8.

1 If the body is to function as an integrated whole, its organs must communicate with each
other and coordinate their activities. Even very simple organisms composed of only a few cells
have mechanisms for intercellular communication, suggesting that such mechanisms evolved
very early in the history of life. In humans, two such systems are especially prominent the
nervous and endocrine systems, which communicate with neurotransmitters and hormones,
respectively. The glands, tissues, and cells that secrete hormones constitute the endocrine
system; such as the pituitary, thyroid, and adrenal glands, among others.
Hypothalamic Hormones
To understand the physiology of the hypothalamic– pituitary system, we must begin with
the hormones produced in the hypothalamus. There are eight of these six to regulate the anterior
pituitary and two that are stored in the posterior pituitary and released on demand. The first six
are described as releasing hormones if they stimulate pituitary cells to secrete hormones of their
own, or inhibiting hormones if they suppress pituitary secretion. The releasing or inhibiting
effect is identified in their names. Somatostatin is also called growth hormone inhibiting
hormone, though it also inhibits secretion of thyroid-stimulating hormone. Its name derives from
somatotropin, a synonym for growth hormone, and stat, meaning to halt something (in this case,
growth hormone secretion). The other two hypothalamic hormones are oxytocin (OT) and
antidiuretic hormone (ADH). These are stored and released by the posterior pituitary. OT comes
mainly from neurons in the right and left paraventricular nuclei of the hypothalamus, so called
because they lie in the walls of the third ventricle. ADH comes mainly from the supraoptic
nuclei, named for their location just above the optic chiasm. Each nucleus also produces small
quantities of the other hormone. ADH and OT are treated as posterior pituitary hormones for
convenience even though the posterior lobe does not synthesize them.
Anterior Pituitary Hormones The anterior lobe of the pituitary synthesizes and secretes six
principal hormonesThe first two are collectively called gonadotropins9 because they target the
ovaries and testes (gonads).
1. Follicle-stimulating hormone (FSH). FSH is secreted by pituitary cells called gonadotropes. In
the ovaries, it stimulates the secretion of ovarian sex hormones and the development of the
bubblelike follicles that contain the eggs. In the testes, it stimulates sperm production.
2. Luteinizing hormone (LH). LH is also secreted by the gonadotropes. In females, it stimulates
ovulation, the release of an egg. It is named for the fact that after ovulation, the follicle becomes
a yellowish body called the corpus luteum.10 LH also stimulates the corpus luteum to secrete
progesterone, a hormone important in pregnancy. In males, LH stimulates the testes to secrete
testosterone.
3. Thyroid-stimulating hormone (TSH), or thyrotropin. TSH is secreted by pituitary cells called
thyrotropes. It stimulates growth of the thyroid gland and the secretion of thyroid hormone,
which has widespread effects on metabolic rate, body temperature, and other functions detailed
later.
4. Adrenocorticotropic hormone (ACTH), or corticotropin. ACTH is secreted by cells called
corticotropes. Its target organ and the basis for its name is the adrenal cortex, studied later in this
chapter. ACTH stimulates the cortex to secrete hormones called glucocorticoids (especially
cortisol), which regulate glucose, protein, and fat metabolism and are important in the body’s
response to stress.
5. Prolactin (PRL). PRL is secreted by pituitary cells called lactotropes (mammotropes). The
hormone and these cells are named for the role of PRL in lactation. During pregnancy, the
lactotropes increase greatly in size and number, and PRL secretion rises proportionately, but it
has no effect on the mammary glands until after a woman gives birth. Then, it stimulates them to
synthesize milk. In males, PRL makes the testes more sensitive to LH, but it is not yet clear
whether this is physiologically significant.
6. Growth hormone (GH), or somatotropin. GH is secreted by somatotropes, the most numerous
cells of the anterior pituitary. The pituitary produces at least a thousand times as much GH as any
other hormone. The general effect of GH is to stimulate mitosis and cellular differentiation and
thus to promote tissue growth throughout the body. You can see that the anterior pituitary is
involved in a chain of events linked by hormones: The hypothalamus secretes a releasing or
inhibiting hormone; this induces a type of pituitary cell to secrete its hormone; that hormone is
usually targeted to another endocrine gland elsewhere in the body; and finally that gland secretes
a hormone with an effect of its own. For example, the hypothalamus secretes thyrotropin-
releasing hormone (TRH); this induces the anterior pituitary to secrete thyroid-stimulating
hormone (TSH, or thyrotropin); TSH, in turn, stimulates the thyroid gland to release thyroid
hormone (TH); and finally, thyroid hormone exerts its metabolic effects throughout the body.
Such a relationship between the hypothalamus, pituitary, and another downstream endocrine
gland is called an axis—the hypothalamo–pituitary–thyroid axis, for example
The Pars Intermedia
The pars intermedia is nearly absent from the adult human pituitary, but present in other
animals and the human fetus. In other species, it secretes melanocyte-stimulating hormone
(MSH), which influences pigmentation of the skin, hair, or feathers. It was once thought to have
a similar effect on human skin, but evidence now indicates that humans have no circulating
MSH. Some anterior lobe cells derived from the fetal pars intermedia produce a polypeptide
called proopiomelanocortin (POMC). POMC is not s ecreted, but is processed within the p
ituitary to yield fragments such as ACTH and pain-inhibiting endorphins.
