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 4th Edition

’
HARRISON S
TM

ENDO CRINO LO GY
 Derived from Harrison’s Principles of Internal Medicine, 19th Edition
Editors
DENNISL. KASPER, md
William Ellery Channing Pro essor o Medicine, Pro essor o
Microbiology and Immunobiology, Department o Microbiology
and Immunobiology, Harvard Medical School; Division o
In ectious Diseases, Brigham and Women’s Hospital
Boston, Massachusetts
STEPHENL. HAUSER, md
Robert A. Fishman Distinguished Pro essor and Chairman,
Department o Neurology, University o Cali ornia, San Francisco
San Francisco, Cali ornia
J. LARRYJAMESON, md, phd
Robert G. Dunlop Pro essor o Medicine;
Dean, Perelman School o Medicine at the University o Pennsylvania;
Executive Vice-President, University o Pennsylvania or the
Health System, Philadelphia, Pennsylvania
ANTHONYS. FAUCI, md
Chie , Laboratory o Immunoregulation; Director, National
Institute o Allergy and In ectious Diseases, National Institutes o
Health, Bethesda, Maryland
DANL. LONGO, md
Pro essor o Medicine, Harvard Medical School; Senior Physician,
Brigham and Women’s Hospital; Deputy Editor, New England
Journal o Medicine, Boston, Massachusetts
JOSEPHLOSCALZO, md, phd
Hersey Pro essor o the T eory and Practice o Medicine, Harvard
Medical School; Chairman, Department o Medicine, and
Physician-in-Chie , Brigham and Women’s Hospital,
Boston, Massachusetts
 4th Edition

’
HARRISON S
TM

ENDO CRINO LO GY

EDITOR
J. Larry Jameson, MD, PhD
Robert G. Dunlop Pro essor o Medicine;
Dean, Perelman School o Medicine at the University o Pennsylvania;
Executive Vice-President, University o Pennsylvania or the
Health System, Philadelphia, Pennsylvania

CONTENTS

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 CONTENTS

Contributors vii 12 esticular Cancer 186

Robert J. Motzer, Darren R. Feldman,
Pre ace ix George J. Bosl
13 Disorders o the Female
SECTION I
Reproductive System 192
INTRODUCTION TO ENDOCRINOLOGY Janet E. Hall
1 Approach to the Patient with 14 In ertility and Contraception 202
Endocrine Disorders 2 Janet E. Hall
J. Larry Jameson
15 Menstrual Disorders and Pelvic Pain 209
2 Mechanisms o Hormone Action 8 Janet E. Hall
J. Larry Jameson
16 Menopause and Postmenopausal
Hormone T erapy 215
SECTION II
JoAnn E. Manson, Shari S. Bassuk
PITUITARY, THYROID, AND ADRENAL
DISORDERS 17 Hirsutism 226
David A. Ehrmann
3 Anterior Pituitary: Physiology o Pituitary
Hormones 18 18 Gynecologic Malignancies 232
Shlomo Melmed, J. Larry Jameson Michael V. Seiden

4 Hypopituitarism 25 19 Sexual Dys unction 241

Shlomo Melmed, J. Larry Jameson Kevin . McVary

5 Anterior Pituitary umor Syndromes 35

Shlomo Melmed, J. Larry Jameson SECTION IV
DIABETES MELLITUS, OBESITY, LIPOPROTEIN
6 Disorders o the Neurohypophysis 55 METABOLISM
Gary L. Robertson
20 Biology o Obesity 252
7 Disorders o the T yroid Gland 68 Je rey S. Flier, Elef heria Maratos-Flier
J. Larry Jameson, Susan J. Mandel,
Anthony P. Weetman 21 Evaluation and Management o Obesity 262
Robert F. Kushner
8 Disorders o the Adrenal Cortex 107
Wiebke Arlt 22 T e Metabolic Syndrome 272
Robert H. Eckel
9 Pheochromocytoma 136
Hartmut P. H. Neumann 23 Diabetes Mellitus: Diagnosis, Classif cation, and
Pathophysiology 280
Alvin C. Powers
SECTION III
REPRODUCTIVE ENDOCRINOLOGY 24 Diabetes Mellitus: Management and T erapies 293
Alvin C. Powers
10 Disorders o Sex Development 146
John C. Achermann, J. Larry Jameson 25 Diabetes Mellitus: Complications 317
Alvin C. Powers
11 Disorders o the estes and Male Reproductive
System 159 26 Hypoglycemia 329
Shalender Bhasin, J. Larry Jameson Philip E. Cryer, Stephen N. Davis

v
 vi Contents

27 Disorders o Lipoprotein Metabolism 339 33 Hypercalcemia and Hypocalcemia 442

Daniel J. Rader, Helen H. Hobbs Sundeep Khosla
34 Disorders o the Parathyroid Gland
SECTION V and Calcium Homeostasis 446
DISORDERS AFFECTING MULTIPLE John . Potts, Jr., Harald Jüppner
ENDOCRINE SYSTEMS
35 Osteoporosis 480
28 Endocrine umors o the Gastrointestinal ract Robert Lindsay, Felicia Cosman
and Pancreas 362
Robert . Jensen 36 Paget’s Disease and Other Dysplasias o Bone 503
Murray J. Favus, amara J. Vokes
29 Multiple Endocrine Neoplasia 390
Appendix
Rajesh V. T akker
Laboratory Values o Clinical Importance . . . . . 515
30 Autoimmune Polyendocrine Syndromes 405 Alexander Kratz, Michael A. Pesce,
Peter A. Gottlieb Robert C. Basner, Andrew J. Einstein

31 Paraneoplastic Syndromes: Endocrinologic/ Review and Sel -Assessment . . . . . . . . . . . . . . . . . . . . 533

Hematologic 413 Charles M. Wiener, Cynthia D. Brown,
J. Larry Jameson, Dan L. Longo Brian Houston
Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 577
SECTION VI
DISORDERS OF BONE AND CALCIUM
METABOLISM
32 Bone and Mineral Metabolism in Health
and Disease 424
F. Richard Bringhurst, Marie B. Demay,
Stephen M. Krane, Henry M. Kronenberg
 CONTRIBUTORS
Numbers in brackets re er to the chapter(s) written or co-written by the contributor.
John C Achermann, MD, PhD, MB
Wellcome rust Senior Research Fellow in Clinical Science,
University College London; Pro essor o Paediatric Endocrinology,
UCL Institute o Child Health, University College London, London,
United Kingdom [10]
Wiebke Arlt, MD, DSc, FRCP, FMedSci
Pro essor o Medicine, Centre or Endocrinology, Diabetes and
Metabolism, School o Clinical and Experimental Medicine,
University o Birmingham; Consultant Endocrinologist, University
Hospital Birmingham, Birmingham, United Kingdom [8]
Robert C Basner, MD
Pro essor o Clinical Medicine, Division o Pulmonary, Allergy, and
Critical Care Medicine, Columbia University College o Physicians
and Surgeons, New York, New York [Appendix]
Shari S Bassuk, ScD
Epidemiologist, Division o Preventive Medicine, Brigham and
Women’s Hospital, Boston, Massachusetts [16]
Shalender Bhasin, MBBS
Pro essor o Medicine, Harvard Medical School; Director, Research
Program in Men’s Health: Aging and Metabolism; Director, Boston
Claude D. Pepper Older Americans Independence Center; Site
Director, Harvard Catalyst Clinical Research Center at BWH,
Brigham and Women’s Hospital, Boston, Massachusetts [11]
George J Bosl, MD
Pro essor o Medicine, Weill Cornell Medical College; Chair,
Department o Medicine; Patrick M. Byrne Chair in Clinical
Oncology, Memorial Sloan-Kettering Cancer Center, New York,
New York [12]
F Richard Bringhurst, MD
Associate Pro essor o Medicine, Harvard Medical School;
Physician, Massachusetts General Hospital, Boston,
Massachusetts [32]
Cynthia D Brown, MD
Associate Pro essor o Clinical Medicine, Division o Pulmonary,
Critical Care, Sleep and Occupational Medicine, Indiana University,
Indianapolis, Indiana [Review and Sel -Assessment]
Felicia Cosman, MD
Pro essor o Medicine, Columbia University College o Physicians
and Surgeons, New York, New York [35]
Philip E Cryer, MD
Pro essor o Medicine Emeritus, Washington University in St.
Louis; Physician, Barnes-Jewish Hospital, St. Louis, Missouri [26]
Stephen N Davis, MBBS, FRCP
T eodore E. Woodward Pro essor and Chairman o the Department
o Medicine, University o Maryland School o Medicine; Physician-
in-Chie , University o Maryland Medical Center, Baltimore,
Maryland [26]
vii
Marie B Demay, MD
Pro essor o Medicine, Harvard Medical School; Physician,
Massachusetts General Hospital, Boston, Massachusetts [32]
Robert H Eckel, MD
Pro essor o Medicine, Division o Endocrinology, Metabolism
and Diabetes, Division o Cardiology; Pro essor o Physiology
and Biophysics, Charles A. Boettcher, II Chair in Atherosclerosis,
University o Colorado School o Medicine, Anschutz Medical
Campus, Director Lipid Clinic, University o Colorado Hospital,
Aurora, Colorado [22]
David A Ehrmann, MD
Pro essor, Department o Medicine, Section o Endocrinology,
Diabetes, and Metabolism, T e University o Chicago Pritzker
School o Medicine, Chicago, Illinois [17]
Andrew J Einstein, MD, PhD
Victoria and Esther Aboodi Assistant Pro essor o Medicine;
Director, Cardiac C Research; Co-Director, Cardiac C and
MRI, Department o Medicine, Cardiology Division, Department
o Radiology, Columbia University College o Physicians and
Surgeons, New York-Presbyterian Hospital, New York, New York
[Appendix]
Murray J Favus, MD
Pro essor o Medicine, Department o Medicine, Section o
Endocrinology, Diabetes and Metabolism, Director Bone
Program, University o Chicago Pritzker School o Medicine,
Chicago, Illinois [36]
Darren R Feldman, MD
Associate Pro essor in Medicine, Weill Cornell Medical Center;
Assistant Attending, Genitourinary Oncology Service, Memorial
Sloan-Kettering Cancer Center, New York, New York [12]
Je rey S Flier, MD
Caroline Shields Walker Pro essor o Medicine and Dean, Harvard
Medical School, Boston, Massachusetts [20]
Peter A Gottlieb, MD
Pro essor o Pediatrics and Medicine, Barbara Davis Center,
University o Colorado School o Medicine, Aurora, Colorado [30]
Janet E Hall, MD, MSc
Pro essor o Medicine, Harvard Medical School and Associate
Chie , Reproductive Endocrine Unit, Massachusetts General
Hospital, Boston, Massachusetts [13–15]
Helen H Hobbs, MD
Pro essor, Internal Medicine and Molecular Genetics, University o
exas Southwestern Medical Center; Investigator, Howard Hughes
Medical Institute, Dallas, exas [27]
Brian Houston, MD
Division o Cardiology, Department o Medicine, Johns Hopkins
Hospital, Baltimore, Maryland [Review and Sel -Assessment]
 viii Contributors
J Larry Jameson
Robert G. Dunlop Pro essor o Medicine;
Dean, Perelman School o Medicine at the University o Pennsylvania;
Executive Vice-President, University o Pennsylvania or the
Health System, Philadelphia, Pennsylvania [1–5, 7, 10, 11, 31]
Robert Jensen, MD
Chie , Cell Biology Section, National Institutes o Diabetes, Diges-
tive and Kidney Diseases, National Institutes o Health, Bethesda,
Maryland [28]
Harald Jüppner, MD
Pro essor o Pediatrics, Endocrine Unit and Pediatric Nephrology
Unit, Massachusetts General Hospital, Boston, Massachusetts [34]
Sundeep Khosla, MD
Pro essor o Medicine and Physiology, College o Medicine, Mayo
Clinic, Rochester, Minnesota [33]
Stephen M Krane, MD
Persis, Cyrus and Marlow B. Harrison Distinguished Pro essor
o Medicine, Harvard Medical School; Massachusetts General
Hospital, Boston, Massachusetts [32]
Alexander Kratz, MD, MPH, PhD
Associate Pro essor o Clinical Pathology and Cell
Biology, Columbia University College o Physicians and Surgeons;
Director, Core Laboratory, Columbia University Medical
Center and the New York Presbyterian Hospital; Director, the Allen
Hospital Laboratory, New York, New York [Appendix]
Henry M Kronenberg, MD
Pro essor o Medicine, Harvard Medical School; Chie , Endocrine
Unit, Massachusetts General Hospital, Boston, Massachusetts [32]
Robert F Kushner, MD, MS
Pro essor o Medicine, Northwestern University Feinberg School o
Medicine, Chicago, Illinois [21]
Robert Lindsay, MD, PhD
Chie , Internal Medicine; Pro essor o Clinical Medicine, Helen
Hayes Hospital, West Haverstraw, New York [35]
Dan L Longo, MD
Pro essor o Medicine, Harvard Medical School; Senior Physician,
Brigham and Women’s Hospital; Deputy Editor, New England
Journal o Medicine, Boston, Massachusetts [31]
Susan J Mandel, MD, MPH
Pro essor o Medicine; Associate Chie , Division o Endocrinology,
Diabetes and Metabolism, Perelman School o Medicine, University
o Pennsylvania, Philadelphia, Pennsylvania [7]
JoAnn E Manson, MD, DrPH
Pro essor o Medicine and the Elizabeth Fay Brigham Pro essor
o Women’s Health, Harvard Medical School; Chie , Division o
Preventive Medicine, Brigham and Women’s Hospital, Boston,
Massachusetts [16]
Elef heria Maratos-Flier, MD
Pro essor o Medicine, Harvard Medical School; Division o
Endocrinology, Beth Israel Deaconess Medical Center, Boston,
Massachusetts [20]
Kevin McVary, MD, FACS
Pro essor and Chairman, Division o Urology, Southern Illinois
University School o Medicine, Spring eld, Illinois [19]
Shlomo Melmed, MD
Senior Vice President and Dean o the Medical Faculty,
Cedars-Sinai Medical Center, Los Angeles, Cali ornia [3–5]
Robert J Motzer, MD
Pro essor o Medicine, Joan and San ord Weill College o Medicine
o Cornell University D. Attending Physician, Genitourinary
Oncology Service, Memorial Sloan-Kettering Cancer Center, New
York, New York [12]
Hartmut P H Neumann, MD
Universitaet Freiburg, Medizinische Universitaetsklinik, Freiburg
im Breisgau, Germany [9]
Michael A Pesce, PhD
Pro essor Emeritus o Pathology and Cell Biology, Columbia
University College o Physicians and Surgeons; Director,
Biochemical Genetics Laboratory, Columbia University Medical
Center, New York Presbyterian Hospital, New York, New York
[Appendix]
John Potts, Jr , MD
Jackson Distinguished Pro essor o Clinical Medicine, Harvard
Medical School; Physician-in-Chie and Director o Research
Emeritus, Massachusetts General Hospital, Boston, Massachusetts [34]
Alvin C Powers, MD
Joe C. Davis Chair in Biomedical Science; Pro essor o Medicine,
Molecular Physiology and Biophysics; Director, Vanderbilt
Diabetes Center; Chie , Division o Diabetes, Endocrinology, and
Metabolism, Vanderbilt University School o Medicine, Nashville,
ennessee [23–25]
Daniel J Rader, MD
Seymour Gray Pro essor o Molecular Medicine; Chair, Department
o Genetics; Chie , Division o ranslational Medicine and Human
Genetics, Department o Medicine, Perelman School o Medicine at
the University o Pennsylvania, Philadelphia, Pennsylvania [27]
Gary L Robertson, MD
Emeritus Pro essor o Medicine, Northwestern University School o
Medicine, Chicago, Illinois [6]
Michael V Seiden, MD, PhD
Chie Medical O cer, McKesson Specialty Health, T e Woodlands,
exas [18]
Rajesh V T akker, MD, FMedSci, FR
May Pro essor o Medicine, Academic Endocrine Unit, University
o Ox ord; O.C.D.E.M., Churchill Hospital, Headington, Ox ord,
United Kingdom [29]
amara J Vokes, MD
Pro essor, Department o Medicine, Section o Endocrinology,
University o Chicago, Chicago, Illinois [36]
Anthony P Weetman, MD, DSc
University o She eld, School o Medicine She eld, She eld,
United Kingdom [7]
Charles M Wiener, MD
Vice President o Academic A airs, Johns Hopkins Medicine Interna-
tional, Pro essor o Medicine and Physiology, Johns Hopkins School o
Medicine, Baltimore, Maryland [Review and Sel -Assessment]
 PREFACE
Harrison’s Principles o Internal Medicine has been a
respected source o medical in ormation or students,
residents, internists, amily physicians, and other health
care providers or many decades. T is book, Harrison’s
Endocrinology, now in its ourth edition, is a compila-
tion o chapters related to the specialty o endocrinol-
ogy, a eld that includes some o the most commonly
encountered diseases such as diabetes mellitus, obesity,
thyroid disorders, and metabolic bone disease.
Our readers consistently note the practical value o
the specialty sections o Harrison’s. Speci cally, these
sections include a rigorous explanation o pathophysiol-
ogy as a background or di erential diagnosis and patient
management. Our goal was to bring this in ormation to
readers in a more compact and usable orm. Because
the topic is more ocused, it is possible to improve the
presentation o the material by enlarging the text and
the tables and providing clearly illustrated gures that
elucidate challenging concepts. We have also included a
Review and Sel -Assessment section that includes ques-
tions and answers to provoke re ection and to provide
additional teaching points.
T e clinical mani estations o endocrine disorders
can usually be explained by considering the physiologic
role o hormones, which are either de cient or exces-
sive. T us, a thorough understanding o hormone action
and principles o hormone eedback arms the clini-
cian with a logical diagnostic approach and a concep-
tual ramework or treating patients. T e rst chapter
o the book, Approach to the Patient with Endocrine
Disorders, provides this type o “systems” overview.
Using numerous examples o translational research, this
introduction links genetics, cell biology, and physiology
with pathophysiology and treatment. T e integration
o pathophysiology with clinical management is a hall-
mark o Harrison’s, and can be ound throughout each
o the subsequent disease-oriented chapters. T e book is
divided into six main sections that re ect the physiologic
roots o endocrinology: (I) Introduction to Endocrinol-
ogy; (II) Pituitary, T yroid, and Adrenal Disorders; (III)
ix
Reproductive Endocrinology; (IV) Diabetes Mellitus,
Obesity, Lipoprotein Metabolism; (V) Disorders A ect-
ing Multiple Endocrine Systems; and (VI) Disorders o
Bone and Calcium Metabolism.
While Harrison’s Endocrinology is classic in its organi-
zation, readers will sense the impact o scienti c advances
as they explore the individual chapters in each section.
In addition to the dramatic discoveries emanating rom
genetics and molecular biology, the introduction o
an unprecedented number o new drugs, particularly
or the management o diabetes, hypogonadism, and
osteoporosis, is trans orming the eld o endocrinology.
Numerous recent clinical studies involving common
diseases like diabetes, obesity, hypothyroidism, hypo-
gonadism, and osteoporosis provide power ul evidence
or medical decision making and treatment. T ese rapid
changes in endocrinology are exciting or new students
o medicine and underscore the need or practicing phy-
sicians to continuously update their knowledge base and
clinical skills.
Our access to in ormation through web-based jour-
nals and databases is remarkably e cient, but also
daunting, creating a need or books that synthesize con-
cepts and highlight important acts. T e preparation o
these chapters is there ore a special craf that requires
distillation o core in ormation rom the ever-expanding
knowledge base. T e editors are indebted to our authors,
a group o internationally recognized authorities who
are masters at providing a comprehensive overview
while being able to distill a topic into a concise and inter-
esting chapter. We are also indebted to our colleagues at
McGraw-Hill. Jim Shanahan is a tireless champion or
Harrison’s, and these books were impeccably produced
by Kim Davis.
We hope you nd this book use ul in your e ort to
achieve continuous learning on behal o your patients.
J. Larry Jameson, MD, PhD
 NOTICE
Medicine is an ever-changing science. As new research and clinical expe-
rience broaden our knowledge, changes in treatment and drug therapy are
required. T e authors and the publisher o this work have checked with
sources believed to be reliable in their e orts to provide in ormation that is
complete and generally in accord with the standards accepted at the time o
publication. However, in view o the possibility o human error or changes in
medical sciences, neither the authors nor the publisher nor any other party
who has been involved in the preparation or publication o this work war-
rants that the in ormation contained herein is in every respect accurate or
complete, and they disclaim all responsibility or any errors or omissions or
or the results obtained rom use o the in ormation contained in this work.
Readers are encouraged to con rm the in ormation contained herein with
other sources. For example and in particular, readers are advised to check the
product in ormation sheet included in the package o each drug they plan to
administer to be certain that the in ormation contained in this work is accu-
rate and that changes have not been made in the recommended dose or in the
contraindications or administration. T is recommendation is o particular
importance in connection with new or in requently used drugs.

