System Test and Diagnosis 1994th

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 Yen & Jaffe’s
Repro­ductive
Endocri­nology
Physiology,
Pathophysiology,
and Clinical
Management
Jerome F. Strauss III, MD, PhD SEVENTH EDITION
Executive Vice President for Medical Affairs
VCU Health System;
Dean, School of Medicine
Virginia Commonwealth University
Richmond, Virginia

Robert L. Barbieri, MD
Kate Macy Ladd Professor
Department of Obstetrics, Gynecology,
and Reproductive Biology
Harvard Medical School;
Chair, Department of Obstetrics and Gynecology
Brigham and Women’s Hospital
Boston, Massachusetts

iii
 CONTRIBUTORS xi

DANNY J. SCHUST, MD ISABELLE STREULI, MD, MSC

Associate Professor Faculty
William T. Griffin, MD, Distinguished Faculty Scholar; Department of Gynecology, Obstetrics, and Reproductive
Director, Division of Reproductive Medicine and Fertility Medicine
Department of Obstetrics, Gynecology, and Women’s Université Paris Descartes, Paris Sorbonne Cité
Health Paris, France;
University of Missouri School of Medicine Department of Gynecology and Obstetrics
Columbia, Missouri Unit for Reproductive Medicine and Gynecological
Chapter 14: Immunology and Reproduction Endocrinology
Hôpitaux Universitaires de Genève
PETER J. SNYDER, MD Geneva, Switzerland
Professor of Medicine Chapter 35: Pelvic Imaging in Reproductive
University of Pennsylvania ­Endocrinology
Philadelphia, Pennsylvania
Chapter 16: Male Reproductive Aging PATRICE SUTTON, MPH
Research Scientist
WEN-CHAO SONG, PhD Program on Reproductive Health and the Environment
Professor of Pharmacology Department of Obstetrics, Gynecology, and Reproductive
Perelman School of Medicine Sciences
University of Pennsylvania University of California, San Francisco
Philadelphia, Pennsylvania San Francisco, California
Chapter 6: Prostaglandins and Other Lipid Mediators Chapter 20: Environmental Factors and Reproduction
in Reproductive Medicine
ROBERT TAYLOR, MD, PhD
FRANK Z. STANCZYK, PhD Professor and Vice Chair for Research
Professor of Research, Obstetrics, and Gynecology Department of Obstetrics and Gynecology
and Preventive Medicine Wake Forest School of Medicine;
University of Southern California Attending Reproductive Endocrinologist
Keck School of Medicine Department of Obstetrics and Gynecology
Los Angeles, California Wake Forest Baptist Health;
Chapter 34: Laboratory Assessment Member
Molecular Medicine and Translational Sciences Graduate
ELIZABETH A. STEWART, MD Program
Professor of Obstetrics and Gynecology Wake Forest School of Medicine
Chair, Division of Reproductive Endocrinology Winston-Salem, North Carolina
Mayo Clinic Chapter 26: Endometriosis
Mayo School of Medicine
Rochester, Minnesota JESSICA TROWBRIDGE, MPH
Chapter 27: Benign Uterine Disorders Research Scientist
Program on Reproductive Health and the Environment
DALE W. STOVALL, MD University of California, San Francisco
Professor San Francisco, California
Department of Internal Medicine Chapter 20: Environmental Factors and Reproduction
University of Virginia
Charlottesville, Virginia; PAUL J. TUREK, MD
Chair and Residency Director Director
Department of Obstetrics and Gynecology The Turek Clinic
Riverside Regional Medical Center San Francisco, California
Newport News, Virginia Chapter 24: Male Infertility
Chapter 14: Immunology and Reproduction
JOHANNES D. VELDHUIS, MD
JEROME F. STRAUSS III, MD, PhD Professor
Executive Vice President for Medical Affairs Mayo Medical School;
VCU Health System; Consultant in Medicine
Dean, School of Medicine Clinical Investigator
Virginia Commonwealth University Department of Medicine and Physiology
Richmond, Virginia Endocrine Research Unit and Biophysics Section
Chapter 4: The Synthesis and Metabolism Mayo School of Graduate Medical Education
of Steroid Hormones Mayo Clinic
Chapter 9: The Ovarian Life Cycle Rochester, Minnesota
Chapter 13: The Hypothalamo-Pituitary Unit, Testis,
and Male Accessory Organs
xii CONTRIBUTORS

ERIC VILAIN, MD, PhD TERESA K. WOODRUFF, PhD

Professor
Department of Human Genetics, Pediatrics, and Urology;
Chief, Division of Medical Genetics
Department of Pediatrics
University of California, Los Angeles School of Medicine;
Director, Institute for Society and Genetics
University of California, Los Angeles
Los Angeles, California
Chapter 17: Disorders of Sex Development
CARMEN J. WILLIAMS, MD, PhD
Clinical Investigator, Laboratory of Reproductive &
Developmental Toxicology
National Institute of Environmental Health Sciences
Research Triangle Park, North Carolina
Chapter 9: The Ovarian Life Cycle
SELMA FELDMAN WITCHEL, MD
Associate Professor of Pediatrics
Director, Pediatric Endocrinology Fellowship Program
Division of Pediatric Endocrinology
Children’s Hospital of Pittsburgh of UPMC
University of Pittsburgh
Pittsburgh, Pennsylvania
Chapter 18: Puberty: Gonadarche and Adrenarche
Thomas J. Watkins Professor of Obstetrics and Gynecology
Northwestern University
Feinberg School of Medicine
Chicago, Illinois
Chapter 33: Fertility Preservation
TRACEY J. WOODRUFF, PhD, MPH
Professor
Director, Program on Reproductive Health and the
Environment
Department of Obstetrics, Gynecology, and Reproductive
Sciences
University of California, San Francisco
San Francisco, California
Chapter 20: Environmental Factors and Reproduction
STEVEN L. YOUNG, MD, PhD
Associate Professor
Department of Obstetrics and Gynecology
Division of Reproductive Endocrinology
University of North Carolina School of Medicine
Chapel Hill, North Carolina
Chapter 10: The Structure, Function, and Evaluation
of the Female Reproductive Tract

A centerpiece of reproductive endocrinology is the utiliza-
tion of assisted reproductive technologies, including in vitro
fertilization (IVF), to build healthy families. In 1978, the
first baby born from IVF, Louise Brown, was proof of the
concept that successful human pregnancy was possible fol-
lowing in vitro fertilization. In the same year, the first edi-
tion of Yen and Jaffe was published and represented the birth
of a field with a strong research foundation, whose findings
had direct applicability to health. Three decades later, the
2010 Nobel Prize in Medicine or Physiology was awarded to
Sir Robert G. Edwards, Ph.D. (b. 1925, d. 2013), for his
seminal contributions to the field of reproductive endocri-
nology and infertility. The publication of the 7th edition of
Yen and Jaffe is dedicated to Dr. Edwards and all the pioneers
who have devoted their energies to advancing the field.
In the first years of the development of the field, a major
focus was on the endocrine mechanisms that supported the
optimal development of oocyte and sperm, their interaction
and the implantation of an embryo in the developmentally
prepared endometrium. Today, interest in germ cell devel-
opment and germ cell biology has gained great prominence,
raising the possibility of application of stem cell-based
therapeutics to treat infertility and gene disorders. Fertil-
ity preservation through the cryopreservation of sperm and
oocytes has emerged as a key element of care for the cancer
patient and others who face concerns regarding retention
of reproductive potential. The importance of these transla-
tional advances is recognized by the addition of new chap-
ters to this edition.
The completion of the sequencing of the human genome
and the reduction in cost in whole genome analysis have
opened new opportunities for finding genes that affect dif-
ferent aspects of reproduction, such as genes that affect the
Preface
age of menarche and the age of menopause; genes that pre-
dispose to endometriosis, uterine fibroids, and polycystic
ovary syndrome; and genes that influence ovarian reserve
and spermatogenesis. These important discoveries, which
will shed light on pathophysiology and new avenues for diag-
nosis and treatment, are highlighted in the present edition.
Since the publication of the last edition of this text, we
have achieved a better understanding of environmental fac-
tors influencing fertility, including obesity. These contempo-
rary issues have been addressed in this edition. Epigenetic
factors are thought to mediate the impact of environmen-
tal exposures on gametes and embryos and the developing
fetus. They are also believed to be responsible for intergen-
erational effects. Although still in its infancy, the science of
epigenetics holds promise for explaining reproductive phe-
notypes and reproductive outcomes.
We appreciate the collaboration of past and new authors
for their critical evaluation of the state of their respective
fields. Their contributions have enriched this text and we
are grateful for their efforts. They have helped carry for-
ward the tradition of excellence that Drs. Jaffe and Yen
created when they brought forward the first edition of this
text.
Acknowledgments
The Editors thank William Drone, Kel McGowan, ­Stefanie
Jewell-Thomas, and Steven Stave of Elsevier; and Karen
Olinger and Deborah Weir of Virginia Commonwealth Uni-
versity, for their assistance in the preparation of this volume.
Jerome F. Strauss III, MD, PhD
Robert L. Barbieri, MD
xiii