Posterior Pituitary Hormones
The two posterior lobe hormones are ADH and OT. As we have already seen, they are
synthesized in the hypothalamus, then transported to the posterior pituitary and stored until their
release on command. Their functions are as follows:
1. Antidiuretic hormone (ADH). ADH increases water retention by the kidneys, reduces urine
volume, and helps prevent dehydration. ADH also functions as a brain neurotransmitter and is
usually called arginine vasopressin (AVP) in the neuroscience literature. This name refers to its
ability to cause vasoconstriction, but this effect requires concentrations so unnaturally high for
the human body that it is of doubtful significance except in pathological states.
2. Oxytocin (OT). OT has a variety of reproductive functions in situations ranging from
intercourse to breast-feeding. It surges in both sexes during sexual arousal and orgasm, possibly
aiding in the propulsion of semen through the male reproductive tract and stimulating uterine
contractions that help transport sperm up the female tract. OT also evidently functions in feelings
of sexual satisfaction and emotional bonding between partners. In childbirth, it stimulates labor
contractions, and in lactating mothers, it stimulates the flow of milk from acini deep in the
mammary gland to the nipple, where it is accessible to the infant. It may also promote emotional
bonding between the mother and infant. In the absence of oxytocin, other female mammals tend
to neglect their helpless infants.
8.2 The classical distinction between exocrine and endocrine glands has been the presence or
absence of ducts. Most exocrine glands secrete their products by way of a duct onto an epithelial
surface such as the skin or the mucosa of the digestive tract. Endocrine glands, by contrast, are
ductless and release their secretions into the bloodstream. For this reason, hormones were
originally called the body’s “internal secretions”; the word endocrine still alludes to this fact.
Exocrine secretions have extracellular effects such as the digestion of food, whereas endocrine
secretions have intracellular effects they alter cell metabolism. Endocrine glands have an
unusually high density of blood capillaries, which serve to pick up and carry away their
hormones. These vessels are an especially permeable type called fenestrated capillaries, which
have patches of large pores in their walls allowing for the easy uptake of matter from the gland
tissue . Some glands and secretory cells defy simple classification as endocrine or exocrine.
Liver cells, for example, behave as exocrine cells in the traditional sense by secreting bile into
ducts that lead ultimately to the small intestine. However, they also secrete hormones into the
blood, and in this respect they act as endocrine cells. They secrete albumin and blood-clotting
factors directly into the blood as well. These do not fit the traditional concept of exocrine
secretions, because they are not released by way of ducts or onto epithelial surfaces; nor do they
fit the concept of endocrine secretions, because they are not hormones. Liver cells are just one of
nature’s myriad ways of confounding our impulse to rigidly classify things.
When a stimulus ceases, the nervous system stops responding almost immediately,
whereas some endocrine effects persist for several days or even weeks. On the other hand, under
long-termstimulation, most neurons quickly adapt and their response declines. The endocrine
system shows more persistent responses. Another difference between the two systems is that an
efferent nerve fiber innervates only one organ and a limited number of cells within that organ;
its effects, therefore, are precisely targeted and relatively specific. Hormones, by contrast,
circulate throughout the body and some of them, such as growth hormone, epinephrine, and
thyroid hormone, have more widespread effects than does the output of any one nerve fiber. But
these differences should not blind us to the similarities between the two systems. Several
chemicals function as both neurotransmitters and hormones, including norepinephrine,
dopamine, thyrotropin releasing hormone, and antidiuretic hormone (arginine vasopressin).
Some hormones, such as oxytocin and epinephrine, are secreted by neuroendocrine cellsneurons
that release their secretions into the bloodstream.
Some hormones and neurotransmitters produce overlapping effects on the same organ.
For example, glucagon and norepinephrine stimulate the liver to break down glycogen and
release glucose into the blood. The nervous and endocrine systems continually regulate each
other as they coordinate the activities of other organ systems. Neurons often trigger hormone
secretion, and hormones often stimulate or inhibit neurons. We have seen that neurotransmitters
depend on receptors in the receiving cell; they cannot exert any effect unless the receiving cell is
equipped to bind and respond to them. This is true of hormones as well. When a hormone enters
the bloodstream, it goes w herever the blood goes; there is no way to send it selectively to a
particular organ. However, only certain target organs or target cells respond to it. Thyroid-
stimulating hormone, for example, circulates everywhere the blood goes, but stimulates only the
thyroid gland. In most cases, this is because only the target cells have receptors for a given
hormone. Such selective responses can also occur, however, because the circulating hormone is
in an inactive form and only the target cells have the enzyme needed to convert it to the active
form. Circulating testosterone, for example, is relatively inactive, but its target cells have an
enzyme that converts it to dihydrotestosterone, which is much more potent.
The Breasts and Mammary Glands
The breast is a mound of tissue overlying the pectoralis major muscle. It enlarges at
puberty and remains so for life, but most of this time it contains very little mammary gland. The
mammary gland develops within the breast during pregnancy, remains active in the lactating
breast, and atrophies when a woman ceases to nurse. The breast has two principal regions: the
conical to pendulous body, with the nipple at its apex, and an extension toward the armpit called
the axillary tail. Lymphatics of the axillary tail are especially important as a route of breast
cancer metastasis. The nipple is surrounded by a circular zone, the areola, usually darker than the
rest of the breast. Dermal blood capillaries and nerves come closer to the surface here than in the
surrounding skin, accentuating the color and sensitivity of the areola. Pregnancy increases
melanin deposition in the areola and nipple, making them more visible to the indistinct vision of
a nursing infant. Sensory nerve fibers of the areola are important in triggering a milk ejection
reflex when an infant nurses. The areola has sparse hairs and areolar glands, visible as small
bumps on the surface. These glands are intermediate between sweat glands and mammary glands
in their degree of development.
