Human Reproductive Biology. ISBN 9780123821843, 978-0123821843

Human Reproductive Biology
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Dedication
To my wife, Betty, and my four sons,

Evan, Ryan, Peter, and Christopher
REJ
To Tom, Jessica, and Sophia
KHL
Preface
A new contraceptive in the works! Hormone replacement the evolution of human reproduction. We have chosen
therapy for menopause increases the risk of heart disease! illustrations and tables that offer clear examples of phe-
Anabolic steroids linked to psychiatric disorders! Headlines nomena discussed in the text. The figures are in full color
such as these appear in the media almost every day to help the student interpret and understand the struc-
as advances in the field of human reproductive biol- ture and function of the reproductive system. Within
ogy are made. Reproductive biology and biomedicine the text, key terms are italicized the first time they are
are of primary concern to people of all ages, includ- used and are also defined in the Glossary. Scientific refer-
ing (perhaps especially) college students. One goal ences at the end of each chapter have been expanded to
of this fourth edition of Human Reproductive Biology is help the student research a topic for writing term papers
to give students a solid foundation in understanding or to follow up on a topic of interest in the literature.
the human reproductive system so they can critically A dedicated student in a class using this text should
evaluate and interpret new findings as they prepare for know and understand more about human reproduction
careers in reproductive biology and medicine, or for than about 95% of adults! This book will help prepare
their own personal interest. students who are considering careers as health care pro-
Scientific research in this area is proceeding with great fessionals or biomedical researchers. The students will
rapidity. The time between publication of the third edi- also derive benefits in their personal lives, regardless of
tion of Human Reproductive Biology and the present (2014) career choice. It is our experience that a student would
has been loaded with new research findings that have need at least one year of college general biology to gain
had a profound influence on our basic understanding of the greatest benefit from taking a course using Human
this scientific discipline. In turn, advances in basic biol- Reproductive Biology.
ogy have had a major impact on the practice of reproduc- We are, by profession, reproductive biologists and
tive medicine. So the fourth edition is “pregnant” with endocrinologists, and we have used our training and
new information and has been updated throughout. Our knowledge to the best of our abilities to make this book
goal is to give you the latest available findings. as scientifically accurate and up-to-date as possible.
This book is meant to serve as the foundation for an Although we are not medical doctors, we have attempted
undergraduate course in reproductive biology or as a ref- to present valid medical information. However, we do
erence text for other courses including human physiol- not take legal responsibility for any medical information
ogy, sexuality, and medicine. The chapters progress from or advice in this book; readers should use medical infor-
the fundamentals of reproductive anatomy, physiology, mation and advice contained herein at their own risk,
and endocrinology to the application of this knowledge and should always check with their physicians regard-
in the understanding of pregnancy, the control of human ing any medical problems or treatments.
reproduction, and diseases of the reproductive system. We would like to extend our sincere appreciation to
All 17 chapters could be covered in a single survey the staff at Elsevier for their help and enthusiastic support
course, or a more in-depth two-course sequence could in the production of this fourth edition, especially Mara
cover the first half of the text as a fundamentals course Conner, Megan Wickline, and Caroline Johnson. A special
followed by the second half as an advanced course or warm thanks to our colleague and friend Dr. Leif Saul,
seminar. Because we have extensive experience in teach- who used his artistic skill and scientific knowledge to pro-
ing this subject to undergraduates, we have focused on vide us with the many new color figures in this edition.
features that add to the teaching value of the book. High-
light Boxes present intriguing topics of special interest, Richard E. Jones
and several of them encourage students to think about Kristin H. Lopez
xi
C H A P T E R
1
Endocrinology, Brain, and Pituitary Gland
INTRODUCTION endocrine cells secrete products called hormones and

release them into the adjacent tissue spaces. The hor-
To understand the biology of reproduction, we must mones then enter the bloodstream and are carried to
first meet the cast of characters involved in this fascinating other regions of the body to exert their effects. Hor-
process. In Chapters 2 and 4, we will study the anatomical mones are chemical messengers in that certain tissues in
components of the female and male reproductive systems. the body are signaled by specific hormones to grow or
However, you will discover that, to function properly, change their physiological activity.
these systems require chemical instructions. In fact, nearly The endocrine system consists of all the endocrine
every aspect of reproductive biology is regulated by inter- glands and isolated endocrine cells in the body. Included
nal molecular messengers called hormones. Reproductive in this system are the hypothalamus, pituitary gland
hormones signal the reproductive structures to grow and (or hypophysis), pineal gland, gonads (testes and ova-
mature. For example, as a boy approaches puberty, circu- ries), and placenta—all organs of primary importance in
lating levels of hormones called androgens rise and cause human reproduction. In addition, the endocrine system
his reproductive tract to mature. In addition, these hor- includes the thyroid, parathyroid, and adrenal glands,
mones induce muscle growth, cause changes in the vocal as well as hormone-secreting cells of diverse organs
cords that lower the young man’s voice, and initiate adult and tissues including the heart, digestive tract, kidneys,
patterns of body hair growth. Hormones also regulate the pancreas, thymus, and adipose tissue. Figure 1.1 depicts
timing of reproductive events. In women, the coordinated these components of the endocrine system.
release of several female hormones orchestrates ovulation, Endocrinology is the study of the endocrine glands
the release of an egg from the ovary, approximately every and their secretions. The science of endocrinology also
28 days. This chapter will introduce you to the endocrine includes the study of paracrines. Paracrines are chemi-
system, focusing on how the brain and pituitary gland cal messengers that are produced by endocrine cells and
regulate reproductive hormones. Your efforts in studying diffuse to act locally on adjacent target cells with the
this material will be repaid as you read further in the text, appropriate receptors. Thus, unlike classic hormones,
as an understanding of this topic is essential for you to paracrines are not carried in the bloodstream (Figure 1.2).
grasp the information in subsequent chapters. Reproductive endocrinologists therefore study both long-
range and short-range chemical signaling among the cells
and tissues involved in reproduction.
BIOLOGY OF THE ENDOCRINE SYSTEM
There are two kinds of glands in your body. Exocrine SCIENCE OF ENDOCRINOLOGY
glands secrete substances into ducts (tiny tubes) that
empty into body cavities and onto surfaces. Examples Suppose you are an endocrinologist who has an
are the sweat and oil glands of the skin, the salivary idea that a particular gland has an endocrine function.
glands, and the mucous and digestive glands of your What would you do to test this hypothesis? A “classi-
stomach and intestines. In contrast, endocrine glands cal” approach used by early endocrinologists is as fol-
do not secrete substances into ducts, which is why lows: (1) remove the gland, (2) observe the effects of
they are sometimes called “ductless glands.” Instead, gland removal on the body, (3) replacement therapy, which
Human Reproductive Biology, Fourth Edition. 3 Copyright © 2014 Elsevier Inc. All rights reserved.
http://dx.doi.org/10.1016/B978-0-12-382184-3.00001-5
4 1. ENDOCRINOLOGY, BRAIN, AND PITUITARY GLAND
involves administration of a preparation of the removed In the past, the technique of bioassay was commonly
gland, and (4) observe to see if the replacement therapy used to indirectly measure the amount of a given hor-
reverses the effects of gland removal. If the replace- mone in glandular tissue or blood. With this method,
ment therapy does reverse the effects, what could you several different amounts of a purified hormone are
conclude? administered to animals, and the physiological or
anatomical changes in target tissues are measured.
A given degree of biological response can then be asso-
ciated with a given amount of hormone administered.
Hypophysis
Ideally, the response should increase in proportion to
the increasing amounts of hormone administered; that
Pineal gland
is, a dose–response relationship, or “standard curve,” is
obtained. Then, a gland preparation or blood containing
Parathyroid glands
(behind thyroid gland) an unknown amount of this hormone is administered
Thyroid gland to other animals, and the biological response obtained
is compared to the dose–response relationship. In this
Trachea way, the amount of hormone in the gland or blood is
Thymus gland
Lungs determined.
A more direct and accurate way to measure the
Heart
amount of a hormone in tissues or in blood is radioim-
Adrenal glands munoassay. This assay uses an antibody against the hor-
mone of interest and a radioactive tracer for detection
Kidney Stomach
and measurement of the hormone. Radioimmunoassay
Pancreas is used to measure blood levels of hormones in humans
and other animals, and it has been a valuable tool in
reproductive biology and in tests for disorders of the
endocrine system. In 1977, Rosalyn S. Yalow received the
Nobel Prize in Physiology or Medicine for her develop-
Ovaries ment of this technique.
Scrotum The use of radioimmunoassay is now becoming less
Testes
prevalent as sensitive nonradioactive methods have
been developed. For example, ELISA assays are used
for measuring a wide variety of hormones and hormone
FIGURE 1.1 Components of the endocrine system (shown in red). products. High performance liquid chromatography (HPLC)
The placenta is not shown. techniques coupled with spectrophotometric analyses are
Endocrine cell
(in gland or dispersed)
Blood
vessel
Hormone
Hormone
Paracrine
Target cell
(change in
structure or
function)
Target cell
(change in
structure or
function)
FIGURE 1.2 Endocrine and paracrine regulation. Hormones may act at a distance, traveling through the bloodstream from their site of syn-
thesis to their targets (endocrine regulation). When they act on neighboring cells, regulation is paracrine.
I. ADULT FEMALE AND MALE REPRODUCTIVE SYSTEMS

