sectioning. The mitochondria are long and narrow.
and they can appear to be bent or twisted. It is likcly
that the cells with vcry small granules arC the ones
classified as chromophobcs by light microscopists.
(However. "true chromoph<:>bes do not have any
n
granules.) The corticotropes are affected by adre-
naicctomy and the administration of glucocorticoids
(86).
Melanotropes
The type I cells fou nd in rats and some other species
are abundant and cuboidal. Tltey have granules with
diameters of 300-350 mIl. T ypc II cells are angular
or Slellale. and they have smaller granules. Both
types undergo changes in animals subjected to ad,
renalcetomy. The "Crooke's cells" found in the pi_
tuilary glands of pat ients wilh Cushing·s disease and
in animals overdosed wilh glucocorticoids are be-
lieved by some to be enlarged, mclano-
tropes. In species that do nol pos.sell5 a pars inter-
media. cells with similar characteristics are widely
distributed 10 Ihe pars distalis. and lhey can also be
present in Ihe neural lobe.
Chromophobes (26)
Several cell types that differ in sizes, shapes. and lo-
cations. but share the COmmOn property of being de-
void of secretory granules. have been described.
They have been called ctllj in some spe-
cies, since they surround colloid-fIlled follicles into
which they send microvilli and occasional cilia. For-
malions Oflhis kind are found in the pituitary glands
of humans. cattle. dogs. and rats. Rabbits are among
the species that do not have them. In these. the term
interslilial (t ill has been applied 10 clusters of stel-
late cells thaI appear to have similar properties (30).
Scveral funclions have been aseribed to the chro-
mop hobes. Since the numbers are greater in young
tha n in older glands (up to 40% of the total popula·
tion in the former and mOre like 25% in adults), and
since they decrease when other cell types increase in
response to adrenalectomy and other conditions, it
has been proposed that at least some arc "stem cells·'
or undilTcrentiated chromophil precursors. However.
young pitui tary glands contain large numbers of
heavily granulated "dark" cells that are rarely seen
in mature glands (7). Moreover. granular cells can
divide by mitosis when they are maintained in cul-

ture. At\Qther conccpt is that chromophobes are dc·
granulated or degeneraling chromophil$, It has also
bc<:n propo&<d that chromophobes perform nu tritive
and phagocytic functions. Roles related to hCTI-!
secret ion have been considered.
MICROSCOPIC ANATOMY OF THE PARS
TUBERALIS
Capillaries of the pars tuberalis carry regulators
from the hypothalam us to the pars distal; •. The ves-
sels have a flallened , fenestrated appearance consis-
tent with high permeability to peptides. Cords of
"""mingly undifferentiated cells Ottupy spaces be-
twecn the capillaries. Some of the cells a rc grouped
into follicles. and microvilli Or cilia can extend to-
ward the lumina. There arc also large intercellular
spaces ,
Whcn hormonc-sccreling cells were r.rst identified
wi thin the pars tubcralis. some observers suggested
that thei r appearance resulted from "invasion'" by
pars distalis components. However. substantial
quantities of gonadotropins can be made there in an·
imals subjected to "hypophysectomy" (36). Histo-
chemical studies. investigations of the biological
properties of pars tuboraH. and observa-
tions or the etTe<:ts of manipulations of the endocrine
un pars tubl;ruli, hi.tulvgy .upport the
that some TSH and ACTH along wilh sma ller
amounts of GH and PR L are secreled. It has also
been suggested that tropic hormones unique to th.
region are synthesiled.
MICROSCOPIC ANATOMY OF THE NEURAL
LOBE
The neural lobe is populated mostly by the dilated
axon terminals of thc hypolhalamo-hypophysial
nerve tracts, sinusoid·m,e and pituicytes.
limi ted numbers of r.broblasts are also present, and
in some species scallercd me1anotrope-likc ..,lIs Can
be identified (13,46).
ElectrolHlense granules with diameters of 100-
250 m" f,lI many of the endings. and the term
Herring body has been applied to large granule ago
gregates. They contain neurohypophysial pc ptidcs
and neuroph}'sins. Most of the structures arc as.<a-
ciatoo with pericapillary spaces.
Synaptic vesicles 20-40 Ill>' in diameter are also
present within the uon terminals, These. and micro-
tubules. are more easily seen in animals that arc de-
hydrated before sacrifice (since much of the !lor·
mane content is then discharged). Small uon
endings d.-oid of granules ean usually be found.
The pituicytes vary widely in si7.e and shape. They
HYPOTHALAMUS AND HYPOPIiYSIS
e xtend long processes bet,,'c.::n the axon cndings. and
the tips also reach the peri capillary spaces. Many
contain pigment granules. The pituicytes arc widely
regarded as speciali7.ed neuroglia l cells that perform
supporti .. and nutritive functions. However. it has
been proposed that they play roles in regulating thc
release of the neuroh)'poph)lSial peptides. Many
large. intercellular spaces are secn in stained
preparation,.
THE HYPOTHALAMUS
The hypothalamus forms the floor and lower lateral
walls of the 3rd ventricle of the brain. It extends
from the optic chiasma backward 10 include the
mammillary bodies. The separation from the thala·
mus is marked by a usually horizontal groove, the
hypothalamic sulcus (which is prominent in some
species and inconspicuous in others). The cerebral
ganglia, optic tracts. and subthalamus provide the
lateral boundaries , Demarcations from the ante-
riorly located olfactory rcgions and the posteriorly
situated central gray and tegmentum of the mid·
brain are indistinct.
Anatomically. the preoptic region of the brain be·
longs to the telencephalon (whereas the hypotha la·
mus, thalamus. and related structures arc compo-
nents uf the <licnccphalun). Huwever. be<;ausc ur the
intimate interrelationships. the prcoptic region is
often regarded as part or the hypothalamus. The
term pmrhalomlls is also used to designate the
preoptic anterior hypothalamus (47).
Most of the ncuron cell clusters are located within
or jUM above a longitudinal bulge (the tuber ci ner·
c um) that extends from behind the optic chiasma to
the mammillary region. Some of the n"uroll'S ex·
tended long axons downward through thc infundi.
bulum to tb" neural lobe of the pituitary gland. Oth·
crs communieate with the adenohypophysis by
releasing regu lators intO blood vC5SCls that pass
through the median eminen"" at the upper part of
the infundibulum (89). The median eminence be·
longs to both the hypothalamu, and the
neurohypophysis.
Component Perts
This part of the brain (a) magrwcel/Illar
fllleI..i, i,e. clusters of mostly large perikarya that
send long axons to the neural lobe: (b) icss uniform
clusters of mostly smaller neuron cell bodics. the
par>-icelllliar (parvocellular) fludei: (c) axon bon.
d ies grouped into wrw /rllC/S; (d) diffuse lit/warts
of mostly fmc nerve fibers: (c) several kinds of Mil·
FOglia that include the ependymal "'lis (taneytes)

bordering the 3rd ventricle of the brain; and (f)
blood ,-,,".,(,/s.
The term "hypothalamic area" is ap-
plied (0 in which groups of impli·
cated in common functiollS do nOi form clearly de·
nlarcatcd struCtures.
The,., are mMked <pec;e< variation, in Ihe <i"e<,
shpes, and ge<>graphical orientations of Ihe hypo-
thalami as a wilole, in the oontours of the 3rd ven·
in the relative shapes, and locations of
Ihe major ccn clusters. and in the cxtents to which
the nuclei are analomically defined. For example,
the rat has a moslly longitudinally direcled hypo-
thalamus. dearly identifiable supraehiasmalic nu-
clei, and a single mammillary protuberance. In oon·
trast, Ihe human h"s a more ve rt ically arranged
poorly defined suprachiasmatic cdl
clusters. and paired mammillary bodies. The infun-
dibular of primates is the oounlerpart of the
paired arcuate nuclei of rodenlS.
Figure 19-6 provides some gencraliled indicalion
of the locations of most of Ihe major cell groups . The
figure is somewhai distorted. since il is not possible
10 oblain a thin of hypothalamus Ihat con-
lains all of the nuclei shown. Periventricuiar nuclei
have oot been included. Thesc are oolumns of cdl.
located ... ithin Ihe gray mallcr Ihal is close 10 the
lining of the ventricle. The fornix passes through tbe
hypothalamus, and tbe term nucleu. is
applied \0 associaled neuron cluslers.
For purposes of discussion, it is often oonvcnient
to divide the bypothalamus into longitudinal and
transverse sections, One scheme is s hown in Table
19-3, but most aulllors include Ihe supraoptic nuctei
in the medial group. More detailcd descriplions, dia·
f ig. 19-6. o;ogrAmmII'ic
of hypothalamic """I";.
11ft oMelior hypothalamic; AR, .r"".,.;
OM, dot""",o<IiOI; OC. optic c/"Onrna;
PH, postor;o, hypothalamic; PO.
p'''''Plic; PV. para • • otricula r; SCH ,
supr.<:Ili.aom.tic: SO. oupr.optic; VM,
v""tr_lI.
grams, and photographs are available in the lilera-
\Ufe (40.47.62.95).
Hypothala mic " Centers"
It i< often to elicit predictable rcspon<c. 10
stimulation of circumscribed regions of Ihe hypo-
thalamus, and 10 invoke changes opposite in dire<:·
tion when the same loci are destroyed, Pituitary
glands implanted into certain regions retain Iheir
ability 10 make hormoncs in the relative amounts re-
leased by in situ organs. wherea' glands embedded
elsewhere synthesize only minimal quanlities of go-
nadotropins, ACTH, and TSH , The invesligalor can
"selcctively" modify the se<:rction of insulin, sluca·
gon, GH, and other hormones, affecl [ceding Or
drinking , invoke aggression Or somnolence, alter Ihe
responses to environmental temperatures. and oon·
trol other functions.
It was therefore proposed Ihal the hypothalamus
conta; n S "h)' pop h y,iotropic", .. feeding". .. d rink_
ing'", "satiety'", "temperature· regulating",
a rou 'a I". "sym pa Iheti c". "parasym pa t heli c". "re'
product ivc behavior". .. pi eaSure·rewa rd". "c mol ion·
ality." and other "conters," Some observers suS'
gested thai. with refinement of the techniques. it
would soon be possible to draw hypothalamic maps
showing the oontrol siles for each of the aclivilies.
It has since been reoognized that (a) a single kind
of re.ponse can be eliciled when mOre than one brain
region is stimulated; (b) the smallest of lesions can
affect uons passing through Ihe arca as well as the
perikarya targeted for deslruction; (c) Io...·;ntensity
stimulation with eVen Ihe finest electrodes can affccI
'" HYI'OTHAl.A Ml}$ AND HYPOPHYSIS

llbl. local"'" of NIlI.<on CfII Groups

Preoptic pO. ;"".u;cui>, 00<1,",

Suprachi..",.I;, "ucl •••
p.,.,.n,,;cul., nuclou,
A","", "ucl,.,
I'o<,«00f "uok .. 0< " ..

Mcdi.I _,ie "ud<u,

V••"....di.l """'0.'
Dot.om<di.1 "ud,.,
An'<"'" Of<.
Pr<m,,,mill"y"",icu.
l."", 'ube",l ""ck.,
Rwochi .. mOli< .,ea

L. ,<",' L.""I _tic ""ck..

L...,. I hypOlh. l. mic "uol<u,
Tub<romommillary "uol."
S'P<*<'P'i< ,,,,,Ie.,

Pr""",", J'O""".,,;cul .. ""<Ie ••

M.dial "ucl,u,
La,,,.1 _ i c nucku,
SUp"op<i< "",Ie.,
Supr>chi,,,,,," ic "o,iou,
11."'''''''"..,,",
Po ... ","""" lOt "uclo.,
Ante';"" h)'poIh.al. mic.!'U

M iddl<. ,.bora l. 'o/"od'b.l" Dotoom«li., nuclou,

C •• d" . pos«,;or. m.mmill. ,),
V.,t""",diol nucl,",
"'"",,1< .......
n.be,.,.,..mm ill"y"ucl,.,
La",. 1tube ..1 nuck.,
La" .., kypolh. l. mio "o"k • •
p.,.'crior lIypotb.l.mic """Ie..
0< ... .
Prcmammill.'Y ouol,.,
M.di.1 rnammillory noeloo,
In,..m,d;'" m. mmill.ry "oel, o,
Lo'e ..1 ""mmillary nod,.,
S.prom. mmiUary . rea

the activities of distantly neurons; and (d)
the response to manipulation of a highly circum·
scribed locus can vary witb tbc species. the sex. the
age. the endocrine status. the nutrit ional history. and
the past of the subject. as well as with the
time of day, the simultaneous stimulation of extero-
and interorcccptors, and thc context in which the
stimulus is presented (47).
It is thercf= more realistic to thin k of the hyflO"
thalamus as a highly c()mplex ()rgan with interre-
lated pans that communicates directly Of indirectly
with all other body components. It receives inputs
from the en"ironment as well as from inleroreceplOrs
and other neurons. it proctsses the information in di.
verse ways. and it IrallSmils signals to. among other
things. the integument. the organs of the digestive.
cardiovascular. respiratory, renal. and reproductive
.ystems. the spinal cord. the skeletal muscles. the
adipose tissue. and the other pam of the brain. It
can even affect the immune functions (29). The hy-
pothalamus activities of other con-
trol sites, and it affccts the tendencies to iniliate,
conlinue, or terminatc many forms of behavior.
The responses 10 slimulation are not as simple a.
some of Ihe early reports suggest (47). The topic is
considered in detail in the section em regulalion of
food intake at Ihe end of this chapter . Some other
examples are ciled.
If eleclrodes are implanted bilaterally within ap-
propriate partS of the lateral hypolhalamus. and a
tube of watu is provided. Ihe animals can be ex-
pected 10 drink each time the current is turned on.
The response can be inV<lkcd in ovcrhydratcd sub-
jects as well as in ones with good waler balance.
However, if the drinking tube is removed. the ani-
mals eventually display different forms of behavior
when the same electrodes are repealedly aClivated.
The new responses arc not predictable. and they may
be totally unrclated to waler intake. eVen ,,·hen a
dish of Huid is for the drinking tube.
Once the new patlern has become cslablished, Ihe
animals no longer use the drinking tube if it is again
presenled al the time of stimulation.
When lesions are made in the same part of Ihe
hypolhalamus, dehydrated animals slOP drinking,
and Ihey oflen refuse to s",.. llow water placed di_
rectly in the mouth. If Ihey are kept alive by foreed
administration of Huids, many recover some ability
to drink and 10 respond 10 osmotic stimuli (a lthough
the lesions are evidem al the time of autopsy).
Laboratory animals have been provided with
mechanisms for V<lluntarily aClivaling Or inactivat·
ing electrodes placed in the lateral hypothalamus.
Since they usually show strong ··motivation" to self·
stimulate. the loci have been called ··pleasure cen·
ters.·· However. iflhe animals are either force-fed Or
chronically overfed until Ibey become obese before
being placed in the test situalion. they make strong
e(forts to avoid the stimulalion . The same regions
can Iherefore be called ·'aversion cenlers:· Olher
pam of the brain have been classified as '·pleasure;·
"aversion:· or ·'silenC· regions on the basis of the an-
imals' responses 10 Ihe opportunity to self-stimulale.
Parts of the anlcrior hypothalamus have been
called "parasympalhetic centers·· and loci within the
posterior region been named ·'sympathelic cen-
ters." Refinement of Ihe teChniques for identifying
neuron cell bodies and their associaled axons has re-
vealed thai there is no absolute separation of the
funclions. Moreover. il i. 10 activate one
acetyleholine-dependent target without affecting
most others.
On the other hand, since responses to stimulation
Or destruction of a few hypolhaiamic loci are repro-
ducible. fUllCtions linked wilh certain of the cell
groups and fiber tracts are described.
The Ma gnoeellular Nu c le i
As the name suggests. the magnocellular nuclci con·
lain clusters of very large ncuron perikarya. They
arc major siles for the production of hormones th:ll
arc transported 10 and released from the neural lobe
of the piluitary gland.
The struclures and their relationships to Ihe hy_
pophysis were described in Chap. 2. The hormones
and the stimuli for Iheir release were discussed ;n
several sections of Ihe leXI (sec especially Chaps. 7,
10, and 16).
The supraoptic nuclei (SON) stra ddle the rostral
and la teral surfaces of Ihe optiC tracts. They conlain
mQSlly giant perikarya with characteristic features.
A Iypical SON cell has a prominent. centrally lo-
cated nucleus, with numerous membrane pores, that
is surrounded by a clear ring of cytoplasm. The nu-
cleolus is large. the e ndoplasmic reticulum and Golgi
apparatus are well developed. and many darkly-
staining Ni!sl granules arc distribuled along the cell
periphery. In some species. clusters of similar peri·
karya can be found nearby.
Most of the vasoprtssin and ils associated ("-ni-
cotinNlimulated··) neurophysin that enter the sys-
lemic blood are synthesized in the SON. However.
Ihe paraventricular nucle i supply some of the hor-
mone. and the peptide is also present in the supra·
chiasmatic nuclei. in other parts of the brain, and in
the cerebrospinal ftuld. CoeXISts
wilhin Ihe same cells, and it is rcleased in response
to slimuli such as Ihe administration of large quan·
tities of NaCI. The pentapeplide can inhibit vaso-
pressin release, and it is believed to contribute to reg·
ulation of the sec ret ion of Ihat hormone (84). Leu-
enkephalin may additionally act in Olher ways to af-
feCI water balance.
Vasopres!in (antidiurelic hormone) is probably
best known for ;IS actions on the collecling duelS of
the kidney. The stimuli for its release include angio-
tensin. a hormone produced in large amounts when
Ihe extracellular Huid volume contracts. Osmorec<:p-
IOrs, pressoreceptOTS. and thermoreeeptors cOmmu-
nicate with the magnoceilular nuclei. and there have
be.::n recent suggestions that some of the hormone-
producing cells respond directly 10 osmotic stimuli
(39).
Vasopressin acts via different mechanisms to stirn·
ulate smooth muscle contraction. When presented in
physiological quantities, it sele<:livc innuences
on blood vessels. It also contributes to blood pressure
regulation by inhibiting renin release. and it may ad-
ditionally act cenlrally to control cardiovascular
funclions (10). High concentrations promote Ihe
contraction of uterine musc le, and roles in parturi·
lion have been proposed. Vel higher levels 51imulale

intestinal The vasopressin that acts eemrally
probably originates in neurons located within the
paraventricular nuclei and other parts of the brain.
Ind ications that vasopressin contributes to re-
sponses to stress come from several sourcC$.
stimuli accelerate release of the oormone, and vaso-
pressin with CR!! to promote the !;Cere·
tion of ACTI!. Antibodies directed against CRI I
cannot fully suppress ilrcss·associated "CTH dis-
charge, and vasopressin antagonim lower the
ACT!! levels (83).
Influences on learning and memory were dis-
cussed in Chap. 7. The"" may be mediated mostly
by metabolites that do not stimulate vaseular smooth
muscle. A highly potent with the follow-
ing st ructure has been identified (I g).
H·Cys-OH
I female reprodUctive tract and mammary glands.
pGlu-Asn-Cys-Pro-Arg-Gly·NH,
Vasopressin is additionally implicated in the modi-
fication of reproductive behavior (g8), and it is pres·
cnt in parts of the hypothalamus that regulate cir-
cadian rhythms (Chap. 20). Rats with genetic
defecls that block vasopressin synthesis suffer para·
doxical sleep defecls. but it is nOi known how much
of the diHieully is linked with the TlCCd 10 drink at
frequent in tervals (22).
There are controversies concerning the physiolog-
ical significance of the effects of high concentrations
on melabolic funclions such as glycogenolysis in the
liver and lipolysis in adipose tissue.
Noomammalian venebrOle magnoceUular nudei do
001 make v""'Pressin. but they synth..i>e related
tides that include arBi";". va"'tocin. The latter play.
role. in water balance regulation and it.timul.... smooth
musele.
Different SON cells make oxytocin. ·'estrogen-
stimulated·· and met-cnkephalin . but
the relative numbers of oxytocin cells arc much
greater in the paraventricular nuclei. Brattleboro
rats have genetic defects that include inability to
make vasopressin. Their SON contain and
both of the enkephalins. ($cc A·2 and A.3.)
The paravtnlricular nudd (PVN) are ncar the
top of the 3rd ventricle. The cell clusters arc dON<lI.
caudal. and medial to of the SON. and they
can extend in broad. vertical bands toward Ihe hy-
pothalamic sulcus. In humans. Ihe cell columns
begin near the dorsal margin of the anterior com·
missure, just behind the part of the fornix that gOCl;
to the mammillary complex. Pressure exened by the
fornix can cause the PVN to bulge into the 3rd ven_
tricle (24). The most inferior portions curve toward
HYPOF'tiYSJS
the SON. In rats. fibers have been traced from the
PVN to Ihe amygdala, Ihe band of Broca, the locu.
ceruleus, and the spinal cord (47).
The cell populations are more diverse than those
of the SON. Half are of the magnocdlular types al·
ready deseribed, and most of this group synthcsi1.c
oxytocin in rodents. cells account
for substantial but smaller proportions of the mag-
nocellular components of the PVN in primates. The
oormone stimulates thc smooth muscle of the uterus
of mammals and the myoepithelial components of
the mammary glands. and it Can act on the oviducts
of ",me nonmammalian vertebratcs. II innu-
enees on blood pressure, water and brain
functions different from the ones associated with va-
sopressin, and it facilitates expression of maternal
behavior in some laboratory species. ne secretion is
accelerated by C!itrogen$ and by Slimulation of the
The plasma concentrat ions rise somewhat around
the time of ovulation and to a greater extent during
parturition. The highcst levels can be attained soon
after lactation is instituted.
Conditions such as waler depriva tion and hemor-
rhage can promote the release of some oxylocin.
while activation of the receptors of the reproducti .. e
tract or mammary gland has been \.:nown 10 elevate
Ihe vasopressin levels. Acetylcboline is one of Ihe
neurotransmiuers that stimulat.. both types of mag·
nocellular neurons.
Oxytocin is present in Ihe spinal cord, in the thai·
amus. and in other pans of the hrain.
Fi.he. do not posses. pa ... ventrkular nuclei. but the)"
make chemically r"lated peptide. in th,,;r preoptic nuc lei .
Tht$<: h••e a unique . trueture located otthe
caudal end of the spina l cord known 0$ the urophYJiJ.
Regulators produced there indude peptides thot affect
the systemic blood pressure.
The hypothalamo-hypophysial nervc tracts that
course Ihrough Ihe infundibulum and tcrminate in
the neural lobe of the pituitary gland carry the pep-
tide hormones and Ihe neurophysins that arc subse·
quently released to the systcmic blood. They com·
prise moslly axons that originate in the SON, but
they also receive fibers from the PVN.
The magnocellular axons that terminate in Ihe
palisade lOne of the median eminence (55) and in
the vicinily of the pars intermedia of many species
may arise mostly (or exclusively) from Ihe PV N. In
addition 10 releasing hormone. into the portal bl<Xld.
PVN neurons arc believed 10 engage in retrograde
transport of molcculc;s upward to the brain (68.84).
The pars intermcdia is rich in tI-cndorphin as well
as in (l'-MSH. Although it receives innervation from
Olher sour<:cs, Ihe magnocellular nuelei probably
play very important roles in the control of its. secre-
tory functions. It is not known whether comparable
mechanisms regulate the mcianotropes of humans
and other species in which no distinCI pars interme-
dia persists.
Vasopressin can promole the release of endorphin.
and endorphin. in turn, accelerates vasopressin re-
lease. Endorphin also aClS peripherally 10 alfcct
waler balance and ",sponses to some forms of stress.
AI leasl some of the endorphin travels to Olher siles
10 perform dilferent functiollS. However, although ef_
feelsof the peplideon a variely of largCls have becn
cSlablished, ;1 is also recognized Ihat endorphin is
synthesized by dilferent neurons and by pars distalis
cells.
Endorphins imeraci in several ways with the glu-
cocorticoid system. Thcy inhibit ACTH secretion in
humans, possibly by acting directly on the pituitary
gland (92). bUI opioids promote CRH ",lease in rats
(17). Glucocorticoids and adrenalectomy are
to alfect the release of hormones derived from
POMC that alfect pigmcntation. and they arc re·
ported to aCI on endorphin·releasing neurons tbat
terminale in the median emincnce. Glucocorticoids
exert influences on food inlakc. and rolcs for cndor.
phins in this function have been suggested (84). In·
sulin is also a major regulator of food intake. and a
peptide cleaved from POMC (ACTH" .,,) identi·
fled in Ihe pars intermedia of genetically obe.,e mice
has been shown 10 funelion as an insulin secreta·
gogue (9). Endorphins are also cleaved 10 smaller
peptides that exerl inAuence, on Ihe brain very dif·
fe rent from the OneS invoked by Ihe precursors (74).
The idea that oxylocin is cleaved to" pentapeptide
Ihat stimulates MSH secretion. and IwO tripeplides
Ihal inhibil (51) was discussed in Chap. 3. However.
the subsla nces have 110\ lived up to their early prom-
ise. Although M1F·1 (Pro-Lcu·Gly·NH,) Can de-
crease MSH release under ccrtain conditions. it is
now doubte<.! thaI this is its physiological function
(SO). Both M1F·1 and T yr-M1F·1 (Tyr·Phe-Leu-
Gly· NH,) are made in vertebrale brains. and they
have been shown to exert SQmc antidepressant ac·
tions. Central ly synthesiled dopamine and GARA
may be the major inhibilors of MSII sec"'tion (91).
As discussed in Chap. 20. homootherms and poibl.
o(herms have different uses for pigmen( cells. MSH ·
releasing faclors probably vary across the species.
TRH is reported 10 be effeclive in frogs bUI not in
rats.
MSHs dearly regulate pigmcntation. but they ad·
ditionally alfect waler and ciectroly(e balance and
appear to funclion within the centralncrvous system
as ncurotransmitters and neuromodulatOfS (71).
Several dilfe",m kinds of MSH molecule. are
known to be made in ooth N-{lcel}'lated and non·
acetylaled forms. It has been sbow n in amphibians
that the PCPlidcs are atetylaled just before or during
release from Ihe pituitary glands. and that the re·
action is inhibite<.! by dopamine (65). In mammalian
brains. the acctylaled molecules are more potent
regulators of behavior (72).
Smaller neurons within (he PVN are implicated
in very different functions. Elcc(rical stimulation can
lead to the release ofTSH and FSH . TRH is present
in the neural lobe, and it is probably made in Ihe
PVN. According 10 some aUlhors. a specific FSlI-
Rli is also synthesi7.cd.
Other regulalors identifie<.! in Ihe neurohypophysis
include oomatOlOlalin and molecules Ihal bind anli-
bodies directed againsl eholeeyslokinin and neuf\)-
lensin. Although some of the peptides may originate
in Ihe PVN. it is known that the non terminals Can
up small molecules from the microenvironment.
The PVN also make functional conncctions with
the sympathetic nerVOUS system a nd with the en·
kephalin·rieh dorsal motor nudei of the vagal
nerVes. Lesions of the PVN invoke hyperphagia that
leads to the development of obesity in mature rats.
and norepinephrinc injections into the PVN increase
the appc(ite. The manipu latiollS probably a lfect food
intake in ways different from Ihe one, secn aflcr Ie·
sions arc made in Ihe ventromedial nuclei. For one
thing, PV N lesions have not been observed 10 inAu-
enCe lipid ntelabolism (or food intake) in weanling
rats (12).
Parvicellular Nuclei
The parvicellular nudei contain diverse populations
of mostly small perikarya. Some arc less well define<.!
Ihan others. and the term hypmh%mir 0"'0 is used
when thc arrangements are diffuse.
The (infundibular) nuclei form masses of
gray mailer near the bollom of the 3rd ventricle.
They lie below the vcntromedial nuclei. and Ihey cx-
tend from the middlc of the hypothalamus to the
premammillary area.
Some authors deseribe two distincl cclllypes and
olhers cite threc. Mosl have a highly developed
Golgi with numerous sacs and vacuoles. T he clee-
trolKlense vesicle" abundant ribosomes. and prom·
inent endoplasmic relicula 3rc all consistent with
high ralCS of protein ,ynthesis and secretory activity.
The arcuale nudei a", major sources of the LRH
lhal enters the porlal blood. If connections between
the medial basal hypolhalamus and other parts of
the brain are disrupted. enough LRH is released to
mainlain leSlosterone secretion in adult males and
Ihe function, of some ovarian cells in fcmales. How_
ever. loss of inputs from the preoptic region leads 10
lermination of the pfC<lvulatory LH surges in mam·
mals with estrous eyeies. The pathways may conlrib-

'"
ute tQ of the menstrual cycles of primates.
but monkeys can ovulate when the culS are made.
LRH is widely dis\ributed , and ther<: is good rea-
son 10 believe thai i( is 31 many sites. It
alTccls reproductive behavior. even afler gonadec-
tomy Or hypophysectomy. and ;1 exerts other inllu-
ences on the brai n. An LRH-lil:e mole.:ulc performs
neurotraosm;Ucr functions in the sympathetic gan-
glia of bullfrogs (48). and some components of mam-
malian reproductive systems oontain receplors that
can in1CraC! with the peptide.
Immunocytochemical sludies have revealed that
one cluster of LR H neurollS o<xupies Ihe lateral por_
tionl of the arcuate nude; and extends rostrally and
laterally 10 lhe internudear regions in rals. A see<;>nd
clusler is loosely distributed 10 the prooplic septal
the bed nucleus ef the anterior commissure,
and nucleus ef t he diagonal band cf Ilroca (54).
The axens not grouped inte defined fiber tracts.
but beth clusters send prcjectiens te the median em-
and to the organum vasculosum of the lamina
torminalis. In somc species. additional projections
have been traced to the periventricular thalamus.
and to parts of the midbrain. Some LRH is also ap-
synthesized in cells of the ventrcmedial
nuclei.
Different arcuate nuclei components provide most
01" tbe C3te\:oolamincrgic neurons of tbe inlundibular
tracts that terminatc on the median emincnce. Other
axons havc been traced to the ventromedial nuclei.
Much of the dopamine is rdcase<J to the palisade
zone. whereas nor<:pinephrine is dis-
charged to the internal wne (54). Species differ-
ences in the r<:lative amounts of dopamine (OA) and
norepineprhine (NE) have been dcscrilxd.
DA from the arCuate nuclei function, more like a
"true" hormone than a ""urotra nsmitter. It i, such
a potent inhibitor of prolactin sec retion that many
believe it is the major PI F. It also affects the seer.,.
tion of growth hormo"". of gonadotropins. and of
other adenohypophysial regulators (see Pans V and
VI). Estrogens excn important innuences over pro-
lactin. growth hormone. gonadotropin. and melano-
cyte stimulating hormone and some of its
effeets ha'e been linked with changes in DA
turnover.
Preoptico-tuberal system course through
the anterior hypothalamus on their way to thc ar-
cuate nucleus. but fibers of thc corticothalamic
tracts first enter the suprachiasmatic nuclei. The me-
dial corticohypothalamic tract carries fibers from
the hippocampal formation and the amygdala.
ACTH and ,e..,ndorphin have been identified within
the arCuate nuclei (41). In at least SOme species.
there is strong binding of antibodies directed against
tWPOHIALAMUS AND HYPOPHYStS
growth hormone hormone. and the
;s also rich in substance P. Ventromedial "'gion$ of
the hypothalamus probably send in regulators that
inhibit LRH release. Lesions there Can invoke pre-
matur<: onset of puberty.
The ""ntromedia/ nudei (V MN) complex
structures whose functions overlap to some ex tent
with those of the areuate. In many species. they
sCX' m to be the major SOUrceS of GRH and of soma-
tostatin. They also contribute to the regulation of
TSH. ACTH. and other hormones. Along with the
arCuate a nd paraventricular nuclci. they are com·
ponents of the hypophysiotropic ar<:a (HTA) . Pitu-
itary glands implanted ther<: retain the ability to se-
Crete adenohypophysial hormone, in relative
amounts that approximate those of glands in their
normal locations. VMN neurons also alfect the s.,.
cretion of ins ulin and of glucagon, and they interact
with autonomic nervous ,ystem afferents and elfer-
ents involved in the control of digestive system
functions.
On the basis of cell densities. the nudei have been
divided into de>fSOmedial and ventre>medial portiC>ns
that are separated by a c.::1I-poor center (54) . A
"capsule of axons·· formed mostly by fibers from the
stria terminalis but containing a fcw from the medial
forebrain bundle and lateral hypothalamus has becn
described. There are elterent oonn<:ctions with tbe
lateral hypothalamus. the anterior area. thc mam-
millary complex. the septum. and the amygdala.
Roles of the VMN and related parts of the hypo-
thalamus in the regulation of food intake dis-
cussed later.
The suprachiosmatic nudt i (SCN) of ratS ar<:
made up of prominent. densely packed cell clustcrs
situated cloo: to the 3rd ventricle. They lie abeve.
and a re partially embedded within. the <>ptic
chiasma. Although wdl defined in many other mam-
mals. the cells are diffusely arranged in humans.
The SCN from the
thalamic tmets. the lateral geniculate nuclei. the ser-
otoninugic neurons of the mesenceph alic raphe. and
other parts of brain. Efferent fibers have been
traced to the peri ventricular area of the hypothala·
mus. and to the dorsomcdial. ventromedial. and ar-
cuate nuclei. Some axons go thc median cmincn<:c
and to the medial forebrain bundles (47), and there
a re connections with thc pincal gland.
The SeN are believed to function as biological
clocks that regulate sleep-waking. locomotor. feed-
ing. drinking. glucocorticoid. pineal enzymc . and
other body rhythms (49). Diurnal variations in the
concentrations of serotonin. catecholamines, and
other regUlators have been found in animals
to natural changes in environmental lighting. De-
struction of the afferents from the retina docs not
abolish the rhythms. but it destroys synchronization
with the photoperiod. SeN lesions seriously impair
many body functions. including estrous cydcs,
The dorsomediol nuclei are distinguishable from .
but less prominent than. the VMN in rodents. and
they are pOOrly defined in primates. They are func-
tionally oonnected with the amerior hypothalamic
area. and with some parasympathetic and sympa·
thetic preganglionic neurOnS.
The mammillary bodies arc oollections of neuron
cell bodies that vary in si7£ and number across the
species. The medial mammillary nuclei are the larg-
est of the group. and in humans these occupy mOSt
of the VQlume of the mammillary bodies, Int erme.
diate (intercalated). lateral. and small. more dor-
sally located supra mammillary clusters can be idcn·
tified in many species. The tuberomammillary and
premammillary nuclei of the posterior hypothalamus
are not usually incl uded in the designation "mam-
millary complex:' They are functionally related to
the periven\ricuiar syStem that is described later,
The medial mammillary nuclei give rise to the
mammillothalamic tract' that travel to the ante rior
nuclei of the thalamus. from there. information is
transmitted to the cingulate gyrus of the forebrain,
The latter. in turn. sends axons to the hippocampal
formation, The "Papez cireuit" is completed by fi·
boo .. that go from the hippocampu. 10 the mammil·
lary bodies_ The circuit waS initially implicated in
the mediation of overt expression of emotion (but not
with the associated conscious experiences). Accord-
ing to more modern concepts. the "limbic system"
includes the orbitofrontal cortex. the septal area and
Orbitol"",,,1
co"e>
MocH,,) r"",b,.in
t>un<lk
'''''.11".",1
p,,,,'ptie
h),pot""l.",u,
Ol'TruT
Fig. 111· 1. 0..-.1
the associated nucleus aecumbens. the amygdala.
the preoptic area. the habenula. and a midbrain
component oomposed of the ventral tegmental area.
the central gray. the raphe. and the interpeduncular
nucleus (3) (sec Fig. 19·7).
When the mammillothalamie tracts arc se"ered.
animals display changes in behavior that ha,'e been
described in various way•. They arC said to show ex-
aggerated tendencies to "freeze" when stressed. to
be reluctant to begin new behavioral acts when ron-
fronted "'ith unFamiliar stimuli. and to respond in-
appropriately when placed in sit uations ;n which
learning is linkcd with punishment (47).
The mammillary nudei also communicate wilh
other pam of the brain via the mammillOlegmental
traCts and Ihe mammillary peduncles. They receive
inputs from the olfactory regions and probably also
from parts of the midbrain involved in taste
perception.
The amygdala of the fore brai n arc made up of
neurOn clusters embedded within the dorsomedial
regions of the temporal lobes in most of the mam_
mals. They are regarded as eQmpOnems of Ihe cere-
bral ganglia. and they receive dopaminergic input'
from the nucleus a(Cumbells, olfactory tubercle. and
other parts of the telenC<':phalon. They arc therefore
inVQlvcd in striatal and autonomic as well as limbic
functiorul. Damage to certain componenls has been
observed to be followed by change. in behavior in
humans and in laboratory animal" Fibers leading
out of the amygdala via the stria terminalis are dis-
tributed 10 the medial prooptic. supraoptic. and Ven-
tromedial nuclei and to the anterior area of!he hy_
pothalamus. Ventral amygdalofugal axons pass to
h)'poI h. t"mn,
B,.;n,kml,pin.,i
input>
& infu nd ibulum
01 I""bk: cir<:Wry OS to

more lateral parts 01 Ihe hypothalamus_ Stimulation
of some paTls of Ihe amygdala has been .epoTloo to
exert influences on g1"Qwth hormone and gluCOCQrt;·
ooid se<:relion opposite 10 Ihe ones seen when loci
within the hippocampus are stimulated. However.
although hippocampal neurons avidly bind oorlico-
sterone. Ihe roles of Ihis brai n region in conlrol of
CRH have nOi tx.en defined (47).
The anterior hYpOlha/amic " " " merges with the
preoptic region, and i1 exte nds caudally beyond Ihe
infundibulum. It contains neurons thaI sense small
temperature elevations. Its roles in adaptation to
warm envil'{lnments a nd in control 01 lhe parasym-
pathetic nerVOUS Iy>tem depend in part on tra nsmis-
sion of inhibimry impulses to the hypO/ha-
la",le area. Indications thai the posterior region
regulale, sym pathetic functions come from obser·
vations thaI stimulation there can invoke cutaneous
vasoconstriclion . dilation of the pupi l. lowering of
muselc lone in Ihe gut a nd urinary bladder. and
Olher elfeclS associa ted wilh Ihc "fight Or nighl" reo
aClion. wherea. lesions lead 10 the development of
hYpOlhermia and lethargy. On the other hand. an old
concepl Ihal Ihe anterior and posterior regions COn·
lain Ihe "centers" for parasympathetic and sympa·
Ihelic funclions. respectively. is outmodcd. Neurons
tinhd with the twO com""""n\< or the aUlonomic
system do not show discrete anatomical separation.
Moreover. when finc electrodes are used it is possible
10 affect OrK: parasympathetic aClivity without af·
fecting Ihe others. Stimulation of some parts of the
poslerior hypOthalamus Can invuke ej.cul.tion and
attempls to copulale. Those respOn= arc androgen·
dependent.
The anterior pillars of the fornix separate the me-
dial from th.lateral zones ofl h. hypOthalam us, The
lateral hYPOlhalamus contains the hypOtha·
lamic. lateral preoptic. and tuberomammillary nu·
clci. It is dominated by ascending and descending
nerve fiber compOnents of the limbic·forebrain·mes·
encephalic reticular forebrain circuit. Fibers oollcc·
tively known as the medial fOf'ebToin bundles ( M FB)
connect this region with the forebrain and midbrain,
They contain large numbers of catccbolaminergie
and serotoninergic fiber!<. and they receive inputs
from the basal olfactory regions. the periamygdaloid
complex. the septal nuclei. and also the magnocc!·
lular. arcuate. and ventromedial nuclei, Visual. gus-
tatory. and trigemina l projeclions bave been identi·
fied . Efferents are sent to Ihc pcriventricular nuclei
and to parasympathctically innervated structures
lhat include the gastric glands (61). The MFB also
carry information from retinal photore<:eptors to the
pineal gland,
The periveniricllloT nudei contain columns of ''Cr)'
HVPQTHALAMlI8 AND HVPOPHVSlS
small neurons thaI run the length of Ihc hypothala-
mus. close to the ependyma . The cells contain only
s mall amoonts of cyloplasm and have been said to
resemble lymphocytes (3). This dopaminc·rich re-
gion implicated in regulation of adenohypophysial
functions.
An extcnsive periven\rieular system comprising
mOSlly fine, unmyelinated fibers courses through Ihe
length of the hypothalamus in the region close 10 Ihe
lining of the 3rd ventricle. It ",ceivC!; inpulS from Ihe
posterior and dorsal hypOthalamic nuclei and from
thc tuberal and supraoplic regions. Fibers thaI run
up and down conneCI Ihe hypolhalamus with Ihe
vcntricular and dorsal pans of the thalamus and
wi th Ihe lower brain ",ern. Some terminations haY<:
been identified in Ihe leclum of the midbrain and in
the relicular formalion of the medulla oblongata.
Specialiwl ependymal cells (ta neytes) border Ihe
3rn ventricle and projecl microvilli into the lumen .
They scnd out long cyloplasmic processes to neurons
and 10 perivascular spaces (17). and Ihey thereby
providc avenues of oommunication among tnc cells.
Ihe cerebrospinal fluid. and Ihe capillary blood .
Complex conglomerales of neuronal. neuroglial, and
vascular clements within the median eminence form
eireumventricular organs (Chap. 2), The neurons
wilhin them are nol "protected" by .he btood·b",in
barrier. Some have ",ceptors for hormones "'leased
into the sySlemic cireulation.
HYPOT HALAMI C REGU LATION OF FOOD
INTAKE AND BODY WEIGHT
This subje<:1 i. discus.'cd at some lenglh beeau,," it
dcmonstratcs thc kinds of difTocuhies thai arc en·
countered when attempt. are made \0 assign a spe-
cifIC function to an anatomically defined brain locus.
Some aspects were considered earlier in Ihis chapler
and in Chap, S. The literatu", is eXlensive and COn·
lroversial, and JUSt a few nf the reviews and "'cent
papers arc ciled,
There is lillie doubt that the ventromedial and lal'
eral regions of the hypothalamus make contributions
\0 Ihe regulation of food intake and bod)' weight.
However. widely divergent Opinions have been ex·
pressed concerning (a) Ih. physiological importance
of Ihe"e regions rel alive to other parts of the brain;
(b) the relationships between the changes in these
parameters invoked by stimulation Or damage to the
hypothalamus and the roles of the Same brain re·
gions in regulalion of other bodi ly functio ns; (c) the
kinds of information thai arc fed into the hypothal·
amus, the palhwa),s for transmission. and the ana·
tomical loci of bolh the and the ta rgets;
and (d) the chemical natureS of the mediators. Ihcir
sites of synthesis. and the mechanisms whereby thcy
acl.
Ventromedial " Satiety" and Lateral
" Feeding" Centers
As already discussed. it has proposoo that Ihe
venlromooial hypothalamus contains "satiely" neu-
rons Ihat provide prote,tion against the ingestion of
exces$ive quantitie, of nutrients. whereas the lateral
hypolhalamus contains a "feeding ccnter" that as-
sures the inlake of sufficient nutrientl to stock the
rescr'o'e depOts and sustain bodily funclions. Obser-
vations supporting the hypothesis inClude the follow-
ing: (0) After destruclion of the VMN and sur-
rounding regions. animals of many mammalian
species cat enormous quantilies of palatable food
and they become grossly obese. They h3'e been ob-
served 10 head for thc food cup before fully reCOVer-
ing from the aneslhclie. (b) Injection of anesthetics
into the same region in nonlcsioncd animals can also
invoke overeating. whercas stimulation can termi·
nate feeding in f<XXI-dcprived animals. (c) Electrical
aClivities of some ventromedial neurons increase fol·
lowing glucose administration. and they dccrease
during fasting. (d) When lesions are made in the lat-
eral hypothalamus. the animals become hypophagic
or totally refuse palatable food that is readily accey
sible, They lose weight and may evensta",<, to dealh.
(eJ If the lateral hypothalamu. i. elcctrically .tim·
ulated. previously force·fed animals will take food.
Thc response is terminated when the is
lurned olf. When are fcd ad libitum , they
gain ",<,ight if Ihe lateral region is repeatedly
ulated . They .harply reduce their intakes when Ihe
lrealment is slopped (6.44,93).
A "hypothalamic obe.ily .yndrome" in humans
has been linkoo with ventromedial injury (76). It is
nol known why patients wilh anorexia nervosa so
dra.tically limil their intakes Ih31 some sla rve to
death. Some therapisl' nave emphasized the impor-
tance of psychological a nd factors (16). bUI
others have pointed out that gonadal
and other signs of hypothalamic disorders precede
the changes in feeding behavior (52.93). According
to one hypolhesi" the brain is oversensitivc to endog-
enous estrogens. The steroids are koown to alfec t
food intake (34 .93). They may directly imeraci with
neuron receptors or alfeclthe feeding by exerting in·
Auences Over dopamine metabolism.
A concepl related 10 the foregoing fondings is Ihat
the ventromedial "satielY" neurons set the upper
limit for buildup of fa t r.",rves, while the "fceding"
neurons c:ontrollhe lo,,'er one. It bas been observed
thai animal. with ventromedial damagc steadily
gain weight for a lime. However, they not only "sta·
bili'c" at a supernormal level bUI subsequently "de_
fend" the higher weight. They transiently red uce
their intakes if subjec ted 10 a period of foree·feedi ng.
and they take smaller quantities of f<XXI, rich in Car·
bohydratcs. fats. a nd calories than of diluted diets.
Animals that are food deprived before being sub-
jected to lateral hypothalamic injury often cat after
the surgery. The ones Ihat bec:ome hypophagic but
are maintained for a timc with force-feeding may re·
cover the ability to voluntarily take f<XXI. They. too,
"stabilize" and "defend" a low body weight. The
"set·point" in such subjects can be elevatoo if yen·
tromooial injury i•• uperimposed. "'hereas the ani-
mals wilh just ventromedial lesions lower the sct·
point if the laterall'<'gion is later damaged.
Proponents of both concepts commonly assume
thai each part of the hypothalamus exerts inhibi tory
influences ovcr the other. The notion is supported by
anatomical evidence for the passage of adrencrgic fi-
bers from the YMN 10 Ihc lateral hypothalamu:s and
for indirect pathwaY' that lead from the lateral to
the ventromedial region (47).
There are disagreemcnt' over thc locali7-3tions of
the "saliely" and "fceding" neurons. While some in-
vesligators have ide ntified specific sitc. wilhin the
ventromedial region thai affeci food intake (15).
othcrs have emphasized the importance nf the elfecl'
of experimental manipulations On nerve traelS pass·
ing through the regions. It is also kno"n that several
other parts of the brain affcct fceding behavior.
The conceplS eited ar.: not unive,..,.rry accepted.
and they are dimcult to reconci le with SOme dilferent
findings.
What 18 "Satie ty" ?
Saticty is subjective. We can observe the behaviorof
an animal and make assumptions. but
we cannot know what thc animal is actually experi·
encing. To some investigators. the term implies con-
tentment . These biologists go 10 great lengths to
demonstrate thai the procedures they use to decrease
meal size or frequency do not bvoke aversions or
loxicities. They that animals subjected tothem
groom and become sleepy when Ihey .top eating. and
that they show other sign. of comfort and '3ti,fac-
lion, Others regard aversion as nOlhing more than an
exagge ralcd form of satiety. The point of vic'" be·
come' especially important when attempts are made
to interpret observalion. made on animals fitted with
electrodes in certain brain regions and given the OJ>-
portunilY 10 "self-stimulate."
The lateral hypolhalamu. is one of Ihc region' in
which animals seem 10 "like" 'Iimulation, If Ihc ex-
perimental setup requires that the subjects run back
and forth through long tunnels 10 oblain repeated
slim ulation. the animals will forgo food. water. and
needed reSt to do so. Since f<XXI deprivalion faeili-

tates the behavior, it has been suggestcd that the an-
n
imals self-stimulate to obtain an "electrical meal
(6 I J. Lcsioos of the ventromedial hypothalamus al..,
increase the "motivation" (45). Animals that are
force·fed before the do not self-stimu-
late. In fact. they will 80 to great lengths to inacti.
vate electrodes programmed to periodically deHver
the current Intact animals that are obese also avoid
the stimulation. It is not known whether the differ.
ences are linked with changes in blood and/or cere-
brospinal Ruid chemistry, or whether some kind of
neuronal signal is initiatcd whcn the fat depots arc
"overstuffed."' The behvioral effects of the obesity
subside when the body weight is lowered to the nor-
mal range. The ventromedial hypothalamus ,,,,-,ms to
be a site for "aversion."'
Aeeord in8 to one point of view, the animals
"enjoy'" hypothalamic stimulation. since "satiety" Or
"pleasure"' neurons are located within the region.
When animals are deprived of the ventromedial hy·
pothalamus. they "lose" much of their ability to ex-
perience pleasure in normal ways. They are there-
fore '"driven'" to seck out compensatory stimuli that
include the ones associated with ingestion of palat·
able food. The aversions of intact. overfed animals to
hypothalamic stimulation are auributed to "exces-
sive satiety'". They may be mediatcd by inhibitory
influence, that ventromedial satiety ncurons ucrt
over more laterally located brain regions which oth·
erwise facilitate ingestive behavior and the motiva·
tion for self-stimulation (45).
Although reasons can be advanced for associating
feeding with pleasure. the relationships must be
complex . Animals "like" to stimulate different parts
of the brain that do not affect food intake. The mo-
tivation to activate electrodes placed in parts of the
posterior hypothalamus that invoke ejaculation or
a ttempts to copulate is abolished by castration. and
it can be restored wilh androgens.
Re latio ns hip s betwee n feed ing and
, ' Emotionality "
Animals wilh venlromediallesions arc often said to
be "finicky" and "lazy." While they eagerly take
large quantities of palatable foods that are readily
available, they may food tainted with unpleas·
ant navors c>r odors . [ntaet Or sha m-lesioned controls
offered the same nutrients usually eat very little at
first. but in time they acc<:pt enough of the food to
maintain body weight. The lesioncd animals are also
"reluctant'" to "work"' for food. whereas intact COn·
trois soon learn to bar-press many times to obtai n
pellets. They "'ill also lift heavy lids placed Over the
food cups, or cross electrical fields if they cannot 0b-
tain food in other ways.
HYPQTHA LAMI)$ AND HYPOPHYSIS
It ha'l been suggested that the ventromedial Ie·
sions impair the abilily to sense or respond to "inter-
nal hunger." Therefore. Ihe motivation to eat de·
pends on environmental stimuli that include Ihc
sight and aroma of good food and the pleasure as-
sociated with the ingestion. [t has even been pro-
posed that obese humans suffcr similar defects (85).
In one st ud y, obese and normal-weight human
adult.s were asked to complete lengthy question'
naires. Excuses were made to temporarily deprive
the subjeelS of their wrist-watches. and the studies
were conducted in rOOmS wilh prominent clocks that
ran eilher too fast or too slowly. Sine<: the experi·
ment spanned Ihe hours prec<:ding and following the
usual dinner lime. the subjects were provided with
food and invited to hdp themselves when they felt
hungry. The lean subjeet.s ate at their usual dinner
times, without rC8ard to information imparted by
the docks. However. the obese subjects ate early
when the docks ran fast, and they delayed the meal
when the elocks ran slo,,·ly. In another
1,2 or 3 sandwiches were placed on the lable and
the subjects were invited to take additional ones
from a nearby refrigerator. Most lean subjects ate 2
sandwiches under aU three experimental conditions.
Most obese subjects ate aU of the sandwiches placed
on tbe table (I. 2 or 3. depending on the test condi-
tions). but they did not open thc I"Cfrigcrntor.
According to the investigator, the fond ings indi-
cate that lean humans cat when they arc hungry,
and they consume JUSt enough to feel satisfied. [n
contrast. obese persons respond primarily to external
stimuli. They cat when the clock annOunC<:s dinner
time. and when they can see or smell palatable food.
Other observers have linked "finickiness" with dif·
ferent factors. One idea is that ventromedial lesions
sharpen the sense of taste. Most of the studies pur-
ported to demonstrate Ihe phenomenon can be inter-
preted in different ways (47). It has been deter·
mined, for example, that the quinine used to make
food bitter exerts postahsorptive toxicity. Animals
with ventromedial lesions retain some ability to as-
sociate the intake of certain foods with subseq uent
illness and to develop aversions that are unrelated to
the taste.
The "laziness" that foUows hypothalamic injury
has been variously attributed to direct effects of the
lesions and to secondary consequences of the obesity
that foUows. However. "'hen animals are trained to
work for food before they are subjected to the dam-
age, they continue to do so afterward. Therefore, the
ventromedial lesions may in some way impair learn.
ing. On the other hand. if animals arc food deprived
after they are damaged. they do work for food even
without the prior training. It can be suggested that
the "motivation to eat" is sharpened by the hunger.
A very different idea is that the obesity body
temperature regulati()/l. The lesioned animals may
suffer excessive elevations when they are required to
work. They would not be e.pected to have the prot>-
lem after weight loss.
Obese humans may ta ke their food when the
the hour is appropriate for very special rea_
sons. Many report that they always feci hungry.
They restrict food intake to avoid beooming even
more obese, and they are often subjected to criticism
by others unaffected by their problem. Therefore.
obese subjects may "feel entitled" to cat at the din-
ner bQur but IIQt before. Because of repeated sugges-
tions that they are gluttollQus, they may hesitate to
open someone else's refrigerator. Obviously. they
have no difficulty thinking about food contai ned
within enck>:sed compartments of their own kitchens.
Factors Affec ting Food Intake in Normal
Subjects
The quantity of food that a healthy animal will lake
before it voluntarily terminates the meal ca n vary
widely with the test situation. This complicates the
problems of assessing the changes that oc<:ur after
experimental manipulations, More food will be eaten
when the diet is palatable and varied than when it is
only minimally ae<:eptable in navor and texture and
is monotOIlQU'. More will be eaten in familiar .ur·
roundings. and only limited amounts of 1IQ''ei sut>-
stances may be sampled the first time they are of·
fered. fear. dehydration, endocrine disorden;.
previous overfeeding, and distu rbing environmental
stimuli arc among the factors that can discourage
eating. Some forms of stress reduce (he intake,
whereas others can it. A\1empts have been
made to linx the direction of response with the rcl-
alive quantities of glucocorticoids or endorphins that
arc released, Animals can also be C<lnditioned to cat
in response to cues unrelated to the kinds of external
stimuli provided by food (98).
Nocturnal animals such u rats and mice take
larger and more frequent meals during the night
than during the daytime. and it is perhaps unfonu·
nate that many of Ihe experiments performed on
them were restricted to the W<lrking day. h is worth
IIQting in this connection that animals with ventro-
medial iesi()/ls do almost all of their "overeating"
during the daylight hours (61).
Fact ors Affectin g " Hunger" a nd " Satiety "
The lisl of substances proposed to contribute to the
physiological control of food intaxe includes chole-
cystokinin (CCK) (87), glucagon (60). calcitonin
(31). gastrin, secretin. pancreatic polypeptide. neu'
rotensin. bombesin. substanct: P. growth hormone
(14), sol1llltomedins. insulin. estrogens. progestogens
(4). prolactin (66), somatomammOlropin, t hyrox·
inc. endorphins, enkephalins. dyllQr·
phin (79). prOStaglandins ( 4), acetylcholine. IIQrepi·
nephrine (4.64). epinephrine. dopamine. serotonin.
glucose. glycerol. fatty aCids. and some of the amillQ
acids, Most of the preceding. and pharmacological
agents alfceting their levels or functions. exert innu·
enCCS On lipid metabolism. A few additionally invoke
changes in the numbers of adip(lC)'tcs (19). Recer-
t<m implicated in the release of the endogenous reg-
ulal<m or in mediation of their actions may be pre ...
ent in the mouth. pharynx. stomach. intestine. fat
depots. liver. skeletal muscle , brain, and elsewhere.
Some arc said to sense chemical changes, others
pressure. and yet different ones temperature or de-
h}'dration. It is possible to set up C<lndilions under
which cases can be made for physiological contri-
butions by any of thc proposed factors. h is often IIQI
much more dinicult to demonstrate that each of the
experimental findings e"n be interpreted in a differ·
ent way (A-I).
The dir«lion of change invoked by a en-
dogclIQus entity can vary with the setup. Thus. al·
though sugar ingestion and elevation of blood glu-
cose levels by other means usually depress the
appetite, rapid infusion of glucose into the duo-
denum can actually increase food intake (32). When
the food is swee tened, bungry animals often take
larger meals but well-fed animals tend to take
smaller ones, Norepinephrine deplet;on increases.
and NE administration decreases nocturnal f<XXI in·
takes in rats. Changes opposite in diTC<:tion "re in·
voked by similar imposed during the day·
light hours. Serotonin depletion and administration
affcct mostly daytime intakes (47).
Fasted rats given .8-adrenergic blocking agents
such as isoproterenol stock diet pellets suhsc-
quently presented , and they also milk that has
a bilter taste. However, they ta ke more sweetened
milk than untreated hungry animals, Well_fed rats
given .8... drencrgie agoniSlS eat more pellets than
well-fed comrols. Hungry animals injected with the
same agents also accept bilter milk, although (hey
take less swcetened milk than hungry controls.
When a specific substance consistently invokes
changes in just One direction. there can be disagree·
ments over the underlying mechanisms. Some inves·
t;gators believe that CCK actS mostly on the brain
as a physiological "satiety factor." Intracerebral ad-
ministration of the peptide is reported to decrease
meal size in sheep, and it has been stated tha t the
CCK levels in the brains of rodents with SOme forms
of hyperphagia and obesity are subnormal. A prot>-
lem with the hypothesis is that mechanisms whereby
fceding affects brain concentrations of CCK are not
known. Different investigators note that the de-
scribed responses to intracerebral administration of
CCK are not elicited in several other species. More-