Review and sel -assessment questions and answers were taken rom Wiener CM,
Brown CD, Houston B (eds). Harrison’s Sel -Assessment and Board Review, 19th ed.
New York, McGraw-Hill, 2017, ISBN 978-1-259-64288-3 .

T e global icons call greater attention to key epidemiologic and clinical di erences in the practice o medicine
throughout the world.

T e genetic icons identi y a clinical issue with an explicit genetic relationship.

 SECTION I

INTRODUCTION TO
ENDOCRINOLOGY
 CH AP TER 1
APPROACH TO THE PATIENT WITH
ENDOCRINE DISORDERS
J. La rry Ja m e so n
T e management o endocrine disorders requires
a broad understanding o intermediary metabo-
lism, reproductive physiology, bone metabolism, and
growth. Accordingly, the practice o endocrinology
is intimately linked to a conceptual ramework or
understanding hormone secretion, hormone action,
and principles o eedback control (Chap. 2). T e
endocrine system is evaluated primarily by measuring
hormone concentrations, arming the clinician with
valuable diagnostic in ormation. Most disorders o the
endocrine system are amenable to e ective treatment
once the correct diagnosis is determined. Endocrine
de ciency disorders are treated with physiologic hor-
mone replacement; hormone excess conditions, which
usually are caused by benign glandular adenomas, are
managed by removing tumors surgically or reducing
hormone levels medically.
SCO P E O F ENDO CRINO LO GY
T e specialty o endocrinology encompasses the study
o glands and the hormones they produce. T e term
endocrine was coined by Starling to contrast the actions
o hormones secreted internally (endocrine) with those
secreted externally (exocrine) or into a lumen, such as
the gastrointestinal tract. T e term hormone, derived
rom a Greek phrase meaning “to set in motion,” aptly
describes the dynamic actions o hormones as they
elicit cellular responses and regulate physiologic pro-
cesses through eedback mechanisms.
Unlike many other specialties in medicine, it is not
possible to de ne endocrinology strictly along anatomic
lines. T e classic endocrine glands—pituitary, thyroid,
parathyroid, pancreatic islets, adrenals, and gonads—
communicate broadly with other organs through the
nervous system, hormones, cytokines, and growth
2
actors. In addition to its traditional synaptic unctions,
the brain produces a vast array o peptide hormones,
and this has led to the discipline o neuroendocrinol-
ogy. T rough the production o hypothalamic releas-
ing actors, the central nervous system (CNS) exerts
a major regulatory in uence over pituitary hormone
secretion (Chap. 3). T e peripheral nervous system
stimulates the adrenal medulla. T e immune and endo-
crine systems are also intimately intertwined. T e adre-
nal hormone cortisol is a power ul immunosuppressant.
Cytokines and interleukins (ILs) have pro ound e ects
on the unctions o the pituitary, adrenal, thyroid, and
gonads. Common endocrine diseases such as autoim-
mune thyroid disease and type 1 diabetes mellitus are
caused by dysregulation o immune surveillance and
tolerance. Less common diseases such as polyglandular
ailure, Addison’s disease, and lymphocytic hypophysitis
also have an immunologic basis.
T e interdigitation o endocrinology with physi-
ologic processes in other specialties sometimes blurs
the role o hormones. For example, hormones play
an important role in maintenance o blood pressure,
intravascular volume, and peripheral resistance in the
cardiovascular system. Vasoactive substances such as
catecholamines, angiotensin II, endothelin, and nitric
oxide are involved in dynamic changes o vascular tone
in addition to their multiple roles in other tissues. T e
heart is the principal source o atrial natriuretic pep-
tide, which acts in classic endocrine ashion to induce
natriuresis at a distant target organ (the kidney). Eryth-
ropoietin, a traditional circulating hormone, is made
in the kidney and stimulates erythropoiesis in bone
marrow. T e kidney is also integrally involved in the
renin-angiotensin axis (Chap. 8) and is a primary target
o several hormones, including parathyroid hormone
(P H), mineralocorticoids, and vasopressin. T e gas-
trointestinal tract produces a surprising number o
peptide hormones, such as cholecystokinin, ghrelin, hormones, are used in numerous physiologic processes, 3
gastrin, secretin, and vasoactive intestinal peptide, including vision, smell, and neurotransmission.
among many others. Carcinoid and islet tumors can
secrete excessive amounts o these hormones, lead-

C
H
ing to speci c clinical syndromes (Chap. 28). Many o

A
PATHO LO GIC MECHANISMS O F

P
T
these gastrointestinal hormones are also produced in

E
ENDO CRINE DISEASE

R
the CNS, where their unctions are poorly understood.

1
Adipose tissue produces leptin, which acts centrally to Endocrine diseases can be divided into three major
control appetite, along with adiponectin, resistin, and types o conditions: (1) hormone excess, (2) hormone
other hormones that regulate metabolism. As hormones

A
de ciency, and (3) hormone resistance (Table 1-1).

p
p
such as inhibin, ghrelin, and leptin are discovered, they

r
o
a
become integrated into the science and practice o med-

c
h
icine on the basis o their unctional roles rather than

t
o
CAUSES OF HORMONE EXCESS

t
their tissues o origin.

h
e
P
Characterization o hormone receptors requently Syndromes o hormone excess can be caused by neo-

a
t
i
reveals unexpected relationships to actors in nonen- plastic growth o endocrine cells, autoimmune dis-

e
n
t
docrine disciplines. T e growth hormone (GH) and orders, and excess hormone administration. Benign

w
i
t
leptin receptors, or example, are members o the cyto- endocrine tumors, including parathyroid, pituitary,

h
E
n
kine receptor amily. T e G protein–coupled receptors and adrenal adenomas, o en retain the capacity to pro-

d
o
(GPCRs), which mediate the actions o many peptide duce hormones, perhaps re ecting the act that these

c
r
i
n
e
D
i
s
o
r
d
TABLE 1 -1

e
r
s
CAUSES OF ENDOCRINE DYSFUNCTION
TYPE OF ENDOCRINE DISORDER EXAMPLES

Hyp e r fu n ct io n
Neoplastic
Benign Pituitary adenomas, hyperparathyroidism, autonomous thyroid or adrenal nodules,
pheochromocytoma
Malignant Adrenal cancer, medullary thyroid cancer, carcinoid
Ectopic Ectopic ACTH, SIADH secretion
Multiple endocrine neoplasia (MEN) MEN 1, MEN 2
Autoimmune Graves’disease
Iatrogenic Cushing’s syndrome, hypoglycemia
In ectious/in ammatory Subacute thyroiditis
Activating receptor mutations LH, TSH, Ca 2+, PTH receptors, Gsα
Hyp o fu n ct io n
Autoimmune Hashimoto’s thyroiditis, type 1 diabetes mellitus, Addison’s disease, polyglandular ailure
Iatrogenic Radiation-induced hypopituitarism, hypothyroidism, surgical
In ectious/in ammatory Adrenal insuf ciency, hypothalamic sarcoidosis
Hormone mutations GH, LHβ, FSHβ, vasopressin
Enzyme de ects 21-Hydroxylase de ciency
Developmental de ects Kallmann syndrome, Turner’s syndrome, transcription actors
Nutritional/vitamin de ciency Vitamin D de ciency, iodine de ciency
Hemorrhage/in arction Sheehan’s syndrome, adrenal insuf ciency
Ho rm o n e Re sist a n ce
Receptor mutations
Membrane GH, vasopressin, LH, FSH, ACTH, GnRH, GHRH, PTH, leptin, Ca 2+
Nuclear AR, TR, VDR, ER, GR, PPARγ
Signaling pathway mutations Albright’s hereditary osteodystrophy
Postreceptor Type 2 diabetes mellitus, leptin resistance