RECEPTORS 5
used to identify hormones and other regulators in bio- Hormone A Hormone B
logical fluids. A method commonly used to measure
mixed steroids in plasma or urine samples is gas chro-
matography with mass spectrometry. Endocrinologists
studying the structure and function of endocrine cells
use techniques such as immunocytochemistry and immu-
nofluorescent staining of cells, imaged with the confocal
microscope.
Genetic engineering has revolutionized endocrine Target cell for Target cell for Target cell for
studies. One major area is the development of probes to hormone A hormones A and B hormone B
measure mRNA production to determine when a gene is FIGURE 1.3 Target cells for hormones must have specific receptors
activated or shut down by a hormone. Genetically engi- on their cell membranes or in their cytoplasm to respond to a particular
neered knockout and knock-in mice and rats are widely ligand.
used to investigate problems of sexual differentiation and
in behavioral studies. Yeast cells genetically engineered
to contain genes for human estrogen receptors, with the receptor molecules interact (bind), and the bound recep-
help of reporter genes, can be used in assays for mea- tor transmits the molecular message within the cell to
suring estrogen activity. These new tools have allowed exert a biological response.
endocrinologists to make advances in our understanding
of normal human reproductive physiology, as well as of
Receptors for Protein Hormones
reproductive disorders such as breast cancer.
Protein and peptide hormones, including the repro-
ductive hormones gonadotropin-releasing hormone
HORMONES (GnRH), follicle-stimulating hormone (FSH), luteiniz-
ing hormone (LH), and prolactin (PRL), bind to recep-
Hormones have diverse molecular structures. Some tors embedded in the cell membrane of responsive
hormones are proteins or smaller polypeptides or pep- cells. These receptors are large protein molecules that
tides. These kinds of molecules are made up of chains typically have three major regions, or domains (Figure
of amino acids containing oxygen, carbon, hydrogen, 1.4). The hormonal signal is received when the ligand
and nitrogen. Other hormones are amines, which are attaches to a ligand-binding site in the extracellular domain,
derivatives of amino acids; these are formed from a portion of the receptor that sticks out beyond the cell.
single amino acids that have been chemically altered. A transmembrane domain anchors the receptor within the
Some hormones are derived from fatty acids. Steroid plasma membrane. Finally, the intracellular domain is an
hormones are molecules derived from cholesterol. extension of the receptor protein within the cell cyto-
Male sex hormones (androgens) and female sex hor- plasm. Binding of the ligand to its receptor causes a con-
mones (estrogens and progestins) are examples of ste- formational (shape) change in the receptor. This triggers a
roid hormones. Androgens are substances that promote biochemical change in the cell’s cytoplasm, causing the
the development and function of the male reproduc- release of a second messenger, the first messenger being
tive structures. Estrogens stimulate the maturation and the hormone itself (Figure 1.5). Examples of second mes-
function of the female reproductive structures. Pro- sengers include cAMP and Ca2+. This “translation” of
gestins (or progestogens) are substances that cause the the hormonal message to the interior of the cell is called
uterus to be secretory. signal transduction. Because signal transduction usually
involves turning on or off a series of enzymes, a few mol-
ecules of a hormone can be amplified to alter thousands
RECEPTORS of molecules inside the cell (Figure 1.6). Response to a
protein/polypeptide hormone can occur in seconds or
Even though all body tissues may be exposed to hor- minutes after receptor binding.
mones, only certain target tissues are responsive to a The biological activity of a given hormone in a particu-
given hormone. Cells of these target tissues have specific lar tissue depends on the local concentration of the hor-
hormone receptors on their surface membranes, or in mone. In addition, the hormone’s activity depends on the
their cytoplasm or nucleus, that bind to a given hormone number of receptors for that hormone that are present.
(Figure 1.3). A molecule (such as a hormone or drug) that Cells can upregulate (gain) or downregulate (lose) receptors,
binds to a receptor is referred to as its ligand. Receptors and the timing of some reproductive functions (such as
are proteins that can accurately recognize a ligand from growth of the ovarian follicle) is dependent on the change
the pool of molecules in its environment. Ligand and in number of hormone receptors present. Upregulation

NH2
Ligand-
binding
domain
Extracellular
Hormone domain
Cell Transmembrane
membrane domain
Intracellular
domain
HOOC
FIGURE 1.4 Representation of a cell surface receptor molecule showing the ligand-binding domain (green) as a portion of the extracellular
domain. The transmembrane domain spans the plasma membrane of the cell, and the intracellular domain extends into the cytoplasm.
Hormone
Receptor
Hormone
Activated Plasma
G protein membrane
G protein
AC
AC active
GTP Adenylate inactive
Membrane- cyclase
bound
ATP cAMP
receptor
ATP
cAMP
PKA
inactive PKA
active
Protein
kinase
Enzyme Enzyme
inactive active
Cellular response
FIGURE 1.5 Mechanism of action of a peptide hormone. The ligand

binds to a cell surface receptor. Usually this activates a G protein, caus-
ing release of a second messenger (here, cAMP). The signal is transduced
to the cell i nterior, where it modifies the activity of cytoplasmic enzymes.
can occur when a gene encoding a receptor is activated, FIGURE 1.6 Signal amplification of a peptide hormone. Binding
of a peptide hormone to its membrane receptor activates a series of
resulting in the production of additional receptor proteins.
biochemical reactions inside the cell. Each step can be amplified, thus
After binding to a peptide ligand, a bound receptor may turning a small stimulus into a large response. AC, adenylate cyclase;
be internalized into the cell and targeted for degradation PKA, protein kinase A.

Receptors 7
Receptor Ligand
Plasma membrane
Matured
endosome
Early
Recycling endosome
of receptors
Degradation
in lysosome
Dissociation
and sorting
FIGURE 1.7 Receptor-mediated endocytosis. After a peptide hormone delivers its message to a target cell, the signaling must be ended.
Groups of ligand-bound cell surface receptors pinch off as a small vesicle and are internalized into the cell. In the cytoplasm, the ligand/receptor
complex is dissociated. The hormone is degraded and the receptor may be recycled back to the cell surface.
(downregulation) or recycled back to the plasma mem- activate or inhibit transcription; the presence of differ-
brane for further use (see Figure 1.7). ent cofactors in different cells helps explain why the
same hormone can have differing effects on various cell
types. Because steroids alter gene expression, and tran-
Receptors for Steroid Hormones scription and translation of a protein require at least
Unlike protein and peptide hormones, which must 30 min, the effects of steroids on the body are typically
act at the cell surface, steroid hormones (such as estro- slow (but long lasting). Whereas protein and peptide
gen, testosterone, and progesterone) are lipid soluble hormones often act within minutes, the effects of ste-
and thus can easily pass through the phospholipid roids are measured in terms of hours or days. Recent
bilayer of the plasma membrane. Steroid receptors are evidence indicates that some steroids also act through
located within the cytoplasm or the nucleus of target cell-surface receptors.
cells. When a steroid hormone binds to its receptor One might expect that each hormone has its unique
(Figure 1.8), the steroid/receptor complex undergoes receptor, resulting in equal numbers of hormone and
a conformational change that exposes a DNA-binding receptor types. This is not necessarily the case. Many
domain. This part of the receptor binds to a regula- hormone receptors, especially steroid receptors, lack
tory region of a steroid-responsive gene, turning on or specificity and can accept more than one type of ligand
off transcription of the gene. Bound steroid receptors molecule. Theoretically, any molecule that can achieve
interact with cofactors, which are nuclear proteins that a three-dimensional fit into the ligand-binding domain