over. low brain CC K concentrations are not consis-
tently found in obese animals . It has be<:n pointed
OUt that fe<=ding invokes peripheral release of thc
pcptide and that systemically administcred CCK
docs OOt enter the brain even when it de<:reases meal
size. One proposed effe<:t of the peptide is delayed
gastric emptying with resulting distension. Messages
may then be relayw from the full stomach to thc
brain. Vagotomy has been reported to abolish the
"satiety" effects. If CCK does. in fact, function as a
physiolOSical "satiety factor;' il must do SO on ly on
a short-range basis. Tolerance to exosenous peptide
develops rapidly. and repeated administration has
little influence on bod)' weight (21).
Amphetamines are among the best known of the
"appetite suppressants", They act in sevcral ways to
profoundly alter catecholamine metabolism (Chap.
S). Sine<: severing of cenain dopaminergic pathways
in the brain leads to changes in fexxl intaxe, the an-
orexigenic cffe<:ts are widely anributed to disrup-
tions of dopamine functions. The concept i$ con_
sistent with observations that the chronic
hyperglycem ia associated ,,'ith insulin deficiency de-
presses dopaminergic neu rOnS and the anorexigenic
actions of amphetamines (63). However. the drugs
evidently interact with receptors different from the
oneS that bind catecholamines (75). Insulin defi-
ciency effccts on fexxl intake probably involve mul-
tiple mechanisms . Insulin-receptive nerve terminals
have been identified in the rat mcdian eminence re-
gion, and insuli n injections into that region reduce
fexxl intake. At least some of the actions require cho-
linergic tl'3nsmission. Additional neurotransmiltcrs
implicated in mediation of thc insulin effe<:ts include
neurotensin. G ABA and endorphins (97).
Amphetamines have also been said to directly
stimulate thc ventromedial hypothalamic neurons.
Thc notion is not easily reconcilcd with observations
that the agents are more dfective appetite suppres-
sants in animals with lesions in those r<:gions than in
sbam operatw controls. Moreover, there arc condi-
tions under which amphetamines augment fexxl in-
take (47).
Differe nt Concepts o f Hypo thala mic Neuro n
Fun c t io ns
The idea that the ventromedial hypothalamus con-
llIins "satiety'· ncurons has been totally rejected by
some investigators. When th e region is destroycd in
",ronfing rats, the animals neither Overeat nor gain
more weight than sham operatcd controls, They do,
however. suffer growth impairment that is rtAected
in thc acquisition o f high fat: lean body rna .. ratios.
i.esioned adults permitted to eat just enough to
HYPOTHALAMUS ANO HYPOPHYSIS
maintain their body weights also acquire high
fat: lean ratios as they lose protein. Despite the fexxl
restriction. they become hyperinsulinemic. It has
been suggested that the hormonal imbalance causes
lesioned animals of both age groups to shin excessive
quantities of nutrients into lipogenic pathways and
to suffer impairw ability to recruit thc reserves (61).
The adults may then be motivated to overeat be-
cause they suffer "tissue hunger". and the hyper_
phagia has been linked with attempts to provide thc
body cells with adequate fuel. When fed ad libitum,
the animals rapidly become obese. The fexxl intake
and body weight 5tabili .. e as the adipocytes enlarge
and insulin resistance develops. Weanling! probably
do not overeat bcQ.use growth hormone and Olner
regulators so profoundly affect the appetite that fur-
ther stimulation cannot be achieved.
It should be pointed out. however, that some in·
vestigators believe that the appetite-control1ing and
insulin-regulating neurons are distinct. It has been
reponed Ihat very small lesions can invoke the mo-
tivation to ingest more food. but that hypc:rinsulin-
emia does OOt develop if caloric intaxe is restricted
( IS ).
A yet different concept is that lesioned animals
become obese because thcy utili .. e nutrients "more
efficiently" than controls. The abilities of mice !X&
""ssing certain genetic defccts to bc<:omc obese when
pair-fed with healthy animals of this same Slrain
have been linked with low NE turnover in brown
adipose tissuc and low ra tes of heat production (53).
However. although animals wilh ventromedial Ie-
sions suffer catecholamine dysFunctions. low cnergy
output is not a major Factor during the dynamic
pbase ofwcight gain. In human subje<:ts. obesity can
be associated with elevated metabolic ratc (28).
The bypophagia of an imals with lateral hypotha-
lamic lesions has been linked with the loss of inputs
from many kinds of receptors. The lcsioncd animals
are said to suffer "sensory neglect" that leads to fail-
ure to appreciate both the "pleasures" of eating and
the internal siSnals that arisc from fuel dcpot depic-
tion. In some cases. central nervous stimulants can
augment the appetite.
So me Con c lusions tha t May Be Dra wn from
the Pre c ed in g Find in gs
In ass=ing the overall picture. it must be recog-
ni?-cd that although life can be sustainw only when
nutrients are conlinuously s upplied to the cells. eat-
ing is intermit\ent. Animals must be motivatcd to
ingest more than Ihey require for immediate needs
SO they can store up reserves. During much of the
day and all of the night. the typical diurnal animal
lives off those reserVes, Severe depletion of the stores
th,..,atens survival. whereas "overslUffing" of th. fat
depots does 001. Controls Over a function as vital as
food ingestion cannot be entrusted to any single
group of re<:eptors.
Under natural conditions, mo,.., than one food is
ncedw to supply all of the required amino adds.
minerals. and vitamins. It is therefore fortunate that
animals tend to eat mOre when they are presented
with mixed diets than with monotonous oneS. The
mixtures of aromas and textures enhance the appe-
tile di,..,clly. Moreover, since smaller quantities of
the individual nutrients are taken, the,.., is 1= sen·
sory adaptation.
On the other hand, animalS feeding in the wild
must be wary of nutrient< containing pathogenic or-
ganisms. toxins, and irritants. They depend heavily
on ordinary receptors for guidance. The "good"
foods a"" the ones Ihat usually invoke plcasu,..,able
sensations. For uample. ripe fruits that supply sug-
ars and vitamins arc swcet, sueeulenl. and aromatic.
whereas unripe ones that irritate the gUI Can be pal-
lid. dry. sour, bitler. insipid. or nauseatingly pun-
gem. II is also necessary 10 recognize substances that
appeal to the olfactory and sustatory receptors but
contain substances that cause illness. Animals pro-
lect Ihemselves to some exlent by laking only minute
quanlilies of novel foods. and by remembering the
events thaI immwiately precwed Ihe onset of
'IIn=.
Even the hungriest animal must ••'oid exposure to
predators. The tendency to take only minimal quan·
tities of food presented in unfamiliar surroundings is
probably related to this. Fear and the ehangCC'l in
hcrmonal and nervous system functions that it in·
vokes probably directly impair stimulation of the
brain regions that facilitate feeding.
It therefore seem. rea"loable 10 take a multifac.
torial approach 10 the study of food int?kc reglliation
under normal a nd pathological condilions (78), Re-
cenl findings suggest that much remains to be
learned. and that entrenched ideas should be rIXX-
ami ned. It has ocen observed. for example, that the
hyperglycemia thaI immediately follows food inges-
tion results from hepatic glycogenolysis. and that the
response is manifested before sugar is absorocd into
the bloodstream (59). The reaction. which has occn
linked with glucagon release. may permit Ihe organ-
ism 10 assess the carbohydrate reserves and Ihe
quantities of carbohydrates required for replenish.
ment. [t h3'l long been reoogni'ed that neurons
wilhin Ihe ventromedial hypothalamus contribule 10
Ihe control of glucagon soxrelion. The glucagon pre-
cursor contains amino acid sequences for other pcp-
tides (8), and meal-associated release of proSlueagon
m"y alTcct additional. as yet undisooverw
functions.
During thc paSt several years, ;1 has ocen recom_
mcndw that patients with diabetes mellitus eat
polysaeeharide·rich foods which presumably release
gluoose slowly. and that they avoid candy, ice C,..,am
and other substances Ihat contain "rapidly availa-
ble" sugars. Contrary to previous beliefs. it is now
rccogni1.ed thaI blood glucose levels rise sharply fol-
lowing the ingestion of some polysaccharide·rich
foods. whereas only minimal elcvations result from
eating certain common foods high in sugar coment
(5 7).
Many animals do m(Jl;t of Iheir drinking at meal
limes. "Prandial drinking" has ocen linked with sen-
sations of dryness in thc moulh and wilh Ihc neW to
moislen food, It is now known Ihat eating leads 10
the release of hiSlamine. and that the amine stimu-
la tes drinking via mechanisms that can be blocked
with specif,c receptor anlagonists (58).
Studies ha"e been performed on the elTects of obe-
sity itself on parameters such as basal metabolic
rate. Ihe increases in oxygen consumption followins
food ingeStion, and the "metabolic costs" of work in
obese subjects (28). The,.., a,.., clear indications that
humans with strong tendencies 10 a"umulatc fat dif-
fcr from those who usually mai ntain normal body
weights, but we nced 10 know mOre about possiblc
relationshipS to dilTercnces in hypothalamic
functions.
It is likely thaI many additiona l regul ators will be
implicated in the oontrol 01 l00d intake and body
weight. We have not yet fully defined the roles of
subslanCe P. neurotensin. and other molecules
known to be present in substanlial concenlrations.
Moreover. new peptides (including a subsla nce
chemically relaled to pancreatic polypeplide 12)) are
being idcntif,w on an almost regular basis. and Ihey
may make as yet unSUSpeCled contributions. "ESlab-
Ii'hed" hormones inOuences that pre'iously
unrecognized . (For example. in addition to
stimulating ACTH release. C RH is now known to
activate neurons in several part. of the brain [I],
and to inhibit gastric acid secretion [90] .)
"II of the preceding observations lead us to won·
der about tbe roles physiologists will a.,;ign to the
hypothalamus in the coming decades.
REF ERENCES
t. Atd.nholf, J, B.. Gr.,". D. L Ri.ier.J .• vate. W..
and Siggins. G, R. Cort icotropin Role •• ing rlctor
Dceroaso' Poo,burS' llYi"'Tpotari'"tiQn$ .nd h·
ci'es Hippocampal Nouron$. Stintct 221: SH- n.
1983.
2. Allon. Y. S" Adrian. T. E.. Allen. J. M.. Tatomoto.
K.. Crow. T. L Bloom, S. R.. and Potal. J. M,
Ncuropcptido Y Dimibu,;on in lho Rat Brain. &i-
121: 811_79.198>.

3. Angevine. J. B.. Jr.. and COlman. C. W. Prinei"l..
of Ntuwo.nQwmy. Odord UniversilY Pre ... No ...
Yo.k.1981.
4. Baile. C. ..... Pulalive Neu,ouan,minors in Iho Hy·
potl1alamu. and F•• ding. Ftd. Pro.:. 11: 1 166-75.
1974.
5. Bakc •. B. L. Fun.1ional Cylology of lhe H ypOphy-
si.1 Plrs Di".H. and Pars Inl.rmedi •. Chap. 3. pp.
45-80 of Knobil and Sawyer. em .. referen •• 56.
6. Balagura. S. Neuro<:hem ical Regu lation of Food
Inlake. pp. 181 - 193 of Martini. L.. Mona. M .. and
Fra,chini. F.• cd, .. Tho Hypothalamu•. Academic
p.ess. N.... York. 1970.
1. Behl'<n" U., and Martin. C. Uh.as"uclural
Change. in Ihc Pars Distali. oflho Maluting Male
Ral. J. M()Tpho/. /36: 53-78, 1972
8. Ben. O. I.. Sanlerre, R. F .• and Mullenback. G. T,
Hamlle, P,eproglucagon Con,ain. the S<quencc of
.nd Two Related Peplide>. No./ur-t )()2:
116_18.1983.
9. Belolf-Ch.in, A.• Morton. J .. Dunmor •• S .. Taylor,
G. W .• and Morris. H, Evidencelh.t the In.ulin Se-
cr."gogue. jl-Cell-Tropin. i. ACTH"_,,. NalUr-t
301: 2H_ 58. 1983,
10. Berecek, K. H.. Webb. R. L.. and Brody. M. J. Ev-
idence f<>r a Cenu.1 Role for Vasopressi n in Cat·
di<)Va$Cul .. R.gulation. Am. J. Phy.iol. ]U:
H852- 59.1983.
II, Be.gland. R, M., and Page. R. B. Can Ihe Piluitary
Secrele Direclly to the Brain? (Affirm .. ive and An-
atomi.al Eviden.e). Etrdocrirwi. 101: 1325-38.
1978.
12. B.mardi •. L. L. HypOlhalamic Pa.avenl,icul ..
Nucleu. Lesions (PVN l) in Weanling Female Ra"
Do NO! Dis.upt No.mal Body Weight Regulatory
Procc"es, Fd. Pro.:, 42: 1346, 1982.
13. Bloom. W.. and Fawcett. D. W. A rtXlbook of I/j,.
to/OU. 9th ed. Saunders. Phil.dolphi •. 1968.
14. B.ay. G. A. Endocrine facIO« in lhe Conlrol of
Food Inllk Pro.:. 33: 1974,
Bray, G, A .. Sclarani. A..• nd Novin. D. Obesity-
Inducing HYpOthalamic Kni fe Cuts, Elfects on li-
pOlysi. and Blood I n,ulin Level,. A",..r. J. Phys;oI.
143: R445-R449. 1982.
16. Bruch. H. Goldtn Cag<. H.",ord University
Cambridge. Mass .. 1974.
11. Budinghanm H. C. Secrelion of C<>rticotrophin
and h' H}'pothalamie Rele., ing Factor in Re-
'ponse 10 Morphine Ind Opioid Peplidos. Nturot"..
docrirwi. 35: 11 1-16. 198 2,
18. Burbach. J. p, H .. Kov.e>. G. 1... De Wied. D.• van
Ni,pen. J. W.• and Greven. H. M. A Major M."b-
olile of Arginine V.sopressin in the Brain i. a
Highly PotCnl NcutOpeptide. 121: Ill(l-
12.1983.
19. C"",ai. K.• and Sullivan. A. C. Elfec1 of PhellO.1)'-
ben",mine on Developmenl of Adipose Tissue in
Lean and Obue ZUCkef Rats. Amy. J. Physio/.
143: E)98-E406. \9 82,
20. Costolf. A. of 1M Ha,
,.,NO HYPOPHYSIS
,SiS. C",,,la';(m wilh Furrclion, Academic Pre".
New York . 1973.
21. C.awley. J. N" a nd tkinfeld. M. C. Rapid Dovel·
opment of Tolerance 10 Ihe Behaviou .. l AClions of
Cholcoy$tokinin. N{JIu" J02: 703-6. 1983.
22, Da",uir. J. Sleep Deficits in Rats with Horedilary
Di.bete. In.ipidu •. No.,." 304: 163_64. 1983.
23 , Doughad.y. W. H. The AdeoohypOphy$i" Ch.p. 3.
pp. 73_116 of Wm •.. R. II .. ed .• T,xlbooI< of E,..
61h cd. Saundm. Philadelphi., 1981.
24. Defendini. R.. and Zimmerman. E, A. The Mag-
nocenular Neurosec.etory Sy$ICm of the Mamma·
lian lI)'pothalamu •. pp. 131-152 of Reichlin el al ..
eds .. rere,enc. 82.
25, Doncf. c.. and Andrie,. M, Evidence for Paraerine
I nt.f.Clion bel wcen Gonadolfoph. and UClotroph.
in Piluilary Cell Aggregale,. £nd""rirwi, 112: 81 3-
22, 1983.
26. Flrquhar. M, G .. PrOCCMins of Se... tory Produc,"
by Cell. of Ihe Anterior Piluilary Gland. pp, 79-
I 22 of Heller and lcde.is, cd ... refcf.nce 41.
27, Farquhar. M. G .. Skulol. l-.y. E. H .. and Hopl-.iru. C.
R. Slructure and FUIIClion of Ihe Antcrior Pituitary
and Di.pol5ed Pituitary Cells. In Vilro Stud ies, pp.
&4-1)5 of Ti,ier-Vid.1 and Farquhar. ed •., ,efe ...
ellCe 94.
28. Felig, P.. Cunningham. J.. levill, M" Hcndle" R..
and Nadel. E. EnerlY Expendilure in Dbe.ily in
Fasting Ind Poolp.andial Stale. A",<,r. J, n),ji"',
144: E45- E51. 1983,
29. Forni. G., Bindoni. M ., Sanloni. A .. Belluatdo, N .•
Marchese. A. E .. Ind Giovarem, M. Radiof ...
qutncy Dest.uction of tbe Tnberoinfundibular Re-
gion of HYpOth.l.m u, Perm,nently Abrogale, NK
Cell Activity in Mice. Nmur-t 306: 181_184. 1983.
30. Foste •. C. L. Rela lionship Belw.en Uhr.",ueture
and Funclion in Ihe Adenohypophysi. of Ih. Rab-
bit. pp. 125_46 of Helle. and Lederi •. ed •.• ,efe._
ence 41.
31. F=d, W. J., Perlo .... M. J.• and Wyau, R. J, Cal-
citonin: Inhibitory Elfect on Elling in R.ts.
106: 850-52.1979.
12. Geiselman. p, 1.. .nd Novin, D. Sugar Infu'ion Cln
Enhance Feeding. ScltlW 1/8: 490- 1. 1982.
n. GOO-bman.A.. and Bcrn. H. A, A TUlbooko/Com-
p<>rQliw t'trdorrino/0ty. Wiley. New York. 1962.
34, Gray, J, M .. and Greenwood, M. R. C. Time
Courses <>f Elfec," of Ova,ian Hormones Otl Food
Intake and Metabolism. J. Ph},.;.I. 243:
E407_E412.1982.
35, G=n. J. D. Electron Microscopy of the Ant.rioT
Piluitary, enap. 5. PI'- 233-41 of Harri, and Don·
ovan •• d•.. ,ef••ence 3$,
36. Gros •. P. S .• and Page. R. S, Luteinizing Il<>rmone
and Follicl<-$Iimulating Ho.mo .. Production in
Ihe Pars Tube",li, of Hypophysectomized Rati.
A",..r. J. Ana'. 1J6; 285-91. 1982.
31. Hamstrllm. B. Gros. Anatomy of the Hypophysi. in
Mammal •. Chap. I, pp. I-56 of Hall;' and [)on{)-
van. ed •.• reference 38.
38. Harri •. G. W.. and Dono.an, B. T. , ed •.. Pi,u_
iMry Gland. Universi ty of California Pre". Berke-
ley. 1966.
39. Hatton, G. I. Some Well-Kept Hypothalamic Se·
Cret. Disclosed. I'd. Pr«. -11: 2869_14.1983 .
40. Haymake r. W.• Anderson. E .. • nd Naut •. W. J. II ..
ed •. Hy[lOlha!omus. Thoma,. Sp,ingEold. III..
\969.
41. Heller. H.. and lederis. K.• od,. Org.>-
nhullon and TI..,,,,,. Cam-
bridge Un;ve"ity Pres •. New Y<>rk. \971.
42 . He,lant. M. IntrOOuction. pp. 1-19 of Ti,ier·Vidal
and farquhar, eds .. refe,erlC<: 94.
43 . Herlant. M .• ond Pastcels. J . l. Histophysiology of
Human Anterio, Piluitary. pp. 2SO_J05 of Bajun.
E .. and Ja'min. G.. e<!s .. and
momS in Pathology. vol. 3. Ye.r Bool:
Medical Publilh«•. Chicago. 1967.
44. Hocb<l, B, G. Feedi",: Neural Controt of Intah.
Ann. Rov. PhY$jol. JJ: H3-68. 1971.
45. Hocb<l. B. G. tlypolhalamic Self-Stimulatioo . nd
Slimulalion E$capc in Relation to !'""d ing and
Maling. Fed. Pr«. 38: 2454-61. 1979,
46. Holmes. R. L lnd Ball. J. N. Th. PiruiluTf Gland.-
A Q>rnp"Tali'" Account. C.mbridge Unive"ity
Press. New York, 1974.
47. hucson. R. L. Tht Limbic Spurn. 2d ed. Plenum
P'''''. Ne,.. Yorl:, \982.
4&. Jan. Y. N .. and Jan. L. Y. LHRH-Liko Peplide as
l Trlnlmine, in Sympalhetic Gangli • . Fronl ,
7: 211-30, 1982.
49. Joseph. S. A .• • nd Kniuc. K. M. The End""ri""
Hypolhalamus: Rocem AnalOmic.1 Studies. pp.
15_47 of Reichlin el a1.. eds .. ",ference 82,
SO. KaSlin. A. J .. V.ud,y. H.. Zadi.,... J . E., and Olson.
R. Q. M IF.1. Tyr.MIF.I. and MSH : Conlrol of
MSH Rei .... and E<trapigmenlary Effecl$. Am".
Zool.13: HI - 58. 1983.
S1. Ka"in, A. 1.. Viosca, 5., and S<-hally. A. V. Regu.
\ation of Melanocyte-Slimulari"g Hormone Re-
lease. Chap. 42. pp. 551-86 of Knobil and 5.",),CI,
ed$ .. refe",nce 56.
52. Katz. J. L. P$ycboendocrine Con.iderations in An·
orexia Ne,,,,,, • . pp . 121 - 33 of Sachar. E, 1.. ed ..
Topic. in P<ychotMOCTjno/Ogy. Grune &. Slrallon.
New York. 1975.
53. Knehan$, A. W. and Rosmos. D. R. N<>repincphrinc
Turnover in Db< .. (ob/ob) Mico: Effect$ of Age.
Fnting and Acute Cold. Am.,. 3. Ph)-'siol. 1<1#:
E567-74,1983.
54 . Knigge. K. M .. Joseph. S. A..• nd Hoffman. G. E,
Organization of LRf· and SRIF_ Neuron$ in the
Endocrine Hypolhalamu •. pp. 49-67 of Reichlin et
• 1. cd ... reference 82.
55. Knigge, K. M.. and Sil,erman. A..J. Analomy of
lh. Endocrine Hypothalamu •. Chap. I, pp. \-32 of
Knobi\ .nd Sawyer. od •. , reforerlC<: 56.
56. Knobi!. E.. and Sawyer. W. H., cd •. I/andbook of
Physiology. sec. 7, vol. 4. Americ.n Physio logica l
Society. Wa.hington, D.C., 1974.
51. Kalata. G. Dietary Dogma Di.proved. SClf"" no.-
487-8.1983.
58. Kr.ly. F. S. HiSI.mine Pl ays" Part in I nduction of
Drinki", by food Intake , Nal"T, 301: 65-6. 1983.
59. Langhan$. W.. Gea,)" N .•• nd Scb.rrer, c. Li""r
Glycogen Conlent Dec",..., Dudng Meal . in Ral$,
Am", J, PhyJloi. U1. R450_R453. 1982,
60, Langbans. W., Zieger. U., Scharrer. E ..• nd Geary.
N. Stimul"t",n of Feed;", in R.ts by Intraperito-
neal Injection of Antibodi", to Glucagon.
218: 1982.
61. LeMagnen. J . L. Body Energy Balance and Food
Inta\;e: A Neuroendocrine Regularory Mechani.m ,
Phy,lol. R ••. 63: 314-86.1983.
62, Locke. W.•• nd Schany. A. V.• ed •. Tht lIypothal-
am", and Pir"ilaTY in If,al,h and Thomas.
Springfield. III .. 1972.
63, LOlovsky. D.. Saller, C. f .. and Kopin. L J . Dop •.
mine Receptor Binding i. Increascd in Diabetic
Ral$. Sdtnu ]U; 1031-33. 1983.
64 , Margules. D, L.. Lewi •. M, J .. Dragovich, J. A.,
and Mar,"les. A. S, Hypotbal.mic Norepi neph.
ri.. : Ci",.dian Rbylhms . nd Control of reeding
Bebavior. Sdt"" 178: 640-2 . 1972,
65. Marten •. G. J, M .. Jon k•. B. G .• • nd van Over·
beel:e, A. P. N «-Acelyl.,ion is Linked 10 «- MSH
release from Pars Int.rmedia of the Amphibian Pi·
lu itary Gland. Nalurt m : 5S8- 60. \981.
66. McLausb lin, C. L-. Baile. C. A .. and Pcikin, S. R.
Hyperph'gia Duri", L.ctation: Satiety Response
to CCK .nd Growth of lbe Pancrea$. J.
Phy< jol, 214: E61-E65. 1983,
67. McSh.n. W. II. Secretory Granule, from Ant.rior
Pituilary •. pp. 161 - 183 uf lidk,
eri . , ed . .. ",ference 41.
68. Mezey. E.. and Palkovia. M. Two-Way Tran,port
in lbe Hyp::othal.mo-H),poph),se.1 SYSlem. Fran'.
N."_ndo,,,jnol.7: 1-29. 1982,
69. Moriarty, C. M., and M<>ri.rty. G. C Biooctiveand
Immunoreactive ACTH in lhe Rat Piluitary: Innu·
enee of St .."" .nd Adrenalectomy , HndocT;noi. 96:
14 t9- H.1975.
70. Moriarly. G. C. Halmi. N, S .. and Mo,ially. C M.
The Effect of Strffi on the Cytology and Immu no-
cytochemistry of P.rs Inlermedi. Cell' in tho R.t
Pituitary. EndOCTjn(Jl. 96: 1426-)6. 1975.
it. Novale •. R. R. Aelion, of Melanocyte.Stimulating
Hormones. Cbap. 35. pp. )47-66 of Knobil and
Sawyer. ed, .. rde",nce 56.
72. O ' Donohue. T. L .• Handelm.nn. G. E .• Miller. R.
L.. and Jacobowitz. D, M. N-Acetylation Regul.,es
the &ha.;oral Act;.ily of «.Meldoot.rapin in a
Muhineurotran.miner Neuron. 1/5: I 125-
27 . 1982.
73. Page. R, B. Piluitary Blood Flow. A",..T. J. Physiol.
U3.- £427_E442. 1982.
74. Pari,h, D, C. Smylh, 0, G" Normanlon. J. R., ond
WQI"enc",ft. J. H. Glyoyl Glulamine. an Inhibi·
tory Neuropoplide Derive<! from p.Endorphin . Na-
<uu 306: 267_72.1983 ,
15, Paul. S, M .. Huliban-Giblin. B.. and SkOlnid. P.
( + )-Amphe1.mine Binding 10 Rat Bypolhalamuo:
Relation 10 Anore,ic Pot.nOJ of Phenylelhylam·
ine •. Sdtnct 118.- 481_90. 1982,
...
16. Plum. r .• and Van Uitcrt, R. y, Nonendocrine
Di.., .... and Di'Ord.Il of the Hypothalamus.
pp. 415-473 of Reichlin 01 a1. <:<1._. refere""e
"
17. Poner. J. C .. Dndo. J. G., and Cromer, O. M. Nc,·
>(HI' and Vue"lar of the Pituitary Gland.
Chap. 2. pp. 33-43 or Knobil and Sawyer. ed •. , ref-
erence 56.
78. I'<>w.... P. $. O/H';ty_ Th. Regulation ()f Wtigh/_
William. &. Wilkins, Baltimore, 1980.
79. P"cwlo<:ki. R.. La$<\n. W., GramlOCh. C, He". A.,
and Reid, L. D. T he Optoid Peptid., Dyoo'phin,
Rhythms, and S"rvatiQn. Sdtn« 219:
71-3,1983.
SO. Pu" ... H. D. Cytology of the Ad.""hypophy.is.
Chap. 4, pp. 147-232 of Hmi ' and Donovan. cds .•
rtf.... nee 38.
81. Purv.s_ H. D. MorpholO!y of the Hypoph)'$i, Re-
lated to H. Function. Chap. 3. pp. 161-2>9 of
YOU!lJ. W. C .• ed _. Sn Inurn,,1 S"mj(m'.
William. '" Wilkin •. Bahim"",. 1961.
82, Reichlin. S.. Balde.... rini. R. J .. and Marlin. J. B.•
Tht lIypDIhalamu$. Ra.en Pre". New Y"'k.
1978.
83, R;,ier. C .. and Vale. W. Mcxlulal;on 0/ St ..,,· ln·
duC<:d ACT H Rele ... by C",liCOlropin.Relea.ing
Flctor. Catecbolamine, and Va",pres<in , Na/u't
10j' 325-27. 1983.
84. ROSII ier. J, Funclion. 0/ I1· End"'pbin .nd Enkcpb·
ali", in ' he Pilu;tary. Front. Nturotnd""itwi. 7:
191-209.1982.
85. Schacbler. S.. and Rodin, J. ()b."t lIuman!; and
Rat>. Wi ley. New Yo,". 19H,
86. Sipet5lein. E. R .. and Millor, K, J, HypeflrOphyof
ACTH. Producing Cell Following Ad",nal.elomy:
A Quanlil'li,c Eleclron Microscopic Siudy, /:.",..
d(}(.",iool, 93: 1257_68. 1973.
87. Smilh. G. P.. and Gibbs,J. Br.in·G"1 Peplidesand
I.. Conlrol of Food Inl.ke. pp, 389_95 of Marlin.
J. 8.. Reichlin. S .. and Dick. K. l.. tds. NtulWt-
,,,,lion and Brain PtpIiJ". RO"en Pr ..., New York.
1981.
88. &\dcrslen. P.. ]lonning. M.. Melin. P.•• nd Ludin.
S. Vasopr=in Al'e'" Female Sexual Beha.ior by
A·1. Farge . .. M. J .. Fioramonli. J .. and Bueno. l.
Proolaglandin E,: A !'i•• fomedulalor in the Ce n·
tral C",nrol of Gastroinleslinal Motili,y and
F•• ding Beh_,iur by Calcilonin. Sci,,,,,,
]]j:
1050-1. 1984
A-2. Hanley, M. R .. Benion. H. P.. Lightman. S. l..
Todd. K.. Bones. E, A.. Frenon. P.. Palmer. S..
HV!'OTHALA.MUS ANO HVPOPHVSIS
Actins on the Br.in Independently of Allerolion. in
Blood Pres,ure. Nmur, JOI: 608-10. 1983.
89. S,.entagolhai. J .. FI., k6. J .. M.... B.. and Hal£ ...
90.
B. Hyporhalamic Call1rot of
A"ademi.i Kiad6. Bud.peS!. 1968.
Am";,,, Pituila,y.
Toohe Y.• G010. Y.• Gunion. M. W.. V.lo. W" Ri_
vie,. J .. and Brown. M. lnhibil;on of Gastric Acid
$core';"n in Rats by I"IraCerebr.1 In)ee''''" of C",_
licolrop;n-Rele •• ing Fac'",. 122: 93S-J1.
1983.
91. T.ruk • • ioh . P. S., lr>d Dougln. W. W. GA BA Di·
reclly Affecl. Eleclrophysiologic.1 Properl;e, of Pi·
tuilary Pa ... 1,lerm.di. Cen •. NOIurt 199: 733_34.
1982.
92. Toylof, T., Dluh)". R. G .. and Williams. G. H.I1·
Er>dorphin Suppr..... Adreooconicolropin and
CQrtisolle.eI. in Normal Human Subjecl' , J. CUll.
End(}(.",i/lOl, M'lab. 57: 592-96. 1983.
93. Thompson , C. I. Conlrols of Eallng. SpeCltum Pub-
lication,. New Y"'k. 1980.
94. Tixier·Vidal. A.. and Farquhar. M. G.. eds. Tht
Ani";'" Pi/uilary. Academic Pres<. New y",k,
1975.
95. True • . R. C .• and Carpen'er. M. B, Human N,u-
roaM/omy. 61h ed. WilHam, &. Wilkin., BallitrlOl'<.
19M.
96. Turner. C. D.. Ind Datln.ra. J . T. ...'all:;ndocrj-
""logy, 6,h ed. Saunde .... Philadelphi•. 1976.
97. Van lloulen. M .. NI""e. D. M .. Gau,hi.r. S.. and
]>()s ne,. B. I. Ori!in of [",ulin.Recepli.e Nor.e
T.rminal. in Ral MedlIn Eminen". EndocrillOl.
113: 1393_99. 1983.
98. We'ngarlen. H, P. Conditioned Cue. Elicit Feeding
in Sated Rat.: A Role for Learni,,! in Meal Initi._
tion. no: 431-3. 1983.
99. Wingotrand. K, G, CMlparali •• Anatomy and Evo-
lu,;on of the Hypophysi •. Chap. 2, pp. of
Harri. Ind Donovan. ed •.• ",rer.nce 38.
100. Yoshida. Y. Eleclron Microscopy of Ih. Anterior
Piluilary Gland Und.r Normal and DitTe",nl Ex·
perimcntal Condilions. pp. 439_454 of Baju... E ..
and Ja.m in, G .. cd •.. and Achi"', m,nts in
Ex/WrimMlal Pathaloty. vol. !. Yc.r Book Medical
Publishers. Chicago. 1966.
Kirh, C. J .. and Michell. R, 11. A V.soprcssin.
I.il:e Peptide in Ih. Mammali .. S),mpal",k
No,"ou. Syslom , Nalurt J09: 258-60. 1984.
A·3 . Schmale. H .. and Rich,er. D. Single Base Dole·
,ion in Ihe Vasopre"in Gene i. Ihe Ca.,e of Di-
."te< In.ipidu. in Bral1leboro Rats, Nalure J()IJ:
795-9,1984.
 20
The Pineal and Thymus Glands
The pineal gland has intrigued physicians and phi-
losophers sinc<: ancient times (7.8). Attempt,; to re-
place old superstition, with scientific coru:eplS of its
funclions can be traced to the seventeenth century,
and interest in Ihc pineal accelerated during the laIc
ninetccnth and early twemieth centuries. However.
the rapid ascent Oflni, part of the brain to respect-
able status within Ihe society of endocrine glands did
001 begin until the 195Qs. The journey ,,"'as difficuh.
since the pineal docs not behave in a manner OnCe
UPCCled of Ihc members of Ihal organl7.iulon, The
consequences of pincaicctomy arc not easily rccog-
nizcd by investigators lacking prior knowledge of the
function •• and they arc not readily rcvcrsc<:l by im-
planting a new gland. Moreover, hormones made by
pineal""y!", are also while
biologically potent components of gland ar<:
derived, in pari from microenvironment. The rc-
spo!l5<sto the administration of pineal hormoncs can
vary with (among other the manner of pre-
sentation, the sex, age and species of the subject, the
time of day, and thc season of the year.
/u recently as ! 973, the pineal was referred to as
"a rudimentary gland whose function in the adult is
not fully known" ( 183). r\ major investigator in the
field selected the title "Possible Functions of the Pi-
neal Gland-' for his contribution to a twermlume
publication that appeared in 1967 (85), and a widely
used lextbook rcvised in 1976 relegated the topic to
a section on "othcr hormone candidates"
There were reporlS that the pineal undergoes age-
related changes in appearance and that childr<:n
wilh tumors often suffer either precocious Or delayed
puberty onset (86). but the relationship to reproduc-
tive s)'litem maturation was not easily demonstra ted
in the laboratory. Today, we understand some of the
functions. and it is more the rule than the uccption
to find one or more papers on the pineal in journals
'"
that disseminate information on the endocrine sys--
tern. reproductive ph)'liiology, or biological rhythms.
Il<:cause of ilS size and location, early endocrinol-
ogi.1S found the thymu s more ac..,,,iblc than the pi-
neal for manipulation and st udy (38). It was recog-
nized that the gland allains maximum absolute si7'<:
and thymocyte content shortly after the time of pu-
berty onset. that it enlarges after castration. and that
it involutes in response to stress. However. the con-
sequences of thymectomy were not easily defined.
Animals subjected to the surgery suffered stress. se-
vere trauma, and infection. and many of the changes
reported can be ascribed to nonspecific factors.
When the operation was performed under ideal con-
ditions, "deficiency syndromes"' observed in one lab-
oralory wcre not easily reproduced in another.
There were several reaSOnS for suspecting that
thymus and pineal gland functions are interrelated
(26.122. I 54, 166). Both organs werC thought to pro-
vide protection against prematur<: maturation of Ihe
reproductive systcm. to regulate water and clectrer
Iyte balance (86.122), and to be involved in the
mechanisms for coping with neoplasia (91_1 80A).
During the 1950s. immunologists began to dis--
cover essential roles of the thymus in the establish-
ment and maintenan.., of lymphocytic functions.
When they demonstrated the devastating conse-
quences of nt<>natal thymectomy in laboratory rer
dents, most endocrinologists lost interest in other
possible functions of the gland. They began to study
humoral mediat()l'$ of immune processes or pursued
investigations in Other are.s. Several other reasons
for turning away from earlier kinds of research on
the thymus gland are discussed later. However. a
few :;cientist. d id demonstrate inHuences on ovarian
differentiation. the secretion of adenohypophysial
hormones, and the control of electrolyte metabolism.
Some new reasons to further examine possible inte,-
...
relationships with the pineal were also presented
(39.115.153,170B) a nd it is now reoognized that
bolh undergo circadian and season-linked
changes (83.171).
STRUCTURE AND INNERVATION OF PINEAL
GLANDS
The marked variations in structures arc mOSt ot>-
vious when one compares Ihc "simple" pineals of
mammals wilh Ihe "complexes" of some other ver_
tebrates (141AJ, The laner include Ihc parapincab
of fishes, Ihc frontal organs of amphibians. and the
parietal ("third") eyes of hlardi. Many of Ihe nOn-
mammalian glands contain phOloreceplors that rom-
munica!. via synaps<:s with olher parIS of the brain.
mammalian pineals respond only indirectly
to light and atTut other organs by releasing secre-
tory produca .
Closer examination reveals Iha\ mammalian
structures differ from each other in gross and fine
structure. One system of classification provides us
with 5 different categories (194). Variations arc en·
cauntered among strains of a singles species. and
even among individuals.
All animals adjust their physiological activity lev_
cis to changes in the external environment . The can·
cept that tbe pineat is a major mediator of tbe syn-
ehroni7.ation tn vertebrates is supported by
camparative studies of gland size (131). The largest
organs are found in seals, walruses, and other ani-
mals living in pOlar regions. Some of the smallest
occur in equatorial species such as the rhinoceros. el·
ephant, and red kangaroo. Alligators and crocodiles
are among the OneS that totally lack even embryonic
rudiments (although they make pineal gland hor-
mones and synchronize their biological functions
with changes in the environment) (165). It has been
pointed OUt that those reptiles evolvcd during an era
in whiCh Ihe seasonal cbanges in climate were min_
imaL Anteaters. sloths. and armadillos are m[uired
to make only Ihe most limited of seasonal adjust-
ments, and they seem to totally lack pineal tissue.
Most other vertebrates evidently have at least small
pineals, although certain of them (e.g. dugongs)
we'"" once not believed to possess them (2(0). lam-
preys are equipped with well..developed complexes,
but myxenoids (which belong to t he same class) ev-
idently have, at most. some sca ttered cells. In this
case. it is possible that tbere is a relationship toother
features described for such animals. Hagfishes lack
true thymus glands (100). and they are also the only
vertebrates that do not osmaregulate.
Pineals undergo reversible changes in size and ap-
PINEAl AM) THYMUS GLANDS
pearance . This may aCCOunt for ropOrts that human
glands weigh 88-1 12 mg (200). 100-180 mg (146).
Or 50- 400 mg (62) . The counterparts in rats rarely
I mg.
Pineal glands derive from the ependymal lining of
the third ventricle of thc brain (146). and in a few
species they cansist of lillie more than thickenings of
the ventricle roof. The same tissue gives risc to the
subcommissural organ. and opinion is divided on
whether the IWO brain compOnents interact. Bilateral
projections of the neuroectoderm fuse to form a mid-
line StruclUre that is hollow, but the opossum is the
only mammal known to retain such a form when de-
velopmenl is completed. In nonmammals, parapi·
neals and related compOllents of the complex seem
to originate in different anlagen. Some mammalian
glands have distinct anterior and posterior regions.
and the possibility that they arise from separate pre-
cursors has been considered.
In humans and many other species. the matu,""
gland is a campaet, conical knob that lies between
tbe superior colliculi and beneath the posterior bor·
der of the corpus callosum. It retains allachment to
the ventricular roof by means of a slender stalk. The
3rd ventricle extends into the stalk for a short dis-
tance as the pineal reCess. A thin tectal plate sepa·
rates the gland from the cerebral aqueduct (146).
In rats and other rodents. most of the tissue mi·
grates upward 10 form the "pineal proper:' while
small numbers of cells remain behind as the very
much smaller "deep pineal." In some species, a dor.
sal evagination of the 3rd ventricle forms a suprap;.
neal that is separated from the gland by
meninges.
Release of Pineal Gland Regulalo rs
A major source of controversy is the question of
whether mammalian pineal glands send hormones
directly into the cerebrO$pinal Huid. It has been
stated that a transition can be traced from the
"'primitive" organs of lower vertebrates that secrete
directly into the cerebrospinal Ruid (CSF). through
"'intermediate"' types that utili ,.. both ventricular
and vascular routes. to Ihe "advanced" structures of
mammals, sna kes, and some olher species that pOur
Iheir secretions into the bloodstream. There has been
a growing tendency to aceept the belief that even if
products di=tly enler the CSF. mammalian
pinealocytes secrele mostly to the perivascular
spaces. The choroid plexuses contain high concentra·
tioll$ of melatonin and other pineal gland hormones.
and thcy are believed to very rapidly transfer Ihe
molecules from the blood plasma to the CSF (ll0).
Subslances inj«Oled inlO either the blood or CSF
soon enler Ihe pi""al gland. (Blood-borne molecules
arc: also taken up by the neurohypophysis. the su-
praoptic crests. and the area postrema [200J.) One
difficulty encountered in the studies is Ihe produelion
by choroid plexus e<:lIs of hormones thaI arc also
synthesi"ed in pincalocytes.
On the other hand. canalicular systems that may
dir«Otly communicate with the 3rd ventricle have
!Jeen descri!Jed for hamsters (187). and regions in
which pincalocytcs penetrate spaces !Jetween the
ependymal cells thaI line the pineal reCeSS seem to
be: present in guinea pigs, monkeys. and some other
species. Moreover. although serotonin docs not read-
ily cross the blood-brain barrier. marked nocwrnal
elevations of CSF serolonin oonccntrations Ihal arc
paralleled by changes in melatonin ooncentralions
have been observed in monkeys (58A). The circa-
dian rhythms are abolished by 10 bright
light. and by propranolol-factors that suppr= pi_
neal gland synthesis of melatonin.
In human fetuses. a hollow evagination of the 3rd
ventricle can !Je identified around 2 months postcon-
ceplion. During the next 3-4 w«oks, a system of tu-
bules gradually fills Ihe space formerly occupied by
the lumen. Parenchymal cells then proliferate. and
Ihe pineal aSSUmeS a compact appearance by Ihe 6th
prenatal month (62). Since meninges cover the su-
perior surfae<:. and ependymal cells line the small pi-
neal receSS that persists, mature pinealocytes may!Je
unable to oommunicate directly with the 3rd ventri_
cle. Human glands are much less sensitivite to light
than the monkey counterparts. and it is possible that
anatomical features accoum for some of the
differences.
Bl ood Flow
Blood now through mammalian pineal glands is
brisk. Posterior cerebral arteries lead into dense cap-
illary netwc>rl<s that drain via numerous pineal veins
into the great cerebral vein. The arteries give off
branches to the choroid plexus, but anatomical find.
ings are not oonsistem with early suggestions that
there is backfiow from the great cerebral vein to the
choroid plexus (71.194). Peptides are believed to
rapidly lraverse the highly fenestrated endothelium.
InnervatIon
Most of the information tran5mi ned from the eyes
to the pineal gland traverses multisynaptic pathwaj'5
that involve the sympathetic nervous system. Fine
rtlillO-hypOlhalamic IraclS originate in the ganglion
layers of the retinas. leave the optic nerves at the
chiasma. and terminate in the suprachiasmatic nu-
clei (SCN) of the hypothalamus. The SCN send
projections to the perioem,kular and IUbe,al regions
of the hypothalamus. The tu!Jeral neurons oommu-
nicate with the lateral hypothalamus. and the mes-
sages then lravel via the medial jort'brain bundles.
through the rostral part of the mesencephalic leg-
mentum. to the imeromediolateral cell columns of
the Ihoracic spinal cord.
Prtgangfionir MUrons originating in
the spinal oord synapse wilh posrganglionir neurons
in the supnior N''''ical ganglia (SCG). Po:ltgan-
glionic sympathetic neurons Ihen ente r the pineal
gland via eilher the ("CHary Mrvt'S Or the blood vessel
pathways (61.1l?186) (fig. 20-1). The terminals
do not form true synaptic contacts with the pineal-
ocytes. Rather. the fibers end in the parenehyma!Je-
tween pinealoe)"les. or in precapillary spaces. There-
fore. the oorepinephrine that is released gelS to its
targelS by diffusion .
Olfactory. aCOUSlic, thermal, and magnetic stim -
uli all modify pineal gland functions. Some of the
information is probably relayed by the SC!'.'. while
additional signal, arc believed to follOW a habenular_
pOSlerior oommiS$ural route that docs nOl inVOlve
either the SCN or the sympathetic ganglia .
There are indieatioru; Ibat the paravemricular nu-
clei of the hypothalamus send axOn! through the pi-
neal stalk and also to Ihe SCN (24). They can
thereby provide the gland with vasopressin, oxytocin.
and the associated ncurophysins. Those peptides a rc
consistently fou nd in Ihe pineal and it has !Jeen pre>-
posed thatlhey mediate physiological adjustments to
seasonal changes in humidity and rainfall. Some dif-
ferences !Jet",een magnocdlular neuron and pineal
gland neurophysins have. however. !Jeen descri!Jed.
In at least some species. Ihe pineal receives pa,a-
$ympatheric innervation. A pathway leading from
the superior .alivatory nuclei that Ira'''",s the
greater petrosal nervell and enters, in part, via Ihe
conary nerves has been described for the rabbit. Ac-
cording to some observers. mammalian pineal, con·
sistently comain cholinergic intramural neurons.
However. it has been asserted that the "choline-ace-
tyltransferase" descri!Jed by some investigators is, in
fact. carnitine acetyltransferase (95). Moreover,
much of the acety lcholine disappears after destmc-
tion of the adrenergic innervation. Fetal pineals of
humans and many other species possess innervations
Ihal degenemte as the glands mature (118). Sero-
looinergic supraependymal fibers thaI degenerate
following destruction of the raphe nuclei ha .. e also
been found in lalS and humans.
The terms "efferent" and pinealopctal have been
applied to fi!Jers that enter Ihe pineal. Afferent or
pinealofugal systems arc: well developed in many
." PINEAL A ND THYMUS GlJINOS

__ -------Aelin..
Primary OPIio "",,(0 - +
Opo'" .... "'es Ae< •• ""Y <>pbe ,racl.

Opt", chiasma - - - I
I Atli<>;>I\Y""'fala",", I, ac,s

- - --·-Sup...,"'.smahc raphe 01

o.her Pe,wentri<;ulo'
e lle<et'ts hypoOMI."",.