Ab brevia tio n s: ACTH, adrenocorticotropic hormone; AR, androgen receptor; ER, estrogen receptor; FSH, ollicle-stimulating hormone; GHRH, growth
hormone–releasing hormone; GnRH, gonadotropin-releasing hormone; GR, glucocorticoid receptor; LH, luteinizing hormone; PPAR, peroxisome proli er-
ator activated receptor; PTH, parathyroid hormone; SIADH, syndrome o inappropriate antidiuretic hormone; TR, thyroid hormone receptor; TSH, thyroid-
stimulating hormone; VDR, vitamin D receptor.
4 tumors are relatively well di erentiated. Many endo- In autoimmune Graves’ disease, antibody interac-
crine tumors exhibit subtle de ects in their “set points” tions with the thyroid-stimulating hormone ( SH)
or eedback regulation. For example, in Cushing’s dis- receptor mimic SH action, leading to hormone over-
ease, impaired eedback inhibition o adrenocortico- production (Chap. 7). Analogous to the e ects o acti-
S
E
tropic hormone (AC H) secretion is associated with vating mutations o the SH receptor, these stimulating
C
T
I
autonomous unction. However, the tumor cells are not autoantibodies induce con ormational changes that
O
N
completely resistant to eedback, as evidenced by AC H release the receptor rom a constrained state, thereby
I
suppression by higher doses o dexamethasone (e.g., triggering receptor coupling to G proteins.
high-dose dexamethasone test) (Chap. 8). Similar set
point de ects are also typical o parathyroid adenomas
I
n
t
r
and autonomously unctioning thyroid nodules. CAUSES OF HORMONE DEFICIENCY
o
d
u
T e molecular basis o some endocrine tumors, such
c
Most examples o hormone de ciency states can be
t
i
o
as the multiple endocrine neoplasia (MEN) syndromes
n
attributed to glandular destruction caused by autoim-
t
(MEN 1, 2A, 2B), have provided important insights
o
munity, surgery, in ection, in ammation, in arction,
E
n
into tumorigenesis (Chap. 29). MEN 1 is characterized
d
hemorrhage, or tumor in ltration ( able 1-1). Auto-
o
primarily by the triad o parathyroid, pancreatic islet,
c
r
immune damage to the thyroid gland (Hashimoto’s
i
n
and pituitary tumors. MEN 2 predisposes to medullary
o
thyroiditis) and pancreatic islet β cells (type 1 diabe-
l
o
thyroid carcinoma, pheochromocytoma, and hyper-
g
tes mellitus) is a prevalent cause o endocrine disease.
y
parathyroidism. T e MEN1 gene, located on chromo-
Mutations in a number o hormones, hormone recep-
some 11q13, encodes a putative tumor-suppressor gene,
tors, transcription actors, enzymes, and channels can
menin. Analogous to the paradigm rst described or
also lead to hormone de ciencies.
retinoblastoma, the a ected individual inherits a mutant
copy o the MEN1 gene, and tumorigenesis ensues a er a
somatic “second hit” leads to loss o unction o the nor-
HORMONE RESISTANCE
mal MEN1 gene (through deletion or point mutations).
In contrast to inactivation o a tumor-suppressor Most severe hormone resistance syndromes are due to
gene, as occurs in MEN 1 and most other inherited can- inherited de ects in membrane receptors, nuclear recep-
cer syndromes, MEN 2 is caused by activating muta- tors, or the pathways that transduce receptor signals.
tions in a single allele. In this case, activating mutations T ese disorders are characterized by de ective hormone
o the RET protooncogene, which encodes a receptor action despite the presence o increased hormone levels.
tyrosine kinase, leads to thyroid C cell hyperplasia in In complete androgen resistance, or example, muta-
childhood be ore the development o medullary thyroid tions in the androgen receptor result in a emale phe-
carcinoma. Elucidation o this pathogenic mechanism notypic appearance in genetic (XY) males, even though
has allowed early genetic screening or RET mutations LH and testosterone levels are increased (Chap. 29). In
in individuals at risk or MEN 2, permitting identi- addition to these relatively rare genetic disorders, more
cation o those who may bene t rom prophylactic common acquired orms o unctional hormone resis-
thyroidectomy and biochemical screening or pheo- tance include insulin resistance in type 2 diabetes mel-
chromocytoma and hyperparathyroidism. litus, leptin resistance in obesity, and GH resistance in
Mutations that activate hormone receptor signal- catabolic states. T e pathogenesis o unctional resis-
ing have been identi ed in several GPCRs. For example, tance involves receptor downregulation and postrecep-
activating mutations o the luteinizing hormone (LH) tor desensitization o signaling pathways; unctional
receptor cause a dominantly transmitted orm o male- orms o resistance are generally reversible.
limited precocious puberty, re ecting premature stimula-
tion o testosterone synthesis in Leydig cells (Chap. 11).
CLINICAL EVALUATION OF ENDOCRINE
Activating mutations in these GPCRs are located pre-
DISORDERS
dominantly in the transmembrane domains and induce
receptor coupling to Gsα even in the absence o hormone. Because most glands are relatively inaccessible, the physi-
Consequently, adenylate cyclase is activated, and cyclic cal examination usually ocuses on the mani estations o
adenosine monophosphate (AMP) levels increase in a hormone excess or de ciency as well as direct examina-
manner that mimics hormone action. A similar phenom- tion o palpable glands, such as the thyroid and gonads.
enon results rom activating mutations in Gsα. When For these reasons, it is important to evaluate patients in
these mutations occur early in development, they cause the context o their presenting symptoms, review o sys-
McCune-Albright syndrome. When they occur only in tems, amily and social history, and exposure to medica-
somatotropes, the activating Gsα mutations cause GH- tions that may a ect the endocrine system. Astute clinical
secreting tumors and acromegaly (Chap. 5). skills are required to detect subtle symptoms and signs
suggestive o underlying endocrine disease. For example,
a patient with Cushing’s syndrome may mani est speci c
ndings, such as central at redistribution, striae, and
proximal muscle weakness, in addition to eatures seen
commonly in the general population, such as obesity,
plethora, hypertension, and glucose intolerance. Simi-
larly, the insidious onset o hypothyroidism—with men-
tal slowing, atigue, dry skin, and other eatures—can be
dif cult to distinguish rom similar, nonspeci c ndings
in the general population. Clinical judgment that is based
on knowledge o disease prevalence and pathophysiology
is required to decide when to embark on more extensive
evaluation o these disorders. Laboratory testing plays an
essential role in endocrinology by allowing quantitative
assessment o hormone levels and dynamics. Radiologic
imaging tests such as computed tomography (C ) scan,
magnetic resonance imaging (MRI), thyroid scan, and
ultrasound are also used or the diagnosis o endocrine
disorders. However, these tests generally are employed
only a er a hormonal abnormality has been established
by biochemical testing.
HORMONE MEASUREMENTS AND
ENDOCRINE TESTING
Immunoassays are the most important diagnostic tool
in endocrinology, as they allow sensitive, speci c, and
quantitative determination o steady-state and dynamic
changes in hormone concentrations. Immunoassays use
antibodies to detect speci c hormones. For many peptide
hormones, these measurements are now con gured to
use two di erent antibodies to increase binding af nity
and speci city. T ere are many variations o these assays;
a common ormat involves using one antibody to cap-
ture the antigen (hormone) onto an immobilized sur ace
and a second antibody, coupled to a chemiluminescent
(immunochemiluminescent assay [ICMA]) or radioac-
tive (immunoradiometric assay [IRMA]) signal, to detect
the antigen. T ese assays are sensitive enough to detect
plasma hormone concentrations in the picomolar to
nanomolar range, and they can readily distinguish struc-
turally related proteins, such as P H rom P H-related
peptide (P HrP). A variety o other techniques are used
to measure speci c hormones, including mass spectros-
copy, various orms o chromatography, and enzymatic
methods; bioassays are now rarely used.
Most hormone measurements are based on plasma or
serum samples. However, urinary hormone determina-
tions remain use ul or the evaluation o some conditions.
Urinary collections over 24 h provide an integrated assess-
ment o the production o a hormone or metabolite, many
o which vary during the day. It is important to assure com-
plete collections o 24-h urine samples; simultaneous mea-
surement o creatinine provides an internal control or the
adequacy o collection and can be used to normalize some
hormone measurements. A 24-h urine ree cortisol mea- 5
surement largely re ects the amount o unbound cortisol,
thus providing a reasonable index o biologically available
hormone. Other commonly used urine determinations
C
H
include 17-hydroxycorticosteroids, 17-ketosteroids, vanillyl-
A
P
T
mandelic acid, metanephrine, catecholamines, 5-hydroxyin-
E
R
doleacetic acid, and calcium.
1
T e value o quantitative hormone measurements lies
in their correct interpretation in a clinical context. T e
normal range or most hormones is relatively broad,
A
p
p
o en varying by a actor o two- to ten old. T e normal
r
o
a
ranges or many hormones are sex- and age-speci c.
c
h
T us, using the correct normative database is an essential
t
o
t
part o interpreting hormone tests. T e pulsatile nature o
h
e
P
hormones and actors that can a ect their secretion, such
a
t
i
as sleep, meals, and medications, must also be consid-
e
n
t
ered. Cortisol values increase ve old between midnight
w
i
t
and dawn; reproductive hormone levels vary dramati-
h
E
n
cally during the emale menstrual cycle.
d
o
For many endocrine systems, much in ormation
c
r
i
n
can be gained rom basal hormone testing, particularly
e
D
when di erent components o an endocrine axis are
i
s
o
r
assessed simultaneously. For example, low testoster-
d
e
r
one and elevated LH levels suggest a primary gonadal
s
problem, whereas a hypothalamic-pituitary disorder is
likely i both LH and testosterone are low. Because SH
is a sensitive indicator o thyroid unction, it is gener-
ally recommended as a rst-line test or thyroid disor-
ders. An elevated SH level is almost always the result
o primary hypothyroidism, whereas a low SH is most
o en caused by thyrotoxicosis. T ese predictions can be
con rmed by determining the ree thyroxine level. In
the less common circumstance when ree thyroxine and
SH are both low, it is important to consider second-
ary hypopituitarism caused by hypothalamic-pituitary
disease. Elevated calcium and P H levels suggest
hyperparathyroidism, whereas P H is suppressed in
hypercalcemia caused by malignancy or granulomatous
diseases. A suppressed AC H in the setting o hyper-
cortisolemia, or increased urine ree cortisol, is seen
with hyper unctioning adrenal adenomas.
It is not uncommon, however, or baseline hormone
levels associated with pathologic endocrine conditions
to overlap with the normal range. In this circumstance,
dynamic testing is use ul to separate the two groups ur-
ther. T ere are a multitude o dynamic endocrine tests,
but all are based on principles o eedback regulation, and
most responses can be rationalized based on principles
that govern the regulation o endocrine axes. Suppres-
sion tests are used in the setting o suspected endocrine
hyper unction. An example is the dexamethasone sup-
pression test used to evaluate Cushing’s syndrome
(Chaps. 5 and 8). Stimulation tests generally are used
to assess endocrine hypo unction. T e AC H stimula-
tion test, or example, is used to assess the adrenal gland
6 TABLE 1 -2
EXAMPLES OF PREVALENT ENDOCRINE AND METABOLIC DISORDERS IN THE ADULT
APPROX.
PREVALENCE IN
S
E
DISORDER ADULTS a SCREENING/TESTING RECOMMENDATIONS b CHAPTER(S)
C
T
I
O
Obesity 34% BMI ≥30 Calculate BMI Ch a p . 21
N
68% BMI ≥25 Measure waist circum erence
I
Exclude secondary causes
Consider comorbid complications
Type 2 diabetes mellitus >7% Beginning at age 45, screen every 3 years, or earlier in high-risk groups: Ch a p . 23
I
n
Fasting plasma glucose (FPG) >126 mg/dL
t
r
o
Random plasma glucose >200 mg/dL
d
u
An elevated HbA1c
c
t
i
Consider comorbid complications
o
n
t
Hyperlipidemia 20–25% Cholesterol screening at least every 5 years; more o ten in high-risk Ch a p . 27
o
E
groups
n
d
Lipoprotein analysis (LDL, HDL) or increased cholesterol, CAD, diabetes
o
c
Consider secondary causes
r
i
n
o
Metabolic syndrome 35% Measure waist circum erence, FPG, BP, lipids Ch a p . 22
l
o
g
Hypothyroidism 5–10%, women TSH; con rm with ree T4 Ch a p . 7
y
0.5–2%, men Screen women a ter age 35 and every 5 years therea ter
Graves’disease 1–3%, women TSH, ree T4 Ch a p . 7
0.1%, men
Thyroid nodules and 2–5% palpable Physical examination o thyroid Ch a p . 7
neoplasia >25% by ultrasound Fine-needle aspiration biopsy
Osteoporosis 5–10%, women Bone mineral density measurements in women >65 years or in post- Ch a p . 35
2–5%, men menopausal women or men at risk
Exclude secondary causes
Hyperparathyroidism 0.1–0.5%, women Serum calcium Ch a p . 34
> men PTH, i calcium is elevated
Assess comorbid conditions
In ertility 10%, couples Investigate both members o couple Ch a p s. 11,
Semen analysis in male 13
Assess ovulatory cycles in emale
Speci c tests as indicated
Polycystic ovarian 5–10%, women Free testosterone, DHEAS Ch a p . 13
syndrome Consider comorbid conditions
Hirsutism 5–10% Free testosterone, DHEAS Ch a p . 17
Exclude secondary causes
Additional tests as indicated
Menopause Median age, 51 FSH Ch a p . 16
Hyperprolactinemia 15% in women with PRL level Ch a p . 5
amenorrhea or MRI, i not medication-related
galactorrhea
Erectile dys unction 10–25% Care ul history, PRL, testosterone Ch a p . 19
Consider secondary causes (e.g., diabetes)
Hypogonadism, male 1–2% Testosterone, LH Ch a p . 11
Gynecomastia 15% O ten, no tests are indicated Ch a p . 11
Consider Kline elter’s syndrome
Consider medications, hypogonadism, liver disease
Kline elter’s syndrome 0.2%, men Karyotype Ch a p . 10
Testosterone
Vitamin D de ciency 10% Measure serum 25-OH vitamin D Ch a p . 32
Consider secondary causes
Turner’s syndrome 0.03%, women Karyotype Ch a p . 10
Consider comorbid conditions

a
The prevalence o most disorders varies among ethnic groups and with aging. Data based primarily on U.S. population.
b
See individual chapters or additional in ormation on evaluation and treatment. Early testing is indicated in patients with signs and symptoms o disease
and in those at increased risk.
Abb revia tio ns: BMI, body mass index; BP, blood pressure; CAD, coronary artery disease; DHEAS, dehydroepiandrosterone; FSH, ollicle-stimulating hor-
mone; HDL, high-density lipoprotein; LDL, low-density lipoprotein; LH, luteinizing hormone; MRI, magnetic resonance imaging; PRL, prolactin; PTH, para-
thyroid hormone; TSH, thyroid-stimulating hormone.
response in patients with suspected adrenal insuf ciency. SCREENING AND ASSESSMENT OF 7
Other stimulation tests use hypothalamic-releasing ac- COMMON ENDOCRINE DISORDERS
tors such as corticotropin-releasing hormone (CRH)
Many endocrine disorders are prevalent in the adult
and growth hormone–releasing hormone (GHRH) to