The Central Control of Reproduction
Successful reproduction is essential to the survival of a spe-
cies. The reproductive system represents a highly-complex
functional organization of diverse tissues and signaling path-
ways that, when properly functioning, ensures a number of
key endpoints, the most important of which are the ade-
quate production of gametes (ova and sperm); successful
delivery of gametes for fertilization; and, in women, physi-
ological preparation for possible pregnancy. Neuroendocrine
systems are the principal drivers of reproductive function in
both men and women. In particular, hypothalamic gonad-
otropin-releasing hormone (GnRH) is the primary, if not
exclusive, feedforward signal to gonadotrope cells of the
anterior pituitary, stimulating the synthesis and secretion of
both luteinizing hormone (LH) and follicle-stimulating hor-
mone (FSH). Together, these two gonadotropins direct the
primary functions of the reproductive axis: gametogenesis
and gonadal sex steroid synthesis.
Given its critical importance to a species, the reproduc-
tive system must be robust, continuing to function prop-
erly in the face of various internal and external influences.
In contrast, in settings of marked physiological stress (e.g.,
significantly reduced energy availability), mechanisms that
temporarily limit fertility—the usual outcome of which is
metabolically expensive in women—are biologically advan-
tageous for the individual and, ultimately, the species.
Appropriate function (or quiescence) of the reproductive
system is governed by a number of intricate relationships.
For example, feedback signals from the gonads (e.g., sex
steroid concentrations) communicate the status of gonadal
function to the hypothalamic-pituitary axis; these signals in
turn influence GnRH and gonadotropin output, rendering
a coordinated and tightly regulated feedback system that
maintains gonadal function within narrow limits. The repro-
ductive system also has extensive interactions with other
neuroendocrine systems, such as those involved with energy
balance and adaptations to stress. The reproductive neuro-
endocrine network integrates these myriad feedback signals,
and the GnRH-secreting neuronal network represents the
final common pathway for the central control of reproduc-
tion. Thus, the regulation of GnRH secretion represents a
major focus of reproductive neuroendocrinology.
Much of our understanding of reproductive neuroendo-
crinology has emerged from the study of rodents, sheep,
and non-human primates, which largely reflects the ethi-
cal boundaries inherent to human research. Since many
CHAPTER 1
Neuroendocrinology
of Reproduction
Christopher R. McCartney
John C. Marshall
neurobiological principles are similar among all mammals,
these animal studies have been (and continue to be) indis-
pensable. Nonetheless, certain aspects of reproductive neu-
roendocrinology may differ markedly among species. Thus,
when available, human data will be prioritized throughout
this chapter, but animal studies will also be discussed when
appropriate, recognizing that specific findings may or may
not be generalizable to humans.
Neuroendocrinology: The Interface
Between Neurobiology and Endocrinology
Endocrinology is the study of cell-to-cell signaling that
occurs via specific chemicals (hormones) that travel through
the bloodstream to influence remote targets. The term
“neuroendocrinology” refers to the involvement of the cen-
tral nervous system—the hypothalamus in particular—in
this process. This field of study has traditionally focused
on hypothalamic neuron-derived factors that influence vari-
ous target tissues, either directly, as with the hormones of
the neurohypophysis, or indirectly, as with hypothalamic
releasing factors that control anterior pituitary hormone
secretion. Neuroendocrine systems direct a wide variety
of critical biological processes such as growth and develop-
ment, energy and fluid homeostasis, responses to stress, and
reproduction.
Neurons are highly specialized and morphologically
diverse cells that transmit information via electrical impulses
called action potentials. Neurons have a cell body contain-
ing the cell nucleus, mitochondria, and synthetic organ-
elles. Neurons also have cell processes that participate in
the reception and delivery of electrical impulses (Fig. 1.1).
Dendrites are short processes—often extensively branched
to increase surface area—that typically receive information
(afferent electrical impulses). The axon is a single cell pro-
cess that generally transmits efferent electrical impulses
away from the cell body in a process called “neuronal firing.”
In unstimulated neurons, the inner portion of the neuron­al
membrane is negatively charged compared to the outer
membrane surface (e.g., this “resting membrane potential”
is typically between -50 to -75 mV in GnRH neurons). Such
electrical polarization reflects transmembrane ionic differ-
ences, which are maintained by protein channels that govern
transmembrane passage of specific ions (e.g., sodium, potas-
sium, chloride). Regulated changes of transmembrane ion
differences may cause the membrane potential to become
more or less negative (hyperpolarization and depolarization,
3
4 PART 1 Endocrinology of Reproduction
Dendrites
Cell body
(perikaryon)
Axon
Axon
terminals
FIGURE 1.1 Morphological components of a neuron.
respectively). Depolarization to a certain threshold results
in a rapid and temporary reversal of membrane potential (an
action potential), which is propagated along the neuronal
membrane. Notably, the amplitude of the action potential
does not vary with the strength of stimulation; instead, once
a threshold is reached, a full action potential occurs—the
so-called “all-or-none” phenomenon. However, the degree
of neuronal stimulation can alter the frequency of action
potentials generated. In this way, neurons transmit informa-
tion to other neurons and effector tissue cells.
Neuronal signals are transferred across neuron-to-neuron
connections (synapses) via chemical neurotransmitters. This
process begins with bursts of neuronal firing, which results
in the opening of voltage-gated calcium channels at the axo-
nal terminal. The influx of calcium promotes exocytosis
of neurotransmitter-containing synaptic vesicles, releasing
neurotransmitters into the synaptic cleft. Neurotransmit-
ters then bind to specific ligand-­dependent ion channels in
the postsynaptic membrane, which can stimulate an action
potential in the postsynaptic cell membrane. A wide vari-
ety of factors serve as neurotransmitters, including amino
acids (e.g., acetylcholine, glutamate, γ-aminobutyric acid
[GABA]), biogenic amines (e.g., norepinephrine, epineph-
rine, dopamine, serotonin), and neuropeptides (e.g., kiss-
peptin, neurokinin B, dynorphin, β-endorphin, somatostatin,
proopiomelanocortin [POMC], neuropeptide Y [NPY]).
Bursts of neuronal firing can also elicit release of ­neuronal
products into the bloodstream to influence remote targets
(i.e., “neurosecretion” of “neurohormones”). Hypophysio-
tropic neurons are specialized hypothalamic neurons that
secrete peptide releasing factors—GnRH, corticotropin-
releasing hormone (CRH), thyrotropin-releasing hor-
mone (TRH), and growth hormone-releasing hormone
(GHRH)—into the hypophyseal portal circulation. These
releasing factors in turn stimulate specific anterior pituitary
cell populations. In contrast, hypothalamic release of dopa-
mine into the portal circulation provides tonic inhibition of
prolactin secretion. Hypothalamic neurosecretion of vaso-
pressin and oxytocin, which are released directly into the
systemic circulation, alter the function of distant tissues
such as the renal tubules and uterus, respectively.
Neuroglial cells (e.g., astrocytes, ependymal cells, oligo-
dendrocytes, and microglia) represent approximately 90%
of cells in the central nervous system (CNS). Neuroglia
do not conduct action potentials, but they perform critical
supportive functions. For example, astrocytes form the sup-
portive framework of the CNS; help isolate synaptic junc-
tions (to prevent nonspecific spread of neuronal impulses);
facilitate nutrient delivery to neurons; and contribute to the
blood-brain barrier. In addition, astrocytes have been impli-
cated in the control of GnRH secretion and the mechanisms
underlying pubertal onset.1 For example, astrocytes may
impact neuronal activity via secretion of numerous growth
factors, and astrocytes abundantly appose GnRH neurons;
these contacts can influence synaptic input, and they may
be influenced by estrogen in both rodents and nonhuman
primates. Similarly, specialized ependymal cells (tanycytes)
in the median eminence appear to modify access of GnRH
neuron terminals to the hypophyseal portal blood.
Anatomy of the Reproductive
Hypothalamic-Pituitary Axis
Portions of the hypothalamus and anterior pituitary gland
constitute the primary effector arm of the central reproduc-
tive axis. In particular, hypothalamic neural systems regu-
late GnRH release into the hypophyseal portal veins, with
GnRH being the signal to gonadotropes (anterior pituitary)
to secrete LH and FSH. In turn, these gonadotropins direct
gonadal (ovarian and testicular) function.
Hypothalamus
The hypothalamus is located at the base of the brain (Fig.
1.2). Although small (approximately 10 grams, less than
1% of total brain weight), it performs critical functions for
maintenance of whole-organism homeostasis. In particular,
primary functions include regulation of hunger and weight
maintenance, various aspects of metabolism, growth, thirst
and renal water handling, body temperature, autonomic
function, sleep, circadian rhythms, and emotion. Impor-
tantly, the hypothalamus is also a primary control center for
reproduction and influences sexual behavior.
As an anatomical structure, the hypothalamus does
not have discrete borders; but in general, it forms the
floor and inferior lateral walls of the third ventricle (Fig.
1.3). The medial portions of the hypothalamus are pri-
marily made up of cell bodies, while the lateral portions
are mostly composed of neuron fibers (axons), such as
those connecting the medial hypothalamus to other areas
of the brain. (Note that the hypothalamus is extensively
interconnected with other brain areas.) By convention,
closely associated collections of neuron cell bodies are
called nuclei; and the paraventricular, dorsomedial, ven-
tromedial, and arcuate nuclei (the latter can be called the
infundibular nucleus in humans) contain a majority of the
neurons that secrete hypophysiotropic hormones into the
portal circulation. GnRH cell bodies do not form discrete
nuclei, but are instead diffusely located throughout the
preoptic area and the mediobasal hypothalamus (Fig. 1.4);
the latter is situated caudal to the preoptic area, extend-
ing from the retrochiasmatic area (i.e., the area situated
behind the optic chiasm) to the mamillary bodies, and
including both the arcuate (infundibular) nucleus and the
median eminence.
Median Eminence
Positioned at the base of the third ventricle, the median emi-
nence is part of the anatomical link between the hypothala-
mus and anterior pituitary. The internal zone of the median
eminence is located along the ventral floor of third ventricle

Corpus callosum Thalamus
Fornix
Hypothalamus
Anterior
commissure
Lamina
terminalis
Optic chiasm
Pituitary
in fossa of
sphenoid
bone
Median Mammillary
eminence body
and is largely composed of axonal fibers from both mag-
nocellular neurons (larger neurons that secrete vasopressin
and oxytocin) and hypophysiotropic neurons as they travel
from hypothalamic nuclei/areas to their final destinations—
the neurohypophysis (posterior pituitary) and the external
zone of the median eminence, respectively (Fig. 1.5). The
external zone contains hypophysiotropic neuron terminals,
which release hypophysiotropic hormones into an extensive
capillary plexus—the proximal end of the hypophyseal por-
tal system. Some nerve terminals in this zone act on other
nerve terminals to influence hormone release (e.g., kiss-
peptin neurosecretion at GnRH neuron terminals appears
to influence GnRH release).
The ependymal layer lining the third ventricle includes a
population of specialized ependymal cells called tanycytes,
which have a short process extending toward the ventricu-
lar surface and a long process extending into the median
eminence toward areas around portal capillaries. The latter
tanycyte projections envelope or retract from GnRH nerve
terminals during high and low GnRH neuronal activity,
respectively. Thus, tanycytes may influence GnRH secre-
tion by physically isolating GnRH neuron terminals from
portal capillaries, a regulated process.2 Tanycytes have also
been proposed to be a link between cerebrospinal fluid and
events at the external zone (e.g., by transporting substances
from the third ventricle to portal blood).
The median eminence is among the so-called circumven-
tricular organs, which lie adjacent to the ventricular system
and represent openings in the blood-brain barrier. While
lipid-soluble molecules can diffuse in and out of the CNS
relatively easily, and cellular transport mechanisms allow
selective entry of ions, the blood-brain barrier functions to
protect certain regions of the brain and hypothalamus from
larger charged molecules, with physical protection pro-
vided by (a) tight junctions between endothelial cells and
(b) neuron-capillary separation by both astrocyte foot pro-
cesses and microglia. However, the CNS requires feedback
CHAPTER 1 Neuroendocrinology of Reproduction 5
Pineal gland
attached to
epithalamus
Midbrain
colliculi
Midbrain
Pons
FIGURE 1.2 Cross-sectional rep-
resentation of the human brain
(sagittal plane), including hypo-
Medulla thalamus, median eminence, and
pituitary gland. (Adapted from
Johnson MH, Everitt BJ. Essential
reproduction, ed 5. Blackwell Sci-
ence, 2000, Fig. 6.1.)
signals—including hormonal, metabolic, and toxic—via
macromolecules of peripheral origin that would otherwise
be excluded by the blood-brain barrier; accordingly, capil-
laries of the circumventricular organs are fenestrated and
permit transcapillary exchange of larger charged molecules
(e.g., proteins, peptide hormones). Thus, the median emi-
nence represents a key access point for central sensing of
peripheral cues. Similarly, fenestrated vessels readily allow
entry of hypothalamic releasing factors into portal blood.
Hypophyseal Portal Circulation
No direct neuronal connections exist between the hypothal-
amus and the anterior pituitary. However, the hypophyseal
portal circulation (hypothalamic-hypophyseal portal system,
pituitary portal system) represents the functional connec-
tion between the median eminence and anterior pituitary
(Fig. 1.4). The superior hypophyseal artery (a branch of the
internal carotid artery) subdivides to form an extensive cap-
illary network in the external zone of the median eminence,
with loops that reach into the inner zone. Capillary blood
then drains into sinusoids that converge into the hypophy-
seal portal veins. Traversing the pituitary stalk to reach the
anterior pituitary, the hypophyseal portal system forms the
primary blood supply of the anterior pituitary. The direc-
tion of blood flow is primarily, but not exclusively, from the
hypothalamus to the anterior pituitary; some retrograde
flow allows for short-loop hypothalamic feedback.
Pituitary Gland (Hypophysis)
The pituitary gland appears as an extension at the base of
the hypothalamus and resides cradled within the sella tur-
cica, a saddle-like structure of the sphenoid bone (Fig. 1.2).
The adenohypophysis (anterior pituitary) is of ectodermal
origin, derived from an upward invagination of pharyngeal
epithelium (Rathke pouch) during embryological devel-
opment. The adenohypophysis is comprised primarily by
the anterior lobe (pars distalis), which contains specialized
6 PART 1 Endocrinology of Reproduction

Paraventricular Dorsal Dorsomedial

nucleus hypothalamic nucleus
area Posterior
Anterior hypothalamic
hypothalamic nucleus
area
Premamillary
Preoptic nucleus
area
Supraoptic
nucleus

Suprachiasmatic Ventromedial
nucleus nucleus
Optic chiasm
Arcuate
Median eminence nucleus

Pituitary
gland
A

Lateral Lateral
hypothalamus III Ventricle hypothalamus III Ventricle

Fornix
Paraventricular
nucleus

Anterior
hypothalamic
area Optic tract Ventromedial
nucleus
Median
Arcuate
eminence
nucleus
Supraoptic region
nucleus
2 Infundibulum
Preoptic
area Suprachiasatic
1 Optic chiasm nuclei
III Ventricle

Mammillothalamic
tract

Posterior
Cerebral hypothalamic
peduncle area
Lateral
hypothalamus

Mammillary
nuclear
B 3 complex
FIGURE 1.3 Nuclei and areas of hypothalamus. A, By custom, the nuclei and areas of the hypothalamus are often divided into three groups
according to their location along the anterior-posterior plane: the anterior group, the tuberal group, and the posterior (or mamillary) group.
The anterior group is formed by the paraventricular, supraoptic, and suprachiasmatic nuclei along with the anterior hypothalamic and pre-
optic areas. The tuberal group—so-called because of its position above the tuber cinereum (from which the infundibulum or pituitary stalk
extends)—contains the dorsomedial, ventromedial, and arcuate nuclei along with the median eminence. Along with the paraventricular
nucleus, the nuclei of the tuberal group contain a majority of the neurons that secrete hypophysiotropic hormones (i.e., hypothalamic hor-
mones regulating hormone synthesis and release from cells in the anterior pituitary). Finally, the posterior group includes the posterior hypo-
thalamic nucleus and mamillary nuclei. B, Cross-sectional representations (coronal planes) of the rostral (1), mid (2), and caudal (3) portions
of the human hypothalamus. (Section B is adapted from Johnson MH, Everitt BJ. Essential reproduction, ed 5. Blackwell Science, 2000, Fig. 6.3.)