I
Tuber.1 hypolhalamus

Solitary tracl
It
Uleral hypOlMI""""
(1/II51.tio<> )
j
Madial Tor""";" buM,,"

I
MeS<>""Op/'lalK; tegmentum M>dl>fa," Mocular
10rmaUO<'l
j t
OliaclOl'y '09'0"0 .
pathwOy' In to,ome<IioIatera, cell columns
kom oplic roe"",. lha' o( lho/atic ",",a l cord amygda1.1, SO'PIal nuclei
"", •.,. "'" SCO
I ,
Super;':' """'"., ganglia _.- - ' - - - Magnc'ore<:<>p'o<'

I
c.,.,ary .......... and bIood _
"".... , p.,hways

I
Pineal gland

fig. 20-1 . Estoblion.<! . .... purportOOd C<>nnIIClioos

bftlw- . _ piooa l g ...... A.... 01 ..... oompon«>lS Of the
btl".

nonmammalian vertebrates. Assert ions they do
not exist in mammals have recently been questioned.
The SupraCIiJasmetlc Nuclei
The nuclei (SeN) are paired wue-
lures that possess intrinsic rhythmicity and evidcnlly
function as independent but coupled biological
docks ( 119). Neural input. front numerous $Ourees
synchronize the activ ities with environmental and in_
tcrnal cues, and several hormones modify ihc func-
Efferents from the SCN ar<= believed to regu-
latc secondal)' osc illators as well as structures tht
would otherwise function on a more continuous
basis. T he ventromedial nuclei of the hypothalamus
are among the brain regions implicated as secondary
oscillators.
In rodents and other small mammals. the SCN
 arC probably Ihe primary regulalors of cireadian
funclions. They show higher electrical and melabolie
activities during Ihe daylighl hours lhan al nigbt
The pallerns persisl whcn eUIS made belowlbe Oplic
chiasma destroy pupillary reflexes and behavioral re-
sponses to visual signals. if Ihe retioobypothalamic
coonectioru; 10 tbe SeN are preserved (119). If path-
ways connecting the retinas and SeN are seve red .
and when an imals are mainta ined in continuous
darkness. the rhythms become free-running. i.e ..
tbey follow an inlrinsic cireadian pallern that is no
longer synchronized with changes in environmcntal
lighting. Although the possibility Ihat Ihe rhythms
require cyclical changes in humoral factors made
elsewhere is !IQ\ easily rule<i out, il has been dem-
onstrated thaI single cells removed from the SeN
continue 10 discharge for up to 14 hours when main-
lained in vitro. Moreover. Ihe aClivitie, are grealest
when the are laken from intact animals during
the daylighl hours (62i\).
Deslruction of the SeN in adult rodents perma-
nently disrupts or abolishes the cireadian pe riodici-
ties of scveral funclions. These ineludc not only
growth hormone and glucocorticoid secretion. renal
elcclrolyte excretion. drinking. pineal enzymc. and
reproductive system pallerns. bUI also Ihe daily vari-
ations in Ihe numbers of brain receptors for ". and
,8.adrenergic. musearinic. cholinergic, dopaminergic
and opiate agonists (78A).
Electrical stimulation of Ihe nuelei in inlaCI ani.
mals alters the phases. and the effecls elici led var),
with the time of day during which the stimuli are
presented.
Diurnal varialions in rales of glucose ulili1.lllion
have been detecled in rat fetuses even before Ihc
neuronal connections are fully eslablished. Maternal
cues synchroni"" the patterru; with photoperiods and
prepare the structures for development of mOre ma-
ture control meehanism! (158A). If Ihe SeN of rat.
are destroyed before the 3rd postnatal week . most
circadian rhythms never develop.
However. although the SeN and their conncc-
lions with the eyC$ have been identified in proloth-
erians, melatherians, rodents, carnivores, primatcs.
and all Olher vertebrale groups in which they have
been investigaled. (119) it is recogni1.ed that tile
brain also C(lntain, other o:;eillators. A second (X)
pacemaker whose locus has nol yel been determined.
seems to be mOre important in primates than in ro-
dents. It evidenlly oonlrols plasma cortisol, urinary
potassium, core body temperature and rapid eye
movement (REM) sleep. whereas the Y pacemaker
(which is probably Ihe SeN) directs slow wave sleep
(SWS). skin temperature. plasma growth hormone,
and urinary calcium rhythms (119A). It has also
been suggested that peak performance for repetitive
lasks that require simple manual is linked
with an oscillator different from the one thaI alfeets
10 reason and remember (liSA). In pri-
I t after the
i the ad-
vances to I cycle. and th.
more eXlen,ive development of lhe cerebral cortices
necessitaled specializations of the hypothalamus
thai included Ihe eme rgence of more oomplex con-
trol mechanisms.
The two systems arc mu tually ooupled, but Ihey
have somewbat different free runnins periodicities.
Under normal condilions. they are in phase with
each otller because they are inHuenced by the same
envirOnmenlal cues. Volunteer human subjeets
maintained in rooms without windows. clocks or
OIher lime indicators who eat and sleep when Ihey
choose display desynchron imtions. It is virtually
tain Iha\ much of the discomfort of "jet lag". and
some of the difficulties encountered in attempts 10
adjust to irregular W<lr k schedules a re directly at·
tributable to disruplions of normal patterns. and it
has been demonstrated that sleep-wake ad-
just more rapidly than body temperature changes
(! ISA). There are clear indications thaI rnanic4e-
pressive disorders in humans arc linked wilh (and
rna)' even be caused by) dysfunClions of the rhythms
(1968.199)_ In some of Ihe palients, delibe rale rear·
flIngem"nt of the timings of sleep and awakening has
been observed to lift de pression. and it can even
cause the subject to go from a depressive to a manic
phase. l ilhium and other pharmacologica l agents
that have proven beneficial are now known to affect
the patterns. Patients wilb severe sleep disorders
who do not suffer mood swings of such magnitudes
have been trcated with regimes involv-
ing isolation from the usual environmental cues and
artificial lengthening of Ihc days (199). T he "cure"
persists after the subjeet returns to a conventional
schedule. bUI lreatment i< again oce<ied following a
long east-west airplane trip or Olher inler_
fereoce with the newly established panern.
Although Ihe secondary oscillators seem 10 be less
important in rodents, it i. known thai SOme circadian
rhythms can be developed after the SeN are de:-
stroyed. The animals do. however, differ from intact
Or sham operated oontrols in their abilities to
undergo pbase shifts when the timings of Ihe oc""
stimuli are varied .
Most of the SeN cells functionally associated
with the relinas bave been called "light-activated".
sinee they increase their electrical activities in re:-
sponse to the illumination. A smaller population o[
"light-supprcsse<i" cells decreases the firing, and the
cells become lotally quiescent wllcn lhe I1ght is very
bright (62A)_ The effects of short.term trealmcnt
arc reversible, bUI chronic exposure to brighl lighl
can damage Ihe system.
."
The pIGPeni.s of the SeN cells arc under acti ve
invcstigation. The localizations of 11 different ncu-
mlran,miners have been idem ified (119) . The list
includes VIP, SS, substance P, CCK. and leu-en·
as well as norepinephrine. acetylcholine.
and serotonin. Studies with carbachol, a-bungaro-
toxin, and other agents support lhe belief thaI an-
ry/choliM mediates inhibitory inHucnccs exc/too on
the pineal gland when light hining Ihe relina a!fecls
the SeN. The e/fecls of carbachol are opposed by
nicotinic bU1110l muscarinic an tagonists (62A). The
SeN are espe<:iaUy rich in serolOnill. and lhe rales
of scrolonin uptake undergo circadian changes. The
nuclei additionally contain tryptophan and
amine oxid!lS<', and the >hydroxyindole acetic acid
10>,<,1$ vary with Ihe lime "f day_ However, although
studies with pharma<:(llogical agenl$ are consistent
with serotonin-mediated inhibitory eontrols exerted
by the raphe nuclei, and interference with SCN syn-
thesis of the amine disrupts the rhythms, the ser<:>-
toninergic innervation does not sum to be essential
for oscillatory activity (62A). Vasopl"f'ssin may be
involved in some ki nd of fine control. Brattleboro
rats unable to synthesize the peptide display normal
entrainment of drinking, locomotor and reproductive
system rhythms. but the freNunning periodicities of
the SCN are elongated. 55 and substa/lCt P regulate
noradrenergic functions in the SCC (83A). and thcy
may perform comparabk functions in the SCN.
Most observers bc:lie\'Cd until quite recently that
mammalian pincal g lands rcceive all of the photic
inputs via the retin<:>-hypothalamic-$CN-SCG path·
way. II is now reeogni7-<,d that the \/tn/rallo/trol ge-
niculolt nudei contain light-activated and lighHup-
pressed cells of the kinds found in the SCN. Many
of the lateral geniculate nuclei fibers project to the
SCN. Components that bind antibodies directed
against ""ian poncuOIic have b«n iden-
tified (62A). However. it has a lso been repOned that
the inputs from these nuclei are not nuded to main-
tain SCN fun<:tions. Pineal glands Can respOnd to
photic and other stimuli when both the SCN and the
SCG are destroyed (7 .176). The information may be
transmitted via habc:nul<>-pineal tracts. Fibers from
both thc habenulae and the striae medullarae have
been found in a fcw spe.;ies (64). Moreover. limited
numbers of pinca locytes TC$pond to electrical stim-
ulation of the habe nula. and babenular ncuron firing
pallerns are affected by dcctrical stimulation of the
pineal gland (176).
Cell Types
Most of tlte cel ls are pinealocytes (parenchymal
cells), but the glands also <:(Intain neuroglial
THYMUS GLANDS
or interstitial eompOnems, neurons, and capillaries
( I 33).
Mammalian pineal(lC}'tes have b«n called para-
neur()flS ( 188), since they derive from the neural ec-
toderm, eontain synapt ic vesicles, produce sub-
stances that function as neurotransmitters, and
secrete their products in res ponse to plasma memo
brane stimulation (95). Thcy a rC regarded as corn·
ponents of the APUD neuroendocri ne system
(141A). It is usually possible to distinguish "light"
and "dark" types.
According to SOme investigators, all pinealocytes
belong to a si ngle population that can undcrgo re-
versible ehanges in morphology and function. An
evolutionary pathway has been traced from pho/Ir
reap/OF ails (PCs) that resemble the rod s of the
retina and synapSe with neurons, through interme-
diate types (RPCs) that have only ruditm'n/ory phI>-
/or«tplOF components and releasc their products to
perivascular spaces, to mammalian·type pineal<>-
cytes that totally lack photoreceptor elements (35).
Some support for the hypOthesis derives from .lUdies
of pineal gland differentiation in reptiles. However,
although lampreys hav" rod-li ke pinealocytes and
mammals have the more "advanced'· cdltypes, the
intermediate forms are found in fishes and the ma m-
malian·type cells in snakes.
The preceding concepts are not easi ly reronciled
with cona in observations (1 07). Elcctrophysiological
.lUdies have revealed heterogeneity among ccll types
classified as PCs. Moreover, some PCs eviden tly
make melatonin whereas others do not. It has there-
fore been proposed that the pineals of "lower'· vcr-
tebrates eontain at leMt two different pinealocyte
populations, both ofwhich may have undergone cvo-
lutionary changes, and both of which may be repre-
sented in the mammalian glands.
There are also disagreements over the numbers
and kinds of "in terstit ial" cells that are present. The
elongated cells located between pinealocytes differ
morpllologica lly from the epe ndymal cells thaI bor-
der the 3rd .. ntricle. However. they are believed to
derive from the samc cmbyron ie precursors, a nd
thcy ha\'C been referred to as ependyma-likt or glial
cells. They perform special functions that may in-
dude secretion of hormones 10 the perivascular
spaces as well as regulation of pincalocyte functions .
Calcareous eoncrctions (corpora arenacea . acer-
vuli, psammoma bodies). made up mostly ofhydrox·
yapIl\ite and some carbonitc apatite (1 41), are eon·
sistendy found in the glands, and their numbers
increase with advancing age. It was at one time be-
lie..d that their presence denotes degenerati\'C or
patllological changes. Howe\'C r, a more =ent !l()tion
is that they are formed under physiological condi_
tions (132).
REGULATORS SYNTHESIZED IN PINEAL
GLANDS
Pincalocytes make very large quantities of ser()tonin.
Most of it is converte<;!to melatonin, tryplOphols, and
other derivativ«. Although the amOUnts released to
the systemic blood do nOt substamially affect the
total circulating serotonin. the pineal may supply
much of the amine found in the CS F.
The biosymhesis begins with avid uptake of
lophan. which is supplied by the diet and delivered
via the blood vessels. Uptake rates of 0.5-0.6 "gfg
have described for rabbits fed the usual diets.
The amino add concentrations in the pineal are af·
feete<;! to some extent by the plasma COIleentrations.
In animals expoSed to natural photoperiods. they
peak at the end of the day.
Tryptophan is rapidly converted to 5-OH-/rypto-
phan (5·HTP). This step. which can be rate limi ting
for the production of se rotonin. is catalyzed by the
tryptophan hydroxylase that is prescn{ in the mito-
chondria of lhe pincalocytes. Pteridine. ferrous iron.
and NADPH are required cofactors (Fig. 20-2).
Tryptophan hydroxylase cone<:ntralions are
greater in the gland than in any other part of the
body, with the possible exception of the raphe nuclei,

Nil,
" I

\,
T,,,"....."

•
I >}'<Iro,,·t...
,'<AOPH, ",,,/o,d_",;,

,,"Ii,

I II l!
N

"
>- OH _T,>'""""ho.

...
I
,,,,ho. ",.mo",." ,..." .....,,<
' ·OH_,,, ..
)
.m","",,'" "","-
,.,;00"1,..,.".,,.
:<;11,

''''():::T'"' " G----c- I!

I
N

" r"...", iM
,s.",,,,"i.1

I "'''''" """"0'1''''
s."""";,-...·...,,·/" ... r"_

I liy.l "''' ,,001<.0..,<th,U" "rtf... t II '0.\' TI

M.,.,.,I"",Mo";",,

"
"N--C--CII,
I ,
Ii 0

Mt"""';. Fig. 20·2. Major pathwly tot

... ...-.t,I" ,p .. m;",1 biosynthesilof mel.ton;".
...
and the ptcridinc levels arc also remarkably high
(88). It is claimed by some observers tbal the pineal
gland enzyme neve, saturated with (al-
though such saturat;on occurs elsewhere in Ihe
brain) (95). However, others report thaI Ihe activity
is augmented by feeding Iryplophan-enrichcd diets
(88). NOCturnal iocl"<'ascs in tryptophan concentra-
tions may aCC(>um for the modest elevations of en·
zyme acilvily reported for some species at thaI lime.
5-HTP never accumulates, since Ihe pincalocyle
cytoplasm contains very large quanlilies of 5-HTP
de<:arboxylase (aromatic acid
ase). The enzyme catalyzes Ihe conversion of 5-HT
to .,erO/on;" (5-hydroxytryptamine, 5- HT), bUI it
also acts on Olher substrates. The cofactor is pyri-
doxal phosphate. In at least SOme species. exogenous
5·HTP very markedly aoxelerales serotonin biOl;yn·
thesis. whereas exogcoous trYPlophan is ineffeclive
(121).
Serotonin that is oot directly utilized. released. Or
degraded is stored in boIh pincalocytes and sympa·
thetic nerve endings. The concentrations can be sev-
eral-fold higher during daylight hours Ihan al night.
and up to 250 times Ihe levels found in other pariS
of Ihe brain. The accumulation is widely atlribuled
10 the very low rales of conV<'rsion to other hormones
during Ihc daytime, but the rates of biosynthesis and
release can vary over wide ranges .
Melatonin
Serotonin N-acetyltransferase (NAn calalyzes Ihe
conversion of 5-HT to N-acelylscrotonin (NAS) .
The pineal gland enzymes (which differ from the
NATs found in olher parts of the brain and in the
liver) arC regulated by the sympalhetic innervation.
Aoxtyl-coe(7)'mc A <eNes a. a siabilircr a. well as
a oofactor.
The reaclion is believed to be rale·limiting for Ihc
biOl;ynlhesis of melatonin (S-melhoxy-N-acetyltryp"
tamine. MLT). Changes in NAT oomenl and aCliv-
ity account for the diurnal varialions in MLT pro-
duction in rodents. In sheep. Ihe availability of the
serotonin precursor can assume major importance.
Thc final step in MLT biOl;ynlhesis requires hy-
droxyindolo-O-mcthyhraO'lfcrase {HIOMT} and S-
adenosylmelhionine (SAM). Thc pineal usually oon-
lains high concentrations of the methyl donor. but
Ihe SAM levels can be fUriher elevated by feeding
mcthionine..,nriched diets. The enzyme calalyzes
trlnsfers of melhyl groups 10 5-OH-tf)·trophol and
10 other substrates.
HIOMT has a limited dislribution. In m(lSl mam·
mals. subslantiallevels are found only in the pineal.
Smaller quantities are found in the retinas. and in
PINEAl AND THYMUS GlANOS
the APUD cells of the intestine. Minule amounts
haV<' also been delectw in the cerebellum. Erythro-
cytes can conV<'rI NAS to MLT in vilro. bul it has
not been established Ihal they COnlain H IQMT.
Allhough Harderian glands MLT. Ihe
Chemical propertiu of the enzyme differ from those
described for the pineal protein (29). Interestingly.
HIOMT activily in Ihe regressed c)'<:s of Ihe mole is
2-10 times higher than in the pineal glands oftbose
anima ls (7) .
Similar light·regulated systems for Ihe produclion
of melalonin have been identified in the eyes of am-
phibians (I 3A). They display imrin'ic rhythmicities
that persisl for up 10 3 day, in culture. The struc·
tures arc directly affc:<:ted by ligh t, are entrained by
photoperiod,. and Can undergo phase shifts. NAT
activi ty peaks in the dark. The melalonin produced
is implicaled as a regulator of both photoreceptor
disk shedding and relinomotor movements. Mam-
malian eyes may also con tain circadian clocks that
oomrollocalized production of MLT. but rat sludies
indicate that phase shifts in response 10 environ men·
tal manipulations require the presence of intact optic
nerves.
Tryptophols
Recentlechnological advance. ha'e made il po,;siblc
to measure the levels of several pineal gland indole·
amines (161), and it is now known that substantial
quantities of serotonin are metabolized in olher ways
(Fig. 20-3). A "type A" monoomitU' oxidast
(MAO) in sympalhe tic nerve lerminals disposes of
ex=s amine. It catalyzes Ihc conversion of 5-HT to
an unslable intermediale. S·hydroxyindole-3.J1cetal-
dchyde. Most of the product i, then aCled on byan
aldehyde dehydrogenasc that converts it \0 5-hy-
droxylndole-3-actlir acid (S·HIAA). Pinealocytes
conlain both A a nd B Iype MAO. thai ca n be dis-
tinguished from each other on Ihc basis of suscepti·
bilities to inhibition by clorgylinc and Catron
(a-melhylphenylethylhydrazine). respectively. and
in other ways. Aloohol dehydrogenases in the cells
reducc much of the aldehyde to biologically ac(iV<' 5-
hfdroxytryptophol (S· HTol). HIOMT Ihen pro-
motes thc formation of 5-methox)·tryptophol (S-
/-lTol), wh ic h is more potent.
The MAO concenlrations are not known 10
undergo circadian changes. The rates at which thcy
serotonin depend upon thc substrate
levels.
Other Indoles
The preceding enzymes can act on Olher substrates
(Fig. 20-3). for example. H IOMT promotes meth·
 ".,..
.• '- • • .•• ""' ......,
1 Fir---r
,

_
' / -. . ..

..
• .......",.,.,..,...... N '" N

..
_........ - O::T" . H I
,
"" .. H

-. 0--..._
"Y'l--,;-"
l.....-A) " "
.......",., no . ...

" "
-
" "
"

. ,., ,,,,,. .' .. . , .. ,'<' .... _ _ .

'"
yialion of 5-HTP. while I·amino acid oxidase Cata-
lyzes the de<:arboxylation of tryptophan. The
tamine formed in the reaction is acted upon by
MAO to yield indoleacetic acid (fAA). The laUer
no known function in animals. but il contributes
to phOlolropism and growth in plants.
An Q.acetylase catalyzes the formation of Q-ace·
tyi·S·hydroxytryptophoi from 5·HTol (180). and of
().acetyl·5·methoxytryptophol from 5·MTol.
Metabolism of Melatonin and other Pineal
Gland Indoles
ML T is 001 believed 10 be fuoher metaboli,.cd
within the pineal gland. However, sine<: neurons out·
side the gland convert MLT to N-acety!·5·methoxy-
kynurenamine (88) (Flg. 2()..4), and since an indole
2.3-<1ioxygcnase cataly>.cs substantial conversion of
pineal tryptophan \0 kynuKnine, the possibility that
there is some direct degradation cannot be ruled out
(l63).
Plasma ML T concentrations rise during the night
(when pineal MLT production is high) and they fall
during the daytime. In intact rats exposed to alter-
nating periods of light and darkness, ooneen trations
of around 50 pgjml and 5 pgjml have be<::n found
for night and day. re'P"<'tivcly. hoprotereool in_
jected during the day can raise the values to 30 pgl
ml. Following pinealectomy. 00 MLT is foond duro
ing either the day Or night.
MLT that is released to the bloodstream is taken
up by many cell types. In the liver. it is hydrox ylated
at the 6-position. and the product (6-OH -MLD is
then oonjugated with sulfate (and to a lesser extent
with glucuronate). Urinary 6-0l-l-MI.T·sulfate ex-
cretion rises and fall s with the changes in plasma
MLT. Humans show similar cyclical patterns, but
MLT metabolism islcss sensitive to light in humans
than in rodents (96).
Pineal gland tryptophol levels are ""ry much
lower than the MLT ooncen trations. Cireadian
changes in the pi neal Can para!1e! the OnCS described
for MLT. but plasma 1.""ls of 5-MToitend to rise
during the daytime and to fall at night. Some of the
circulating S-MTo] may arise from peripheral me-
tabolism of O-aeetyl-5-methoxytryptophol (30).
Catecholamlnes: Biosynthesis, Metabolism,
and Functions
Sympathetic Il<:uTOns take up phenylalanine. and
they utili?.e tryptophan hydroxylase to oonvert the
amino acid to tyrosine (29). The tyrosine is then me-
tabolized to norepine phrine ( N E) along pathways
described in Chap. 8. The prOOUCt is stored in nerve
PINEAL ANO THYMUS GLANDS
terminals that also take up serotonin. Tyrosine is im-
plicated in the regulation of pteridine biosynthesis in
the brain (200A) and it may perf()rm similar func_
tions in the pineal. Alternate pathways for catechol·
amine biosynthesis may account for the presence of
octopamine in the pineal gland.
Circulating catecholamines are taken up, bUltbey
do not accumulate for several reaSOnS. The mole-
cules can diffuse away. be sequestered in nerve
terminals. or undergo degradations t hat are eata-
Iyzed by MAO. catecholaminc-O-methyltransferase
Or both enzymes. The very rapid removal
of catecholamines probably acoounts for the failure
of systemic stress to markedly inH ucnce tl1Ctabolic
eVents within the gland. COMT activity is higher
during the daylight hoors. and it may assume espe-
cial importance at that time (95).
It is not known whether phenylalanine competes
with tryptophan for the tryptophan hydroxylase. Ac-
oording to some authors, a single en?yme acts on
both substrates, but only the affinity for phenylala-
nine is affected by the pteridine levels (88). Others
state that there are twO separate enzymes (95).
More NE is usually made 3t night and more S-HT
during the hours of daylight.
NE binds to Il, -type adrenergic receptors On the
pinea toc)'le •. This lead. to the g<'ne<ation of cAM P
and the activation of cAMP-dependent protein ki-
nases (87). MClSt of the cbanges in pineaiocyte en-
zyme activity that follow ean be mimicked with iso-
proterenol and cyclic nuclootides, and most can be
blocked with propranolol. However. the existence of
smal l numbers of a receptors that intcract with
phentolamine. phenoxybenzamine and related
agents has recently been demonstrated (l SI) . Evi-
dently, the binding affinities are of thc tI", type. It is
believed that such receptors are located postsynapt-
ically and that they regulate Il, receptor functions.
Octopamine behaves like NE, but dopamine does
not interact directly with the receptors.
The sensitivity to N E undergoes ma rked circadian
variations. only some of which can be attributed to
'"down regulation" of Il, receptor numbers. Pinealo-
cyles display intrinsic rhythmicities that affect Ihe
responses to NE (16), even when they are main-
tained in culture.
Postganglionic neuTOns that originate in the SCG
release NE. In animals exposed to alternating pe-
riods of light and darkncss each day (LD). the firing
rates accelerate during the nighttime, and the activ-
ities of several pineal gland enzymes are thereby
augmented . Althoogh NE turnover also increases,
the pineal NE content rises somewhat. Undcr ordi-
nary conditions. messages conveyed by the retino-
hypothalamic tTacts synehronize SCN activities
 " ..
,, .• .
cc.',
H H H ,0
C-C-_C"-Qc -e-OJ
• • •

""-"- •

, ..•
o: """"':-<- _CIoI

••
•

..,. .11 ......, ,

•
.... 0' , ...

•... *". - ---"- -'.'.

'"
with changes in environmenlal lighting. and im-
puls.s from Ihe SeN, in turn, control Ihe diurnal
change, in SCG firing panern •. The effects vary
with the intensities a nd wavelenglhs of the photic
signals as well as with the sensitivities of the pineal.
ocyles . Bright light decreases NE ,..,Iease, pouihly
because it the rdease of acclylcbolinc from
Ihc light-activalcd SeN cells. Dim lighl can have
very different effects. As discussed earlier. oontinu-
(lUS 10 very bright light ( LL) irreversibly
damages Ihc SeN. The rhythms controlled by the
hypothalamic nuclei arc disrupted, and Ihe ability 10
laler 10 LD is 10K
The SeN al:;o regulate SCG firing in animals Ihal
a rc blinded or maintained in continuous darkness
(OD). They receive information from IIOn-relinal
wurces and it to synchn)nizc pin(al en7_yme ac·
with light-independent physiological func_
tions. The SCG are 001 totally cantrolled by the
SCN. The neurOnS receive innerva tions fn)m OIher
parts of the brain, and they may pOSSeSS intrinSic
rhythmicity. However. the photic signals that reach
the pineal glands o f animals with SCN lesions are
not believed to pass through the SCG . Sineesome of
the effects are st imulatory. it has been suggested
that a special pineaiocytc population is affected.
REGULATION OF TRYPTOPHAN
HYDROXYLASE ACTIVITY
Tryptophan hydroxylase (Til ) has a half_life of
around 75 minutes. It i, therefore believed that pi-
nealocytes continuously synthesize the enzyme. In at
least SOme species, the activity rises to 1.5 times
basal val ues during the middle of the dark period.
The diurnal rhythm persists in DD animals. but il i,
abolished by LL. Propranolol can block the noctur-
nal elevation. However. suggestions that the enzyme
is controlled by cAMP have not been subslantiated
(88). Serotonin levels are high during the daytime.
The possibility that they then exert some negative
feedback control over TH docs not seem to have
been investigated.
AMINO ACID DECARBOXYLASE ACTIVITY
The activity of this en7.yme is twice as high in rats
exposed to LL as in rats maimained in continuou,
darkness. Since NE release declines during the day-
time. while destruct ion of the sympathetic innerva-
tion has effects similar to those of LL. it has becn
suggested that NE exerts inhibitory influences.
However, thc effects of LL take days to develop.
changes in Ihe activity of tbis
PINEAL AND THYMUS GLANDS
probabl y make no COIltribution to the diurnal sen:.>--
tonin and mclawnin rhythms (88).
REGULATION OF N-ACETYlTRANSFERASE
ACTIVITY
NAT is a highly labile In LD rats. the ac·
varies a 30-70 range, and it peaks at
night when the NE levels arc high. Lighl
both the synlhesis of new protein and the activity of
enzyme. The pineal glands the
polential for rhythmicity during fetal life. and they
express il during the second week when Ihe norad-
renergic innervation i, established (147). Pups main-
tained in continuous darkness display the diurnal
rhythms, and they re,pond vigorously when sud-
denly eXpOSed to light.
Under normal conditions, noradrenergic receptor
numbers are high at the beginning of the dark pe-
riod. The SCG then release large amounts of NE.
and both NAT coment and activity rise rapidly. Tile
effects of NE can be mimicked with isoproterenol
and cyclic nucleotides. and thcy are exaggeraled by
MAO inhibitors and pbosph<Jdiesterases. A short
burst of light deliyered during thc nighnimc rapidly
lowers the enzyme activity but docs not substantially
aff""t the protein conlent. In contra<t. a period <>f
darkness imposed during the usual daylight hours
has lin]c immediate effect because Ihc NAT content
of t.be gland is low and thcre arc few hormone
NAT rhythms persist for at least two weeks when
the animals are maintained in darkness and when
the retinas are destroyed. The changes in NAT lev_
cis are attributed to cyclical variations in noradrc-
nergic receptor numbers.
NAT act ivity is differently in birds. The
pineal glands of chickens pOSsess intrinsic rhythmic.
ity that persists in culture (16). They are
sensitive to light. and blinded chickens msintain syn-
chronizations wilh the photoperiods
cAMP probably exerts several effects. Some evi-
dently involve the production of new mRNAs and
protcins. sinee they can be bloc ked with cyel()hexi·
midc or actinomycin D. However, it has not been es-
tablished that Ihe nucleotide directly induces NAT
(88). cA MP also hype,polarizes cdl membranes,
and it s/(Jbili;es NAT molecules.
Pineal glands conlain a protease thai rapidly inacti·
vole. NAT (3t). The effect' becomo apparenl soon after
tho gland. afe and oXl'\l&Cd t Q ordinary C"tt"rC
modia. Althouah ttlc decline i. unaffecled by aelirlO!lly<in
D. il i, aeeeleTa\.d by cyclone. imide High coneen·
Iration. of acetyl-CoA (bul nol Co-A) prole<1 the NAT
aga;nsl lhe prOlease_ They do nOI. bowever. rellOre aeli.·
ily that has been lost. The quantities required arc Broatcr
than Ihc one. round in thc glands. It i, therdore
IhOl the maintenance of NAT aCliv;ly depends on cont;n-
uou. pl'\Xluclion of a I.bil. prOtein IhOl eilber interacts
directly with Ihc enzyme or affects acetyl-Coi\ mela\»
li,m . cAMP may regula,. proouction of Ihe prOlein.
NAT activity is modified by several other factors.
NE augments thc taurine content of the pinealo-
cytes. and high levels of that amino acid stim-
ulatory influences (12). Taurine binds to ,6-adrcncr-
gic receptors. and its actions can be blocked with
propranolol (gg).
VIP immunoreactivity has been demonstrated for
pineal gland nerve fibers. and exogenous peptide can
augment NAT activity via mechanisms that do not
depend on the adrenergic receptors. The responses to
VIP are affected by both environmental lighting and
prior exposure to fl. agonists (203).
Severe forms of stress can somewhat elevale Ihe
NAT activity during daylight hours. The cffects are
exaggerated by agcnts that block NI3 into the
nerV<' terminals.
dopamine i, believed to requif<' con-
version to NE before it can affect NAT acti.ity. His-
tamine, gamma-{lminobutyric acid. and somc other
pineal components do not obvious influenees
(204)_
REGULATION OF HIOMT ACTIVITY
Melatonin levels are highest during the hours of
darkness in both nocturnal and daylight-{lctivc spe-
cies. and they also rise gradually during the winter
months in animals cxposed to natural photoperiods.
Although HIOMT activity usually increases some-
what at night. thc diurnal variations in MlT depend
primarily on the changes in pineal gland NAT oon-
tent in most mammab. Sheepaf<' among the speeies
in which the availability of serotonin substrate limits
MLT production (121). When light is presented
during thc night, MlT does not show Ihe
abrupt change de:;cribed for NAT activity. How-
ever. linte M l T i, stored. and the concentrations
$001\ decline to daytime levels ( 161)_
Up to IQ.-fold increases in pineal MLT content
can be accomplished with linl. change in the
IHOMT activity in rats exposed to regularly recur·
ring periods of light and darkness. On the other
hand. stilson,,/ changes in MlTare at least partially
with variations in rates of HIOMT syntb""is.
The quantity of enzyme increases gradually during
the wimer. It Can exert rate-limiting influences when
very large amOuntS of N-acctylserotonin aCCumu-
late. Exposure to long photoperiods leads to gradual
reduction in H10MT, and Ll eventually brings
about enzyme depiction. When animals arc main-
tained in continuous darkness. the Ml T levels aro
intermediate between ones seen during the day and
the night in lD controls.
11 is suspected that the sympathctic innervation
regulates the HIOMT. since destruction of either
the SCN or the SCG can block the effects of dark-
ness. However. in cultured glands. neither norepi-
nephrine nor cyclic nuc1eotides have been observed
to incf<'ase the activity (although tho!;c agents stim-
ulate NAT production)_
IHOMT is also rcsponsiV<' to several s/eroid h,,-
mones (27). The consequences of manipulating thc
concentrations vary with the species, the time of day,
the quantities administef<'d. and the influences ex-
erted (Wer pituitary hormone leV<'ls_ It is tberefore
not surprising that connieting data arc found ;n thc
literature.
PinealocyteS have u tradiol rt crprars. and these
are translocated 10 the nuclei when tbe steroid i. pre-
sented. The hormone nerts biphasic inAuences on
HIOMT activity. but il also affeets several other as-
pects of pinealocytc function (29.152). Low ronccn-
trations usually aceelerate M LT production. as they
elevate RNA polymerase activity and promote in-
corporation of labeled amino acids into proteins.
While this is consistent with H 10MT induction. the
synthesis of different proteins is also affected. The
innuenees on ML T can be blockcd with actinomycin
D. a-aman;l;n. cycloheximide. or puromycin (27).
HIOMT tends to decline after ovariectomy
in rats. and low doses of estradiol can restore the
normal levels. (The ages of the animals at the timc
of surgery. the gonadotropin and the interval
that elapses between surgery and the enzyme mea-
suremcnts can all affect Ihe f.ndings _)
Somewhat bigher dOSCiS inhibit. In intact
HlOMT activity and urinary MLT tend to decline
during when estradiol peaks. In
women. plasma MlT is f<'portcd to be high at lbe
time of the menses and to fall prior 10 QYulation
(\52).
The inhibitory inAnences are not blocked witb the
cited. It has been suggested that they result
in part from interference with NE activation of pi-
ncalocyte adenylate cydase. Ovaricetomy augments.
wllereas estrogen injections depress. NE-directed
cAMP generation. However. problems with this ex-
planation include the to innuence NAT aC-
livity and the low H IOMT aClivity of (Wariecto.
mi1.d animals.
In intact females. very high concentrations of es-
tradiol Can depress H IOMT activity by inhibiting
FSH and LH release. They also romplete with N-
acctylserotonin for COMT. as they undergo 0-
methylation . On the other hand. they inhibit MAO
and elevate the .. rotonin levels.
."
The estradiol receptors arc regulated by the ad-
renergic innervation. They fan to low levels (but arc
not totally losl) following destruction of the SCG.
The numbers arc als<> affected by estrogens.
Progesterone seem. 11} exert mostly inhibitory COn-
trols ovcr H IOMT activity. However. small amounts
can <:ounlcraci the decline> secn afler ovariectomy.
The effects evidently do 1101 require estrogen "prim-
ing" (29). although SOme progesterone influences on
other aspc<:1i of pineal physiology arC dependent on
prior cXp<):'lu,e to estradiol.
There is only limited information on the effects of
androgt/U, Pincalocylos lake up teSIOSterone and
DHT, convert testosterone to x.-roduccd metal><;>-
lites (induding DHT), and aromatize teWlSteronc 10
estradiol. Biphasi. influences On H10MT similar 10
the ones described for estrogens have been reported.
HIOMT activity is additionally said to be in-
creased by glu=rticoids, mineralocorticoid., and
ML T, and to be affected by pituitary and hypotha-
lamic hormones (19,202) and other regulators.
Lilli e is known of the factors that control HIOMT
activity in OIher tissues. There are indications that
these differ from the ones described for the pineal.
PINEAL GLAND PEPTIDES
Several biologi.:ally active peptide.. found in pineal
gland extracts have been impliCated in mediation of
the endocrinc functions Or in regulation of hormone
biosynthesis. They are difficult to study because (a)
most are prescnt in small amounts; (b) soveral arc
similar in chemical makeup 10 peptides made else-
where and they therefore cross-react in immunoas-
says; (c) some of the neurons deliver peptides to the
pineal glands. and ependymal cells of the choroid
plexus synthesize a variety of potent substances; and
(d) the pineal avidly takes up molecules of compa-
rable sizes from the bloodstream.
Arginine vasopressin (A VP). oxytocin. and the as-
sociated ncurophysins arc believed to originate in the
paraventricular nuclei of the hypothalamus. Thcy
are easily identified in mammalian glands. but no
A VP seems to be present in chickens and other ver-
tebrates that utilize arginine vasotocin (A vr) as
their antidiuretic hormone (65). In pigs. the hypo-
thalamic magnocellular nudei make lysine Ya&opres-
sin. and in these the pineal contains LVP. LRH. Cf-
MSH. MSH releasing and inhibiting honnones. and
enkephalin! are probably also taken up. rather than
synthesized by the parenchymal cells. However. an·
tibodies directed against a--MSH, LRH. and SS
bind to distinct populalions of pinealocytcs. There
arc unrooved questions concerning whether the
are identical wilh peptides made else-
PINEAL ANO ffiYMUS GLANDS
where thai bind Ihe antibodies. A substance
that closely resembles but can be diSlinguished from
TRH has al&O described .
Arginine vuotocin is in the pineal glands
of that synthesize the peptide in their
neurohypophy=. The peptide was tentatively iden·
tified in mammalian pineals. Subsequently. several
inv<:stigators suggested that the immunoassays uti·
lized were actually measuring a differem peptide of
approximatcly the same size that has an identical
terminal tripeptide (134). Others believe that very
small amountS of A VT are synthesized (20). and
that the peptide performs physiological roles. It hu
r<:cently been reported that rat pineals contain 1.8-
7.7 pg during mOSt of the year, but dramatic changes
in Augusl can raise the levels several hundred fold
(139). Although some state that AVT is made by
ependymal cells of the pineal recess. olhers regard
the pinealocytcs as more likely sourees. There is con-
siderable interest in the controversy. since exogenous
A VT is highly potent. As few as 60 molecules in·
jected into the cerebral ventricles can inhibit CRH
release. Morcover. systemically administered AVT
affects reproduclive system functions that are he-
lie.ed to be regulated by the pineal gland (54).
VIP has been consistently found. and il is believed
to be biologically important. However. it is distrib-
uted to neurons and is therefore probably
derived from extrapineal sources (131). Angioten·
sin-like substances and renin·likc activity have also
been reported to be present. but synthesis of A-II
within the gland awaits confirmation.
Thre<lnyl-seryl·lysine (TSL) has been i&Olated
from pincal glands and shown to antireprod·
uctive and some other activities with potencies thai
vary markedly with the species of test animals (193).
A different peptide of unknown strocture with re-
lated biological properties hu been given the name
pineal antigonadotrophin (PAG). It may be similar
to gonadotropin-inhibiting substance (G IS) found in
human urine Ihat is biologically effcctive in labora-
tory animals. Related urinary components that dis·
appear after pinealeetomy Seem to he present in
other species. A peptide similar to. but not identical
with. hypothalamic LRH has al&o been described
(114).
Although information on peptide secretory prod·
ucts is limited. it is certain that pinealocytcs actively
engage in the biosynthesis of regulatory proteins.
The rates are affected by NE and by gonadal hor-
mones. and they are infiuenced by pbotoperiods. It
has been proposed that the "Irue" pineal gland pep-
lides are cleaved from large precursors that are
sembled on the ribosomes. The names pre-propi-
nealin. propinealin, and pinealin have been given to
hypothetical substances that serve, respectively, as
the primary RNA transcript, the prohormone that is
formed from it when the signal sequenU' is removed,
and a protein or peptide fragment of the prohormonc
that is $Ccr<,:ted along with the other biologically ac-
tive endocrine products (34).
Other Pineal Gland Co mponents
Prostaglandins are implicated in the regulation of
MLT secretinn (28). are present in very
high concentrations. a nd it has been suggested that
in add it inn to serving as cofactors for hydroxylase
reactions. they perform other functions. Exogenous
molecules have been shown to affect H IOMT
ity (II). Fine control may be aecomplished . sinec en·
zymes that differ in isoclc<:tric points and sensitivi·
ties to pteridines have been described. Morcover.
light adaptation seems to affect the rdative concen-
trations of the isozymes (37). Pteridines arc also re-
ported to exert influences on the reproductive system
(46). Little is known of the functions of
melanins. and several other substances consistently
found in pineal glands ( 141) .
PINEAL GLAND REGULATION OF SEASONAL
CHANGES IN REPRODUCTION
Seasonal breeding patterns increase the probability
that the young will be born during limes of the year
when faeton such as e nvironmental temperature,
humidity. and the availability of food are conducive
to survival. In many the absolute amOunt of
light per day. progreSllive changes in photoperiod
length. Or both . provide signals for the synehroniza·
tions. It can often be demonstrated that the pineal
gland mediates or modifies the responses. However.
it is important to recognize that (a) light can exert
pineal·independent and (b) reproductive
functions are affected by nutritional status. non·
photic $Cnwry stimuli. social interactions. and OIber
factors. Some animal types are much more $Cns;ti'e
than others to changes in en.ironmental tempera-
ture, specific food CQmponents that may be influ·
enced by rainfall. and population densities.
Studle& Performed on Hamste...
Hamsters have been favorite subjects, since: they
react in obvious ways to changes in day length, pi.
nea lectnmy, and the administration of pineal gland
hormones. When adult males experience: fewer than
12.5 hours of light du ring each 24-hour period, the
testes regress. spermatogenesis ceases, teStOSterone
and prolactin (PRL) levels fall . and lhe accessory re-
productive organs undcrgo atrophy. Pituitary gona·
dotropin content and hypothalamic LRH also de-
cline. Usually, there is concomitant depr<,:SIlion of the
plasma FSH and LH, but gonadal regression Can
proceed when the concentrations remain high. In fe-
males, estrous cycles are arrested. and the uteri be-
come infantile. The ovaries do not form preovulatory
follicles Or corpora lutea. but growth of the intersti-
tial components can actually increase the "'eights of
the organs. Circulating PRL declines. but FSH and
LH levels do not (148). (While low estrogen levels
depress PRL pineal innuences do not de-
pend on this [92J.) Both to continuous
darkness and blinding can invoke similar responses
at other times of the year.
Once under way. the regreSllion cannot be rapidly
reversed by lengthening the pltotoperiod. In fact. the
involution continues evcn when attempts arc made
to mimic springtime environments. Ultimately (afler
14-20 or 30 wee ks for the Djungarian and golden
varieties. respectively [33]), insensitivity to the in·
hibition is manifested. Hibernating hamsters
undergo testicular and ovarian recrudescence while
still confined to Iheir winter burrows, and they arc
reproductively competent when they emerge. Nei-
ther blinding nor continuous darkness can block the
recovery. Some 22 weeks of exposure 10 long days is
then r<:quir<:d to r<:gain responsiveness 10 light dep-
rivation. It seems, therefore, that endogenous factors
are important modifiers of the respon$CS to Ihe
environment.
Golden hamste... Can hibernate even when labo-
ratory temperatures exceed those experienced out of
doors during the winter. Orchiectomy prolongs,
whereas both endogenous and administer<:d testos-
tcrone can shorten . the time spent in that state.
However. since the effc<:ts of ovaricctomy and eStro-
gen injections are inconsistent. the photoperiod proh-
ably cxerts steroid-independent influences on hiber·
nation (67).
Some lestieular growth and testosterone sccrctinn
can be achieved by administering prolactin (P RL) to
"winter"' animals. However. the stimulation is not
sustained even when plasma PRL remains elevated.
S uitably timed LRH injections augment FSII and
LH relea$C and restore the plasma gonadotropin
concentrations. but such treatment docs nOl over-
come the effects of light depri vation. On the other
hand, when animals recti.ing LR H injections are
also provided with PRL-sccreting pituitary implants,
reproducti.e functions are recovered. The PRL may
be needed to promote the formation of adequate
numbers of testicular LH recepto ....
Pinealc<:tomy, SeN or SeG lesions, and r<:tra-
chiasmatic knife Cuts that interrupt the pathways
from the retinas to the pineal glands all interfere
with (but do not totally abolish) the dark-invoked
regression. Hamsters subjected to such surgery he-
fore exposure to short photoperiods can remain alert

and reproductively competent throughout the year.
However. light deprivation and blinding can still
somewhat decN:ase lesticular size and hormonc se-
eretion. ln hamsters that have undergone regression.
subsequent pinealeetomy has very differenl conse..
quences. It retards Ihe recrud=nce that occurs
during the next long photoperiod (73).
Meletonln Medletlon 01 the Effects of Light
Deprlvetlon
It has been proposed that MLT is the primary me-
diator of Ihe responses to short photoperiods (148).
M LT production and release accciera te during the
hours of The time period during which pi-
neal MLT levels remain high is extended by short
photoperiod! (59). and H10MT activity increases
during the winter under natural conditions. When
intact animals receiving 12.5 or more hours of light
per day are injected with M LT every afternoon for
several week.!, the reproductive organs involUle. The
hormone is reported to excrt inhibitory innuences OIl
the hypothalamus, the pituilary gland. the gonads.
and other target organs.
In the white-footed mouse. which shows similar
responses to photoperiods. il has been demOllstrated
that implants releasing 45 ng of molalonin per day
over extended time periods invoke complele gonadal
regreSliion when they a'" placed in the medial p"'Ojr
lic. suprachiasma tic or retrochiasmalic regions. al·
Ihough Ihe anima ls are exposed to 16 hou .. of light
in each 24-hour period (5gB). The quantilies of
MLT "'leased are not too different from the
amoums that can be secreted by the pineal glands of
unoperaled an imals. Neither beeswax implants at
those sites. nor melatonin implants in other brain re·
gions mimic the effects. Sine<: the sensiliv.;: struc·
tures are all siwated close to the 3rd ventricle. some
melatonin could be transported via the CSF. The be·
lief that tile SeN are major targets for the hormone
arc consistent with ol.>scrvations that lesions in lbat
region abolish some responses to ML T injections.
In hamste .., the described rcsponststo exogenous
M l T are markedly affected by the conditions under
which Ibe hormone is administered. Dail y injections
of dosages thai are effe<:ti ve in the afternoons fail to
promote gonadal regression if they are given in the
morning. Single daily afternoon injections are inef-
fective in animals subjected to pinealectomy or pi-
neal gland denervalion. as well as in oneS with SCN
lesions. Moreover. implants that continuously re-
lease M LT are sa id to be: '\:ountemntigonadolrupic"
(or progonadmropic). since they block the effects of
short photoperiod. in intact animals. and of a fter·
PINEAL AND THYMUS GV.NOS
noon MLT injections in animals exposed to long
days.
Proponents of the MLT hypothesis have made thc
following suggestions (148). first. MLT is. in facl,
the mediator of thc gonadal regreSliion. but high con-
centrations and/or fairly long periods of expo&ure
arc required. Intact animals secrete large quantities
al nighl, even when the days are long. ML T that i.
injected in Ibe afternoon sumntates with endogenous
hormone. and threshold levels are thereby auained.
However. ,ince M LT is metabolically degraded. ef·
fective levels do not build up when the hormone is
given to imaet animals in the morning. or to animals
that have been subjected to pinealeetomy or SCG
destruction . The conccpt is supportcd by <>bserva·
tions that three ML T injections per day that arc
properly spaced can invoke regression in pinealec-
tomizcd animals (59). SCN lesions disrupt endogc-
nous ML T rhythms. and thcy may reducc total hor-
mone production. 3 M LT injections per day arc
effective in Ihese animals as wen. eil her because of
the greater total dosage or the in.",ased probabili ty
that a t least some of Ihe adm inistered hormone ar·
rives when the secretory rate or sensit ivity is high
(Ig). The phase of Ihe photoperiod during which pi-
nealeClomized or SCN·lesioned animal, receive Ihc
inject ions does not seem to be important. Second. in
intact animals. ML T injections may be more efTee·
tive in the afternoon. because some target cells
undergo circadian variations in sensitivity. Not all
observers agree on this point. but diurnal cydes for
the nu mbers of brain MLT receplors have been de-
scribed. Third. the pineal gland is onc of the targets
for both endogenous and injected M LT. Recepto ..
have been identifIed there. a nd ML T can exert p0s-
itive fcedbaek inHuences on its own secretion. Ex·
ogenous hormone may be more potent if il arrivC$
during the hours when NAT and HIOM T activity
pea k. and sensitivity to the inhibitory influcnces may
also be high at that time. ( In rats. MLT is reported
to dcpressserotonin metabolism when it is given duro
ing the middle of the light period but nol al night
[55]). fourth. MLT promotes the release of. and/or
synergi,.C$ with. other pineal gland regulators.
Therefore, a single injection should be: more effecti"e
in animals ... ith normally funetiOlling gland,. Fifth.
intact hanISters usually have very low pla.ma MLT
during the light phase. Implants that continuously
release ML T could exc rtpharmtu%gica/ innuenccs
Ihat indude ex treme down regulation of receptor
numbe ... Animals receiving them may therefore lose
sensitivity to darkness because they arc "chemically
pinealectomized.··
A major effect of both short photoperiods and
MLT ..emS to be exaggerated .. nsitivily 10 the neg-
alive feedback influences of gonadal steroids, Min_
Ule amounts of exogenous testosterone block FSH
and LH ..crclion in caSlraled hamsters exposed to
Shorl days, but relatively large doses arc required
when the days a'" long. Castrated animals pre-
I,.,alcd wilh MLT become as sensitive as uninjeeled
controls Ihat are light-deprived (118). Intraventric-
ular injections of MLT are believed to inhibit FSH
and LH re!case by aCling on hypolhalamic neurons
that secrete LRH. but the responses oould involve
neurons wilh MLT ree<:ptors in other parts of Ihe
brain, I nlrapituilary implanlS decrease gonadotrope
sensitivity 10 LR H, pos;sibly because of direct effects
on those adenohypophysial celis. The gonads seem to
provide addilional target sites, sine<: systemically ad-
ministered MLT exerts inhibitory influences in hy_
poph)'sectomizcd animals (19). Diminished ovarian
responsivity 10 gonadoHopins may partially explain
Ihe cessalion of eSlrous cycles in light-deprivcd fe-
male naltl$lers (in which Ihe eirculaling gonadotro-
pin levels arc usually high [151 j). At leasl $Orne ac-
tions of MLT do IIOt depend on the releaiiC of Olher
pineal gland regulators.
On the other hand. it has not been firmly eSlab-
lished that all the major cffects of lighl deprivation
arc linked with MLT. Pineal gland lipids. prOieins.
and other components undergo photoperiod-as>oci-
ated ehanles in concentrations, Peplides. pterdines.
and Iryptophols arc among the products shown to
possess antigonadotropic potencies. and it seems rca-
$Onable to believe thai those molecules have physio-
logical roles. Certain of the changes in
gonadotrOpin secretion that Can be reve .... d by pi-
nealectomy arc steroid independent and the)'
may be linked with other mediators. Some observers
altribute rocrudesccnee to the re1eaiiC of stimulants.
Moreover. Ihe possibility Ihat many of the described
effects of exogenous M LT are pharmacological re-
quires further investigalion.
Some Observations In Other Species
Laboratory rats retain year-round fertility. and they
arc much kss affocted by darkness and pinealeetomy
than many other mammals. It is Iherefore some-
times stated Ihat these animals arc suitable subjocts
for the study of pineal gland functions in "non sea-
$Onal breeders." However. many of the differences
between rats and hamsters rna)' be quamirmi"l'.
II is nol known to what extent the gaps have been
artificially widened by daily uposurc of inherently
noclurnal animals to breeding room Or laboratory
lighling from the limc of birth. the ad libitum pre-
sentation of processed. enriched food of unvarying
composition, and many decades of geoctie iiClection
for uninterrupted produclion of large litters. (It has
been reported Ihat Ihe durations of adull rat estrous
cycles arc affected by the amount of light presented
during Ihe neonalal period [72]. Ihat hamsters brcd
for many generations under artificial conditions re-
quire longer periods of light deprivation to initiale
gonadal regression than was formerly the case
[148J, and that laboratory-raised progeny of wild
mice are more resistant than their parents to the in-
hibilory effects of bright light)
When to natural pholoperiods. ralS tend
to produce feW<'r and smaller lillers during Ihe win-
ter monlhs. The )'QUng have low birth weights. and
Ihey mature slowly. Blinding, light deprivalion. food
,.,striClion. destruction of the olfactory apparatus.
and neonatal androgen injections can all retard Ihe
maturation at any time of the )'ear. Blinding com-
bined with olfactory bulbeclomy reduces pituitary
gland weight and prolaelin secretion. and it can in-
voke gonadal regression in adult rats. Pineaketomy
attenuales and reverses the effecls of food and sen-
sory depri vation: and it can acceleratc pubertal mu-
turation in p,.,viously healthy ju,·cniles.
As in hamsters. gonadal involution is associated
with low PRL levels. The pineal evidently exerts in_
hibilory influences Over the laetolropeS. A mela-
tonin";.nsitive dopaminergic syslem Ihat inhibits
PRL release has been identified ncar the SeN
(58B). and pinealectomy has been shown 10 accel-
erate PRL secretion in some mammals (33). Estro-
gens usually stimulale the lactotropes, and ovariec-
tomy lowers the plasma PR L. The combination of
blindness plus anosmia (whiCh inVOkes increased
MLT produclion) depresses laetOirope aClivity in
both intact and o_ariectomized females (92) , On the
other hand, PRL scnsiti7.es the hypothalamus to the
negative feedback innuences of gonadal sieroids. and
il can (at least under $Orne circumstances) deprCSll
FSH and LH levels. Moreover. PRL augments pi-
neal H 10MT activity (33).
The "sensitizing" effecls of neonatal androgen in-
jeclions have been lin ked with exaggeration of ste-
roid-negative focdback. When male rats Ireated in
this way mature. their accessory reproduclive organs
undergo $Orne wintertimc involution (192).
Rats have pineal gland Ml.T rhythms oflhe kinds
described for hamsters. and they evidently undergo
diurnal variations in rcsponsitivity 10 Ihe hormone
(150). Plasma MLT concentrations fall 10 undelocI-
able levels after pincaloclomy. Peptides with anti-
gonadolropic potencies are found in the urinc< of in-
lael bUI not pinealectomized animals.
ML T aClS at several siles to decrease reproductive
systcm functions, and il can invoke 80nadal involu_
tion in anosmic rats. MTol, HTol, and other com-
ponenl! of pineal gland extracts have been reported
...
to exert spocia] innuences. For example, whereas in-
injections of ML Ton thc morning of
proestrus block the subsequent LH surge. MTol
seems to be a more effeelivc inhibitor of FSH se<:re-
lion in rats than in hamsters. Subcutanwus injec-
lions of MLT do not substantially affect the gona-
dOlropin Icy.ls, but they have been ""pOrted 10 bring
about reductioll.'l in ovarian and u{orin: weights and
10 retard testicular and accessory reproductive organ
development (6).
Decr. sheep and goats have much longer gestalion
periods Ihan small rodents. Most species breed in the
autumn and deliver their )'Qung in the spring or early
summer.
Partially domesticated $Qay rams maintained out
of door:; in tem!""a!c zone, undergo leslieular
,..,gression when thc days a", long. and they became
,..,productively active as the photoperiods shorten.
The annual regression/recrudescence cycles can be
shortened to 8 months by exposing the animals to
artificial environments that alternatc 4 month pc-
riodsof l6-hour days and 8·hour nights (16:8) with
4 month periods of 8-hour days and 16·hour nights
(8: I 6) (97). However, rams ront;nuously eXpOSed to
16:8 "'fractory to long photoperiods and re-
cover testicular functions by the 16th week .
Reerud ..""nc-e Can be ha<tened by abruptly pro-
senting an 8:16 lighting scbedule. The elfects of
g:40 are sim ilar. probably because the signals are
perceived at the "right"' time of the day. In contrast.
g:28 fails to accelerate. although it provides "more
dark" than 8:16 (3).
The regression phas<: is associated with low cir_
culating FSII and testosterone and with decreas<:d
LH discharge frequencies. The animals Can be stirn·
ulated by LRH, but both the pituitary gland re-
sponses and the secondary ehnges in testicular
functions dilfer from the ones secn when LRH is
given during recrudescence. (In regressed animals.
only small increments in testosterone level$ arc elic-
ited, and the testes resume inVOlution soon after the
injections are terminated (97).)
U nlike the Situalion described for rams
sccrete mQff PRL when they are sexually inactive
(33). h bas been suggested that high PRL levels
markedly exaggerate hypothalamic sensitivity to the
negative feedback infiuences of gonadal steroids.
Since PRL rises soon after exposure to the long pho-
toperiod. it probably contributes to Ihe gonadotropin
d«:line. On the other hand. in common with rats and
halmters, sheep decrease their PR t when they
respond to light restriction. Sharp reductions follow
switches from 16:8 to 8:28, 8:40, or 8:16 lighting
schedules (3).
ANO THYMUS GlANOS
Superior cervical ganglionectomy abolishes most
of the responses to changes in photoperiods. II also
lowers plasma MLT to undetectable lcyeb. Not sur-
prisingly, pinealectom)" has similar e!fcc",. The rc-
productive cycles can also be disrupted by continu-
ous administration of ML T.
Ewes become anestrOuS during the SUmme r and
they lose the ability to accomplish the LH surgcs re-
quired for ovulation. They, too, have low FSH and
high prolactin levels at that time. Their responses to
photoperiods can be disrupted by SCN and SCG
As in other mammals, MlT production acce ler·
ates during the hours of darkness. Howevcr. tOla124-
hour production of the hormone seems to be highcr
in summer than in winter. This is attributed to much
higher nocturnal peaks in animals to long
photoperiods (3). It therefore possible that MlT
is thc major mediator of the summertime gonadal
regression. However, some investigators believe that
pineal peptides ma ke suh:\.tant;al contributiollS to the
control:;.
Sheep differ from rats and hamsters in other ways.
They respond to in photoperiods as well as
to absolute numbers of daylight hours. Moreover.
fertility in rams is improved during late summer by
falling environmental "mf"'r(t/""s
Fe .. ets display yet different reSpOnse plIll"ns (70).
Under natural conditi"" •. females Ii.ing in England ha.,
been observed to begin ,he bre<;ding sea.on in M.. Or
April. They rarely O'o"lliate without matins. Endogenous
factors accoont largely fot the termination of
tive acti.i ty. which can as <arty Juty Or as tate
a. September. The phot"""riod «ert. some limite<.! influ·
enee. on the timins· "Long days" (12 or more hours of
light in 24) acce lerate the onset of estru •. even when Ihe
inten.ity of the .timutus i. low. lIowever. 'hey are elfec·
li.e only when presented fOf seve,.,.l wttb to animah
that.re receptive. (Sensitivity pea'" .fter a lang interval
of ...,tru •. ) ··Short d.y."' terminate the
estru" but prolonsed exposu", i. al"" needed for inhibi-
tion. Ferrets ",em to be affected mostly by the .timuta_
tory elfect. of long photoperiods. (In contr;lIl. hamster
0),<:1" respOnd mO$tiy to lhe inhibitory influence. of .hort
one •. )
When ferret. are .ubjocted to pinealoctomy or demuc·
tion of the SeG. it i. no I"",er pOS$ible 10 .coekrate eS-
tTII. with Ions photoperiod, or 10 delay it with .lIort one •.
Howe .. r. 'pOntaneou. annual eyc les pcrsi.l.
MLT injected during lang photoperiod. ean invoke .neS·
tTII' in estrOuS femates. Thi. effect also wee ... to
accompli>h. Under dilferent conditions Mt T can termi·
nate the '·pllotorefractorine.. '· that develops when the
animal • • '" eXpOSed to tong dlIys for txtended time
periods.
Eviden'ly, the pineat ,l. nd e"erlS fine eontrol. over 'he
 witb en.ironmenl,1 Ho", ... r, il
has liule C>r no influence on rtproducti •• 'ystem matura-
tion or the initiation of "\'lIrian cycl«.and it. rol •• in ltg-
ulalion of Ibe timing and duration of e,lru. art highl)'
limited.
In ",allabies. th. pineal is implicated a. a regulalor <>f
sea,.,nal delays in impl.nl.1Hln (I $71.
Pineal gland functions in birds diffcr in many rc-
SpeClS from the ones described for mammals. Gen·
eralizations can be made. but species differences in
roth morphology and physiology arc much grealer
in this class of vertebrates (108).
The cells utilize the same biochemical pathways
to make ML T. and NAT activity i, oflen rale·lim.
iting (16). In inlact birds maintained under wndi.
tions resembling natural environments, M LT levds
in tll(, pineal, brain. and blood are higher at night
than during the daytime. The imerval during whiCh
NAT activity remains elevated Can be prolonged by
limiting the numbers of hours of daylight. Howe''';:r,
th. absolute concentrations of MLT can vary widely
with the devc\opmental stage and with the level of
reproductive activily. probably because of gonadal
influences on HIOMT aClivity (142). The retinas
convey information to tile pineal glands. and roth
light Hashes to the retinas and blinding affccttbe en-
zyme activities_Different kinds of pbo(oreccptors are
present in Ibe brain. Although at least some are Qut·
side that orian, thert arc controversies concerni",
whether substan tial numbers art in the pineal
(Newly hatched birds have more photoreceptor type
pinealocyles than older birds_) DestrUClion of (he
eyes fails to arolisb synchroni7.ation, of NAT cycles
with photoperiods or NAT and HIOMT responses
10 photic stimuli (16). Direct retinal contributions to
pineal hormone levels seem to be important in some
species but not in others. The NAT rhythms of
retinas parallel those of the pineal. They persist and
continue to respond 10 light afler pinealectomy. but
they do not maintain the plasma MLT level s.
Tbe glands also display jmrjnsjr rhythmicity tbat
i$ oot abolished by denervalion. When the pineals
are aulouansplanled \0 the eyes. the absolute ML T
concentrations in body fluids decline bUI the diurnal
changes continue (142). In sparrows, heterotrans-
plants impose donor rhythms On pinealecotmized
hosts (l08). Cullured organs relain previously ac·
quired timing, and tbeir cycles persist longer when
to alternating periods of light and darkness
than 10 either LL or DO (80). Explanted chick pi.
neals show higher NAT activity in the dark than
when exposed to light. Some other in vitro responses
have been categorized as For example,
cultured pineals obtained from ducks are reported to
mOre rapidly oonverl 5·HT to ML T when they are
directly illuminated. Exogenous presentation of the
5·HT prceursor and Olher as yet undefined artifacts
of the in vitro system, 3$ well as the pammeter se·
lecled for measurement. may account for discre!>""
andes between predicted and measured changes.
Neurotransmiller COntrols are superimposed in in·
tacI birds. NAT activity rises before the beginning
of the dark phase, and it falls before dawn when
thcre are regular changes in the environment. The
glands recei"e cholinergic as "'ell as adrenergic in·
nervations, and they are affected by electrical stim-
ulation of either the habenula or the SCG. Unlike
thc findings in mammals. superior cervical gangli.
onectomy has lillie inftuence on the MLT rhythms
of birds exposed to ordinary photoperiods. It dOC$,
however. alfect Ihe spontaneous frring rates of pineal
oomronents. It also hastens the 1000s of NAT
cycles in birds maintained in continuous darkness
(142)_
Cyclic nucleotides, cholera toxin, and phosphodi-
esterase inhibilors can all increase NAT activity
when they are presented to organ-<:ultured pineal
glands (108). However. NE predominantly
inhibilory The suggestion that pinealocytcs
have mostly <>-type adrenergic rtC(PlOrs docs not
fuUy explain the dilfer-.::nces between birds and
mammals. since isoproterenol (a ,8-agonist) also lnw_
ers NAT activity.
The SCN are functionally associaled with the pi-
neal gland•• buI the relalion,hip< differ from the
ones found in mammals. It is possible that the nuclei
are major targets for pineal gland hormones (108).
Their destruclion invokes changes of the kinds that
follow
There arc indications that I/IOMT activity is reg-
ulated primarily by gonadal hormones,
NAT responds mO:$tly to the photoperiod. Some in
vitro studies involving the presentation of androgens
Qr estrogens to cultured glands provide some support
for the notion. In quail and some other birds,
HIOMT activity is reported to be high in juveniles.
to decline during the rapid ovarian growth phasc.
and to rebound in malUrt birds that are reproduc·
tively active (142). However. the pineal may be an
important regulator of reproduclive cycles in only
limited numbers of species. Even in Ihese. the major
funclions of pineal hormones have been lin ked with
the regulation of locomotor and other diurnal
rhylhms. Depending on the species and ages of
tcst subjeclii. pinealectomy can stimula!e, inhibit, or
exert no obvious effec\.S on the reproduClive
equally variable effects of MLT and MTol injec-
lions have been encounlered (142)_
On the basis of the few observations made. it has
been suggested thaI Ihe pineal exerlS fine oontrols
Over the reproductive systems of otber vertebratcs_
The influences may be progonadal in cyclostomcs