C
population (Table 1-2) and can be diagnosed and man-

H
evaluate pituitary hormone reserve (Chap. 5). Insulin-

A
aged by general internists, amily practitioners, or other

P
T
induced hypoglycemia also evokes pituitary AC H and

E
primary health care providers. T e high prevalence and

R
GH responses. Stimulation tests based on reduction or

1
clinical impact o certain endocrine diseases justi es
inhibition o endogenous hormones are now used in re-
vigilance or eatures o these disorders during routine
quently. Examples include metyrapone inhibition o
physical examinations; laboratory screening is indicated
cortisol synthesis and clomiphene inhibition o estrogen

A
p
in selected high-risk populations.

p
eedback.

r
o
a
c
h
t
o
t
h
e
P
a
t
i
e
n
t
w
i
t
h
E
n
d
o
c
r
i
n
e
D
i
s
o
r
d
e
r
s
 CH AP TER 2
MECHANISMS OF HORMONE ACTION
J. La rry Ja m e so n
CLASSES O F HO RMO NES
Hormones can be divided into ve major types: (1)
amino acid derivatives such as dopamine, catechol-
amine, and thyroid hormone; (2) small neuropeptides
such as gonadotropin-releasing hormone (GnRH), thy-
rotropin-releasing hormone ( RH), somatostatin, and
vasopressin; (3) large proteins such as insulin, luteiniz-
ing hormone (LH), and parathyroid hormone (P H);
(4) steroid hormones such as cortisol and estrogen that
are synthesized rom cholesterol-based precursors;
and (5) vitamin derivatives such as retinoids (vitamin
A) and vitamin D. A variety o peptide growth factors,
most o which act locally, share actions with hormones.
As a rule, amino acid derivatives and peptide hormones
interact with cell-sur ace membrane receptors. Steroids,
thyroid hormones, vitamin D, and retinoids are lipid-
soluble and interact with intracellular nuclear receptors,
although many also interact with membrane receptors
or intracellular signaling proteins as well.
HORMONE AND RECEPTOR FAMILIES
Hormones and receptors can be grouped into amilies,
re ecting structural similarities and evolutionary ori-
gins (Table 2-1). T e evolution o these amilies gener-
ates diverse but highly selective pathways o hormone
action. Recognition o these relationships has proven
use ul or extrapolating in ormation gleaned rom one
hormone or receptor to other amily members.
T e glycoprotein hormone amily, consisting o thy-
roid-stimulating hormone ( SH), ollicle-stimulating
hormone (FSH), LH, and human chorionic gonado-
tropin (hCG), illustrates many eatures o related hor-
mones. T e glycoprotein hormones are heterodimers
that share the α subunit in common; the β subunits are
distinct and con er speci c biologic actions. T e over-
all three-dimensional architecture o the β subunits is
similar, re ecting the locations o conserved disul de
8
bonds that restrain protein con ormation. T e cloning
o the β-subunit genes rom multiple species suggests
that this amily arose rom a common ancestral gene,
probably by gene duplication and subsequent diver-
gence to evolve new biologic unctions.
As hormone amilies enlarge and diverge, their
receptors must co-evolve to derive new biologic unc-
tions. Related G protein–coupled receptors (GPCRs),
or example, have evolved or each o the glycoprotein
hormones. T ese receptors are structurally similar, and
each is coupled predominantly to the Gsα signaling
pathway. However, there is minimal overlap o hormone
binding. For example, SH binds with high speci city
to the SH receptor but interacts minimally with the
LH or FSH receptors. Nonetheless, there can be subtle
physiologic consequences o hormone cross-reactivity
with other receptors. Very high levels o hCG during
pregnancy stimulate the SH receptor and increase
thyroid hormone levels, resulting in a compensatory
decrease in SH.
Insulin and insulin-like growth actor I (IGF-I) and
IGF-II have structural similarities that are most appar-
ent when precursor orms o the proteins are compared.
In contrast to the high degree o speci city seen with
the glycoprotein hormones, there is moderate cross-talk
among the members o the insulin/IGF amily. High
concentrations o an IGF-II precursor produced by cer-
tain tumors (e.g., sarcomas) can cause hypoglycemia,
partly because o binding to insulin and IGF-I receptors
(Chap. 34). High concentrations o insulin also bind to
the IGF-I receptor, perhaps accounting or some o the
clinical mani estations seen in conditions with chronic
hyperinsulinemia.
Another important example o receptor cross-talk
is seen with P H and parathyroid hormone–related
peptide (P HrP) (Chap. 34). P H is produced by the
parathyroid glands, whereas P HrP is expressed at high
levels during development and by a variety o tumors
(Chap. 31). T ese hormones have amino acid sequence
TABLE 2 -1 receptor, retinoic acid receptor, peroxisome proli erator 9
EXAMPLES OF MEMBRANE RECEPTOR FAMILIES AND activated receptor) that bind thyroid hormone, vitamin
SIGNALING PATHWAYS D, retinoic acid, or lipid derivatives. Certain unctional
domains in nuclear receptors, such as the zinc nger

C
SIGNALING

H
DNA-binding domains, are highly conserved. However,

A
RECEPTORS EFFECTORS PATHWAYS

P
T
selective amino acid di erences within this domain

E
G Pro t e in –Co u p le d Se ve n -Tra n sm e m b ra n e Re ce p t o r

R
(GPCR) con er DNA sequence speci city. T e hormone-binding

2
β-Adrenergic, LH, GSα, adenylate Stimulation o domains are more variable, providing great diversity
FSH, TSH cyclase cyclic AMP pro- in the array o small molecules that bind to di erent
nuclear receptors. With ew exceptions, hormone bind-

M
duction, protein

e
c
kinase A ing is highly speci c or a single type o nuclear recep-

h
a
Ca2+ channels

n
Glucagon, PTH, Calmodulin, tor. One exception involves the glucocorticoid and

i
s
m
PTHrP, ACTH, Ca 2+-dependent mineralocorticoid receptors. Because the mineralo-

s
MSH, GHRH, CRH kinases

o
corticoid receptor also binds glucocorticoids with high

f
H
α-Adrenergic, Giα Inhibition o cyclic
a nity, an enzyme (11β-hydroxysteroid dehydroge-

o
r
somatostatin AMP production

m
nase) in renal tubular cells inactivates glucocorticoids,

o
Activation o K+,

n
allowing selective responses to mineralocorticoids such

e
Ca2+ channels

A
c
TRH, GnRH Gq , G11 Phospholipase C, as aldosterone. However, when very high glucocorticoid

t
i
o
concentrations occur, as in Cushing’s syndrome, the

n
diacyl-glycerol,
IP3, protein glucocorticoid degradation pathway becomes saturated,
kinase C, voltage- allowing excessive cortisol levels to exert mineralocor-
dependent Ca 2+
channels
ticoid e ects (sodium retention, potassium wasting).
T is phenomenon is particularly pronounced in ecto-
Re ce p t o r Tyro sin e Kin a se
pic adrenocorticotropic hormone (AC H) syndromes
Insulin, IGF-I Tyrosine kinases, MAP kinases, PI (Chap. 8). Another example o relaxed nuclear recep-
IRS 3-kinase; AKT tor speci city involves the estrogen receptor, which can
EGF, NGF Tyrosine kinases, Ra , MAP kinases,
ras RSK
bind an array o compounds, some o which have little
apparent structural similarity to the high-a nity ligand
Cyto kin e Re ce p to r–Lin ke d Kin a se
estradiol. T is eature o the estrogen receptor makes
GH, PRL JAK, tyrosine STAT, MAP kinase, it susceptible to activation by “environmental estro-
kinases PI 3-kinase, IRS-1 gens” such as resveratrol, octylphenol, and many other
Se rin e Kin a se aromatic hydrocarbons. However, this lack o speci c-
Activin, TGF-β, MIS Serine kinase Smads ity provides an opportunity to synthesize a remarkable
series o clinically use ul antagonists (e.g., tamoxi en)
Abb revia tio ns: IP3, inositol triphosphate; IRS, insulin receptor substrates; and selective estrogen response modulators (SERMs)
MAP, mitogen-activated protein; MSH, melanocyte-stimulating hormone; such as raloxi ene. T ese compounds generate dis-
NGF, nerve growth actor; PI, phosphatidylinositol; RSK, ribosomal S6
kinase; TGF-β, trans orming growth actor β. For all other abbreviations,
tinct con ormations that alter receptor interactions
see text. Note that most receptors interact with multiple ef ectors and with components o the transcription machinery (see
activate networks o signaling pathways. below), thereby con erring their unique actions.
similarity, particularly in their amino-terminal regions.
Both hormones bind to a single P H receptor that
HORMONE SYNTHESIS AND PROCESSING
is expressed in bone and kidney. Hypercalcemia and
hypophosphatemia there ore may result rom excessive T e synthesis o peptide hormones and their receptors
production o either hormone, making it di cult to occurs through a classic pathway o gene expression:
distinguish hyperparathyroidism rom hypercalcemia transcription → mRNA → protein → posttranslational
o malignancy solely on the basis o serum chemistries. protein processing → intracellular sorting, ollowed by
However, sensitive and speci c assays or P H and membrane integration or secretion.
P HrP now allow these disorders to be distinguished Many hormones are embedded within larger precur-
more readily. sor polypeptides that are proteolytically processed to
Based on their speci cities or DNA binding sites, yield the biologically active hormone. Examples include
the nuclear receptor amily can be subdivided into proopiomelanocortin (POMC) → AC H; progluca-
type 1 receptors (glucocorticoid receptor, mineralo- gon →glucagon; proinsulin →insulin; and pro-P H →
corticoid receptor, androgen receptor, estrogen recep- P H, among others. In many cases, such as POMC and
tor, progesterone receptor) that bind steroids and type proglucagon, these precursors generate multiple bio-
2 receptors (thyroid hormone receptor, vitamin D logically active peptides. It is provocative that hormone
10 precursors are typically inactive, presumably adding an secretion is a releasing actor or neural signal that
additional level o regulatory control. Prohormone con- induces rapid changes in intracellular calcium con-
version occurs not only or peptide hormones but also centrations, leading to secretory granule usion with
or certain steroids (testosterone →dihydrotestosterone) the plasma membrane and release o its contents into
S
E
and thyroid hormone ( 4 → 3). the extracellular environment and bloodstream. Ste-
C
T
I
Peptide precursor processing is intimately linked to roid hormones, in contrast, di use into the circulation
O
N
intracellular sorting pathways that transport proteins to as they are synthesized. T us, their secretory rates are
I
appropriate vesicles and enzymes, resulting in speci c closely aligned with rates o synthesis. For example,
cleavage steps, ollowed by protein olding and trans- AC H and LH induce steroidogenesis by stimulating
location to secretory vesicles. Hormones destined or the activity o the steroidogenic acute regulatory (StAR)
I
n
t
r
secretion are translocated across the endoplasmic retic- protein (transports cholesterol into the mitochondrion)
o
d
u
ulum under the guidance o an amino-terminal sig- along with other rate-limiting steps (e.g., cholesterol
c
t
i
o
nal sequence that subsequently is cleaved. Cell-sur ace side-chain cleavage enzyme, CYP11A1) in the steroido-
n
t
receptors are inserted into the membrane via short genic pathway.
o
E
n
segments o hydrophobic amino acids that remain Hormone transport and degradation dictate the
d
o
embedded within the lipid bilayer. During transloca- rapidity with which a hormonal signal decays. Some
c
r
i
n
tion through the Golgi and endoplasmic reticulum, hormone signals are evanescent (e.g., somatostatin),
o
l
o
hormones and receptors are subject to a variety o post- whereas others are longer-lived (e.g., SH). Because
g
y
translational modi cations, such as glycosylation and somatostatin exerts e ects in virtually every tissue, a
phosphorylation, which can alter protein con ormation, short hal -li e allows its concentrations and actions
modi y circulating hal -li e, and alter biologic activity. to be controlled locally. Structural modi cations that
Synthesis o most steroid hormones is based on impair somatostatin degradation have been use ul or
modi cations o the precursor, cholesterol. Multiple generating long-acting therapeutic analogues such as
regulated enzymatic steps are required or the synthe- octreotide (Chap. 5). In contrast, the actions o SH are
sis o testosterone (Chap. 11), estradiol (Chap. 13), highly speci c or the thyroid gland. Its prolonged hal -
cortisol (Chap. 8), and vitamin D (Chap. 32). T is li e accounts or relatively constant serum levels even
large number o synthetic steps predisposes to multiple though SH is secreted in discrete pulses.
genetic and acquired disorders o steroidogenesis. An understanding o circulating hormone hal -li e is
Endocrine genes contain regulatory DNA elements important or achieving physiologic hormone replace-
similar to those ound in many other genes, but their ment, as the requency o dosing and the time required
exquisite control by hormones re ects the presence o to reach steady state are intimately linked to rates o hor-
speci c hormone response elements. For example, the mone decay. 4, or example, has a circulating hal -li e
SH genes are repressed directly by thyroid hormones o 7 days. Consequently, >1 month is required to reach
acting through the thyroid hormone receptor ( R), a a new steady state, and single daily doses are su cient
member o the nuclear receptor amily. Steroidogenic to achieve constant hormone levels. 3, in contrast, has
enzyme gene expression requires speci c transcription a hal -li e o 1 day. Its administration is associated with
actors, such as steroidogenic actor-1 (SF-1), acting in more dynamic serum levels, and it must be adminis-
conjunction with signals transmitted by trophic hor- tered two to three times per day. Similarly, synthetic glu-
mones (e.g., AC H or LH). For some hormones, sub- cocorticoids vary widely in their hal -lives; those with
stantial regulation occurs at the level o translational longer hal -lives (e.g., dexamethasone) are associated
e ciency. Insulin biosynthesis, although it requires with greater suppression o the hypothalamic-pituitary-
ongoing gene transcription, is regulated primarily at the adrenal (HPA) axis. Most protein hormones (e.g., AC H,
translational and secretory levels in response to elevated GH, prolactin [PRL], P H, LH) have relatively short
levels o glucose or amino acids. hal -lives (<20 min), leading to sharp peaks o secretion
and decay. T e only accurate way to pro le the pulse re-
quency and amplitude o these hormones is to measure
HORMONE SECRETION, TRANSPORT, AND
levels in requently sampled blood (every 10 min or less)
DEGRADATION
over long durations (8–24 h). Because this is not practi-
T e level o a hormone is determined by its rate o cal in a clinical setting, an alternative strategy is to pool
secretion and its circulating hal -li e. Af er protein pro- three to our samples drawn at about 30-min intervals,
cessing, peptide hormones (e.g., GnRH, insulin, growth or interpret the results in the context o a relatively wide
hormone [GH]) are stored in secretory granules. As normal range. Rapid hormone decay is use ul in certain
these granules mature, they are poised beneath the clinical settings. For example, the short hal -li e o P H
plasma membrane or imminent release into the cir- allows the use o intraoperative P H determinations
culation. In most instances, the stimulus or hormone to con rm success ul removal o an adenoma. T is is
particularly valuable diagnostically when there is a pos-
sibility o multicentric disease or parathyroid hyperplasia,
as occurs with multiple endocrine neoplasia (MEN) or
renal insu ciency.
Many hormones circulate in association with serum-
binding proteins. Examples include (1) 4 and 3 bind-
ing to thyroxine-binding globulin ( BG), albumin, and
thyroxine-binding prealbumin ( BPA); (2) cortisol
binding to cortisol-binding globulin (CBG); (3) andro-
gen and estrogen binding to sex hormone–binding
globulin (SHBG); (4) IGF-I and -II binding to multiple
IGF-binding proteins (IGFBPs); (5) GH interactions
with GH-binding protein (GHBP), a circulating rag-
ment o the GH receptor extracellular domain; and (6)
activin binding to ollistatin. T ese interactions provide
a hormonal reservoir, prevent otherwise rapid degrada-
tion o unbound hormones, restrict hormone access to
certain sites (e.g., IGFBPs), and modulate the unbound,
or “ ree,” hormone concentrations. Although a variety
o binding protein abnormalities have been identi ed,
most have little clinical consequence aside rom creat-
ing diagnostic problems. For example, BG de ciency
can reduce total thyroid hormone levels greatly but the
ree concentrations o 4 and 3 remain normal. Liver
disease and certain medications can also in uence
binding protein levels (e.g., estrogen increases BG) or
cause displacement o hormones rom binding proteins
(e.g., salsalate displaces 4 rom BG). In general, only
unbound hormone is available to interact with recep-
tors and thus elicit a biologic response. Short-term per-
turbations in binding proteins change the ree hormone
concentration, which in turn induces compensatory
adaptations through eedback loops. SHBG changes in
women are an exception to this sel -correcting mecha-
nism. When SHBG decreases because o insulin resis-
tance or androgen excess, the unbound testosterone
concentration is increased, potentially leading to hir-
sutism (Chap. 17). T e increased unbound testosterone
level does not result in an adequate compensatory eed-
back correction because estrogen, not testosterone, is
the primary regulator o the reproductive axis.
An additional exception to the unbound hormone
hypothesis involves megalin, a member o the low-
density lipoprotein (LDL) receptor amily that serves
as an endocytotic receptor or carrier-bound vitamins
A and D and SHBG-bound androgens and estrogens.
Af er internalization, the carrier proteins are degraded
in lysosomes and release their bound ligands within the
cells. Membrane transporters have also been identi ed
or thyroid hormones.
Hormone degradation can be an important mecha-
nism or regulating concentrations locally. As noted above,
11β-hydroxysteroid dehydrogenase inactivates glucocorti-
coids in renal tubular cells, preventing actions through the
mineralocorticoid receptor. T yroid hormone deiodinases
convert 4 to 3 and can inactivate 3. During develop- 11
ment, degradation o retinoic acid by Cyp26b1 prevents
primordial germ cells in the male rom entering meiosis,
as occurs in the emale ovary.
C
H
A
P
T
E
R
HORMONE ACTION THROUGH RECEPTORS
2
Receptors or hormones are divided into two major
classes: membrane and nuclear. Membrane receptors
M
e
primarily bind peptide hormones and catecholamines.
c
h
Nuclear receptors bind small molecules that can di use
a
n
i
s
across the cell membrane, such as steroids and vita-
m
s
min D. Certain general principles apply to hormone-
o
f
H
receptor interactions regardless o the class o receptor.
o
r
Hormones bind to receptors with speci city and an
m
o
n
a nity that generally coincides with the dynamic range
e
A
o circulating hormone concentrations. Low concentra-
c
t
i
tions o ree hormone (usually 10−12 to 10−9 M) rapidly
o
n
associate and dissociate rom receptors in a bimolecular
reaction such that the occupancy o the receptor at any
given moment is a unction o hormone concentration
and the receptor’s a nity or the hormone. Receptor
numbers vary greatly in di erent target tissues, pro-
viding one o the major determinants o speci c tissue
responses to circulating hormones. For example, AC H
receptors are located almost exclusively in the adrenal
cortex, and FSH receptors are ound predominantly in
the gonads. In contrast, insulin and Rs are widely dis-
tributed, re ecting the need or metabolic responses in
all tissues.
MEMBRANE RECEPTORS
Membrane receptors or hormones can be divided into
several major groups: (1) seven transmembrane GPCRs,
(2) tyrosine kinase receptors, (3) cytokine receptors,
and (4) serine kinase receptors (Fig. 2-1). T e seven
transmembrane GPCR family binds a remarkable array
o hormones, including large proteins (e.g., LH, P H),
small peptides (e.g., RH, somatostatin), catechol-
amines (epinephrine, dopamine), and even minerals
(e.g., calcium). T e extracellular domains o GPCRs
vary widely in size and are the major binding site or
large hormones. T e transmembrane-spanning regions
are composed o hydrophobic α-helical domains that
traverse the lipid bilayer. Like some channels, these
domains are thought to circularize and orm a hydro-
phobic pocket into which certain small ligands t. Hor-
mone binding induces con ormational changes in these
domains, transducing structural changes to the intracel-
lular domain, which is a docking site or G proteins.
T e large amily o G proteins, so named because
they bind guanine nucleotides (guanosine triphosphate
[G P], guanosine diphosphate [GDP]), provides great
12 G prote in–couple d Ins ulin/IGF-I
Cytokine /GH/P RL S e ve n tra ns me mbra ne Tyros ine kina s e