Secretion and Metabolism of Hormones

Steroid hormone
After a hormone molecule is synthesized within an
endocrine cell, it must be released from the producing
Receptor cell before exerting a physiological effect. Because they
can easily pass through biological membranes, steroid
hormones are not stored but are released at the rate at
which they are synthesized. In contrast, synthesis and
secretion (release) are often separately controlled steps
for peptide hormones. They may be stored in secretory
Receptor-
hormone
vesicles that can then fuse with the cell’s plasma mem-
complex brane, releasing the hormones into the extracellular
Translation
environment.
Once in the bloodstream, hormones may find their
target receptors to exert physiological effects, or they
may be metabolized (chemically altered or degraded)
Transcription Protein before reaching their targets. Peptide hormones are eas-
mRNA ily metabolized by enzymes in the blood plasma, and
both peptide and steroid hormones are metabolized by
FIGURE 1.8 Mechanism of action of a steroid hormone. Lipid- the liver and excreted by the kidneys. Metabolism can
soluble steroids enter the cell cytoplasm by diffusion and bind to
receptors in the cytoplasm or nucleus. The steroid/receptor complex
also occur in target cells. Notably, target tissue metabo-
binds to regulatory regions of DNA, affecting the expression of specific lism may convert a steroid hormone to a more biologi-
steroid-responsive genes. cally active form, to a steroid with weaker activity, or to
an inactive metabolite.
The lifespan of a hormone molecule is limited and is
of a steroid receptor can interact with that receptor. For typically described as the molecule’s half-life, the time it
example, there are three major naturally occurring estro- takes for the blood plasma concentration of an amount
gens, each of which can activate a single estrogen recep- of secreted hormone to be reduced to half. The half-life
tor. Because of differences in their chemical structures, of peptide hormones is usually in the range of minutes,
however, they bind to the estrogen receptor with differ- whereas the half-life of steroids may be hours.
ent affinities (strengths). Estradiol has greatest affinity Thus, to understand the action of a hormone on its
for the estrogen receptor; for this reason it is considered target, we must know the local concentration of the hor-
a potent or “strong” estrogen. Estriol and estrone are mone, which is affected by the rate of its synthesis and
“weak” estrogens. Estrone binds to the estrogen recep- secretion, its half-life, and transport through plasma or
tor about 10% as well as does estradiol, and estriol binds extracellular fluid to its target cell; the proportion of hor-
only 1% as efficiently. mone available to receptors, which in the case of steroid
hormones is influenced by the plasma concentration of
binding proteins; and the number of unbound receptors.
Sex Steroid Binding Globulins
Although peptide hormones can travel freely in
plasma, gonadal steroid molecules are quickly attached SYNTHETIC HORMONES
to sex-steroid binding globulins in the blood after being
secreted into the circulation. Hitching a ride on these cir- Molecules that activate hormone receptors, thus mim-
culating proteins allows the lipophilic steroids to circu- icking the natural hormones produced by endocrine
late more freely in the aquatic bloodstream. The binding glands, occur in our environment and in the food we
proteins release only a certain number of steroid mol- eat. For example, in addition to the naturally occurring
ecules at a given time, freeing them to leave the blood- human estrogens, exogenous compounds (from a source
stream and travel to target cells. Typically only a small outside our bodies) can have estrogenic effects. Weak
proportion of the secreted steroid (2–3% in the case of estrogens synthesized by plants, called phytoestrogens,
estradiol) is free in the plasma. The availability of steroid can bind to estrogen receptors. One of these phytoestro-
hormones to target cells is regulated by the concentra- gens is genistein, found in the soybean plant. Scientists
tion of carrier proteins, whose levels change under cer- have also become aware of numerous man-made chemi-
tain conditions such as pregnancy and obesity. The ratio cals with estrogenic effects. Many of these xenoestrogens
of free to bound steroid is an important factor in the bio- are pesticides related to DDT, or industrial chemicals
logical activity of a steroid hormone. such as those used in the synthesis of plastics. An

Synthetic Hormones 9
active search is underway to identify these compounds Tamoxifen is one of the antiestrogens developed to
and determine their possible effects on human health and inhibit the growth of estrogen-dependent breast can-
impacts on wildlife (see Box 2.2 “Xenoestrogens and cers. This compound effectively blocks the estrogen
Breast Cancer” in Chapter 2). receptor’s ligand-binding site and thus prevents natural
The pharmaceutical industry has taken advantage estrogen from stimulating the growth of breast tumors.
of the estrogen receptor’s lack of specificity to synthe- However, because estrogen also maintains bone den-
size a wide variety of artificial estrogens. These analogs sity, it was feared that women taking tamoxifen would
are compounds that are chemically similar to estrogen. develop brittle bones. Surprisingly, the drug did not
Analogs that mimic estrogen-like effects are called have this deleterious effect; in fact, tamoxifen actually
agonists. Some analogs, however, bind to the estrogen helped maintain bone density. Thus, the drug acts as
receptor without eliciting an estrogen-like cellular an estrogen antagonist in breast tissue but an agonist
response. These antagonists block the receptor, prevent- in bone tissue; it is a selective estrogen receptor modulator,
ing the binding of natural estrogen. Estrogen antago- or SERM. This “tamoxifen paradox” may be partially
nists oppose the biological actions of estrogen and are explained by the discovery of a second estrogen recep-
therefore also called antiestrogens. Synthetic analogs of tor, ER-beta, which appears to have a different tissue dis-
other reproductive hormones have also been produced tribution than the original receptor, renamed ER-alpha.
(See Box 1.1). (The more abundant ER-alpha is usually referred to as
BOX 1.1
GnRH MIMICS AND BLOCKERS

Gonadotropin-releasing hormone (GnRH), released Some GnRH analogs have been found to inhibit go-
from the hypothalamus of the brain, is the master hor- nadotropin secretion by binding to GnRH receptors on
mone that regulates secretion of a suite of other hormones FSH- and LH-secreting pituitary cells, but not stimulating
essential for reproduction. Once GnRH was discovered, gonadotropin secretion. They occupy the receptors and
one of the first ideas was to give it to men and women block natural GnRH from binding; these molecules that
to treat certain kinds of infertility resulting from hypotha- prevent the action of GnRH are called GnRH antagonists.
lamic dysfunction. For example, women who are deficient They are like a rusty key stuck in a lock, which will not
in GnRH release have gonadotropin levels that are too low open the door and will not permit the use of a good key
to cause ovulation. to do so.
In an attempt to find the most effective type of synthetic The GnRH inhibitory agonists and GnRH antagonists
GnRH, many molecules similar but not identical to GnRH are medically useful for their ability to shut down gonad-
were manufactured. These are termed GnRH analogs. The otropins and, consequently, lower gonadal steroids and
GnRH analogs that stimulate gonadotropin secretion are inhibit egg and sperm maturation. Typically, these drugs
called GnRH agonists (an agonist is a substance that mimics are given as daily or monthly injections, an implant, or
the action of the naturally occurring hormone). Attempts a nasal spray. They are employed to treat endometriosis
to treat infertile patients with injections of GnRH agonists and uterine fibroids by reducing circulating estrogen lev-
resulted in an initial promising surge in FSH and LH levels, causing the affected tissues to shrink. They are also
els. But to everyone’s surprise, most of the GnRH agonists being studied as potential contraceptives. In fertility clin-
stopped working after about 10 days because they reduced ics, inhibitory GnRH analogs are used to prevent prema-
the number of GnRH receptors on FSH- and LH-secreting ture ovulation so its timing can be controlled by the use
cells in the pituitary gland. These so-called agonists, when of fertility drugs in in vitro fertilization and gamete in-
given to a person for several days, become GnRH inhibi- trafallopian transfer procedures (see Chapter 15). Despite
tory agonists, a contradiction in terms if there ever was one! their utility, these GnRH agonists often have side effects,
It was discovered that GnRH treatments work only when including menopausal-like symptoms (hot flashes, insom-
the hormone is administered in pulses about 90 min apart, nia, vaginal dryness), osteoporosis, and headaches, and
mimicking the natural secretion pattern of GnRH. Using a they can increase the risk of ovarian cysts. The dramatic
small pump placed under the skin of the abdomen or the effects of these molecules in both promoting and suppress-
arm, pulses of synthetic GnRH can stimulate FSH and LH ing fertility illustrate the central, essential role of GnRH in
secretion and restore fertility in some cases. reproduction.
(Continued)

BOX 1.1 (cont’d)
GnRH
GnRH receptor
Natural
GnRH ↑ FSH, LH =
gain of fertility
Pituitary
cell
Pulsatile
GnRH administration
↑ FSH, LH =
stimulatory gain of fertility
agonist
Loss of
receptors
Constant
administration
GnRH
↓ FSH, LH =
inhibitory
loss of fertility
agonist
GnRH
GnRH
GnRH receptor
blocked
GnRH
↓ FSH, LH =
antagonist
loss of fertility
The effects of various GnRH analogs.

When GnRH (blue ligand) binds to its cell surface receptors on pituitary cells, the cellular response is increased secretion of gonado-
tropins. A synthetic GnRH analog binds to the receptor and acts as a stimulatory agonist (green ligand) when administered in pulses.
However, when administered continuously, a GnRH agonist (red ligand) can actually act as an inhibitory agonist, thus reducing gonado-
tropin secretion. A GnRH antagonist (yellow ligand) occupies the GnRH receptor without eliciting a cellular response, thus blocking the
action of natural GnRH.
“the estrogen receptor.”) The possibility of developing the pituitary gland or hypophysis (Figure 1.9). This gland
pharmaceuticals that mimic a hormone’s effects in some synthesizes and secretes hormones that travel in the blood-
tissues, but block them in others, paves the way for so- stream and influence many aspects of our body, including
called “designer drugs.” the function of other endocrine glands. For example, if the
hypophysis is removed (an operation called hypophysec-
tomy), our reproductive system becomes nonfunctional,
and even sexual behavior is affected. Therefore, this gland
HOW THE BRAIN AND PITUITARY
plays a very important role in our reproductive biology. A
CONTROL REPRODUCTION
realization of the importance of the hypophysis led early
endocrinologists to call it the “master gland.” We now
The Pituitary Gland
know that the activity of this gland, which is connected to
The sphenoid bone lies at the base of your skull, and the base of the brain by a stalk, is itself greatly influenced
in this bone is a small, cup-shaped depression called the by brain messages. Indeed, one might think of the brain as
sella turcica (“Turkish saddle”). Lying in this depression is a the conductor of a marvelous chemical symphony played
round ball of tissue, about 1.3 cm (0.5 in) in diameter, called by the pituitary orchestra.