When a woman is nursing, secretions of the areolar glands and sebaceous glands protect
the areola and nipple from chapping and cracking. The dermis of the areola has smooth muscle
fibers that contract in response to cold, touch, and sexual arousal, wrinkling the skin and erecting
the nipple. Internally, the nonlactating breast consists mostly of adipose and collagenous
tissue.Breast size is determined by the amount of adipose tissue and has no relationship to the
amount of milk the mammary gland can produce. Suspensory ligaments attach the breast to the
dermis of the overlying skin and to the fascia of the pectoralis major. Although the nonlactating
breast contains little glandular tissue, it does have a system of ducts branching through its fibrous
stroma and converging on the nipple. When the mammary gland develops during pregnancy, it
exhibits 15 to 20 lobes arranged radially around the nipple, separated from each other by stroma.
Each lobe is drained by a lactiferous23 duct, which dilates to form a lactiferous sinus opening
onto the nipple. Distally, each duct branches repeatedly with the finest branches ending in sacs
called acini. The acini are organized into grapelike clusters (lobules) within each lobe of the
breast. Each acinus consists of a sac of pyramidal secretory cells arranged around a central. Like
an orange in a mesh bag, the acinus is surrounded by a network of contractile myoepithelial cells
Their role in milk release, and other aspects of the lactating breast.
Breast Cancer Breast cancer occurs in one out of every eight or nine American women
and is one of the leading causes of female mortality. Breast tumors begin with cells of the
mammary ducts and may metastasize to other organs by way of the mammary and axillary
lymphatics. Signs of breast cancer include a palpable lump (the tumor), puckering of the skin,
changes in skin texture, and drainage from the nipple. Two breast cancer genes were discovered
in the 1990s, named BRCA1 and BRCA2, but most breast cancer is nonhereditary. Some breast
tumors are stimulated by estrogen. Consequently, breast cancer is more common among women
who begin menstruating early in life and who reach menopause relatively late—that is, women
who have a long period of fertility and estrogen exposure. Other risk factors include aging,
exposure to ionizing radiation and carcinogenic chemicals, excessive alcohol and fat intake, and
smoking. Over 70% of cases, however, lack any identifiable risk factors. The majority of tumors
are discovered during breast self-examination (BSE), which should be a monthly routine for all
women. Mammograms (breast X-rays), however, can detect tumors too small to be noticed by
BSE. Although opinions vary, a schedule commonly recommended is to have a baseline
mammogram in the late 30s and then have one every 2 years from ages 40 to 49 and every year
beginning at age 50. Treatment of breast cancer is usually by lumpectomy (removal of the tumor
only) or simple mastectomy (removal of the breast tissue only or breast tissue and some axillary
lymph nodes). Radical mastectomy, rarely done since the 1970s, involves the removal of not
only the breast but also the underlying muscle, fascia, and lymph nodes. Although very
disfiguring, it proved to be no more effective than simple mastectomy or lumpectomy. Surgery is
generally followed by radiation or chemotherapy, and estrogen-sensitive tumors may also be
treated with an estrogen blocker such as tamoxifen. A natural looking breast can often be
reconstructed from skin, fat, and muscle from other parts of the body.
8.3 The development and metabolism of most tissues are affected by growth hormone, insulin,
insulin-like growth factors, thyroid hormone, and glucocorticoids.
Muscular system Growth hormone and testosterone stimulate muscular growth; insulin
regulates glucose uptake by muscle; other hormones regulate the electrolyte balances that are
important in muscular contraction.
Skeletal system  Skeletal growth and maintenance are regulated by numerous hormones—
calcitonin, calcitriol, parathyroid hormone, growth hormone, estrogen, testosterone, and others.
Integumentary system  Sex hormones affect skin pigmentation, development of body hair and
apocrine glands, and subcutaneous fat deposition.
Nervouse system  Hormones exert negative feedback inhibition on the hypothalamus; several
hormones affect nervous system development, mood, and behavior; hormones regulate the
electrolyte balances that are important in neuron function.
Reproductive system  Gonadotropins and sex steroids regulate sexual development,
spermatogenesis and oogenesis, the ovarian and uterine cycles, sex drive, pregnancy, fetal
development, and lactation.
Digestive system  Insulin and glucagon regulate nutrient storage and metabolism; enteric
hormones control gastrointestinal secretion and motility; gut–brain peptides affect appetite and
regulate food intake and body weight.
Lymphatic/immunity system  Thymic hormones activate immune cells; glucocorticoids
suppress immunity and inflammation.
Circulatory system  Angiotensin II, aldosterone, antidiuretic hormone, natriuretic peptides, and
other hormones regulate blood volume and pressure; erythropoietin stimulates RBC production;
thymic hormones stimulate WBC production; thrombopoietin stimulates platelet production;
epinephrine, thyroid hormone, and other hormones affect the rate and force of the heartbeat.
Respiratory system Epinephrine and norepinephrine dilate the bronchioles and increase
pulmonary airflow.
