Reproductive Physiology
BS. Nguyễn Hồng Anh
KEY POINTS
1 The female reproductive process involves the central nervous system (primarily
hypothalamus), the pituitary gland, the ovary, and the uterus (endometrium). All
must function appropriately for normal reproduction to occur.
2 Hypothalamic gonadotropin-releasing hormone (GnRH) simultaneously regulates the
luteinizing hormone (LH) and follicle-stimulating hormone (FSH) in the pituitary
through pulsatile secretions. The pulse frequency determines the relative amounts of
LH and FSH secretion.
3 The ovary responds to FSH and LH in a defined, sequential manner to produce
follicular growth, ovulation, and corpus luteum formation. The cycle is designed to
produce an optimal environment for pregnancy; if pregnancy does not occur, the
cycle begins again.
4 In the early menstrual cycle the ovary produces estrogen, which is responsible for
endometrial growth. After ovulation, progesterone is produced in significant
quantities, which transforms the endometrium into a form ideal for implantation of
the embryo. If no pregnancy occurs, the ovary ceases to produce estrogen and
progesterone, the endometrium is sloughed, and the cycle repeats.
[1] The reproductive process in women is a complex and highly evolved
interaction of many components. The carefully orchestrated series of events that
contributes to a normal ovulatory menstrual cycle requires precise timing and
regulation of hormonal input from the central nervous system (CNS), pituitary
gland, and ovary. This delicately balanced process can be disrupted easily and
result in reproductive failure, which is a major clinical issue confronting
gynecologists. To manage such conditions effectively, it is critical that
gynecologists understand the normal physiology of the menstrual cycle. The
anatomic structures, hormonal components, and their interactions, play a vital role
in the function of the reproductive system. Fitting together the various pieces of
this intricate puzzle creates “the big picture”: an overview of how the
reproductive system of women is designed to function.
NEUROENDOCRINOLOGY
Neuroendocrinology represents facets of two traditional fields of medicine:
endocrinology, which is the study of hormones (i.e., substances secreted into the
bloodstream that have diverse actions at sites remote from the point of secretion);
and neuroscience, which is the study of the action of neurons. The discovery of
neurons that transmit impulses and secrete their products into the vascular system
283to function as hormones, a process known as neurosecretion, demonstrates that
the two systems are intimately linked. For instance, the menstrual cycle is
regulated through the feedback of hormones on the neural tissue of the CNS.
ANATOMY
Hypothalamus
The hypothalamus is a small neural structure situated at the base of the
brain above the optic chiasm and below the third ventricle (Fig. 7-1). It is
connected directly to the pituitary gland and is the part of the brain that is
the source of many pituitary secretions. Anatomically, the hypothalamus is
divided into three zones: periventricular (adjacent to the third ventricle); medial
(primarily cell bodies); and lateral (primarily axonal). Each zone is further
subdivided into structures known as nuclei, which represent locations of
concentrations of similar types of neuronal cell bodies (Fig. 7-2).
284FIGURE 7-1 The hypothalamus and its neurologic connections to the pituitary.
285FIGURE 7-2 The neuronal cell bodies of the hypothalamus.
The hypothalamus is not an isolated structure within the CNS; instead, it
has multiple interconnections with other regions in the brain. In addition to
the well-known pathways of hypothalamic output to the pituitary, there are
numerous less well-characterized pathways of output to diverse regions of the
brain, including the limbic system (amygdala and hippocampus), the thalamus,
and the pons (1). Many of these pathways form feedback loops to areas supplying
neural input to the hypothalamus.
286287FIGURE 7-3 The hypothalamic secretory products function as pituitary-releasing factors
that control the endocrine function of the ovaries, the thyroid, and the adrenal glands.
CRH, corticotropin releasing hormone; TRH, thyrotropin releasing hormone; GnRH,
gonadotropin releasing hormone; FSH, follicle stimulating hormone; LH, leutinizing
hormone; T4, thyroxine; ACTH, adrenocorticotropic hormone; TSH, thyroid stimulating
hormone; and E2, estradiol.