Preoptic
area
Optic chiasm
Mamillary body
Arcuate nucleus
Superior hypophyseal
artery
Hypophysial
portal system
Adenohypophysis
Vein
FIGURE 1.4 Anatomical relationship between hypothalamic GnRH
neurons and their target cell populations in the adenohypophy-
sis (anterior pituitary). GnRH neuron cell bodies are located in the
preoptic area and the mediobasal hypothalmus. GnRH axonal pro-
jections terminate at the median eminence, where GnRH is secreted
into the hypophyseal portal system. (Adapted from Johnson MH,
Everitt BJ. Essential reproduction, ed 5. Blackwell Science, 2000, Fig. 6.4.)
cell populations that produce specific hormones: gonado-
tropes (the gonadotropins LH and FSH), mammotropes
(prolactin), corticotropes (adrenocorticotropic hormone),
thyrotropes (thyroid stimulating hormone [TSH]), and
somatotropes (growth hormone). The intermediate lobe is
vestigial in adult humans, but includes a small population of
cells (e.g., POMC cells) in contact with the posterior lobe;
and the pars tuberalis is a slender layer of tissue (e.g., LH-
producing cells and TSH-producing cells) surrounding the
infundibulum and pituitary stalk.
In contrast to the adenohypopysis, the neurohypophysis
(posterior pituitary) is comprised of neural tissue and forms
as a downward extension of neuroectodermal tissue from the
infundibulum during embryological development. It is thus a
direct extension of the hypothalamus. The neurohypophysis
includes the infundibular stalk and the pars nervosa (poste-
rior lobe of the pituitary). The supraoptic and paraventricular
nuclei include magnocellular neurons that produce oxytocin
and arginine vasopressin ([AVP]; also known as antidiuretic
hormone [ADH]) respectively; these axons project to the
posterior lobe of the pituitary, where oxytocin and AVP are
secreted into a capillary network that drains into the hypoph-
yseal veins (i.e., directly into the general circulation). The
posterior lobe also includes specialized glial cells called pitui-
cytes, which envelope or retract from magnocellular nerve
terminals during high and low neuronal activity, respectively.
Gonadotropin-Releasing Hormone: The Final
Common Pathway for the Central Control
of Reproduction
Gonadotropin-releasing hormone, previously called lutein-
izing hormone-releasing hormone (LHRH), is synthesized
CHAPTER 1 Neuroendocrinology of Reproduction 7
Tanycytes Portal capillary loop
Third ventricle floor
Supraopticohypophysial
fibers
INTERNAL ZONE
Adrenergic/peptidergic
axon
GnRH axon
EXTERNAL ZONE
Portal capillary plexus
FIGURE 1.5 Diagram of the median eminence.
and released from a relatively small population of special-
ized hypothalamic neurons. GnRH was initially isolated
from porcine hypothalami and shown to stimulate pitu-
itary gonadotropin release.3 Although the primary function
of GnRH is to regulate pituitary gonadotropin secretion,
GnRH also appears to have autocrine and paracrine func-
tions in diverse tissues (e.g., ovary, placenta).4
The regulation of GnRH secretion is complex and involves
overlapping pathways, which likely increases the robustness
of central reproductive function. However, there are no
known parallel or backup pathways for the stimulation of
gonadotropin secretion. Thus, natural fertility is absolutely
dependent on appropriate GnRH secretion. For example,
mice with mutations of the GnRH-1 gene are hypogonadal,
but reproduction can be restored via GnRH-1 gene ther-
apy5 or transplantation of fetal GnRH neurons.6 Similarly,
a variety of human conditions associated with absent (or
near-absent) GnRH secretion lead to pubertal failure, hypo-
gonadotropic hypogonadism, and infertility, all of which can
be fully reversed with exogenous GnRH therapy.7
GnRH secretion is influenced by numerous factors
including sex steroids, energy availability, and stress. In
some mammalian species, GnRH secretion is also affected
by circadian rhythms, photoperiod (e.g., seasonal breeders
such as sheep), social cues, and pheromones.
GnRH Structure
Gonadotropin-releasing hormone (GnRH-1 in particular)
is a decapaptide, with the amino acid structure (pyro)Glu-
His-Trp-Ser-Tyr-Gly-Leu-Arg-Pro-Gly-NH2. The amino acid
structure of GnRH is identical in essentially all mammalian
species; and with the exception of the central Tyr-Gly-Leu-
Arg segment, the amino acids of GnRH are highly conserved
among vertebrate species.8 The GnRH-1 gene (GNRH1) is
located on human chromosome 8 (8p11.2-p21) and produces
a 92 amino acid precursor peptide called prepro-GnRH,
which includes a signal sequence (23 amino acids), GnRH
(10 amino acids), a proteolytic processing site (3 amino
acids), and GnRH-associated peptide (56 amino acids) (Fig.
1.6). The latter peptide can stimulate gonadotropin secretion
and inhibit prolactin secretion, although its precise physio-
logical role, if any, remains unclear. The actions of GnRH are
mediated through the GnRH type I receptor.
Another form of GnRH (GnRH-2) and its receptor
have been identified in a variety of animal species including
8 PART 1 Endocrinology of Reproduction
Nucleus
GnRH precursor molecule
(prepro-GnRH)
–23
Processing
1 2 3 4 5 6 7 8 9 10 Gly
Lys
Glu His Trp Ser Tyr Gly Leu Arg Pro Gly
Arg
GAP (56aa)
+92
A B
FIGURE 1.6 Schematic of GnRH synthesis. A, Representation of prepro-GnRH, including a 23 amino acid signal sequence, GnRH, a proteo-
lytic processing site (Gly-Lys-Arg), and GnRH-associated peptide (GAP). The arrow indicates the site of proteolytic cleavage and C-amidation.
B, Schematic of neuronal GnRH synthesis and secretion.
humans.9 GnRH-2 is a decapeptide with similar struc-
ture to GnRH-1: (pyro)Glu-His-Trp-Ser-His-Gly-Trp-Tyr-
Pro-Gly-NH2 (underlined amino acids denote differences
compared to GnRH-1). However, the gene for GnRH-2
is located on human chromosome 20 (20p13). GnRH-2
is widely expressed in the CNS and extra-CNS tissues,
and it may contribute to reproductive behavior regulation
in some species. In lower animals, GnRH-2 can act via its
own receptor, which is structurally and functionally distinct
from the GnRH type I receptor. Although a homologue of
the GnRH-2 receptor gene has been detected in the human,
it includes a frameshift and premature stop codon. Thus,
GnRH-2 signaling in humans may act through the GnRH
type I receptor, although the physiological role of GnRH-2
in humans remains unclear.
Anatomy of GnRH-Secreting Neurons
GnRH neurons are a heterogeneous population of hypo-
thalamic neurons. They are relatively few, numbering
approximately 1500 to 2000, and the majority of GnRH
neuronal cell bodies are located in the arcuate (infundibu-
lar) nucleus (part of the mediobasal hypothalamus) and
the medial preoptic area.10 Although GnRH neurons are
rather loosely affiliated anatomically, they are function-
ally integrated and form a complex network with numer-
ous interconnections, in addition to connections to other
neuronal populations. The GnRH neurons in the medio-
basal hypothalamus appear to be requisite for gonado-
tropin secretion, and GnRH neuronal axons project to
the median eminence via the GnRH tuberoinfundibular
tract. The physiological function of other GnRH neurons,
which arise from the anterior and posterior hypothalamus,
and project to the limbic system and posterior pituitary,
Pro GnRH gene
Cytoplasm
Transcription
Primary
Pro GnRH transcript
peptide
Translation Processing
GnRH decapeptide
GAP
mRNA
Transport
to cytoplasm
Portal vessel
respectively, remains unclear, although some of these cir-
cuits may possibly be involved with various behavioral
responses.
Embryological Development of the GnRH
Neuronal Network
The ontogeny of GnRH neurons in vertebrate species is
unique among neuronal systems of the CNS: nascent
GnRH neurons are initially identified outside of the CNS
in the nasal placode (sometimes called the olfactory plac-
ode). However, GnRH cells migrate during embryologi-
cal development, as directly observed in embryonic nasal
explant cultures and in embryonic head slices (mouse
model).11,12 The specific migratory pathway of GnRH
neurons was first demonstrated in mice by documenting
the presence of GnRH-immunoreactive cells in different
areas at different stages of embryonic development (Fig.
1.7).13-15 Specifically, GnRH expression is first observed
within the nasal placode circa embryonic day 10 or 11.
By embryonic day 13, GnRH cells are primarily located
around the cribiform plate, and GnRH cells begin to reach
the hypothalamus by embryonic day 14, approaching their
final positions around embryonic day 16. This migratory
pathway has been confirmed in both nonhuman primates16
and humans.17
Successful migration of GnRH neurons is inextricably
intertwined with olfactory system development, likely
reflecting the close functional relationship between repro-
duction and the olfactory system (e.g., pheromones) in
mammalian phylogeny. The nasal placode gives rise to
nasal epithelium and olfactory sensory neurons, the latter
of which extend axonal projections to the olfactory bulb.
Vomeronasal neurons are a subset of olfactory neurons
 CHAPTER 1 Neuroendocrinology of Reproduction 9

poa
ob
ob poa
vno gt
gt
gt ob
11E
vno
13E vno

14E vno

16E
A

OB

CP

BF

OP/VNO

B
FIGURE 1.7 GnRH neuron migration during embryogenesis. A, Location of GnRH-immunoreactive cells (red circles) as a function of embryo-
logical age (mouse). On embryological day 11 (11E), GnRH cells are located in the nasal (olfactory) placode and presumptive vomeronasal
organ (vno). GnRH cells migrate across the cribiform plate toward the olfactory bulb (ob). GnRH neurons then follow the caudal branch of the
vomeronasal nerve toward the forebrain and hypothalamus. By day 16 (16E), GnRH neurons largely reside in the preoptic area (poa) of the
hypothalamus. Abbreviations: gt, ganglion terminale. (Adapted from Schwanzel-Fukuda M, Pfaff DW. Origin of Luteinizing Hormone-Releasing
Hormone Neurons. Nature 338:161-164, 1989.) B, Sagittal brain slice (mouse, embryonic day 15) demonstrating the migratory route of GnRH-
immunoreactive cells. Staining is for GnRH and peripherin (a neuronal intermediate filament). OP/VNO, olfactory placode-vomeronasal organ;
CP, cribriform plate (CP); OB, olfactory bulb; BF, basal forebrain. (Adapted from Wierman ME, Pawlowski JE, Allen MP, et al. Molecular mechanisms
of gonadotropin-releasing hormone neuronal migration. Trends Endocrinol Metab 15:96-102, 2004.)