Activin/MIS /BMP Growth fa ctor

TGF-β S e rine kina s e Tyros ine kina s e
S
E
C
T
I
O
N
I
Me mbra ne
I
n
t
r
G prote in
o
J AK/S TAT
d
P KA, P KC
u
Ra s /Ra f
c
t
i
S ma ds MAP K
o
n
t
o
E
n
d
Nucle us
o
c
r
i
Ta rge t ge ne
n
o
l
o
g
y
FIGURE 2 -1
Me m b ra n e re ce p t o r sig n a lin g . MAPK, mitogen-activated protein kinase; PKA, C, protein kinase A, C; TGF, trans orming growth actor.
For other abbreviations, see text.

diversity or coupling receptors to di erent signaling
pathways. G proteins orm a heterotrimeric complex that
is composed o various α and βγ subunits. T e α subunit
contains the guanine nucleotide–binding site and hydro-
lyzes G P → GDP. T e βγ subunits are tightly associ-
ated and modulate the activity o the α subunit as well
as mediating their own e ector signaling pathways. G
protein activity is regulated by a cycle that involves G P
hydrolysis and dynamic interactions between the α and
αβ subunits. Hormone binding to the receptor induces
GDP dissociation, allowing Gα to bind G P and disso-
ciate rom the αβ complex. Under these conditions, the
Gα subunit is activated and mediates signal transduction
through various enzymes, such as adenylate cyclase and
phospholipase C. G P hydrolysis to GDP allows reas-
sociation with the βγ subunits and restores the inactive
state. As described below, a variety o endocrinopathies
result rom G protein mutations or rom mutations in
receptors that modi y their interactions with G proteins.
G proteins interact with other cellular proteins, including
kinases, channels, G protein–coupled receptor kinases
(GRKs), and arrestins, that mediate signaling as well as
receptor desensitization and recycling.
T e tyrosine kinase receptors transduce signals or
insulin and a variety o growth actors, such as IGF-I,
epidermal growth actor (EGF), nerve growth actor,
platelet-derived growth actor, and broblast growth
actor. T e cysteine-rich extracellular ligand-binding
domains contain growth actor binding sites. Af er ligand
binding, this class o receptors undergoes autophosphor-
ylation, inducing interactions with intracellular adap-
tor proteins such as Shc and insulin receptor substrates
(IRS). In the case o the insulin receptor, multiple kinases
are activated, including the Ra -Ras-MAPK and the Akt/
protein kinase B pathways. T e tyrosine kinase receptors
play a prominent role in cell growth and di erentiation
as well as in intermediary metabolism.
T e GH and PRL receptors belong to the cytokine
receptor amily. Analogous to the tyrosine kinase recep-
tors, ligand binding induces receptor interaction with
intracellular kinases—the Janus kinases (JAKs), which
phosphorylate members o the signal transduction and
activators o transcription (S A ) amily—as well as
with other signaling pathways (Ras, PI3-K, MAPK).
T e activated S A proteins translocate to the nucleus
and stimulate expression o target genes.
T e serine kinase receptors mediate the actions o activ-
ins, trans orming growth actor β, müllerian-inhibiting
substance (MIS, also known as anti-müllerian hormone,
AMH), and bone morphogenic proteins (BMPs). T is
amily o receptors (consisting o type I and II subunits)
signals through proteins termed smads ( usion o terms
or Caenorhabditis elegans sma + mammalian mad). Like
the S A proteins, the smads serve a dual role o trans-
ducing the receptor signal and acting as transcription
actors. T e pleomorphic actions o these growth actors
dictate that they act primarily in a local (paracrine or
autocrine) manner. Binding proteins such as ollistatin
(which binds activin and other members o this amily)
unction to inactivate the growth actors and restrict their
distribution.
NUCLEAR RECEPTORS
T e amily o nuclear receptors has grown to nearly
100 members, many o which are still classi ed as
 Ho mo dime r S te ro id He te ro dime r Re c e pto rs Orphan Re c e pto rs 13
Re c e pto rs
ER, AR, P R, GR TR, VDR, RAR, P P AR S F-1, DAX-1, HNF4α

Liga nds

C
H
A
P
T
E
R
2
DNA re s pons e
e le me nts

M
Liga nd induce s Liga nd dis s ocia te s core pre s s ors Cons titutive a ctiva tor

e
c
coa ctiva tor binding a nd induce s coa ctiva tor binding or re pre s s or binding

h
a
n
n
i
s
o
m
i
Activa te d Activa te d Activa te d
s
s
s
o
e
r
f
S ile nce d
p
H
x
o
E
r
m
e
n
o
e
n
G
e
– + – + – +

A
Ba s a l

c
t
Hormone Hormone Re ce ptor

i
o
n
FIGURE 2 -2
Nu cle a r re ce p t o r sig n a lin g . AR, androgen receptor; DAX, dos- activated receptor; PR, progesterone receptor; RAR, retinoic acid
age-sensitive sex-reversal, adrenal hypoplasia congenita, X-chro- receptor; SF-1, steroidogenic actor-1; TR, thyroid hormone recep-
mosome; ER, estrogen receptor; GR, glucocorticoid receptor; tor; VDR, vitamin D receptor.
HNF4α, hepatic nuclear actor 4α; PPAR, peroxisome proli erator