Urinary system  Antidiuretic hormone regulates urine volume; calcitriol, parathyroid hormone,
aldosterone, and natriuretic peptides regulate electrolyte absorption by the kidneys.
Feedback from Target Organs
The regulation of other endocrine glands by the pituitary is not simply a system of
“command from the top down.” Those target organs also regulate the pituitary and hypothalamus
through various feedback loops. Most often, this takes the form of negative feedback inhibition
—the pituitary stimulates another endocrine gland to secrete its hormone, and that hormone feeds
back to the pituitary or hypothalamus and inhibits further secretion of the pituitary hormone. The
hypothalamo–pituitary–thyroid axis as an example. The figure is numbered to correspond to the
following description:
1 The hypothalamus secretes thyrotropin-releasing hormone (TRH).
2 TRH stimulates the anterior pituitary to secrete thyroid-stimulating hormone (TSH).
3 TSH stimulates the thyroid gland to secrete thyroid hormone (TH).
4 TH stimulates the metabolism of most cells throughout the body.
5 TH also inhibits the release of TSH by the pituitary.
6 To a lesser extent, TH also inhibits the release of TRH by the hypothalamus.
The negative feedback inhibition in this process consists of steps 5 and 6. It ensures that
when the TH level is high, TSH secretion remains moderate. If thyroid hormone secretion drops,
TSH secretion rises and stimulates the thyroid to secrete more hormone. This feedback keeps
thyroid hormone levels oscillating around a set point in typical homeostatic fashion. Feedback
from a target organ is not always inhibitory. Oxytocin triggers a positive feedback cycle during
labor . Uterine stretching sends a nerve signal to the brain that stimulates OT release. OT
stimulates uterine contractions, which push the infant downward. This stretches the lower end of
the uterus some more, which results in a nerve signal that stimulates still more OT release. This
positive feedback cycle continues until the infant is born.

8.4 The hormone secreted from the endocrine glands

Hyposecretion and Hypersecretion
Inadequate hormone release is called hyposecretion. It can result from tumors or lesions
that destroy an endocrine gland or interfere with its ability to receive signals from another gland.
For example, a fractured sphenoid bone can sever the hypothalamo–hypophyseal tract and thus
prevent the transport of oxytocin and antidiuretic hormone (ADH) to the posterior pituitary. The
resulting ADH hyposecretion disables the water-conserving capability of the kidneys and leads
to diabetes insipidus, a condition of chronic polyuria without glucose in the urine. (Insipidus
means “without taste” and refers to the lack of sweetness of the glucose-free urine, in contrast to
the sugary urine of diabetes mellitus.) Autoimmune diseases can also lead to hormone
hyposecretion when endocrine cells are attacked by autoantibodies—antibodies that fail to
distinguish foreign matter from one’s own tissues. This is one of the causes of diabetes mellitus.
Excessive hormone release, called hypersecretion, has multiple causes. Some tumors result in the
overgrowth of functional endocrine tissue. A pheochromocytoma, for example, is a tumor of the
adrenal medulla that secretes excessive amounts of epinephrine and norepinephrine. Some
tumors in nonendocrine organs produce hormones. For example, some lung tumors secrete
ACTH and overstimulate cortisol secretion by the adrenal gland. Whereas certain autoimmune
disorders can cause endocrine hyposecretion, others cause hypersecretion. An example of this is
toxic goiter, in which autoantibodies mimic the effect of TSH on the thyroid, causing thyroid
hypersecretion. Endocrine hypersecretion disorders can also be mimicked by excess or long-term
clinical administration of hormones such as cortisol.
Puberty begins at ages 8 to 10 for most girls in the United States and Europe, but
significantly later in many countries. However, a 1997 study of more than 17,000 girls in the
United States showed 3% of black girls and 1% of white girls beginning puberty by age 3, and
27% and 7%, respectively, by age 7. Puberty is triggered by the same hypothalamic and pituitary
hormones in girls as it is in boys. Rising levels of gonadotropin-releasing hormone (GnRH)
stimulate the anterior lobe of the pituitary to secrete follicle-stimulating hormone (FSH) and
luteinizing hormone (LH). FSH, especially, stimulates development of the ovarian follicles,
which, in turn, secrete estrogens, progesterone, inhibin, and a small amount of androgen. These
hormone levels rise gradually from ages 8 to 12 and then more sharply in the early teens. The
estrogens24 are feminizing hormones with widespread effects on the body. They include
estradiol (the most abundant), estriol, and estrone.
Most of the visible changes at puberty result from estradiol and androgens. The earliest
noticeable sign of puberty is the onset of breast development. Estrogen, progesterone, and
prolactin initially induce the formation of lobules and ducts in the breast. Duct development is
completed under the influence of glucocorticoids and growth hormone, while adipose and
fibrous tissue enlarge the breast. Breast development is complete around age 20, but minor
changes occur in each menstrual cycle and major changes occur in pregnancy. Thelarche is soon
followed by pubarche, the appearance of pubic and axillary hair, sebaceous glands, and axillary
glands. Androgens from the ovaries and adrenal cortex stimulate pubarche as well as the libido.
Women secrete about 0.5 mg of androgens per day, compared with 6 to 8 mg/day in men. Next
comes menarche, the first menstrual period.This is about the minimum needed to sustain
pregnancy and lactation; thus, the body reacts as if to prevent a futile pregnancy when it is too
lean. In addition to its role in regulating appetite, leptin stimulates gonadotropin secretion.