believed to be involved with pheromone detection; these
axons originate in the vomeronasal organ and largely extend
to the accessory olfactory bulb. At the level of the cribiform
plate, some olfactory (vomeronasal) axons separate and
form a branch that extends caudally into the forebrain. Of
great importance, migrating GnRH neurons maintain adhe-
sion to these axons; thus, these olfactory neurons form a
critical guidance track for GnRH neuronal migration across
the nasal epithelium and through the forebrain toward the
hypothalamus.18,19
The dependence of GnRH neuronal migration on nor-
mal olfactory system development is exemplified by Kall-
mann syndrome, a form of congenital hypogonadotropic
hypogonadism accompanied by absent sense of smell (anos-
mia). In this syndrome, faulty development of the olfactory
system renders an inadequate guidance infrastructure for
migrating GnRH neurons, leading to failure of GnRH neu-
rons to reach the hypothalamus. The first identified cause
of Kallmann syndrome was deletion of the Kallmann syn-
drome 1 sequence (KAL1 gene), which is located on the X
chromosome (Xp22.3) and encodes anosmin-1, a secreted
matrix glycoprotein expressed in the presumptive olfactory
bulb. Although precise mechanisms are unclear, anosmin-1
is believed to be important for the formation of olfactory
elements that provide migratory guidance to GnRH neu-
rons as they move out of the nasal placode. Evaluation of
a 19-week-old human fetus with X-linked Kallmann syn-
drome demonstrated GnRH-immunoreactive cells within
a tangle of olfactory and vomeronasal nerves at the dor-
sal surface of the cribiform plate, along with the absence
of olfactory tracts and bulbs.20 In a second human fetus
(16 weeks) with X-linked Kallmann syndrome, GnRH was
detected along terminal nerve fascicles in the nasal mucosa
only.21 This syndrome illustrates that, without the guid-
ance framework provided by the olfactory neuronal sys-
tem, GnRH neurons fail to migrate into the hypothalamus
10 PART 1 Endocrinology of Reproduction
and thus cannot release GnRH into the hypophyseal portal
system.
A number of additional single-gene defects have been
associated with Kallmann syndrome, including mutations
of prokineticin 2 (PROK2) and its receptor (PROKR2),22
fibroblast growth factor-8 (FGF8) and its receptor (fibro-
blast growth factor receptor 1 [FGFR1]),23 nasal embryonic
LH-releasing hormone factor (NELF),24 and chromodomain
helicase DNA binding protein 7 (CHD7).25 The importance
of these genes in GnRH neuronal development is corrobo-
rated by mouse studies. For example, in fetal mice lacking
either PROK2 or PROKR2, GnRH neurons are trapped in
a tangled web of olfactory/vomeronasal axons, with few, if
any, reaching the forebrain.26 Although these gene products
are clearly important for GnRH neuron ontogeny, their pre-
cise roles remain uncertain.
Mouse studies suggest other important factors underly-
ing GnRH neuron migration during prenatal development.
For example, the chemokine (C-X-C motif) receptor 4
(CXCR4) is expressed on murine GnRH neurons and
interacts with a secreted chemokine stromal cell-derived
factor-1 (SDF-1), which is present as a gradient in the
nasal mesenchyme. This gradient, with highest concentra-
tions at the cribriform plate, provides directional informa-
tion as GnRH neurons migrate toward the cribiform plate;
and GnRH cell migration across the nasal compartment is
markedly impaired in CXCR4 knockout mice.27 As another
example, extension of the caudal branch of the vomerona-
sal nerve toward the ventral forebrain involves chemoat-
traction via interactions between netrin-1—a chemokine
expressed as a gradient in the forebrain—and its receptor,
deleted in colorectal cancer (DCC). In mice without either
DCC or netrin-1, the caudal branch of the vomeronasal
nerve extends toward the cerebral cortex rather than the
ventral forebrain; GnRH neurons follow this path, ulti-
mately residing in the cerebral cortex.28,29 A number of
such interactions have been implicated in (a) guidance of
olfactory neurons toward the forebrain and (b) the associa-
tion between migrating GnRH neurons and axons of olfac-
tory/vomeronasal nerves, but their specific roles in humans
remain unclear. For example, no human mutations affecting
DCC or netrin-1 have been described to date.
After reaching the hypothalamus, GnRH neurons detach
from olfactory nerve axons and may disperse further before
resting. A critical next step is extension of GnRH neuro-
nal axons to the median eminence, where GnRH may gain
access to the hypophyseal portal system.
GnRH Neuronal Firing and GnRH Secretion
GnRH neuronal activity is marked by bursts of action poten-
tials (burst firing), the patterns and rates of which change
across time. Changes of GnRH secretion are presumably
related to changes of GnRH neuron firing rates, although
the precise relationship between these events is unclear.
Variable firing rate patterns (e.g., times of high and low
firing rates) appear to be intrinsic to GnRH neurons, but
they can also be altered by neurotransmitters and neuro-
modulators (e.g., glutamate, GABA, kisspeptin). Although
sex steroids can markedly influence GnRH neuronal firing
rates, GnRH neurons lack the primary receptors mediating
sex steroid feedback (i.e., estrogen receptor alpha, proges-
terone receptor, androgen receptor); however, many studies
suggest that sex steroid actions on GnRH neuronal activ-
ity are mediated primarily by afferent neurons (e.g., those
secreting glutamate, GABA, kisspeptin, etc.).
GnRH neuron cell bodies are relatively scattered across
the mediobasal hypothalamus and preoptic area, yet GnRH
is secreted into the hypophyseal portal system in a coor-
dinated, pulsatile fashion. Specifically, GnRH secretion is
marked by episodic bursts of hormone release into the portal
system, as demonstrated in rats,30 sheep,31 and monkeys.32
Once released into the portal vascular compartment, GnRH
is rapidly degraded via enzymatic proteolysis, and the half-
life of GnRH in the blood is very short—approximately 2 to
4 minutes. Thus, GnRH presentation to gonadotrope cells
is intermittent.
Pulsatile GnRH secretion is absolutely required for
long-term stimulation of gonadotropin synthesis and secre-
tion. Yet there is a relatively narrow window of GnRH
pulse frequency and amplitude that will optimally stimu-
late gonadotropin secretion. Intermittent GnRH stimu-
lation of gonadotrope cells can increase (or maintain)
GnRH receptors on gonadotropes—the “self-priming” or
“autopriming” effect. Thus, intermittent GnRH stimula-
tion facilitates or maintains gonadotrope responsiveness
to GnRH. However, more frequent exposure to GnRH
pulses can reduce gonadotropin responses to GnRH33; at
one extreme, continuous GnRH receptor stimulation leads
to marked desensitization of gonadotropin synthesis and
secretion. In a classic experiment involving rhesus monkeys
with hypothalamic lesions that abolished GnRH secretion,
intermittent (once an hour) exogenous GnRH administra-
tion restored pituitary gonadotropin secretion. However,
changing from intermittent to continuous GnRH adminis-
tration resulted in marked desensitization of gonadotropin
release (Fig. 1.8).34 This desensitization is largely related
to reduced GnRH receptor expression on gonadotropes
(i.e., receptor downregulation).
The foregoing phenomenon can be exploited therapeuti-
cally with the use of long-acting GnRH receptor agonists.
Such agonists are peptides with structures very similar to that
of GnRH, but with amino acid substitutions that enhance
receptor binding affinity, increase resistance to proteolytic
degradation, or both (Fig. 1.9), thus providing continuous
GnRH receptor stimulation. Although initial GnRH receptor
agonism temporarily increases gonadotropin release (gonado-
tropin “flare”), continued agonism leads to desensitization
of gonadotropin secretion with accompanying reductions of
gonadal sex steroid concentrations to castrate levels (“medical
oophorectomy,” “medical castration,” “pseudomenopause”),
usually over 4 to 8 weeks. These agents are useful in the
therapy of gonadotropin-dependent disorders such as central
precocious puberty, endometriosis, and prostate cancer.
Peptide GnRH receptor antagonists are also available
for clinical use. These antagonists reversibly bind to, but do
not stimulate, the GnRH receptor (i.e., competitive antag-
onism). Thus, these agents do not cause an initial “flare”
of gonadotropin secretion, and they reduce gonadotropins
more rapidly than GnRH agonists—usually within 24 to 72
hours.
GnRH Stimulation of Gonadotrope Cells
The specialized cells that synthesize and secrete gonado-
tropins (i.e., gonadotropes) are located mainly in the lateral
 CHAPTER 1 Neuroendocrinology of Reproduction 11

20 Pulsatile Continuous Pulsatile 200

15 150

FSH (ng/mL)
LH (ng/mL) 10 100

5 50

0 0
–10 –5 0 5 10 15 20 25 30 35
Days
FIGURE 1.8 The influence of pulsatile vs. continuous GnRH administration to GnRH-deficient monkeys. Intermittent exogenous GnRH admin-
istration reconstitutes normal gonadotropin secretion. However, continuous GnRH infusion leads to a marked reduction (downregulation) of
luteinizing hormone (green) and follicle-stimulating hormone (purple) concentrations. Resumption of pulsatile GnRH administration restores LH
and FSH secretion. (Adapted from Belchetz PE, Plant TM, Nakai Y, et al. Hypophysial responses to continuous and intermittent delivery of hypoptha-
lamic gonadotropin-releasing hormone. Science 202:631–633, 1978.)

GnRH pGlu His Trp Ser Tyr Gly Leu Arg Pro Gly NH2

Agonists
Leuprolide D Leu NEt

D-amino acid substitution D Ser

Goserelin (tBu) NH2
enhances activity
D His
Histrelin (ImBzl) NH2

Gly Nafarelin D Nal NH2

Tyr Leu
Triptorelin D Trp NH2
Ser Arg
Buserelin D Ser NEt
(tBu)

Receptor binding Trp Pro Receptor

binding only Antagonists
and activation
His Gly Cetorelix D Nal D Cpa D Pal D Cit D Ala NH2
D-amino acid
NH2
substitution
Ganirelix D hArg D hArg NH2
in antagonists pGlu D Nal D Cpa D Pal
(Et)2 (Et)2
D Ala

A B
FIGURE 1.9 Structure of GnRH and GnRH receptor agonists and antagonists. A, Schematic of GnRH-1 in its folded conformation. Folding
around the glycine in position 6 enhances GnRH receptor binding. Substitution of the glycine in position 6 with D-amino acids stabilizes the
molecule in the folded conformation, which increases affinity for the GnRH receptor and reduces metabolic clearance. The amino-terminal
(red) is involved with receptor binding and activation, and GnRH antagonists involve modifications of these residues that prevent receptor
activation. The carboxyl-terminal (green) participates in receptor binding, but not activation. Substitution at position 10 (e.g., replacement
of glycinamide by ethylamide) can increase binding affinity. B, Amino acid structure of GnRH along with selected GnRH receptor agonists
and antagonists. Solid black circles represent amino acids that are unchanged compared to native GnRH. (From Millar RP, et al. Gonadotropin-
releasing hormone receptors. Endocr Rev. 25:235–275, 2004.)

portions of the anterior pituitary gland and constitute 7% to
10% of the adenohypophysis cell population. GnRH action at
the pituitary gonadotrope begins with GnRH binding to the
GnRH type I receptor on the plasma membrane.8 The GnRH
type I receptor is a member of the seven-­transmembrane
receptor family, a G protein-coupled receptor, and encoded
on chromosome 4. GnRH receptor density varies in differ-
ent physiological conditions and exhibits a positive correla-
tion with gonadotrope responsiveness to GnRH (e.g., with
both being high in rodents during preovulatory gonadotropin
surges35). GnRH receptor density appears to be modulated
primarily by GnRH, with intermittent GnRH stimulation
leading to increased GnRH receptor expression; this is a
central facet of the self-priming effect of GnRH, and an
important mechanism by which GnRH action is modulated
in different physiological states.
A majority of gonadotropes synthesize and secrete both LH
and FSH. A detailed description of intracellular mechanisms
of GnRH action on the gonadotrope is provided in Chapter
2. Briefly, GnRH receptor binding activates the guanosine
12 PART 1 Endocrinology of Reproduction

994
1 Pulse/hour 1 Pulse/3 hours 1 Pulse/hour
50 500

45 450
FIGURE 1.10 LH and FSH concen-
trations in gonadectomized (but 40 400
sex steroid-replaced) monkeys after
35 350
arcuate nucleus ablation—a model
of isolated GnRH deficiency. Exoge-

FSH (ng/mL)
30 300

LH (ng/mL)
nous GnRH administered in a pulsa-
tile fashion every hour reconstituted 25 250
LH and FSH secretion. Changing
GnRH pulse administration from a 20 200
relatively high frequency (hourly) to 15 150
a relatively low frequency (every 3
hours) resulted in decreased LH but 10 100
increased FSH secretion. (Adapted
from Wildt L., et al., Frequency and 5 50
amplitude of gonadotropin-releasing
hormone stimulation and gonadotro- 0 0
pin secretion in the rhesus monkey. 20 15 10 5 0 5 10 15 20 25 30 35 40
Endocrinol 109:376–385, 1981.) Days

triphosphate (GTP)-binding protein Gq/11 leading to an

increase of second messengers inositol 1,4,5-triphosphate
(IP3) and 1,2-diacylglycerol (DAG). Further intracellular
signaling involves increased intracellular calcium and activa-
tion of various protein kinase C (PKC) isoforms, mitogen-
activated protein kinases (e.g., extracellular signal-regulated
kinase [ERK], c-Jun NH2-terminal kinase [JNK], and p38),
calcium/calmodulin-dependent kinase II (Ca/CaMK II), and
adenylate cyclase.
Each gonadotropin consists of two protein subunits, α and
β. The 92 amino acid α-subunit is common to both LH and
FSH—in addition to human chorionic gonadotropin (hCG)
and TSH. β-subunits for LH (LHβ) and FSH (FSHβ) are
121 and 117 amino acids in length, respectively, and account
for the biological specificity of these two hormones. GnRH
stimulates gene expression of LHβ, FSHβ, and α-subunit,
and the latter noncovalently dimerizes with either LHβ or
FSHβ to form LH or FSH, respectively. Gonadotropins also
undergo variable post-translational modification, primarily
glycosylation (addition of oligosaccharide moieties to spe-
cific amino acids), which influences bioactivity and elimina-
tion half-life.36 The gonadotropins are then packaged into
secretory granules for eventual secretion.
Although GnRH is the primary stimulus for LH and FSH
synthesis and release from a common cell type, concentra-
tions of these two gonadotropins vary differentially through-
out ovulatory cycles, with FSH predominance in the early
follicular phase and LH predominance in the late follicular
phase. This sequential pattern of FSH and LH predominance
is important for normal follicular maturation, ovarian steroid
production, and subsequent ovulation. At least two mecha-
nisms govern differential gonadotropin secretion throughout
ovulatory cycles. First, both estradiol and inhibins selectively
inhibit FSH release from gonadotropes during the midfol-
licular and luteal phases.37,38 Second, different patterns of
pulsatile GnRH release differentially affect gonadotropin
synthesis and secretion. Specifically, rapid (high frequency)
GnRH pulses favor LH, while slower (low frequency)
GnRH pulses favor FSH synthesis and secretion. For exam-
ple, studies in ovariectomized, GnRH-deficient monkeys
LH
GnRH
0 1 2 3 4 5
Hours
FIGURE 1.11 Close temporal relationship between pulses of LH
(­jugular vein) and GnRH (pituitary portal system) in the sheep model.
(Adapted from Moenter SM et al. Dynamics of gonadotropin-releasing
hormone release during a pulse. Endocrinology. 130:503–510, 1992.)
reveal that a decrease in the frequency of exogenously-
administered GnRH pulses from one pulse per hour to one
pulse every 3 hours results in a 65% increase in plasma FSH,
despite a 50% decrease in LH (Fig. 1.10).33 Similar findings
have been described in sheep39 and humans.40,41 Detailed
studies in rats demonstrate that rapid GnRH pulse stimu-
lation favors α-subunit and LHβ mRNA expression, while
slow GnRH pulses favor FSHβ mRNA expression.42 The
mechanisms effecting differential LH and FSH expression
in response to changes of GnRH pulse frequency include
variations of GnRH receptor number on the gonadotrope
cell surface43 and alterations of gonadotrope activin βB and
follistatin expression (discussed later in the chapter).44
A pulse of GnRH release stimulates a pulse of LH release
on a one-to-one basis, and LH (or α-subunit) pulse patterns,
as assessed by frequent sampling of peripheral blood, accu-
rately mirror GnRH pulse patterns in animal studies (Fig.
1.11).31,45 Similarly, exogenous GnRH pulses elicit LH