How the Brain and Pituitary Control Reproduction 11
Cerebrum
Thalamus
Pineal Hypothalamus
gland
Infundibulum
Pituitary gland
Midbrain
Pons Brain
Medulla stem
Cerebellum oblongata
Spinal cord
FIGURE 1.9 Section through the middle of the brain showing the pituitary gland, hypothalamus, and pineal gland. Note that the pituitary
gland (hypophysis) rests in a depression in the sphenoid bone and is connected to the hypothalamus by the pituitary stalk.
Hypothalamo–Neurohypophysial Connection
travels across the synapse and initiates electrochemical
The hypophysis has two major regions (Figure 1.10). changes leading to nerve impulses in the next neuron.
One is called the adenohypophysis, which is discussed The other general kind of nerve cell is the neurose-
later in this chapter. The other is the neurohypophysis (pars cretory neuron (Figure 1.11). A neurosecretory neuron
nervosa, or posterior pituitary gland). The neurohypophy- is similar to a regular neuron in that it can conduct a
sis is an extension of the brain; it develops as an out- nerve impulse along its axon. The speed of this electrical
growth of the portion of the embryonic brain that later conduction is, however, much slower than in a regular
becomes the hypothalamus. To understand the function neuron. Also, neurosecretory neurons are specialized to
of the neurohypophysis, you must first know that there synthesize large amounts of neurohormones in their cell
are two general types of nerve cells in the body. bodies. These neurohormones are then packaged into
Most of the nerve cells, or neurons, in our nervous sys- large granules that travel in the cytoplasm down the
tem consist of a cell body (containing the nucleus) along axon, and contents of the granules are released into the
with extensions of the cell called dendrites and axons spaces adjacent to the axon ending. The neurohypophy-
(Figure 1.11). Dendrites conduct a nerve impulse toward sis contains long axons of neurosecretory neurons sur-
the cell body, which is usually in or near the central ner- rounded by supporting cells. The cell bodies of these
vous system (brain and spinal cord). A sensory nerve is axons lie in the part of the brain called the hypothalamus.
really a collection of long dendrites carrying messages The hypothalamus forms the floor and lower walls of
to the central nervous system from the periphery. Axons the brain (see Figure 1.9) and contains a fluid-filled cav-
carry information away from the cell body. Motor nerves ity, the third ventricle. This ventricle is continuous with
contain axons that stimulate a response in the body, such the other ventricles in the brain and also with the central
as muscle contraction or glandular secretion. When one canal of the spinal cord. The fluid in the ventricles and
neuron connects with another, information is passed from central canal is called cerebrospinal fluid. The weight of
the first to the second cell; this site of communication is the hypothalamus is only 3 percent of that of the whole
known as a synapse. The axonal ending of the first neu- brain, but it functions in a wide variety of physiological
ron secretes a chemical called a neurotransmitter, which and behavioral activities. For example, there are areas

Hypothalamus milk is ejected from the nipples (see Chapter 12). Also,
oxytocin causes the smooth muscle of the uterus to
contract, and thus it plays a role in labor and child-
birth (see Chapter 11). In the male reproductive tract,
oxytocin may facilitate sperm transport. Vasopressin
causes the kidneys to retain water, i.e., the amount
of urine formed in the kidneys is reduced and more
Optic chiasma water remains in the body. Vasopressin also causes
Median blood vessels to constrict and blood pressure to rise.
Pars tuberalis eminence When oxytocin and vasopressin are released from the
axons in the neurohypophysis, these neurohormones
Pars intermedia
enter small blood vessels (capillaries) in the neurohy-
Pituitary pophysis that drain into larger veins and then enter the
stalk
general circulation.
Adenohypophysis
The adenohypophysis (adeno, meaning “glandular”)
consists of three regions: the pars distalis, the pars inter-
media, and the pars tuberalis (Figure 1.10). The pars
distalis (or anterior pituitary gland) occupies the major
portion (70%) of the adenohypophysis. The pars interme-
dia is a thin band of cells between the pars distalis and
Pars distalis Pars nervosa the neurohypophysis. In the adult human, the pars inter-
media is sparse or absent. The pars tuberalis is a group
FIGURE 1.10 Major subdivisions of the human hypophysis (the
neurohypophysis and the adenohypophysis) and their relationship to
of cells surrounding the pituitary stalk. During embry-
the brain. The pars tuberalis, pars distalis, and pars intermedia are all onic development, the adenohypophysis forms from an
part of the adenohypophysis. In adult humans, the pars intermedia is invagination (inpocketing) of the cell layer of the embryo
often absent. that later becomes the roof of the mouth. This invagina-
OC, optic chiasma (nerves from the eyes). Anterior is to the left. tion of cells then extends toward the neurohypophysis
growing from the embryonic brain.
The adenohypophysis contains several types of endo-
in the hypothalamus that regulate body temperature, crine cells. When we stain the adenohypophysis with
thirst, hunger, sleep, response to stress, and aggressive laboratory dyes, some cells acquire a pink color. These
and sexual behaviors. cells are called acidophils (phil, meaning “love”) because
Of importance to our discussion of the hypophysis is they have an affinity for acid dyes. Some acidophils syn-
that the cell bodies of the neurosecretory axons in the thesize and secrete growth hormone (GH). This hormone
neurohypophysis lie in paired groups (neurosecretory is a large protein that stimulates tissue growth by caus-
nuclei) in the hypothalamus. More specifically, these are ing incorporation of amino acids into proteins. The other
the supraoptic and paraventricular nuclei. (Note: a neuro- type of acidophil in the adenohypophysis synthesizes
secretory nucleus is a group of cell bodies of neurosecre- and secretes prolactin (PRL), which is also a large pro-
tory neurons and should not be confused with “nucleus” tein. As we shall see in Chapter 10, prolactin acts with
as meaning the body within a cell that contains DNA.) other hormones to cause the female mammary glands to
The axons of the neurosecretory neurons in these nuclei become functional and secrete milk.
then pass down the pituitary stalk (which connects the Other cells in the adenohypophysis, the basophils,
hypophysis with the brain) and into the pars nervosa stain darkly with basic dyes. These cells synthesize
of the neurohypophysis (Figure 1.12). The granules and secrete hormones that are proteins or glycopro-
released by these axons contain two neurohormones— teins (large proteins with attached sugar molecules).
oxytocin and vasopressin (or antidiuretic hormone). One of these hormones is the glycoprotein thyrotro-
Both oxytocin and vasopressin are polypeptides pin. The abbreviation for thyrotropin (TSH) comes
consisting of nine amino acids. The two neurohor- from the older name, thyroid-stimulating hormone.
mones differ only slightly in the kinds of amino acids This hormone causes the thyroid glands to synthesize
in their molecules, but these slight differences result in and secrete thyroid hormones (e.g. thyroxine), which
very different effects on our bodies. Oxytocin stimu- in turn control the rate at which our tissues use oxy-
lates contractile cells of the mammary glands, so that gen. Other basophils in the adenohypophysis secrete

(A) (B)
Dendrite
Cell body
Axon
Neurotransmitters Neurohormones
FIGURE 1.11 A regular neuron (A) and a neurosecretory neuron (B). Dendrites carry nerve impulses toward the cell body, whereas axons
carry nerve impulses away from the cell body. Neurotransmitters are secreted by the axon endings of regular neurons, whereas neurohormones
(dark dots in B) are released from the axon endings of neurosecretory neurons.
Paraventricular
nucleus corticotropin (ACTH), a polypeptide hormone that
travels in the blood to the adrenal glands and causes
Ventricle III
secretion of adrenal steroid hormones (corticosteroids)
Hypothalamus such as cortisol. Cortisol in turn raises blood sugar
Hypophysiotropic
area levels, reduces inflammation, and combats the effects
Supraoptic Median eminence of stress. Still other basophils in the adenohypophy-
nucleus
Neurosecretory neurons of sis secrete the polypeptide hormones lipotropin (LPH)
Pars HTA secrete releasing and melanophore-stimulating hormone (MSH). Lipotro-
distalis hormones or pin breaks down fat to fatty acids and glycerol. MSH
release-inhibiting hormones
into the median eminence. causes synthesis of a brown pigment, melanin, which
These neurohormones reach is present in cells called melanophores. Finally, the
the pars distalis via the basophils of the adenohypophysis secrete two kinds
hypothalamo-hypophysial
portal system. of natural, opioid-like “pain-killers”—the endorphins
and enkephalins.
Of particular interest to our discussion of human
Neurosecretory axons from
the supraoptic and reproductive biology are the final two hormones
paraventricular nuclei secrete secreted by basophils of the pars distalis. One of these
Pars nervosa oxytocin and vasopressin. is follicle-stimulating hormone (FSH). We shall learn in
FIGURE 1.12 Regions of the hypothalamus involved in the func- Chapter 4 that FSH plays a role in sperm production in
tion of the hypophysis. the testes. In the female, FSH stimulates the ovaries to