Several levels of feedback to the hypothalamus exist and are known as the
long, short, and ultrashort feedback loops. The long feedback loop is
composed of endocrine input from circulating hormones, just as is the feedback of
androgens and estrogens onto steroid receptors in the hypothalamus (2,3).
Similarly, pituitary hormones may feed back to the hypothalamus and serve
important regulatory functions in short-loop feedback. Finally, hypothalamic
secretions may directly feed back to the hypothalamus itself in an ultrashort
feedback loop.
The major secretory products of the hypothalamus are the pituitaryreleasing factors (Fig. 7-3):
1. Gonadotropin-releasing hormone (GnRH), which controls the secretion of
luteinizing hormone (LH) and follicle-stimulating hormone (FSH)
2. Corticotropin-releasing hormone (CRH), which controls the release of
adrenocorticotrophic hormone (ACTH)
3. Growth hormone–releasing hormone (GHRH), which regulates the release
of growth hormone (GH)
4. Thyrotropin-releasing hormone (TRH), which regulates the secretion of
thyroid-stimulating hormone (TSH)
The hypothalamus is the source of all neurohypophyseal hormone
production. The neural posterior pituitary can be viewed as a direct extension of
the hypothalamus connected by the finger-like infundibular stalk. The capillaries
in the median eminence differ from those in other regions of the brain. Unlike the
usual tight junctions that exist between adjacent capillary endothelial lining cells,
the capillaries in this region are fenestrated in the same manner as capillaries
outside the CNS. As a result, there is no blood–brain barrier in the median
eminence.
Pituitary
The pituitary is divided into three regions or lobes: anterior, intermediate, and
posterior. The anterior pituitary (adenohypophysis) is quite different structurally
from the posterior neural pituitary (neurohypophysis), which is a direct physical
288extension of the hypothalamus. The adenohypophysis is derived embryologically
from epidermal ectoderm from an infolding of Rathke pouch. Therefore, it is not
composed of neural tissue, as is the posterior pituitary, and does not have direct
neural connections to the hypothalamus. Instead, a unique anatomic relationship
exists that combines elements of neural production and endocrine secretion.
The adenohypophysis itself has no direct arterial blood supply. Its major source
of blood flow is also its source of hypothalamic input—the portal vessels. Blood
flow in these portal vessels is primarily from the hypothalamus to the pituitary.
Blood is supplied to the posterior pituitary via the superior, middle, and inferior
hypophyseal arteries. In contrast, the anterior pituitary has no direct arterial blood
supply. Instead, it receives blood via a rich capillary plexus of the portal vessels
that originates in the median eminence of the hypothalamus and descends along
the pituitary stalk. This pattern is not absolute, however, and retrograde blood
flow has occurred (4). This blood flow, combined with the location of the median
eminence outside the blood–brain barrier, permits bidirectional feedback control
between the two structures.
The specific secretory cells of the anterior pituitary are classified based on
their hematoxylin- and eosin-staining patterns. Acidophilic-staining cells
primarily secrete GH and prolactin and, to a variable degree, ACTH (5). The
gonadotropins are secreted by basophilic cells, and TSH is secreted by the
neutral-staining chromophobes.
REPRODUCTIVE HORMONES
Hypothalamus
Gonadotropin-Releasing Hormone
GnRH (also called luteinizing hormone–releasing hormone, or LHRH) is the
controlling factor for gonadotropin secretion (6). It is a decapeptide produced
by neurons with cell bodies primarily in the arcuate nucleus of the hypothalamus
(7–9) (Fig. 7-4). Embryologically, these neurons originate in the olfactory pit and
migrate to their adult locations (10). These GnRH-secreting neurons project axons
that terminate on the portal vessels at the median eminence where GnRH is
secreted for delivery to the anterior pituitary. Less clear in function are multiple
other secondary projections of GnRH neurons to locations within the CNS.
The gene that encodes GnRH produces a 92-amino-acid precursor protein,
which contains the GnRH decapeptide and a 56 amino acid peptide known as
GnRH-associated peptide (GAP). The GAP is a potent inhibitor of prolactin
secretion and a stimulator of gonadotropin release.