1 26 68
Kp-145, precursor SP
NH2
68
Kp-54, Metastin
108
Kp-14
109
Kp-13
112
Kp-10
pulses in GnRH deficient patients. Since measurable GnRH
is effectively confined to the hypophyseal portal system,
which is inaccessible in humans, GnRH pulse frequency is
inferred from LH pulse frequency (or α-subunit pulse fre-
quency46,47) in human studies. While pulses of GnRH stim-
ulate pulsatile release of FSH, the longer serum half-life of
FSH renders FSH pulses more difficult to identify via fre-
quent sampling of peripheral blood. Also, while short-term
LH secretion is very closely tied to continued GnRH stimu-
lation, FSH secretion is less acutely dependent on GnRH
stimulation.48,49 For example, with GnRH antagonism, the
percentage reduction of LH exceeds that of FSH.50
Neuronal Inputs into GnRH Neurons
The governance of GnRH neurons is highly complex and
involves numerous interacting neural systems utilizing vari-
ous neurotransmitters and neuromodulators. The neuronal
populations upstream of the GnRH neuron play key roles
in puberty and are important mediators of sex steroid feed-
back and the influence of nutritional cues and stress on
the GnRH pulse generator. Numerous neurotransmitters
appear to be involved in the regulation of GnRH secretion,
including dopamine, norepinephrine, glutamate, GABA,
and nitric oxide. The control of GnRH secretion has been
the subject of intense investigation, and the recent discov-
ery of several neuronal populations upstream of the GnRH
neuron (e.g., kisspeptin neurons) has markedly enhanced
our understanding of reproductive neuroendocrinology.
Kisspeptin
The kisspeptin system is believed to be requisite for normal
GnRH secretion, serving as a “gatekeeper” of puberty and
helping to mediate the effects of sex steroids and metabolic
cues on GnRH secretion. Kisspeptin was originally called
metastin because of its ability to suppress metastatic spread
of human melanomas and breast carcinomas. However, in
recognition of its discovery at Pennsylvania State Univer-
sity in Hershey, Pennsylvania, it was later named kisspeptin
after Hershey’s chocolate KISSES®. Herein we will use the
following abbreviations51: KISS1 and Kiss1, the human and
nonhuman kisspeptin genes, respectively; KISS1R (Kiss1R)
and KISS1R (Kiss1R), the human (nonhuman) kisspeptin
receptor genes and gene products, respectively.
The KISS1 gene product is a 154 amino acid precursor
protein (kisspeptin 1-145). Variable proteolytic modifica-
tion yields kisspeptins of different lengths: kisspeptin-54,
-14, -13, and -10, with the numbers referring to the
amino acid length of bioactive kisspeptin fragments (Fig.
CHAPTER 1 Neuroendocrinology of Reproduction 13
121 145
15.4 kDa
FIGURE 1.12 Schematic of the pre-
COOH
121 cursor kisspeptin-145 and the func-
5.9 kDa tional kisspeptin (Kp) fragments,
including size and cleavage sites.
121
Note that all functional kisspeptin
1.7 kDa
fragments maintain amino acids
121 112-121. SP, signal peptide. (From
1.6 kDa Roseweir AK, Millar RP. The role of
kisspeptin in the control of gonadotro-
121 phin secretion. Human Reproduction
1.3 kDa Update 15:203–212, 2009.)
1.12). Importantly, all functional kisspeptins maintain
the 10 amino acids of the carboxy-terminal (kisspeptin
amino acids 112 to 121), which are important for recep-
tor binding and function. Kisspeptin is the natural ligand
of KISS1R—also known as the G-protein coupled receptor
54 (GPR54)—a seven transmembrane domain, G protein-
coupled receptor.
The importance of the kisspeptin system in reproduction
was initially revealed by members of two consanguineous
families with KISS1R mutations leading to pubertal failure
and normosmic hypogonadotropic hypogonadism.52,53 Inac-
tivating KISS1 mutations leading to pubertal failure and
normosmic hypogonadotropic hypogonadism have also been
described in four sisters.54 Mouse models with targeted
knockouts of Kiss1 and Kiss1R exhibit hypogonadotropic
hypogonadism with impaired sexual maturation, reduced
gonadal size, failure of estrous cyclicity (females), impaired
spermatogenesis (males), and infertility.53,55,56 However,
the notion that kisspeptin is an absolute requirement for
puberty and reproductive function in mice is somewhat
controversial.57,58 KISS1R and KISS1 mutations neither
interrupt GnRH neuron migration to the hypothalamus nor
impair GnRH synthesis.
Single boluses of kisspeptin markedly stimulate LH
release in rodents, sheep, monkeys, and humans. This effect
of kisspeptin is mediated by stimulation of GnRH neurons,
as supported by the following: kisspeptin fibers appear
to project to and form synaptic contacts with GnRH neu-
rons59,60; the kisspeptin receptor is expressed by a majority of
GnRH neurons61; kisspeptin can directly depolarize GnRH
neurons62,63; and kisspeptin stimulation of gonadotropin
secretion is completely blocked by GnRH antagonists.64,65
However, kisspeptin may also work indirectly, as kisspeptin
increases GABAergic and glutamatergic postsynaptic cur-
rents onto GnRH neurons in the presence (but not absence)
of estrogen in the mouse model.66 Kisspeptin does not stimu-
late LH secretion in Kiss1R knockout mice,56 suggesting that
kisspeptin acts exclusively through its cognate receptor.
It remains unclear to what degree kisspeptin acts at
GnRH cell bodies versus nerve terminals, but some stud-
ies suggest that kisspeptin neurons can form synapses with
GnRH neuron terminals in the external zone of the median
eminence, and that kisspeptin can stimulate GnRH release
(exocytosis) from GnRH neuron terminals.67,68 Although
kisspeptin may possibly have direct effects on gonadotropes,
available data suggest that this does not play a major role in
kisspeptin’s ability to stimulate gonadotropin secretion. For
example, pulsatile GnRH can restore normal reproductive
function in patients with KISS1R mutations.69
14 PART 1 Endocrinology of Reproduction
The numbers of kisspeptin neurons are high in the
human arcuate (infundibular) nucleus, similar to findings
in monkeys.65,70,71 Extensive study in the rodent model
discloses two primary populations of kisspeptin-expressing
neurons in the hypothalamus: one in the arcuate nucleus
(mediobasal hypothalamus) and the other in the anteroven-
tral periventricular nucleus (AVPV) of the preoptic area.72
Of interest, kisspeptin expression in the AVPV is much
higher in female compared to male rodents, which appears
to reflect organizational effects of sex steroids during early
development73,74; and the kisspeptin neurons in the AVPV
appear to be specifically important for LH surge generation
in rodents. Sexual dimorphism of kisspeptin expression has
also been described in sheep75 and humans.71 However, in
primates, including humans, the majority of the kisspeptin
cell bodies reside in the arcuate nucleus; and although a
study of adult women revealed rare kisspeptin neurons in
the medial preoptic area, a population homologous to the
rodent AVPV has not been identified.70
Neurokinin B
Neurokinin B (NKB), a peptide encoded by the tachykinin
3 gene (TAC3), is a member of the tachykinin family—
a family that also includes substance P and neurokinin A
(products of the TAC1 gene). There are several neuroki-
nin receptors (NK1R, NK2R, NK3R), and although NKB
can produce some agonism at NK1R and NK2R, NKB binds
preferentially to and acts primarily via its cognate receptor
NK3R (TACR3 gene).76 Studies of patients with idiopathic
hypogonadotropic hypogonadism from consanguineous
families revealed that homozygous loss-of-function muta-
tions of either TAC3 or TACR3 can cause pubertal failure
and severe hypogonadotropic hypogonadism—highlighting
the importance of NKB in human reproduction.77,78 In con-
trast to Kiss1 and Kiss1R knockout mice, Tacr3 knockout
mice remain fertile, although they can demonstrate repro-
ductive defects.79,80
Animal studies demonstrate that a selective NK3R ago-
nist (senktide) stimulates LH secretion in the rat,81 sheep,82
and monkey,83 albeit not as potently as kisspeptin. This
effect appears to be influenced by the sex steroid milieu.
For example, senktide administration to ewes increases LH
secretion during the follicular phase, but not during the
luteal phase.82 In addition, senktide increases LH release
in the presence of physiological estradiol in rodents, but it
reduces LH release in estradiol-deficient animals.81 Mecha-
nisms underlying these apparently paradoxical observations
are unclear.
Stimulation of LH secretion by NKB is mediated by
GnRH secretion, as GnRH receptor antagonism abolishes
LH responses to senktide in the monkey.83 Yet, there are
few or no NKB receptors on GnRH neurons, and LH is not
rapidly stimulated with central senktide administration.
However, kisspeptin neurons express NK3R; and in ovariec-
tomized and estradiol-replaced rats, senktide increases c-fos
expression in kisspeptin neurons.81 Additionally, desensiti-
zation of Kiss1R markedly reduces GnRH responsiveness to
senktide in monkeys, while similar desensitization of NK3R
does not impair GnRH responsiveness to kisspeptin.84
Moreover, a recent study suggests that continuous kisspeptin
infusion can restore pulsatile LH secretion in patients with
loss-of-function mutations of TAC3 or TACR3.85 Taken
together, these studies support the contention that NKB
primarily influences pulsatile GnRH secretion indirectly by
stimulating kisspeptin release.86,87
Endogenous Opioid Peptides
Endogenous opioid peptides (EOP), which include endor-
phins, enkephalins, and dynorphins, participate in myriad
processes such as motor activity, cognitive functions, water
and food intake, and regulation of neuroendocrine func-
tion.88 Most active EOPs share a common sequence (Tyr-
Gly-Gly-Phe-[Met or Leu]) at the amino-terminal, although
endorphins, enkephalins, and dynorphins are derived from
different precursor proteins that undergo regulated post-
translational processing (Fig. 1.13).89 Endorphins such as
β-endorphin are products of the precursor protein proopi-
omelanocortin (POMC). POMC can be preferentially pro-
cessed to produce adrenocorticotropin hormone (ACTH)
and β-lipotropin, as occurs in corticotropes (adenohypophy-
sis) under the control of corticotropin-releasing hormone
(CRH). However, in the hypothalamus, POMC processing
primarily yields β-endorphin and α-melanocyte-stimulating
hormone. Hypothalamic β-endorphin participates in the
regulation of reproduction, temperature, and cardiovas-
cular and respiratory functions, and it acts primarily via μ
(micro)-opioid receptors. Enkephalins are derived from
proenkephalin, and their primary functions appear to relate
to autonomic nervous system modulation, mainly via δ
(delta)-receptor activation. Dynorphins are products of the
precursor prodynorphin and act chiefly at κ (kappa)-opioid
receptors. Importantly, while β-endorphin, enkephalins, and
dynorphins acts primarily via μ-, δ-, and κ-opioid receptors,
each can act as agonists at more than one receptor subtype.
Numerous studies provide evidence that hypothalamic
opiates partly mediate sex steroid negative feedback on
GnRH release. For example, GnRH neurons express few if
any progesterone receptors, but β-endorphin concentrations
increase in hypophyseal blood during the luteal phase—when
sex steroids suppress GnRH secretion—in monkeys.90,91
Moreover, naloxone and naltrexone (opiate receptor antago-
nists acting primarily at μ- and κ-opioid receptors) increase
LH pulse frequency when administered to luteal phase
women92 or progestin-treated postmenopausal women.93
Similarly, morphine suppresses GnRH secretion from medio-
basal hypothalami isolated from fetal and adult humans—an
effect that is reversed by naloxone94; and chronic high-dose
opiate administration can cause hypogonadotropic hypogo-
nadism by suppressing GnRH and LH secretion.88
Several animal studies implicate dynorphin as a principal
mediator of progesterone negative feedback on GnRH pulse
frequency in females.95 For example, dynorphin neurons in
the arcuate nucleus co-localize with progesterone receptors
in ewes,96 and dynorphin-containing varicosities are closely
associated with GnRH neuron cell bodies in the mediobasal
hypothalamus.97 Progesterone treatment in ewes increases
dynorphin A concentrations in third ventricle cerebrospinal
fluid,98 and central infusion of dynorphin in goats reduces
volleys of multiple-unit activity in the mediobasal hypothala-
mus and reduces LH pulses.87 In luteal phase ewes, specific
κ-opioid receptor antagonists—but not antagonists to δ- or
μ-opioid receptors—reversed progesterone inhibition of LH
secretion and LH frequency when locally administered into
the mediobasal hypothalamus.97 However, other EOPs (e.g.,