and anurans. but antigonadal in lizards and oIas-
mobranchs (45).
Studies on Humene
There are for questioning the widespread be-
lief that human reproductive systems are oot af-
fectoo by pbotopcriods. However. the sensitivities to
changes in environmental lighting seem to be lowcr
than in many other mammals. In nort hern Finland.
the days arc V<'ry short in winter and very long in the
A four·year survey revealed that concep-
tion rateS for single births peake<! during J une-Au-
gust and fell to the lowest points in January. The
seasonal differences for multiple-birth concepliom
were similar in timing but of grealer magnitude
(152). Relationships to changes in gonadotropin lev-
cis are suggested by the ease wilh which supel"OYU-
lat;on can be achieved wilh hcmn<.>ncs in
laboratory. farm. and 7.00 animals. and with the high
incidences of multiple birtlu; in wome n giV<'n high
dosagcs of such agent. to achieve oonception. II has
also b«n reported that Eskimo WOmen living in na-
tiV<' habitats do not menstruate during the 4 da rkcst
months. Less imprtSsive, but real. differences in con-
ception rates have been reported for women in more
teml"'rate •. All of the preceding a rc consistent
with the ootion that pineal-me<!iated effects of short
photoperiods lead to lowering of human fcrtility. The
need to exereise caution when using statistical data
has been pointed up by surveys showing cor-
relations between conception rates in Germany,
Sweden. and England and the circulation of library
books in IhTtt large cities (10). However. are
additional reasons to implicate the pineal.
Humans have ML T rhythms of the kind. de-
scribed for other mammal •. Blood are highest
during bour.; of darkness, and urinary excretion
(which varies with plasma concentrations)
can be 7 times greater during darkness, and
re<.:umbency than during waking in both mcn and
women. The timings of the daily cycles sbift slowly
when artificial photoperiods are imposed. Annual
rhythms that include January and July pea ks have
also been observed (I 55).
Environmental light. rather than sleep. seems to
be the controlling factor. ML T production can be in·
hibited by to bright sunlight (but not by
presen tation of photic stimuli of lower inten.itics
tht are effective in laboratory animals). The re-
sponses are greater during the winter mOllths. prob-
ably because of adaptation. to the
MLT producti<.>n can also be inhibited with propran-
olol (95). Blinding disrupts MLT rhythm. (96) .
Puberty ()Ilset is often accelerate<! in girl. blind
PINEAL AND THYMUS GLANDS
from the time of birth. possibly because sustained
high MLT invo,,"s loss of serISi!ivity 10
Ihe inhihitory effects. MLT levels vary with the
menstrual cycles in sighted women, and shon bums
of bright light pres.ented to subjects during the night
can affect the timings of the cycles. nCr-
V<.>Sa patient. put Out subnennal quantities of gona-
dotropins, and a t least some have atypical MLT
rhythms. Intensive athletic training can affect both
menstrual cycles and MLT rhythms. The effects of
both and training have been linke<! with re-
ductions in body fat content or fat:lean weight ra_
tios. and obesity is known to inAuence the ages at
which puberty and menopause occur. It is therefore
interesting to oole Ihat MLT levels in healthy hu-
mans Can vary with body weight (5). Pineal gland
functions decline with age in laboratory animals
(161). and some investigator.: repOrt de<:reases in pi-
neal. plasma, and CSF ML T in aging humam. Ev-
idently, daytime blood levels arC only moderately de-
pressed. but nocturnal elevations are severely
dampene<! (75). Parallel declines in reproductive
system functions are common .
Many children with pineal gland tumors suffer
either precocious Or delayed puberty. and surgical
oorrection has been known to restOre normal repro-
ductive function. (ISS). The," have been reports
that changes in ML T secretion during the peri pub-
ertal period are consistent with some inhibitory innu-
enCO of the hormone on reproductive system matu-
ration. A gonadotropin-inhibiting peptide (G IS) has
been detected in human urine. and other agents ex-
tracted from pineal glands of different species are bi-
ologically active in humans. Although some recovery
of the functions can occur after their removal. the
SeN are clearly involved in Ihe regUlation of prj·
mate MLT rhythms (158). and both lesions and tu-
mors of the suprachiasmatie region are associatcd
with disturbanccs In gonadotropin secretion
palleTns.
These and other observations strongly suggest that
the pineal gland exertS SOme inhibitory
that contribule to fine control of reproductive pro-
cesses in humans. If this is true. we may be harbor-
ing harmless (oot necessarily beneficial) character-
istics inherited from OUr forebears . At least in
amuent societies, the advantages of clustcring births
during the springtime and summer arc not obvious.
There are additional reasons for questioning im-
portant innuences on human reproductive systems .
Some recent studies fail to support roles for mela-
tonin in timing of pubertal onset (47 .I 82.A-4). Since
gonadal hormones affect HIOMT activity. some
changes in MLT levels associated with reproductiV<'
functions may represent effhCl$ rather than causes.
Abnormal or dampened ML T rhythms have been
auribu\ed to changes in adrenergic re<:eptor func-
tions, and si muhaneously occurring modifications of
such in other parts of the body may ac-
count for concomitant variati<>ns in gonadotropin so-
Similarly. destruCti<>n of SeN can have di-
verse effe<:ts on the neuroendocrine that do not
necessarily in volve intern:lationsh ips with the
gonads.
PINEAL GLAND INFLUENCES ON
PIGMENTATION
Ven-brates utilize changes in the quantities. quali-
ties. and a rrangements of integumentary pigments
for eamounage. aggression. thermon:gulation. con-
trol of uhraviolet ray penetration. aUraetion of scx-
ual partners. and signaling of !<'adi= to mate .
They possess sc,'Cral kinds of effectors. along with
diverse me<:hanisms for controlling their functions.
It has bttn known for a long time that mela"""yte-
stimulating hormone. (MSHs) Can darken the skins
of SOme e<:totherms and that pineal glands contain
substances that oppose Ihe effects. The identifica tion
ofMLT as a potent " lightening" agent (94) is often
cited as a major landmark in Ihe hisWy of
pinealology.
··PhySlologlcal" vs. "Morphological" Color
Changes
EClotherrns have dermal chromalophOl7' with mov-
able. pigment·laden organelles that mediate ··phys-
iological" resp::mses. The color changes involvc
reversible translocations of pn:cxisting cell comp:;>-
ocnts but no synthesis or loss of pigments. Usually.
then: an: 2 01 mOle different cen lypeS. and these can
be organized into functioning unils (6 1).
Me/anophOl't" are the darkest of Ihe chromat<>-
pho!'CS. They have long. dendrite-li ke processes thai
e xtend over Ihe of other types. How-
ever, when their organdies (mdanosomes) :u;sume
perinuclear positions (i.e. an: consperscd Or aggre-
galed). the skin appears light. When the melana-
somes migrate toward the cell peripheries (disperse) .
the skin looks dark. Although the underlying events
are ordered . complex. and in somc Cascs timc-con-
suming. Ihe darkening has been li ke ned 10 blowing
on a spoonful of chareoal initially placed in the cen·
ter of a white cloth. I, idophore. (lcukopllorcs) con·
lain geomelrically arranged plates (reAectosomes)
with white. crysta lline substances that reflect and
scalier light. They can thereby impart whitish, sil.
very. golden . pink. Or blue tones and iridescence. The
darkening actions of MSH often include si muhanc-
conspersion of iridophore organelles and dispcr·
si<>n of mc1anosomes. Xamhophores and erylhro-
phaus appear yellow and orange to red, respeclively.
because they accumulate pteridin.. and ca rotenoid•.
The pteridincs a rC synthesized by the cells and col-
lected in ptcrinosomes. Carotenoids are obtained
from the diel and accumulated in vesicles that a re
called erythrosome.s. Since the pigments
an: lipid·soluble. chromatophores of this group
also known as lipophores. A single cen can contain
IWO or more differenl kinds of pigment organelles
(lOA).
Since the skins of most endotherms a re covered
wilh fea thers. fur, or hair, cens that function in this
way could serve no obvious purpose. h is therefore
not surprising Ihal birds and mammals do 001 have
ehromatophores. Thcy possess ch,omll/(JCytes that
sy nthesize the same kinds of pigments and package
them in to granules, but there an: no movable organ-
elles. Epidermal melanocytes lransfer Ihe pigments
to cens thai do 001 ma ke them, and s ubSlantial
quanlities can accumulate in structu res such as Ihe
fealhers and fur. The '"morphological" responses
media ted in this way arc linked with changes in pig·
ment content. They develop slowly. and they persist
for long time periods. The melanocyte i< in many
ways a mOre primitive cell type (196A).
Melanocytes an: found in all classes of vertc-
brates. and Ihe epidermal pigment cells of amphibi-
ans an: of this kind. They arc present in developing
pineal ilands (14 I A). in the eyes. the choroid pie,.
uscs. the basal ganglia of Ihe brain. the a drenal
gland. Ihe carotid and aortic bodies, the gut. and
along blood vessel walls. Amelanotic mclanocytes
are unpigmented cells with similar fealures thai rap-
idly darken when presented with e' DEenous DOPA.
(They diffcr from melanoblasts. the din:ct precur·
sors of the colored cells.) Melanophage.< ta ke up but
do not sy nthesize melanins.
All pigment cells except Ihc ones in Ihe head orig.
inate in the embryonic ntural crests. They may
undergo preliminary differentiation to chromat(>-
blasts priQr to migration. but there reaSOnS to be·
lieve peripheral cues from the destination sites de·
termine the maturation pathways. The possibilily
that transdiffen:ntiation can OCcUr has been consid·
ered (lOA).
Unfortunately, Ihe terminology in the field is not
consistent. Some a Ulhors usc the tcrm chromataqlt
10 designa te pigment ce ll, and me/anQSome to
mean an organclle that accumulales mclanins even
if it cannot engage in conspcrsi<>n..:lispersion rC-
sponses. Malure mclanin-containing organelles of
melanophores have also been referred \0 as
The appeara nce of the integument a t any given
time depends on combinations of light adsorption,
d iffraction . and interference. It is affected
by Ihe intensities. dire<:tions and wavelcngths of thc
".
light, numbers and kinds of pigment producing
and accepting cells, the associations they make wilh
neighboring structures. and the qualities and quan.
tities of the pigments. The anatomical arrangements
can be quile In frogs. xantbophores arc
dosest \0 the surface. A single layer of iridophores
separates them from Ihe underlying melanophores
(198). More elaborate pallerllS have bun described
for some of Ihe fishes and reptiles.
Melanins and Other Integumentary Pigments
Eumelanins are high molecular ",<,ighl polymers of
tyrosine metabolites thaI associate wilh proteins.
Most a ppear dark brown or black, but ascorbic acid
and other reducing agenu can lighten the color
(79). Phaoomelanins differ from the "true" mela·
nins in thaI they comain sulfhydryl groups deri ved
from cysteine or g]utathi""e. They Can appear yel-
lew, gelden. crange. er red. The quamities f",mod
can vary with the availability of cysteine. Some cells
<:<lntain both pigments, whereas olhcrs have jusl ene.
Trichromes are chemically relaled 10 phaeomclan·
ins, but they have lower molecular weighl5.
Melanin biosynthesis begins wilh Ihe of
tyrosine-first 10 DOPA. and then to dopaquinone
(Fig. 20·5). Bolh of Ihe reactions Qre ""talyze<i by
<:<lpper-dependent lyrosill(lSts Ihat arc usually pres-
enl in large amounts.
Three iso,ym.. Ihat differ in carbohydrale cootenl
h;>ve \><;en idontified in pU'ified preparations. Dopaqui.
none and some of il$ melaboliles can polyme,ize in vilro
to form black pigment<. In mel.nin'producina cells,
much of Ih. dopaquinon. sp<>nlancously rurrang.. 10
I.ucodopachromeand dopachrome. CySleinyl_DOPA and
<>Iher pheome lanin preeu....,... or. ""'de when c)'$t<in. or
glutalhione .... p.... nl in hiah concentrations (129).
The formation of 5,6-(lihydro.yindote from dopa·
chrome i•• cctle .... ted by • dop«hromt oon",,,;OII/oX/Of".
An iNlQ/, .:iJJ!vt,,'on/aClor then prGmQ1" the production
of 80th of the conv... ion facIO .. ar.
associated with th. ty,,,,,in,,... and may be id.nlic.1 with
lbe described iso"yme •. An indole-blocking /",ror op-
po$Cs the l.st ,eaction (129). Th. indole quinone can p0.-
lymerize di ... ctly or lirst be _ .. rted to molanochrome.
The cndopl.umic reticulum and Goigi app;oralu. C<>-
operate to form pt<mdanosomes thai take up thc int.r_
m.diate •. When association. with the proteins and pOly·
mcri,.... tion$ at< com pleted , th. org.nell •• ore ",,1I.d
m.lanosom •• or pigment g .... nul ••.
Melanocyto stimulating hormones bind 10 rt<.pton on
lbe pigmenl cell plasma membranes. The hormones .re
intern.lized and t .... nsport.d 10 p... melanosomes. Within
a rew hou ... the tyrosinase activity increases and ,""I.nin
production (m.lanogene,i.) proceed. r.pidly. This i. at-
tributed at IWt in parI to ... mo.al <>f natutllly occurring
i>tNEAL AND THYMUS GlANDS
.nzym. inhibit"". MSII. a re implicated in Ih. "swileh·
ing" from indole-bloc king 10 indole-convetiion acti.ilies
and from phcomelani. to .umelanin production. They
may play additional roI •• in acceleration of the tral1$f.r
of m.lanin. \0 other ceillype" The cell. liso enlarge Ind
ut.nd long d.ndritic proc ... cs. findi"" con,i.tent with
Ih. growth·promoting function. of MSH. in feluses. C.1I
prolif..... tion is soon .timula t.d in some tissu.s. but it con
be reta rd.d in oth....
Tyrosinase Icti.ity is del.rmin.d by genelic faCIO..,
.nd it Can by modified by the en.ir""m.n!. Humal1$ that
.r. dark . kinned have high.r activities in Ih.ir .pidermal
""Il •. and ther ..... indi.idual difference, in "'pon, •• to
the $Iimul.ting eff«I' of ult raviolet radiati"". The char-
.ct.rislic markings <>f Siamese cal. have be.n aliribuI.d
10 temperature.mediat.d augmentation <>f Ihe otherwise
low aCli.ity in Ihe ""nip$ .nd other cool pan. of lh. body
(9).
lridophores C(ln(ain crystalline deposils of purines.
Guanine is the most abundanl of them, and cells con-
taining large amounts a re sometime. called guano
ophores. Olher iridophores C(lmain
uric acid. adenosiM. or isoguaniM (Fig. 2Q.6A).
The lipid-soluble pigmen ts of lipophores indude
pleridincs, carotenoids. and ribonavin (Fig. 2Q.68).
Xanthophores appear yellow or orange when prescnl
alone. but they can impart green colorations 10 ani·
mals thai would olherwisc look blue. Erythrophores
are red .
Pigment Organelle Migration
Chromalophores have large numbers of micrQ/u-
bullS Ihat run parallel to the direction of granule
transport; a ctnlral apparatus containing centrioles
and the amorphous, el«lron-dense matter to which
the microtubles are anchored: inltrmedialt-lypt; fil-
amems; and fine. actin-wnlaining microjilaments. It
is certain thaI the microtubules and filaments partic-
ipale in Ihe migralions, but lhe mechanisms are nol
",<,II understood. Colchicine, an agent widely used to
disropt microtubule polymerizations and functiom,
markedly diminishes but docs not totally abolish
granule movements. It ltas theref",. been suggested
that the tubules orient the directions of the transpOrI
but do not exert "push·pull" effects. The granules
are said to behave as if Ihey are embedded in a re-
versible clastic or COlllractile <:<lntinuum devoid of
microtubules thai collapses during aggregation. The
filamenl5 are comlXmcnts of a microlrab«ular MI-
or lattice that interconnects pigment granUles,
microtubules, and cell membranes. Cytochalasin B
interferes with actin Iilamenl organi'..(Ilion. [t uerts
reproducible innucncos on dispersion and <:<lnsper-
sion, bUI Ihese vary with the species and C(:11 Iype
invesligated. Dispersion evidently differs from <:<In-
 ,)0--

- "'"
- -
.-
,
;:--
C 7 " ....

I
!..
C;: , i')"'"

1
/ •

):):::J::----.. •
!
_.-
un _.
o "

...
..........
, ,
.... '"".•. ..
·" PINEAL ... ND THYMUS GLANDS

"

X,.,hop",'"

• I .." ".
Fill. 2M. (A)
(8) .. ,
spersion in seV<'ral ways that include a reQuirement
for ATP energy (171 A).
It was forme rly believed that dispersion involves
cell depoiari1.ation with oonsequent uptake of
cellular Na · . and gel--ool changC1J in the cytoplasm.
Extracellular Na' i. reQuired. and both hypotonic
environments and high hydrostatic pressures (which
lower cell visC()City) facilitate the movemenlS. How·
ever, melanocyte stimulating hormones of pituitary
crigin do nol depolarize the membranes. and depo-
larizing ooncentrations cf K+ cannot mimic the hor.
mone actions. The Na - is now bo lieved to bo 1'<'-
quired fcr hormone·rcceptOT binding (124),
Melanocyte Stimulating Hormones
Melanocyte stimulating hormcnes (MSHs. mdano-
tropins, intermedins) arc the major stimulants for
mciallOS'Jme dispersicn in noninnervaled mdano-
phorC1J, and also the promolars of melanogenesis
(melanin synthesis). a- MSH is secreted by the pars
in tcrmedia cr neurointermediate lobe of mOSI verte·
bnlles. and it is the primary hormooc.I1-MSHs ""'ere
discussed in Chap. 3. They have boen identified in
pituitary gland However. it is now bolieved
by at least some invesligators that thc peptides al'<'
formed a rtifactual1y during the extractions (170A) .
Additional peptides oontainc<i within POMC that
can act on pigment cells include ACTH, endorphins.
and ,,/·MSHs. Melanogenesis·l'<'gulating hormones
in humans are still not defined. a-MSH is made in
the central neT'o'oUS system, but it is probably not se-
creted into the sy:stemic blood in appreciable quan_
tities. As !lOtcd in previous chapters, it is bclie.-ed to
serve as a neuT(ltransmiller. neuremooulator. Or
both. Influences On memory. bohavior. lipolysis. and
other functions have been described for laboratory
animals. and the hormone is addilicnally implicated
in the regulation of fetal growth and adrenOC<:lrtical
functions. Several POMC that alTect pig-
mentation have been identified in human tissues
(18IA).
MSH Regulation of Pigmentation
MSH promotes melanosomc dispersion and melan-
ogenesi5 when it is added to extracdlular fluids. but
intracellular administration is ineffective (I 24A).
The hormone elicits dose-(]cpendent elevation of
cAMP levels, and its acticns can be with
cxogcnouscAMP Or dibulyryl cAMP (170A). Phos·
phodiesterase inhibitors exaggerate or prolong the ef·
feelS. PrOlein kina.es are and th=, in
turn, catalyze protein phosphorylation •. One or more
of Ihe affected proteins i. implicated as a promoter
fer Ihe synthesis of the mRNA that directs the pro-
ducticn of tyrosinase. Calcium ions are believed to
mooulate transduction of the hcrmone signal$. Thcy
may contribute to adenylate cyclase activalion, the
events tbat follow, and to PG gener3ticn . (Calcium
ionophores promote melal1050me dispersion when
presented alone in the pr=nce of Ca", and thei r
efTeclS arc blocked with verapamil. Mcreover, agents
that lower cytosol Cal< promote conspersion.) How_
ever, although MSH accelerales Ca'" uptake frem
the surrounding fluids, cAMP probably exerts eal-
cium·independent influences. Calcium ehelalors
block the effects of MSH but not of cAMP. Prosta-
glandins. methylxamhines, and catocholamines can
promote dispersion when cells are bathed in calcium_
froc media. The agents may release the ions from
intractllular sequestra tion sites that include mela-
nosomes as well as mitochondria .
When MSH promotes melanosome dispersion, ;t
usually simultanoously brings about l'<'f1ecrosome
conspersion. In at least limited numbers cf species,
MSH has been observed to promote dispersicn of
xanthophores and crythrcphores (124A). ACTH
contains all thirteen amino acids found in n--MS I!.
It interacts weakly with MSH receptors On melano-
phom, and it has been observed to exert inHuences
on carotenoid droplet" Endorphins have been re-
ported to potentiate MSIi cffoclS in lizards. The ter-
minal tctrap"ptide derived from was
named lm!/uiI()tropin potentiating jac/or because il
enhances MSH·stimulated melanogenesis in mouse
skin, Naloxone can cause pigment aggTCgation in
gcldfish xamhophores via mechanisms that are an·
tagonized by On the other hand. it
has also been found that although endorphins sensi·
tize amphibian melancphores to isoproteronol, they
decreases the responsivity to MSH (124A).
In SOme species. eGMP mimics the effects of
MSH. In others. il exerts opposing actions, possibly
by interfering with cAMP·mediated phosphoryl -
ation of tubulin. Acetylcholine acts On SOme cell
types to promote oonspersion, and cGMP may Ihen
serve as the second messenger,
Melatonin Regulation 01 Pigment Cells
M LT promotes mclanosome conspersion in many
species. Its ability to oppose MS H has been linked
wilh lowering of the cAMP levels. It inhibits melan-
ogenesis in the hair bulbs of Siberian hamsters. p0s-
sibly via activation of the indole·blocking factor de-
scribed earlier (129). It is also believed to act
physiologically to inhibit MSH release in at least
!;Orne spe<:ics. Studies on male weasels are consistent
with this concept. Those animals changes in
pelage coloration for camouflage. They grow white
coots in preparation for the winter. Intact animals
on
acquire brown fur aflcr lhe springtime moll. but by-
pophys«\omy prevents Ihis by removing Ihe 500=
01 MSH. ]( intaCI animals are givcn ML T implant&,
Ihey acquire "winter-type" coa ll in the spri1l& (168).
presumably because MSH secretion is inhibi ted..
Some in_lipton rqIOrt IIIaI both constanl ill u·
mill3 lion ;nlla animals and pi roealec:lomy el",lt
the pituitary MSH COIIlcnl of nu alld mi«. How-
ever, mhcl'$ do not observe changes in pigmentation
afler either pineal gland dcncrvalion or M LT ad·
ministration in those 1'Odcnu ( 143).
Ol.lecholaminc:s in(mla wilh /HdrcnerJic recep-
tors on melanophonJ. promote cAMP generation.
and invoke mcla/lOl5Ofne dispersion. They act via ....
type n=plors 10 brint abou t conspersion. II is likely
Ilia! MLT inlcracu wilh .... , ypc =eptors on some
cells. since Ihe effects Ire anlapiml by alpha
blockers such as phentolamine and Ihymoxaminc.
Serotonin receptor blockcl'$ arc inefl"C<:live (1241\).
Small peptide! cleaved from OlIyloein ha ve been
implicated as rcgulatort or MS H $Ccrelion (66). but
their roles are contro.ersill (see C haps. 3 and 19) .
The pineal gland contai ns and il make
active peplides of t his kind. It has also
been suggested tha t MLT affeelS the release of
MSH regulators made elsew here. Morco.er. pineal
choroid an d th e ce rebrospi nal flu ids
of some SpeclCS {i ncluding humans) are reporled 10
contain melanotropic-lipolropic peplides thaI differ
chemically from ACTI{ a nd MSH (167).
Melatonin eloa...
Bioassays tlLll dete<;( minute quantilies of
inlJ" agenli were dc",iopcd long before the chemical
of pincallJland hormones _ known. They
ha\'C been largely rqIlaocd by men: tOphist icated
techniques (99).
The S-poinl ITItla noc:yte (M I). which is
baud on the Ippea,..1>OI: of the cells following Ire,n ·
menl ,..jth the tesl Blcnt, provides I scmiqulnlilati\'C
measure of Ihe potency. Cells ,..jth muimlll1y Ig·
gregated melal105Olt>eS I rc Aid 10 be punclolr.
whereas ones with maxilTlllJ dispersion I re c lassifM:d
as "lieu/tilt. The three intermed iate stages In:
punctatMtellate, $Ie llate, and slellltc:.reticulale
(74).
TIle obvious drawbocks 01 the Melhod include subjec-
IIv;ly nd Impreeis;"". f'hoIometr;C t.chniq .... lhll w«e
subsequenlly inlroducod did IlOl .lim;"'I. III or Ih. pr0b-
lems. It was 500d rOCOlni.cd lhal infllKnct$ of lhe tesl
5ubslll'leet 01\ iric!ophotCl IlI"eet the readilllS. I nd Ihl l
variable. such as lhe li lol from which Ihe colll",e laken.
the agel of the Ini mal •.• nd thc "".son of llIe ye.r
markedly Iher Ih. """,i,i.ities.
PINEAl. ANO THYMUS GUilDS
Melatonin and MSH Regulation 01 Amph ibian
Melanopho,es
Very young llIdpoles blanc h when lhey a re placed in
the da rk. mostly because they re lcuc MlT (185).
" Pinealeclomy" (cautery 0{ the diencephalic roof)
abol ishes lhe n:sponse..... hile feedinlJ pineal ,lands
can in..xe paling in intaci animalJ exposed 10 li,ht
(198). M LT acts on dermal (but not
on epidermal melanocytcs) when it is presented to
tadpole skin in vitro. and it ant"oni,es the da,ke'"
ing effecuo{ MSH . AI this stag<. Ihe ILlve
not yet acquired the physiological mechanisms fOf
inhibiti", MSH secretion. and their la teral eyes are
undeveloped.
W ith advancing maturity. the response becomes
men: wmplc:ot. The laleral eyes now relay mcssatcs
that lead to MSH inhibition. MlT still promotes
consperion, but it may additionally act on the hy·
pothalamus 10 promote release 0{ an MSH inhibitor.
It is likely thaI ladpole blal>l'hing occurs because
the animals synthesize M l T in Ihe dark. but Clnno!
yel use pholic signals 10 inhi bit its 'c lease . Most
adult a mphibians d<l not become pal. whe n they Ire
transferred to dark environm. nu. Their melano-
phores lose the se nsitivity 11) ML T, and adapta lions
to backgrou nd involve mostly ch.nges in Ihe MSH
level<_ G ..... frog< maintoiMd for in
tanks with black bottoms and sides have high MSH
leve ls a nd black skins. Ones thaI are brigh tly ill u·
minated and kept in wbile tanks ha . e pa le skins and
kI ..... MSH lev. Is. Sil>Ol: blinded fl"OlJO with inla" pi.
nea l and pituitary glands d<l not make the adapta_
lions (lgS), the laleral eyes probably pick up mQSt
of the s ignals ( 198).
OUte r RlI9ulalors of Pigmentation
The «IfItroi mechanisms vary widely aCf"()$$ tbe ipe-
aC$. Suggestions that the a mphibian pars t ubcrllis
1eCn:ICS a "W sllbs/ona" or ITItlallOC)lle<onccnt,..t-
ing hor"""", (MCH) distinct From MlT come from
studies inyulving selective removal 0{ hypophysial
components (140). ACTH _msto be lhe primary
.... imulatOf of melanogenesis in some 0{ the filhes.
PR l is implicated lL'Ia regulalor 01 ACTH secrelion
in cenain of them and Il$ a difC(:t stimulant for u n·
tbopllores in others. PRL .nd ca n innu.
ence molting in some animal types, and thyl'QJ.ine
Iw also been observed 10 promote melanosolTlt di$-
persion in a few. promote consper.
sion in mOSt of the CC10thcrnu, and paling reactlon$
to frigbt have been linked with thit, However, the
same substances disperse melanosomcs in certain
species. Additional regulators thaI can affect the
 functions of pigment cells include g()nadal steroids.
gonadotropins, and prostaglandins.
I3ct()thernts capable of engaging in rapid or elab-
orate responses often possess chromatophOfel; that
are singly or dually inncrvated. Catccholamines are
the major neurotransminerll, and ..... and ,8·type ad·
renergic receptors can he present in varying propor.
tions. Generally. activation of the ,8 types to
cAMP genemtion and melanosome dispersion,
whereas the a types mediate oppo$ing effeclS.
In some cases, the cells lack hormone recept()rs. J n
others, those regulators Can either modify the
of neurotransminers Or affect mostly pigment pr(l-
duct ion and cell growth. Vertebrate chromatophores
that are not innervated Can display pha rmacological
responses to neurotransmitters. (For cxample. frog
cells are not believed to be physiologically acted
upon by acetylchol ine, but that agent promOtes me.
laoosome dispersion.) Tail-fin ehomatophorcs of am-
phibian larvae are among the cel1lYpes that are di_
rectly affocted by light (l96A).
Photoreceptor! sense much more than intensity
and wavelcngth. light that directly stri kes Ihe lat-
eral eyes impinges on parts of tbe rctinas different
from the ones affected by background rcn.ction. The
term albedo designates the ratio of thc intensities
from the two SOurceS. Yet diff.rent signals may be
perceived by the pineal complex and other parts of
the brain. A rapid change in the environment can
promote Ihe simultaneous discharge of twO Or mOre
regulators. and it can invoke responses very different
from the ones that follow chronic stimulation . The
pigmentation systems of a few of the vcrtebrales are
highly sensitive to environmental temperature. hu·
midity, or both. Many ectotherms undergo diurnal
changes in coloration, and in some these ron-
tribute to the regulation of body temperature (140.)
MSH interacts with catocholamine receptors. and
pharmacological agents affecting the receptors mod·
ify responses to the hormone. There are species with
innervated ehromatophores in which both MSH and
cAMP promote mclanosome dispersion. others in
which they cause conspersion. and yet different ones
in which no Te!lponses are secn. Killifish continue to
display responses to changing backgrounds after hy-
pophysect()ll1Y, but their melanophores respond to
MSH if they are first denelVllted. Chameleons (with
innervated cells) do not ehangc color whcn MSH is
administered in vivo.
PINEAL GLAND INFLUENCES ON OTHER
PHYSIOLOGICAL FUNCTIONS
Thermoregulation. locomotor aciIVity. oxygen COn·
sumption. electrolyte metabolism. acid-base balance,
and cardiovascular adjustments are interrelated
functions that undergo diurnal variati()lIS. There is
good evidence for pineal gland participation in the
fine controls. at least in reptiles, birds, and
mammals.
It has been suggested that desert li7.ards use their
epiphysial complexes primarily for thermoregulation
(123). Their se nsory systcms inelude well..cJevelopcd
"parietal eyes" that sefVC as "photothermal dosim-
eters." "true" pineal organs that arc highly sensitive
10 red light. lateral eyes that pick up yet different
forms·of photic information. and thermoreceptors
that are affected by both internal and environmental
temperatures. Projections to the hypothalamus. thai·
amus. and other brain regions relay signals that
modify behavior as well as pbysiological processes
(143). The circuitry is complex. and it is only par-
tially understood.
The parietal eyes evidently provide protect ion
against the development of hyperthermia. l.izards
deprivcd of their functions bask in the sun for longer
time periods than sham.operated controls. even
when environmental temperatures are maintaincd at
constant levels. They also seek out warmer surround-
ings when the illumination is controlled. Parietalec-
tomy is additionally reported to affect panting
thresholds, to invoke thyroid cell hyperplasia, and to
interact with the lateral eyes in the regulation of
metabolic rate (143).
The "pineal proper" is an oscillator that seems to
be involved mostly In the regulation of several bio-
logical rhythms and the synchronizations of the pat-
terns with environmental factors. Howevcr, its func-
tions cannot he separated from those of the parietal
eycs. Since it is impossible to remove one component
of the epiphysial complex without damaging the in_
nervation of the other. it is difficult to investigate the
interactions.
Parietalectomy is reported to disrupt (but not
abolish) pineal_regulated daily and seasonal loco-
m()tor rhythms. It also removes one source of Ml T,
as it elevates HlOMT activity in the pineal gland.
Pinealectomiled lizards tend to seck out ccoler sur·
roundings than intact and 10 have lower in·
temal temperatures. Although parietal.ctomy acts
in the opposite direction in otherwise intact animals,
it the effects of pinealcctomy. Addi·
tional indicat;()ns that the pineal contributes to par-
ietal eye regulation of body temperature include the
observed effects of both pinealcctomy and Ml T in-
jections on pant ing thresholds and thyroid gland
functions.
lizards darken when the environmental temper-
ature falls. and this facilitates beat absorption across
the skin. The respon .. probably involves inhibition
of MlT secretion. since HIOMT levels are reported
to drop t() their lowest levels on the coldest days. (AI-
th()ugh the hormone probably does not contribute to
."
camouflage reactions in these animals, it can pro-
mote mclanosome C(lnspersion.)
The thermoregulatory roles of pineal glands differ
across the species in birds. Sparrow. have marked
diurnal variations in body temperature thai are syn-
chronil-cd with lhe photoperiods. Pineal.elomy do.
creases the cycle amplitudes (so thai both p<:ak and
trough values approach the daily mean). It alSQ abol.
ishes Ihe " free-running" cycles that would otherwise
persist in subjects kepi in thc dark. Diurnal 10;><:<,>.
molor activity rhythms are also disrupted. However,
although the heat generated by muscular activity
normally contributes to daytime temperalure eleva-
lions, there arc indications Ihat the tWO functions
can be "uncoupled" (17). If the gland of another
bird is implanted afler lhc surgery, donor rhythm'
are imposed (lOS). Dcwuclion of the SeN has COn-
sequences similar to the ones invoked by pinealee-
torny. There are findings consistent with the concept
that the SCN act in ways to regulate the
functions. Evidently. the nuclei serve as I(1Fgels for
MLT and require intermittent stimulation. Contin-
uous administration of the hormone disrupts the
rhythms.
The pineal gland may perform comparable func-
tions in chickeru and quail under normal conditions.
However. the SCN can evidently utili>.e alternate
signats 10 maimain locomotor rhythms if the pineal
glands are excised. PinealCClomy drxs impair lhe
ability to rope wilh heat streS$, at least during the
night (143). In s/orlin8$. pinealeCOlomy disrupts but
does not abolish the rhythms, and the timing can be
manipulated by administering MLT intermittenlly
(108).
Body temperature eydes in mOSt mammo/.r are
synchronized with Ihe p/lQtoperiods. Pinealectorny
can affect the synchroni1.ations to ordinary stimuli,
and it al$O inAuen..,s the ability 10 shirt the timing
when the environment is manipulated (even in spe-
cies in whiCh it docs not disrupt locomotor rhythrrl$).
At least some of the influences of the pineal gland
hormones are exened on neurons involved in the reg_
ulation of glucocorticoid and growth hormone
rhythms. The pineal gland is also affected by those
and other endocrine secretions. Exposure to cold in
some way alters the activities of pineal gland en·
zymes in rats and bats. O ne consequen.., could be
modification of the signals sent to the hypothalamus
(113).
MLT and MSH may both act On hypothalamic
neurOnS directly involved in thermoregulation. MSll
has been shown to bind to those sites in mammals.
and exogenous hormone can lower body tempera-
ture. (Glucooorticoids reduce fevers, but the doses of
MSH used in the studies did not stimulate the adro-
AND n1YMUSGlANOS
nal corle."< ( 120J.) ML T injections havc less consis-
tenl effects. They have been reported to elevate the
temperalures in some species and to lower Ihem in
others (61).
Sin<;c thryoid hormones affect activilY level s, ox-
ygen consumption, and body temperature, inftuenccs
on the TRH·TSH·thyroxine system are probably
imponanl . Although the lilerature contains some
apparently conflicting data, several authors have
concluded that thc pineal exerts mostly inhibitory ef·
feets (110. 152). The major targets may be
acting neuronS. Hamsters treated with moderate
amounts of M LT display parallel inh ibition of repro-
ductive systcm and TRH functions. However. phar-
macological regimcs invoke down regulation of both
receplor types (196). In addition to reversing effects
of blinding (A-4), there have been reports that pi-
nealectomy affects the Ihyroid glands of hypophy-
sectomized ralS.
Some of the links between thermoregulation and
water and electrolyte metabelism have been dted in
carlier chapters. The pineal gland may funct ion as
both a regulator and a target organ, sioee it receives
magnocdlular nuclei projection,. It also affects Me-
reid metabolism and the secretion of Gil (A-4).
It was at one lime suggested that thc pineal gland
synthesizes and secretes an "adrenoglomerulotro-
pin·· Ihat directly sti mulates '.ona gtomerulQ&a <;cns
of the adrenal cortex. 1\ is now widely believed that
the componenl of pineal extracts reported to e."<ert
such activity is an artifact that arises in vilro from
eyclization of 5_HT (200). Serolonin is present in
high con<;cntrations, and it Can stimulate the adrenal
glands, but the observation is probably not physio-
logically relevant. Very little (if any) of the cireulat_
ing serolonin comes from the pineal.
Some other suggestions that the pineal augments
mineraloconicoid activity rome from reports that
(a) pineal extracts elevale aldosterone secretion in
humans and aldooiterone produclion in rats (b) pj.
neal glands accelerate regeneration of aldooterone-
secreting (but not glucortiCQid·producing) cells
whcn they are implanted into enucleated adrenal
glands (c) pincalectomy reversc, the sodium·retain_
ing effects of reserpinc; and (d) pincalcctomi1.oo ralS
would rather drink a 3% saline solution than tap
water. On the other hand, different laboratories re-
port that a component of pineal gland extracts in_
vokes hyperkalemia. that ML T depress .. aldoste-
rone production, and that pinealectomy can lead to
sodium retention. Studies with ext racts must be in-
terpreted with caution. since the glands contain bi-
ologically potent substances that are not true hClr·
monCS. Ubiquinones are present in
quantities, and they ar<: said to inhibit aldosterone
secretion {I 52). The same substances arc made by
many cell types.
Since mammals deprived of their pineal glands
usually manage to maintain "'asonably good electro-
lyte balance:. it is lihly that the gland oxen. only
fine controls. the natu", of which may vary with the
physiological stalUS.
The possibility that the pineal also contributes to
the "'gulation of caldum metabolism is C<)m;istent
with observations that fishes deprived of the glands
display defects. and that hyperplasia of the calei-
tonin-sec"'ting cells and of the conse-
quences of parathyroide<:tomy can oc<:ur in other
Y(:nebrates (143).
M LT injections have been reponed to invoke sleep
onset in cats and to enhance the eife<:ls of barbitu-
rates in rats. They are also said to bring on sensa-
tions of fatigue and to facilitate sleep onset in hu-
mans. Manic-4epressive illness has been linked with
abnormal MLT cycles and light sensitivity (191).
Chlorpromazine dcpresses HIOMT. and MLT Can
worsen psychotic symptoms (A-4). Cenain patients
may benefil from inc reased exposure 10 bright sun·
light. but administration of pincal cxtracts is said to
help others (l5).
FUNCTIONAL ANATOMY O F THE TH YMUS
GLAND
The human thymus is a somewhat ftaltened. bilobed
lymphoepilhelial organ located in the antcrior me-
diastium . A thin C<)nnective tissue capsule that con-
tains fibroblasts and collagen f'brils surrounds the
gland, leads into the interlobar septum. and sends
out fine extensions that subdivide the gland inlO l0b-
ules (Fig. 20-1A). Each lobule comprises an outer
cortex and an inner medulla (Fig. 20-7B and Cl.
Branches of Ihe internal thoracic aneries enter at
Ihe hilus, course along the septa. and terminate in
capillaries within both Ihe medulla a nd cortex. Most
of the postcapillary venules drain Ihe medullary re-
gions. There are elferent, but no alTe",nt.lymph ves-
sels{I60).
Tb<: stroma is a three-dimensional network made
up mostly of epithelial (fils that contain tonofibrils.
They send wtlonl!> branching cytoplasmic processes
that join those of their neighbors. Desmosomes and
cell interdigitations strengthen Ihe stroma (which is
more abundam in the medulla than in the
The term ,."tieular is applied to the epithelial cells.
but phagocytic cells of the stroma that are derived
from mesenchyme and lack the desmosomes and
tonofibrils are called interdigitating reticulum cells
(82). The stroma additionally contains fi ne collagen-
ous and relicular fibrils situated mostly in the vicin_
ity of the blood vessels. and an aSSOrtment of limited
numbers of OIhcr cell types. Thynwcytes are
crowded into the intersticies of the networks. They
are more abundanl in Ihe cortex than in the medulla
(Figs. 20-70 and E).
In much of the thymus. the blood is separated
from the stroma by nonfenestraled endothelium,
pericytes, endothelial basement membranes, perivas-
Cular spaces (that can C<)ntain macrophages, mast
cells. eo:;inophils, adipocytes, fibroblasts, and plasma
cells. as well as lymphocytes), reticular cell base-
ment mcmbranes. and extracellular fibrils. Although
circulating macromole<:ules do oot readily gain ae-
cess 10 the stroma. cells can enter and ex it via dia-
pedesis. and some vessels that arC not su rrounded by
perivascular spaces have fenestrated endothelium.
The f,ndings have sparked controversies over the
possible existence of a '·thymus-blood barrier"· in Ihe
fully developed gland.
The morphological diversity of the epithelium
probably has functional sign iftcance (17 5). The cells
differ in sizes, shapes, nuc1ear:cytoplasmic ratios,
and associations with fibrils. Many have lysosome-
like bodies and nestS of vacuoles and vesicles. Some
possess granules that resemble the OneS found in
cells Ihat secrete peptide-type: hormones. and others
contain smaller granules. The dilTerenccs in elcctron
densities displayed by "light"' a nd "dark'· rcticular
cells are related to the numbers of ribosomes and
tonofilaments. the chromatin distribution, and the
nature of the cytoplasmic "ground subslance·· (115).
Myoid cells with concentrically arranged. striated.
actin and myosin containing filaments are also con·
si'lem ly found. (At least in birds. these are often
dose ly associated with the cells that contain small
granules (82{.) In the medulla. concentric arrange-
ments of epithelial cells that can become kerati1.ined.
calcified , or cyslic form Hassal!'s corpuscles with di-
ameters of 20 to several hundred mi11imicrom; (Fig.
20-8).
Similar glands are found in most other mammal,.
but there arc variations in sizes. numbers. and loca-
tions. Guinea pigs have two separate organs located
in the neck region. whereas Ihe Australian quokhs
possess both cervical and thoracic thymuses (Ill).
Birds typically haY(: 14 lobes arranged in chains on
eilher side of the neck. Reptiles, and
fishes also possess multiple organs. Some findings in
"lower"· vertebrate, underlie speculations thai the
thymuses may perform functions taken over by lhe
mammalian lymph nodes. The capsules of amphib-
ian thymuses provide only partially effective bar-
riers, and pigmented cells commonly en ter the
glands. tn leleost a si ngle layer of cells often
separates lhe stroma from the pharyngeal lumen.
The glands can merge with neighboring muCuS-SO-
creting epithelium, and lymphocytes may be ex-
changed with IhClSC of the adjacent kidneys (lOO).
La mpreys form unencapsulated. loosely organized
Fig. 20-7 . Sttuotu .... of thymus . KiNon. A. ",ilh 0..-. .. mIIrg .... lfIod n...e",/" Chromalin. (6) lumen 01
L.M. X 22. (I) Co.pw\8 "t S<Jo1.... OJ glV><!. (2) w.,..;tlve blOod ... pillary . E. OJ thymic eone •. E.M , X .500.
septa. (3) blood v •• NI• . 1obIJ.... 8 . Port of ( I) Nuclei or """,II Ihymic Iymphocyt.... (2) "'-'OM< oj
thym;c _ . ErQ, _ t ot . '.. .....1.' to recl • • in A.
L,M. X 215. (1) Co.psule BI ourlace oj '<>00". (2) cort• • , ,.'me<lium-siu
ioJ1a, ...11,d (4)
thymic
thymic
(3) """'- or ep;th@tial
in rnito,*" ( 5)
(3) r"I'lfIoduIll. ( 4 ) H.Mall"s (tnymir;) C. SU",ey """ ...... 01 small IhymiC Iymphocyle ",ith matginalflod
ot thymic _ , 011'''' s imil", 10 ,o<:IangIo in
S. E, M , X &30, (1) Co.poulfl. (2) cortex. (3) medulla . (4)
nucleoplasm. indicating .",."",1"""
.actlOla 0< seoo<>da ry Iyocsomo in
<lMl h. (6) <lig<rsIMr
ot
Hissall '. OOI'P<>*' .... ( 5) blOod c.P11a, ..... O. s...v.y 01 F. Sma" Ihymic Iymp/>Xyta (T oeIt) Itom
thymi<: cone • . Enlaf\l9lT>8n1 01 _rea simil. , 10 to<:llogto A in con .. 01 thy"", • . width E.M . X 16.000. (1)
C. e .M . X 1800. ( 1) Small thymic Iymphocyll •. ( 2) Heterochtomolin. (2) euchromatin. (3) nucINt perM. (.)
medilHn-sized Ihymi<: lymphocytes, ( 3) nuclei 01 ep;u..Iial
.... Iioul .. ' C<tlI • • ( 4) ma"'Ophag • . ( 5) 1hymi<: lymphocytes
""""If ",ambo'" ,,". (5) ,iboSOl'l'lU. (6) GotQi zono. (7)
milOCflOrM1rIa . (6) surl .... (Coli ) m.mtx."..
,- 1;' ...... ..... --
, So
... •

, '/ ,". -
"'III!!""'
........
., - . :.:i'
"' "I"-. ,•.,••
f'..
{-.r \
, ·1
-0 ..... .i h
A .'',
.. I!<. • . ,vMI -0-
..
•"{.'
'f'

. : 'f!]
.. \ -, ...,
.. . ."'-""1
.. "'(' - .
0 '
M ,.
., .. ' • '<t
,
.; ,"
.' I !

""p; - . , ./ "
' .

":v
I
....
. .

I ',
• ".... ...... ,:, -. :::
.,
f.
LV·' ' .' ,
. -
)
I
r
•

, .) .
M'

6.'- .r:
"

.:. ; '
_ -_ .- ....-..t . . . ,..
'

\ of..- -:.
• . ''''""'\
M I ..
<- / ...u . ... .
"I , "
..
--"
j ( " ;- .