Therefore, if body fat and leptin levels drop too low, gonadotropin secretion declines and a girl’s
or woman’s menstrual cycle may cease. Adolescent girls with very low body fat, such as avid
dancers and gymnasts, tend to begin menstruating at a later age than average. Menarche does not
necessarily signify fertility. A girl’s first few menstrual cycles are typically anovulatory (no egg
is ovulated). Most girls begin ovulating regularly about a year after they begin menstruating.
Estradiol stimulates many other changes of puberty. It causes the vaginal metaplasia described
earlier. It stimulates growth of the ovaries and secondary sex organs. It stimulates growth
hormone secretion and causes a rapid increase in height and widening of the pelvis. Estradiol is
largely responsible for the feminine physique because it stimulates fat deposition in the mons
pubis, labia majora, hips, thighs, buttocks, and breasts. It makes a girl’s skin thicken, but the skin
remains thinner, softer, and warmer than in males of corresponding age. Progesterone27 acts
primarily on the uterus, preparing it for possible pregnancy in the second half of each menstrual
cycle and playing roles in pregnancy discussed later. Estrogens and progesterone also suppress
FSH and LH secretion through negative feedback inhibition of the anterior pituitary. Inhibin
selectively suppresses FSH secretion. Thus, we see many hormonal similarities in males and
females from puberty onward. The sexes differ less in the identity of the hormones that are
present than in their relative amounts—high levels of androgens and low levels of estrogens in
males and the opposite in females. Another difference is that these hormones are secreted more
or less continually and simultaneously in males, whereas in females, secretion is distinctly cyclic
and the hormones are secreted in sequence. This will be very apparent as you read about the
ovarian and menstrual cycles.
Menopause A female is born with about 2 million eggs in her ovaries, each in its own
follicle. The older she gets, the fewer follicles remain. Climacteric begins not at any specific age,
but when she has only about 1,000 follicles left. Even the remaining follicles are less responsive
to gonadotropins, so they secrete less estrogen and progesterone. Without these steroids, the
uterus, vagina, and breasts atrophy. Intercourse may become uncomfortable, and vaginal
infections more common, as the vagina becomes thinner, less distensible, and drier. The skin
becomes thinner, cholesterol levels rise (increasing the risk of cardiovascular disease), and bone
mass declines (increasing the risk of osteoporosis). Blood vessels constrict and dilate in response
to shifting hormone balances, and the sudden dilation of cutaneous arteries may cause hot
flashes a spreading sense of heat from the abdomen to the thorax, neck, and face. Hot flashes
may occur several times a day, sometimes accompanied by headaches resulting from the sudden
vasodilation of arteries in the head. In some people, the changing hormonal profile also causes
mood changes. Many physicians prescribe hormone replacement therapy (HRT) low doses of
estrogen and progesterone usually taken orally or by a skin patch—to relieve some of these
symptoms. The risks and benefits of HRT are still being debated.
Menopause is the cessation of menstrual cycles, usually occurring between the ages of 45
and 55. The average age has increased steadily in the last century and is now about 52. It is
difficult to precisely establish the time of menopause because the menstrual periods can stop for
several months and then begin again. Menopause is generally considered to have occurred when
there has been no menstruation for a year or more.
The Ovarian Cycle
We will now see, in three principal steps, what happens in the ovaries and in their
relationship to the hypothalamus and pituitary gland. Much remains unknown about the timing of
folliculogenesis. Authorities disagree on how many weeks or months it takes a selected follicle
to reach the point of maturity and ovulation. One view, adopted here, is that the follicle that
ovulates in a given cycle is not the one that began developing in that cycle 2 weeks earlier, but
one that began 2 months earlier. We do not see one wave of oogenesis end before the next one
begins, but overlapping waves of oogenesis, each spanning parts of three monthly cycles.
1. Follicular phase. The follicular phase of the cycle extends from the beginning of
menstruation until ovulation—that is, from day 1 to day 14 in an average cycle. The portion from
the end of menstruation until ovulation is also called the preovulatory phase. The follicular phase
is the most variable part of the cycle, so unfortunately for family planning or pregnancy
avoidance, it is seldom possible to reliably predict the date of ovulation. Preparation for the
follicular phase begins almost 2 months earlier. Shortly after ovulation in month 1, a new cohort
of preantral follicles descends from the cortex deeper into the ovary and begins to grow. Each
follicle develops an antrum and attains a diameter of about 2 mm by late month. At that time,
there is a 5-day selection window in which one of them is selected to mature and ovulate in the
next month. That follicle is called the dominant follicle.
This is the state of things going into month During the follicular phase, FSH stimulates
continued growth of all follicles in the cohort, but of the dominant follicle above all. FSH
stimulates the granulosa cells of the antral follicles to secrete estradiol. In response to estradiol,
the dominant follicle up-regulates its receptors for FSH, LH, and estradiol itself, thereby
becoming increasingly s ensitive to these hormones. At the same time, estradiol inhibits the
secretion of gonadotropin-releasing hormone (GnRH) by the hypothalamus. The anterior
pituitary gland secretes less and less FSH, but an increasing amount of LH. Most antral follicles
suffer from the reduced FSH level and degenerate (undergo atresia). The dominant follicle,
however, has the richest blood supply and the greatest density of FSH receptors, so it continues
to grow, reaching a diameter of about 20 mm by the late follicular phase. It is then regarded as
the mature (graafian) follicle.