Prodynorphin
Proenkephalin
Peptide F
POMC
γ-MSH
Leu Enkephalin
Met Enkephalin
FIGURE 1.13 Schematic of endogenous opiate precursors. POMC, proopiomelanocortin; MSH, melanocyte-stimulating hormone; CLIP,
­corticotropin-like intermediate lobe peptide; ACTH, adrenocorticotropic hormone; LPH, lipotropin. (From Akil H, et al. Endogenous opioids:
overview and current issues. Drug Alcohol Depend. 51:127–140, 1998.)
β-endorphin) in other hypothalamic areas may be involved
as well; for example, in the aforementioned study,97 κ- and
μ-receptor antagonists locally administered into the preoptic
area increased LH and LH pulse frequency.
Kisspeptin, Neurokinin B, Dynorphin (KNDy)
Neurons
In the arcuate nucleus, kisspeptin, NKB, and dynorphin are
frequently coexpressed in the same neuron. For example,
kisspeptin neurons in the arcuate nucleus have been found
to coexpress NKB and dynorphin in mice,86 goats,87 and
sheep.99 For convenience, and as a playful nod to kisspeptin
(namesake of Hershey’s chocolate KISSES®), such neurons
are increasingly being called KNDy neurons (Kisspeptin,
Neurokinin B, Dynorphin). Available data from human
autopsy studies are consistent: 77% of kisspeptin cell bodies
(and 56% of kisspeptin axon fibers) in the arcuate (infun-
dibular) nucleus coexpress NKB.71
Kisspeptin, Neurokinin B, Dynorphin (KNDy) neurons
in the arcuate nucleus form an extensively interconnected
network surrounding the third ventricle. KNDy axons also
appear to project to the median eminence: in rats, Kiss1/
NKB fibers from the arcuate nucleus project to the inter-
nal zone of the median eminence where they are in close
proximity to GnRH fibers.100 As with kisspeptin neurons,
KNDy neuron neuroanatomy exhibits sexual dimorphism in
sheep, possibly related to perinatal sex steroid exposure.75
As discussed further below, KNDy neurons appear to
be intimately involved with sex steroid feedback on GnRH
secretion, and some investigators have suggested that the
KNDy neuronal network represents a fundamental compo-
nent of the GnRH pulse generator, with NKB stimulating
and dynorphin inhibiting kisspeptin release.
CHAPTER 1 Neuroendocrinology of Reproduction 15
α-Neoendorphin
Dynorphin A
Dynorphin B
OctaPeptide HeptaPeptide
α-MSH β-MSH
CLIP
γ-LPH β-Endorphin
ACTH
β-LPH
Gonadotropin-Inhibitory Hormone
The role of gonadotropin-inhibitory hormone (GnIH)
and its orthologues, also called RF-amide related peptides
(RFRP), in the central control of reproduction has been
recently reviewed.101 Briefly, GnIH immunoreactive cells
have been identified in hypothalami of a number of species
including monkeys, and GnIH-immunoreactive fibers can
be found in close proximity to GnRH neurons and in the
median eminence. GnIH can reduce GnRH neuronal activ-
ity, and GnIH also appears to have hypophysiotropic actions
to directly inhibit pituitary gonadotropin release. A recent
study in sheep revealed reduced GnIH expression in the
preovulatory period in ewes, suggesting a reciprocal rela-
tionship with GnRH release, and infusion of GnIH blocked
the estrogen-induced LH surge.102 GnIH has also been
implicated in the regulation of food intake (increase), sexual
motivation (decrease), and the influence of stress on repro-
duction. In sum, a growing body of data suggests that GnIH
is an important factor controlling GnRH and gonadotropin
secretion in a number of animal species, although an under-
standing of its role in humans awaits further investigation.
The GnRH Pulse Generator
As described above, intermittent GnRH receptor stimu-
lation is an absolute requirement for physiological main-
tenance of gonadotropin secretion. Although the precise
basis of pulsatile GnRH release remains unclear, a number
of observations support the concept that neuronal systems
within the mediobasal hypothalamus effect pulsatile release
of GnRH into the hypophyseal portal system. In animal
models, volleys of multiple unit electrical activity (i.e.,
detection of activity in multiple neurons near an electrode)
16 PART 1 Endocrinology of Reproduction
250
150
MUA (spikes/min)
LH (ng/mL)
50
3000
2000
1000
0
0 120 240 360 480
Time (min)
FIGURE 1.14 Temporal association between volleys of multiple unit
activity (MUA) in the hypothalamus and luteinizing hormone (LH)
pulses (green) detected in peripheral blood in an ovariectomized
monkey. (Adapted from Knobil E. The electrophysiology of the GnRH pulse
generator in the rhesus monkey. J Steroid Biochem 33:669–671, 1989.)
in the mediobasal hypothalamus coincide with the initia-
tion of LH pulse secretion (Fig. 1.14).103 Similarly, elec-
trical stimulation via electrodes placed in the mediobasal
hypothalamus stimulates GnRH release into the hypophy-
seal portal system in monkeys.104 Mediobasal hypothalami
isolated from fetal (20 to 23 weeks gestation) and adult
humans release GnRH in discrete pulses, with a frequency
of approximately one pulse per 60 to 100 minutes94; and
mediobasal hypothalami separated from the remainder
of the brain can maintain pulsatile LH secretion in mon-
keys.105 Lastly, selective radiofrequency ablation of the
arcuate nucleus (part of the mediobasal hypothalamus) in
adult female monkeys obliterates gonadotropin secretion.106
These data suggest that the mediobasal hypothalamus, the
arcuate nucleus in particular, houses all requisite compo-
nents for GnRH pulse generation (i.e., the GnRH pulse
generator) and that pulsatile GnRH release does not require
innervation from outside of the mediobasal hypothalamus.
Nonetheless, mechanisms underlying episodic GnRH pulse
generation, and what neuroanatomical components consti-
tute the GnRH pulse generator, are uncertain.
Several studies suggest that pulsatility is an intrinsic
property of GnRH neurons. For example, pulsatile GnRH
release is exhibited by immortalized GnRH-secreting neu-
rons107,108 and by cultured GnRH neurons obtained from
fetal rats, sheep, and monkeys.109-111 If GnRH pulse genera-
tion is an intrinsic property of GnRH neurons, then coordi-
nation of GnRH release could be facilitated by cell-to-cell
interconnections among GnRH neurons.112,113
Recent data suggest that afferent inputs (e.g., kisspeptin
neurons) are important for normal GnRH secretion, and
some investigators have suggested that kisspeptin (KNDy)
neurons represent a key component of the GnRH pulse
generator, with NKB and dynorphin influencing kisspeptin
stimulation of GnRH neurons. As described above, volleys
of multiunit activity in the arcuate nucleus are temporally
associated with LH pulses; however, in addition to GnRH
neurons, the arcuate nucleus contains numerous kisspeptin
(KNDy) neurons. Also, kisspeptin release into the hypophy-
seal portal circulation appears to be pulsatile in sheep and
monkeys. Although these kisspeptin pulses were not clearly
coincident with peripheral LH pulses in ovariectomized
ewes,114 kisspeptin pulses occurred approximately once per
hour and corresponded to GnRH pulses 75% of the time in
midpubertal rhesus monkeys.115
Although kisspeptin administration did not influence the
frequency of LH pulses or volleys of multiple unit electrical
activity in the arcuate nucleus in one rat study,116 admin-
istration of a selective kisspeptin antagonist into the arcu-
ate nucleus suppressed LH pulse frequency in another.117
Also, central administration of dynorphin in goats inhibits
both MUA volleys in the mediobasal hypothalamus and pul-
satile LH release, whereas NKB provokes MUA volleys.87
Human studies also imply that kisspeptin may play a role
in the GnRH pulse generator. For example, continuous
intravenous infusion of a relatively low-dose of kisspeptin
can increase LH pulse frequency in adult men.118 Another
recent study in adult men suggested that a single injection
of kisspeptin may reset the GnRH pacemaker.119 In the lat-
ter study, the interval between the kisspeptin-induced LH
pulse and the immediately preceding endogenous LH pulse
was variable, but on average shorter than the normal LH
interpulse interval (as expected). In contrast, the interval
between the kisspeptin-induced LH pulse and the subse-
quent endogenous LH pulse was similar to normal inter-
pulse intervals (circa 2 hours), suggesting that kisspeptin
administration reset the hypothalamic GnRH clock.
Hypothetical models regarding how KNDy neurons may
be involved with GnRH pulse generation are shown in Figure
1.15. However, some data suggest that kisspeptin may not be
requisite for GnRH pulse generation. In particular, frequent
sampling studies reveal that humans with KISSR mutations
demonstrate pulsatile LH release, albeit at low amplitude.53,120
Similarly, a recent study suggested that puberty occurs and
fertility is preserved in female mice with either (a) congeni-
tal absence of kisspeptin neurons or (b) congenital absence of
neurons expressing Kiss1R.57 When taken as a whole, avail-
able data imply that kisspeptin action may not be an absolute
requirement for pulsatile GnRH secretion, but that kisspeptin
is required for normal GnRH pulse secretion and normally
exerts an important influence on GnRH pulse generation.
Physiologic Development of Reproductive
Neuroendocrine Function
Patterns of GnRH secretion change markedly across
human development. Reproductive neuroendocrine events
throughout early maturation, including both before and
during the establishment of reproductive competence, are
discussed in detail in Chapter 18. Briefly, GnRH and gonad-
otropin secretion is robust in utero, peaking in midgesta-
tion. In males, gonadotropin secretion markedly stimulates
testicular androgen secretion, which is important for nor-
mal genital differentiation. The gestational increase of sex
steroid (e.g., estradiol) production from the fetoplacental
unit provides negative feedback to limit fetal GnRH and
gonadotropin secretion. Birth is followed by a marked but
transient (3 to 9 month) increase of GnRH and gonado-
tropin secretion (the “mini-puberty of infancy”), perhaps
related to the withdrawal of fetoplacental sex steroids.
 CHAPTER 1 Neuroendocrinology of Reproduction 17

Kisspeptin/NKB/Dyn
Neuron

Pulse onset: ↑NKB→↑NKB Kisspeptin 

Pulse termination: NKB
Dyn 
KNDy ↑NKB→↑Dyn
 GnRH
GnRH
KNDy Kiss1r (kisspeptin receptor) Arcuate
GnRH 
 NK3R (NKB receptor)
 KOR (Dyn receptor)
GnRH (pg/min)

30

20 GnRH
Neuron ?
10  
0 Median
0 0.5 1.0 1.5 2.0
Eminence
A TIME (hr) B
FIGURE 1.15 Working model regarding how KNDy neurons may participate in the generation of GnRH pulses proposed by Lehman and col-
leagues (A) and Wakabayashi and colleagues (B). A, By this model, neurokinin B (NKB, magenta) stimulates and dynorphin (DYN, red) sup-
presses kisspeptin release, with kisspeptin (green) stimulating GnRH neuronal firing. The onset of a GnRH pulse is triggered by an initial increase
of NKB, which stimulates further NKB release (positive feedback loop) and increases kisspeptin output. NKB stimulation of KNDy neurons also
stimulates DYN release; and after a short period of time, the increase of DYN suppresses kisspeptin (and NKB) release. This withdrawal of kis-
speptin stimulation terminates the GnRH pulse. (From Lehman MN, Coolen LM, Goodman RL. Minireview: kisspeptin/neurokinin B/dynorphin (KNDy)
cells of the arcuate nucleus: a central node in the control of gonadotropin-releasing hormone secretion. Endocrinology. 151:3479–3489, 2010.) B, By
this model, KNDy neurons in the arcuate nucleus form a neural circuit, within which neurokinin B (NKB, magenta) accelerates and dynorphin
(Dyn, red) reduces KNDy neuron activation. These reciprocal effects of NKB and Dyn produce episodic activation of KNDy neurons, with KNDy
neuronal activation increasing kisspeptin release at the median eminence. Kisspeptin in turn stimulates GnRH release into the hypophyseal portal
system. KOR, kappa opiate receptor. (Adapted from Lehman MN et al. Minireview: kisspeptin/neurokinin B/dynorphin (KNDy) cells of the arcuate
nucleus: a central node in the control of gonadotropin-releasing hormone secretion. Endocrinology, 151:3479-3489, 2010; and Wakabayashi Y et al.
Neurokinin B and dynorphin A in kisspeptin neurons of the arcuate nucleus participate in generation of periodic oscillation of neural activity driving
p­ulsatile gonadotropin-releasing hormone secretion in the goat. J Neurosci. 30:3124-3132, 2010.)