I .· . .'. ,
"'"'(JJf
." .- ...
..,' '''
... .. - .. . --

:;t ' -f1\ :>. j\,";' - tz·

'..,".,
o
Y ' {:
. "' .
,
"
.....W".
"--.
'.,
.,,"....
.>"

."
•
'"
...
"
Fig. 20.8. Porn"" ot tfle
an 8-ye. r<>l<! bOy . An ""sinopI'OIic myeloCyte Ia iuot OIJI_
the lelt·h.,>d ot H. ...
910.
clumpS of epithelial and lymphopoietic tissues (hal
are SQmetimes referred to as "protolhymuscs." The
hagfish.s 3re thc on ly members of thc subphylum
known 10 totally lack oomparablc cpithelio-Iympho-
cytie associations. Those animals do, howe"cr. p<.l5'
sess some ability \0 engage in cellular immunity re·
sponses (100).
Develop ment and Maturation
T hymus glands dilTcrentiate from cp itheliomcscn·
chymal rudiments of the embryonic pharyngeal
pouches in all of the jawed vertebrates. During Ihc
early slages. they closely resemble olher developing
endocrine glands. They are then colon;7.ed by he-
matopoietic Slem cells. and in most mammals lhey
arc the first of the "lymphoid organs" to undergo
maturation (110). Howe,·er. the hormone-secreting
epithelial components are retained throughout life.
PINEAL AND THYMUS GLANDS
"""MI. ot 11>9 thymus gil"" ot
boay. EosirHIz",,, st"." X
INTERACTIONS WITH OTHER EMBRYONIC
CELL TYPES
The primordia of the thyroid. parathyroid. thymus.
aoo cells are initially in close
proximity. The extents to which thc various cell
types intermingle during the migrations that folio'"
differ among the vertebrate groups. The most com-
plex patterns have been described for mammals
(60,123).
In humans, the beginnings of the medial portion.'
of the liWroid glands can be identifIed in the pha-
ryngeal noor as early as I? days postconception.
Most of the cells lie between the ventral borders of
the 2nd and 3rd pharyngeal pouches (the former of
whiCh swell and provide the pharyngeal tonsils).
Small amounts of thyroid tissue appear later in the
4th pair of pharyngeal pouchcs. These can con trib-
ute to the latera l regions of the fully formed gland.
but most of those cells regress. During the 5th pre·
natal the inferior para/ ny,old gland primordia
bewme reC<Jgni7able in the dorsal wings of the 3rd
pair of pOuches. as thymic anlagen begin their de-
velopment in the venterolateral extensions. The su-
perior parathryoids arise from the 4th pair of
pouches, along with some thymic cell precursol"$ and
the aforementioned thyroid cell •. The small 5th pair
of pouches give!< rise to the fUlure calcitonin-secret-
ing cells Ihat will be incorporated into Ihe thyroid
gland (184),
By the cnd of the 61h week, hoIh the thymic and
parathryoid primordia lose Iheir connections with
the pharyngeal wall. bUI IhymuHhyroid ligaments
form . As each of Ihe bilaleral clumps of Ihymus tis·
sue migrates medially and caudally towaro the me·
diastinum some paralhyroid cells are dragged along.
Cell segregations follOW, but these are often incom·
plete (so that parathyroid cells Can be incorpOrated
inlo the thymus. while thymic clements may reside
in the parathyroid and Ihyroid glands) . ne main
portion of each developing thymus component fuses
with its counterpart 10 form a midline struclure, but
the caudal regions elongale. beC<Jme narrow. and
undergo fragmentation . Although most deteriorate.
SOme fragments can form small. independent masses
of tissue Or become inC<Jrporated into the thyroid
glands (90). This probably explains the frequent oc-
CurrenCe of small clumps of Ihymus lissue in the jaw,
the base of the skull. and Ihe deeper regions of the
mcdia.tinum.
In biros. reptiles. amphibians, and fishe!<, the vcn,
tral borders of the 51h pair of branchial pouches
the forerunners of true ultimobranchial bod·
ies. while the thymus usually develops from the dOT·
sal portions of one or more of the pouche •. Bird Ihy·
muses Iypically originate in the 3rd pairs of pOuches.
and Ihe parathyroid anlagen in the 3ro and 4th. In
some of the amphibians and fishe!<, pairs of thymic
form. bUI some undergo regrcs;ion
have parathyroid gland •• and in
these and the amphibians. Ihcre is little or no inter·
minsling of the various cell types (61 J.
THYMUS GLAND PRECURSOR CELLS
The rapid migrations of embryonic lissues that occur
during early development make it difficult 10 resolve
all of the controversies Over the natures of the pro-
genitor eeillypes (93). The epithelial Stroma of the
thymus originates mostly from the branchial pouch
mdodeFm. but ectoderm may make a small C<Jmri·
but iOfl in at least some species. Underlying mnr ".
chyme plays essential roles in the support of epithe-
lial dilTercmiation , However. although neural crest
cell s migrute into the mesenchyme and participate in
the formation of Iht tissue. slUdies with explants in·
dicate that mesenchyme from Olher parts of the body
can be substiluted. Epitheliomesenchymal interac-
tions lead to the production of an eXlraceliular mao
trix (78) , The conneClive tissue Ihat form. the cap-
sule and sepia originates in mesenchyme, but
components from olher sources arc later in·
corporated.
Thymic primordia are at first hollow. As the epi.
thelium proliferates, cell cords oblilerate the lumina .
Invasion by hematopoielic stem cells begins al this
slage (before Ihc vasculature is established) (78).
Colonizalion is well advanced beforc the end of thc
3rd month in humans. at 16 days postconception in
the mouse, at 12 days after fertilization in the chick.
and even o:arlier in amphi bians. In contra.l. although
the palatinc tonsils accumulate precursors during
month, 3- 5, the human spleen does not become lym-
phopoietic unlil lhe end of Ihe 5th prenatal month.
whi le the lymph nodes developafler birth. Siudies in
which developing glands ,,-ere removed from toad
larvae JUSt 5 days )lOSt·fertili1alion arc consistenl
wilh Ih. belief that cellular associations leading to
the establishment of thymus funclions can precede
obvious accumulalions of Iymphocylic elements
( I00). (Thymocyte precursors do, however. require
considerable time to undergo the ncc<:ssary matura·
tion once the contact is made.)
Pluripotential hemalopoietic stem cells can be
identified in the yolk sacs of young embryos, and it
wa. believed umil lhal lhc,c arc tho ""Ic
precursors of the thymocyte •. liowcver. evidence has
been presented for the of blood-forming
sites within the embryonic mesoderm (93.195). The
cells enler the developing liver. and thcy proliferate
rapidly. They may also undergo somc preliminary
differentialion into large. basophilic "prethymic pro-
genilo,," before via the hepalic blood Ve!<Sei5.
The cells must then leave those vessels to enter the
developing thymus. It ha. been <uggcsted that Ihe
mesenchyme produees diffusible chemOiaxins thai
act directly on the endothelium 10 facil itate the pro-
cess (78) . They then auract the cells to Ih. gland.
Afler the initial "seeding." the thymus enters a
"nomeeeptive" phase. during whiCh it Stops admit·
ling new thymocyte prOgenitors. The residents make
associations wilh Ihc epilhdium and prepare for cell
division, as the blood vessels for the Ihymus dcvdop
and the gland continues to grow. After an appropri·
ale time period has elapsed. a 'econd "wave" of pre·
cursor cell upta ke Can be demonstrated. (When
glands from One animal are implanted into another.
they become populaled by host cells al Ihis time.)
The scC<Jnd phase of cell upta ke may be needed
moslly to balance Ihe ralios of the various cell types
within the Ihymus. Another refractory period fol.
loW!; . Some of the residents proliferate rapidly. but
population growth is restricted in tWQ ways: (a) up
to 95% of the progeny die within the gland, and (b)
the thymus supplies cells to the periphery. Some-
thing like 1-2% of the developing cells eventually
colonize '·Ihymus-dependenf· rogions of the spleen
and lymph nodes. Therefore, although a few lym-
phocyles may be long lived, it becomes necessary to
renew the populations on a regular basis. The gland
accomplishes Ihis by undergoing
uptake and nonroceptivity throughOut life. Late in
gestalion and poslnatally, most of the progenitor
cells are supplied by the bone marrOw and these are
delivered via the bloodstream (201).
The timing of the evenlS may be necessary for as-
suring that the optimum numbers of thymocyle prc-
cursors are always present. According to one hypolh-
esis, the progenitor cells wilhin the Ihymus exert
negative feedback in"ucnces over the production of
the chemolaxins (93). As Ihey mature. they lose the
ability to do this. and re«ptivity is temporarily
restored.
The demarcation of Ihe thymic lobules into cortex
and medulla is well advanced by the 14th gestational
week in humans (77) and at a comparable develop-
mental stage in other mammals. Most of the progen-
itor cells accumulate in the cortex. The epithelial
cells in that region provide conditions that favor
nopid Thi. i. ill part, \0 tho
release of stimulanu from the epithelial cells and/or
to the crealion by those cells of a highly special ized
microenvironment. In time, the large cells mature
inlO medium·sized and small lymphocytes that ac-
Cumulate at the corticomedullary junclions. How·
ever, Ihere are good reasous \0 believe that a differ-
ent population of proliferating cells that is limited in
size takes up residence in the medulla.
The onset of the proliferative phase is associated
with the appearance of a nuclear terminal
deoxynucleotidyl transferase (TdD. The Cn7.yme is
implicated as a mulagen that may be involved in
production of va rieties of cell types that differ in
their abilities to make specific proteins. [t is also
presenl in bone marrow lymphocylic procursor cells
(but not in stem cells Ihat will eventually give rise to
erythroid or myeloid progeny). Hormonally active
thymus gland eXlracts and &OllIe purified fractions
obtained from them can induce the enzyme in vitro.
In studies of normal human infant Ihymuses. some
60%-85% of eortical cel1& (but only 3% of the mcd-
ullary ones) were observed to contain TdT (77).
As the cell' stop dividing and undergo maturation,
they no longer interact wilh antibodie:s directed
againsl Ihe TdT en7.yme. Their further maturation
wilhin Ihe thymus is associated with Ihe appearance
of speciftcsurface antigens. Some are linked with the
differentiation. while others will be used later when
Ihe cells perform their immunological functions. The
molecule:s can be induced in vitro by presenting the
cell$ with substances obtained from thymus glands
and with some pharmacological agents. No addi_
tional cell divisions a re required. Several hormones
have been identified and a few have been chemically
characterized (2,42). However, it is not yet koown
how many regulators are produced under physiolog-
ical conditions.
The processes have been studied most intensively
in mice. Studies on other species support the belief
tbal the general patterns are similar for all of the
mammals (although the specific macromolecules in·
volved are different) (7S). The Tlry-I (theta) antigen
appears on mOSI "prethymocyte:s (bul nOlon B-type
lymphocyte precursors). It can be identified on sma ll
numbers of cells in the glands of mouse embryos at
13 days postconception, and On 95% (including large
dividing ones) by day 17. During the next "age of
differentiation. the cells within the cortex retain the
Thy-I. and they additionally acquire the TL antigen.
At this stage. they are known as immatuTt Ihymlr
cy/es. The.. ce11& are highly sensitive 10 cortisol. but
they do not display immunocompetence. Some cells
within the medulla acquire immunocompelence. and
they are referred to as "ma ture thymocyle:s." They
loa ouly 'lIlal! alIl<)UBI> "r TII)·_I, alld arc TL-
negative and resistant to cortisol. They may differ·
entiate directly from prethyrnocytes via a special
pathway, but the pos.sibility that they are at some
stage TL·positive has not been ruled OUI.
The Ly/ anl;8'!1IS are linked wilh funClional char-
acteristics. All Ihymocytes that become immuno-
compelent are believed 10 be Lyt-I positive al some
stage. The T. (helper) cells relain this marker. Cy-
totoxic (T,) and suppressor (T,) are Lyt-2. Lyt·3
positive, and they are believed to differentiate from
Lyt-I,2,3 precursors (78). (Related, but somewhal
dilTercnt Lyt antigens (109) are found on the $ur-
faces of "nalUral killer"' INKJ cells (69) that eon-
tribute to $Orne aspects of cellular immunity.)
Hu m ora l Me d letor, o f Th ymocyte Ma turatio n
e nd F un ction,
Early in life. the thymus plays essenlial roles in the
devt/opmenl of the immune system. Laler. it per·
forms moslly mainlenanct fUnClions. In mice and
many other small animals with short gestation pe-
riods. Ihe gland is mOSI obvioosly needed for a lime
period thaI inlo the first postnatal week.
Neonatal thymeClomy permanently impairs the abil-
ities to rejecl foreign tissue lransplants and 10 cope
 with viral and certain bacterial infections. If the sur-
gery is delayed until the 2nd postnatal week, the con-
sequences are far less seriws. The animals eventu-
ally become Iymphopcnic, but they do quite well
under ordinary laboratory oonditions. However. they
cannot restore the immune system arter it has
artificially damaged by X-irradiation Or antilymph<.>-
eytic sera. In humans. the --critical period" oc<;urs
before binh. Infants bom without thymus glands suf-
fer defects oomparablc to those of noonatally thy-
mectomized rodents.
The very first humoral mediator may well be a
chemotaxin secreted by the cells. The
epjlhelium is then believed to release substances that
promote proliferation and differentiation of thym<.>-
cyte progenitors. It is pc&ible. however. that cell«11
oontacts are also essential for early development.
The immune functions of neonatally t hymectomi1-cd
rodents (and of oldcr ones whose glands ha"e been
destroyed) can be f"<'stof"<'d with thymus implants.
There af"<' indications that donor tissues eneloscd in
millipore chambers permiuing movements ()f mac-
r()molecules but not of cell' only inoompletely sub-
stitute f()r tissue that Can be directly colonized by
h()St Ihymocyte Pf"<'cursors. Macrophages within thc
thymus are probable SOurCeS of additional Iympllo-
cyt..activating factors (126) . The '"education" of
thymocytes also requires to macromolc-
cules whose producti()n is di=ted by histocompat·
ability genes.
The epithelial cells relcase hormones to the blood·
stream. These act on rone marrow and lymph node
cells as well as on circulating "post-thymic cells"
(which do not return 10 the gland). Some of Ihe mol-
ecules may be identical with (lIlCS that act within the
thymus_ The best of the circulating h()rm()nes
include "veralthymosins. thymopoictin. thymic hu-
moral factor (THF). and S"rum thymic factor
(FTS) (2,42). The concentrati()llS in the blood vary
with age. and the decline late in life is linked with
the higher incidences of immune disorders at that
time. Blood also oomains hormone inhibitors.
Thymocytes that leave the gland require activa-
tion before they can perform their functions. Thc
cells respond to MHC-<::oded molecules (A-3) (as
well as to specific antigcns). There is still consider-
able oonfusion concerning the numbers and kinds of
stimulants that arc required. Onc problcm is that a
single agent can bave several names, and it may be
produced by two ()r more cell Iypes. An()ther is that
the actions of a regulator can vary with the condi-
tions under which it is preS"n{ed. AllemplS are DQW
under way to systemati1.e the nomenclature. The
term interleukin is applied to substances that are
produced following leu kocyte--!eu kocyte interactions.
Each type may consist of '-families" of molecular
species. Interleukin-I is made by macrophages, and
it is identical with a regulator formcrly called Iym_
phocyte--activating factor (LAF)_ It is a member of
a group of agents known as m()nokines.
2 is a product of antigen activated T cells (A--6), and
it therefore belongs to the Iymphokines. Its other
names include thymocyte-dependent growth factor
(TDGF)_
There are also problems involved in determining
the roles of '"second messengers" generated by the
regulators. since a single substance can stimulate
when presented at one time and inhibit at another.
11 can also simultaneously stimulate certain cells
types as it dcpresses the activities of others. Cyclic
nuelootides have been implicated in many of the re-
sponses (191). and prostaglandin invoh'emcnt has
also demonstrated (58)_
THYMUS GLAND INVOLUTION
Humans are said to allain thcir maximum thymus
weight:body weight r3ti()S during late fetal Or early
pooltnatal life. As the TC.';t of thc body grows during
infancy and childhood, the glands continue to en-
large-especially during the two years and
again at ages 7 through II (81). The greatest abso-
lute weight is reported to be achieved around the
time of puberty.
Androgens and C!ltrogen, regulate immune func-
tions (A-2). and they limit thymus gland size. Small
doses of those hormones can normalize the hyper-
plastic thymuses of castrated animals. and larger
ones shrink the glands of intact animals. However,
"age involution" is said to begin as early as the 5th
postnatal year (when circulating steroid levelS
arc low)_ It in"()I,,es reductions in the thym<.>-
cyte:micular cell number and oortical:medullary
volume rati()S. Aceumulations of adipose and
connective tissues in the interlobular septa beoome
obvious in young adults. They gradually invade and
replace much of the lymphocyte-laden cortex. Lipid-
rich '-foamy" cells (believed to be macrophasges) in-
Crease in numbers. as epithelial cysts lined with cil-
ialed or mucus cells and mast cells appear in Ihc
medulla.
Concepls ()f Ihe magnirude of age involution in
healthy individuals have been revised in recent years.
The initial data Wef"<' obtained from hospital autop-
sies. M()St of the older subjects had been chronically
ill or poorly nourished, and it is known that infec-
lions. stress, food deprivation. and a wide variety of
therapeutic agents can cause shrinkage of the
glands. In contrast. children and adolescents who
come 10 autopsy are more frequently victims of ac-
cidents or acute fulminating infections. Recent ob-
servations made on the glands of adults who were
healthy shortly before the timc of death. and on
biopsies of patients undergoing surgery. indicate that
."
substantial amoonUi of epithelium and some lym-
phocytic components al'<: present 3S late as the 71h
decade (8 I).
Studies On other ve rtebrates demonstrale lhat
many physi(}iogical facton inHucnces that arc
superimposed OvCr the ones associated wilh aging
(83) . In some spe¢ies. thymus weights undergo 0b-
vious seasonal cycles that have bc<:n linked wilh Ihe
numbers of hours of sunlight pcr day. Adul! and ju.
venile mule decr, fox cubs, and frogs are among the
animals observed \0 bve lowesl weights during mid-
winler. The glands shrink during Ihe m()lling ....,awns
in birds. and Ihe enlargements that occur during Ihe
post-breeding periods 3re oflen uninnuenced by gon-
adectomy. Ther<: are also diurnal variations in thy-
mus "",ighls (I 71 ). Tadpolc metamorphosis is pre-
ceded by a sharp reduction in thymus tissue.
Extreme involulion has been described for salmon
during spawning. and s imilar cbanges can be in·
voked in nonspawning individuals by performing
gonadcclomies.
Glucocorticoids consiSlenlly invoke dose.depen.
dent reductions in the weights of mammalian thy·
in many species, and Ihe phenomena have
been uiled for bioassays. (Ther. ar.. bowever.
marked differences in the responsiveness of "corli·
and ··corticoid·resistant" mammals;
humans belong 10 the second category.) Tbe eff...:1S
differ in some ways from those that follow eslrogen
or androgen administ ration . and combined adrenal-
...:tomy·gonad...:tomy invokes more impressive Ihy-
mus gland hypertrophy than either proc<::du re alone.
Involulion associated wilh food deprivalion is re-
lated in part to elevated gluCQCOTlicoid levels. How.
ever, chronic conditions also 10l'l<:r Ihe concentra-
tions of (or responses 10) growth hormone. prolactin.
and of other regulators that promote thym us gland
enlargement. Un kTIQwn factors can affect the influ·
enees otherwiile associated with the nutritional StalUs
and steroid hormone levels. It has been reported that
the glands of marmots undergo involution during
preparations for hibernation that are associated with
gonada l inaelivity. decreased secretion of glucocor·
liooids. and ac<:umulation of fat reserves (g3).
Pa thologica l conditions in which the gland en·
larges include aUloimmune disorders such as myas-
thenia gravis and some forms of hyperthyroidism.
Sudden infant death syndrome (SlOS. crib dcath)
was at one time believed to T<:$ult from suffocation
ileoondary to thymk hyperplasia (status Ihymolym·
phaticus). The idea has been discarded for several
reasons. Studies on large numbers of infants re-
vealed that thymus glands are normally within thc
range found at autopsy in many victirru; of SIDS
(22.23). Hyperplast ic glands of animals subjectcd to
PINEAL AND THYMUS GLANDS
oombined gonadeclomy·ad renalectomy have never
been observed to invoke suffocalion. MorC()Ver, when
infanlS do in facl have very large thymuses. the find·
ings may reflecl adrenocortical failu re. The causes of
SIDS are not known, but most clinicians now link it
with autonomic system defel:IS Ihat aff...:t the f unc·
tions of respiratory system neurons or with fulmi·
nating infections of the kind. Ihat are TlQt easily de-
lected by ordinary methods.
In addition to growlh hormone and prolactin.
physiological rcgulators that can increase Ihe of
the thymus include progcsteroll<' and mineraloconi-
coids. These may act. in part. via interferenl:<' with
the binding of glucocortiooids to tlleir reaptors. hut
high-affinity progesterone receptoTS have been
idenlified .
In trinsic characteristics modify the responses to
Ihe microenvironments (43). Glands la kcn from in·
fant donors conlinue to grow in hoots whose own thy·
muses 3re undergoing involution. whereas glands
laken from old animals fail to undergo "rejuvena·
tion" when Ihey arc implanted into young hosts.
Each lobule possesses some aUlonomy Ihal is mani-
fested by the persistence of a fairly constanl corti ·
cal ;medullary ratio. When one lobe is destroyed.
there is no ooll!;istenl compensatory hypeTlrophyof
the Olher. If many young thymus glands arc im-
planted into a single =ipienl. each can continue 10
grow as if it were pre.sent alone, The thymuses of old
adre nalcctomized. gonadectomized. or doubly oper_
ated animals arc larger tllan those of age-matded
sha m-operated oont rols, but they are smallcr than
ones found in operaled young adults.
The phy.iologicol signijicanl:t' of involu tion is !lOt
1'1<:11 underslood. It has been suggested Ihal older
persons need smaller thymuses because they have
accumulated more peripheral "memory" cells. How·
ever. certain problems such as the increased tenden·
cies to develop autoimmune disorders and to bar'oor
malignant tumors have been linked with deteriora·
tion of the glands. and hormones obtained from thy·
mus extracts Can exert beneficial effects (A·I),
Although it ileems reasonable to oonclude that
"age involution" is associated with decreased func-
tion. gland Si1.c and lymphocyte content in younger
individuals may be inwrst ly related to Ihe ability to
exert some important influences. It has been sug·
gested that thymocytes or their precursors inhibir
the release of hormones made by epithelial cells and
thaI the hypertrophied glands of castrated animals
con/ain. but do nol se<:rete. large quantities of cer·
tain regulators (36), The presenee of steroid hot-
mone receplors in the glands, the sex-related differ_
ences in Iheir numbers, the changes in the numbers
with age and following experimenta l manipUlations
 of the endocrine system. the existence of a popula·
tion of ceils that responds to androgens but is !'<:Sis-
tant to gluOOCOTtiooids (130). and the sex·related dif·
ferences in immune responses (191) 3re all
oonsistent with the oonc<:pt that gonad-<liroxted in-
volution is physiologically important.
Anempts have been made to link glucocorticoid
cffecl$ with the ability to cope with stress (Chap. 6).
It has been suggested that (a) the epithelial cells re-
lease mOre of SOme substance that contributes to sur·
vival during limes of emergency; and (b) thymocytes
discharged from the gland mediate as yet unspeci·
fied functians by either carrying chemica! messen·
gers to peripheral organs Or interacting with the cells
that they contact. One problem with the concept is
that lhyme<:tomy performed after the critical period
for immune system maturation exerts only subtle in·
Huences over the ability to cope with acute s tress.
Another is that sustained influences of glucocorti·
coids that lead to extreme shrin kage of the gland and
lymphocyte depletion Can impair the ability 10 resist
infections. In severely debilitated patients, there are
circumstances under which the administratian of
glucocorticoids can be beneficial. even though the
thymus glands 3rC involuted . The enlarged thymuses
seen in adrenocortical insufficiency States are often
incapable of carrying out their immune functions.
It has been widely assumed that chronically ele-
vated steroid levels account For stress·associated im-
pairments of immune responses. However. adrenal·
eetomi"ed ralS gi"en corticosteroid pellets that
release constant dosages of hormone during control
and Stress periods. and even stressed hormonc-defi·
cient adrenaloxtomi"ed animals show some suppres-
sian of immune responses (although they do not be·
come Iymphopenic) (80A). Moreover.
proliferation responses to mitogens were observed to
be in rats given no control over the elec-
trical shock stress. whereas ral! exposed to stimuli of
lhc same intensities but given the opportunity to
thcn terminate the stimuli did not display the
suppression (9IA)_ Different kinds of interrelalion'
ships are suggested by observations that athymic
mice havc adrenocortical deFects (135). In SOme pa.
tients with adrenocortical insumciency. generalized
cach •• ia acCOunt, for some of the immune system
dysFunctians. In others. the steroid deficicncy is
known to be caused by autoimmune destruction of
the adrenal glands.
The name rhymoslalin has been given 10 a sub-
Slance that can inhibit thymosin aClions (98). AI·
though it has not been established that thymostatin
is a true hormone. its discovery raises IWO possibili·
ties: (a) the qualitative nature of the thymus emuent
can vary under physiological conditians; and (b)
since high conecntrations of thymus gland extracts
can exert effects different from those obtained with
low concentrations, some regulators may be secreted
in physiologically significant amounts only when Ihe
glands are strongly stimulated.
THYMUS·GONAO·ADRENAL INTERACTIONS
Indications that the thymus glands play important
roles in differentiation of the ovaries were presented
in Part V. Abnormalities described for congenitally
athymic mice include low pituitary and blood levcls
of FSH and LH, delayed vaginal opening. reduced
numbers of Functional ovarian follicles. and prema·
ture loss of fenility_The conditions can be corrected
by implanting thymus glands SOOn after birth ( 145).
In previously healthy mice, thymectomy performed
2-4 days after birth invokes ovarian dysgenesis.
depression of the gonadotropin levels, premature
aging of the reproductive system. and tendencies to
develop ovarian tumors (11 2) . The surgery is !lOt ef·
fective if it is delayed beyond that time. Related in·
fluences of thymectomy have been described for rats.
and ovarian dysgenesis been found in women with
congenital athymia.
As discussed in Part V. neonatal injectians of an·
drogen. Or estrogen. interFere with reproductive sys-
tem maturation. Female rats treated in this way do
not establish normal ovarian cycles after attaining
adulthood. injections of thymus gland cell suspen·
sions are reported to provide protection again't the
effects of those Slcroids {84).
Several findings suggest links with the immune
functions. The ovarian follicles of neonatally thy·
mectomi ,,,,d mice become heavily infilirdtcd with
lymphocytes. and antibodies directed against oocytes
can be identified (112). Moreover. thymosin fl. can
stimulate Ihe release of LRH (144). (Thc same pep-
tide affects lymphocyte differentiation, but other
thyrn(ll;in with higher potencies for s uch ac-
tivity do !lOt stimulate LRH
Thymus-gonad interaetions may be exerted at
severalleveis. and the possibility that thymus glands
secrete hormones that seioxtively regulate hypotha·
lamic. adenohypophysial. or gonadal functions has
not been ruled out. Indirect effcets are suggested by
observations that thymus glands takc up estrogen
conjugates and release Free estradiol (159), while
neonatal thymectomy alters the secretions of growth
hormone and other regulators that modify responses
to gonadotropins. The estrogen receptor< of fetal
thymus glands are believed to play roles in thymus
differemiation. while those of adults are known to af.
fcct immune functions (174).
Very young male rats and mice secrete androgens
that "condition" the hypothalamus For it, Future
roles in regulalion of the reproductive Nec-
natal castration "feminizes" the hypothalamus. but
steroid hormone injeetions during the fin! week after

birth do not block reproductive systcm development.
I n animals with intact gonads, neonatal thymectomy
lowers plasma FSH and Llllcvcls ( 144), but sper-
matogenesis is established after puberty (137,1 38).
The growth of thymus glands after the
"critical periods" for establi.o;hmen t of e<=llular im-
munity and the persistence of androgen receptors
throughout adulthood suggest that interactions with
the reproductive syStem extend faT beyond the peri-
natal period. Somc indications for regulatory roles
that may involve interactions with the adrenal cortex
and pineal gland are cited later.
Hooded male rats enter a rapid phase of accessory
",productive organ gTOwth when thcy arc approxi-
mately 6i1 weeks old. If they are subj«ted 10 skarn
thym«tomy at that time, maturation is transiently
arrested (102). T he response is pmoobly physiolog-
ically appropriate, since the surgcry involves sub-
stantialtrauma, and metabolic reserves should be di-
verted to the processes of recovery.
The rne<:hanisms ntay be linked with the release
of glucocort icoids. si ne<= animals that arc also unilat-
erally have prostate glands. semi-
nal vesicles. and other structures similar in sizc to
those of unoperated controls. Moreover. inje<:tions of
moderate amounts of corti$Ol\e delay the maturation
in both operated and unoperated rats (101). In con-
trast, rats Ihymecmmized at 610 weeks continue their
reproductive system maturation. When they receive
the same cortisone d(l:!.ages, wound healing is de-
layed. However. altered "'ponses to the glucocorti-
coids, rather than changes in plasma levels, are sug-
gested by other observatioM. Although all operated
rats tested a few times after surgery had plasma cor-
ticosterone levels greater than those of controls, the
differern:es between thyme<:tamized and sham thy_
mectomized rats were not statistically significant
(177).
The d=ribe<i effects of both Ihyme<:tomy and
sham operation are =n only in animab prepared to
entcr a rapid phase of reproductive organ growth.
They are not seen in the SlIme Slrain if the surgery
is performed at 4i1 to 6 weeks of age, or if it is de-
layed until after the 7th week. tn Wistar rats that
undcrgo the maturation somewhat later. the effects
of the procedures can bedemonstrated at 7-8 wuks.
The thymus may exen different kinds of inAuences
on aging animals. siru:e prostate glands (but nOI
seminal vesicles) can be very much enlarged in
hooded ralS several months after thymectomy at age
(104). Zinc rates and some re·
sponses to gonadotropin inje<:lions are also modified
in adults (164).
&ason-<lependent inHuences of thyme<:tomy have
been observed in younger male rats raised in labo-
PINEAL AND THYMUS GLANOS
ratories that are temperature-eontrolled but exposed
10 natural sunlight. Animals born during the sum·
mer months and autopsied at 7 weeks have greater
body weights and heavier 3<xessory reproductive or-
gaM with higher enzyme activities and citrate con·
tents than ones born during the winter. Thymectomy
further increases the parameters when it is per.
formed on 31-33 day old sum mer animals, but it
does I10t have this effe<:t in the winter (115). The
(XlSSibility that piMal glands exert inAuenccs in the
winter Ihal limit growth and mask or oppose the ef.
feets of thymectomy has been considered. (Since rats
do not undergo the kinds of reproductive system in-
volution described for hamsters and SOme other spe-
cies, such influences of the pineal gland could favor
survival of animals born at times of the year when
food is scarC<!. in part by reducing food rcquire-
ments.) Other indications of pineal-thymus interac-
tions come from observations of adrenale<:tomized
animals maintained in continuous light. In these.
melatonin injections alfe<:ted feeding and urinary ex-
cretion rhythms in thymectomized. but not in sham-
thymectomized rats (68).
Thyme<:tomy performed after day 34 does 1101 ac-
celerate reproductive system maturation. As was dis-
cussed. a diffe rent kind of reaction can be invoked if
the surgery is delayed until around 45 days, after
which refractoriness is again manifested. Age-de-
pendenee has been demom;tra ted for thymeclomy in-
fluences exerted on the ovaries and On the immune
system. Similar phenomena have been observed for
responses to pineal gland hormones. For example.
ML T injections affect rat reproductive systems duro
ing pOStnatal days 20-4(1, but nOt before or after
that time (89). While the underlying me<:hanisms
may be differe nt (162), inhibitory influences on the
rcproductive system arc also age-linked in hamsters.
It is likely that only the right combinations of cir_
culating hormonc level5 and target organ re<:eptivi.
ties can support the responses .
Additional indications of thymus-adreoocortical
interactions have been providcd by different kinds of
studies (25.36,41.44,52).
THYMUS GLAND INFLUENC ES ON OTHER
ENDOCRINE FUNCTIONS
The early literatu", contains numerous observations
consistent with antagonism (38) .
Thyroid hormones promote tadpole metamorphosis
(49), and it has been reported that adding bils of
thymus to the food counteracts the effe<:1S (63.190).
Thyroid gland hyperplasia and reduction in colloid
COntent. along with elevated serum protein-bound io-
dine conient and elcvated metabolic rate. have
 described in thymeclomized guinea pigs (36). More·
over, it has been stated thaI thymus gland extracts
can counteract some signs of hyperlhryoidism (such
as creatinuria). Thym us feeding also opposes T. cr·
fe<:ts in chickens. However, T, increases Ca l. up-
lake and cAMP production by thymocytes (A-5),
and some of the more reCent Sludie, ,uggesl that
thyroid funclion i, depressed in athymic mice. The
condition, under which the measurements are made
probably profoundly alTect thc kindsof data Ihnt can
be COllected. In the Ihymcctomi7.ed rats cited previ-
ously. '''1 uptake was observed to be sign ificantly el·
evated 18 days after the su rgery but 001 at seve ral
other times investigated (105).
The concept thaI the thymus gland plays roles in
the regulation of .f()malic grow/It and dtllf/opmenr of
juveniles grew oul of observations that the gland is
large relative to the body si'.e during the times when
bones are rapidly elongaling and body weight is in·
creasing. Some early anatomical studies of the d-
fects of thymectomy performed during the juvenile
period failed to support the notion (127.128). i\ few
studies purporting to demonstratc that fecding thy·
mus tissue aeecierates growth must be discarded be-
cause of unsalisfactory designs. I n the
days when investigators worked withoul commer·
cially prepared diets and research grants, control an-
imal' were often underfed (as judged by modern
standard,). Therefore. Ihe effects 01 Ihymus supple·
ments may be related solely 10 the nutritional con-
tent of the preparations.
Unfortunately. some publications Ihal appeared
in the 1930s caused so much oonfusion Ihat research
in Ihis area was _ir!Ually arrested for a lime. Exper-
iments were deseribed in which rats were thymec-
tomized, permitted to atlain adulthOXld. and Ihen
bred. The procedure was repeated several timCll. and
it was Slated thaI with each s uccessive generation,
the offspring .howed progressive reduclions in birth
weights, vigor. and rates of growth and maturation.
In contrast. when thymus gland extracts were given
to successive generations of intact animals. there
were progressive changes opposile in direClion .
(Eighth·generation "Mnales were .<aid to average
6.5 gram. in body weight. 10 possess teeth and
opened ears. to open their eyes at 1.5 days, grow hair
by day 2. and have descended testes by day 2 or 3.
In contraSI. newborn controls weighed 4.6 gram s.
Their ears opened on days 2.5-3.5 and their eyes on
days 14_17. Teeth began to crupI at days 8-10, hair
growth be<:ame visible at J2- J6 days. and the lesles
descended on days 35-40 [166].) It was addilionally
staled Ihat pineal gland extracts invoked dwarfing.
NOI surprisingly, numerous attempts to reproduce
the findings were unsuccessfu l (122) .
More reCent investigations in othcr laboratorics
revealed that the Ihymus affects the maturation and
functions of adel1Ol1ypophysial somatolropes (14).
Mice born without Ihymus glands grow slowly. and
they have IOVI circulating growth hormone COnCen·
trations ( 112). The bone defects in nc<>natally thy-
mcctomi'.ed have been linked wi th defective so-
malotrope functions (13). It has been suggested thaI
when exogenous Iymphocyles ameliorale Ihe condi-
tions. they do so by acting On the endocrine a. wen
as the immune s)·stems ( 136). Growth hormone, in
turn. is said to be "thymolropie" (191) . si nce it pro-
motes growth of the gland.
Suggestions that thc thymus affccts calCium "Ii>-
lobo/ism come from studies performed in many spe·
cics. Salamander larvae are said to develop hypocal·
e<:mic tetany if they are fed bits of thymus tissue
before, but not after. they have acquired functioning
parathyroid gland, (189). Weak. fragile skektons
have been described for tadpoles. puppies. mice. and
rabbits .ubjected 10 thyme<:tomy at early ages (38 ).
but not all early studies in mammals can be ac-
cepted. It has been pointed OUI that puppies were
often raised in cagCl that did not permit adequale
exercise.
Thymectomy performed during Ihe juvenile pe-
riod slows Ihe rate of removal of injectcd calcium
gJuconale in rats (50). a nd it increases the suscepti-
bility 10 development of cardiovascular nccr05is in
rats with secondary hyperparathyroidism resulting
from renal inju ry (1 03). Patients with myasthenia
gravis and en larged thymus glands have calcium and
phosphate metabolism defects, and thymic extraCIS
can affcct the hlOXld cone<:ntrations of tbose minerals
(172). Thymus glands arc reported 10 contain calci·
tonin.like (57) and other hypocalcemic peptides
(116). Interrelationsh ips with calciferols were cited
in Part IV.
Thymus glands have additionally been linked with
the regulation of sodium. polassium, chloride, and
water balane<: (76). Observations that they synthe-
heparin·like mucopolysaccharides (32) have
been linked with immune functions. However. il has
been found that heparin injections affecl water and
ele<:lrolyte in rats and
that the effects are exaggerated by thymeclomy
(Chap. 10). Mast e<:lIs of many species contain hep-
arin and histamine. and responses to stress are re-
ported to include the conversion of cenain of the
lymphocytes 10 such cells (40.41). Thymcctomy se-
verely depletes plasma heparin levels (53), it affccts
lipoprotein lipase activity (51). and it enhances the
tolerances of rats to eXOgenou s histamine (169 ).
Several hypotheses can be advanced \0 explain the
involvement of the thymus gland in so many differ·
enl physiological processes. first. the roles in e<:llula r
immunilY require that Ihe thymocytes make proper
distinction. between " se lr' and ··l1On·self:· In addi·
tion to engaging in the destruction of what is "for-

eign." the cells aClively maintain self-tolerance
(173). The pr<)CeSSCS may involve interactions with
all OIher cell types within the organism. Second. it is
now rerognizcd that cell differentiation is closely
linked with the selective appearance and disappear-
ance of surface: antigens. The thymus gland develops
before the functi()ns of SQme endocrine structures are
established, and it has been directly implicated in
the regulation of the ovarian. adrenocortical. and pi-
tuitary gland differentiation. Third. it is becoming
increasingly apparent that hormone acts on
multiple targets. It is difficult. for example. to find a
cdl type that is 001 affected by T , . gluC<JOOrticoids.
calciferol!. or estrogens. There are indications that
the thymus releases many substances \0 the blood·
stream. and thaI each Can perform more than One
function. Fourth, target organs engage in negative Or
p<:>Sitive feedback control of the secretion of Ihe hor-
mones to ... hich they respond , The thymus gland pos-
se,ses receplOrs for. among olher things. androgens.
estrogens. progestogen!. and glUCOCOTliroids. and it
is affected by (among olhers) growth hormone. pro-
lactin. parathyroid hormone. and T ,. Fifth. it is
likely that the thymus gland exerts fine COIItrois over
endocrine funClions, but does OOt perform a unique
and obvious funclion comparable to TSH stimula-
tion of thyroid glands. Or LH regulation of gonadal
steroid production . Moreover. the infiuences 3re af-
fected by factors that include age. sex. season. nu-
tritional Slatus. and stress. Reproducible effect$. of
can be demonstrated only under care-
fully rontrollcd experimental conditions. Investiga_
tors interested in defining function$. have there-
forc been motivated to examine many different
potentia1 target organs. studies of otner
hormones ...ould probably reveal effects of the
regulators on ceUs previou!ly!101 demonstrated to be
responsive.
REFERENCES
1. Abromoff. P.. and LaVia. M, F..•ds , Biology of
ImmUM McGra ... _Hill. New York.
t 970.
2. Aiuti. F., Wig>et l, H., cd.,
Ho<lIIONs and T L}·mpJ",..,.I ... Acad.mic Pr ....
N.,. York. t980.
3. Almeida. O. F. X,. Lincotn. G, A. Photope-
riodic R.gulation of Reproductiv. Activity in thc
Ram : Evid.nce for 1he Invol v. ment of Circadian
Rhylhms in Mel.tonin and Prol.ctin Secretion.
Bio/. 17.- t062_75. t982.
4. Ala.:huk. M. D.. N. Fromitrs of Phyli-
ofogy. MIT Press. Cambridg" Ma .... t915 ,
5. Adrendt. J. Assay of Melatonin and Oth.r 5-
PINEAL AND THYMU$GLAN D$
M.thoxy.lndol." Cu".nl Statu, and Usefuln ...
in Physiotogical aod Clinicat In.cl tigatiOIl$. pp.
247-60 of Oksch. and PhC1, .d$.. ,.rerence t25.
6. Kappers. J. A Su .. ey of Ad.a", •• in Pi·
n.al Rese.rch. Chap. t. pp. 2-n of Reitct, ed .•
ref.renee 148.
7. Arifns Kappers. J. Evolution of Pi""al Cooeepts.
pp. 3-23 of Obche and pevet. eds .• r.rerence I 25.
8, Atifns Kappers. J, Short History of Pin.al Dis-
covery and Research. Pro!. Brain 51.. 3-22.
t 979.
9. Armstrong. F. B.. and Benneu. T. P.
Try. Oxford University Pre ... Ne .. Vork. 1979.
to. Aschoff. J. Tw.nty V.ars On. Th. Annual Col·
$tOn wture, pp. 277-88 of F<>Ilen and Folkll.
.d •.. ref.rence 56.
lOA. Bagnar•• J. T, Dev.lopm.ntal A.pects of Ven._
brate Chromatophores. Amer. Zool, 13: 465-78,
t 9g3.
11. Balemans. M. G. M. tndote Metabolism in 'he Pi_
n.. 1Gland of th. Rat : Some Regulatory Aspecl •.
Pro,. BTain 51.- 22 t _8. t 979,
12. Ben",n. B,. and Ebelo. I. Other Pineal P.ptides
and R.tated Substance_ Physiological Implica-
Ii"". for Reproduc'ive Biotogy. Chap. 7. pp. t65-
87 of R.iter .• d,. ref.r.nce 150.
13. Berek, L. , Bhoo. Z.• I. K" Anderli k. P.•
and Asz6di. K. O..eal Changes in Mice Follo ... ing
Neona,at Thymectomy. U.- 72t_1.
t968
13A. Be;har«:. J. C. and turone. p, M. Circadian
Clock in X' """UJ Eye Controlling Retinal Sero-
tonin N_Acetyhron'f.' ..... Natu,", ]OJ: tll_15.
1983
14. Bianchi. E .• Pi.rpooli. W .• and Sorkin. E,
logical Chang .. in th. Mousc Ant.rior Pituitary
oft.r Neonatal Thymectomy: A Light and Elec-
tron Microscopical StUdy. J. End«rino/, 51: 1_6.
1971-
IS. Big.lo .... L. B. Som. Effects of Aqueou. Pineal
btroct Administration on Sehizophr.nia Symp-
t"",s, Chap. 9. pp. 225-62 of AI1schule, .d.. ref·
erence 4 .
t6. Binkk y. S, A, Pineal Biochemimy: Comparative
Aspects and Circadian Rhythm •. Chap. 6. pp.
155-72 of Reiter. ed .• rerercnce 149.
t7. Binkl.y. S .• Klulh. E,. and M.nak.r. M, Pineal
function in Sparrows; Circadian Rhythm$ And
Body Temperature . Sd." u IN: 3t 1-14. 197t,
tg. Bittman. E. L.. Gotdman, B. D,. and Zucker. I.
Testicular Responses to Mel atonin arc Altered by
L.,ions of the Suprlchia.mltic Nud.i in Golden
Hamsters. BioJ. R. prod. lJ: 641-S6, t979,
t9. Blask. D. E. Pot.ntial Sit •• of Action of Pineal
Hormones Wi\hin the Ne"roe"docr''''' Reproduc-
live Axi •. Chap. 8. pp. 189-216 of R.iter .• d.. ref·
erence t SO.
20. Blask. D. E .. Vaughan. M, K.. and Reitc<. R. J.
Pi""al Peptides and R.production. pp. 2tO-23 of
R.I.in .• d .. referellCe tS6.
 21. Bloom. W .• and fawe<:tl. D. W. A Tn:lbook of
Hi.tolot y. 10th ed. SaunderS, Philadelphia. 1975.
22. Boyd. E. of the Thymu. Gland ,n
HeaUh .00 Di$<:u" Am" . J, ()is. CMldffn 45:
1162_1214.1932
23. Boyd. E, w.ight or the Thymu. and it, Compo.
nent Part, and Number of l1 a$$<\11 Corpuscle, in
and Di .. a, •. Am". 1. DiJ, CM/dre. 51.-
313-35,1936.
24. Duii', R, M.. V.li •. D, N,. and S"... b. D, F. Ex·
trahypoth,lamic V'sopre»in and O.ytocin In·
nervalion or fetal and Aduh Rat Brain. Pro,.
Brdin 5J: 159_67. 1980.
25. Bumner. B.. and Szymi k. N. Elfect of T hymec-
tomy on Steroid Secretion in Adrenal V'nou.
Blood in Male Emio",·rwi. 8: 31_7.
1974.
26. C.meron. A. T. The Thymu . and Pincal Glan<h.
Chap. 6. pp. 263-73 of Roam AdvolI«s in E,..
douirwiogy. 3rd ed , R. BI.kiston'. Sons. Pbil.·
ddphia 1936.
n . Cardinali. D, P. Hormone Elfects on the Pineal
Gland. Chap. 10. pp. 243-72 of Reiter .• d .. rd·
erence 149.
28. C.rdinali. D. P.. Riua. M. N .. Pereyr •. E.. and
Solv.yra. C. G. Role or Prosl.,I.ndins in Rat Pi-
ne.1 Neuroefl'ector Junction. Cbang.. in Mela·
lonin and Norepinephrine Re.lea .. in Vitro. Ell-
do.cr;IIO!, /11: 530--4. 1982.
29. Cardinali. D. P.. and Wortman. R. J. Hydroxyin.
dol..o.Methyl T .. n.rer .... in Ral Pineal. Rel-
ina and H.rd.rion Glond . Eftd<>cri""/ot;)' 91.'
247- 52.1972.
30, Camr. S. J .• Laud. C. A .• Smilh. I.. Leone. R,
M .. Silman. R. E.. Hopper. R. J,. Larson·Carter.
D. L.. Finnie. M. D. A .• and Mullen. p, E. S·
in Rat Pine,1 Gland. and
Other Tissu ... Prog. BrMn Ruh. 51: 267_9. 1919.
31. Chan. A..• nd Ebadi. M . Evidence ror I;:.i"eno<
of a SerOlOnin N·Acelyhr.nsf.ra .. Inacliv'ling
Substance in Rat Pineal Gland, £ndorr.
8: 20S_27. 1981.
32. Clark. S . L. Jr. 1"=l>Oralioo of Sulfate by lhe
M<.>u .. Th)'mus; It, Relation to Secretion by
Mcdullary Epith.lial C.II. and to Thymic Lym ·
phopoiesis. J. Exp. MM, /]8: 921_49. 1968.
33 . Clarke. J. R. Pby,iological Problem. of Sea,.,na]
Breedi", in EUlberian An;mals. Oxford Rtv. Rt-
prod. HioJ, 1: 244_312.1980
)4, Collin. J.·P. New Dal" and Vi.ta. on lbe Mech ·
ani.m, or Secretion of Proteins ond Indol .. in ltlc
Pino.loeyle and ilS Phylog."lic
Precursors; Th. Pin.alin H)'pothesi, "nd Prelim·
ina ry Commen" on Membran. T .. ffic . pp. 187-
210 of Obche and Pev.t. ed, .. ref.r.rlCe 125.
lS. Collin. J.·P .• and Ok,ehe. i\. SlrUClural and
Functional Relllion, hips in Ihe Nonmammalian
Pineal GI,nd, Chap. 2. pp. 27-67 or Rciter, ed .•
rer.rence 149.
36. Com ... J, Hormonal !nt.... tiOll$ or the Thymu, .
Chap. 4. pp. 59- 96 of Luckey. ed .• rer.renco 98,
) 7. Crem<r.Banel •. G. Th. Elfect or Pteridinc< on
Mull iple forms of Hydro.yindole-O- Melhyl·
I.. n.fera.e (lliOMn in lhe Retina ,nd the Pi_
ne.1 G land. Prog, 5]: 231-9.1979.
38, Crotli. A. Diseases oj 71tyro<d. Paralhyroid
ami Lea & Febiger. Philadelphia . 1938.
39. Csabo. G.. Dunay. c.. Fischer . J .. and Bodoky.
M. Hormonal Relation.hips or Cytogon.. i. in
Lymphalk Organ" 11L Elfecl of lhe Pineal Body·
Thyroid.Thymus System on M.st Cell Prod"c·
lion. AMI. 71: 565-80. 1%8,
40. C .. bo. G,. and Hodin ••. L. The Thymus a. The
Source or M,$l Cell. in the Blood . Acla BioJ.
Sd. Hung, ]j IJJ: 333-4. 1970.
41. C. aw. G.. Him. L. HorvOlh. C .• Ae<. T .. and
Mold. K. Thymus and Sue». 1. End«riMi. 13:
423-31. 1962.
42. Dardenne. M .. and Bach. J._f, Th)'mic Hor·
mones. Chap. 6. pp. 113-31 or Kendall. cd .. I'd·
erene<: 83.
43. Dd.ndi. V.• and Metcalr. D.• eds. The Thrm ••.
Wi'tar lrulitule P...... Philaddphia. 1964.
44. Dcschaux. P,. Flo, ... J. 1... and Font.,nc<. R. In·
Huenco de I. Thymeclomi< ,ur Ie. GI.ndes Sur·
renale. , 1m. Phy. ioJ. 81{)(htm, 8]: 115_21.
1974.
45. Dc VI.mini. V. D.. and OIc .... J. The Pi .... 1and
Rcpr<Xiuetion in Fi. h. Amphibians and Reptile$.
Chap. I. pp, 1-29 of R.iler. ed,. rerer.""e ISO.
46, !lbel •. I. A Chemical Study of Some Biologically
Active Pine. l Fraction,. Prog. Brain Rseh. j ]
309_21. 1979.
47. Eh"'nkranz. J. R. L.• Tomo'kin. L.. Comite. F.•
Johnsoobough. R. E.• Bybee. D. E.• D,
L. and CUller, G. 8.. Jr. D.ily RhY lhm of Plasma
Melalonin in Normal and Precoci<.>u. Puberty. J.
CIi•. E..d""rjnol. M""b. 55: 307-10. 1982.
48. ElIi •• G. 8.. Losee. S. H.. and Tu", •. F. W. Pi·
nealeclomy AboIi.he. the Shorl.f'botop<riod.ln.
duced Attenuatcd CU"oti(ln Rc<pon><: in Male
Golden lIamll .... , Chap. 1 t. pp. 87-94 or Mat·
the ... , and Seamark. ed". reference 106.
49. Etkin. W .. and Gilbert.l. I.•• d•. Mf/aln()l'phwis.
Appleton--Century·CraflO. N.w York. 1968,
50. Et"". G. The Elfe.t or Thymeclomy on P"fOlhy.
roideclomi,.. d Animals Trealed with Parathyroid
Hormone or Calcium Gluconate, M.S. The.i •.
Long Island Unive ... ity. New York. 1963.
F.chet. J .• Szabo. J. K .• and C .. h. G. Elfect or
Thymectomy on LipOpn"e;n lipase Activity in
lhe S.rum and Ihe Hearts of R.I>.
]1).708: 1- 3. 1964.
"C>.
52. Fa.hel. J.• V.llent. K,. Palkovil •• M .• and Z.
InAu.nce of tho Thymu, on Adrenocorlieal Il)'.
I>Craclivily in Hyperthyroidi.m. Acla Mtd. A«ld.
Sci. Hung. M : 281_7. 1964.
53. fachel. J.. V.llent. K" and Slark. E. The Elfecl
or Thymectomy. Adren.lectomy .nd Corticoid
Tr.almenl on lhe Serum Heparin !.ev.1 in the
Rat. ACla Phy#oJ. Acad. Sci. flung, T ]6:
1965.
54. Fe''''lrom. J. D.. Fi,h.r. L. 1\.. Cus.ack. B. M,.
and Gilli .. M. A, Radi(>immunoiogic Detection