orphan receptors because their ligands, i they exist,
have not been identi ed (Fig. 2-2). Otherwise, most
nuclear receptors are classi ed on the basis o their
ligands. Although all nuclear receptors ultimately act
to increase or decrease gene transcription, some (e.g.,
glucocorticoid receptor) reside primarily in the cyto-
plasm, whereas others (e.g., R) are located in the
nucleus. Af er ligand binding, the cytoplasmically
localized receptors translocate to the nucleus. T ere is
growing evidence that certain nuclear receptors (e.g.,
glucocorticoid, estrogen) can also act at the membrane
or in the cytoplasm to activate or repress signal trans-
duction pathways, providing a mechanism or cross-
talk between membrane and nuclear receptors.
T e structures o nuclear receptors have been stud-
ied extensively, including by x-ray crystallography. T e
DNA binding domain, consisting o two zinc ngers,
contacts speci c DNA recognition sequences in target
genes. Most nuclear receptors bind to DNA as dimers.
Consequently, each monomer recognizes an individ-
ual DNA moti , re erred to as a “hal -site.” T e steroid
receptors, including the glucocorticoid, estrogen, pro-
gesterone, and androgen receptors, bind to DNA as
homodimers. Consistent with this two old symmetry,
their DNA recognition hal -sites are palindromic. T e
thyroid, retinoid, peroxisome proli erator activated,
and vitamin D receptors bind to DNA pre erentially as
heterodimers in combination with retinoid X receptors
(RXRs). T eir DNA hal -sites are typically arranged as
direct repeats.
T e carboxy-terminal hormone-binding domain
mediates transcriptional control. For type II recep-
tors such as R and retinoic acid receptor (RAR), co-
repressor proteins bind to the receptor in the absence o
ligand and silence gene transcription. Hormone bind-
ing induces con ormational changes, triggering the
release o co-repressors and inducing the recruitment
o coactivators that stimulate transcription. T us, these
receptors are capable o mediating dramatic changes
in the level o gene activity. Certain disease states are
associated with de ective regulation o these events. For
example, mutations in the R prevent co-repressor dis-
sociation, resulting in an autosomal dominant orm o
hormone resistance (Chap. 7). In promyelocytic leuke-
mia, usion o RARα to other nuclear proteins causes
aberrant gene silencing that prevents normal cellular
di erentiation. reatment with retinoic acid reverses
this repression and allows cellular di erentiation and
apoptosis to occur. Most type 1 steroid receptors inter-
act weakly with co-repressors, but ligand binding still
induces interactions with an array o coactivators. X-ray
crystallography shows that various SERMs induce dis-
tinct estrogen receptor con ormations. T e tissue-
speci c responses caused by these agents in breast,
bone, and uterus appear to re ect distinct interactions
with coactivators. T e receptor-coactivator complex
stimulates gene transcription by several pathways,
including (1) recruitment o enzymes (histone ace-
tyl trans erases) that modi y chromatin structure, (2)
interactions with additional transcription actors on
14 the target gene, and (3) direct interactions with compo- glucose uptake and enhanced glycogenolysis, lipoly-
nents o the general transcription apparatus to enhance sis, proteolysis, and gluconeogenesis to mobilize uel
the rate o RNA polymerase II–mediated transcrip- sources. I hypoglycemia develops (usually rom insu-
tion. Studies o nuclear receptor-mediated transcription lin administration or sul onylureas), an orchestrated
S
E
show that these are dynamic events that involve rela- counterregulatory response occurs—glucagon and epi-
C
T
I
tively rapid (e.g., 30–60 min) cycling o transcription nephrine rapidly stimulate glycogenolysis and gluco-
O
N
complexes on any speci c target gene. neogenesis, whereas GH and cortisol act over several
I
hours to raise glucose levels and antagonize insulin
action.
Although ree-water clearance is controlled primar-
I
n
t
FUNCTIO NS O F HO RMO NES
r
ily by vasopressin, cortisol and thyroid hormone are
o
d
u
also important or acilitating renal tubular responses
c
T e unctions o individual hormones are described in
t
i
o
to vasopressin (Chap. 6). P H and vitamin D unc-
n
detail in subsequent chapters. Nevertheless, it is use-
t
tion in an interdependent manner to control calcium
o
ul to illustrate how most biologic responses require
E
n
metabolism (Chap. 32). P H stimulates renal synthesis
d
integration o several di erent hormone pathways. T e
o
o 1,25-dihydroxyvitamin D, which increases calcium
c
r
physiologic unctions o hormones can be divided into
i
n
absorption in the gastrointestinal tract and enhances
o
three general areas: (1) growth and di erentiation, (2)
l
o
P H action in bone. Increased calcium, along with vita-
g
maintenance o homeostasis, and (3) reproduction.
y
min D, eeds back to suppress P H, thus maintaining
calcium balance.
GROWTH Depending on the severity o a speci c stress and
whether it is acute or chronic, multiple endocrine and
Multiple hormones and nutritional actors mediate the cytokine pathways are activated to mount an appropri-
complex phenomenon o growth (Chap. 3). Short stat- ate physiologic response. In severe acute stress such as
ure may be caused by GH de ciency, hypothyroidism, trauma or shock, the sympathetic nervous system is
Cushing’s syndrome, precocious puberty, malnutrition, activated and catecholamines are released, leading to
chronic illness, or genetic abnormalities that a ect the increased cardiac output and a primed musculoskel-
epiphyseal growth plates (e.g., FGFR3 and SHOX muta- etal system. Catecholamines also increase mean blood
tions). Many actors (GH, IGF-I, thyroid hormones) pressure and stimulate glucose production. Multiple
stimulate growth, whereas others (sex steroids) lead stress-induced pathways converge on the hypothala-
to epiphyseal closure. Understanding these hormonal mus, stimulating several hormones, including vasopres-
interactions is important in the diagnosis and man- sin and corticotropin-releasing hormone (CRH). T ese
agement o growth disorders. For example, delaying hormones, in addition to cytokines (tumor necrosis
exposure to high levels o sex steroids may enhance the actor α, interleukin [IL] 2, IL-6) increase AC H and
e cacy o GH treatment. GH production. AC H stimulates the adrenal gland,
increasing cortisol, which in turn helps sustain blood
MAINTENANCE OF HOMEOSTASIS pressure and dampen the in ammatory response.
Increased vasopressin acts to conserve ree water.
Although virtually all hormones a ect homeostasis, the
most important among them are the ollowing:
1. T yroid hormone—controls about 25% o basal REPRODUCTION
metabolism in most tissues T e stages o reproduction include (1) sex determina-
2. Cortisol—exerts a permissive action or many hor- tion during etal development (Chap. 10); (2) sexual
mones in addition to its own direct e ects maturation during puberty (Chaps. 11 and 13); (3)
3. P H—regulates calcium and phosphorus levels conception, pregnancy, lactation, and child rearing
4. Vasopressin—regulates serum osmolality by con- (Chap. 13); and (4) cessation o reproductive capability
trolling renal ree-water clearance at menopause (Chap. 16). Each o these stages involves
5. Mineralocorticoids—control vascular volume and an orchestrated interplay o multiple hormones, a phe-
serum electrolyte (Na+, K+) concentrations nomenon well illustrated by the dynamic hormonal
6. Insulin—maintains euglycemia in the ed and asted changes that occur during each 28-day menstrual cycle.
states In the early ollicular phase, pulsatile secretion o LH
T e de ense against hypoglycemia is an impressive and FSH stimulates the progressive maturation o the
example o integrated hormone action (Chap. 26). In ovarian ollicle. T is results in gradually increasing
response to the asting state and alling blood glucose, estrogen and progesterone levels, leading to enhanced
insulin secretion is suppressed, resulting in decreased pituitary sensitivity to GnRH, which, when combined
with accelerated GnRH secretion, triggers the LH surge 15
and rupture o the mature ollicle. Inhibin, a protein Hypotha la mus

produced by the granulosa cells, enhances ollicular CNS

growth and eeds back to the pituitary to selectively

C
H
suppress FSH without a ecting LH. Growth actors

A
Re le a s ing

P
T
such as EGF and IGF-I modulate ollicular responsive- fa ctors + –

E
R
ness to gonadotropins. Vascular endothelial growth

2
actor and prostaglandins play a role in ollicle vascular-
ization and rupture.
During pregnancy, the increased production o pro-

M
e
c
lactin, in combination with placentally derived steroids Pituitary –

h
a
(e.g., estrogen and progesterone), prepares the breast or

n
i
s
Ta rge t hormone

m
lactation. Estrogens induce the production o progester-

s
Trophic fe e dba ck

o
one receptors, allowing or increased responsiveness to inhibition

f
hormone s +

H
progesterone. In addition to these and other hormones

o
r
m
involved in lactation, the nervous system and oxytocin

o
n
mediate the suckling response and milk release.

HO RMO NAL FEEDBACK REGULATO RY
SYSTEMS
Feedback control, both negative and positive, is a unda-
mental eature o endocrine systems. Each o the major
hypothalamic-pituitary-hormone axes is governed
by negative eedback, a process that maintains hor-
mone levels within a relatively narrow range (Chap. 3).
Examples o hypothalamic-pituitary negative eedback
include (1) thyroid hormones on the RH- SH axis,
(2) cortisol on the CRH-AC H axis, (3) gonadal ste-
roids on the GnRH-LH/FSH axis, and (4) IGF-I on the
growth hormone–releasing hormone (GHRH)-GH axis
(Fig. 2-3). T ese regulatory loops include both posi-
tive (e.g., RH, SH) and negative (e.g., 4, 3) compo-
nents, allowing or exquisite control o hormone levels.
As an example, a small reduction o thyroid hormone
triggers a rapid increase o RH and SH secretion,
resulting in thyroid gland stimulation and increased
thyroid hormone production. When thyroid hormone
reaches a normal level, it eeds back to suppress RH
and SH, and a new steady state is attained. Feedback
regulation also occurs or endocrine systems that do not
involve the pituitary gland, such as calcium eedback on
P H, glucose inhibition o insulin secretion, and leptin
eedback on the hypothalamus. An understanding o
eedback regulation provides important insights into
endocrine testing paradigms (see below).
Positive eedback control also occurs but is not well
understood. T e primary example is estrogen-mediated
stimulation o the midcycle LH surge. Although
chronic low levels o estrogen are inhibitory, gradu-
ally rising estrogen levels stimulate LH secretion. T is
e ect, which is illustrative o an endocrine rhythm
(see below), involves activation o the hypothalamic
GnRH pulse generator. In addition, estrogen-primed
e
A
c
t
i
o
n
Adre nal Go nads
Thyro id
FIGURE 2 -3
Fe e d b a ck re g u la t io n o f e n d o crin e a xe s. CNS, central ner-
vous system.
gonadotropes are extraordinarily sensitive to GnRH,
leading to ampli cation o LH release.
PARACRINE AND AUTOCRINE CONTROL
T e previously mentioned examples o eedback control
involve classic endocrine pathways in which hormones
are released by one gland and act on a distant target
gland. However, local regulatory systems, of en involv-
ing growth actors, are increasingly recognized. Para-
crine regulation re ers to actors released by one cell that
act on an adjacent cell in the same tissue. For example,
somatostatin secretion by pancreatic islet δ cells inhibits
insulin secretion rom nearby β cells. Autocrine regula-
tion describes the action o a actor on the same cell rom
which it is produced. IGF-I acts on many cells that pro-
duce it, including chondrocytes, breast epithelium, and
gonadal cells. Unlike endocrine actions, paracrine and
autocrine control are di cult to document because local
growth actor concentrations cannot be measured readily.
Anatomic relationships o glandular systems also
greatly in uence hormonal exposure: the physical
organization o islet cells enhances their intercellular
communication; the portal vasculature o the hypotha-
lamic-pituitary system exposes the pituitary to high con-
centrations o hypothalamic releasing actors; testicular
semini erous tubules gain exposure to high testosterone
levels produced by the interdigitated Leydig cells; the
16 pancreas receives nutrient in ormation and local exposure term. Emerging evidence indicates that circadian clock
to peptide hormones (incretins) rom the gastrointestinal pathways not only regulate sleep-wake cycles but also
tract; and the liver is the proximal target o insulin action play important roles in virtually every cell type. For
because o portal drainage rom the pancreas. example, tissue-speci c deletion o clock genes alters
S
E
rhythms and levels o gene expression, as well as meta-
C
T
I
bolic responses in liver, adipose, and other tissues.
O
N
Other endocrine rhythms occur on a more rapid time
I
HORMONAL RHYTHMS
scale. Many peptide hormones are secreted in discrete
T e eedback regulatory systems described above are bursts every ew hours. LH and FSH secretion are exqui-
superimposed on hormonal rhythms that are used or sitely sensitive to GnRH pulse requency. Intermittent
I
n
t
r
adaptation to the environment. Seasonal changes, the pulses o GnRH are required to maintain pituitary sen-
o
d
u
daily occurrence o the light-dark cycle, sleep, meals, sitivity, whereas continuous exposure to GnRH causes
c
t
i
and stress are examples o the many environmental
o
pituitary gonadotrope desensitization. T is eature o
n
t
events that a ect hormonal rhythms. T e menstrual the hypothalamic-pituitary-gonadotrope axis orms the
o
E
cycle is repeated on average every 28 days, re ecting
n
basis or using long-acting GnRH agonists to treat cen-
d
o
the time required to ollicular maturation and ovu- tral precocious puberty or to decrease testosterone levels
c
r
i
n
lation (Chap. 13). Essentially all pituitary hormone in the management o prostate cancer. It is important to
o
l
o
rhythms are entrained to sleep and to the circadian be aware o the pulsatile nature o hormone secretion and
g
y
cycle, generating reproducible patterns that are repeated the rhythmic patterns o hormone production in relat-
approximately every 24 h. T e HPA axis, or example, ing serum hormone measurements to normal values. For
exhibits characteristic peaks o AC H and cortisol pro- some hormones, integrated markers have been developed
duction in the early morning, with a nadir during the to circumvent hormonal uctuations. Examples include
night. Recognition o these rhythms is important or 24-h urine collections or cortisol, IGF-I as a biologic
endocrine testing and treatment. Patients with Cush- marker o GH action, and HbA1c as an index o long-
ing’s syndrome characteristically exhibit increased term (weeks to months) blood glucose control.
midnight cortisol levels compared with normal indi- Of en, one must interpret endocrine data only in
viduals (Chap. 8). In contrast, morning cortisol levels the context o other hormones. For example, P H lev-
are similar in these groups, as cortisol is normally high els typically are assessed in combination with serum
at this time o day in normal individuals. T e HPA axis calcium concentrations. A high serum calcium level in
is more susceptible to suppression by glucocorticoids association with elevated P H is suggestive o hyper-
administered at night as they blunt the early-morning parathyroidism, whereas a suppressed P H in this situ-
rise o AC H. Understanding these rhythms allows ation is more likely to be caused by hypercalcemia o
glucocorticoid replacement that mimics diurnal pro- malignancy or other causes o hypercalcemia. Similarly,
duction by administering larger doses in the morning SH should be elevated when 4 and 3 concentrations
than in the af ernoon. Disrupted sleep rhythms can are low, re ecting reduced eedback inhibition. When
alter hormonal regulation. For example, sleep depriva- this is not the case, it is important to consider second-
tion causes mild insulin resistance, ood craving, and ary hypothyroidism, which is caused by a de ect at the
hypertension, which are reversible, at least in the short level o the pituitary.
 SECTION II