A marked sex difference of gonadotropin release is evident
at this time, with LH concentrations being higher in males
and FSH levels higher in females. The possibility that kiss­
peptin is important for the minipuberty of infancy is sug-
gested by a patient with a compound heterozygote mutation
of KISSR, who had micropenis, undescended testes, and
undetectable serum gonadotropins at 2 months of age—a
time usually marked by robust gonadotropin secretion.121
By late infancy or early childhood (earlier in boys than
in girls), GnRH and gonadotropin secretion markedly
decreases, leading to a hypogonadotropic phase of child-
hood marked by low sex steroid concentrations—the “juve-
nile pause.” Studies of gonadotropin secretion in children
reveal low LH and FSH concentrations, a high FSH-to-LH
ratio, and low LH pulse amplitude and frequency.122 Mech-
anisms accounting for low GnRH secretion during this time
appear to include inhibition of the GnRH pulse generator
(“neurobiological brake”) by higher-order neuronal systems
(e.g., involving γ-aminobutyric acid [GABA]- and neuro-
peptide Y-secreting neurons) and a developmental removal
of stimulation (e.g., involving neurons secreting glutamate
and norepinephrine).
Near the close of the first decade, a marked nocturnal
amplification of pulsatile LH secretion indicates the neu-
roendocrine beginnings of puberty. A majority of studies
suggest that early pubertal subjects demonstrate sleep-
entrained increases of LH (GnRH) pulse frequency and
amplitude.123 Gonadotropin concentrations rise across
puberty,124,125 stimulating gametogenesis, gonadal sex ste-
roid secretion, and the development of secondary sexual
characteristics. Mechanisms underlying puberty are poorly
understood, but likely reflect developmental remodeling
of inhibitory and stimulatory neural circuits in the hypo-
thalamus. For example, puberty has been associated with
reductions of GABAergic inhibitory neurotransmission and
an increase of excitatory neurotransmitters such as gluta-
mate. Kisspeptin and NKB also appear to play important
roles in human puberty, as inactivating mutations of KISS1,
KISS1R, TAC3, or TACR3 result in pubertal failure; and a
gain of function KISS1R mutation has been reported as a
cause of central precocious puberty.126 In addition to these
transsynaptic mechanisms, neuroglial cells may contribute
to the pubertal reactivation of GnRH secretion (e.g., by
secretion of growth factors).1
Patterns of Pulsatile GnRH Secretion in Adults
Human studies employing frequent blood sampling and
pulse detection analysis have documented significant
changes of LH (and by inference GnRH) pulse frequency
throughout ovulatory cycles. Briefly, average LH (GnRH)
pulse frequency is around one pulse every 90 minutes in the
early follicular phase, and this gradually increases to approx-
imately one pulse per hour by the late follicular phase.
Although monkey studies suggest that GnRH pulse fre-
quency slows during the mid-cycle surge,127 human studies
suggest no change in either LH or α-subunit pulse frequency
at midcycle.128,129 LH pulse frequency slows markedly dur-
ing the luteal phase, approximating one pulse every 3 to
8 hours. These day-to-day changes of GnRH pulse frequency
appear to be important for normal hormonal changes across
ovulatory cycles.130,131
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have been sufficiently described above (p. 55), and it remains only to
be mentioned that the bones of the palatine arch are but rarely
absent, as for instance in Murænophis; and that the symplectic does
not extend to the articulary of the mandible, as in Amia and
Lepidosteus, though its suspensory relation to the Meckelian
cartilage is still indicated by a ligament which connects the two
pieces. Of the mandibulary bones the articulary (35) is distinctly part
of Meckel’s cartilage. Frequently another portion of cartilage below
the articulary remains persistent, or is replaced by a separate
membrane-bone, the angular.
4. Membrane-bones of the alimentary portion of the visceral
skeleton of the skull.—The suspensorium has one tegumentary bone
attached to it, viz. the præoperculum (30); it is but rarely absent, for
instance in Murænophis. The premaxillary (17) and maxillary (18) of
the Teleostei appear to be also membrane-bones, although they are
clearly analogous to the upper labial cartilages of the Sharks. The
premaxillaries sometimes coalesce into a single piece (as in Diodon,
Mormyrus), or they are firmly united with the maxillaries (as in all
Gymnodonts, Serrasalmo, etc.) The relative position and connection
of these two bones differs much, and is a valuable character in the
discrimination of the various families. In some, the front margin of the
jaw is formed by the premaxillary only, the two bones having a
parallel position, as it has been described in the Perch (p. 53); in
others, the premaxillary is shortened, allowing the maxillary to enter,
and to complete, the margin of the upper jaw; and finally, in many no
part of the maxillary is situated behind the premaxillary, but the entire
bone is attached to the end of the premaxillary, forming its
continuation. In the last case the maxillary may be quite abortive.
The mobility of the upper jaw is greatest in those fishes in which the
premaxillary alone forms its margin. The form of the premaxillary is
subject to great variation: the beak of Belone, Xiphias is formed by
the prolonged and coalesced premaxillaries. The maxillary consists
sometimes of one piece, sometimes of two or three. The principal
membrane-bone of the mandible is the dentary (34), to which is
added the angular (36) and rarely a smaller one, the splenial or os
operculare, which is situated at the inside of the articulary.
 5. Cartilage-bones of the respiratory portion of the visceral
skeleton of the skull.—With few exceptions all the ossifications of the
hyoid and branchial arches, as described above (p. 58), belong to
this group.
6. Membrane-bones of the respiratory portion of the visceral
skeleton of the skull.—They are the following: the opercular pieces,
viz. operculum (28), sub-operculum (32), and interoperculum (33).
The last of these is the least constant; it may be entirely absent, and
represented by a ligament extending from the mandible to the hyoid.
The urohyal (42) which separates the musculi sternohyoidei, and
serves for an increased surface of their insertion; and finally the
branchiostegals (43), which vary greatly in number, but are always
fixed to the cerato- and epi-hyals.
7. Dermal bones of the skull.—To this category are referred some
bones which are ossifications of, and belong to, the cutis. They are
the turbinals (20), the suborbitals (19), and the supratemporals. They
vary much with regard to the degree in which they are developed,
and are rarely entirely absent. Nearly always they are wholly or
partly transformed into tubes or hollows, in which the muciferous
canals with their numerous nerves are lodged. Those in the temporal
and scapulary regions are not always developed; on the other hand,
the series of those ossicles may be continued on to the trunk,
accompanying the lateral line. In many fishes those of the infraorbital
ring are much dilated, protecting the entire space between the orbit
and the rim of the præoperculum; in others, especially those which
have the angle of the præoperculum armed with a powerful spine,
the infraorbital ring emits a process towards the spine, which thus
serves as a stay or support of this weapon (Scorpænidæ, Cottidæ).
The pectoral arch of the Teleosteous fishes exhibits but a
remnant of a primordial cartilage, which is replaced by two
ossifications,[10] the coracoid (51) and scapula (52); they offer
posteriorly attachment to two series of short rods, of which the
proximal are nearly always ossified, whilst the distal frequently
remain small cartilaginous nodules hidden in the base of the pectoral
rays. The bones, by which this portion is connected with the skull,
are membrane-bones, viz. the clavicle (49), with the postclavicle (49
+ 50), the supraclavicle (47), and post-temporal (46). The order of
their arrangement in the Perch has been described above (p. 59).
However, many Teleosteous fish lack pectoral fins, and in them the
pectoral arch is frequently more or less reduced or rudimentary, as in
many species of Murænidæ. In others the membrane-bones are
exceedingly strong, contributing to the outer protective armour of the
fish, and then the clavicles are generally suturally connected in the
median line. The postclavicula and the supraclavicula may be
absent. Only exceptionally the shoulder-girdle is not suspended from
the skull, but from the anterior portion of the spinous column
(Symbranchidæ, Murænidæ, Notacanthidæ). The number of basal
elements of each of the two series never exceeds five, but may be
less; and the distal series is absent in Siluroids.
The pubic bones of the Teleosteous fishes undergo many
modifications of form in the various families, but they are essentially
of the same simple type as in the Perch.
 CHAPTER V.

MYOLOGY.

In the lowest vertebrate, Branchiostoma, the whole of the

muscular mass is arranged in a longitudinal band running along each
side of the body; it is vertically divided into a number of flakes or
segments (myocommas) by aponeurotic septa, which serve as the
surfaces of insertion to the muscular fibres. But this muscular band
has no connection with the notochord except in its foremost portion,
where some relation has been formed to the visceral skeleton. A
very thin muscular layer covers the abdomen.
Also in the Cyclostomes the greatest portion of the muscular
system is without direct relation to the skeleton, and, again, it is only
on the skull and visceral skeleton where distinct muscles have been
differentiated for special functions.
To the development of the skeleton in the more highly organised
fishes corresponds a similar development of the muscles; and the
maxillary and branchial apparatus, the pectoral and ventral fins, the
vertical fins, and especially the caudal, possess a separate system
of muscles. But the most noteworthy is the muscle covering the
sides of the trunk and tail (already noticed in Branchiostoma), which
Cuvier described as the “great lateral muscle,” and which, in the
higher fishes, is a compound of many smaller segments,
corresponding in number with the vertebræ. Each lateral muscle is
divided by a median longitudinal groove into a dorsal and ventral
half; the depression in its middle is filled by an embryonal muscular
substance which contains a large quantity of fat and blood-vessels,
and therefore differs from ordinary muscle by its softer consistency,
and by its colour which is reddish or grayish. Superficially the lateral
muscle appears crossed by a number of white parallel tendinous zig-
zag stripes, forming generally three angles, of which the upper and
lower point backwards, the middle one forwards. These are the outer
edges of the aponeurotic septa between the myocommas. Each
septum is attached to the middle and the apophyses of a vertebra,
and, in the abdominal region, to its rib; frequently the septa receive
additional support by the existence of epipleural spines. The fibres of
each myocomma run straight and nearly horizontally from one
septum to the next; they are grouped so as to form semiconical
masses, of which the upper and lower have their apices turned
backwards, whilst the middle cone, formed by the contiguous parts
of the preceding, has its apex directed forward; this fits into the
interspace between the antecedent upper and lower cones, the
apices of which reciprocally enter the depressions in the succeeding
segment, whereby all the segments are firmly locked together
(Owen).
In connection with the muscles reference has to be made to the
Electric organs with which certain fishes are provided, as it is more
than probable, not only from the examination of peculiar muscular
organs occurring in the Rays, Mormyrus, and Gymnarchus (the
function of which is still conjectural), but especially from the
researches into the development of the electric organ of Torpedo,
that the electric organs have been developed out of muscular
substance. The fishes possessing fully developed electric organs,
with the power of accumulating electric force and communicating it in
the form of shocks to other animals, are the electric Rays
(Torpedinidæ), the electric Sheath-fish of tropical Africa
(Malapterurus), and the electric Eel of tropical America (Gymnotus).
The structure and arrangement of the electric organ is very different
in these fishes, and will be subsequently described in the special
account of the several species.
The phenomena attending the exercise of this extraordinary
faculty also closely resemble muscular action. The time and strength
of the discharge are entirely under the control of the fish. The power
is exhausted after some time, and it needs repose and nourishment
to restore it. If the electric nerves are cut and divided from the brain
the cerebral action is interrupted, and no irritant to the body has any
effect to excite electric discharge; but if their ends be irritated the
discharge takes place, just as a muscle is excited to contraction
under similar circumstances. And, singularly enough, the application
of strychnine causes simultaneously a tetanic state of the muscles
and a rapid succession of involuntary electric discharges. The
strength of the discharges depends entirely on the size, health, and
energy of the fish: an observation entirely agreeing with that made
on the efficacy of snake-poison. Like this latter, the property of the
electric force serves two ends in the economy of the animals which
are endowed with it; it is essential and necessary to them for
overpowering, stunning, or killing the creatures on which they feed,
whilst incidentally they use it as the means of defending themselves
from their enemies.
 CHAPTER VI.

NEUROLOGY.

The most simple condition of the nervous central organ known in

Vertebrates is found in Branchiostoma. In this fish the spinal chord
tapers at both ends, an anterior cerebral swelling, or anything
approaching a brain, being absent. It is band-like along its middle
third, and groups of darker cells mark the origins of the fifty or sixty
pairs of nerves which accompany the intermuscular septa, and
divide into a dorsal and ventral branch, as in other fishes. The two
anterior pairs pass to the membranous parts above the mouth, and
supply with nerve filaments a ciliated depression near the extremity
of the fish, which is considered to be an olfactory organ, and two
pigment spots, the rudiments of eyes. An auditory organ is absent.
The spinal chord of the Cyclostomes is flattened in its whole
extent, band-like, and elastic; also in Chimæra it is elastic, but
flattened in its posterior portion only. In all other fishes it is
cylindrical, non-ductile, and generally extending along the whole
length of the spinal canal. The Plectognaths offer a singular
exception in this respect that the spinal chord is much shortened, the
posterior portion of the canal being occupied by a long cauda
equina; this shortening of the spinal chord has become extreme in
the Sun-fish (Orthagoriscus), in which it has shrunk into a short and
conical appendage of the brain. Also in the Devil-fish (Lophius) a
long cauda equina partly conceals the chord which terminates on the
level of about the twelfth vertebra.
The brain of fishes is relatively small; in the Burbot (Lota) it has
been estimated to be 1/720th part of the weight of the entire fish, in
the Pike the 1/1305th part, and in the large Sharks it is relatively still
smaller. It never fills the entire cavity of the cranium; between the
dura mater which adheres to the inner surface of the cranial cavity,
and the arachnoidea which envelops the brain, a more or less
considerable space remains, which is filled with a soft gelatinous
mass generally containing a large quantity of fat. It has been
observed that this space is much less in young specimens than in
adult, which proves that the brain of fishes does not grow in the
same proportion as the rest of the body; and, indeed, its size is
nearly the same in individuals of which one is double the bulk of the
other.

Fig. 41.—Brain of Perch.