and Measu<em.nt of Nonapeptide, in tho Pineal
Gland. IiMoe,jncl. 106:243-51. 1980.
Fiske. V. M. Discovory of the Relation Iktwoen
Lithl and Pintal Func.ion . Cha p. 5, pp. 5_11 of
Alto.hule . • d"> reference 4,
56. Follett, D. K , and Foll.t. D. E., eds. Biological
C/rxkJ in Sea,onal Cydu Wiley.
NewYoTk,1981,
57 , Galente. L. Thymic and Parathryoid O,igin of
Calcitonin in Man. LA.w1 2.- 537_8. 1%8.
58. Garaci. C. R., fa.aUi. C., Del Gorbo, Y.,
E.. and Joff•. B. M. I, Thymesin AClion Me-
di.,ed by Prostaglandin Release? ]03:
1163-4.1983.
58/\. Garriok. N. A"> Tamarkin. L., Taylor. P. L.• Mar-
key, S. P .• and Murphy. D. L. Ligh t and Propran-
olol Suppre.. the Nocturnal Elevotion of Seroto-
nin in the Cerebrospinal Fluid of Rhosu£
Monkey•. ]]1: 474-6. 1983.
58B . Glo ... J . D"> and Lynoh. G, R, Melatonin , Iden·
tiflcltion of Sites of Antigonadal Action in Mouse
Brain. Sci.n« 114: 821-23, 1983.
59. Goldman. B.. Hall. Y"> Hollister. c.. Reppert. $ ">
Ro)'ohOUdhury. P .. Yellon, S .. and T ama.ki•. L.
Diur ...1 Changes in Pineal Melatonin Content in
Four Rodent Speoies; Rdationship to Pllotope.i-
odi,m. Biol. U : 778-83. 1981,
60. Gorbman. i\. , a nd 8un. H, A. A 0/
O>IIIpd"'livt Endrx,hw!of)'. W iley. 1962,
01. G<><brnan. A ,. Di<, hvtr, W. W., Vigna. S, R..
Clark. N. B" and Ralph. C. L. Com{l<l'atj". En·
drx,'llOiagy, Wiley, New Y<>rk, 1983.
62. GroUman, A, Clinl",1 EMrx,11I/lJagJ' aM Its
Physiologi",1 BaJis. Lippincott. Philadelphia.
1964.
62A. Gtoos. G., Mason. R.. and Meijer. J. Electrical
and Pha.mac:ologioal Properties of the Sup ra·
chiumatic Nuclei. hd. Prrx. fl: 2190_9S. 1983,
63. GuderMlSoh. F, The Prese nt Statn of the Thy.
mu, Problem, A Re.iew of Non-Surgicll Expet-
imonlation in This Field , Mtd. Rtc. 146: 101-16.
1937.
6 4. Guerillot. c.. Lefft.y. P .. Primr. A .• and D.
Lage, C. ContTibut ion to the Study of the Pineal
Stal k No,"e Fibt., in tbe Il.tt. Prog. B,ain lach.
52:97- 102.1979.
65. GUldner. F.·H. Plasticity in the Retino-llypothi-
lamio Pathway. pp. 253-6 of Mal1heW$ and $ea.
mark. ed, .. refer.nce 11>6.
66. Hadley. M. E., and H. uby, V. J . Neu.ohypophy.
.ial Peptidos and the Regulation of MelaflOphotc
S timulating Hormone (MSH) Seo .etion. Alii".
Zao/.l7: 809-21. 1977.
67. Hall. V. D.. and Goldman, B. D. Hi berna,ion in
the Female T urkish Ham"er ( Mesocticetu,
brandti): An Inv"'igation of the Rolo of the Ova.
•;es and of the PhotOperiod. BiO/. 27:
81 1_15.1982.
68. Halpe.n, C. C., and MaTlin. C. R. Effect of Me·
latonin and Thymectomy on Food and Fluid In·
AND THYMUS GLANDS
take and Renal E.cretion Rhythm$ of Ad.enal-
ectomi,ed Rat$. Ftd. P,rx, )1: 327. 1972.
69. Herberman, R, B., and Onaldo, J. R. Natural
Killor Cells: Their Role in Defenses Ag.in.t Dis-
e.... 1/4: 24-30, 1981.
70. He.be.t . J. The Pine.1 Gland Ind PhotOperiodic
Control of the Ferret's Reproducti .. Cycle. pp.
261_14 of Follett and Folktt. cds .. rere",,,,,e 56.
71. Hodde, K- C. The Vucul l .ization of the Ra, Pi·
neal Otgan. Prog. B'aln Rsch. 52: 39-44, 1979.
72. Hoffman. J. C. The Influence of Photoperiod, on
Reproductive FU""'io.. in Female Mammals .
Chap. 3, pp. S7-17 of Greep. R. 0 .• ed .. /land-
/KJQk of Phy. loIof)', 1«. 7, V(ll .. 2. Ame.ioan
Phy,iological Society. Washington. D.C.. 1973.
n. Hoffman. K. Pinealln.ol.. ment in the Photope-
.iodic Control of Reproduction and Other Func-
t;ons in the Djunga.ian Ha m$to. Phodopus Sun·
g<>rus. Chap. 4. pp. 45-81 of Reiter. ed .. refe",nce
'w.
74. Hogben. L.. and Siome. D. The Pigmentary Ef-
System. VI. The Dual Cha .. cter of End<>-
ctin. Coordination in Amphibian ColouT Change.
PrIX. ROy. SiX. Lo/rJon B IQ!J: 10-53. 1931.
75. Iguchi. 1-1 •• Kato. K.-l. and Ibaya.shi. H. Age·De-
pendent Reduction in Serum Molatonin in
H,"lthy H umon Sub}«l$. J. IiMrx, '"of.
Metah. 55: 27_9. 1982.
76 , J.anu,. S, D .. and Mart in. C. R. An E,"a·Adre·
n.1 R<:>pon>< 1U SutJiulIl L.... Revo.led by
Thymectomy . Gtn <l Com{l<lr. EMlXTinoi. 10:
147_S4.1968.
77. Janos.sy. G .. Pi..o\o, G., .nd Thoma" J, A. Dif·
f.rentiat;on of Human Thymocyte •. pp. 15-29 of
"iuti and Wig.-II, eds., reference 2,
18. Jotdan. R. K.. Ind Robinson. J . H. T Lymphocyte
DitTeren'iation. Chap. 8, pp. 151_77 of Kendall.
ed .. tefetence 83.
78A. Kafl:a. M. S .. A.. Naber. D.•
Moore. R, Y .. and Benedito, M. A. Circ.o.di.n
Rhythms in Rat Btain Neurotro nsmil1er Recep-
tors. FtJ Pro<. 41: 2796_80 1, 1983.
79. Katase. , M. Ultramuctural Study of the Pineal·
AdenohypOphysial Relationships in RalS. Prog.
B,ain Rsch .. 52: 19S_9. 1979,
80. Kasal. C. A .. Menaker, M" and J, R.
Cireadi"n Clock in Culture: N-Acetyltransfe ....
Activity of Chiek Pintal G land, o.oilllt.. in
Vitto. 203: 6S6-8. 1979.
80A. Keller. S. E., Wei .. , 1. M.. $o hl iefe.,S, J. Mille',
N, E.. Ind Stein. M. Str.... lnduced Supp.... ion
of Immuni ty in Adrenalectomized Rats.
221: 130 1--4. 1983.
81. Ke ndall, M. D. Ag. and Seasonal Ch.ng.. in the
Thymu" Chap. 2. pp, 21-35 of Ke ndall, ed .. ref·
eT.nc.83.
82. Kendall . M, D. The CellS of the ThymU$. Chap .
4. pp. 63_83 of Kendall. ed .. refetence 83.
83. Kendall. M. D., ed. Th. T hymu. GlaM. Ao.·
d.mic Pt .... N.w Y<>rk. 1981.
83A. Kessler. J. A .• Adl ... J. E .• arid Blad. 1. B. Sub-
• Ian« P and Somatostatin Regutate Sympathetic
Noradrener,ie funelion . 211:
1983.
84. Ki nd. F. A.. Oriol. A.• Pi. A. F., arid Maqu<:O. M.
Preyention of Steroid· l nduced Sterilily in Ne,..
nalal R"" wilh Thymic cen SU'p<n.i<)n. PrIX.
SIX. Exp. Bioi. Md. 120: 252_5. 1965.
85. Kilay. J. 1. Possible f unction. of the Pineol
Olarld. Chap. 32. pp. 641_64 of Martini. l.. and
Ganong. W. F.. ed •., Aca·
demic Press. New York. 1961.
86. Kitay. J. I.. and AltSChule, M . D. PiM(J1
y
Gland, Ha,vard Uni e,..ily Press, Clmbrid,e.
Mass .. 1954.
81. Klein. D. C. Cir<adian Rhythm, in Ihe Pineal
Glarld . pp. 203-23 of Krt iger. D. T ., ed,. end,..
aiM Rhyrhms. Raven Prt". Nev.' Yor k. 1919.
88. Klein. D. C. Auerbach . D. A.• Namboordiri. M,
A. A.. and Whele,. G. H. T. Indole Metaboli,m
in th. Mamm.lian Pineal Gla nd. Chap. 8. pp.
199-221 of Reite,. ed,. referen« 148.
89, Lana. u.. Aubert. M. L.. Conne. B, S ,. Bradtke.
J . C .. and P. C Infl uence of bog.,.
lI0II' Melatonin on Melalonin Secretion arid Neu-
roendocrine Reproouctiye Axi. of Intact Male
Rat' Durina Se.ual Mal uration. EIldIX,ilWl. J I 1:
1933.
90. Langman. J . M. dicol Emb'J'ology, 2d ed. Wil_
liam. &0 Wil kin., Baltimore. 1969,
91. Lapin. V. Pi neal lnfiuen« 00 T umor. Prog.
52: SH_H. 1979.
91 A. Lludenslager. M. L.. Ryan. S. M,. Drugan. R. C ,
Hy",n. R. L.. and Maier. S. F. Copina Ind Im-
munosuppression, I ""$Capable but Not Escapable
Shock Suppresses Lym phocyle Proliferalion. Srl-
."u 121: 568-iO. 1983.
92. Leadem. C. A.. Ind Blosk. D. E. Pine.l Gland In·
hibition of ProlaCtin Ccll Achyily i. Independenl
of Gonadal Rellression. N.wrtXlldlX';nol. 35:
133_8. 1982.
93. Le Douarin. N. M.. and JOlertau. F, J . The On·
togeny of the Thymus. Chap. 2. pp, 21_62 of Ken-
dall. ed .. rtfertnce 83.
94. Lerner, A, B.. ClSe, J . D.• and Takaha.hi. Y. Iso.
lation of Molalonin and 5·Methoxyindol.,.)·
Acetic Acid from S.wine Pineal Gland •. J. Bioi.
CM",. 1J5: 1992-7. 1960.
95. Lewy. A. J. Biochemistry and Regulalion of
Mammalian Melatonin ProduCtion. pp. 77-128 of
Rel kin, ed .. rtfertnce 156.
96. Lewy, A. J .• and Newsome. D. A. Differen t Type.
of Melatonin Circadian S.Crtlory Rhythms in
Some Blind S ubjeCts. J. Clin. Elldo("irool. M.MI>.
56: 1103-7. 1983.
91 . Lincoln. G . A" and Shon, R. V. S"",nal Br.ed.
ing: Nature', Contraceptive. R«. P' o:. HOTm,
36: 1--41. 1980.
98. Luckey. T. D.. ed. H"",wl>t• . Uniye"ity
Pall Pre ... Baltimore. 19 7),
99, Lynch. H. J. A=y Methodology. pp. 129-50 of
Rellin, ed .• ,ereren« 156.
100. Manning. ,\t, J. A Comparalive View oflho Thy-
mu. in Vertebrate •. Chap. I. pp. i-20of Kendall .
ed .. rtference 83.
101. Marlin. C R. Adrcno«>rtic.1 Influencu on
Growth of Reproductive S"uctu, •• of Thyme<).
lomi,ed and Sham Thym« tomizcd R.t •. Ende-
c,in()I.75: 161-12. 1964.
102. Martin. C R. InHuence of Thymectomy on
Growth of !kc<>ndary Reproduetiyt St",c\ure, in
Rats. A",." J. Phy,lol. 206: 193-1. 1964.
103. Martin. CR .. and Leh r. D. I"\errol.tion,hip of
the Thymu, Gland. Gonad, Ind Adrena l COrle.
in Experimental Cardio,-ascular Necrosis. Ab-
stracts of the Twentieth International Phy,ioiot-
ieal Con,rtS<. Brussel •. 1956.
104. Martin, C R__ Rosurr. B,. and Mille,. L. K. Eff«t
of A,e on Ihe Ventral Prostale Gland Re.pon,e,
to T hymec\omy. PhFiologiSi /0: 243. 196 7.
lOS. Martin. CR .. Weller. C. and Cosla. P. Thyroid
1·131 Up\ake and Organ Weights after T hyme.,.
lomy and Sham Operation, Physlo/O:i" 8: 228.
1965.
106. Matthews. C, D.• and Seamark. R. f .. cd •. PiNal
Fwnt:lion, Else.ier North· Holland. New York.
1981.
107. Meiniel. A. New A.pectS of the Phylogenetic
EV(>IU1ion of Se"">'Y Cell Line, in the Vertebra te
Pineal Complex , pp. 24 - 47 of Oksehe and pevet .
cd, .• rcferen« 125.
108, Meaker. M,. Hudson. D, J,. and Takahashi. J. S.
Neural and End<)Crine CompO""ntS of Circadi.n
C lock< in Bird •. pp. I 71_8) of Follett .M Folk".
ed •.. refcfence 83.
109. Meruel", D.. Paolini . A,. Flieger. N .. orre,. M .•
and J. Ly 11.2: A Cen SUffaee A ntigen
Ihat Ma)' Identify Lymphocyte, Susceptible to
Trall$fo'mation by Oncogenic Agen ... F,d. Pro<.
40: 2111-20. 1981.
11 0. Mess. B,. T renlini. G. P.. R6zs! •• C. and de Gae·
lani. C F. Some Endocrine Elf..:" of the Pineal
Gland wilh Special Refertnce to Reproduction,
Prof. Broin RJCh. 52: 341-66, 1979.
Ill. Metcalf. D. TM Thymus. Sp';n$er.verla,. New
York. 1966.
112. Michael. S. D.• Taguchi. 0 .. and Nishi,uka. Y.
Effect of Neona.al Thymectomy On O.aria n D.,.
vel""ment and Pla.ma LH. FSH . GH. and PRL
in the Mouse. Blo/, R . prod. 11: 1980.
113. Miline. R. Discu"ions, pp. 29-30. 312-3 of Wol·
"enholme. G. E. W .• a nd Knight. J., ed •. Th. Pi_
lItol Gland, Chur<hill Liying"o"". London. 1971.
11 4. Millar. R, P., Denniss, P .• Tobler, C .• and Sym.
ington. R. B. Immunological, Bi<)Chemical and
functional Dilference. in Pineal and HYpOlh a.
bmic Lutein;li", Hormone Relea.ing Hormone.
pp. 151-63 of Matthe",. and $eama,\:.. ed •.. ref·
e,ence 106,
115. Miller. L. K. Thymic lttf/u.naJ OIl Ih. Gro\<llh 0/
Acc."OTy R,pnx/uclivt! in Mal.
Hood,d ROlf. Ph.D The,i •. Hunter College.
CUNY. 19iO.
116. Milutani . A. A Thymic Hypocalcemic Compo.

.. nt. Chap. 10, pp. 193-204 of Luckey. ed .. ref-
e",nce 98.
117. MoUer. M .. and nn Veen, T. Flu<)Teoeen<:<: Hi ..
to<hemimyof the Pin..1 Gland. Chap. 3. pp. 69-
93 of Reiter. ed ,. reference 149.
118. Maller. M, Pre.enee of a Pineal Nerve (Nervu.
pin..li.) in Fetal Mammal •. PMg. Brain Rsch.
52: 1979.
118A, Monk. T. H .. Weit2mann. E. D .. Fookson. 1. E ..
Moline. M. L., Kronaue!. R. E-, and Gander. P.
H. Task Variable. Determine Which Bioloiical
Clo<k Contn)ls Circadian Rhythm. in Human
Performance. Naw" JfH: 543-45. 1983.
119. Moore. R, Y. Organization and function of a
Cennal Nervous System Cir<:adian Oscillator:
Th. Suprachia.matic Ilypothalam ic Nueleu •.
Ftd. Pro<:. 42: 2783-89, 1983.
119A. Moore·Ed., M . C. The Circadian T iming System
in Mammals: Two Pacemakers Pmidc Ovc.
Many Secondary O.dllat,," , hd, Pro<:. n:
2802-()8.1983.
120. MU 'phy, M. T .. Richard •. D. B.. and Lipton, J.
M. AntipYr<:tic Potency of CeOl.ally Admini.·
te",d a- Metanocyte Stimutati"3 Hormone, Sci-
"net )11, 192-3. 1983.
121. Namboordi.i. M, A- A.. Sugden. D, Meffo.d. I.
N,. and Klein. D. C. .. Ele-
vates Serum Melatonin. Abst •. "" 383. Endoc.ine
Society. San Antonio. 1983.
t22. Neb"". W, O. The Rel .. ion of .he Thy"'", . ,od
Pin..1 Gland. to Gen i.al Func.ion. Chap. 21. pp.
1121 -48 of Allen. E., ed., S.x Inu",,,1 S"W'-
ri()JU, William. and Wilkin<. Baltimore. 1939.
123. Norri., D. O. V",.bro,. Endocr;n%ty. Lea ok
Febig••• Philadelphia. 1980.
124. Novales. R. R. Actions of Melano<y.e-Stimulat"
jn, Hormone. Chap. 35. PI' 347_66 of Knobil. E..
and s.wyer. W. H .. e<i ... HamJbool< al Phys;ol·
O/IY, sec. 7. vol. 4. pt. 2. American Physiological
Sociely. Washington. D.c.. 1974.
124A. Novates. R. R. Ceilul" Aspects of Hormonally
Controlled Pigment TratlSIocation, Within Chrl>-
na.tophores of PoikilOlhermic Vertebrate •. A_r.
ZOO/. 13: 559-68. 1981,
n.
125. Ok$<:"e, A.. a nd revet. p .. cd., Pi"",1 Organ,
Plwiobialogy-Bi«htoJVJmel ry- Endocrinology, 10 I·
... ie,. Am,.e rdam, 1981.
126. Oppenheim, 1, J .. Sladte •• 8. M .. Si ..",ni.", R.
P.. Ma,e. M .. and Mathie.on. B. Lympho.ine"
Thei. Role in Lympboc)1ic Responses, Prope.ties
of lnle.leukin I. Fed. !'roc. 41: 257-62.1982,
127. f'lIppenh.ime., A. M. The Effect. of Early Extir_
potion of the T hymus in Albino RaIS. J. Exp.
Med.19: 319-38,1914,
128. Park. E, A.• and MeClu",. R. D. The R.. ults of
Thymus in the Dog. Alii". j, Dis.
Chil<!,.n 18: 317-521.1919.
129, Pawele •. J. M., aod Kor .... A. M, Th. 8i".yn.
thesis of Mammalian M.I,nin. A_r. Sci"'li'l
70: 136-4$, 1982.
PIN£AL AND THYMUS GLA NDS
IJO. Pearce, P.. Kh.lid, B. A. K... nd Funde •. J. W.
Androgen. and .h. Thymus. limJocri'lOi. 109.-
1013_7.1981.
131 . pevet. P. Anatomy of the Pine.1 Gland of Mam ·
mals. pp. 1_75 of Relkin. cd .. ",ferenee I 56.
132. Povel. P. Peptide. in the Pin,al Gland of Verte·
brates. Ult.",tructu.al, Hi.tochemieal. lmrnuno-
ey.""hemical and R.dioimmunological Aspects,
pp. 211-35 of Oksche and pevet. &s .. refe.ence
I 25,
133, Peveto P. Ultrastructure of the Mammal;an Pi.
""al()Cyt • . Chap. 5. pp. 121 - 54 of Reiter. ed .. ref.
erence 149.
04. revet. P.. B"ij" R. M .. Do,tcrom. J.. Vivien.
R()Ch. B.. Holde" F, C .. Guerne. J. M. Reioha".
A" Swaab. D. F.• Ebel •. I. . • nd Nea",u. C. Pep-
.id.. in the Mammalian Pineat Gland. pp. 173-
84 of Mauhews and Seam.. k.• d. .. ",fe",nee 1(16.
135. Pic.p;toli. W., and So.kin. E. Alte ..... ion. of the
Adrenal Corte, ,nd ThY'oid in Mice with Con·
genital Absence of the Thymus. N.", Bioi,
138: 282- 5. 1972.
1J6. Pierpaoli. W" and So.kin, E. Ilormones. Thymu.
and Lympboc)'tic fu"".i""J. Exptri."U" 18:
1385_9.1972.
137. Pl agge . J. C. Elfect of T hymec.omy at Binh on
Spermatogenesis in the Albioo Rat. PrO<. SOC.
expo Biol. MM. 44: H-60. 1940.
138, Plagge. J. C. TIle Thymus Gland in Reta.ion to
Ho ....onc. and Reproduct •• <!'r«CS>e> in the
AlbirlO Rat. j . M&pnol. 68: 591-45.1941.
139. Pr«hd. M, M.. Audhya. T. K , and Sehlesinge •.
D, H. A Seasonal Variation in /lrginine Vasot()Cin
lmmUllOactivity in Rat Pineal Gland •. End«,;·
'101.111: 1474_8, 1983
)40. Pr",,,, •. C. L .and B.own. F. A.. Jr .. ('Ompa,aliw
Animal PhyJiology. 2d ed. Saunders. Philadel.
phia.1961.
141. Quay. W. B. General Bicx:hemi stryofthe Pineal
Gl,nd of Mamm.I •. Chap. 7. PI' 17)_98 of Rei_
•.,.ed .. r<:forenee 149.
141A. Ralph, C. L. E.oIution of Pineat Control of En.
dcx:rine Funetion in Lowe. V....b.. te>. Arner.
Zoo/. 13: 597-605. 1983.
142. Ralph, C. L. The Pineal and Reproduction in
Bird •. Chap. 2. pp. 31_43 of Reiter. ed ... efer<:nce
150.
143. Ra lph. C. L. Finh, B. T .. and Tut .. r. J. S. The
Role of the Pineal Body in Ilc.othcrm The.mo.eg·
ulation. Am.,. Zoo{, 19: 2n - 93. 1979,
144, Reb.r. R. W .. Miyake. A .. Low. T. L. K" and
Goldstein. A, L. ThymO$in Stimulate. Secretion
of Luteinizina Hormone.Releasina Foe.o •. Sci-
."'" 1I4: 6M-71. 1981,
14S. Rebar. R. W.• M,...,ndini. I. C .. IknitS<hkc. K..
and Pc".' J. E. Reduced Gonadotropins in Ath-
mic Mice: P",.ention by Thymic T ra"'pl"n ••• ion.
t·ndocrinol. 107. 2130-2. 1981.
146. Reichlin. S. Neuroendoc.inology. Chap. II. pp.
589-645 of William •. R. H.. ed .. Ttxlbook of
 d<xrinoiogy. 6th 0<1. S.und.... Philadelphia.
1981.
147 . R.iter. R. J. ,h.
EIT.cu of Pinal
Gland and or Melal""in . I'ronl.
7: 287-316.1982.
148. Roiter. R. J .. Tho Pine.land hs H<}I"mones in the
Conlrol of Reproduction in Mammal •. End"",.
•. I: 109-31. 1980.
149. Reiter. R. J. Pi..",1 Gland. ><>i. I. A_r"",,.
altd Bi<xMmiSiry. CRC Pre ... Iloc. Raton. 1981.
150. Reiter, R. J. Pi",al Gland. ><>i. 2. R'produ0-
Ii", EjJws. CRC Pr .... Boca Rat'"'. 1981.
lSI. Reilt" R. J .. Richard"",. B. A.. Johnson. L Y..
F.rguson. B. N .. and Dinh. D. T. Pi""al Mela·
lonin Rh)'lhm: Reduction in Aaing Syrian Ham·
stcrs. 110: 1372-3. 1980,
152. R.iter. R. J .. Vaughan. M. K.. Vaughan. G. M ..
Sorrentino. S .. J r.. and Donofr io. R. J. The Pi"..1
Gland as an Organ of Internal Secreti.",. Chap.
S. PI'. 54_174 of AIt..,hulc, cd., refere"". 4.
153. R.I.in, R. Misccl lanOOlls Effec., of the Pine.l ,
PI'. 241_72 of Rel ' in . od .. reference ) 56.
15 4. Rel kin. R, Pine.I·H<}I"mone I nlcraCII<;mS. PI'. 225-
45 or Rclkin .• d .. reference 156,
155. Rel kin. R, Human Pi".a!. PI'· 273-310 of
Relkin. ed .. r<:f.re"". 156.
156. Rel kin. R. Th, Pin",1 (,"/and. Elsevier Biomedi·
cal. New York. 1983.
157. Renf .. e. M. B.. Li""oln. D. W" Almeida. O. f .
W .. and Short. R. V. Abolition ofa Seasonal Em-
bryonic Diapau .. in • Wallab)' by Pincal Dener_
vation. Nl""ff 293: 138-9, 1981 .
158. Reppert. S. M .. P.rlo .... M . J. Ung.ri.ide., L G ..
Mi,n" in. M .. T.m"" in. 1.. , Orloff, D. G.. Hoff-
man. 11. J .. and KI.in. D, e. Effects of Damage
to th. Su prach i",matic Area of tbe Anl .. ior Hy.
pothalamu, on th. Daily Mclatonin and Cortisol
Rhythms in the Rho,u, Monkey. J. N<urosd I:
1414_25.1981.
IS81\. Roppert, S. M. and W. J, Mate,nal
Coordination of the f.tal Bi<>iogical Clock in
Ute",. Sd. nc< 1}(): 969_71. 1983.
R.ynold,. H" Nathan. p .. Sriva'laY>. l. S" and
He«. E. Y . R.I .... of Estradi<>i f.om Fetal So.
vino $crum by Rat Thymu,. Spleen. Kidney,
lung and lung Macrophage Cultures, t;ItdIX:N-
noI, 110: 2213-15.1982,
160. Rhooin. J. A. G. Hi'tology, Odord University
P..... New Y<}I"k. 1974.
161. Rnllall. M. D. M.thod, for Measuring Pin.al
H<}I""",""'. C hap. II. PI'. 274_302 of Rei l... od .•
,of... nc.149,
162. R<>ilag. M. D., DipinlO, M. N., "nd S1tt«>n, M.
II. Ontog.ny of the Gonadal Response of Golden
Hamster> to ShQrt Photope.iod. Blinding, and
M.latonin . 8iol. R,prod.17: 898-902.1982.
163. Rnll.g. M. D.. Panke. E. S .. Tr. l:ul.ungsi. W.,
Tral:ul,unS.i, C .. and Reiter. R. J, Quantification
of Daily Melatonin Synthesi. in lbe Ilamster Pi_
ncal GI.nd. EndIX:rinoJ. 231_42.198-0.
164. Roooif. B.. and Martin. e. Th. InHu.""e of Thy.
mectom), and Sham Ope rall<;m on P,oslate Gland
Re.pon .., of Hood.d Rats 10 Gon.dotropin •.
'" COntf'l'r. /:.·""""rinoJ. 16: 484-92, 1971.
165. Roth. J. 1-. G.rn, W. A" Roth, E. C .. Ralph. e.
L . and J.cobson. F_ Nonpineal Mdawnin in the
All ig.to, (Alii""",
1/0: 548-50.1980,
166. Rowntre<:. L G .. Ciark. J . H ., Sltinborg. B. S ..
H.nson. A.. Einhorn. N. H., and Shannon. W. A.
further Sludie. On Ihe Thymus and Pin •• 1
Gland .. AM. Inl, M .d. 9: 359- 75. 1935.
167. Rudman. D.. and $cOlt. J. W. MelanotrOpic·li·
potropic Peptid•• of the Pineal Gland and Other
CNS R'aion •. Chap. 4. PI'. 44_53 of AII$Cbule,
od .. reforenee 4,
168. Rust. e. e., and Meyer. R. K. Hai, (:(,10". Molt.
and Tesli, Si,.. in M. Ie. Short·tailed Weasel.
T .. at«l with Melatonin, 16J: 921 _ 2,
1969.
\69. Sackler. A. M.. Sadie •• M. 0 .. Marlin, C. R.,
and Sackl." R. R. Thymectomy .nd Histami".
Tolerance. F.d. PrIX:. 11: 363. 1963.
110. Saund.... G. e. Development of lhe Immune R",
.ponse. Sectioo 4 of Abramoff and l.Via. cds ..
ref.renc. I.
170A. Sawyer, T. K.. Hruby. V. J., Hadley. M. F.. and
Eng.l . M. H. <>-Melan<><yte Stimulatina Hor·
mone: Chemical Nalure Mech.ni.m of A",
tion , Am",. ZOO!. 2J: 529-t>5O. 1983.
1708. $c'labri"", G., F.rioli. M. E" Ba$Ollni. M .. N",
buloni. R.. and Fraschini. f. Endoc.ine Retula.
ti"" of Thymic Biosyn,hesi. of Poiyamino [)ccar·
box)'I .... in Adult Rat. Amer, J. Ph,.,iol. }]7:
E6-EIO, 1979.
171. $ch.ving. t, E.. Halberg. F.. and Pauly. J. E .. «I"
Ch",rwbiology. Igah Shoin . Tokyo. 1914.
171 A. $chliwa. M ... rtd Eut.neucr. U. Comparative UI -
"a,tructure and PhysioiollY of ChromOlOphore$.
wilh Emphasis.", Ch.nge, "ssociated with Intra-
ce Hular Transport , Zool. 23: 479_94. 1983.
172. H" Price. M .. and Odell. e. A. Effect
of l yophili2Cd Thymic Extracts on Serum Cal-
cium and Phosphor .... 1: 261 - 1.
1953.
173. ScOlt. D. W.. Darrow, T. L., and GrOui., B. R.o-
osnition and Regulat;on by Modified Self. Ann,
N.Y. &i. 392: 1_7. 1982.
174. Sc,opanti . I.. Gulino. A .. and Pasqualini . J . R.
The Fetal Thymu, of Guinea Pig .. an Estrogen
Target Organ. EltdlX:riltO/, III: 1552- 61. 1982,
\ 75. Singh. J . Th. Ultra.t.ucture of Epi lhelial Relic·
"Iar Cell •. Chap, i. PI'. I 33-1 50 of Kendall. ed.,
ref.rence 83.
116. Semm. P.• • nd Vollrath . L. EI.ctrophysiologyof
tho Guinea-pill Pineal Organ: Sympathetic Innu·
enee and Differenl Re.ction$ 10 li,ght .nd Da,k·
no". Prog. R.<h. 51: 107-10. 1919.
177. Sinin.ky. S. l .. and Martin, C. R. Influence of
Th}'mectomy on Plasma CortiCO:lt.ron. in the
1La,. &. Compar, EndocriltlJl. 8: J78-81.
1967,
178. Sis •• e. l..,nd Ture k. F. W. Doily Mol.,on;n I..
jectioo. Mimic tb. Short D.y·lnduC<X! I""rea ••
 PINEAL ,.,NO THYMUS GL,.,NDS
'"
in Nogal;', Feedb.ck Effe<:ts of Testosterone on 192. Vanecek, J., and lIIocro. li, H, Effec," of Photo-
Gonadotropin Secreti"" in Homsters. Bioi. Rt- period on the Growl h of Reproductive Org.n$
prod. 17: 602_8. 1982. on Pineal Rhythm in Male
179. Smith. E. L. Hill, R. L.. Lehman. I. R .. lefkow_ Rats Treated Neonatally with Testosterone Pra-
itz. R. J .. Handler. P.. and While. A. pionate. Bioi, 517_22. 1982,
of 7th ed. McGraw.Hill, New 193. Vaugh.n. M. K.. Johnson. L Y.. Dinh. D. T ..
York. 198). Brainard . G. C .. Pe1lerOOr8. L J.• G uerra, J. C,
180. Smith. I., Larson-C.rl<r, D. L.. la.d. C. A.. and Roit ... R, J, Inn uenceofTh,.Ser. Lys (TSL).
leone, R. M .• Silman. R. E .. COrler. S . J.. Fr.n_ A Recently Isolated Pinc.1 Ptptid<. on O ' arian
cis. P.. Mull en. P. E.. Hooper R. J . L.. and Fin- and Uteri ne Weights and 8troo, Cycles in Mice.
ni •• M. D. A. Hamsters and Ral$, Cbap. 19. PI'. 165-12 Or
Tentalive Identification in Pin •• 1 Gland. , Prot. Mauhe"" and Scamark. <d ... referellC<: 106,
STain 52: 258-51. 1979. 194. Vollrath. L COmp.rali" Morphology of the Ver·
180A, Stanberry. L. R.• Das Gupla. T. K.. and Beani., lebrate Pineal Comple •. /'Tog, Rsch. 51:
e. W. Photop<rto<!ic Con trol of M elanoma 25_37, 1919.
G rowth in Ham'te .. : In"ucnce of Pi.colectomy 195. Volp<. E. P. A Biologi"', Journey. ZooJ,
and Melalonin. II J: 469-75. 1983. 23: 239-53. 1983.
181. Sugden. D.. and Klein, D. C. Characteri,,ation of 196. Vriend. J.. Richardson. B. A.. Vaughan. M. K..
f'oolynaptie Pineal " ,. Receptors U.ini"'·HEA T. Joh"",n. L Y.• and Reiter. R. J. Effects of Me-
Abstf. .. 384. Endocrine Soci.I)', San AnlOnio. latonin "" Thyroid Physiology of female Ham·
198). 'tcrs. 15: 79_85. 1982.
181A. Tan.la. L, Na l .i, Y.• Na kao. K,Oki. S .. YO$h· 196A. Weber. W. Pbot",ensiti.ity of ChromatOphore"
im .... T .• and Imura. 1\, 1'· Melanolropin-Like ZooJ. 13: 495_506. 1983.
[mmuflOreactivity in Bovine .nd Human 196B. Wehr, T. A.. Sack. D.. RO$Cnl hal. N .. Dun""n.
n<>eorlicolropin·Prooucint! T i",ue •. J. C/in. f.:". W .. and Gillin . J. C Circadian Rhythm Distur·
dOi:riflOl. 56: 1080-83. 1983. banees in Manie-Dep",,,,i.e Illness. Fed. PrIX. 41:
182. Tet'uo. M .. Poth. M.. and Markey. S. P. Mela· 2809_14.1983.
tonin Melaoolite E.orelion During Childhood 191. Westerberg, L Pineal Organ: Clinical
and PUberty. J. C/in. EndOi:ritw/. 55: 311 - PI'. 345_54 of Ok.che and P•• el. eds .. ",ference
313 . 1982. I 25.
183. Truex. R, C .. and Carpenter. M , B, Human 198. Wiloon. J. A. of Anlmol PhYJioJoty. 2d
"""",,,,my. 6th cd. William, &. Will in$ Balti· ed. Ntw York . 1919.
more, 1973. 199. Winfree. A. T. Human Body Clocks a nd Iho Tim-
184. Tuchmann.Duple .. i,. H .• and Haegel. M, D. fl· ing of Sleep. 197: 23-7. 1982.
Embryo/ai:}'. Springer·Verlag. 200. Wurtm.n. R. J.. Axelrod.J ... nd Kelly. D. E. Tilt
New York. 1974. Academio Prm. New York. 1968.
185. Tu,,,,,r. C. D.. and Bagnara, J, T. &M,al Endo- 2ooA. Yamaguchi. T .. Nagat.u. T .. Sugimoto. T .. Mat·
uiflOloty, 6th cd. Saunders. Philadelphia. 1916. suur• . S .• Kondo. T .• li,u k•. R.. and Narabay_
186. Ueck, M. Innervation of Ihe Vertebrale Pineal .. hi. H. Effects of Tyrosine Admin;'t,al;on on
Prog. BNlin 51: 45_87. 1979. Scrum DiOpterin in Norm.1 Controls and Patients
187. Ueck. M. Var i.. ion in StruCture and function of wilh Pa,k;"",.·. Di",.",. Sci."" 219: 75_77.
Pineal Sys!em •. PI', 151-68 of Oksch. and P... I. 1983.
cd, .• reference 125. 201. Yoffey, J. M. Stem lnd the Thymu, with
188. Ueck. M.. and Wake. K. The Pine.locyle--A Special Reference to Cellul.. Mittralion S tream •.
Parancuron. Prog. Brain R.d,. 5]: 141 - 7. 1979. Cbap. 1. PI'. 185-202 of Kendall, cd •.• reference
189. Uhlenhulh. E. furthe, Proof of the E.iSlenceof a
Sp<cific Tt l.ny Producing SUMtance in Ihe Thy.
".
202. Yount!. L M. The Pincal Indolt Ho,mo ... in
mu. Gland. J. G. n. PhysioJ, I: 33-6. IlIIS , CU$hint!'s Di ...", a nd Acromegaly. pp. 2-12 of
19-0. Uhlcnhuth. E. Nalure of Ihe RCl.rding Mal1hews and Seamark. cds .• ref<rence 106.
of the Thymus Upon Amphibian Metamorphosis, 203. Yuwiler. A. Liilbl and AgoniSlS Alter Pineal N·
J. Phy.loJ. I: 305_1 3. 1919. Ac<:tyhr.nsfera", Induction by VaSOllcti .. Inles·
191. VanAr5dd. P. p.. J r.. Allergy, Immunology and tinal Peptide. Sci.",. nQ: 1082-3, 1983.
Hormone •. Chap. 25. Pl'. 1108- 24 of Williams. 204, lou.• M. Pharmacology of the Ral Pineal Gland.
R. H .. ed. oj End«,;ltOlogy. 6th cd, Chap. 9. pp. 230-242 of Reiter. ed .. reference
$.a"nders. Philadelphia. 198 1, 149.

Additional references added in proof will be found on page 894.

 Additional References from Chapter 6
A·I. Barneu. C. A.. Palmour. R. M .. Lilwaeh. G .. and
Seegmiller. J. E. In Vitro Slabilization of the Un·
oceupied Glu<XIOO!1icoid Receptor by AdeOO$ine
Y·Diphosphate. f.·ndoe,iMJ. 111: 2059-68. 1983.
,0.·2. Du80i •. C. C. and Almon. R. R. Inert ... d Con-
Icnl of GluC<l<OOrtiCQid Receptors in Mouse in
Moo .. Muscular Dymophy. £ndoe,. lUck. 10: 3-
10.198 4.
A·3. Gametchu. B.. and H."ioon. R. W. Characteri ..·
lion of a Monoclonal Antibody to Ihe Rat Li.or
Glucocorticoid Receptor. £ndoe,iMJ. 112: 214_
279.1984.
Additional Refe rences from Chapler 8
A·I. 8ro"'n. M. R.• and Fisher. L. A. Brain P.ptide
Regulat ion of Adrenal Epinephrine Secretion.
Am" . J. Phy.loI. 247: E41_E46. 1984,
,0.·2. Dubo<:ovieh. M. t. p,. •• ynaptic Alph.·Adr.oore·
ceplOl'S in the Cen".l Nervou. S),stem, Ann. N.Y.
Arod. Sci. 430.1-25. 1984.
,0.·3, Es ler. M .• Jenning •. G .. Korner. P.• Blombery. P.•
Sachariu. N .. and l.oonard, P. Measurement of
Total and Organ·specific Norepinephrine Ki ..,ic<
in Human •. Am". J. Phf$iOI. U7: E21-E28,
1984,
A·4. Gnld"ein. M, Regulatory Meehanism, <If Dopa.
mine Biosynthe,i, at the Tyros;ne Hydroxyla ..
Step, Ann, N.Y. Arod. Sci. 430: 1-5. 1984.
A·5. Halter. J . D.• Ikard. J. C" and Pone. D.. Jr. I. let
Function and Sire.. Hyperglycemia: Plasm. Glu·
cose and Epinephrine [nl<raClion . Am." J. Phy.-
iol. 147: E41-E52. 1984.
A-6, Inscl. P. A. Idenlificat ion and Regulation of Ad·
renerg;c Receptors in Target Cells. Am". J, Ph>,"
;0/, 147: ES3-E58, 1984.
,0.·7. I..G.mma, E. F.. Adler, J. E .. and BI.cl-.. I. B.
Impul.. Activi,y Differentially R.gulate.
[lcu]Enkephalin and C.techolamine CharaclO"
Additional References from Chapter 9
,0..1. BIO 14.6 Ham"." Ar. Deficienl in Natriur.tic
Sdrna 223: 820-2. 1984.
,0.·2. DuBose. T. D.. Jr. Carbonic Anhydra$O·Oepon·
dent Biearbonate Tran,pon in the Kidney. Ann.
N.Y. Sri, .29: 528_37.1984.
A·3. Knlata. G. Doesa Lacl-. of C.lcium Cou.. Hyper.
tension' Sclr"" 115: 105-6. 1984.
,0.·4. Koodo. T .. Taniauchi. N.. Hirano. T .. and Ka"'a k·
.mi. Y. In.cli.. Form of CarboniC Anhydrase in
Er)'throcyte> from Primary Ald<JOleroni.m. Ann.
N.Y. Acad. Sci. 419: 302-5. 1984.
'"
,0.-4. Grondie •• P.. Miller. A .• Schmid!!. T. J .• and Lit·
.... ck. G. Purification of the Unacti.ated Gluco-
corticoid Receptor and Its Subsequent In Vitro
Activation. J. Bioi. Ch'm. 159: 3113-80. 1984.
A·5. Lieberman, S .. Greenf,eld. N. J .. and Wolfson. A.
A Heuri,tie Prop0$31 fo r Understanding Steroid·
ogenic Proce ..... Endoer, N.v, 5: 128- 48. 1984.
A-6, Munck. A .. Guyre. p, M .. and flolbrool<. N. J.
Ph)"iological Funclion. of Glucocorticoid. in
Stress and Their Relation to Pllarm'OQlogical ,0.0-
tion •. f:nd"",. R(V. 5: 25_44. 1984,
in the Adrenal Med ull •. ]14: 1102-4,
1984.
A·S. Matsui. H. Adrenal Medull.ry s<eretion in Re-
>ponse to Dienceph alic Stimulation in The Rot.
38: 164_8. 1984.
A·9, McGonigle, P.. fluff. R. M .• and MOlinolf. P. B.
A Comprehen.i •• Method for the Quan'ila!i""
De\ermination of Dopamine Re«ptOf Subtypes,
Ann. N.Y. Acad, S<:I. 430.-77-'l(). 1984,
A·IO. ROlh, R. fl. CNS Dopamine AUlore«pto": Di ..
•
!ribution. Pharmacnlogy. and Function, Ann. N. Y.
Arod. Sci. 430. 27_53. 1984.
A·I1. Snider. S. R.. . nd Kuchel, D. Dopamine: An 1m·
portanl N.urohonnonc of the S)'mpathoadren.1
Syst.m. SiRnincanc. of Iner .... d p.ripheral Do-
pamin. Rd •••• for the Hum.n Sire.. Respon ..
and Hyperten,ion . End"",. R(V. 4: 291-309, 1983.
A·1 2. U· Prich.. d. D. C. Biochemic.1 Charac'.ri.,ic<
Regulation of Bri.n " rAdreno-roceptoTl.
Ann. N. Y. St!. 4M: 55-"75. 1984.
A· 13. Young. J. 8., Rosa. R. M ., and Landsberg. L, Di,·
ooeia,ion of S)'mpathctic Ne"",", System and
Adrenal Medullary Respon ..s. A_,. J . Phy,i(}/'
247: E35_E40. 1984.
1\·5. Sariban-50hraby. W.. Burg. M.. Wiesmann.
W.P .. Chiang. P. K.• and Jobnson. J. P. Me\hyl.
ation Incre.se. Sodium TranspoM into A6 Apical
Membrane VC$icles, P""iblc Mod. of Ald"'te-
rone AClion. Sc;."" 225: 745-6. 1984.
A-6, Tashian. R. E.• and fl.well.Emm.". D.• <1$. BI·
oIogy and Chtmisuy of Ihr Carbonic Anhydra....
N.Y. Aad. Sci . Monograph #429. !984.
... Additional References from Chapler 17
".1. Cooy. V. ThyroglobIJlin and Thyroid Hormone
S),",he.; •. EN/{)(:" IIMh. 10: 73_88. 1984.
1\·2. Engl<r. D .• and A. G. The Deiodinaiion
of tb. todolhy.oo ine, and their Deri •• ,ive. in
Man. em/ocr_ 5: 1984.
"·3. Haber. R. S .• and Loeb. J. N. Early Enhancement
of ...... iye Polusium Elllu , from Rat Liver by
Thyroid Hormone: Relation 10 Induction of
Na$.i\ TP. ,c. EnJocrinoi. 11$: 291_1. 1984.
A-4. Kaplan, M. M .. and Shaw, E. A. Type II 1000-
Ihyronine 5'·D<iodinalion by Human and Rat
PI""".,. in Vitro. J. CUM. Endocrinol. M""b. 59:
253-7,1984.
Additional
A·I. Fudenbers. H. H.. and Whitten. H. D. Immune>-
stimulation: Synthetic and Biological Modulato ..
01 Immunity. Ann. R ..... Pharmacol. Taxirol. 14.-
147- 74.1984.
A·2 , Grossma •. C. J . Res.l.,ion of the lmm."" SY$-
tom by $e, Steroid•. £""oc,. Rty. j: 435-55 .
1984.
1\·3. Meuer. S. c., Acuto. 0 .. He'cond. T.. Schloss-
man. S. F. J .. and Reinhe". E. L. The Human T·
Cell receptor . Ann. Hr •. ImmwlOl. 2: 23-5(1.
1984.
PINEAL AND TlfYMUS GLANDS
"'-5.Nora}'.n. P.. Uo .. , C. W" and Towle, H. C.
Rapid Ind uction of • Specific Nu clear mRNA
Precursor by Thyroid Hormone. P'oc. Narl. AN/d.
&/, USA 81:4687_91. 1984.
"·6. 0,,"._
M. H.. Henneman". G.• Doctor. R. and
Visser. T. J. Metabolism of 3.1'.DiiodOthyr<>nine
in Rat Hep""")'t"" I.,erae'ion of Sulf.tion with
Dciodination. £'ldoc, j'lOl. 1'5: 887_94. 1984.
A-7. Wt .. man. A. P..• nd McGregor. A. M. Autoim·
mune Thyroid Disea.. : Development< in Our Un·
derstandins. t·.doc,. j: 31)9-55. 1984.
from Chapter 20
A·4. Pre.lock. J. P. Tho Pineal Gllnd: Sui" Implica·
tion$ and Clinical Correlalion •. t·nt/"",. Rn. 5:
282- 308.1984.
,\·5. $egal. Land lngba •• S. H. An Immediate In·
erea.. in Calcium Accumul.tion by Rot Thyme-
cyt .. I nducod by T.jiooothy"",i",,: Its Role in the:
Subsequent Metabolic Responoe. EndocrinJ)/.
115: 1984,
A-6. Smith. K. A. Int .. 2. Ann. Rn. Immuno/.
2.319_33.1984.
 Index

Major references appear in bold type.

A. ,I"" •. «II. (... GIUCOJ.OII). 3S. for a""""'""""""",p,,,' <omplc,c>. "",,,,,pill pou<hc .. 508
57.IS8.1$9
"".rm>eokl$i<al.",." u>«l '"
<I<""'Y.101
'"
for <'''oc<fl-tC«:P"" c-..",pk, ... 666
for pr<lJC"'l<rono·""",pIOr compte ....
"",Io""ion of. ..., p"b<ny OIl ...
Ih),m".. ""'''.
11l-4. 38'
"",,,,,,,,,,icoid, . nd.

A,. <1<1 .. . D. «II. (>« Som01","'in,).

3S.57. ISS. 1$9 ••
for Ih)'ro;d i"K>nnono •• 7S9- 762
"CE (..., ",","",n,in conveninl
F.llopi.n _.6. 16.
107. 509. 5 IO. 5U. S2.l. Hi.
A23187. 011«" OIl SUo 150. SS I. 611. 611·1. 6H
Acnl bindin, '" """'p'C.... 113
",("TH "i",olo';", of ""o;doc<lI<>i .. "'<<"<SO')' ",()o"O<lucli,.. o...,n.
<n,y"",). 18·9. 3<11. )43
(I«
,<. <K). m. 501.
684. 715. 716. 8).4
p;n<.I . nd.669.847

'" '" <.... 1.0<. '" I •Ow"'" '" 1,."-"".,,••.

1',......
• lOO>lCron< >CCfC\;on. l so. I
caldum "'''' .... 411
6(l1-«l3.621
ond,,,,,,. "im.lotion. /r01
."
pr<1>U,i,1 ,t,nd .. 509
'<.
",,,,ium up .. "'.'po" ""'''''
0f)'n<11os.414
. nd"""nodiols.nd ""II
proIil<rolion. S15
r>rol..,lin =<pIO.... 197
prO$l'l< ,t.nd. %. 509. 51), SI '. S19.
m;'octlon,hio.190 CO"""n''' I;'''' required 10 S19. S84. 601. 6Ol-l. 603·
00"""..,
vow,h ...,"";0'. 1\10. 79<1
in,ol;. =reI iOll. 19l
PTH ><>:«1"". 4(>7
m. inlO;n. SJ5-1i.
d;h)'dfOlC>I(>I""Onc
II«reI;"n. S)S
.n" 9.709. 834
",,,,,urn. S08. Si l. S19.
on
S1I. 609.

""pon ... '0 hormon<s. 111 1<".,.,,"'.... Sl6. 601 .. ",;n. 1 96. 106.12J. 509.
"'''Sil. ad",n. 1.odtO$<n ...,,...,i.. .. <ndocrin< ",nd,. m -Io SIt. S3S. S79. sro. SIll. S%'
IIo<m<>ll<.612
"'I. A ·I!. A ·IIl. ...,An,iQlOn.;n.!. II
bulbou,...,h",1 (CO",,,,,,',) ".nd•. m . ,.,.,.i<s601·2
v.ri.,ion,. 5(17.\ 10
• odlll.11·9.3<l1 <h,"'; .. 5(19. 51 l. "S. 52_ rd'l;"n,hi.,. '0 pm<1< numbo ...
"'AG. doo<>. 508. II S. S13. Sl9 5(17-510
blOO<l «>O«.">I Oon .. eorti>Oi biod i. &. copol.lOI)" <><pn •• 507 ,,<roO:! m<"boI i, m in. % . IlS
""ni,. \08. 511 . SIS. 519. Sll. S41. "1<,... .l4'. .148. 16 I. .108. 5(19. SI0.
'"
",bort;.,. indll<1io.
pl.nl-dorh·O<I .•ynlhc' i< 1./0
S49. lSI. 609
<rc1ic. 1 <"""I<' in <"*2_
S 13. SB. S40. 621. 621. 634.
66Z. 664. 665-3. 681. 68s-1lO.
PO •• aloe>. 112. 710 dep<n<l<n« "" ",nadal hormon<>. Q91. 101. 703. 8)1
Abortion . • pon .. "..,... W, "/llin •. 509. SIO. Sil. S15. 513. 533.
.neuploidy. pOI»,oid)' ond. 5(ls. <i;ff<"'"t;O(;"" of. 6. 513. 601 661·1.667·8. 711.114
<lhyl .1<0lI01 ">«I to .vo>id. 712 i nd;ff<rc'l 'I>£<'. S I I ·1 IJ "'«I• • oI,m ide. J27
10,..1 ph . .. <kf«I" FSH. nd. 6S3 ;n rom,lo 12l-4 PTH·li);< o<lion .. 410
o,·. ri«tomy.I.,eC<1omy .nd. 706 in m• ., m. mnul •. S I&-S1(l ,"os)'n, h"";" 1M. 167
'0
PfOI<"os<n, ovoid. drew "" fclo'.
SI9.55(1
",I.. in prol«1ion .p;n". 710 ;n Tfm
,
in oo,,,,",m, I;•• "'''<OCoI<>' 124-

60S
add",i .. nd. 1.1
d<hyd .. ,;on and. 166
""'''')'icbol in<
"l>O i<. IUDs 'od. 721 cpicnd)'",i .. .108. Si l. \ 16. \35. 5J6. action •
•," oui", of <mbr)"os. f01 50(; 11S·s(). 136. 601·2. 621 . 68l. <ak,"m . nd. Il1. 410
",liP (..., "'odt<lS<" bind in, pro'ein.).
S)'·)
M::" T. o<eI)'I-CM-ocyll r.ln.f<r.lS<
o,,"'!rn'" S(11·SIO
in m.1<>, 601
"'mat", .. ,in .nd. 61
aJOO;"" ,n"ron;,.. (... "'I"",n<).
n. 261 . 26.4. 331. 19S. 768.
;n 0<11'< • • 1eon«. 2» m,m",",,), ,tand' 6. ll. 16. l11. 121 . 79!.852
i. 0" >1)". 6)S 3.10. m. 386. 393. 430. 440- 1S
""'«pt",,- no<"'''. r.,.. h.,..",o .. I J9- 449. \08. S4S. S49. 644. MS. i«;,hi n .nO. IJ
68, . 70S. 711. 112. 11S. n 4-'. 5«()nd m<",<"I<' . 13-4. l83.

.,
",ici"m .nd. lJ9 7)0, 800, 83<1 164. 811
 INDEX

"c<t)'leh<>li"" l«lm_l fa")" :Kids, 169 morpholo&icol ,"'nge •. 6S4-S

rompo,"" with lIormon<>, 5 kOlon<S. 16(;. 1.7 zinc.nd.121
de",n,iti»t"" to, 141 melatonin, JS ,poe,,", ditro",nces. SW
"<"<I)'I ..",tcoin. ro.'AS. (sec N_
,.
<>10,"= ACT II. IIdrenocortirolropin.
in h)'poIh,l.mu .. iH """')'I,,,noni n). S, 306. S_B. <oni<ol""";n. 4, 41
in nu<Icl, lSi .nti",,,,, dr"", of. lSI
;nhibi,."..,r. )(IJ Ao<" 'II ... n.f...,, . NAT. sec N· bi ndi", to """''''.".. ""lei"",. nd. 2 J 3
in pi"".1 &land" 849. US " '01) i,,,,
",fo",,,, to MSII =<pi.".. 8 J I
in SCro.' .• nd liJh' e!lt<" 00 pine.1. Mid-Rase Ral,""" biN,say.l5S

'"
i nfi """...,. CO
catochol.min< ')"nth<si .. 291
,h'<""'ato()hort$. 811. 873
dopami .. into,ocuron •.
'Y"'pothet ic ')'''0''. 23 1·2
food in11k<. 841
"..clei.
.mooth mu",l<.
.n.....,i."'.274
"",ium tn n$pOn. 38)
inRuon"".,. rele,se . ...,.,ion of
"OH .)88, Ol
CRH. 261. 16-0
doparnin,.131
<>,«hobmi .... nd, 194
v<>Wlh hormone. 192
ooid. 310
insulin , 19S. 1%-1.101
59H
"'fJ"<.6S8
ox)''''''in.U4
panereat;'; poi),pop<id<, 1&9. 101
proloo'in.l9!
somalo·""in ,101
in<ono,ion, wi,h
271
dopami"". lSS. S98
kinin ....... m. 357
opi<>id poplidcs, J92
ptOSU&landin.. Z94
",",,,tonin. J09
som.1O. .. ,i •. 61
1311. 16-0
"""'PI.,.... ""'in. dium.ol ,,,·Union ..
SCN.nd,851
.-01<. in retu lOtion.,r
><Iren.1 medull •• S9. Ill. 2JI
,u,,,,",,,,ic bolanee. 271
pancreatic 192, 101
f"'ton .1f«1i".
><I",n.le<lomy.330
cal<i"m l26. 40'), 41l'"
« II
82. 8(,.7
"'u"'''. lS9. 591
O<1;">lo<llymphoC)" ... II*
d;OI. lJ2 porS diOl.li, 'yo«. 824. 827
"u,,,,,,,,,iroid,. III , 22 2. III chromophobo-s and. 8:10
in."li",161.165-163 pOrS lub<: ... 827. 8:10
teton<>, 166.1, III ffiMC , 0<1. 258. 824
8).4 al<los"""'" on(\. 33 I ,hemi"ty. '),pOS. 8l
mioo .. locortiroid., 321 pop<i"'" ",I.. "" '0. 49. 253
, Ido."""",. HI. 332 c"""",,ic ACTlt, h"CTII, 70S
pa"'lh)'mid hormor.c, ll,!l MSI!. 817
""t... iu",. 326. }l7-$
>tn".. 221
])O<oncies or v.,iou. fom". 88
function. 1S<e inn"" .... on lId",nol
h)""".n. "'.lOboIic ""'1«$ of. 3lS 2Sl
inn""n",. on ""'in. 258. 390-1
bon< """"n"" 10 !'Til. 469 ph.rrn>«>kllkal .,.,nlS . lI«1i".
<>leif"",1 """.boIi.m. 437. 453 O)'.""'oto ... m01)..."])OII<.l4O,
I ",h )"d",,)"Ia>< act i, ity. 411
<>lei"m bal,""". ,,""'tion. 40'1
PTH .nd, 488
'" 239. 240
in o", ... to nucH &.\6
cole,u," ioni",i"". 431 in J"'. 153
,,"ron<q<l\<'Oi,;n ,he I:idn<y. 183 in 1"'" ;ntcrrno<lia. S)
1»'''''.10 «Jnve";"" '0 l"tolO, 185. inn""nee.co
m adon)'I." ... lSS
"'n in""nJio"n'in .,.<om . 339 ad", .. 1 cone,. so.
4, II S.
""""n"" to 1.25-0.437
rnc<-hani'''. fe, .,.inlOini .... l22-J2'o'
25l--7.35IJ
."""bi<no....
Kid I nd, l55. 292
. mmon'''t'ncsi •. 327.9 blood lSl
blJtro,,)'''cm •. lll. 326 <>leiu", "",.k<, Intn.iocotion.
e..,.,hroc),«. I" "" .nd. J1S..,
mitochondria .nd. l26 <>lmoo"l;n . . nd.254
Acidic n..cl<>' ])<Olein .. 9 <AMP JC'I<rSti"., 2S(1, ll5
.nd "croid """"""" 141 «II dilf.",n,i .. ;"n. pnllir.",'ion.
A<idopIIiI (0' yP/!il . ..,,; """"it) 0011.
"f 8lS. 826 cGMP I nd, 21S
of pa,.,h)'fOid ",nd., 34. 46S 'Oo""<o,ot .ide-<:h.in 01e"1I<,
M",,"<ply. 18S
bone J'OWIh. 438
<>leiferot m<"boli,m in, 440
DNA '" lS6.1
aJ""oronkoid .)'nth",.,
honno"" 790 ""''<lion. SO. 51-3, 111.151·'
h),poraiJ'C'mia. in,"lin ",i."""". in foto,. LDL dqrod.ot;on .nd.