produce mature germ cells in their enclosed tissue sacs been observed that menstrual cycles of women are often
(see Chapter 2). The other hormone is luteinizing hor- altered or even stopped by stressful environmental and
mone (LH), which causes interstitial cells in the testes psychological stimuli (see Chapter 3). This pointed to an
to synthesize and secrete androgens (see Chapter 4). In influence of the brain on reproductive physiology. It was
the female, LH causes the ovaries to secrete female sex not until 1947, however, that J. D. Green and G. W. Harris
hormones (estrogens and progestins) and induces the provided anatomical evidence that neurosecretory
release of an egg from the ovary (see Chapter 2). Because neurons in the hypothalamus could influence the func-
FSH and LH play vital roles in the function of the gonads, tion of the adenohypophysis. Recall that some of the
they are grouped under the term gonadotropic hormones neurosecretory neurons in the hypothalamus send their
or “gonadotropins.” The pituitary cells that release axons down the pituitary stalk and into the neurohy-
gonadotropins are termed gonadotropes. These cells are pophysis, where they release oxytocin and vasopressin.
scattered throughout the pars distalis and comprise Other neurosecretory neurons existing in paired nuclei
7–15% of cells in the anterior pituitary. Although most in the hypothalamus do not send their axons down the
gonadotropes contain both FSH and LH, some stain for stalk to the pituitary. Instead, their axons end in an area
only one of the gonadotropins. Thus, gonadotropes may in the floor of the hypothalamus near the pituitary stalk,
be a heterogeneous population of cells that differentially called the median eminence. (Note: sometimes the median
synthesize and release FSH and/or LH depending on eminence is considered part of the neurohypophysis.)
physiological state, maturity of the cell, or other condi- The cell bodies of these neurons are clustered in sev-
tions. Figure 1.13 summarizes the hormones secreted by eral pairs of nuclei in the hypothalamus, and together
the pituitary gland. these nuclei are named the hypophysiotropic area (HTA,
Figure 1.12). These nuclei are given this name because
the neurosecretory neurons in this region secrete a fam-
Hypothalamo–Adenohypophysial Connection ily of small polypeptides (neurohormones) that either
It has been known for some time that the reproduc- increase or decrease the amount of hormones secreted
tive cycles of many animals are influenced by such envi- by the adenohypophysis.
ronmental factors as light, behavior, and stress, and the If the neurohormones controlling adenohypophysial
same appears true for humans. For example, it had long function are released from neurosecretory neurons at the
Hypothalamus
Pars distalis of adenohypophysis

Neurohypophysis
Opioids
Vasopressin GH
Oxytocin LPH
ACTH
MSH
PRL
LH
FSH
TSH Adrenal
cortex
Pigment Fat cells

cells
Mammary Ovaries Thyroid Kidney

glands Testes
Pain
Progesterone, estrogens Testosterone Thyroxine Corticosteroids Growth Nerves
FIGURE 1.13 The pituitary, connected to the hypothalamus at the base of the brain, has two lobes. The neurohypophysis stores and releases
two hormones made in the hypothalamus: oxytocin and vasopressin. Oxytocin causes contraction of smooth muscle in the uterus, breast, and
male reproductive tract. Vasopressin acts on the kidneys to cause water retention. The adenohypophysis secretes nine other hormones: growth
hormone (GH) promotes growth; corticotropin (ACTH) causes the adrenal cortex to secrete corticosteroid hormones; follicle-stimulating hormone
(FSH) and luteinizing hormone (LH) interact to regulate the function of the gonads; prolactin (PRL) causes milk synthesis in the mammary glands;
thyrotropic hormone (TSH) stimulates the thyroid gland to secrete thyroxine; lipotropin (LPH) affects fat metabolism; melanophore-stimulating
hormone (MSH) stimulates melanin synthesis in pigment cells; and opioids (endorphins and enkephalins) reduce pain.

median eminence, how do they reach the adenohypoph- Primary capillary plexus
ysis to influence pituitary hormone secretion? In 1930, of median eminence
Hypothalamus
G. T. Popa and U. Fielding described a specialized system
of blood vessels extending from the median eminence
to the pars distalis (Figure 1.14). The superior hypophy-
sial arteries carry blood to the median eminence region. Internal
These arteries drain into a cluster of capillaries in the carotid
median eminence known as the primary capillary plexus. artery
Hypophysial
The neurohormones diffuse into these capillaries and Superior portal veins
into the blood. Then they are carried down to the pars hypophysial
Capillaries in
arteries
distalis in small veins. These veins divide into a second neurohypophysis
capillary bed surrounding the cells of the pars distalis, Secondary
capillary plexus Inferior
the secondary capillary plexus. The neurohormones then hypophysial
in pars distalis
leave the blood through the walls of these capillaries and artery
Inferior
enter the spaces between the pars distalis cells, where hypophysial vein Internal
they cause these cells to either increase or decrease carotid
hormone synthesis and secretion. This efficient system artery
Inferior
allows, for example, a very small amount of the neuro- Cavernous hypophysial
hormone gonadotropin-releasing hormone (GnRH), undi- sinus vein
luted by the general circulation, to be delivered directly FIGURE 1.14 The hypothalamo–hypophysial vascular system.
to its target—gonadotropes in the pituitary—and pre- Arterial blood enters the median eminence and the neurohypophysis
cisely influence their activity. via the superior hypophysial and inferior hypophysial arteries, re-
A portal system is a vascular arrangement in which spectively. Both of these arteries are branches of the internal carotid
blood flows from one capillary bed to another with- arteries, major vessels supplying the brain. Neurohormones secreted
into the median eminence region enter the blood in the primary capil-
out going through the heart. Thus, the vascular system lary plexus. They pass down the hypophysial portal veins to the sec-
connecting the median eminence with the pars distalis ondary capillary plexus in the pars distalis. Then they leave the blood
is called the hypothalamo–hypophysial portal system, and and cause the pars distalis cells to secrete or stop secreting hormones.
the small veins connecting the primary and secondary When hormones are secreted by the pars distalis, they leave the hy-
capillary plexi are the hypophysial portal veins. Once the pophysis in the inferior hypophysial veins, which drain into a large
vessel, the cavernous sinus. Neurohypophysial hormones enter cap-
hormones of the adenohypophysis are secreted, they illaries in the neurohypophysis, which also drain into the cavernous
leave the pituitary via the inferior hypophysial vein sinus. Small blood vessels connect the capillaries of the pars distalis
(Figure 1.14). and neurohypophysis.
Releasing and Release-Inhibiting Hormones TABLE 1.1 Hypothalamic Neurohormones Controlling the
Synthesis and Release of Hormones from the Pars Distalis
The neurohormones released by the axons of the
Neurohormone Abbreviation
hypophysiotropic area of the hypothalamus can either
increase or decrease the synthesis and secretion of hor- Gonadotropin-releasing hormone GnRH
mones of the adenohypophysis. When a neurohormone
Prolactin release-inhibiting PRIH
increases output of a particular adenohypophysial hor- hormone (dopamine)
mone, it is called a releasing hormone (RH). For example,
Corticotropin-releasing hormone CRH
the neurohormone that increases the output of thyrotro-
pin is called thyrotropin-releasing hormone (TRH). When a Thyrotropin-releasing hormone TRH
neurohormone lowers the secretion of a particular ade- Growth hormone-releasing hormone GHRH
nohypophysial hormone, it is termed a release-inhibiting
Growth hormone release-inhibiting GHRIH
hormone (RIH). Thus, the neurohormone that decreases
hormone (or somatostatin)
the secretion of prolactin is prolactin release-inhibiting hor-
mone (PRIH). Those of particular interest to reproductive biologists are in bold.
As seen in Table 1.1, most hormones of the adeno-
hypophysis are controlled by a releasing hormone, these neurohormones are known. The others are rec-
and some are known to be controlled by both a releas- ognized as a result of experiments demonstrating their
ing and a release-inhibiting hormone. Each releasing or presence, but their chemical nature is yet to be described.
release-inhibiting hormone is probably synthesized by a In 1977, Andrew Schally and Roger Guillemin shared the
different group of neurosecretory cell bodies in the hypo- Nobel Prize in Physiology or Medicine for their research
physiotropic area. The chemical structures of several of on hypothalamic neurohormones.