I. Upper aspect. II. Lower aspect.
a, cerebellum; b, optic lobes; c, hemispheres; e, lobi inferiores; f, hypophysis; g,
lobi posteriores; i, Olfactory lobes; n, N. opticus; o, N. olfactorius; p, N. oculo-
motorius; q, N. trochlearis; r, N. trigeminus; s, N. acusticus; t, N. vagus; u, N.
abducens; v, Fourth ventricle.
The brain of Osseous fishes (Fig. 41) viewed from above shows
three protuberances, respectively termed prosencephalon,
mesencephalon, and metencephalon, the two anterior of which are
paired, the hindmost being single. The foremost pair are the
hemispheres, which are solid in their interior, and provided with two
swellings in front, the olfactory lobes. The second pair are the optic
lobes, which generally are larger than the hemispheres, and
succeeded by the third single portion, the cerebellum. In the fresh
state the hemispheres are of a grayish colour, and often show some
shallow depressions on their surface; a narrow commissure of white
colour connects them with each other. The optic lobes possess a
cavity (ventriculus lobioptici), at the bottom of which some
protuberances of variable development represent the corpora
quadrigemina of higher animals. On the lower surface of the base of
the optic lobes, behind the crura cerebri, two swellings are observed,
the lobi inferiores, which slightly diverge in front for the passage of
the infundibulum, from which a generally large hypophysis or
pituitary gland is suspended. The relative size of the cerebellum
varies greatly in the different osseous fishes: in the Tunny and
Silurus it is so large as nearly to cover the optic lobes; sometimes
distinct transverse grooves and a median longitudinal groove are
visible. The cerebellum possesses in its interior a cavity which
communicates with the anterior part of the fourth ventricle. The
medulla oblongata is broader than the spinal chord, and contains the
fourth ventricle, which forms the continuation of the central canal of
the spinal chord. In most fishes a perfect roof is formed over the
fourth ventricle by two longitudinal pads, which meet each other in
the median line (lobi posteriores), and but rarely it remains open
along its upper surface.
The brain of Ganoid fishes shows great similarity to that of the
Teleostei; however, there is considerable diversity of the
arrangement of its various portions in the different types. In the
Sturgeons and Polypterus (Fig. 42) the hemispheres are more or
less remote from the mesencephalon, so that in an upper view the
crura cerebri, with the intermediate entrance into the third ventricle
(fissura cerebri magna), may be seen. A vascular membranous sac,
containing lymphatic fluid (epiphysis), takes its origin from the third
ventricle, its base being expanded over the anterior interspace of the
optic lobes, and the apex being fixed to the cartilaginous roof of the
cranium. This structure is not peculiar to the Ganoids, but found in
various stages of development in Teleosteans, marking, when
present, the boundary between prosencephalon and
mesencephalon. The lobi optici are essentially as in Teleosteans.
The cerebellum penetrates into the ventriculus lobi optici, and
extends thence into the open sinus rhomboidalis. At its upper
surface it is crossed by a commissure formed by the corpora
restiformia of the medulla.
 Fig. 42.—Brain of Polypterus. (After Müller.)
I., Upper; II., Lateral; III., Lower aspect.
a, Medulla; b, corpora restiformia; c, cerebellum; d, lobi optici; e, hypophysis; f,
fissura cerebri magna; g, nervus opticus; g’, chiasma; h, hemispheres; i, lobus
olfactorius; k, sinus rhomboidalis (fourth ventricle).
As regards external configuration, the brain of Lepidosteus and
Amia approach still more the Teleosteous type. The prosencephalon,
mesencephalon, and metencephalon are contiguous, and the
cerebellum lacks the prominent transverse commissure at its upper
surface. The sinus rhomboidalis is open.
The brain of the Dipnoi shows characters reminding us of that of
the Ganoids as well as the Chondropterygians, Ceratodus agreeing
with Protopterus in this respect, as in most other points of its
organisation. The hemispheres form the largest part of the brain;
they are coalescent, as in Sharks, but possess two lateral ventricles,
the separation being externally indicated by a shallow median
groove on the upper surface. The olfactory lobes take their origin
from the upper anterior end of the hemispheres. Epiphysis and
hypophysis well developed. The lobi optici are very small, and
remote from the prosencephalon, their division into the lateral halves
being indicated by a median groove only. The cerebellum is very
small, overlying the front part of the sinus rhomboidalis.

Fig. 43.—Brain of Carcharias. (After Owen.)

ac, Nerv. acusticus; b, corpus restiforme; c, cerebellum; d, lobus opticus; e,
hypophysis; g, nervus opticus; h, hemisphere; i, lobus olfactorius; i’, olfactory
pedicle; k, nerv. olfactorius; l, epiphysis; m, nerv. oculo-motorius; tr, nerv.
trigeminus; v, nerv. vagus.
The brain of Chondropterygians (Fig. 43) is more developed than
that of all other fishes, and distinguished by well-marked characters.
These are, first, the prolongation of the olfactory lobes into more or
less long pedicles, which dilate into great ganglionic masses, where
they come into contact with the olfactory sacs; secondly, the space
which generally intervenes between prosencephalon and
mesencephalon, as in some Ganoids; thirdly, the large development
of the metencephalon.
The hemispheres are generally large, coalescent, but with a
median, longitudinal, dividing groove. Frequently their surface shows
traces of gyrations, and when they are provided with lateral
ventricles, tubercles representing corpora striata may be observed.
The olfactory pedicles take their origin from the side of the
hemispheres, and are frequently hollow, and if so, their cavity
communicates with the ventricle of the hemisphere. The optic lobes
are generally smaller than the hemispheres, coalescent, and
provided with an upper median groove like the prosencephalon. At
their base a pair of lobi inferiores are constant, with the hypophysis
and sacsus vasculosus (a conglomeration of vascular loops without
medullary substance) between them.
The cerebellum is very large, overlying a portion of the optic
lobes and of the sinus rhomboidalis, and is frequently transversely
grooved. The side-walls of the fourth ventricle, which are formed by
the corpora restiformia, are singularly folded, and appear as two
pads, one on each side of the cerebellum (lobi posteriores s. lobi
nervi trigemini).
 Fig. 44.—Brain of Bdellostoma. (Enlarged, after
Müller.)
I., Upper; II., Lower aspect. Letters as in Fig. 45.
 Fig. 45.—Brain of Petromyzon. (Enlarged,
after Müller.)
I., Upper; II., Lower aspect.
a, Medulla oblongata; ac, nerv. acusticus; b,
corpus restiforme or rudimentary
cerebellum; d, lobus ventriculi tertii; d’,
entrance into the third ventricle; c,
hypophysis; fa, nerv. facialis; g, nerv.
opticus; h, hemisphere; hy, nerv.
hypoglossus (so named by Müller); i, lobus
olfactorius; k, sinus rhomboidalis; l,
 epiphysis; m, nerv. oculo-motorius; q,
corpora quadrigemina; tr, nerv. trigeminus;
tro, nerv. trochlearis; v, nerv. vagus.
The brain of the Cyclostomes (Figs. 44, 45) represents a type
different from that of other fishes, showing at its upper surface three
pairs of protuberances in front of the cerebellum; they are all solid.
Their homologies are not yet satisfactorily determined, parts of the
Myxinoid brain having received by the same observers
determinations very different from those given to the corresponding
parts of the brain of the Lampreys. The foremost pair are the large
olfactory tubercles, which are exceedingly large in Petromyzon. They
are followed by the hemispheres, with a single body wedged in
between their posterior half; in Petromyzon, at least, the vascular
tissue leading to an epiphysis seems to be connected with this body.
Then follows the lobus ventriculi tertii, distinctly paired in Myxinoids,
less so in Petromyzon. The last pair are the corpora quadrigemina.
According to this interpretation the cerebellum would be absent in
Myxinoids, and represented in Petromyzon by a narrow commissure
only (Fig. 45, b), stretching over the foremost part of the sinus
rhomboidalis. In the Myxinoids the medulla oblongata ends in two
divergent swellings, free and obtuse at their extremity, from which
most of the cerebral nerves take their origin.
The Nerves which supply the organs of the head are either
merely continuations or diverticula of the brain-substance, or proper
nerves taking their origin from the brain, or receiving their constituent
parts from the foremost part of the spinal chord. The number of
these spino-cerebral nerves is always less than in the higher
vertebrates, and their arrangement varies considerably.
A. Nerves which are diverticula of the brain (Figs. 41–45).
The olfactory nerves (first pair) always retain their intimate
relation to the hemispheres, the ventricles of which are not rarely
continued into the tubercle or even pedicle of the nerves. The
different position of the olfactory tubercle has been already
described as characteristic of some of the orders of fishes. In those
fishes in which the tubercle is remote from the brain, the nerve which
has entered the tubercle as a single stem leaves it split up into
several or numerous branches, which are distributed in the nasal
organ. In the other fishes it breaks up into branchlets spread into a
fan-like expansion at the point, where it enters the nasal cavity. The
nerve always passes out of the skull through the ethmoid.
The optic nerves (second pair) vary in size, their strength
corresponding to the size of the eye; they take their origin from the
lobi optici, the development of which again is proportionate to that of
the nerves. The mutual relation of the two nerves immediately after
their origin is very characteristic of the sub-classes of fishes. In the
Cyclostomes they have no further connection with each other, each
going to the eye of its own side.[11] In the Teleostei they simply cross
each other (decussate), so that the one starting from the right half of
the brain goes to the left eye and vice versa. Finally, in Palæichthyes
the two nerves are fused together, immediately after their origin, into
a chiasma. The nerve is cylindrical for some portion of its course, but
in most fishes gradually changes this form into that of a plaited band,
which is capable of separation and expansion. It enters the bulbus
generally behind and above its axis. The foramen through which it
leaves the skull of Teleostei is generally in a membranous portion of
its anterior wall, or, where ossification has taken place, in the orbito-
sphenoid.
B. Nerves proper taking their origin from the brain
(Figs. 41–45).
The Nervus oculorum motorius (third pair) takes its origin from
the Pedunculus cerebri, close behind the lobi inferiores; it escapes
through the orbito-sphenoid, or the membrane replacing it, and is
distributed to the musculi rectus superior, rectus internus, obliquus
inferior, and rectus inferior. Its size corresponds to the development
of the muscles of the eye. Consequently it is absent in the blind
Amblyopsis, and the Myxinoids. In Lepidosiren the nerves supplying
the muscles of the eye have no independent origin, but are part of
the ophthalmic division of the Trigeminus. In Petromyzon these
muscles are supplied partly from the Trigeminus, partly by a nerve
representing the Oculo-motor and Trochlearis, which are fused into a
common trunk.
 The Nervus trochlearis (fourth pair), if present with an
independent origin, is always thin, taking its origin on the upper
surface of the brain from the groove between lobus opticus and
cerebellum; it goes to the Musculus obliquus superior of the eye.
C. Nerves taking their origin from the Medulla oblongata (Figs.
41–45).
The Nervus abducens (sixth pair) issues on the lower surface of
the brain, taking its origin from the anterior pyramids of the Medulla
oblongata, and supplies the Musculus rectus externus of the eye,
and the muscle of the nictitating membrane of Sharks.
The Nervus trigeminus (fifth pair) and the Nervus facialis
(seventh pair) have their origins close together, and enter into
intimate connection with each other. In the Chondropterygians and
most Teleostei the number of their roots is four, in the Sturgeons five,
and in a few Teleostei three. When there are four, the first issues
immediately below the cerebellum from the side of the Medulla
oblongata; it contains motory and sensory elements for the maxillary
and suspensorial muscles, and belongs exclusively to the trigeminal
nerve. The second root, which generally becomes free a little above
the first, supplies especially the elements for the Ramus palatinus,
which sometimes unites with parts of the Trigeminal, sometimes with
the Facial nerve. The third root, if present, is very small, and issues
immediately in front of the acustic nerve, and supplies part of the
motor elements of the facial nerve. The fourth root is much stronger,
sometimes double, and its elements pass again partly into the
Trigeminal, partly into the Facial nerve. On the passage of these
stems through the skull (through a foramen or foramina in the
alisphenoid) they form a ganglionic plexus, in which the palatine
ramus and the first stem of the Trigeminus generally possess
discrete ganglia. The branches which issue from the plexus and
belong exclusively to the Trigeminus, supply the organs and
integuments of the frontal, ophthalmic, and nasal regions, and the
upper and lower jaws with their soft parts. The Facial nerve supplies
the muscles of the gill-cover and suspensorium, and emits a strong
branch accompanying the Meckelian cartilage to the symphysis, and
another for the hyoid apparatus.
 The Nervus acusticus (eighth pair) is strong, and takes its origin
immediately behind, and in contact with, the last root of the seventh
pair.
The Nervus glossopharyngeus (ninth pair)[12] takes its origin
between the roots of the eighth and tenth nerves, and issues in
Teleostei from the cranial cavity by a foramen of the exoccipital. In
the Cyclostomes and Lepidosiren it is part of the Nervus vagus. It is
distributed in the pharyngeal and lingual regions, one branch
supplying the first branchial arch. After having left the cranial cavity it
swells into a ganglion, which in Teleostei is always in communication
with the sympathic nerve.
The Nervus vagus or pneumogastricus (tenth pair) rises in all
Teleostei and Palæichthyes with two discrete strong roots: the first
constantly from the swellings of the corpora restiformia, be they
thinner or thicker and overlying the sinus rhomboidalis, or be they
developed into lateral plaited pads, as in Acipenser and
Chondropterygians. The second much thicker root rises from the
lower tracts of the medulla oblongata. Both stems leave the cranial
cavity by a common foramen, situated in Teleosteous fishes in the
exoccipital; and form ganglionic swellings, of which those of the
lower stem are the more conspicuous. The lower stem has mixed
elements, motory as well as sensory, and is distributed to the
muscles of the branchial arches and pharynx, the œsophagus and
stomach; it sends filaments to the heart and to the air-bladder where
it exists. The first (upper) stem forms the Nervus lateralis. This
nerve, which accompanies the lateral mucous system of the trunk
and tail, is either a single longitudinal stem, gradually becoming
thinner behind, running superficially below the skin (Salmonidæ,
Cyclopterus), or deeply between the muscles (Sharks, Chimæra), or
divided into two parallel branches (most Teleostei): thus in the Perch
there are two branches on each side, the superficial of which
supplies the lateral line, whilst the deep-seated branch
communicates with the spinal nerves and supplies the septa
between the myocommas and the skin. In fishes which lack the
lateral muciferous system and possess hard integuments, as the
Ostracions, the lateral nerve is more or less rudimentary. It is entirely