'"'
lrophic l. J4-5
"o<t)1 Co-A. A«'yl «><nz)'m. A in," 1in rocevt'" n um \>orS. offini,;e" lipopt<>tei. """'PlO .... 2S3
AtOt)'1 Co-A .,.!box)'I . ..
acti.i t y, f:Ktors .i'f«;ti", '"
PR".34J
m;ne,.loconiroid ooc'<lion. l41·

biolin.oil"'lc.169 ",m.tomed" 1e,,1.. 7%

181
in .ulin. 169
.
p/l<><P/>Or)-lIt ion_
<l<""""phorj'lation, 169
,
retulat;". off.ttY:Kid .,'n'he.i ..
"<"<, yl «><n,ymc A. Ot<¢1yl-CcA
ro-lOctor, .lltbtlim of N" T. 85<1
ptQt •• se i"""i""ico .nd. 858·9
",ncoui"" from f. ttY :Kid .. 166
"' ..... Iion f,,,," p)'",,",,<o. in,ulin .nd.
"""OIotrop< numb=, 82S
"","atO'ropo ",,])On ... to T R II in.
m
ToBG ,yn'hni" 7lO
tumor cdl ",,])Ono<> '0 TRH.
dopa"";"". J92
Ac"";n.684·S
'"
formation from _rosin, SSO, 68S
inh ibito" .. """t"""p<i.".. III
Aero",mo, 576. l78, sao, 681
,n,ibodi .. ",i'" m.mbra",

'"
u'" in ')'ntl><>i, of
"",')'l<hoiin<.75
",m])O""n", 7ll
.n,p"" "",iv.ted by",,_itotion.
U, PNMT.2'!3
cI,ole<.!<ife<Ol., I 9 ""'t;on. 6.!2. 684-t> boh • • ior. hrni .... ll8
choics"roI. H 169·7t), 131. f:KtOrS ,uPJ>(IninJ. 6.!4 bod)' <om""nlu"'. 770
253-25S
in.ulin .nd, 171 _Z
"f.h,,",68S
h),.lu",nidue 'nd. 6.!S
blood "oco«, lIS
<.1<i"", m'lOboIi,,,, in fe,u,. 4SS
 ,hok>,,,,01 "", .. boli,m, 93, 2J4,
252·250
&lroOl<no,,,i,.255
lH 00<""'01>. S91
2S8
"""",,,., )"i' l>io4i.$. J37
""""&landi ••
pIOtidi"" ,y"hosi •. 190
",ni. 'ut»'ra', lev,", 148
.. " ap""i,¢. J<,O
>l; i. pi"", ... ,;.,.
.,.
"<!di"",·. di ... ",. 49. 229. 2s! .
."
U5· 1) con,roI of ","';"rn ,... n.pot!. GTP.11P
,,'
,ndom'''''um. J>«". ... 'io •• f",
"",""",,1M
h"'m" ....-c«:pl<)t o;o4i"" 119
.... 'i"".
6-&9.90 li'hium. 370. 174
,,,,...,io3 «toTo'ion of "",IOtonin ,
". ,"*.,,,''' m¢mlm "" p ""i"",<I<I.. 76-4
mom br>n< p/Io<pllol ipi<!" III
102, 251 ¢'''OCCn of ",prod"""", ",¢m\H'ttn. pro, ...... 6J6
b<l,•• "", SS4 """ h)'"""),,,mie ... n'" 198
F'SH ind""'ion of o",ma,. ",. $o"oh ac,i"., io•. I tS- In
«II" S32 ad",o<rP< """pion ' 00, 180
&luoOOotl ioid .,r,m on di"'ibu'ion. 114
.... ;n Imi •. lS8
;n o,·.ri,. (., .. , ""II" 5n
&lu¢oooniCQid .,..""" M
111
som .. "m«!i. ni"'ol.,iM of
in ,pemt' lO>OO. 681
h<>m\OT>O in",,"";on, in "1ul .. "", of.
.. ni....,. SOl
s"'fOidoson,i" 253
'hyroi..! hormo .. "im"'atN
.. 1)9
"
poptHl<>. 133.

Mh".,iolUl honnon<>. 7. 560

com".m!
W,'"
"""ro''''n.m'''''rs, IS.
wi,"
"tpn;20';o,,"1 androt< n" IhJ
M.mon<>, SS3--.\ ' nsiot<n,in .. J.\O
",ami"" «porion«.• nd ""pon"", "'. ",!tito.io. 4J8. 4lJ. 481·3

'"
M 'on'I)'.,.in
;n . k.k,.1 "'0",1<, 'II
<o'crhol'mi0C>.1ro 21'. J.46. 812.

'" 131. 273.114. 16J.

, ,
oo<""io.
di umal 26-4
,n,)'m.'ie <kittt •• nd. 219·241
ad",""*,.i",, .,od.."., •. 21.
hyd.o,)'''''' <klici<ney. HO
"""I<i . 04. 8J6
I«f<,'o. , f.<I"" .1I"«,i.1. 259-260
Ami (",,,,,,,,,,,,0), 5S. 259.260.
384. In, 834
'-';ol<o,io. J21.l4S. J59
''lini"" ... ""ocin. 1S9
<..«hol.mi.", sa
dopomiru:. 28S. 281, 288. 468
,yo'!I<,i, in u"''"'' """",n. '00. 70S "pi..",.,""".
Adap"'ion. to <.-ironmen' (... SI"'''. 769.804
("old. " •. S
Addi",n', di .....,. 216. 2l2. 219
."",pi""".,nnc. 119. 461.8)(;
CR H,259
"efl! 00<"" ioo.258 ¢nd........ 11H. 141.8
, ",,,immoni'p.d,77S """"'." ,'3 . .\J9. 649. MS. 690.
h),,,,,,,al«mea. m
i. po,kn", ",I .. i...... wi,h ,hyro'" FSH. S12" . .\J9. 649
di",... , 778 &1 ....'0 •. 119. 120-122. 184. 4S)
.. in pi,mm"'io .. 49. 229.1S8. 818 I'o""h homI"",. i. '"'in. I 27
Menoh),poph)" i, (00< !'i,.;",),. ,o>«ifi¢ G RI!. 1'l4
IIonnon<> , od J9·s(! hCG. 53S. 6)6..7
blood 'OWl),. 41. 819·21. 824. hi".m, .... 119.161. J 14. 69Q 77(1
«II 'Yl><" 41"8. 'It.. 824·830 LH. 119. HS, S91. 6).6, 6S3
co"' ..... 'i.. "'<>fl>hol<>ty. 82)·824 l RII .5'16
,,.
componen' "."" .uMi,i.ion •. )9"9. I)'.in< ..

MSH. 119.371
811
lao

dovoiopm,.'. IJ3. 1hJ. 698, SIr.. 7.

CLIP. MSH. 2S9
". """",,,,,,,,,,.728
CRI!. 5J.2S9-OO. SJ.<. 843 funetion., "n,,,,' nOt"",. 40.14 PT"'''&I. odin" US. 214.346, 461,
OAMP and, 2.\9 O...,.,on. ««1>lon 'n. J2(. 35( • .\<lO, 4ll. 676, 164. NQ 19J. 794
l S2 SSS. )94. 6-44. W). 160. 191. !'TH. 119. Ill. 4l8. 4Sl. 468. 472.
GAB .... 261 801. Sil <82·.1. 481
&lo<o<:oni<o"'" 262-16<1 honno"" ""","ion. (s« ,o>«iil< ""ro'oni •. .109. II 4, 3 11
","-,omy, 816
hypo>io.71}
4O.S4 som .......'i"•.
'hrombo...... 767
380. 794
miero>ropic ,.",om)'. 41 ......1. 824-
"""'otran,m i".", 161 TRI!. 119.760
""",pi"""
pi""., rio<:. 259. 26 I
&laoo. 61. &II
«tul.,;on of. s« 'rii<>do'h)",ni"". 88.\
TIH.' (9. 76J..4. 171
taTS" ""U """,,ono<, Pl,uito')'
PtQIO¢,in.871 "om ",,'l,or. 47. 82'1 •• ..,...,i"" ;.",,,inal poP'i"". 281.
.. ro,onin , 261 . .10.1. J51 A<kno<1n< m
""... 65.152. 731. 192 <Io. mi ...... inn .....,.. on _nyl. ", .o«o.d m"",,"6' h)'po'f><>i . . nd, 119

,i,,,,,
,h)'mid
CRF. 260
14J "",(a .. ""i,i'y, 127
doriv«l from ,AMP. 121
".l.i"m. ",'moduli .......\\P
;n,<rxt;"n .. 1}6, 214
"ro",.,in" J99 i. pl£mcnt 8611 ",m"".. n" of G. GIN. N
.".'" '«Opton fOr. 1,\,\
A<lid;" .. (... Q<1oh<,imid¢). 117
"<Ii. (00< M iorofi I."",.,,)
",k> in kid .. y ,u,,,,"*,,' .. io • . J5J
Adon""i"" 'ripho'phat< (S« 9(1.1,
161. 161. I Jl. 1"16. 180.
<_;., ,,",.od.,,,,.12S.6
&I,","", •• nd
<ok:i'onin «11 •. 100
",l<I<>mo. and. 1J6 21S, 291, ))3-6, 380. 409. 412, "'DlI. a.,;di u""ic hermon<.
a lmodulin. and. lJ7 42J . .\1$.690. 147. 1SH. 8611. " . _..i•. ' J. 58·9, 76. :169.
i. ,hrom.,,,,,l>otn. U3 m
in ;.,,,,,i.,1 bnah bonl< •. al if<",I,
and. 448
'"
Adon)ia", ¢)<To... "'" 00< ."MP
"",iono of. 119 ,i,.. 381--6. l1S·7
of.4, 1. JJ. >4. 37, lS8. 160.
i. >1;<1<,,1, Smoo,h m",,1e. 411. 411 O¢,i.a, ''''. fO¢'on olf""'i'l 8l1, 834
"'''i''''''')'t,n D ""ioo, ..... el\«'" 117. _n""inc. 'hrophylli.,. 12 J \>100<1 k"cI ... .,..",.,in ond. J60
m ¢''''if<''''.,471 cll<mi,,'Y. 18.9, 77. 31 1
infl"n«' on colcium. I J.<. no. 410. 681, 8JI <Iolkic"")'. di.b¢I .. ;.,ipido, (00<
ao4 'oscn '<1ion., 60S ,1101"", 'O"n. r""' olio. n_ f); . ",,,,, in,ipid",). 369-10
, AMP ""","'ioo 01 N... T. 858 ion" 111 .. uoq<nic, """'tQtCnie. 310
OM INDEX

ADH (COlli.) ,'.!COIo, ')'llom. lSS 386. 8ll

"".. n,;,;,.,ion 10, 379 .... ,.... I.""" i. ft,u..,.. 391 GAllA. aJotam>le. 318
16. 386. 39(1. IH.. \ .... ,..... "'n,'on. 346. ,l(i9·1I1. 373. 384
o",,1<i .0<1. 260. )n.)85.833 hypcrtly«mi • . 160
lU. 1.14 '."'txtion. krlJO,io,390
MIF.. 19J
PO" i.,,,,n«ll •• 49, 8.14 '''''''",n.in If. ).46. ,I(i I
pi"..1. W.l <aki.m. ",Imo<lulin .. l8O, 19J, 431 _"iom . 389
po.'''"Cnlri<lIlor "uclei "d. 809 <at"'hoJ. mi .... od",,,,,rP< J><'<fII'II<'y.370
'"Prochi ..
)9I,3S2
.,,,i< nuct<i. 39)..;1. >36, rcttpton .nd. 385. 391
enlorido ion .. 37()
"""" 160. ).46. 792
IhcmlOO><tp"'''' 58. 133
elf""" of o«=. J7().!. 382 CRH. 260. SJ.4 ....,cr d<pri-.,ion, .... ,.., loo<Ii"..
cocop<, Jll. 382 """"""'iooids. )84 Sa. 260. 835
SIAml.310 ,l(i9.l8l·4 Adipoqla ("'" Adipose Ii..... ). 4
fllll<';onO, n 260 OOr:othyr<>id. thyroid 394 <AMP ,"ncr>lion
inn ....... "'" I'''n' period' for ...... n.. 317. J1S """,pj""phrin< •• d. III
ACTH >«reI;., •• 16, m«h. ni,m,ofac,ion. Il. JJ7.9 proIl.,.t.ndi., ond. 128
1)9,260. W. 192, 334 <A MP ,"..",ion .nd. 370. l19. fructo>< .pt.k• . 169. 120
ad", • • 1 ror\<, lSO.381 aJ..."..,o, idalion.174
. Idomrot>e ...,.."ioo, 332. JS4
Jlucoconiooid """rction , 76, 384.
<al<ium .nd. l70.)85
pI'tQop/1or)'lation Qr membta ..
"urooo upta.c. I J. 180
"ococorticoid. o!>d, 183-4. 220
In. 393 proldn •. 380 ""''IMn< and i ••• I;.
trophic ..... ion .. 384 K>I":'A TPa..,.. lS5 804
o"'pM,i, ... in. bI.<Id<:,. 317-S """ium .!>d. 319 in,olin'I<$olo"", botricr. SO. 16l
oom,"."";. o.,._i,m. 193 <omooIW ... i'h aid", ......... )69 mi<1o'illi. pi"""'>'''''' 180
• ,0n'.";"1 en'y .... ).<9 <)"oIosinl en.n"" . """i.,ed wilh • ")'C<1'OI·)..phosplt .. c f"""ation i•.
.nll""' •• ;.....in. in _ . .\46 l7H IM,220
_ 110 .... d;"ribll,ion. 112. :lSI. dOli ttotri<, h)'1>O'he<i .. )81 ")>:0$0" .y.'h . ... hormone
JU, III mi<1ol ubolos. ",",,,,f.I.m<nl.. and. .nd. 800

.,
_ &]t>«»<. m ))9. 380 in Ih)'m.,. ;.,'ol",ion .nd. 875. SSI
blood )49. :161. 371 . lJl. 00"";.0'1 ond. l70 Ii"... acli ,i Iy. )'$i'
181.381.381.390. UJ proItqI.ndin .nlqoni.m.l46, 357. fi..'ins. . nd. 163
bod)' Itmp<""",.. lS3, 391 """"".000.
".'",,,,ad;
ondc••'''.>pOT1,.J.82
Ih)'lhrn ...... p. J9J. 134.
SC"'R P.nd. 3S4
"";ium ellect' on '«<plO< "'ndint.
188
""",pj.. phri .. ond. 120-1 . 1-14.
27<.277
m ""ion .. 1I9 TSH.nd.l-14
C RH =ion. JS4 $Om.,O>I.,i. " nl ...oni.m.lSO lOIIIatomcdi ... OOi .... in,oli. and,
n"
DNA mi'o>io, 191
010<.«>1)'1< m... boh...,. "'ytO<in
,"""o.;.m, 392
phorrn>«>l<>$ic>l ...
=00."" 10. 313
. ftWi",

u ....
"'
IriO<')'",)"«,oI m<t. boli"" in. 16.1-4,
16S.l74
• "tOoC<llub, nuOd .01 ..... 346. 384 of. l85 di<ttrylipid . . nd.161
(lRH,lfOW\h hor",,,,,,, ...,,,,.ion. Adipose Ii ...... olso «< Fot di"ribulio ••
Yll. 191. 792 313 Adipol'\"1«
h•• rt. lIS. III "'ndin,tO. """ium ond. 379 .rom..... onlym.,. i •. '16. SSl.
in,..';,.,., 833-4
leomin" memory. bch. ,i"'.39Q.
di"ribulion. 316. 317. 378
1),P<'S.Ip;I"" lJJ
M' ••)'.the';.. 96.
'00 .,.,""'
In. 3)4 """",ion 581. 031
ADB ""'tabolilo. .nd, 8)4 """i. «$ion. i.vol,"" i. .n<I o>,ooporo.i .. 450
h."..)',; .. ><Ii(>OS< ,i .."". In. 3,. ""ulolion. 388. 8lJ """"ibtllion . I" blood "'"",,n. i.
Ii....,.. lIS. )93 b,a"""""P'''' ><lui' m.l<: .. 58l

.
ono, roI, ..1XS. ,190.
.. 134. m. S)4 m "rom.1 «II •• nd, ... 5
metabolic ""'. 392
!>lSI! o«",,;on. 192
n>1numic hormon< ",1<0«. )85
,
.;i",um,· •• ,ti<ulo, orp ••• nd. 383.

OVI.T. ).89
",own (8A T). . . nd. 759
<o1""'<>Iam i!>C. Ih)'roid 110"""""
",ul"ion.769
""u"'." 76
po!>C,...... Ii,'. ry ".nds. 391
noci<cpt= 389. 834 <okif<rol """'I< in. 411. 4,l()
"''''O<O«t>lon. sod ,um I<nlO<$. SI. <01«koI'min". . nd.277
""<1uril"'n. 335. 833
pl>oopholipo..,.. 380
389. ilJ
1"iolo,;ool prol>l<m, ol>OC'i"""
<>'''''''•••
COMT ;n.1'I7
nd. JJ. %
00"'''; ' ,. metaboli'm. lS2. 334. wilh. 3.88 ",.,ribulio., 10 body rn,t>boIic ""0 .
••
PR,... 332.)8<1
«<relio •. [..,,,,,,, .tIe<ti",
""",)'khoJin<. J88
m
(... Fa! di"ribu'io.). SO.
prosl2.£landin ')'.,..,.i..
>80 ad .. n<:rP< re«plOf "'mulolio •• 216. 220. 603
.,
:!\)<.
<¢n.I,Io>r"""li. p,<"im.1 ,"\>utes. 280. J89 ''''''1<. m... boli,m in. 644
aldosl.ro". 321 f.t:I<a. bodr ""i<><
<e.in rtl<.... ,.7. 3S4. 3ll 'nP>"n,;n II. 321. 345 . .1<16. 361. ""ben)' timi"" 0'10."",,1
"'l'rooioc,ive ""n";,,,.I34 384. 388·9. 390. i3l . nd. o7()
.apollO<> '0 "'cu. 388. 834 .. )(il ,',nlromcdi.1 h)""lhol,moli<1ion,
r. ..I. 192 <hcmor<c<ptoa. pharm><oIosinl . nd.842
.mOOlh mLI>Cte. l71. 833 ",.IS " """" ."",k o,idalion Il. ISO
$Odi.m meuboli"". '''"'pot!.
331. ""lI'<ill<. 390 phoophooi<>'c=. cAM P .nd.
382. 188. 392 C'h)'IOkonol. l7Q 190 M,
..i ... )88. 19! lilhium,37() ",,",tom«li • • and. 80l
TRH 5<CfCtion. 392 0<01 170 """,'h horrnono "'SuIOlion. 786. 80S
u .... ,,,.,,,,,,,. lSI
unn< ""um<. 369. 377
<hlori<k ion .. 370
ond""""i ••. 33S
."
hi"", • .,i,," , >«u",ulatio. pr«cdinl-
 , _ " 2JO inl<1'>C1ion. with 18.
""""nl<'< 10 .nod• .,,,,,, .n<!. 230 ,nvolu,ion followi"l
"",ret;on of PfOCCS .. ron<. J.«
,roph;c "<,ion,, 2.lO. J.«
ADH ('''5Opf<"inJ f<lohnion of, 60,
'"
iwr<n i., in. 342
.non",m; •• o,ida ... in. 199
JS4 rqui"ion of. S99. 600
,""" .nd.219 om;,hi"" decarbo.)' .....
1q"1. 'i"" of. )2 1. )24. 'IOro;doson<si" )SI
}t9·51 """.."in r=P"'''$. ,SI
," f"u" 108 fq<n<r> ' ion follo";"I"nu<1• • ,ion •
• . dd in. D.2M
.u,,,;mmunc des,,,,,,,,,,,, o( 88, hyp<rtcn,",n a nd, 142
• If"",'", food ;.lOk•• C. BI'! in. 449 ",ptOtI",,; ". ')'I1<m """ ... ,ion .
",II "",hf... ,i."... "' ...... 1. lXi
ACTIt . n<!, 67
'W
"'OS• • nd of. 220
.np.,1<n.'" 11,108 "ructUr<. (= Zona &Jom<:rulo<o.
<AMP. 214 F."'"",I . .. 36. 1:\0..111
fOF. ,,"OWlh fllt1= 67, 214 ,"mon, """,-",nioal.yndrom< .nd.
i","lin, U4
!'OF,.. 114
,"
Ad«n.1 mod"lI. 110< N_pin<phri"".
,1I0I0>.. ,,,, m."bo.);.m ;0. 9llJ2· 4. 1
>«1)'loholinc f<I"Ja,,,,,,of. 19. 171
<ompt" ..",.,. h)''''''''''''')'. lS7 ><I"'n.l"o""".,,,,"
inn\OO<>«:o on Acrt! .nd, 2S2 f""",ion, . nd, 2JO, 271·2
""leium mcubohm>, <16. ' IHi ADf! ''''.260 ' )'mpO,h,"i< ,,11>."1'"
f.""",,,,,,
imo..,", gSl
piluil>'Y «11 mO<Pholo$Y. 1m.
S28.
cAM I' • ..,. 2S4

o1<>olopm<n' of
."';.2S1 ._..,id fOllowin,. 272
;0. 1l). 292
blood 1lJppli<d by CO<1<'. 2lS
pt.,,,,a Pro\cin CUP.nd.49 ",II. of. APUIl hYJ>O,h..i, and.
l4J honn""" ",<I, 11;9 "".",1 cr,,"
oriai., 11I
prmoe.i. f"""tion,. 600 MSH,""' • • 9.611 CG){P in. 41)
"""".... 10
211 ,,,
"""imi'),10 "">'<Iopi", JO""''' 01<><101>"'<0'.
"ucoroni«>id •• nd. 211
...",,,>On of PQMC-<I<,j>'oo Ih)'mu. '00.114. au NGF ..d. Ill. 18), 290-1
""plick •. 8ll dcl"«1. in .. h),mi< onimol•. 88) 011"«1, of6-0f!·DDPA. 0..011.

,.
><",i';,-;'y 10 "OSCow, f,u I. 132 , 2,9. 706-7 dop;imin<.l11
243 ACTIl.nd , 2J.6.1. 111, 612 •• in. 181
","ium .,<,,,,ion. ",lei",,,,o •• d. ,horio.i< 1OO..:I"\<OI>i..."d. 253. Ji&Io,..,.-.n 'V>' """"'''. 214·S
m function, COO1po.r«! . ym",,'Itc1;<
n<.""".l11
'oI<ran<'<. 3)9 EGF. FUF f<I""tion of. 70s hormone ".s. 189·194
'."'i,'o l ,nc-<. sa l, i.lOk< .<>d. ))1-, in. 706 &I""""",Koid . . nd, ,91
.. I, <f'l,,';nl ,00. 111
blood ,uwly. 255
n.
Ii JXll)<01<i ,00 . 2SS
min<r.lloc<lniooid. '<1.1.,;", WOO\.,.
I>NMr,29J
NGF .nd. 190-1
f.... I. In 1)9. 70(,.7 .. I' bol'n«. 708 ""'''''ion. 59. 7_
mojo.- ).4. 50. 232 . 1J4-3. MSlh . nd. 49. 107, ST' ,n\i<'p;t\l>f)" ","",>I.II 3
11(>1 ...,oi<Iov..... 158. 107 broin "U<'OI'«'<plor> . Ik<;'irq. 27 •
>p«i<> ,·..
.... l••oq«. in. S67
lJO. l hCG , nd.1HI
. ulf.,ed 1Ionn0«l.1)9
r,,'ins ."d.274
ki.i" •• nO.))1
.Ike"

-,
14. )6,37, 2JO.l12 lrop;C of ItCH. 106 ",I.,. .. of <pin!"<h,.inc.
""m"n i" inn""o<e$ on. 814 X.f<,. I>OrI<.611 m
,j«, and. 816 DII EAS, "LKOCorIiroitl, . .d , """'. ",,,,,,i,,, , "d. 271
Ad", .. I,lO.d" . nd"'l""" 41. lJl i",",n'.,ion , }71
ro",'m;"n to olher III ">e, perin. ul <h.n",. 1()6.1
JCn<1;c dcl«,,, "",""",<tOid
MAO< in, 299
inn""",", on ""'Opomio< in. 196
um..)". h.i, IfO"" h, SSt ')" 'h<>i • • nd.2)9-41
612.670 ",pro<!lK1;" < m".,,-,ion ')'mpo'I1«'omr .nd. !71
bon< """.",ion. 481i ..d. 1)9-41 "ructo",.)4. )7
hINd<>. lSI. 66Q i>oTm<>nc> of. 93-6. Bl·l45 VIP ill. Xl
,,,
"product;" 'l'''.m <I<",lopmon,. . nO,,,,,,n,. 41. 1)1. 136-1
bioo)'",h";,, 136-1
Ad",n.l;n, OM Epinephrine
M", ..",h<. 612, 610
limina ofpuhcrly, 5Sl. horrno<>< ,00. 789 M"'nc<Ji< """ron, («<
in .,.,.,m.,,,,,,,"...1 wOm'n . SS l llS·8 o.""hol.m i..,.
I«""ioo. "'ASII. CASU .n<!. 612 DHEA. DIlEAS- 'n. 611. 1>4). io .""",t. oucl<i. 'ob<ro1nfundib"l.,
>«ftl;"", ACTH , 00, 239. 140 W ,)... om , 836
<<>nC' 110< AI<Ioo""o".. """""", lll, 237·8 i. I'to,,-I
GIlK'O<oniroitl" <1e.), SO blood "'vel.;. ><lui' 0'1.10<. SSl m""",,ion, NOF o"'. 105
A("T1t ",*"1 .. ",,, of. 4. l S1-2S7. 1.
m
"*"·<1<,,,."<I<n, .hon"" i n
""",1<roid.I I'TH ,nac<>ni", 486
P'OI<11000"<. 93. 234. 2)1. 237
11,..OIt ·I'fOI"'I<rtm<. 9). 234.
roI" in "'Iul.,;on of
EGF >«""ion ...1,,-.1)' ".od•.
",n,i'ivi')' '0. 611 23). 2}7. 646 opidid,mi,. S79
,ulf.. ed BO·I f. llopi.n ,ul><$.
cCi MI' .n<!. )SO
diolll.1 ,'ori.,ion,;n ",n,i';"i'l· '0.
'P«i<. d ilf.",,,,,,,, 2JO.I pi""., ."rodiol m:tpt"'" 859
in nocrK'<' 0" I'TIt «<"""",,. 468
1>4. 11>4 10<"',;"•. ))1 ""o<1<ron< """," """, 600
LDL r=pIOn, mem""'"" ..I, . ppc'ito. 16O 'h)Toid 11'00. 764
•• ,31 inno"'"ion.2S7 "'0'"" "I<rin< ",,,,,. 109
 INDEX

M",,,"'l;O ««fI!"'" (se< O'o<hobmin< r«tt>W>. 610 i. "".1.,., ","",I<, Ji",,,,,,,,,iroid,

r<ecfl!on), 215-6. 177·281 hi",,,, in< d i"ribution. 30'1 ...0. 187, 211
d i"ribu,i.,.. 197. 219. 2so. 1n 1&4. .. ...,,,,,i,,., u.. in 118
346. )Ii 1. 791. 851. 1S6. !/is, . nd"""n .. 584, 6Ol. 6O\l.1O AI"", pheromone>. II
m ,<0,0>'0",,,..53 • . 611 "'bumio. pI.. m.
facto" . lI"«1inJ. 141. 143, 281. 2&4, cald' oni ... 477.• 8Q.1 calciu m bind inl-415
76'1. SSO. 3S8. sn ,,,.d,ol' min< 1) .... ",I<a«d. 295 <OneC"'' ' ;O"' in t>lood. 108.243
.. ,ri"" binolill£ '0. 8S9 "'"",,0'. 610 fa tty.dd ,,,,n,po<!. 163. 169
'H"', 276. 211. 279. 2SO. 2114 FSH, S93. 61 1 J1)«I'yia'ion. oone",,''''';o. 161
Ad"'r>OroI1kot"",in . ... ACTH J1""""n.191 . nd .ffini' y for fOl' y acid" 16'
Adrcnodo,in. B4. 254 1'O"1h Itormo"". 612. 789.90 Itonno". bin<Ji0l- pIt)>ioIogi<.1
Ad""""".i\.01.yndrome. 519, 5SO. 107 1'O"·,h honno,", ",,,,•• i,,C im"""'n«.

.
[(18..9
Ad""IOI.lo",orulo'ropin. 374 hormo"". 789 .Id<»'eroll<. lJ9
AoqOOtio .• 1'
AFt' he" 5SO. 5J.8, 101
AI<. ",o,.""i.,.. ,n,nW' •• S>O<io«<l
inhibin. iohibi. f."",;on •• od. 533.
on
LH. 593. 1\09.6"
,
.n<J"""n .. ",lea>< fmm ,,,,,i• • nd.

roni<O$l<1"OM.14J
... i'h lRH.1\09.10.610 roni .... 108,242·3
body , h.n", • • fIo, PVN nou,ohypoph)1;" P<i>lidcs. 372 es,...
diO)l.641
Inion.. 835 _".",no:. I»' plx<n... 711 ,hy",.i"". lSI
!>n,n dopam,"" <<>nICO,. 281 rd .. in.657.1 11 Al<ioo bluc. pi,.i"l)· cdl .... ininJ. 816.
CoIIP$. cald.m , ... n • .,.,n, 447 Io<omotor b<h",'ior. 288 m
",k ilhol m<\.Oboli.m. 441·2 mel.,onin 872 "l<I>lo<,oll<.3JO.I
",II. "'l'0. 'Hto'" "rue'"'" f."",ion """"" .... ",n.i,; >it)' lQ AlOChl<i< fuch,;n. pi'"i",)" 0:11 ... ini.,.
. "'.." n ooI<i. ""po"ICS '0 ACTH,612 82H
.. ,,,,,,,n'.67 1 O<l ",".I«1om y. 3.10 AlOOme!
chromoph"",,, of .denob) •. ca!<irero". 442. «0 ellomi"'}.19)
m ,>k'lQoi n.. mx: inh ibition, 292
",...... '.'<0. 655·7
IlIlIo",,". ,"00 •. o.domctri" m. S44
dihrdrotcs,o<, ..on<. 527
FSH. 530. 53 1, Hoi, 539. 611 . 621
Aklooteron". SO. 93
•• ".-ohotmo".. 332
h HXl,h.lamo-h)'popIt)'1i. , ')'''' '''. homlon<. 6Ol. 785. 7<10. to $lu<o<on;oO)i<l ,"",,,,on..
••
1i,,<t.6()t)
TcBG TIIG. T OPA prO<lv<1;On.
195.791. !I05
i1l<, ""I] o. ha."ion. di.btto,
lZl. l.lo
'0 pI • • m. PfO" ins. 10'!. ))9
""d. 804 1>iO$y "'hc,is. 95. nl·1J5, 3Jl
k'.. 602. 150, 751 ,"ow,h "im"'."", 601 in f<l. , adren.l. 707
0"00 in,ulin, 602. 726 blood 1e,·0I •. n <l. 339
_)'I< ""puIOl;on .. 531. 67 1 ..... ;" . """ 10 de",..", ...", of 0:1" ,ynth<.izinJ. 2)(1
>l"roidoc<ncsi. in. 637 201 eIICct. of .. I, de"";>"ion .nd
po",' h)',oi\l $I.nd .. """."'. -!(is Lit. 534. HO. 621 l30
pi"". 1", . d. I11<I"o" in. <l'r""" on ",prodU<l"'" eilo:mi",)". 9S,:tl.l. 130
cako """" co""",,;"n. .)·... m. 847, as. <1," "'00:.339
(.,..mlOOm. bodieJ). IS2 MSII. mol"""io <hi. on 3:10. ll3
tklici<l>C)".
011"«1. of o... riec,omy Ott MLT .mphi .... " ,kin. 812 Addison', di"".... IId. 229
fIloou"ion,859
in. 86S
r<GF.290
<10
DOC '''''''01<0'. 311
..It CfO" ins. 323
pI"",n\.O. _ "oro .. """"" i.,.. PDCF.602 """"nd.1)' ron",,!u<n«>. 330

'" pItosplt ..e in diet, 4)1i <!I'«" of e.",SS. Jll

""" ..to $la lld .. 602. 60J ..,;". 602 ....P< pMnom.non
"'m inal "<sick<, 602
"'010,01 441
!'Til , H 8
som.lO",o<Iin .. 8(12
es,,,,,,,",
••
. nd. 394
PO ..nd, ll2
00 .. m.... f,..gili,y. ",mO<l<:lins. teSto".",n". S27 "atriu,.." i< itonnollCO .nd. )&)
449-lSO.437
.nd. 19 , imm",", '),''0''. 222- f""",ions oompoml wi,h I.25--D. 4)5
ionuc ..... 0 "
ADH """"'ion. 12l
6O\l-611 ,hymo:,omy. "'I"oo""'i", ')1' 0",
So""'i 426 '." ',en.in prO<luction.384
,hym.'J1.n<J . '")'rojd honnones. 161 bicatbonate tno""", in kidllCY,

"t<.
""roOd
prO<l ... 'iOl1, 881
0:11 <on'On'. 67. 341. 181·)
r=p'<>r.< in, 812
"im uTi
rek.",. !94
,,,,,0" R.iO .. 663
at«bo!. m;no
'"
",o ,mlll«li., o uclei. IS3 ')""<>' n"mbt .. oflbnormol f<><m«l.
<oncen,,;uion, of"'lula,,,,, in biood
1<'0 .... I."roi<l .. duri"C m.o"ru. '
.... 641
"'
"",utin.tion of >pOtm. """"
•• ,ibodi". Ol3in" LDft.
"",Ia,,,,,'o. S66 ron'raception .nd. 113
pone...,.,i< 191 "",.'i"o'ion , .." for t>JtSIIo"'Y.

somotomc<lin .. 797
som' IO$ .. ,in. 739
ro"",n"otlon. of"'lul .."" in o,hot
".iO,
m<l.,,,,,i •. ",,,,brospin. '
1>0\.0""." , 00 .. n.io.ll(
• nz' ......
,,,,,,,.\.0>< distrib.'ion in
583-4. 586
s,,·r<dLOCU>< oo,; .. ily. 607. 61 1
'"
Agression, "'"
_ • • nd. H7 . .I(;)
pI>c""",one •• "d, 23
866 pi ..... o'.. ion <h..... . $SOOi.1«I wi'h.
'"'
AlB. AlBA. olpho .mi no i"""',),"< ooid .
in, ulin .nd tlOn>pOrt, In
AI.ni".. 'yn,hooi, from P),,,"v.to. 162.
'"
 p,,,.,,ium ..,,,.,,ion. 111_8. 1J9 Allomon< .. 20 Am inosl"''''himid<:.24O
proI<in 336 MIo,"n. 19'1-200. 101. 103. b(I;, ew.x.. Q'
..Ii ,",)" N",K .. ,io. l18 Alpha A("T1l =mion, 239
..It 'ppeli'e,)32
SCA RP. 334
><k""" fpo-p/'t).;, (ocidO])hi
821
...."'n.'
.",<Ht>i< ..HI. 219
«II p<<>Iif<r:"ion. 257
m"scl<.lJI """""'.", ;>10" ($C< A. A, «11.1. 11 <l>oIes.Iorol >«umuI1lion. 211
$OCI; um ",,,,,,;0.. l39 Alph.·mo'hyi po,,"' j'rooino. 'j·""i ... 2l-)} 431
I" ..port;n kHln<y. )31·6 . .. 'nM';,ion. 290 l'",,,,.nicoKi tHo.)·n' .... i., 2)9
;" <0100. 336-1 Alph.> ,"bun;" of IIyroprol<in Amioopoptida",.
Ihi,..,. III !>or1llOOC1. $C< FSIl. Lil. TSIl. "", .. boI; .... 78, 3-41 . 349
wi,"
;n' • ...,';on' hCG .• nd Subuni"
"'fa.
" !l idi. oon,o"ion to I>radlk;n;".
ADH .182, 33:1. 384
""porin. ,hfm ••. 39S-6
prQt<""'>II<. 144. 212.11 1
ALS, . nl ii),mphocj1ic e,pori"","'"
"",lIi,u, 00<1.:101
... tion .. 117. 61>6
Am;.OIl"n".'" " ''''*''''
.)'n,lIe.i .. 061
ooOlroi <>lUNA

probo';n.393 ;"n ... """,on Amm"" '.m ion.

\mnl ""nod. fOtorr""... lJ). 1M. I.lS·1ht;mula, io n ofC. <<In''<man to "'-':' . 181. 329
m«h. ni.m,o[lI<1ion obootJ>!;on. 447 .'.<e'
;"n. al<!ostor<>n< defo.:ic ... ), ,11<1.

••
..";"m
.... ;, .. n' olf«;" on

.teroid. wdiom
1)1·8
<>,,""'"
,""," Ia'ion of m<Ia'oni"
.)·n' .... ;•. 8S9
'<JlIlation of IHoM
'"
f""" .. ion;n IS). 327·329
l i"""""iroid •• nd. JJI
'ron,port '00.3)4·)36 b6 "".... 'om and, 311·9
• I<l.,.,.",,,,, ;OO""ed pro",;n, " imol.'«1 oodi"m d'rale adm ini""''''n .nd .

.ifc<1,
'lpkol
)4l. 134.
M «II, 'ock;n, """to; ..
J)8
Am<nort"II<>.
l'uoo"<"os<ne,; .. 219

an,. d;"",",;" 0;.' " .-.1 '"

",,""i , m ,"e"';on .0<1. 329
mi...,,, loron;w;d PO"'''''Y. 2" <00,,..,.,,,;.«.119 ,o,ici\)'. lal. 329
ph.>fmaroloci<>' "",nl> .lfwi",
f."", ;on,. 330-311
""'j' '''' .nd. 722
h)·ponhYI<>ioli.m .nJ . 746
Am""," , f""" ..;on .......,,"1<.
.toroid mctaboli,inl "",)m<> in. 706
bindi", '0 . ndrot<n m:<pton.1JO 1"",.,,,,,,. 1. nu,riti.,., .nd. 69' Am"""i< auiol
r=",,,," 'n""", ;".. 330-' "u,nt;""....lti", ""d . 610 """iool in. 11)
"""'pto,," d i",,!>o,ion of or.ol ron,,,,,,,:,,,;'o> u>«l 10 i"vok<, fu"""",,,,, 691
br"in. H8
«>I<>n. <oop/t>£u ... m a ll into"i .... proIII<1i" '", 00. S99
&Of"d>l >to,oid. in. 636
0" "","""" boh","Q'.
'"
337. 3JS Am ilond •.
Cll •...,,.,,'" '"motS.
794 .ldo>loronc lI<1"'n., sodium """"""'. ;" n... """ on .-.:".-0<1",,;," ')'" m
..... n.338 lJ7. 3S1 nu, u""ion. Is.!
kiolncy. ))1-3 «ln "",ion of 1'f'O.. 1I rei n tG ho,mo .. , suppl ,ed by ,rophobI"t.
",OIj'p<>. "croid
r=pwo.l'u<oron;o:oi<!
11)
'0.
•. JS4
Am;no typo hotnton., ($C< .po<;;k I1CG "'""-<,,.
69'1

'" bill<l;".. 1<4. 2l2. 194.

prQt<.",..,....
I..,.
\);O$)'n'IIe,'" ollem;," ),.
=00<1 """"'otCf hypo' .... i. "d.
n ...
Q"'0<;', ;n.1I2
Pl<'I<''''ror.< in. 636. 106
1>'OIoo';n ;n . 730
11 3_9 p,o"ql.II<I'n •• pr<:pOnum n",. 712
Ami"" .dd. (= 'p<Oific . mi"" T R It ;n.
' 1. Il TSH in. 762
po$! "'" "",i,.., by <"<II .. <oni<n for. AMP. adonosin<
m form .. "", f,om <AMP. III
fll<1,," . Ik<'in, m.",k phosr/lO<)'la", an<! .
II 112
"1><>£O'!, 181 phMhof"",ob".", ><1;'·;')·. l',.rol)'O;,
IIu<oconiro;d .. 21S . nd. 171>-7
in,o li•. 114. 8Ol. 805 Am",",""", B. 241
PDGF. WI elK"" Of! pi'";"!)" 3.27
sodi"m. In 802 Am]>I"",m;1'>C$. 286
..,m1l0med;0 •. K .rId. 302. Wl
Ih)roid horrnon... 76l
,If«" Of!
b<h.,·;",.. l88. 2%
.. hotmon< p<o<"non. 72·14 ..,«hQl.ornino ooq"'''''' ion. 291
blood OH and. dopami"" ",Ie.",. 118
c.",",iol. 12. 172·3 fo>o<l in .. ko. """'pion for. 842
<",'O,ion. PTIl .nd. 469 """'Oo',mi "e" h)-poIJl)ttmi. ,
;ml»l.""", .If«;"
l'l>«IS<nio. I), (87. 21 3-9
on ptOt.;n
.)' nl....;.. 172. 218
;n,olin .nd. 841
MAO ac';,i' y.297
Am(>h;bi. ".
'" "''''''0.
i.fl"" """ on
ADH .. ,ion. on . ki •. urinl!)" bladder.
J77·S
fQO(l;"take.'. ' . Id""",,no elf« .. on "ri ..!)" bI.dd<,
>«fOlio • • 197. , ... n.porI. ))4. ))7
19). 794 <1-...• porm r=",""'.
jlon .boorpl""'.
LRII >ttf<l;on, 196
12 507. lO8
<ok;'",,;n f"n<lion .. 48}
po..".... i< i>lol" insuho ><t"""'n. m,.. m<><ph.,.;,. !>or"",,,,,.
,92,1%
.,
. nd. 398. SS4
I'TIl "'$"lalioo of N• . P ,,-«<lion. oroIa<1'" ,.t."",;,... )93
'hymuo . n"'Bon i.m. in'oiu''''n
k",,,,,,nic. 117 i>«tto.I;nt- S34
m<taboli,m, l'uroclM1i<oid. . nd. I), ",.,...'in elf«l. on a. metalloli.m.
. I,imooran<hi., bodi ... 4SS
'"
 INDEX

A m"" it.;. n
.(...,.".)
prol.C1;n ,Ifm, on $\;, •. ..
and ,<v".lik, ><Ii,ity of ""ndiol.
."..1 ""0'_""',,,. 602. 717
in fem. k>.
.",.'1. I'bido. 51l. 603. 621. 660
'nd. }'IS bindi"1 '0 bo .... 150
proo'.iJand,. <Ife(:l> "" blWde, "81'. S!7 486-7. 607
sOOi"m '",n.pon. )11 .."minol 6(:(1 heoli ... mincn.1 ront."t.
. j; 'n. ".,",,"', •• Til. II ; n. $ I. 16S pI.,ma pro .. i." lOA. 58S m".""io". 441
""n. "",n"... col", MSH. MLT .nd. bias)'",h",i" 94. 96 ""' ... Wi .... 14J. 60'1

.,
ao"n"",ni"I,yndrom< . nd. 119.
'" . 6. 41. )98 di,o,;"
wa"" dri,·, S50. 101 EGF 6>6. goo
Arn",,<>p/1,1 cdl>. 326 .,inc ""d. 602 rood, ';"m;n. m;nmll me"boI;,m.
Arnpt,o .. rici. B. »S-b .>' . .>' ... S18, 534
"'mpl.. "'trosen, .nd. 510 FS H a<1ion.. 6>6
Am"M,eo,'on of ...."',,n ... b'I FSU ....1..... S9<

...
", 837 lQ.h)"'r<>.)'lat«! """,id. 000.

in 0<1=.1 00,,"' . 1J6. 7

po>to,.I .. "'1". scrond.
657.660
'"f#.
."oc'ot","", o,he, ... i. "'lion,. in .pK!id)·mi" 60 1
in 1<"1 o"'ry, SlJ.
""wth .""n. 50. 607
hoi' JrO'O,h , 150. 607
., rompOn<n' ofl,mbi< ')'''000. 837 in tc,,1 t .. Ill. H4. 610 "".n. ""I.
604
""" ;<alh.I, mk "....;..:tion. 10. 8>6
pa,.,.on,rkula, nucki projo;;'ion.
'0. U4
i" Ij,Ct. 110
i. o"ri" or "".It.
621. 63>. 6)1.
40. ()016.7, MI. 612
.Il00., m... """ndi, ,on in,"
883
imm ... [."";on,, 608. 831
'0 ,ubofoi.r"ndibul .. "10 ....1«II •. S40 LH ..... tio •. 194. S'XI. 609. 721
' .... 0.01.,;"" and. 113 liv<l.606. 722
.ontrom«li.l nucki . nd. &>6 in ,,,,,i,,in'."';lial ""II .. S81·584 r<mi_"",,". 607
eo_)"'''''' .... '.ooli... in. 131 ;n So""'i 516 I,RIl "'10 . ... 594
ru"",;o." mOlionohil" '0 ••
'onom", blood 194 llS-b
0<1.00' 'Y"'''.
_to
337 ,i",O<I ,o. ' ·oriltion •. 58. ',om"""ion .nd. 608
hil'f>OC3m"". and. 838 i n \OIOIl"I< •• ()016. 1 o,·.rio>. llS
""ul .. ,on ofGH ...1<1;on. 794. o[ ... 25 formOlion. 634
7'JS. 838 ;n domi". n, ., •• b.,i .. i" """"- eo,,,,,,,. ,)·n,"".i •.
"'I"I .. ion of
" aroma .. ",. 649

.
lO<r<1ion. 838 ,' ..... ' ion. wi,h "*". !c• .".. 1S4 [o>Ilkl. .""" •. SJ8. 5000. 61S. 650
&lococor1iroid ><I;on. "". ll9 che",i"I)'o 94. %. 237 o" . ri. n 604
,n""",,,, on body
i.n""""", "" ".I,
182
'pp<\i'c. J60 ,
ronco",,,,, io", i n "",i<" lor I),m pt,. "",n"nul e)·ck •. S50
p<nilc ..fie.... 5S)
LH in , 591
"""""" .. In In. 791. 7'Jl
""""'n "oIPn',60'·2
.. j"", ""I.'red by ",*", pi""'l. KIOMT ><I;vi'y. 860
In ..,
..... oolio '"'''''''1''' Androt<"'). J94. i" 17<1 pit"i"!),. l55
604. 605 to ""'oro .," sro
IIoha,'ior. ","""",,,,pi. """'PI.,.... lU. S91
...... I$CS,. (... "";. J>e","fIlion). 6. 58- """, .. ...;,,,-, to dih)·d "",,,o,,<ron<". pI •• m. TOG. T<OG. T arA.
61.67. 229.281.161
AnoJ>/l)'lui .. RC"S. SII.SJI ..d. lOS. lOS ,n " '"
rmi"al 600
"rOO""io •. 186. 750. 111
!>O'«ri<>r h)'poth,l.mu. ron"'" of
,\<>«" ..1 " ..... n<i<nt .nd Prot<".ro"" "",""",ition ['" "prod ..,;,. """"vi.,... S)3
IIorm<>roc """',."'. 80. 89. 473 "n,)·"",. !-IiI proIa<1;n r«<ptors. 602
hormones. }!;9 ron ..... ;on to 231·8. 637--40 »<OIO<Ii • ...,..,;on. 59\1
facwn. .. I., in. i •• vlin. 70'1 FSH .nd. 539 ,)'n, ...i.. 602-606. 601
""wth h"""""'. 788 in """",1."'.01. 6SS "''''''.... 10 eolei,oni • . 48)
TRI!. in dominan, fQlli<k>. 650 ","ntion or N•. K. CI. SO•. C• • P.
Aoo"""n bindins pro'.'m.. AOl'$ in r,101 Sono>li. fQll"",!a, ""II •. S39
bindi", '" "",mOlOIDl.!J2
biosyn,,,,,,i, i. So<1o>1i ""II .. 527
FSH .nd.
hypOph)""""'r .nd. S33
"'''o''oron<.
. nd. SlJ
DHT. and""" nOO;ol,
''''0",,1'''010<> Ind. 2. 1
ronv<nio" to otllo, """,ido in "'$Ii..

"'
dcl<mini .... ion b'I. S6()
.roo""" h)'pO'''''';' .nd. SSO
d'V"'>tio" .• «",ion. 131. SM·9
.,
",Ih"ry eland .. I«n' ,I. nd,. 60S
•• S50. 601
>Orond'I)' ... eh.rao,,,ri,,ko. 550.

,lelc"l m"><Ic • • 87
m)Ql....,,;c "",ion .. 604
niH .nd. lJ3 b)' ron!t£""'" t<1u""," SS8 . kin Ie".",. 601
di"'iootion.'ro",pon. l32 in o,·,ri.o [olli,., .. AuK!, ()016.7 'p<rm"""'nes'" lU. 600
in 532. S7'J infloc""" on 600
in ",,","la , R.id. 178 ,,81' ."O;Ii,..ion. 5JJ 22J. 539.
"ndrot<nir.,., •. ""'....1 .cr.",o,)' ",prod L>C1; '" "'P" 608. 8" . S82. 881
,Ifc<"
on o"ry. S)9 ",,,.,,,,ion. [""",ion. 601 TSIl h<1o in blood. 770
",nod",,,,,,, ....""ioo """',,,, .nd. r."",ion .. 60) in .."k.l.. ft"id. III 178
proo,. ,.. «II proM""",,,,,. 131
'"
"""""'ro",, """"",ion "*",i 0". S61.
.,
",",in.1 vffido "",toi". RNA.
i"" ",,,,,ion>
eotocllQlami .... 561

"'
539.
l>'Ol«1ioo "*",io". 2lJ.
88)
"rom.1 ''''''p:n
.n"",.i. m.601
<AMP. 652
FSH. 6SI.
JllK'O<Or1i<Oid.. 229. 604. 60Ii
Androt<n. (... T<>,o".rono. adipMC ti""". 60S ""v.," 1Iorm<>roc. 606. 789

.,
Dih)'drot<".,,"ron<. DHM. 'rom. "", indL>C1;"". 649 in,"li • • 60)
....). 9<. 59< IIohaviot.001 prolac,in.003
, ". W k )94. 486. S6). 604. 'we";"". 606. 607
'1'I><,ilO. food '."l •. 3'1-4. 486 . I""n' pOriOO. rOf ><lion •. 608
ni'"",," bol.n«. 601 k '"" I p<""". 1i, y ,00. SO)
 """,h.n i,m of oction. 6OS·9 biO<I'"("";' .ubs'",.. , 348
."""in...,".,
";"" m'.....b<>.0010",,"''''
.... 609
in <p;did)''''i" 601
in Senol;, follkula, SJ9. s.oo
,n ' <plI."n,- 341. JS2
in",Ii •. 348

.nd.
w",""
609
oyol.",. PDE> cll<mi"<),. S30. HI
.. """,,,.Iik. "",ion •. 127. 140
. " "um;" hormon",. )83
Anliol.n'; . . ..... 18. 341
RNII , proIc;n ,)·n,I><>;'. 60S inn""""", on «Idi,m .nd . 349
..<1."",i,,,, in I;..", SS8. ;niliOlio" of ,penn.,,,,,,,,,,,,"
600 ""IioI,nsill<>S<n •. _ lIo";n ",bo,,,,,o.
'h;'roi<l hormone> ,.d, 600 kidocy.60l-604 Anliolon,;n" SOC . ,'" [. II •
.If«"on
...,...... , o<Imini"""i<)n
0,-.00.22l
,h,mu. « II •• "" , 121 Sl9. SOl.
pro ... " JIa"d
d ill".",n,i"io.. .I I 9
fu",,""''' 60l
'"
'"o.)',,( .... 79. 3-41. )-I3·9.l(i1
i""""in.. nd.342
."
o'P.i.a,;O""" oo,i, .. io",'
""bony 'iminl- sn
.. <Ictal "''''''I<. 60S
PRII. PRR and. 343
,i,,,, of. 35
l!)..1 ,,'f"ed. inhibi,ion of LH «1<>.". i. br1i •. 31S.361
po,m;"i,.., oction .. 60S
phoromon,,,nd.2S bj· .pctm.,owo. 602 in kidn<)'. 3lJ
"""p'on
"<1<>< .. .-0""
'"to",ni" \>i.d;". '0.
..nedio",,. Sl'. S30
"""'o<l.nolon<. 518. S89
in neoroh)·l>Qph )'.i •• l(i1
i. pineol. &60
'W 97. S31. SUo S$9 u","'''
.,
Aoo"" .. 361
551 r<t:ul.,i<)n or <pidid)·mi,. proIto"'. <homi",.,.. (n"',- 18. 341
orOm ... .. i.d..."iO" "i. bindi", '0. .. mi ..1 ,'<Si<I< •. 601
""",ed by O"f)" 645
rom ",ti",". of", i"""
'I"'ci<s diil".",,,,,,,_ 13
)-19· SO

do[«,i,", S09-.I(). 6OS-6 ,..M.... of. .lS3 <k&<*I ..;"". ",o.. bi>li.m, )-I ). 349
. nd. S60 IIndfO",,,,,,,ionos fu .... ion •. S$.9
Tfm ro<i<nt<, 5.1() ' nd',*nl< !>01'o<y. 236 inn"",.,., 0.
..,,""'" binOi • • '0. .1\00:1. "", 601. bio<)'n,,,,"",, 94. % . 181 '_.-00< """p,....... 3lS
00' i. o<Iren.1 ""n... 236-1 . 1doo(OfOnO .",,,.,ion • .19
in "",,'ou' in i nf. nt<, iu von il< •. 61 0. I I b!ood """,. f<. S9
in Seneli. foIl;"u l., 139 blood ",".me. So
.. , .. , 1><110";.,, .nO. tH .nd. 598 PGf, an,>son;.m. 105
,..
in <oi<lidl'ni;. DI!T oo"""",,,,,io •.

in .,tol u,""," S40

<lI<mi>lf)" M. 231
<1<>.""",. SS(i
"""".,,,,.,,,, in .n(",1 fluid. 6-f(i
".. i".61
,hi",. 59
ACE inhibi,= .nd. 319
in Ih,.... w.-. "".,·<,.iO" 10 ""0<10.-00<.'''"""".
...
i. 'h;'mu" ",FIld«,om), onO. S40.

PfOlC"CfOn< biodi". '0.