2. Ovulation. Ovulation is the rupture of the mature follicle and the release of its egg and
attendant cells, typically around day 14. Dramatic changes over the preceding day signify its
imminence. LH induces several momentous events. The primary oocyte completes meiosis I,
producing a haploid secondary oocyte and the first polar body. Follicular fluid builds rapidly and
the follicle swells to as much as 25 mm in diameter—more than twice the usual thickness of the
ovary. It looks like a blister on the surface of the ovary. The follicular wall and adjacent ovarian
tissue are weakened by inflammation and a proteolytic enzyme. With mounting internal pressure
and a weakening wall, the mature follicle approaches rupture. Meanwhile, the uterine tube
prepares to catch the oocyte when it emerges. It swells with edema; its fimbriae envelop and
caress the ovary in synchrony with the woman’s heartbeat; and its cilia create a gentle current in
the nearby peritoneal fluid. Ovulation itself takes only 2 or 3 min. A nipplelike stigma appears
on the ovarian surface over the follicle. It seeps follicular fluid for 1 or 2 min., and then the
follicle bursts. The remaining fluid oozes out, carrying the oocyte and cumulus
3. Luteal phase. Days 15 to 28, from just after ovulation to the onset of menstruation, are called
the luteal (postovulatory) phase. Assuming pregnancy does not occur, the major events of this
phase are as follows. When the follicle ruptures, it collapses and bleeds into the antrum. As the
clotted blood is slowly absorbed, granulosa and theca interna cells multiply and fill the antrum,
and a dense bed of blood capillaries grows amid them. The ovulated follicle has now become a
structure called the corpus luteum,35 named for a yellow lipid that accumulates in the theca
interna cells. These cells are now called lutein cells. The transformation from ruptured follicle to
corpus luteum is regulated by LH; hence, LH is also called luteotropic hormone. LH stimulates
the corpus luteum to continue growing and to secrete rising levels of estradiol and progesterone.
The most important aspect of the luteal phase is a 10-fold increase in progesterone level. This
hormone has a crucial role in preparing the uterus for the possibility of pregnancy.
Notwithstanding its luteinizing role, however, LH secretion declines steadily over the rest of the
cycle, as does FSH. This is because the high levels of estradiol and progesterone, along with
inhibin from the corpus luteum, have a negative feedback effect on the pituitary. (This is the
basis for hormonal birth control) If pregnancy does not occur, the corpus luteum begins a process
of involution, or shrinkage, beginning around day 22 (8 days after ovulation). By day 26,
involution is complete and the corpus luteum has become an inactive bit of scar tissue called the
corpus albicans.
 With the waning of ovarian steroid secretion, the pituitary is no longer inhibited and FSH
levels begin to rise again, ripening a new cohort of follicles. All of these events repeat
themselves every month, but bear in mind that the follicles engaged in each monthly cycle began
their development prenatally, as much as 50 years earlier, and the oocyte that ovulates each
month may have begun ripening 2 months earlier, not necessarily in the cycle when it ovulates.
Follicle maturation and ovulation normally occur in only one ovary per cycle, and the ovaries
usually alternate from month to month.
The Menstrual Cycle
The menstrual cycle runs concurrently with the ovarian cycle. It consists of a buildup of
the endometrium through most of the sexual cycle, followed by its breakdown and aginal
discharge. It is divided into a proliferative phase, secretory phase, premenstrual phase, and
menstrual phase. The menstrual phase averages 5 days long, and the first day of noticeable
vaginal discharge is defined as day 1 of the sexual cycle. But even though it begins our artificial
timetable for the cycle, the reason for menstruation is best understood after you become
acquainted with the build up of endometrial tissue that precedes it.
1. Proliferative phase. The layer of endometrial tissue (stratum functionalis) lost in the last
menstruation is rebuilt during the proliferative phase. At the end of menstruation, around day 5,
the endometrium is about 0.5 mm thick and consists only of the stratum basalis. But as a new
cohort of follicles develops, they secrete more and more estrogen. Estrogen stimulates mitosis in
the stratum basalis and the prolific regrowth of blood vessels, thus regenerating the functionalis
(fig. 28.16a). By day 14, the endometrium is 2 to 3 mm thick. Estrogen also stimulates
endometrial cells to produce progesterone receptors, priming them for the progesterone-
dominated secretory phase to follow.
2. Secretory phase. The endometrium thickens still more during the secretory phase, but as a
result of secretion and fluid accumulation rather than mitosis. This phase extends from day 15
(after ovulation) to day 26 of a typical cycle. After ovulation, the corpus luteum secretes mainly
progesterone. This hormone stimulates the endometrial glands to secrete glycogen. The glands
grow wider, longer, and more coiled, and the lamina propria swells with tissue fluid (fig.
28.16b). By the end of this phase, the endometrium is 5 to 6 mm thick—a soft, wet, nutritious
bed available for embryonic development in the event of pregnancy.
3. Premenstrual phase. The last 2 days or so of the cycle are the premenstrual phase, a period of
endometrial degeneration. As we have already seen, when there is no pregnancy, the corpus
luteum atrophies and the progesterone level falls sharply. The drop in progesterone triggers
spasmodic contractions of the spiral arteries of the endometrium, causing endometrial ischemia
(interrupted blood flow). The premenstrual phase is therefore also called the ischemic phase.