Of particular interest to us are the neurohormones GnRH is actually derived within the neuron from
that control synthesis and release of FSH, LH, and PRL a larger protein called prepro-GnRH (Figure 1.16). This
from the pars distalis. We shall discuss these in some protein contains the 10 amino acids of GnRH, plus a
detail because research about these neurohormones has “signal sequence” of 23 amino acids (which plays a
had a profound influence in controlling human fertility role in breaking up prepro-GnRH into its component
and treating reproductive disorders. parts), a sequence of three amino acids used for molec-
ular processing, and a 56-amino acid sequence called
GnRH-associated peptide (GAP). Before secretion of
Gonadotropin-Releasing Hormone GnRH, the prepro-GnRH molecule is split into GnRH
Evidence that a substance released by the hypothalamus and GAP.
controls pituitary LH secretion was confirmed in the early
1970s when luteinizing hormone-releasing hormone (LH-RH)
The GnRH Pulse Generator and Surge Center
was isolated and its chemical nature identified, primarily
through the efforts of Andrew Schally. Many thousands of GnRH is not released continuously from the hypothal-
hypothalami from domestic mammals were obtained to amus. Instead, it is secreted in pulses every hour or so into
extract and purify this neurohormone. LH-RH is a polypep- the hypophyseal portal system. In response, the pituitary
tide, consisting of 10 amino acids, and its function has been gonadotropes release FSH and LH in a pulsatile fashion.
examined in a wide variety of research and clinical studies. The pulsatile pattern of GnRH secretion is essential for
Surprisingly, when LH-RH is administered to humans or to gonadotropin secretion, and thus is central to reproduc-
laboratory mammals, both LH (Figure 1.15) and, to a lesser tive function. This is demonstrated in the treatment of
degree, FSH are secreted in increased amounts into the men and women whose infertility is caused by insuf-
blood. Therefore Schally concluded that there may be only ficient gonadotropin levels. Initially, it was thought that
one releasing hormone in humans that controls synthesis simply giving the patients GnRH agonists would restore
and secretion of both LH and FSH. This is despite evidence fertility. Surprisingly, after initial stimulation of FSH and
that the hypothalamus of some mammals contains LH-RH LH, these agonists stopped working. Only when GnRH
as well as a follicle-stimulating hormone-releasing hormone agonists are administered in natural pulses by an intra-
(FSH-RH) that causes release of mostly FSH and a little venous pump is normal gonadotropin secretion restored.
LH. Although future research may show that the human It is thought that continuous exposure to GnRH down-
hypothalamus secretes both LH-RH and FSH-RH, let us regulates its receptors or the GnRH signaling pathway in
for now accept that a single releasing hormone increases pituitary cells.
both LH and FSH secretion from the pituitary; we call this In humans, the GnRH-secreting cells are mainly
gonadotropin-releasing hormone (GnRH), realizing that this located in a part of the HTA called the arcuate nucleus,
is identical to the LH-RH discussed in the older scientific though others are scattered elsewhere in the hypothala-
literature. About 1000 to 3000 neurons in the HTA secrete mus. This nucleus is at the base of the hypothalamus
GnRH (see Box 1.2). Many of these neurons send their near the median eminence; it also contains regular neu-
axons to the median eminence to exert control over pitu- rons that synapse with the GnRH neurons. Pulsatile
itary LH and FSH secretion. Some GnRH neurons, how- secretion of GnRH is controlled by activity of cells in
ever, send axons to other brain regions and may influence this region, known as the GnRH pulse generator. Pulsa-
sexual behavior. tile release of GnRH is an intrinsic property of GnRH
neurons, and the frequency and amplitude of these
pulses may be influenced by synapses with regular
25
neurons as well. Neurons in the hypothalamus modify
21 GnRH secretion through several neurotransmitters.
17 Kisspeptins, a family of peptides released by neurons in
LH (ml U/ml)
Women
13
9
Men Signal GnRH-associated
5 polypeptide GnRH peptide (GAP)
1
–5 0 8 16 32 64 128 10 amino
23 amino acids 3 aa 56 amino acids
Time (min) acids
FIGURE 1.15 When a single injection of GnRH is administered to Prepro-GnRH

men (▲) and women (●) at time zero, levels of LH rise in the blood,
peak after 32 min, and then decline. Levels of FSH (not shown) also rise FIGURE 1.16 Components of prepro-GnRH, the large protein that
after GnRH administration, but not as high as LH. gives rise to GnRH and GAP.

Feedback Control of Gonadotropin Secretion 17
close anatomical association with GnRH cells, appear to
act directly on GnRH neurons to stimulate GnRH secre-
Pineal Gland
tion (Figure 1.17). In addition, norepinephrine, dopamine, The pineal gland, a single outpocketing from the roof
gamma-aminobutyric acid (GABA), glutamate, and even of the brain (see Figure 1.1), may also influence the
GnRH itself (acting through autocrine signaling) have release of FSH and LH. In the seventeenth century, it
been proposed as GnRH regulators. Another neuropep- was believed that this gland was the “seat of the soul.”
tide, gonadotropin-inhibitory hormone (GnIH), nega- Now we know that the pineal synthesizes and secretes
tively regulates GnRH by inhibiting GnRH cell function the hormone melatonin, which can inhibit the reproduc-
and gonadotrope response to GnRH in mammals, tive systems of male and female mammals. Exposure of
though its exact function in humans is not yet known. humans to light suppresses melatonin secretion, whereas
Thus, GnRH secretion can be stimulated or inhibited by exposure to dark increases it. Light does not directly
a complex pattern of neuronal activity in the brain. affect the pineal. Instead, light entering the eyes increases
At mid-cycle in females, GnRH-secreting cells release activity of nerves in the accessory optic tracts leading to
even more GnRH, resulting in a surge of FSH and LH the brain. These impulses cause the part of the sympa-
from the pituitary. The GnRH surge center activity con- thetic nervous system that innervates the pineal gland to
trolling this event also resides in the hypothalamus. The decrease release of the neurotransmitter norepinephrine.
importance of the GnRH pulse generator and surge cen- This then causes a decrease in melatonin synthesis and
ter in the control of the menstrual cycle is discussed in secretion. Because of this influence of the daily light cycle
Chapter 3. on melatonin secretion, levels of melatonin in the blood
exhibit a daily cycle. In humans, plasma melatonin levels
are highest during sleep, between 11 pm and 7 am. When
the daily light schedule is shifted by 12 h, it takes four
KISS or five days for the daily rhythm in melatonin to shift
Neuron
to the new light cycle. In addition to daily light cycles,
+ sleep and activity patterns can also influence melatonin
+ cycles in humans. Conversely, melatonin levels can affect
sleep–wake and other circadian rhythms. Melatonin may
– play a role in normal puberty (see Chapter 6), as levels of
GnRH this hormone in the blood of prepubertal children drop
Neuron markedly just before the onset of puberty.
We have much more to learn about the role of the
pineal in reproduction. Analogs of melatonin have been
made in the laboratory and found to inhibit the human
reproductive system when given orally. These analogs
GnRH could act on the hypothalamus, pituitary gland, or
gonads to inhibit reproduction. Considering this hor-
Estradiol + mone’s potential impact on reproduction, it is surprising
that melatonin pills are being sold over the counter in
the United States with little control over dosage or con-
sideration of side effects.
Pituitary
FEEDBACK CONTROL OF
FSH
GONADOTROPIN SECRETION
Ovary LH
+ Feedback Systems
FIGURE 1.17 Proposed mediation of estradiol feedback in women. In your house or apartment, you probably have a
In response to GnRH, the pituitary releases LH, which is trans- thermostat on your wall that controls the activity of
ported to the ovaries. Estradiol, secreted by the ovaries, then feeds your heating system, and you can set the temperature
back on GnRH. Because GnRH neurons lack estrogen receptors, of your room by manipulating a dial on the thermostat.
both positive and negative feedback is thought to be mediated by Now, suppose you set the thermostat at 65 °F. This tem-
other neurons in the hypothalamus. Kisspeptin-secreting neurons
are good candidates, as they are responsive to estradiol, synapse
perature is called the “set point.” The thermostat con-
with GnRH neurons, and release kisspeptins that stimulate GnRH tains a small strip, made of two metals, that expands
neuron activity. or contracts depending on the temperature. If the room

BOX 1.2
KALLMANN SYNDROME AND THE ORIGIN AND

M I G R AT I O N O F G n R H C E L L S
Kallmann syndrome is one of the many possible causes (sex linked) or are autosomal, and it is five to seven
of human infertility (see Chapter 15). People with this times more common in men (see Chapter 5). About
syndrome exhibit a curious association of infertility one in 10,000 men are born with this condition. Fer-
with anosmia (the inability to smell). Examination tility of Kallmann syndrome sufferers can be restored
of their nervous system has revealed an absence of with the administration of GnRH stimulatory ago-
certain olfactory (smell) structures in the brain as well nists, but they would still remain anosmic for life.
as a lack of GnRH neurons in the hypothalamus; the What is the explanation for the association of
latter deficiency accounts for their low secretion of olfactory and reproductive abnormalities in people
gonadotropins (FSH and LH) and infertility. with this syndrome? During normal embryonic de-
velopment, the olfactory nerves carry neural infor-
Developing
brain
mation from the olfactory lining in the nasal cavity to
the pair of olfactory bulbs at the base of the cerebral
hemispheres of the brain. From there, the olfactory
sense is carried in nerve fibers of the olfactory tracts
to the hypothalamus and other brain areas. Once the
olfactory system is formed in the embryo (at about
LV day 25 of pregnancy), GnRH cells, which originate in
F the developing nasal cavity (nose), migrate along the
olfactory nerves and tracts to the hypothalamus, where
ON
they take up residence in the arcuate nucleus and pre-
pare to play a role in controlling pituitary FSH and
A LH secretion and reproduction in the adult. People
with Kallmann syndrome, however, do not develop a
OL normal olfactory system, so the GnRH cells have no
“olfactory highway” of nerve fibers to guide them on
their journey to the hypothalamus. Thus, the GnRH
Diagram of a section through the head of a human embryo show- cells of people with Kallmann syndrome remain
ing the migration route of GnRH neurons (green dots) from the stuck in the nose! Why is development of the GnRH
nasal cavity to the hypothalamus. Failure to migrate, as in Kall- neurons so interwoven with that of the olfactory sys-
mann syndrome, results in GnRH cells remaining in the nose and tem? Chapter 8 discusses the important role of social
in infertility. A, arcuate nucleus of the hypothalamus (GnRH cells
migrating to here control gonadotropin secretion in the adult); F,
chemical signals (“pheromones”) in the reproduction
forebrain (route of migration in brain); LV, lateral ventricle; OL, of mammals, including perhaps humans. The intimate
olfactory lining in developing nasal cavity; ON, olfactory nerve association of the development of GnRH cells with
fibers (route of migration outside brain); large arrows, migration the olfactory system may have evolved because of the
pathways of GnRH cells. Adapted from Schwanzel-Fukuda et al. importance of linking sensory chemical information
(1992).
from the opposite sex to gonadotropin secretion and
Kallmann syndrome is inherited; genes associated
fertility.
with this disorder are located on the X chromosome
temperature drops below 65 °F, the thermostat sends an information into a message (“input”). In your thermo-
electrical current through the wires leading to the heater, stat, the input travels along wires from the temperature
and the heater is activated. When the room temperature receptor (bimetal strip) and then to a “controller center.”
reaches 65 °F, the heater shuts off. Thus, the product of The controller center contains the set point and also gen-
the heater (heat) influences the activity of the heater by erates an outgoing message (“output”). Wires leading
feeding back on the device in the thermostat that con- from the controller center in the thermostat to the heater
trols the heater activity. carry this output message. These output wires are acti-
A simple feedback system is depicted in Figure 1.18. A vated when the room temperature is below the set point.
receptor detects changes in the system and translates this The “effector” (heater) then responds by producing an