""",",""', i""""i<)n of. 602
SO I
231·8. 128. .120. SJI.
M.
sn 64S.
ion..,,,,,,,. on ",n uri(ion ,i '" in,- 11l
""""d by o'-.ry, 646. 6-<1
phosph,";"." A, .. (i,'"",,,. 1'(;
'I'o''''',i., 10J
....p''''' in ;"",,,;ne. o' ...... l(il
<lJbl<>ml<., OtP" .nd. r,t;
A", io"n,in" I (A·I)
,in<
.. i"" of. 148
,tr"", on , )) I
p<>" m,nor»""'. 17 """ ,."ion '0 A· II. ) 11. 34 1. 34S
AMrosto.-on<. 'li. '1' , ,}9 (o"'''und. j4!
"''''''. <lill'•• ;oo. m;"ro,ubuh .nd. chem ;",-;·.S39 form .. ion.lli. J40. 34 1
,1\00:1. ""
'"
TcllG. , '''''mi. ,.d. S36
'0 foil iou,,, fluid. 6l1. 630. 640
in Son",i «II" 18f>.&
Anom;,. soc H,m"ol>Qiooi,
I
i nfl """"" on
J21

biood ,· ...d,. 31l

'0 "'>I ;,u I., flu id. Senol; «II. ,R<!, A<I<Ii"",,', di ..... , 222. 218 kidney. ;13
"""""r<.
.""",ion'"
"".rian (h«> «II .. 63S. 640_ 649
<n<et,on m".bol;" ""0. 1'5
m< •• """_i",, orol
",n'oxopli"" . nd. 119
,,)coin dilf""noo, in

"""",,, 324
.ngio!< n,in II (A·II)
341

",om. 1« II.. 631

,,,,. rian ,.m ..... 6)7
",'I<n" ,,'i,h ,hy",;d di ......
of. 11'
,,'.Ii.'," ",",patt<! w;(h A·I. JI3
, nlalOOi" •. 340
,,,,,i,, .111·2 An<uploidy. I>ios)·n( .... i•. rel< .... 7<1. 31 1. 341. 348
«<""ion. f><ton .1ICe(i", ,hromooomo Ia,- d.l<1ion • • OO SOI·2 f,("\ol...
,horion;" ",.oOO"o(>1n, . KG , S3S ch.-omosome "".diliu"",io" .od. ACE inh;bi,,,,,- 349
o."i"", ... n,., foo'OfS. S41·2 ""H.m
126. SJ3 ,",co'qc.nd.141·3 hcmorrhO£•. 381
Ul. S34. S3S. 6S2 [",ili , .. ioo ' nd. "(OXOllu'" nuid ,,".,,,,,.324.
in ,"""''' I.to •. 6.1.\ panh<noern<>i, ' nd. SOl m
pi .. m. pr<>1<i.,- S36
'''''''"''''0<, potOOri". "".'.-0'.
SlS
W, <",,,,",¢ri,,,,,
""""OO.ry .. ' .nd. proI(", •• di"" lSi>.
.oo iu", «"rio,;"". 314
•.,..,, dimorphi,m .nd. SS3 .pon"."",I> .bortion ".d. S05
An,io1<n.in 'onvenin, .n,),me. ACI;.
""". 34<>
i. h)·I>Q(hol.mu,. 260
"'u",," 34.
'"'f..... S8l in .. Ii'·of)· 83.nd •. 361
,)·n,h<ll< .• ",boll<. 60S. 60S oo,i<)n •. 341. 348 Jluroronl<oid. and. 211. l38·9
.)'",,,,,,1<. "oed ., 722 I>ra<i),ki.in in"",i, .. ion. 11 tonin . . nd. J41
"fIO' "'""bj'.603186
uptake
);.Ilidi" iooo<i'·"""'.314.)SO
oo(i"i(y. IIDH .nd. 346. 348
biood·OOoin barrio,. CVo. .1Id.
<k&rod"""'. 341 . 349
upl. l<. m ... boli,m i. ,"""". ""i, i')·. <hl<>rid<:. «>d i"nt. zin<. )43 influ,,,,,,, on
M di>lribu(io". J.4I! ACTH k<re,ion. }41. J59
')'P<"- "" .. i," III in br3in. JIS ADJI "'1<. ... 260. 321. WI, 313.
"",sb"""'l'n" 94 ,'"""""n;""id indu"ion. 121 '00
viril i,OIio". ",.",ulini",ion by i<i<n(i()' "'i' h kinin ... II. JSO. ])TOO,..,.ndin, .nd. 361
0"4n • • <i<vdopm<n' . nd. 555 i"hibilO .... 1'. J.Il\.9 . 1dos'<fOnc·i nde""""," ' ",*"'01 ion
0>1"",.", ,,,,,,fo, (0 fem. " ,iblinl- o/fec" on of o1«lrol,'<>, 3SO
')'"'""i,-
'" reOO.
"""ro.... ""diol ..
SI5
9(i
liCE
kinin holf·lik. HIS
340
,ulO«J,ta,ion in kid""y. JS3
.Idostomn< ." ".,ion. 321.324 J.49..

'"
calcium . nd. 35Q.1
 INDEX

An,iQ«"".' (<,.,,) A_mio IOn i•. l51. 186

in r.,u," 708
po••,.,iom and,
""'OttJUlao"m in kidr><y.
blood P"",Ott, 221. 324.lS2
",",,.1 ",.,,01. 3SS
...00
o:omtMn«! " ';,h bI ;nd".... mol .. onin
occrclion.lo<i01ropc f.... I'''''''

inflocn«. on lM'b<ny liming. 610

i.floc""". ",,,,""oc,,,, •• ),.tem
.. m;nal pI"m. rom""""",,.
ronl",,"p,ion ond. 722
",matomed;." 198. $Ol
' pe"" """". deh),droscn'"
;"",'mo.71)
JI """"",,;wid •• 0<1. 12 I m"."lion.863 <om"o""i.,, 768, 7') • • 860
bfai • • lSS ",produ"'ivo ,)',,,0'1 ""pon .." 10 Tdl. ,.,..,; ..1
<. k'urn. "..,"Olio.din nt<taboli,m. mol"on;' .863 dc<>,)""",,<>Iid)'1 ' .. n.f......
m 111.180.191. .W
"pi nary Oil i.y. 352 220-1. 2J1. 294, 291. 3OS, )90. ""0$1'"",,-,, 0.40
«"In.1 ront,..,. of <10<11'01)'10 Ih),rolropc>, 117
lS8 An"boo<. di.ulfiram. 192-3 TRH. 761
,i«um'"C"'ricob, O'P"'. SFO. Anloriof <ommi".",. LRH in. 835 I,)'ploph. n h)'dro,)'I.oc, 303
OVLT. lS9 A.rorior h)'polh.l.mi< . .... 8)1 . 838 .'OtOtIoI>i •. 689
011.111, TSII se< ..'",". 3S9 ...o";1I'on, "'ilh ,'<mromcdiol "."ri. ""'" '0 blod horrnon< <11"""" 118
sI<lCorof1iroid """",ion.)48
in,"lin >«,..,;0.. 197
bean. III '"
do=m.di.1 nudoi projo<Iion' 10. 136
'nflocn«. on
o$cd to iderr'ify ho""<>ne-oe<n:lion
.i.... :l4, 47
h)'pol"'I.",;., honnonc .. 13
cCMP. C'lo .nd. ll3 FSH ><erolion , 193 NGF.61
.."•• LRH "'I ..... 611 peplide "",mone< ",,,,,rali,,,
pO""' .m <W<1;,,".).<6
prolactin >«"";00.351. lS9
",,"'.)'m ""Iholie. 'ympalilclic <"M P. 118
pil"itary al>nd «I I• • 824
'1"Iom,. Il)' 138
proslaJlandin ,),nlhffi .. 321. 3S1. 'nl ...... l;oo. ,,';'h fIO'lOrior "nli<iPlllo'y ront"" of hormone ..1<....

'"
lS.l. )SS hypolh.lamic oro,. 838
«onin "'.,.,.,. J.4<; ,<>I« ;n IhormolO!:ula,'Oo. 838 <aleilonin, '80
JGA. Aim 'nd . )..06 An",iot pilUil1ry, 41. 019. 818 • • I"'hol.m; .....
«on in '" 0.''''.
C'_imid, an<l.).48
"rOO """on. 348 Anl,bodi..
" 'i,,,n ... nli body rom ,nd
pstrin. lIO .nd, 471
in,.I,o. 60.
.. II • r>l)Cl il •• 32 I. .lOO .omplemo., O<1iv,, ;on. 226 pin<. lhor""""", Sbl
>Odium "",«ion, I<\<n,ion. 346. d;.t:<:,., 0'1,1 1;,.,,1,12 Anl,di.lOlie """"on<:. ><e ADH
m hi". mi"" .. ""><, 309 Anli·infurmm,,"'l' ""nlS
. ympa'h<1k ,),<lom. 160. 311. 324. iOIO,10."'.·1.101 Infl.m",,,'on). 108
JjI·9 .nti·th)' ro&lOOuli.>. .n,i _m icrosom.l. A",iljntph.,<·,.,ic ..... ALS, cellu l1l
(hin', 311 . :W;. lSt Ihl"'oid d),r.""ion and. 111 imm"n"y and. 67
'''<''IDOJ''"' lS9 . """iated wilh 0,. ,... · di ........ 77.-..1 ,h),m«kHn)'.nd KmVory rrom, 221.
""II.. o:on",rv."".. J60 UTS. HTS, TSIg. n'-"6 U,
,"". lIo""rulo ... 146. )49·35 1 U TS-P. (TDIo). An I;· M ;;IIori,,, """"0"". A M lI.
<AMP. No, K ""d,l50 m Miillorian duel inhibi,o< ho.
inlor>ction, with <roM·mr"l iv 'I y. I"<'bi<,," ."""i"cd MOl), 20. 116. 51 S. 513. 11'-"
AllH.346 w;'h.122 7. 136.
dopam'''' ..,m.,O$"';•. lS9 dir<:<.1cd qain" Anlio,id •• ". oh)'ioIot.ical. '3. I S- 19
1'1 • • C•. prootap.nd in" lS2 ..,,_m.1 m,mi:>n" compo"".I .. ,,""Iithyroid ."." {..., Th)1"<>id
l>1onl peri<><!. fo< act",n>. Jro m 711·1
r«<pO'" OCC.""I1<Y .nd, 146 "Cn!. 251. 591. 327 ,,""Itum fonnOl ioo (..., Ov.ri. n
="=
.ffmilic<, <ff«" of A·II. K. 3$0.
di,,'-;bolion.361
ADIt . 391
oar.. 449
",Icilonin. 416.. 411
0011>.'
foll icl<.). 621. 629. 630
10".0'1 f.OCI;on . nd. 6)1_J
'''lO&<n" <!omi .. nl folliol... 60<1
., blood .'....,1., Iocol oclion • • n<!. CRIl.8.).4
<"ym •• uoed in """'holami""
follicle.""., ...
o,·,ri ••q'" and. 6:l4
11<."'' '.
J><Ilrohypopily;>i>. :l46. 388
.ynl""''' 271, 272 "oroid. in, 640, &t6
An"ely. <11<<Il0l001; .. , and , 211.
.rythtopoi"",1:IJ7

.,
offix" of .ldoOloro.... N. 00 <>1f()l<n •. S37 Apofoni' ;n, 12
numbor>,312 *,,,,",,0'..0.,;,,>. 592 ApomOr-pO'''''' dopom; ... ' Ion;".
off«" of ..""",n,. P«'C<"trt>n<. FSH. LH. 191 <homi",",'.186
OnRH. 591 •.1. 594 M honnone ..1<_
A",;olons'n" ,nli<>tcn" n III (A· III) LR H. MI. 860 J.ro'I'1h iIonnono. ",malo""in. 192
341 . )49-j() LRH.617
r"...,.,ion. :l48, )(9 VOW'h hormor>c, 138. 7')5. 7%. $03 lute;n;,;n, hormone. 191
inflocnces on hCG. WI serotonin. 191
.100.1O"'n< .ynlh.. i,,)l) inlO!'COP"on ond. 12l vomi(" 1 ,.d, lSS
blood 3j() pr<&n.n<y "", . nd. 71)1·3 Apoproloiru; of VLDu, 168
"'''''''''', nli .. . ynlh«i>.)j() !l ·Y onl'''.' 51!. 111 A"",tOn,fotri •. 11
"""",00.
... n;n 349 in,ulin, in PIl'i"',, 191 A!>PO';Ie (00< Food in lOk Sail 'WO(".)
,on. &Iom< ...I0... :l49· ro NSILA, .nd, M, 7')8 roclon .II«Iinl- J2. 67
inIO"""io .. "'ilh A·II,)j() in'olin r«<P\O<$. 134, 180. 191 394. 4U. 136. 61)4, 607
An'",m)'<On.
Anor..,i . ... "''''''
MSH. 827. 860
NOF. immo_j'mPllIhOClomy .nd.
'''''''''ron<.
aldo<l"""'.331.1
j(), S36
.bnottnaJ ,.,.lalonin rhylhm .. 866 2)1.212 an",,'oni,in 11 . 121
r."""n body " ,io> .nd, 866 ",,""r.:ali< pOi)'l><pl i<k. 8 12 JI-OH·bolj"'" 181
"nodOl",";. I<vd. and. 610. 888 PNMT.29.H ",I<i'on; •. 4Ja. 476, 418.480
h)'polh.l. mic d)-.fu""ion ptt<<<!;n. lIfoin,,,lin oonn<ni .. pepl;de.">eo ",leium.476
0""" ')'m",om .. 139 of. 191 CCK·P"L
''''''I>'n •. do""mi It< .nd, 839 ""umphy.in,. )86 food rompo""n". 343
 •• SI
&lu<o<oni<:nid •. 11 H
II>"'''''. IS1. 188
VO""·,h hormon •. 488. 1)0. 78S. SOl
h>'p<>, h. Jamu.
injo'Y. 18l. &40
Pln'·m,ncol., "uclei.
""",pinept"i ... 'n. 811
,n,ulin, Ill, 18l. 130
i,,,, I;, 0$<1\(;<0<)'. lOC'>
olfactory. ""< pe=ption. 8oo.IOl
"",I hn>ocJ)",mi<: "", ... 2(11
ph<ochromocylom •. III
61
PTH. 463
",,,,,I i",.ffi<;eO<j'. SOl
ood'um. 476. 4SO
,h)T';'; hotnt.ne •. 1. j. 146. 147
TR It m."rotil ... J66
,;"". 11
"",ot,n,n
dimi!>,nioo.341
<11'" ,,, "'"
""dioinhib;,,,, foe,<>n. " .....
.. """. II I
!"Cu ll i k"'; n OCt;,·., ion ..UI . 31<
PTO<I'nin """ " >1ion. 341
,\PUD
"" """'''''ve< of
1Id"'n<>m<du II.')'. 61
",l<i"""n....,"'tiO£. 1. 62 .• 74·j
" ,,,oin,.,,in,161 . 2
'n.
.,
8'14
mol""",,)"'" 62. 86J
po""hyroid S<cr<'o,'! protein in.
pi"""IOC1t<$ aod. ill
pi,u''''I)'. 40. 816
,h)'mo, &1>00 <ornpo ..
,h,.,oid lIond 'Q"'I>O'"'"". <6<. Wi
h l"po>lh<si •• • 1·2
Araehidoni< oeid. "A. >r&Chid"".",
PlttUI'$OI". '19. 102
biQl.)·nt ...... . '19. '03
",\e... from
obem,,,,,,.. IOl
con'·......., lQ \e"ko'""n, .. 107. lOS
101
die,,')' .,,,=s. '19
,nnue"""on
calcium <h,,, .. I.. lSJ
honnont """"io •. 91
1)0>1",,; •. 1)1
.. 168
mom!:>n"" nuidi')'.21l
"",,'a,lnd,n ",od",,'io •. ll3
lI'O";' k;n ... o.ch"i,y. Il'I
1<q1lCi''''';o" in cdl lipid<. 102
,hromi>o>" <$ and. 101
A"'''I<. infuodibulor nU<i<i, <0. Ill .
a, compo""n" of h)'lloplt)'>io, ,<>pic
''''•. S36
Cltocholam 'T>< ",1<0",. 836
""pomi.. '0 poh...,. .0,.. of
m«li •• om'ne"",. 831
'0"'" ""pit,; .. '0 ;n ,em,,1 >OTte.
fo '"<0""''';'''''' wi,h
"","""I
!>'<Optic '1><I<i, SSS
'otnCh;"matie ".""i.
$ )6
v,"trom«!,al nl><l<'. 136
;n.)7
"CtH.<ndorphin>,336
GRit 794·1, 836
""""h hormone. 14
lRIl. Ill. 671. III
'"",";.."",;. e. 270 "",,,,,,,.,,, hrOO1he,i •. dcf<mi";,,,;on.
"''''"'t'''''''n. S4. 7'13, 7'11 116.160
,.b$l''''''' P. Slb 'nli<"roc<n •• od. j6().1
infl""","" on prot>\<m, wi, h <o"""p'. j6().]
FSII. I..II """,';on. j93
III ",,,,,,, ion and. SlS-6
L.-"""".. i< ocid .m;no ""ida... n.291.
30'. S}I
i",.h. """";"". food inl>.l <, ]<).1 """,..I. foc,,,,, ati"e<, ;"'
mo,,,,,,,,1 <"}d... pnm ..... lIS "CTIt , od ",1",«1 pepti<!oo. 391
loc.,ion. fi .. .,rue'"",. 40. 11.1 ".""OOl>m in,,'. "(h' -or. fti(ht
prrop1iro1UOCClI. roni<othal.mi< ,,...,, .... po."'. 274
A",.
pro;oct;O""
PGO,«ma, 66
hi'''mi"" and , 1 14
"norioO<leros; ..
h<>rm<>'"" ,.kon"p ffOm ('SF, $49 PTIl ,00. 41>4. ggS
AOJ,ini .. ,hrm", and. !23. 8S1
.. "",," ,i,1 ,,,,;no acid. 171 "",hheim·Z<>ndck. "·Z. mouse 1<".702
'nR"",.... on hormonc >«,...,...." 13 " oc:o<bi< >cid
"o_,h hormo ... J19. 1'I(l 7'13 JO"""" f""",ion., 13·14
",,,,,,,,.u nd.794 .. ""ummodoIOlOt. 111
'n,u"n. 1% in ><l",nal ron«.
"'" ;. 1 I _ " " , i , mi<1"",.,.1 c),,,,,hrom,,.P450
,llI<ocon""';d •• nd. 2 ' S a..o,2SS
u" a, ,permi nc .• perm'd inc I>'«U"". i" ad1'<:.ol m«lul lo. 2SS
no Aellf .nd. 291
A'l;n;"" ' ..Of"·. . .i •. "vp, ... "DIt ;n bone
A'l,n,,,,, .,"'toein, "VT, 66
bioo)·n,hcs; •. m..""""lIula, nuel<i.
OO IO£On .. 41 9
m; """,t; 'a' ",n. 1 J. 024
nonm.mm.I .. 134 <>strobIa" 426
ehemi,,'Y. 77. J71 , k;" pi*meno" ell(:(" "'.
dh,ribu"on. 06. 312. 19a
fo'",io •• i. no.momma"an
""''' , 00. ll.l
'h)'roid honno"" .)·nt ...... . .d. 748
'on"bral<' . 377. 397 A",...I ",prod",,'ion (0«
,n f.,
;" 00","0«><";",, 1 n"id.)1l
o>c<. ; "I<raet;""" " i 'h <0<1;",1.
49\1. 50Q 5Q6. 7
A,ponic acid. l RII ="" ion . nd. S%
PRL. J91 ",lie)']"'" 67
,n pi"". 1lIand. 66, l73. 860 inn"""",, on
",.","",'. ",",,;e. ,·.n" "'n•.SOO ADIt.." iOn'.380
,nn""""" on <1I(:(,h'on"" of IU D>. 711
APH (,·• ...,..,..in) """,,",". 21>0 ponuriti.n. 711
819 ad", ...1cor\<,. 219 ""hm • . bronchiola,
«"",,","'''')' h, ..",o",", of. .".n*'n •• and. 2"
M hi,"mi"" . od.11. 11lI!. ) 10
CRIl ",1< ..". 66. WJ Ie>J kOtricno:' and. 11lI!. 310
hypo'''''lamic 7. 66 ki"n, and. ll7
l7J. 19l "T·lo. d;')'drola<k)·"""". "1·l
113 «prod"",;vo fun"''''''' 860 A,h<,,,,,,\e,<>s"
"ro'o"inerei' .. 66. l60 diab<tC'l m< 11;lu,.nd. 2()S
,mOOlh mu .. l<. 834 ;ooul;•• "d. WS
Ul<rin<: m ...I<. l72 in InOnkC)'Uod, 71 S
"th,.mi<:.ude mi«. "" Thym"' &1. ""
."
'"''''''.
. ."",ph)';",
bola"",. 7, 37l.
,,,,,,,,,'<d ";'h.
386
"Tr. >oXn",ine tripI'\<KpIl"'.
.. CA MP "","01'$01". 119
",ka ... MIF, and. 19J bIDs rnlh",i,
Aroma,. .. % from ,I...,.. m,"bQfi,m.
IlF'f"I>Iod "h.nt' •• SS6 in,ul in '<>d. 161 . Ill. 176
,n ""',.c"MP and. SIl-4 ....,"'i.. """,ph.to afl<l , 162
&lu<o<oni<:_ ."" ;nd,.:<;on. 64j &lucoron;eoid. and ",,,,,,,,,,,,n of. 118
lOr1.Idolropin, and . 131 ;on ... """ on
FSl! ioduotion. lJO. 1l9. SSl. jU. odcnrl",o <)"la5<. 310
636 . ..", .kIosl<ro.. ",*0 1.,...., of N"
aodroten' and. 636 '",",pon. B.J.6
lB. h('(; and. ISo! hone mi.o",t; ... ,io •. • 23
in adip<>« Ii" ... and. %. 1<0. j3J ",,«hol.m'n< upUt.. 2'/7
;" ad",,,,1 <one•. 131 JT>.0\e d;,po,,;o'.
,n !:>n,n, .nd,,*n oc'ion. and. 608. U8.871
<leh)<I""" ..... 71S
,. fc,.1 0>01)', S2l in,ul; .·",*u l>tcd &I <K'O>C borrie,...
;. f"II;e"Ia, eoll•. .139. 631-40. 609 'W
i. ; nl<"t;' i.1 «II. ofado". 1M ;od;& ,,,,n,pon. 'h)'roid &I.nd. 74J
;. 1",·dif«lIlumon. S84
i. pineal. 860 m
due' inhilli,o< ",,',on ..
in Sertol i «II .. 1l9. SSl-4. lU. ",0",1, 1I)'",*n p/lt»p/l<>r)'1 .... 131
."
phoophofructO\';; ..... 111'>.7
>..0. SM ,n ...,t<1;Qn ""ules. 91).1
sn wi,h ".I<i.",. 4(19. 41l
ofjuve. il... lSl ')'"ho.i .. o';d.,' .... p/losflh<>rylation.
inhibitOR of. SSO, 556. 551 ,h)T<>id h<>rrr>-. aod. 717·8
no ",..,;0
<l<f«" ,,11"«1;0$. .ISO u" ;n "",te,n ruction .. 119
'" INDEX

II TF\"" (= NojK. Ca,/MI ATP. In) A",,,;on , ".ven.;on «nl<,,- in f"",on 'ltl'''''''''''''.
in bono. mi ..... Ii ..';.m . nd. 423 hypo'h,la"'.'.53) l<'nodQ\roptS. S2S. 326, 127
in .ndom<lfium. _ '<'<>II< and. fOr«d ""dio, Orod, all. 840
.... ,ion.lti!>' '0..
,o.'y. 1 39
muropro1<in. ",,,,pro1<in ' YI'O$.125
penodi< acid·Schill". PAS. ,uini"*"
in
;.h iM""
707
or.
117. 423. 74J
"" i •• i" f""" •• '"*"'"
rod, SOO
AV,V. " ' «0'..,0,,..1 ofJ'"
82S, 816. 817
lI>"",oi Ii< kuk.,.,)1<1
.pmni.,ionaoo, 511 hi," rni"" '),0'''''';' in. 71
,h«'mos< ....;.. n..t. III «n,,..1 con' '''' of _ Jm$.u .... in 0" 01)'. ovula,ion .rod, 631. 6SJ
,0.11'<>;' ofl<f1l1inal "dl" ov.';"n ""'OT bol.n«, ""'nure,ic IIAT . brown odipooe ,i"""
foil"'''''' 510. 521. 611-4, 0>1() oo,",on<. 159 """"hot,min<. thyroOd honnono:
Avid;. 'l'o ,hesi,. 67 ""ul.. ion. JIfJ
"'"""",,,.... 625 "vp, . ",nin< " • ..",.. .. i.. ... ADII mcUlboti< nol< of, 71fJ
. ",m.ta'" "",jv; 'r'04. AVT. "'" a",.;"" va"" ",in ,Ocrm_nc>i.. od.1l9
0$"'<1$<"' .1Id. 6Sl A·Z. A"'hh<im·7..(l .... """",II<)' "'''. BDGF. 1>one-<ktiV<d \I.r<Iwth r"",or.
""""'''''iooid••
f""",ion. of, 521. 531·1. 632
JOl"(\(I'fOIIinund 97. MO
Atrial p<pticleo ond ""n",..,.; .. 333
'"'
"",,,.'in<.280
A.-permia. S<6
IkMv;Ot. mood (. )", ... Ps)'<hi<
de"...,.i",,)
nd. 486

inn"""",,. on ."""",ion. lS3. 861

att1)'kholin. feC<ptOt>. 333. 792
C RH """"ion. 26 1.l64
B. boo .. «II. of pane"",,", i""s. (00<
P''''''ellIi< io1<1 •. lo",lin) S7.
a"""i"ed <'"' ' ' '
pism'ntat""'.867
in d<in
"""'h """,,on< "", ... ,;on, 192
lRH """"ion.
po'.""""' ""')T",,,,i<I< s«mion. 57
'"
"""",,ion of
Ii"""'" . nd. 201
CRH a nd. S60
"....".landfOBOlIUrod. SS9
"''''''''''''''''' .nd, S4'
"," ,>«>ids, 19·20 in di.he,., melli'us. 203 .mpl\ctami .... rod.219
1w>nnOl'l«. )
",mpott<j " ,;th faclOr> .... ul .. i"'" 2(1;').1 an,i"",i.1
Au,ocri"" functiono, lO. 3l
<>'roc<n., 'c"""<"," . nol. Wi
in po"",.,.'"' id•.,., 4
"""",,,,,,,plOt$.
B ",II" B 1)'mp/loc)'k'I
I,
uki.m. iO i.",lIit<t>C< "d. S<l l
Klind;'I,,,,', .)'nd"""" ond. 546-7
X YY <h,om""""'" ,nO . SOl
in P;'"'''')' &l>nd. 659 Ilo"'imo,o', orod. JJ7 apomorphine ' nO , 188-9
in ,""i •. 531. 399, 600 in ",Io"'.m. 721
.,.,.",,;0•.
• •_iated wi,. 'hcrmorq.ula' ion .
LRIl.nd.659 U"7 on
""""''''''''''' . nd. W).I <>fiJin of. in m.m ...... 226 a.,odoted ""'ith .... "T ron", .."",.
AU' oOmmu"" ",action" d;s<• ..,. ...... <>f 216 3%. 397
. If<<1i III odf<noronicol. ",prod"", j,,, ,.) ",idi,i, in nd. 777·1 . voidan«. po.,;",.nd "",ivo. 39]

.,functioo .. SSt
Add;"",', di..,."". 216.222. 778.

diOO«l<n of.." .. ion. 541

,,<';h,y. rompb", .Ik<!i"ll . perm
IIlrbi,,,,,,..
inn""""" on
"'''0"'
,,"o.n. hormone ><cr<,ion, 7'14
honngno bind;", ptOt<in,. 110
.x'inction.39O).1
rondi' ioninl. im"";.' inl.
"'1>'"".,;"',.1<11<0< ,,,
duri!l£ """ponom poriod. 123
<aliol.'" ."".,i"'. food
m<ml>ra .... nd. 112-3 T BPA birodi", to ,hYfoid 0110<1. "" oc,",vior.!J9-40
".5«1omy .nd, 715 OOrmn .... 751 .... followiol
.11«1;", thyroid function. LR II f<:CCplO< num"" ... 6SQ hypoth," mi<: inju T)". 18).
.",'boOk> dif«1ed "pin" LRII ... 1< . ... MS
IhYroi'op«.71J mcl,nonin of h)'po'h.]. mi< <On''''''''
83M3
<.optholm<» onod. del»U$Ol.' 0<' ;""0, S7S 01'<<1. of IIofmon<>. 6. 61
O.. ' ... ·di.....,. 202. 17 ..1 """.."".,in """""nll'",n. 168 ACTIl.nd ",toted P<!>1ideo. 37·S.
H••hi"",,,,·, th)ToO<Iit i.. 202. 776. T RIt " ,",oni,m. 768 lS8,391 , 8J4
m Bo",...,.,,,,ors. "re'ch =<p'on AI)H (,'ol<>l>'=in). ,d.,«1
hiltorompotibi lity """pi<, and ADH ,..,Ieuo. lS. 3SS. 390 76. 391·2
,,,,,,,po"".'H nd.7JI .nd "'To,onin ",;1ion. on IIcon. 304 aldos'«One.l29.2:lO
m)". "h<ni. ' '''' ',. "",.,Iei"",
'M""" in pa,k., .. ",I.. i",••
i" fl",,,= on .... ," .rod .. I, in.. ko.
lS9. 36()
.m nioti<: R"id
.n.:.I"'II<"" 5(1, SSl-9. 60). 600.
no 60S, 601. 8)1. 840
en"r&<m<., . """,,'ed ofrrnin..anJio,on';n ')'>1<1'1. 14S di h ydo'OO"""".Tone me .. l>oli1<l.
" 'i'h. 7J8. 882.S3S i" JG « II .. 340. l4J
and , 7'>(}
J.",,,,,. o.,i.M:(;. ,,.
"'nin ..."",ion. "' ... "'. S9. 346. in (¢tit ......
'",'o"orono.660
SS3

-
onti·H PL.nd .72) IIlfT boO i... )4S, ) 40 caki(cro". <.16um Orod,
di.betel ",<lIi,u •. 202. 773 1Il",1 CRIl .1S9
cndoo<ri..,·immunc ')'"''''
' .
m' n< 'n._w 7<. 273. 2S8
inl<roc,ion •• nod. 773 Po .... in",n·, di",.", . nd. 2M OIIinophn..,.177
aJoroooniooid. and. 221. In. 170 mcl.no<y",,- in. 3(;7 O>''''II<n,. SJ.4. SS9. 19t, 661. 72J
5<, SJI Bonicr m<thod, fOf """'r3«"pOion (>e< in prima1<l. 563
rhc"m ..oO<I.rtltri,i.
in pa,i<.!> ..;,It thyo<>id & ..1 "",,,t>olic no'o, 8 MR (0«
7t 4·S """ooon
m
i<oid<. 1. 2 IS. 2' 6. 229.

""J.
'"
."..1 <o.,ra«:pti_ arod 'Y"''''''''''
M<1>botk
ho""o,.,.. orod.
7.... S l<'" ark<,omy . nd. S33
.i " .min<.314

'"
"ot()flQm;" bob"",
o«,)k!loliOO<al«loola",i,.,.
!Iasophi I (C)""nop/1 ill ",II. of

ol<i, " blut . • l<I<h)<Io f"" h, i. (AF)

i • • • 'i •. 160
Lt • . l6t
196,
.. 271 .tainio," MSI" . 88. lli. S7I
h)'po'ha"",k qio., .fl<ctin*" 133. bet>. dell •• pmm ...... ,)'pe$. 821. oXl'lO<in. 76. 561
m 826. 821. 811 29l
 _.Ie"'''''. )}4. SS9. 1\Ii9.567231
in primot... S63
pro,ec,ion oca;n"
olf«,.. loll
'"'0><'0' ' ' '
I>'o><u".oo'o,. 561. 699
PTH. 411).-4. Jl3
thyroid h<>rmonos. S}4. 723. 7411
T RH . j1. 761
TR H m<taboli,cs. 16S
'rypo.am;n< meu bo!ilCS.)OS
o.,·iron mon'al . ..,.;.1 f.<tors all«'inl-
561.563
fl.i d in13k o<c Drinkioq.. FI.id
in,ak Th;n,
II[)II. '""'<>«"";n.II . .l4II. W)
liCE innibi,,,,, and. 349
",mpois;'" .... ,or dnnkin,. J10
dnnl<;n,. a"""iOlro ,..' inJ. A V ) V
and. )l9
h,.porton'" .. Ii .. . nd. JS9
..I, <ldici<nq. 122
tilom""on", <lnn"n,. JS94)
food deprivation . nd ( = food
dcj)ri,·.,;on). 167
hom.n. p«n ...1 oo.monc> '00. }OJ
)I. Yon, ... " '00. }41
hIporp),<"<mi • • hHIOII)",mi. , 00.
'W
h)"po>pilr>«''''''I· . nd. 391
hypoOh.l.mie ··ecnle"··. 8)1·3
"',"'m ill. o)· .... ion •. 8J(;
-",.!e •.. ··fcmole-. SOl. S.l
-m"'oli ...•·• -f,m;n; ... ··. SSJ
m.. orn.l. 6. III
Q')'lO<in and. 191. 334
prol .. ,;n.nd. 47. S99
ontl ron'oxcp'i,'<> . nd. 669. 116,
119·2()
pIl<romol>< •• M. l' ·1 1. >t>J
-plc.......... ""';" .........
_;ou.
"i",."';"", 31 1. 8)). 839-<10
'00. 61'
"'''l'''OC)' '00, 71 f>. 7
probkm. of ;n"'·.tip';oq.. SB. ).6,
... ual ("'" s." ...1 boh»';o,.)
A DH and. 814
.. h."·;O"'I ......... (sec E" .....
I><ho';0... 1).118. 119. 619,
662. 66-!
bi ... ual . .,.".ho;.. ,;oo.
""femini,.tion .nd. ISJ
,<>tw.""", .nd. lb()
",Ie;to.;n 11<"" ",1.. 0<1 pop,Mk. 473
ecn ,,,,1 ""wo' ",lOrn ......on.
""ola' ioq.. III
ond"'ll<n.. oo, SSJ
prroptie "",<>II in prim ..... 1S8
«"'001 ,""<, "'Pt.,;on. IS9
dihrdro'o"",,,,ron<. 561
li,"do, pros<S1<ron< ;m plan, .. nd.
'W
LR H .nd. 1. 11. 59(;. 1>60. Sll
!>OS'<rior hn""h.lam.," 81%, 340
ptOropul"O'Y vocal; .. ,;on,.
, 00'<II<n, . nd. IS8·9
. .,..."..«t()ne .nd. Sl9
prolactin . nd. )99. _
rro::pli"i'r, ("RH and. j.6()
''''''II<n.. _"orone .nd. 664
in prim"",. 123. 6)9
",I.,'on,h;p '0 'll<'« "u",bo". S07
",rotonin, Sj9
00<;01. O",';ron",.n ,.1 fae,,,,,
. ft«tinJ.l18
",o,.;nJ. J.Ol
wbmi .. ;ven<SoS. Sl)
!O'« ""fottO«>. hormo ..... nd. l jol
,i"","""""", for acti vO!iornIl
hormo .... Sj4
lie,. ""II. of 1<I<noIIy_h)..... 12l-.!
lie,. ecll, of ",,,,,,,,.. ie ;,1<:" (0«
i'ancn:o,k i"",..
\7. 117.200-1.103.410
In,.
Iloto ondotl>hio, (0« F.n<lorphio.1. 49.
61.86-1. Ill·8. 191. 263. 217.
In. 1()1. 1()7. HI . 761. 191.
824. 134. 3lS. 836. 842. 171
BGA. oono """"o'i,,, act;.ity,
'"
!!GP. bon< Gla pro'';n ( ...
Qs'co<>lein). 19
Ai<.. bon.lO ion.
roo<"<n,,., ioo.;n 1>0<1)' nuid •. lZS
<11"""" ofN. ."d O. 325
","""";"" from fOO<l .. 311
;nfl 000«0 on iod ;do ' r.on .port.
thyroid. 747
;o«,,;n.I't>o,por!. ,..1e;IO"io , 00.
m <. Ie;"m ,","1><;"1 pro«in .. 439
",n.1 ",.\>s<)<pt;<>II. O.,,'.,,;on. 32 .. 7
.kl",tcrone and. l)7
PTiI .rid. 438. 46-4. 469. 410
.ooi.m . nd . 436-7
Hk"".II;n<. GliB"
inno'O«O on
'"''to"'''''. 13 I
&rowth OOfTflOO< "",... , ioo. 192
;n,.hn ""'t01ion. 197
lactottop<>. prol""' ;n sec",,;"". 131
T RII :oxt01ion. 110
H;,. bi,·bit J<J. 80
BiIU,"ido • ., .",1 h)'!)osly« mics. 198-9
<I(l
<hok'1lOroi in, 169-10
."""ion ofl\omlon< • • nd
m<1.boIit<>, ,W
If. IS3
Cllieiforo!" 4)0. 433·S
<"'"",n ..
141
th)'mid bormof>C'. IS4
d"" 'oo, no
Row. <n<ct, of
("CK·PZ.60. 81
<1""'1)' lip;d" I)
<"roc<n., 669
Ii "" ron IOn, of diet. 1 J(I
<>fal ""","",pli"". 1 17
sec ... ,;". 60. 81
<n<ct. on aboorp,;on of 10,-
><>I"bio ";!O"';"" 14. 42i
""<rom 0"'" i n. 11
..It •. HMG-CoA ..,t;"i'y .nd. 11()
.oo;.m ;n. 31l
S;olotical <locks
<roopl.,,,,;';.61
"",)'""hroni .. ,;oo .. di<Ordrn
."",;.. t<J wi'h. 8j I
,,;ne.I , •. ;n 818
.0prKh; ....... ie n..,oIo; ... 6J-4. , 6J-4,
836-7.850-1
,'.ntfom«l i.1 n""lei. 26<1. 3SO
X. Y Pll«OUk,,,. second. ry
",dilator>. iSI
Bioloj.i<.1 ,h),th.,. (SOC O",ad;. ".
O",.rn. nn,,",l. s.,.",n.1
".riation.).
<."",n"" •. onJoso_" ultrodi.n. 62
ftc< ,"oni ... 03. ill
0;"';0. IJ
f.ltl' .dd O)'nth. ", .nd. 169
"", 0)'1"00),<1>" 'nd , 13
Biph.,ie. moltip••• k ..... ion. of
...." .. \oro. 114-1
.o<t)'1<1101i0<.19l-6
AC1"I1.211
<.l<ium.4SS
<"M P, III
I 2. 1.2S·D. "6-1. 488
..""",n.. LH """';<>11 ."d. 1901. 1060.
66S. 72J
slucoconiooi<l .. 192
10nad.1 ",roid •. 619-60
_ " r o ... , 660
""",1<<<''''',191.660
&row,h""""""". 114.196, SOl
)l IOMT act;"i,),.
Lit S91
"''''II<n. '00. 319
prol"' in.l97
101
,h)'mid 'om"",... 761
Bird .. 'P<'<",I f,ato"'. of ondo<ri",
,)""m •
Ond"",", .y",..,;.o<I. Si4
b."" ofF, brid ... 226. 771
"'leilonin fu""tion .. 484-l
oIoaca, ««PI""'" uf>""",,,omo.. SOlI
orop ..c. 6. 47
eu Pto<l""'i"". 6. m
.,';d ;" .rnt... i.. 67
<JJ >11<11 .. _00. 484
",';dll<1. ""II "aoo. SO'!
<s'roc<n ,fr<ct. on C. ""LObolli"".
bon<:.441.487
h)'potll1"mie ronlrol of PRL. 197.
m
"'Ol;", I><""'w... 6
min<ra loronkoKh . nd .. It d.nd•.
'"
po"" ... tk 189
"',,""n<>C000 .... :107
";11<.1
d;= 1'ho!O"n';,;v;'r. 818
intn".", NAT 'il)"hm •.
t,..n,pl.n'ati"" , 00. 818. 86S
... prod "'" ;"0 ho, mo ... ,""ul""",
of, i6\
,horm""'lUI,,;on .nd. 814
pi'oi"!), &1>00" 812. 813. 814. i18
prolact in ron,,01 of Ca. P. ",ldfcrol
",."bo!i. m.44O
prolact in. con"ol of """'tion . 191.
m
PTII·lik "",ion. of inwlin. 481
sc, 'hromooornc>. 506
.. ' dotormin" ion ... t"'ll<n •• nd. l11
u·y prod"",;.", by f, .... 1es,
'"
o,'an. n do"ok>pmcn'. o"OI<>,i.
.
f","",,,<on. 12_
,
thl'mu. Jla oo" f..,of> , 1I"«1i ... sil<.
" Iti_n<hi. ll>odi ... 4!l4-1
Hinh <on. 1(sec I'>,..n,;on)
in .. SO'!
",I.,;n, . nd 709·10
Illaoo";"..;n 872
01.,,0<)'''' (. 1", ... 6. 61(1
bl."""",Io. om bfyol>l. ". ,rophobI.<1.
"'
dol;,'<o)' '0 "'",U" e>'roc<n.
_'''tOne. 1'(;.. VIP ,00. 663
<I<",OO""ioo of
.... 0"",;d)',nd.687
«>I>I"'tt".ieit)·.72 1
im plon"'io" 'im;n, and. 688
lUDs,nd.721
 INOEX

HI."oc)'''. ("",'.) ""10";,,, hn""h.l.mi< Sl8 dr..,,,oo

donn.n" di." , u.. ,.d,
691-3 PfOC<',orono.7 10 ADiI ",1<• ..,. 389. 390
e,I'O";"'" 689. 690
[""".,ioo. 663. 687
""""<ye""" 3S7. 767
128
.....,hol."'i.. rek.s<. 29S
",nin-an"",.n.in s)'''om . 319
h.!<hill£. 688. 690. 694 PGE>. lOS. 2l2. l62. JS7. 6.\3. 164 ,nYol<n,ln·11 p1oo.<lion. 3S!
hi"'mi"" ««p, .... 690 PGF,.. 1). l)7 reni. =,ioo.)43
impl,.,",,,, •. m«h, .i,m .. 694 !'TH.41>4 men0I'O.'" 'nd. 611
i. m.""pial .. I.... ' ion.1 di.p.O""'. rel.,;n.710 Blood-\.,,;, borrior. of
.""rn,.,O",.
'"
in'or.,,"on.
.""urio,or. S09
endom<lrium. 688
TSII.76)
"'''''on;n. J04
""m>t"".,'n. 139
.nliOOdie""in"
. nd.722
"'1«'010)' 71 I
.,olcn.in •• 399 FSH . nd. lll
h)" "'''''P/>C,694
pros<Wron<
"I,,""" ··mil1<-. 693
689 Blood on,)'me>
ACE. )48
f."",,,,... S31. S7.
OPO"" "'''Uf. ,ion .nd. 600
ulefine ««pli"ily l<>, 688·9 hormone <kJruIallon. 110 Blood "c",fs. "'" .1", alood now
PI."oki. i•. u'etosJobin C OMT.197 .n"uk".in producllon in. lSI
l'f\I&C>l<ron< bind in" cuos<n IipoprolO in Ii""",," 168 0"';010.,;.·11 ««p'"".I<><.1 "",ions
,),n,""", •• d.689 prek. llil<re'n ><Ii ... 'o .... 317 .nd.361
pro,«tioo "",in" '",phobl." BIoo<l &1 U<OiC. I« GI"""" in blood. ,00 ruMP, 150
n:i«'ion , 701 IIl""rsJr.. mi , COMT i • . 297
81i ndi Il£. blind""". ,1I"<ct. on 'ndocri "" Blood p!ol<l<t.
.pl<m .arene"," ««I'""," 230 d;o"',,, ",.Ih,u, .nd. 161
,Io«><""i«:>id. ";0..1 ,h),'hm •. 64-S.
263-1
.w<&>'i"n. foelO'. .
• .. cclIo1.m;n«.27.
I'I«1'' ' 0 ..1ooot'""""lIIi, ... PfOfI'''os<n.,
,mol; ", o.d. 7)1
""".,h _".
mdoto,in .nd. 793
•• 189 in re,in •. oral ront""'pli", .nd.
hi>!.min<.6ll 71S-9
hum • • "", .. "",i. rh)1hm.ond. 8(,6
",dOlO.i. =,ion in bird .. 86S
non·photic "im"1i 10 SCN. li",'
LH.6S3
pro>!."" ndi" .. 61. 226
>cro,on i•. )03
i.,
''';'')'I&1)<oro1 •• nd. 717
f""on .rr...
Ailil. 3S4. 833
<I<:"";,'"ioo .nd. ISS Ih",mi:>o,"""". """,""y<;lin .nd. ADIl """I. ,nd >cn,i'iv,y '0 "'DH.
m
piu"n""m ;'
la<'O\fOj)< fuoclion'. 363
,,; ....1 _ " " inn""n<C<. &63
'"'
hi, ...,i,.. in.m
in o ... ri. n folliel<o. 631
FCF.800
hi>!, mi ... 12
Ih)"oid [unc,ion. ";nulond. 874 ",ul.,ioo .nd. 6S3 PIX'F. SOl
li",io, of """'' 1" 00 .. '. 610. 669 mo,""mln< o,ida"" in . 2'19 HH. 463

."
dc><n,i,il11ioo 10 M I.T ond. 866 PGH, .rr..... 100 'h)'roid I>omt ....... 7.....
reprod."ive 'y'lO'" ",,,.,,,,ion . piot<l<I do,.;.'w VO""h ("""'. PDGF. TSH.163
592. 602. 0).6, 800- 1 , ""'1h or. «UOSCn •• nd. 732
BIood·bai. bomef. 150. 838. 849
.nd Jiu""", "", .. boIi,m in \>rOin . 181
.."""nin """'k """'C<.
thromOO..... )n'Mosi, in. 10l
n. 303 hi".",i".. hl ... minc ,.,..pl"", in.
m.31l
,.d in,ulln 1<>,,1. in b<oin. 181 Blood 1'...... 1<. 4. SS, .19 I,"",.in, in.
a.d Jio<OCOtlkoid i.hiMion of CRH. ",",,,,I cO.lIoI of mcl'noxyl" in """,,,1 .... 11 •• 867
0<"'\00; ••If.", On • .l(U
'"
oo\o<l>ol,ami". •• ,,')'. 213. 117
• rr<ct. of.=. 389
' .I i""n'i" ond. 351
Av, V.nd.3S9
<II«" or
",matorne<lin bindinl
' as<.lori,o,i.."
'0. S02
honnonc ond •
", •• do\rop;n "" ••pon .nd. 591 ADH. 58. 16. 371. 38S. 833 48S. 78l
m.tu",,"" or. 319 "DII.1\1loal. JH Blood ,01.""
prol..,'ioo "",i." ,., iOle.,i" n. 11. 3S2. 3S8 OJjUSl""'. lS '" .""""IIUI., lOlIi.m.
imm un."" 'm "",h«tomy 00d)' we .... ,. 3lJ 321·2
dc'''''''''ion.212 b",d)'k'ni • • 78 orr..,,, of
",pi<! <h.0J<' in "",i. cak;iu"', 463 ""I<i"",. 324. 43 I ADII (,""""""in). 18
Blood <OaII.I"ion "",..,holom'.". 14S-6. 27 •• 27S. old".l<,oll<. )30
",k;.",.nd.410 m JiUCOCOt1i«:>id .. I S. 211
"" ..ado. III f,l", ''''n''''in' .... 303 h)'porsJ)<omio.l60
OOI&."'ion foeoon .nd
... iv .. ion. 3S7
CGRP ... "i""". "'..
""plide.473 ADH ""''''tion. 58
prol<nin acti.-.tioo.)41 60S .llIi<>lOn.i. II pro<iu<1ion. 160
."'OI<n, • .".1 .""",lIula' n"ld .'<>Ium •. )23 ..11 in .. . .. J.6(I
"'nl"""ptl .... nd.714 Ji""oc<>n'coid" " ..... 215. 220 11000 IOOfJIhopone'ie protein. 799
"",,-or·niv., ""po"", VO""h I>omto... JM.i B.'-iR (... 110..1 m... boIi, "' ...
w ocllol.rn; .... . nd. 6. 174 h,morrhap:. l8j M,"boIic ""0). 7S4·1
&1 """"'" iooid • • nd. 2 IS lS7. 35S ,h)'roid hIlrmonos and. 7SS-9
hoporin.39l mi ..",loCOr1koid •• 321 . 383'" BOOy 'empo" '."'. f""on olf«ti". 5. 6
pr"" .... ndl ... 216 aldo"""",,,. 330. l31. 33"1 dread,'n "...,m.k .... to<
,i,..,inKond,19 .".1 <oot"""lIIil'«, 717 .ore. ' kin. 'll
lliood di>tribu,ion. now. f"""", oxyloci., 3JI. 8)4 ",ntrol - .. nl<,,- in hYP<l,h.lomu<.
ACE ;nhibi"m, 3-<9
MlH. 76. 382. 38S
706
Sa-dihydro _ _ '.",no.1Ot\
."
. nloriol'. "",«riOT f<l,ion • • nd. 838
""..,hol.min",.211 ","","fIC)' .....1"'.'",""pli,'" 669 md.,..,i •• MSIl .11«" 00. 814
""""mi,... 273. 187. 3Sl prol""ln.393 .";ph)'Si.1 ",mpl... SH
epiocphri ... 214-S !'TH .•"" r"" ",..lk<1i,..
""01<0" 66S. 710 sodium. 32,·)24 ACTH.770
121 ·l, 228 Ihyroid _nos, 746 ADIl. II. 388
hi".m;,.., lO'J. 110 urop/ll'i" U"'ton,in .. 398-9. 01 eok;i"",. 409, 431
 auccoobmillC>. 22S. 27S- 769. 77 1 &.
OOI<pi .. p.n"",I20 >#". "",,;',0<1 "h.n" .. 487
cndo<phin .. ncurotcn.in. "",,*hoI. ",lc ifcm) "",umuIOl ioo. 428. '42, OSO
".
<liocOotanolor>c,5U
Ow..:11 "f dc1i<i<ncy. 431
calc ium ronlen', "',",V<T , 41 S
Jlo<o<otticoidl, 11 5. 11!. 770. 87. caki"m in""""io", wi,h
.i"amine, 314. 110 ""ki1<rok.4SI
in\crl,cu'in-1. 126 die .. ')' .lI'«t.. 4SO
_no "Ie,,,,

."
ncurole".i" .nd, 60 cak ium
p;nc.i .. n:plo,,,, ,nd .."'" <oki'ooin and. 477, 4&0
"sol"bili,y p<O<i."c .nd. 47<)
I'MN p)·,occn., 22S PTH .nd. 470
])«IlC$loc<n.. ""II ",""",.1. «9
.• ). mptotl>crm.1 """" morphoccnCl" pro,dn Ond,
,h)·,hm mctllo<! ond. 714 ;W
prostq!.ndin .. 67. 102 cold'<lnin and. 483
PTH.464 """,c<n. and. 441
.. rotonin.110 Ilucoconko.h . nd, 486
.o",.'0... ,in. 763 PTH o"".OJI, 470
,h),roid h<>,mon<> . .12. 394. 7 <16, ""II ')'''''' Is« O<'robI ..... OIC,), 42l-
7S7. 169, S74 m
nH. 7.7. 7b8. 769 Mr.",,,, ,,,ion, ",mao"""in a nd.
TR H ""'10""li1<l, 766
,,,;,,,)·IJI)''''rot<. 13 bont ..."."hotcnt,", ",..,1< ;n .nd,
vcntromcd"l n",ku, k'lion>. 841
lin" to WIlle'.
39S·7
m.t.oboli,m, '"
fibmbl •• ". PTII ,If« .. on 471
fu"",ion .. mOO"IOI i"".
N'/K_A TI'> ... and Ihcrm<JtC"",il. ;."""Ia,;oo$.hil"-

'" .. k i,onin .nd, 48!.J

JI .. 'c dchyd"",n, .. I'TH .nd, 47Q.1
' nd.7.18 PTI! a"d CT i" noc"""
o"''';,n 669 corn".fCd. 484
' kin !M&rncn"'ion and. 861 <011.",,, I"" Col ...... o.l<obI.."1
ch.rIF'. li"m>. 87J-4 corn"",i'ion.417
tern",,,,,.,,, ,Ifcct • .,. ,)·,..,.in"., <owe"nd. II
"ti.i'y. h)·J fQ""tion,419-420
8o<lr Is« 01", Food in" •• ) . S<'O,bI< "' ... Fc and. 4 19
di.b<tc. mell i,u, mdli," •• nd. WI ca kir"rol> . nd, 419-420
cw..:" of "!>ril,. 417-$
/I-OH·but)'f:I",181 .)'nol>c.i., 418 .... 22
d<>N!mi ... 289. S39 Jlu<OC<l"i<oi<Io ond. 486
"'rovn.. 0(;9.139 ",'<Obia>" . nd, 426
JI ...",n. ISS P,,,,, .. ,,,ndi.,, 4116
JI)WfQl. 182 som .. orn«lin .. 802.
""W," dd",,, in "'"rmi< mi«. Gil ""d.
h""""nt. Sl)4
hlfll-f"dic".I6$
""I ron",,,:cpt;,·c.. 716
."
Ifmpt,OC)·' .... nd,S8S
" "oc<" <O<Itcn, .nd. 717 l S-I) In-h)'<lfOX)I'1< in. 43)
Pf'llC"CfOrt< implon", 720 2S-D 24·h)·dro»·losc in, 4SO
proIo"J«! f."in" 16S l.l S- D ...""",,.. in. 4SO
,h)''''';d hormone> . .II , 746. 7S1 1<101 bone ph)'>ioIosY, 441·2
011«" on ... ' nd"""nl and. 441
l>1oOO i>«"u". 32J &io<o<ottiooid <11'«,., ll8
..,rotc" ",<>duo,i",
cflkk",), oHood u,ili,., ion a nd, S42
,,"0"'" and tom
"';"it),. ",,"i'y. mechonic. 1"""
h)1>O,ha"mi< ,,,,,,rot.. ISI-3. 8).8-343 and. 4SO, 487
<O"lto"''"'''' o"cf<"<ln'roI "".. 839 ",leal<, 472
..... 'k'r·· centen in. U9 and"",,". and. 416·7, 603. 607
".,..,n,ne.la, """lei ,,,<1. 8)) "".. dcril'C<l JfO'"·,h r.oW. 416
.cn,romcdi. l. "'ml ""on. and, ",kifcr,">. 009. 43J. 481
S18. 839 cakium.4S7
""'nopou", and, 671 ,,·,.cl<>. e,.. ri.n "l"1ct; and. 441
pNwchromOC)'''''''''nd.273 Jluoorortiooid' ond. 487
pr<p''''y and. 716-6 melli,u,. 198
I<'·""'n" rot. I S2, 09
·<lcfcn.... of. !'oIlowin,
'''"""n'
If""'. and. 486.1. W8
hormon<, 488, 7!1i,
m. n ir>ula''''.',839 788. 7%--9
,'''lu, "'".... nd. 183 .S(lF .M. 799
Bombesin.61 0<31 ron"t<.pti ..... "d. 487
inn",,,,,,, o n PTI!. 47(). 471. 486
l>1oOO ,,"'.,... oom .. ", .. ,in and. Jlucorortiooid d roco. on
m ",,,,en,,, 10.486
catCCOolomin< """"ion, 29S >ta",nol "arialion<. 4J3
food ,,,, .... «1 ",matom«!i".. 66. 7%--9. 3Q2-3
JlucaJOl' "",""ion. 192 fa"i",a nd. SOS
JrOWI" 00"""", ",te'l<. 794 beali"l- "",o<Ial "oroI4. and. 4S7
IOm""" .. in ",le. ... 794 '''fDiCn .. 441. 6U
 INDEX

Bonc (canl.) blooyn' ...... ofpcptid", rd.,nllO ",t CO ; ·I'Z. 60. 189
""wth tlctot. SOl bonnones. n. 33. 61 C1I.It. 259. 843
Pf'Vh'f'I<"i o!>d. 481 dev<lopmon'. m"u""ion. ro<1or> dipeplide>. 75
pm""lin.481 ofkcti., ,ndorpItin-do;riv"" ""plid<>. 83S
Pfoo"Jlanol in. ond. 67. 412. 481 . brltin p owth PfOfn"'inl o<1;.i,y. <>Irot<n,. 4. 563. 598. 6ll