Ischemia brings on tissue necrosis (and menstrual cramps). As the endometrial glands, stroma,
and blood vessels degenerate, pools of blood accumulate in the stratum functionalis. Necrotic
endometrium falls away from the uterine wall, mixes with blood and serous fluid in the lumen,
and forms the menstrual fluid.
Menstrual phase, when enough menstrual fluid accumulates in the uterus, it begins to be
discharged from the vagina for a period called the menstrual phase (menses). The first day of
discharge marks day 1 of a new cycle. The average woman expels about 40 mL of blood and 35
mL of serous fluid over a 5-day period. Menstrual fluid contains fibrinolysin, so it does not clot.
The vaginal discharge of clotted blood may indicate uterine pathology rather than normal
menstruation. In summary, the ovaries go through a follicular phase characterized by growing
follicles, then ovulation, and then a postovulatory (mostly luteal) phase dominated by the corpus
luteum. The uterus, in the meantime, goes through a menstrual phase in which it discharges its
stratum functionalis; then a proliferative phase in which it replaces that tissue by mitosis; then a
secretory phase in which the endometrium thickens by the accumulation of secretions; and
finally, a premenstrual (ischemic) phase in which the stratum functionalis breaks down again.
The first half of the cycle is governed largely by follicle-stimulating hormone (FSH) from the
pituitary gland and estrogen from the ovaries. Ovulation is triggered by luteinizing hormone
(LH) from the pituitary, and the second half of the cycle is governed mainly by LH and
progesterone, the latter secreted by the ovaries.
Hormones of Pregnancy
The hormones with the strongest influences on pregnancy are estrogens, progesterone,
human chorionic gonadotropin, and human chorionic somatomammotropin. The levels of these
hormones in the maternal blood over the course of the pregnancy provide a good indicator of the
well-being of the fetus. They are secreted primarily by the placenta, but the corpus luteum is an
important source of hormones in the first several weeks. If the corpus luteum is removed before
week 7, abortion almost always occurs. From weeks 7 to 17, the corpus luteum degenerates and
the placenta takes over its endocrine functions. Human Chorionic Gonadotropin Human
chorionic gonadotropin (HCG) is secreted by the blastocyst and placenta. Its presence in the
urine is the basis of pregnancy tests and can be detected with home testing kits as early as 8 or 9
days after conception. HCG secretion peaks around 10 to 12 weeks and then falls to a relatively
low level for the rest of gestation (fig. 28.18). Like LH, it stimulates growth of the corpus
luteum, which doubles in size and secretes increasing amounts of progesterone and estrogen.
Without HCG, the corpus luteum would atrophy and the uterus would expel the conceptus.
Estrogens secretion increases to about 30 times the usual amount by the end of gestation.
The corpus luteum is an important source of estrogen for the first 12 weeks; after that, it comes
mainly from the placenta. The adrenal glands of the mother and fetus secrete androgens, which
the placenta converts to estrogens. The most abundant estrogen of pregnancy is estriol, but its
effects are relatively weak; estradiol is less abundant but 100 times as potent. Estrogen stimulates
tissue growth in the fetus and mother. It causes the mother’s uterus and external genitalia to
enlarge, the mammary ducts to grow, and the breasts to increase to nearly twice their former size.
It makes the pubic symphysis more elastic and the sacroiliac joints more limber, so the pelvis
widens during pregnancy and the pelvic outlet expands during childbirth.
Progesterone The placenta secretes a great deal of progesterone, and early in the
pregnancy, so does the corpus luteum. Progesterone and estrogen suppress pituitary secretion of
FSH and LH, thereby preventing more follicles from developing during pregnancy. (This is the
basis for contraceptive pills and implants; see Deeper Insight 28.4, p. 1097 .) Progesterone also
suppresses uterine contractions so the conceptus is promotes the proliferation of decidual cells of
the endometrium, on which the blastocyst feeds. Once estrogen has stimulated growth of the
mammary ducts, progesterone stimulates development of the secretory acini—another step
toward lactation.
Human chorionic somatomammotropin (HCS) is secreted in amounts several times that
of all the other hormones combined, yet its function is the least understood. The placenta begins
secreting HCS around the fifth week and output increases steadily from then until term, in
proportion to the size of the placenta. HCS is sometimes called human placental lactogen
because, in other mammals, it causes mammary development and lactation; however, it does not
induce lactation in humans. Its effects seem similar to those of growth hormone, but weaker. It
also seems to reduce the mother’s insulin sensitivity and glucose usage such that the mother
consumes less glucose and leaves more of it for use by the fetus. HCS promotes the release of
free fatty acids from the mother’s adipose tissue, providing an alternative energy substrate for
her cells to use in lieu of glucose.Other Hormones Many other hormones induce additional
bodily changes in pregnancy.
A pregnant woman’s pituitary gland grows about 50% larger and produces markedly
elevated levels of thyrotropin, prolactin, and ACTH. The thyroid gland also enlarges about 50%
under the influence of HCG, pituitary thyrotropin, and human chorionic thyrotropin from the
placenta. Elevated thyroid hormone secretion increases the metabolic rate of the mother and
fetus. The parathyroid glands enlarge and stimulate osteoclast activity, liberating calcium from
the mother’s bones for fetal use. ACTH stimulates glucocorticoid secretion, which may serve
primarily to mobilize amino acids for fetal protein synthesis. Aldosterone secretion rises and
promotes fluid retention, contributing to the mother’s increased blood volume. The corpus
luteum and placenta secrete relaxin, which relaxes the pubic symphysis in other animals but does
not seem to have this effect in humans. In humans, it synergizes progesterone in stimulating the
multiplication of decidual cells in early pregnancy and promotes the growth of blood vessels in
the pregnant uterus.