Feedback Control of Gonadotropin Secretion 19
Regular neurons
Arcuate nucleus of hypothalamus

Higher
center
Input Controller Output Feedback

center effects of
(set point) gonadal
hormones Blood
GnRH
Effector cell
Receptor
Feedback loop Change Gonadal
eminence
in system Effect hormones Gonads
Median
GnRH (ovaries
FIGURE 1.18 A simple feedback system. The receptor detects the or testes)
level of a particular component of the system and translates it into a FSH, LH
message (input) to the controller center. The input is compared by the
Pituitary
controller center to its programmed set point, and this center computes Portal
stalk
whether a regulatory response is required. If necessary, the controller veins
center generates a signal (output) that is transmitted to one or more
effectors, which respond by producing some effect. This effect produces
a change in the system, which then feeds back as a feedback loop on
(pars distalis)
Hypophysis
the controller center after being received by the receptor. Other circuits GnRH
(higher centers) can modify the activities of the controller center by Blood
temporarily altering the set point or by inhibiting the operation of the FSH LH
controller center. cell cell
FSH LH
“effect” (heat). In turn, the effect produces a change in
the system (an increase in room temperature) that has
a feedback effect on the controller center. This is called FIGURE 1.19 Schematic diagram of the control of the reproductive
system by the brain and pituitary gland and the sites of feedback by
a feedback loop. In some feedback systems, other circuits
gonadal hormones on this control.
(“higher centers” in Figure 1.18) can modify the activi-
ties of the controller center by temporarily altering the
set point or by inhibiting the operation of the controller by having feedback effects on the systems controlling
center. gonadotropin secretion.
Many aspects of our physiology operate as feedback In women, moderate plasma levels of estrogen reduce
systems that regulate our internal environment at a the secretion of FSH and LH from the pituitary. This nega-
steady state; this regulation is called homeostasis. Homeo- tive feedback effect of estrogen (Figure 1.19) is even more
static control systems in our body operate through nega- effective in combination with high levels of a progestin.
tive feedback. In the endocrine system, negative feedback In the normal menstrual cycle, high levels of progester-
occurs when the plasma level of a hormone rising above one and moderate levels of estrogens in the blood during
a set point inhibits further secretion of that same hor- the luteal phase of the cycle (the period between ovula-
mone into the blood. In reproductive physiology, there tion and menstruation) lower gonadotropin secretion by
are also important occurrences of positive feedback, in negative feedback and thus prevent ovulation at this time
which the secretion of a hormone influences the control- (see Chapter 3). Similarly, combination contraceptive pills
ler center so secretion of that hormone increases even containing moderate levels of an estrogen and high levels
more. Both positive and negative feedback are impor- of a progestin are highly effective at inhibiting gonado-
tant in controlling secretion of the gonadotropins from tropin secretion and thus ovulation (see Chapter 13).
the adenohypophysis. It may help you to think that the hypothalamus con-
tains a controller center with a gonadostat that works like
the thermostat in your heating system. This gonadostat
Regulation of Gonadotropin Secretion by
contains a set point for levels of sex steroids (estrogens,
Negative Feedback progestins, or androgens) in the bloodstream. When
As discussed in Chapters 2–4, FSH and LH cause levels of these steroids are higher than the set point, the
secretion of sex hormones by the gonads (testes or ova- gonadostat signals the hypophysiotropic area to stop
ries). These steroid hormones (androgens, estrogens, secreting GnRH, and thus secretion of FSH and LH from
and progestins) are products (effects) of the action of the adenohypophysis declines. If circulating levels of
gonadotropins on the gonads, and it turns out that ste- steroids are below the set point, the gonadostat signals
roid hormones influence the secretion of LH and FSH the hypophysiotropic area to release more GnRH, and

circulating levels of FSH and LH rise. This negative feed- Positive Feedback
back system operates in males and females to maintain
sex steroid levels at a steady state. Thus far, we have been talking about negative feed-
Because GnRH neurosecretory neurons probably do back on pituitary FSH and LH secretion (see Figures
not have receptors for sex steroids, the negative feedback 1.18 and 1.19). There is, however, a stage in the human
effects of these steroid hormones must act on other neu- menstrual cycle when high levels of plasma estrogen
rons in the brain, which in turn inhibit GnRH cells. As increase the secretion of LH and FSH from the adenohy-
mentioned before, GnRH neurons are closely associated pophysis, which in turn further increase estrogen release
with a population of neurons that secrete the protein from the ovary. This temporary escalation of hormone
known as kisspeptin. Kisspeptin-secreting neurons pos- release is an example of positive feedback. It results in
sess receptors for androgens, estrogens, and progestins, a “surge” of gonadotropins (primarily LH) in the blood
and thus these neurons are proposed to be critical play- and the subsequent release of an egg from the ovary
ers in the negative feedback of steroids on the hypothala- (see Chapter 3), ending the positive feedback cycle. It is
mus (Figure 1.17). Some of the negative feedback effects important to understand that the negative and positive
of sex steroids can also act directly on the FSH and LH feedback effects of estrogen have separate and different
pituitary cells by decreasing their sensitivity to GnRH. set points. High levels of estrogen in the blood (above
In addition to secreting steroid hormones in response the positive-feedback set point) have a positive feedback
to FSH and LH, the gonads (testes and ovaries) also effect on gonadotropin secretion, whereas moderate lev-
release glycoprotein hormones that influence gonado- els of estrogen (but still above the set point for negative
tropin secretion. Inhibin, produced by the gonads, enters feedback) have a negative effect on gonadotropin secre-
the circulation and acts directly on pituitary cells to tion (Figure 1.20). The positive feedback effect of high
selectively suppress the secretion of FSH but not LH. levels of estrogen operates by stimulating neural activity
Thus, inhibin acts as a feedback regulator to control FSH in the hypothalamic surge center, which then increases
secretion. Activin opposes the action of inhibin, stimu- GnRH secretion. As with negative feedback, kisspeptin-
lating the release of FSH. Activin is also synthesized in secreting neurons have an important role in mediating
the pituitary, brain, and other tissues, and it may have positive feedback of steroids on the hypothalamus.
local (paracrine) effects as well as behave as a blood- The positive and negative feedback effects of gonadal
borne hormone. Although they exert opposite effects steroids on LH and FSH secretion can operate directly on
on FSH secretion, activin and inhibin are closely related the pituitary itself as well as on the brain (Figure 1.19),
proteins in the transforming growth factor beta (TGF- i.e., the response of FSH- and LH-secreting cells in the
β) superfamily. Both are dimers, or complexes formed adenohypophysis to GnRH may vary depending on the
by the joining of two protein subunits. Activin is made kinds and amounts of steroid hormones bathing these
from two similar or identical beta subunits, whereas cells. For example, it has been shown that high estrogen
inhibin has a beta subunit and an alpha subunit. levels increase the sensitivity of the pituitary to GnRH.
Another glycoprotein that is produced by many cell Progestins can also increase pituitary sensitivity to
types, follistatin, binds to activin and blocks its action. GnRH in women. In males, androgens have a negative
Activin, inhibin, and follistatin are also produced by the feedback on gonadotropin secretion not only by influ-
placenta, and their possible roles in pregnancy are yet encing the brain but also by decreasing the response of
to be discovered. the adenohypophysis to GnRH.
FIGURE 1.20 The actions of positive and negative feedback on GnRH and, therefore, gonadotropin (FSH and LH) and sex steroid secretion
in females and males.