PITUITARY, THYROID,
AND ADRENAL
DISORDERS
 CH AP TER 3
ANTERIOR PITUITARY: PHYSIOLOGY OF PITUITARY
HORMONES
Sh lo m o Me lm e d
T e nterior pituit ry o en is re erred to s the “ s-
ter gl nd” bec use, together with the hypoth l us, it
orchestr tes the co plex regul tory unctions o ny
other endocrine gl nds. T e nterior pituit ry gl nd
produces six jor hor ones: (1) prol ctin (PRL), (2)
growth hor one (GH), (3) drenocorticotropic hor-
one (AC H), (4) luteinizing hor one (LH), (5)
ollicle-sti ul ting hor one (FSH), nd (6) thyroid-
sti ul ting hor one ( SH) (Table 3-1). Pituit ry hor-
ones re secreted in puls tile nner, re ecting
sti ul tion by n rr y o speci c hypoth l ic rele s-
ing ctors. E ch o these pituit ry hor ones elicits spe-
ci c responses in peripher l t rget tissues. T e hor on l
products o those peripher l gl nds, in turn, exert eed-
b ck control t the level o the hypoth l us nd pitu-
it ry to odul te pituit ry unction (Fig. 3-1). Pituit ry
tu ors c use ch r cteristic hor one excess syndro es.
Hor one de ciency y be inherited or cquired.
Fortun tely, there re e c cious tre t ents or ny
pituit ry hor one excess nd de ciency syndro es.
Nonetheless, these di gnoses re o en elusive; this
e ph sizes the i port nce o recognizing subtle clini-
c l ni est tions nd per or ing the correct l bor tory
di gnostic tests. For discussion of disorders of the pos-
terior pituitary, or neurohypophysis, see Chap. 6.
ANATO MY AND DEVELO PMENT
ANATOMY
T e pituit ry gl nd weighs ~600 g nd is loc ted
within the sell turcic ventr l to the di phr g sell ;
it consists o n to ic lly nd unction lly distinct
nterior nd posterior lobes. T e bony sell is contigu-
ous to v scul r nd neurologic structures, including
the c vernous sinuses, cr ni l nerves, nd optic chi s .
T us, exp nding intr sell r p thologic processes y SH in so totropes, l ctotropes, nd thyrotropes.
■ J. La rry Ja m e so n
h ve signi c nt centr l ss ef ects in ddition to their
endocrinologic i p ct.
Hypoth l ic neur l cells synthesize speci c rele s-
ing nd inhibiting hor ones th t re secreted directly
into the port l vessels o the pituit ry st lk. Blood sup-
ply o the pituit ry gl nd co es ro the superior nd
in erior hypophyse l rteries (Fig. 3-2). T e hypoth -
l ic-pituit ry port l plexus provides the jor blood
source or the nterior pituit ry, llowing reli ble tr ns-
ission o hypoth l ic peptide pulses without signi -
c nt syste ic dilution; consequently, pituit ry cells re
exposed to rele sing or inhibiting ctors nd in turn
rele se their hor ones s discrete pulses into the sys-
te ic circul tion (Fig. 3-3).
T e posterior pituit ry is supplied by the in e-
rior hypophyse l rteries. In contr st to the nterior
pituit ry, the posterior lobe is directly innerv ted by
hypoth l ic neurons (supr opticohypophyse l nd
tuberohypophyse l nerve tr cts) vi the pituit ry st lk
(Chap. 6). T us, posterior pituit ry production o v so-
pressin ( ntidiuretic hor one [ADH]) nd oxytocin
is p rticul rly sensitive to neuron l d ge by lesions
th t f ect the pituit ry st lk or hypoth l us.
PITUITARY DEVELOPMENT
T e e bryonic dif erenti tion nd tur tion o nte-
rior pituit ry cells h ve been elucid ted in consider-
ble det il. Pituit ry develop ent ro R thke’s pouch
involves co plex interpl y o line ge-speci c tr n-
scription ctors expressed in pluripotent precursor
cells nd gr dients o loc lly produced growth ctors
( ble 3-1). T e tr nscription ctor Prop-1 induces
pituit ry develop ent o Pit-1-speci c line ges s
well s gon dotropes. T e tr nscription ctor Pit-1
deter ines cell-speci c expression o GH, PRL, nd
18
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 Fig. 209.—Bronze platter. Diameter about 9 inches. British
Museum. Drawn by Wallet.
It was noticed by those who saw the veil of oxide drawn away
from the ornamentation of these bronze vessels that a large
proportion of them were Egyptian rather than Assyrian in their
general physiognomy. Some of them displayed motives familiar to all
those who have travelled in the Nile valley. Take, for instance, the
fragment we have borrowed from one of the best preserved of them
all (Fig. 209).[412] Neither the minute lines of palmettes in the centre,
nor the birds that occur in the outer border, have, perhaps, any great
significance, but nothing could be more thoroughly Egyptian than the
zone of figures between the two. The same group is there four times
repeated. Two griffins crowned with the pschent, or double tiara of
upper and lower Egypt, have each a foot resting upon the head of a
kneeling child, but their movement is protective rather than
menacing. Instead of struggling, the child raises its hands in a
gesture of adoration. Between the griffins and behind them occur
slender columns, quite similar to those we have so often
encountered in the open architecture of Egypt.[413] Between the
groups thus constituted are thicker shafts bearing winged scarabs on
their campaniform capitals. These same columns and capitals occur
on another cup from which we detach them in order to show their
details more clearly.[414] In one instance the terminal of the shaft is
unlike anything hitherto found elsewhere; it is a sphere (Fig. 210);
but the contour of the next is thoroughly Egyptian (Fig. 211), and the
symbols on the last three, a scarab and two uræi, proclaim their
origin no less clearly (Figs. 212 to 214).

Figs. 210–214.—Columns or standards figured upon a bronze cup; from

Layard.
 Fig. 215.—Bronze platter. Diameter 8
inches. British Museum. Drawn by
Wallet.
We gather the same impression from a platter only cleaned quite
lately and consequently not to be found in Sir H. Layard’s works; it is
now reproduced for the first time (Fig. 215). The whole decoration is
finely carried out in line with the burin. The middle is occupied by a
seven pointed star or rosette, nine times repeated. Around this
elegant and complex motive there are concentric circles, the third of
which, counting from the centre, is filled up with small figures hardly
to be distinguished by the naked eye. We divine rather than see
lions, birds, seated men, and certain groups of symbols, such as
three lines broken and placed one above the other, which are
continually recurring in the hieroglyphic writing of Egypt. The fifth
zone has conventional papyrus stems alternating with rosettes. The
sixth, much larger, is filled with ovals surmounted by two plumes and
the uræus, that is by the royal cartouch of Egypt in its usual form.
The interior of each oval contains very small groups of figures
separated from one another by four horizontal lines.
 Fig. 216.—Part of a bronze cup or platter. Diameter about 9 inches.
British Museum.
We may quote a cup figured by Layard as a last example of this
exotic style of decoration. In the centre there are four full-face heads
with Egyptian wigs (Fig. 216). Around them a mountainous country is
figured in relief, and sprinkled with trees and stags engraved with the
point. The wide border, which is unfortunately very much mutilated,
is covered with groups of figures apparently copied from some
Egyptian monument, if we may judge from the attitudes and
costume. One figure, whose torso has entirely disappeared, wears
the pschent and brandishes a mace over his head; the movement is
almost identical with that of the victorious Pharaoh with whom we are
so familiar. A goddess, who might be Isis, stands opposite to him. In
another part of the border there is a misshapen monster crowned
with feathers and resembling the Egyptian Bes.[415]
 Fig. 217.—Bronze cup. Diameter 11 inches;
from Layard.
Side by side with these platters we find others on which nothing
occurs to suggest foreign influence. Take, for instance, the example
reproduced in Fig. 208. In the centre there is a small silver boss,
while the rest of the flat surface is occupied by the fine diaper pattern
made up of six-petalled flowers that we have already met with on the
carved thresholds (Vol. I. Fig. 96). The hollow border is ornamented
with four lines of palmettes united by an undulating line, a motive
which is no less Assyrian than the first (Vol. I., Figs. 128, 138, 139,
etc.). In Fig. 217 we reproduce a cup on which its original mounting,
or ring by which it was suspended, is still in place. The whole of the
decoration is pure Assyrian. The rosette is exactly similar to many of
those found on the enamelled bricks (see Vol. I., Figs. 122, 123). In
the first of the three zones, gazelles march in file; in the second, a
bull, a gazelle, an ibex, and a winged griffin, followed by the same
animals attacked by lions and making fourteen figures in all; in the
third zone fourteen heavy-crested bulls follow one another round the
dish. All these animals are among those most constantly treated by
the Assyrian sculptor; their shapes and motions are as well
understood and as well rendered as in the bas-reliefs. The bulls
especially are grandly designed. Moreover, the idea of employing all
these animals for the adornment of such a surface is entirely in the
spirit of Assyrian decoration. We shall meet with it again in the
shields from Van; we figure the best preserved of the latter on page
347.
It would be easy to give more examples, either from Layard or
from our own catalogue of these objects, of the purely Assyrian style
on the one hand, or of that in which the influence of Egyptian models
is so clearly shown, on the other. It is enough, however, that we have
proved that these little monuments may be divided into two clearly
marked classes. Did the two groups thus constituted share the same
origin? Did they both come from the same birth-place? Further
discoveries may enable us to answer this question with certainty,
and even now we may try to pave the way to its solution.
There would be no difficulty if these bronze vessels bore
cuneiform inscriptions, especially if the latter formed a part of the
decorative composition, as in the palace reliefs, and were cut by the
same hand. But this, so far as we know at present, was never the
case. In some fragments of pottery we have found cuneiform
characters (Fig. 185), and the name of Sargon has even been read
on a glass phial (Fig. 190), but—and we cannot help feeling some
surprise at the fact—none of these objects of a material far more
precious bear a trace of the Mesopotamian form of writing. I do not
know that a single wedge has been discovered upon them. A certain
number of them are inscribed, but inscribed without exception with
those letters which Phœnicia is supposed to have evolved out of the
cursive writing of Egypt.[416] They were not introduced with any idea
of enriching the design, as they always occur on the blank side of the
vessel. They are close to the edge, and their lines are very slender,
suggesting that they were meant to attract as little attention as
possible. They consist of but a single name, that of the maker, or,
more probably, the proprietor of the cup.[417]
 May we take it that these inscriptions afford a key to the mystery?
that they prove the vases upon which they occur at least to have
been made in Phœnicia? We could only answer such a question in
the affirmative if peculiarities of writing and language belonging only
to Phœnicia properly speaking were to be recognized on them; but
the texts are too short to enable us to decide to which of the Semitic
idioms they should be referred, while the forms of the letters do not
differ from those on some of the intaglios (Figs. 156 and 157) and
earthenware vases (Fig. 183), and upon the series of weights
bearing the name of Sennacherib.[418] The characters belong to that
ancient Aramæan form of writing which seems to have been
practised in Mesopotamia in very early times as a cursive and
popular alphabet.
The inscriptions, then, do little to help us out of our
embarrassment, and we are obliged to turn to the style of the
vessels and their decoration for a solution to our doubts. The
conviction at which we soon arrive after a careful study of their
peculiarities is that even those on which Egyptian motives are most
numerous and most frankly employed were not made in Egypt. In the
first place we remember that the Egyptians do not seem to have
made any extensive use of such platters; their libations were poured
from vases of a different shape, and the cups sometimes shown in
the hands of a Pharaoh always have a foot.[419] Moreover, in the
paintings and bas-reliefs of Egypt, where so many cups and vases of
every kind are figured, and especially the rich golden vessel that
must have occupied such an important place in the royal treasure,
we only find the shape in question in a few rare instances.[420]
After this general statement we may go into the details. In these
the hand of the imitator is everywhere visible; he borrows motives
and adapts them to his own habits and tastes. Take as an example
the platter to which a double frieze of hieroglyphs gives a peculiarly
Egyptian physiognomy (Fig. 215). An Egyptian artist would never
employ hieroglyphs in such a position without giving them some real
significance, such as the name of a king or deity. Here, on the other
hand, an Egyptologist has only to glance at the cartouches to see
that their hieroglyphs are brought together at haphazard and that no
sense is to be got out of them. This is obvious even by the
arrangement of the several characters in the oval without troubling to
examine them one by one. They are divided into groups by straight
lines, like those of a copy book. The Egyptian scribe never made use
of such divisions; he distributed his characters over the field of the
oval according to their sense and shape. The arrangement here
followed is only to be explained by habits formed in the use of a
writing that goes in horizontal lines from left to right or right to left.
There is, in fact, nothing Egyptian but the shape of the ovals, and the
motive with which they are crowned. The pretended hieroglyphs are
nothing but rather clumsily executed pasticcios. And it must be
noticed that even this superficial Egyptianism is absent from the
centre of the dish. In those Theban ceilings which display such a
wealth of various decoration we may find a simple rosette here and
there, or rather a flower with four or eight petals, but these petals are
always rounded at the end; nowhere do we find anything that can be
compared to the great seven-pointed star which is here combined so
ingeniously with eight more of the same pattern but of smaller size.
On the other hand this motive is to be found on a great number of
cups where no reminiscence of Egypt can be traced. The ruling idea
is the same as that of the diaper-work in the thresholds from
Khorsabad and Nimroud (see Vol. I., Fig. 135).
After such an example we might look upon the demonstration as
made, but it may be useful to complete it by analyzing the other cups
we have placed in the same class. That on which the scarabs on
standards and the opposed sphinxes appear (Fig. 209) seems pure
Egyptian at first sight; but if we take each motive by itself we find
variations that are not insignificant. In Egyptian paintings, when the
scarab is represented with extended wings they are spread out
horizontally, and not crescent-wise over its head.[421] We may say
the same of the sphinx. The griffin crowned with the pschent is to be
found in Egypt as well as the winged sphinx,[422] but the Egyptian
griffins had no wings,[423] and those of the sphinxes were folded so
as to have their points directed to the ground. In the whole series of
Egyptian monuments I cannot point to a fictitious animal like this
griffin. It is in the fanciful creations of the Assyrians alone that these
wings, standing up and describing a curve with its points close to the
head of the beast that wears them (see Fig. 87), is to be seen. It is
an Assyrian griffin masquerading under the double crown of Egypt,
but a trained eye soon penetrates the disguise.
The arrangement, too, of the group is Assyrian. When the
Egyptians decorated a jewel, a vessel, or a piece of furniture by
combining two figures in a symmetrical fashion, they put them back
to back rather than face to face.[424] Very few examples can be
quoted of the employment in Egypt of an arrangement that is almost
universal in Assyria. In the latter country this opposition of two
figures is so common as to be common-place; they are usually
separated from each other by a palmette, a rosette, a column or
even a human figure (see Vol. I., Figs. 8, 124, 138, 139; and above,
Figs. 75, 90, 141, 152, 153, 158, etc.), and it was certainly from
Mesopotamia that Asia Minor borrowed the same motive, which is so
often found in the tombs of Phrygia and in Greece as far as
Mycenæ, whither it was carried from Lydia by the Tantalides.[425]
The same remarks will apply to the cup partially reproduced in
our Fig. 216. The ornament of the centre and of the outer band is
Egyptian in its origin, but the mountainous country with its stags and
its trees, that lies between—have we found anything like it in Egypt?
The mountains are suggested in much the same fashion as in the
palace reliefs, and we know how much fonder the sculptors of
Mesopotamia were of introducing the ibex, the stag, the gazelle, etc.,
into their work than those of Egypt. The rocky hills and sterile deserts
that bounded the Nile valley were far less rich in the wilder ruminants
than the wooded hills of Kurdistan and the grassy plains of the
double valley.
There is one last fact to be mentioned which will, we believe, put
the question beyond a doubt. Of all antique civilization, that which
has handed down to us the most complete material remains is the
civilization of Egypt. Thanks to the tomb there is but little of it lost.
Granting that these cups were made in Egypt, how are we to explain
the fact that not a single specimen has been found in the country?
About sixty in all have been recovered; their decoration is
distinguished by much variety, but when we compare them one with
another we find an appreciable likeness between any two examples.
The forms, the execution, the ornamental motives are often similar,
or, at least, are often treated in the same spirit. The majority come
from Assyria, but some have been found in Cyprus, in Greece, in
Campania, Latium, and Etruria. Over the whole area of the ancient
world there is but one country from which they are totally absent, and
that country is Egypt.
We may, then, consider it certain that it was not Egyptian industry
that scattered these vessels so widely, from the banks of the
Euphrates to those of the Arno and the Tiber, not even excepting
from this statement those examples on which Egyptian taste has left
the strongest mark. Egypt thus put out of the question, we cannot
hesitate between Mesopotamia and Phœnicia. If the cups of
Nimroud were not made where they were found, it was from
Phœnicia that they were imported. The composite character of the
ornamentation with which many of them were covered is consistent
with all we know of the taste and habits of Phœnician industry, as we
shall have occasion to show in the sequel. On the other hand we
must not forget at how early a date work in metal was developed in
the workshops of Mesopotamia. Exquisite as it is, the decoration of
the best of these vases would be child’s play to the master workmen
who hammered and chiselled such pictures in bronze as those that
have migrated from Balawat to the British Museum.
We are inclined to believe that the fabrication of these cups
began in Mesopotamia; that the first models were issued from the
workshops of Babylon and Nineveh, and exported thence into Syria;
and that the Phœnicians, who imitated everything—everything, at
least, that had a ready sale—acclimatized the industry among
themselves and even carried it to perfection. In order to give variety
to the decoration of the vases sent by them to every country of
Western Asia and Southern Europe, they drew more than once from
that storehouse of Egyptian ideas into which they were accustomed
to dive with such free hands; and this would account for the
combination of motives of different origin that we find on some of the
cups. Vases thus decorated must have become very popular, and
both as a result of commerce and of successful wars, must have
entered the royal treasures of Assyria in great numbers. We know
how often, after the tenth century, the sovereigns of Calah and
Nineveh overran Palestine, as well as Upper and Lower Syria. After
each campaign long convoys of plunder wended their way through
the defiles of the Amanus and Anti-Lebanon, and the fords of the
Euphrates, to the right bank of the Tigris. The Assyrian conquerors
were not content with crowding the store-rooms of their palaces with
the treasures thus won, they often transported the whole population
of a town or district into their own country. Among the Syrians thus
transplanted there must have been artizans, some of whom
endeavoured to live by the exercise of their calling and by opening
shops in the bazaars of Babylon, Calah, and Nineveh. Clients could
be easily gained by selling carved ivories and these engraved cups
at prices much smaller than those demanded when the cost of
transport from the Phœnician coast had to be defrayed.
In one of these two ways it is, then, easy to explain the
introduction of these foreign motives into Assyria, where they would
give renewed life to a system of ornament whose resources were
showing signs of exhaustion. This tendency must have become
especially pronounced about the time of the Sargonids, when
Assyria was the mistress of Phœnicia and invaded the Nile valley
more than once. To this period I should be most ready to ascribe the
majority of the bronze cups; the landscapes, hunts and processions
of wild animals with which many of them are engraved, seem to
recall the style and taste of the bas-reliefs of Sennacherib and
Assurbanipal rather than the more ancient schools of sculpture.
In any case it would be difficult, if not impossible, to distinguish
between the vases engraved in Mesopotamia by native workmen
and those imported from Phœnicia, or made at Nineveh by workmen
who had received their training at Tyre or Byblos. The resemblances
between the two are too many and too great. At most we may unite
all the platters found in Mesopotamia into a single group, and point
out a general distinction between them and those that have been
discovered in the Mediterranean basin. The ornament on the
Nimroud cups is, on the whole, simpler than on those found in
Cyprus and Italy; the figure plays a less important part in the former,
and the compositions are more simple. The Assyrian cups, or, to be
more accurate, those found in Assyria, represent the earliest phase
of this art, or industry, whichever it should be called. In later years,
after the fall of Nineveh, when Phœnicia had the monopoly of the
manufacture, she was no longer content with purely decorative
designs and small separate pictures. Her bronze-workers multiplied
their figures and covered the concentric zones with real subjects,
with scenes whose meaning and intention can often be readily
grasped. This we shall see when the principal examples of this kind
of art come under review in our chapters upon Phœnicia.[426]