8.5 Main disease and disorders of the endocrine system

Pituitary Disorders
The hypersecretion of growth hormone (GH) in adults causes acromegaly thickening of
the bones and soft tissues with especially noticeable effects on the hands, feet, and face. When it
begins in childhood or adolescence, GH hypersecretion causes gigantism and hyposecretion
causes pituitary dwarfism . Now that growth hormone is plentiful, made by genetically
engineered bacteria containing the human GH gene, pituitary dwarfism has become rare.
Thyroid and Parathyroid Disorders Congenital
Hypothyroidism is thyroid hyposecretion present from birth; it was formerly called
cretinism, now regarded as an insensitive term. Severe or prolonged adult hypothyroidism can
cause myxedema, and both can be treated with oral thyroid hormone. A more conspicuous, often
striking abnormality of the thyroid is endemic goiter. It results from a deficiency of dietary
iodine. Without iodine, the gland cannot synthesize TH. Without TH, the pituitary gland receives
no feedback and acts as if the thyroid were understimulated. It produces extra TSH, which
stimulates hypertrophy of the thyroid, visible as a swelling in the neck. Endemic goiter has
become almost nonexistent in developed countries because of the addition of iodine to table salt,
animal feeds, and fertilizers. It occurs most often in localities that have neither these benefits nor
access to iodine-rich seafood notably central Africa and mountainous regions of South America,
central Asia, and Indonesia. The word endemic refers to the occurrence of a disease in a defined
geographic locality. The parathyroids, because of their location and small size, are sometimes
accidentally removed in thyroid surgery or degenerate when neck surgeries cut off their blood
supply. Without hormone replacement therapy, the resulting hypoparathyroidism causes a rapid
decline in blood calcium level and leads to fatal tetany within 3 or 4 days. Hyperparathyroidism,
excess PTH secretion, is usually caused by a parathyroid tumor. It causes the bones to become
soft, deformed, and fragile; it raises the blood levels of calcium and phosphate ions; and it
promotes the formation of renal calculi (kidney stones) composed of calcium phosphate.
Adrenal Disorders
Cushing syndrome is excess cortisol secretion owing to any of several causes: ACTH
hypersecretion by the pituitary, ACTH-secreting tumors, or hyperactivity of the adrenal cortex
independently of ACTH. Cushing syndrome disrupts carbohydrate and protein metabolism,
leading to hyperglycemia, hypertension, muscular weakness, and edema. Muscle and bone mass
are lost rapidly as protein is catabolized. Some patients exhibit abnormal fat deposition between
the shoulders (“buffalo hump”) or in the face (“moon face”) Long-term hydrocortisone therapy
can have similar effects. Adrenogenital syndrome (AGS), the hypersecretion of adrenal
androgens, commonly accompanies Cushing syndrome. In children, AGS often causes
enlargement of the penis or clitoris and the premature onset of puberty. Prenatal AGS can result
in newborn girls exhibiting masculinized genitalia and being misidentified as boys. In women,
AGS produces such masculinizing effects as increased body hair, deepening of the voice, and
beard growth.
Diabetes Mellitus
The world’s most prevalent metabolic disease is diabetes mellitus, affecting about 7% of
the U.S. population and even more in areas such as Scandinavia and the Pacific Islands. It is the
leading cause of adult blindness, renal failure, gangrene, and the necessity for limb amputations,
and warrants a more extended discussion than the less common endocrine diseases. Diabetes
mellitus (DM) can be defined as a disruption of carbohydrate, fat, and protein metabolism
resulting from the hyposecretion or inaction of insulin. The classic signs and symptoms with
which patients often first report to a physician are “the three polys”: polyuria (excessive urine
output), polydipsia35 (intense thirst), and polyphagia (ravenous hunger). Blood and urine tests
can confirm a diagnosis of DM by revealing three further signs: hyperglycemia (elevated blood
glucose), glycosuria38 (glucose in the urine), and ketonuria (ketones in the urine). DM was
originally named for the sweetness of the urine stemming from glycosuria.
 A little knowledge of kidney physiology is necessary to understand why glycosuria and
polyuria occur. The kidneys filter blood plasma and convert the filtrate to urine. In a healthy
person, the kidney tubules remove all glucose from the filtrate and return it to the blood, so there
is little or no glucose in the urine. Water follows the glucose and other solutes by osmosis, so the
tubules also reclaim most of the water in the filtrate. But like any other carrier-mediated transport
system, there is a limit to how fast the glucose transporters of the kidney can work. The
maximum rate of reabsorption is called the transport maximum. In diabetes mellitus, glucose
enters the tubules so rapidly that it exceeds the Tm and the tubules cannot reabsorb it fast
enough. The excess passes through into the urine. Glucose and ketones in the tubules also raise
the osmolarity of the tubular fluid and cause osmotic dieresis water remains in the tubules with
these solutes, so large amounts of water are passed in the urine. This accounts for the polyuria,
dehydration, and thirst of diabetes. A person with untreated DM may pass 10 to 15 L of urine per
day, compared with 1 or 2 L in a healthy person.