Summary 21
Control of Prolactin Secretion receive these hormones, which then travel in the blood
of the hypothalamo–hypophysial portal system to the
The control of PRL secretion by the brain differs in endocrine cells of the adenohypophysis. The releasing
some respects from brain control of LH and FSH secre- hormones then increase the secretion of specific adeno-
tion. If the hypophysiotropic area of the hypothalamus hypophysial hormones, whereas the release-inhibiting
is destroyed, secretion of PRL from the adenohypophy- hormones have the opposite effect.
sis increases, whereas secretion of LH and FSH declines. Because one of these hypothalamic-releasing hor-
Therefore, there is a prolactin release-inhibiting hormone mones increases the secretion of both FSH and LH, it is
(PRIH) secreted by neurosecretory neurons in the hypo- called a gonadotropin-releasing hormone. Because GnRH
physiotropic area that inhibits prolactin secretion. The regulates the release of gonadotropic hormones, which
major PRIH is dopamine; other factors such as GABA themselves control gamete production and hormone
and somatostatin may also play more minor inhibitory release from the gonads (ovaries and testes), GnRH plays
roles. In addition to tonic inhibition by dopamine, PRL a central role in human reproduction. The surge center
may be positively regulated by substances that serve of the hypothalamus causes a surge of LH secretion just
as prolactin releasing factors. Candidates for releas- before ovulation by increasing GnRH secretion from the
ing factors include TRH, which stimulates thyrotropin HTA. The pineal gland secretes the hormone melatonin,
secretion, oxytocin (a posterior pituitary hormone that which exerts inhibitory effects on gonadotropin secretion.
serves reproductive functions), or neurotensin (a neu- Feedback systems control FSH and LH secretion from
ropeptide). Finally, estrogens increase the response of the adenohypophysis. FSH and LH cause the gonads
prolactin-secreting cells in the adenohypophysis to PRH. to secrete gonadal hormones (estrogens, progestins,
Knowledge of the hypothalamic control of prolactin androgens, glycoproteins), that can decrease (by nega-
secretion is important because of this hormone’s role in tive feedback) further secretion of FSH and LH. Estrogen
milk synthesis by the mammary glands (see Chapter 12) also can have a positive feedback effect on LH secre-
and the association of abnormally high levels of PRL tion in women. Prolactin secretion from the pars dista-
with certain kinds of infertility (see Chapter 15). lis is controlled by a prolactin release-inhibiting factor
(dopamine) from the hypothalamus, along with possible
SUMMARY prolactin-releasing factors.
Exocrine glands secrete their products directly into

Further Reading
ducts, whereas endocrine glands release their products
(hormones) into the bloodstream. Specific hormones Adlerkreutz, H., Mazur, W., 1997. Phyto-estrogens and Western diseases.
Ann. Med. 29, 95–120.
influence the growth and function of certain target tis-
Blanco, S.D., Kaiser, U.B., 2009. The genetic and molecular basis of
sues. Hormones can be proteins or smaller polypeptides, idiopathic hypogonadotropic hypogonadism. Nat. Rev. Endocrinol.
amines, steroids, or fatty acid derivatives. Methods used 5, 569–576.
in the science of endocrinology include bioassay, radio- Caprio, M., et al., 2002. Leptin in reproduction. Trends Endocrinol.
immunoassay, nonradioactive methods such as ELISA, Metab. 12, 65–72.
Cullinan, W.E., et al., 2008. Functional role of local GABAergic influ-
and molecular techniques. Paracrines are local chemical
ences on the HPA axis. Brain Struct. Funct. 213, 63–72.
messengers that are not transported in the blood. Edson, M.A., et al., 2009. The mammalian ovary from genesis to revela-
The pituitary (hypophysis) has two major parts: the tion. Endocr. Rev. 30, 624–712.
neurohypophysis and the adenohypophysis. Neurose- Gordon, K., Hodgen, G.D., 1992. Evolving role of gonadotropin-releasing
cretory neurons in the hypothalamus synthesize oxytocin hormone antagonists. Trends Endocrinol. Metab. 3, 259–263.
Guerra, M., et al., 2010. Cell organization of the rat pars tuberalis: evi-
and vasopressin, which travel to the neurohypophysis
dence for open communication between pars tuberalis cells, cere-
in neurosecretory cell axons. The adenohypophysis con- brospinal fluid and tanycytes. Cell Tissue Res. 339, 219–222.
tains three regions: the pars distalis, pars tuberalis, and Kalra, S.P., 1993. Mandatory neuropeptide-steroid signaling for the
pars intermedia (reduced or absent in humans). Cells preovulatory luteinizing hormone-releasing hormone discharge.
in the pars distalis secrete follicle-stimulating hormone, Endocr. Rev. 14, 507–538.
Kaur, K.K., et al., 2012. Kisspeptins in human reproduction—future
luteinizing hormone, prolactin, corticotropin, growth
therapeutic potential. J. Assist. Reprod. Genet. 10, 999–1011.
hormone, thyrotropin, lipotropin, endorphins, and Krsmanovic, L.Z., et al., 2009. The hypothalamic GnRH pulse genera-
enkephalins. Other pituitary cells secrete melanophore- tor: multiple regulatory mechanisms. Trends Endocrinol. Metab.
stimulating hormone, and the pars tuberalis could also 20, 402–408.
secrete FSH and LH. McDonnell, D.P., 1999. The molecular pharmacology of SERMs. Trends
Endocrinol. Metab. 10, 301–311.
Neurosecretory neurons in the hypophysiotropic
Nillsson, S., et al., 1998. ERß: a novel estrogen receptor offers the potential
area of the hypothalamus secrete releasing hormones or for new drug development. Trends Endocrinol. Metab. 9, 387–395.
release-inhibiting hormones into the median eminence Peyeon, C., et al., 2009. Role of melanin-concentrating hormone neuro-
region at the base of the hypothalamus. Here, capillaries peptin in sleep regulation. Peptides 30, 2052–2059.

Roseweir, A.K., Millar, R.P., 2009. The role of kisspeptin in the control Stojilkovic, S.S., et al., 1994. Gonadotropin-releasing hormone neurons:
of gonadotrophin secretion. Hum. Reprod. Update 15, 203–212. intrinsic pulsatility and receptor-mediated regulation. Trends
Rothman, M.S., Wierman, M.E., 2008. Female hypogonadism: evalu- Endocrinol. Metab. 5, 201–209.
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Schwanzel-Fukuda, M., et al., 1992. Biology of luteinizing hormone- Tsusumi, R., Webster, N.J., 2009. GnRH pulsatility: the pituitary re-
releasing hormone neurons during and after their migration from sponse and reproductive dysfunction. Endocr. J. 56, 729–737.
the olfactory placode. Endocr. Rev. 13, 623–634. Tsutsui, K., et al., 2012. Gonadotropin-inhibitory hormone: discovery,
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Human Reproductive Biology

To my wife, Betty, and my four sons,

INTRODUCTION endocrine cells secrete products called hormones and

I. ADULT FEMALE AND MALE REPRODUCTIVE SYSTEMS

I. ADULT FEMALE AND MALE REPRODUCTIVE SYSTEMS

FIGURE 1.5 Mechanism of action of a peptide hormone. The l­igand

I. ADULT FEMALE AND MALE REPRODUCTIVE SYSTEMS

I. ADULT FEMALE AND MALE REPRODUCTIVE SYSTEMS

Secretion and Metabolism of Hormones

I. ADULT FEMALE AND MALE REPRODUCTIVE SYSTEMS

GnRH MIMICS AND BLOCKERS

I. ADULT FEMALE AND MALE REPRODUCTIVE SYSTEMS

BOX 1.1 (cont’d)

The effects of various GnRH analogs.

I. ADULT FEMALE AND MALE REPRODUCTIVE SYSTEMS

I. ADULT FEMALE AND MALE REPRODUCTIVE SYSTEMS

I. ADULT FEMALE AND MALE REPRODUCTIVE SYSTEMS

I. ADULT FEMALE AND MALE REPRODUCTIVE SYSTEMS

Pars distalis of adenohypophysis

Pigment Fat cells

Mammary Ovaries Thyroid Kidney

I. ADULT FEMALE AND MALE REPRODUCTIVE SYSTEMS

I. ADULT FEMALE AND MALE REPRODUCTIVE SYSTEMS

FIGURE 1.15 When a single injection of GnRH is administered to Prepro-GnRH

I. ADULT FEMALE AND MALE REPRODUCTIVE SYSTEMS

I. ADULT FEMALE AND MALE REPRODUCTIVE SYSTEMS

KALLMANN SYNDROME AND THE ORIGIN AND

I. ADULT FEMALE AND MALE REPRODUCTIVE SYSTEMS

Arcuate nucleus of hypothalamus

Input Controller Output Feedback

Feedback loop Change Gonadal

I. ADULT FEMALE AND MALE REPRODUCTIVE SYSTEMS

I. ADULT FEMALE AND MALE REPRODUCTIVE SYSTEMS

Exocrine glands secrete their products directly into

I. ADULT FEMALE AND MALE REPRODUCTIVE SYSTEMS

I. ADULT FEMALE AND MALE REPRODUCTIVE SYSTEMS

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FIGURE 1.5 Mechanism of action of a peptide hormone. The ligand