Fig. 218.—Bronze cup. British Museum.

Meanwhile, we shall not attempt to establish distinctions that are
nearly always open to contest; they would, besides, require an
amount of minute detail which would here be quite out of place. To
give but one example of the evidence which might lead to at least
plausible conclusions, we might see pure Assyrian workmanship in
the cup figured below (Fig. 218),[427] where mountains, trees, and
animals stand up in slight relief, both hammer and burin having been
used to produce the desired result. Among these animals we find a
bear, which must have been a much more familiar object to the
Assyrians living below the mountain-chains of Armenia and
Kurdistan than to the dwellers upon the Syrian coast. In the inscribed
records of their great hunts, the kings of Assyria often mention the
bear.[428] Nothing that can be compared to these wooded hills
peopled by wild beasts is to be found on the cups from Cyprus or
Italy. I may say the same of another cup on which animals of various
species are packed so closely together that they recall the
engravings on some of the cylinders (see Fig. 149).[429]
On the other hand, there are plenty of motives which may just as
easily have had their origin in one country as the other. The two
vultures, for instance, preparing to devour a hare stretched upon its
back, which we figure below (Fig. 219).[430]

Fig. 219.—Border of a cup; from Layard.

It may be thought that we have dwelt too long upon these cups;
but the sequel of our history will show why we have examined them
with an attention that, perhaps, neither their number nor their beauty
may appear to justify. They are first met with in Assyria, but they
must have existed in thousands among the Greeks and Italiots.
Light, solid, and easy to carry, they must have furnished western
artists with some of their first models. As we shall see, they not only
afforded types and motives for plastic reproduction, but, by inciting
them to find a meaning for the scenes figured upon them, they
suggested myths to the foreign populations to whom they came.

§ 5. Arms.
 We shall not, of course, study Assyrian arms from the military
point of view. That question has been treated with all the care it
deserves by Rawlinson and Layard.[431] From the stone axes and
arrow-heads that have been found in the oldest Chaldæan tombs, to
the fine weapons and defensive armour in iron and bronze, used by
the soldiers of Nineveh in its greatest years, by the cavalry, the
infantry, and the chariot-men of Sargon and Sennacherib, the
progress is great and must have required many long centuries of
patient industry. In Assyria no trade can have occupied more hands
or given rise to more invention than that of the armourer. For two
centuries the Assyrian legions found no worthy rivals on the
battlefields of Asia; and, although their superiority was mainly due, of
course, to qualities of physical vigour and moral energy developed
by discipline, their unvarying success was in some degree the result
of their better arms. Without dwelling upon this point we may just
observe that when war is the chief occupation of a race, its arms are
sure to be carried to an extreme degree of luxury and perfection.
Some idea of their elaboration in the case of Assyria may be gained
from the reliefs and from the original fragments that have come down
to us.

Figs. 220, 221.—Chariot poles; from a bas-relief.

It was from the animal kingdom that the Assyrian armourer
borrowed most of the forms with which he embellished the weapons
and other military implements he made. Thus we find the chariot
poles ending in the head of a bull, a horse, or a swan (Figs. 220 and
221).[432] Elsewhere we find a bow no less gracefully contrived; its
two extremities are shaped into the form of a swan’s head bent into
the neck.[433]

Figs. 222, 223.—Sword scabbards, from the

reliefs; from Layard.
The sword is the king of weapons. By a kind of instinctive
metaphor every language makes it the symbol of the valour and
prowess of him who wears it. It was, therefore, only natural that the
Assyrian scabbard, especially when worn by the king, should be
adorned with lions (Figs. 82, 222, 223). These were of bronze, no
doubt, and applied. In the last of our three examples a small lion is
introduced below the larger couple. The sword-blade itself may have
been decorated in the same fashion. The Assyrians understood
damascening, an art that in after ages was to render famous the
blades forged in the same part of the world, at Damascus and
Bagdad. The Arab armourers did no more, perhaps, than practise an
art handed down to them from immemorial times, and brought to
perfection many centuries before in the workshops of Mesopotamia.
At any rate we know that two small bronze cubes found at Nimroud
were each ornamented on one face with the figure in outline of a
scarab with extended wings, and that the scarab in question was
carried out by inlaying a thread of gold into the bronze (Fig. 224).
Meanwhile we may point to an Assyrian scimitar, the blade of which
is inscribed with cuneiform characters.[434]
In the reliefs we find a large number of shields with their round or
elliptical surfaces divided into concentric zones.[435] A recent
discovery enables us to say how these zones were filled, at least in
the case of shields belonging to kings or chiefs. In 1880 Captain
Clayton found, on the site of an ancient building at Toprak-Kilissa, in
the neighbourhood of Van, four shields, or rather their remains,
among a number of other objects. These shields are now in the
British Museum. Upon one fragment we may read an inscription of
Rushas, king of Urardha, or Armenia, in the time of Assurbanipal.
[436]

Fig. 224.—Bronze cube damascened with gold;

from Layard.
This inscription, which is votive in its tenor, combines with the
examination of the objects themselves, to prove that these shields
are not real arms, made for the uses of war. The bronze is so thin—
not more than a millimetre and a half in thickness—that even if
nailed upon wood or backed with leather it could have afforded no
serious protection, and its reliefs must have been disfigured and
flattened with the least shock. The edge alone is strengthened by a
hoop of iron. The shields are votive, and must have been hung on
the walls of a temple, like those we see thus suspended in a bas-
relief of Sargon (Vol. I. Fig. 190), a relief in which a temple of this
same Armenia is represented.[437] But although they were made for
purposes of decoration, these arms were none the less copies of
those used in actual war, except in the matter of weight and solidity;
thus they were furnished with loops for the arms, but these were too
narrow to allow the limb of a man of average size to pass through
them with any freedom.

Fig. 225.—Votive shield. Diameter about 34½ inches.

Drawn by R. Elson.
For us the most interesting point about them is their decoration,
which is identical in principle with several of the bronze platters lately
discussed (see Fig. 217). This may be clearly seen in our
reproduction of the shield which has suffered least from rust (Fig.
225).[438] In the centre there is a rosette with many radiations; next
come three circular bands separated from each other and from the
central boss by a double cable ornament. The innermost and
outermost zones are filled with lions passant, the one between with
bulls in the same attitude. And here we find a curious arrangement of
which we can point to no other example: both lions and bulls have
their feet turned sometimes to the centre of the shield, sometimes to
its outer edge. The general character of the form is well grasped in
both cases; but the design has neither the breadth nor firmness of
that upon the cup to which we have already compared this shield
(Fig. 217). The armourers were inferior in skill to the gold and
silversmiths—we can think of no more appropriate name for them—
by whom the metal cups were beaten and chased, although they
made use of the same models and motives. No one would attribute a
Phœnician origin to these bucklers; they were found in Armenia and
were covered with cuneiform inscriptions. They must have been
made either in Assyria, or in a neighbouring country that borrowed all
from Assyria, its arts and industries as well as its written characters.
The Assyrians attached too much importance to their arms and
made too great a consumption of them to be content with importing
them from a foreign country.

Fig. 226.—Knife-handle. Bone.

Louvre.
 When we turn to objects of less importance, such as daggers and
knives, we find their handles also often modelled after animals’
heads. We have already figured more than one example (Vol. I., tail-
piece to chapter II., and Vol. II., tail-piece to chapter I.). But
sometimes they were content with a more simple form of decoration
belonging to the class of ornament we call geometrical, which they
combined with those battlement shapes that, as we have seen, the
enameller also borrowed from the architect (Vol. I. Fig. 118). A by no
means ungraceful result was obtained by such simple means (Figs.
202 and 226). These knife-handles are interesting not so much on
account of their workmanship as for their tendency and the taste
they display. They were objects of daily use and manufacture. Cut
from ivory and bone, they were sold in hundreds in the bazaars. But
in every detail we can perceive a desire to make the work please the
eye. The evidence of this desire has already struck us in Egypt; it will
be no less conspicuous in Greece. In these days, how many useful
objects turned out by our machines have no such character. Those
who design them think only of their use. They are afraid of causing
complications by any attempt to make one different from the other or
to give varied shapes to tools all meant for the same service. They
renounce in advance the effort of personal invention and the love for
ornament that gives an interest of its own to the slightest fragments
from an ancient industry, and raises it almost to the dignity of a work
of art.

§ 6. Instruments of the Toilet and Jewelry.

The preoccupation to which we have just alluded, the love for an

agreeable effect, is strongly marked in several things which are now
always left without ornament. A single example will be enough to
show the difference. Nowadays all that we ask of a comb is to do its
duty without hurting the head or pulling out the hair; that its teeth
shall be conveniently spaced and neither too hard nor too pliant.
These conditions fulfilled, it would not be out of place in the most
luxurious dressing-room. The ancients were more exacting, as a
series of ebony combs in the Louvre is sufficient to show (Figs. 227–
229).[439] They have two rows of teeth, one coarse, the other fine,
and each is ornamented in the middle with a figure in open-work
(Figs. 228–229) or raised in relief on a flat bed (Fig. 227). Only a part
of the latter comb is preserved. The frame round the figures is cut
into the shape of a cable above and below, and into rosettes at the
ends. On one side of the comb there is a walking lion, on the other
the winged sphinx shown in our engraving. Its body is that of a lion, it
is mitred and wears a pointed beard. In the second example we have
a lion with lowered head within a frame with a kind of egg moulding.
The forms are so heavy that at first we have some difficulty in
recognizing the species. In our last specimen both design and
execution are much better. A lion is carved in the round within a
frame ornamented with a double row of zig-zag lines. The modelling
has been carried out by a skilful artist and is not unworthy of a place
beside the Ninevite reliefs.

Fig. 227.—Comb. Actual size.

Louvre.
We know of nothing among the spoils of Assyria that can be
compared to those wooden spoons that the Egyptian workman
carved with so light a hand;[440] but two objects found at Kouyundjik
prove that the Assyrians knew how to give forms elegant and
graceful enough, though less original, to objects of the same kind.
One of these is a bronze fork, the other a spoon of the same