Pulsatile Secretion
289[2] GnRH is unique among releasing hormones in that it simultaneously
regulates the secretion of two hormones—FSH and LH. It is unique among
the body’s hormones because it must be secreted in a pulsatile fashion to be
effective, and the pulsatile release of GnRH influences the release of the two
gonadotropins (11–13). Using animals that had undergone electrical
destruction of the arcuate nucleus and had no detectable levels of
gonadotropins, a series of experiments were performed with varying dosages
and intervals of GnRH infusion (13,14). Continual infusions did not result in
gonadotropin secretion, whereas a pulsatile pattern led to physiologic
secretion patterns and follicular growth. Continual exposure of the pituitary
gonadotroph to GnRH results in a phenomenon calleddownregulation,
through which the number of gonadotroph cell surface GnRH receptors is
decreased (15). Similarly, intermittent exposure to GnRH will “upregulate”
or “autoprime” the gonadotroph to increase its number of GnRH receptors
(16). This allows the cell to have a greater response to subsequent GnRH
exposure. Similar to the intrinsic electrical pacemaker cells of the heart, this
action most likely represents an intrinsic property of the GnRH-secreting neuron,
although it is subject to modulation by various neuronal and hormonal inputs to
the hypothalamus.
The continual pulsatile secretion of GnRH is necessary because GnRH has
an extremely short half-life (only 2 to 4 minutes) as a result of rapid
proteolytic cleavage. The pulsatile secretion of GnRH varies in frequency and
amplitude throughout the menstrual cycle and is tightly regulated (Fig. 7-5)
(17,18).
The follicular phase is characterized by frequent, small-amplitude pulses of
GnRH secretion. In the late follicular phase, there is an increase in frequency and
amplitude of pulses. During the luteal phase, however, there is a progressive
lengthening of the interval between pulses. The amplitude in the luteal phase is
higher than that in the follicular phase, but it declines progressively over the 2
weeks. This variation in pulse frequency allows for variation in LH and FSH
throughout the menstrual cycle. For example, decreasing the pulse frequency of
GnRH decreases LH secretion but increases FSH, an important aspect of
enhancing FSH availability in the late luteal phase. The pulse frequency is not the
sole determinant of pituitary response; additional hormonal influences, such as
those exerted by ovarian peptides and sex steroids, can modulate the GnRH
effect.
290FIGURE 7-4 Gonadotropin-releasing hormone is a decapeptide.
FIGURE 7-5 The pulsatile secretion of gonadotropin-releasing hormone in the follicular
and luteal phases of the cycle.
Although GnRH is primarily involved in endocrine regulation of
gonadotropin secretion from the pituitary, it is apparent that this molecule
has autocrine and paracrine functions throughout the body. The decapeptide
is found in neural and nonneural tissues; receptors are present in many
extrapituitary structures, including the ovary and placenta. Data suggest that
291GnRH may be involved in regulating human chorionic gonadotropin (hCG)
secretion and implantation, and in decreasing cell proliferation and mediating
apoptosis in tumor cells (19). The role of GnRH in the extrapituitary sites remains
to be fully elucidated.
Gonadotropin-Releasing Hormone Agonists
Mechanism of Action
Used clinically, GnRH agonists are modifications of the native molecule to either
increase receptor affinity or decrease degradation (20). Their use leads to a
persistent activation of GnRH receptors, as if continuous GnRH exposure existed.
As would be predicted by the constant GnRH infusion experiments, this leads to
suppression of gonadotropin secretion. An initial release of gonadotropins is
followed by a profound suppression of secretion. The initial release of
gonadotropins represents the secretion of pituitary stores in response to receptor
binding and activation. With continued activation of the gonadotroph GnRH
receptor, however, there is a downregulation effect and a decrease in the
concentration of GnRH receptors. As a result, gonadotropin secretion decreases
and sex steroid production falls to castrate levels (21).
Additional modification of the GnRH molecule results in an analogue that
has no intrinsic activity but competes with GnRH for the same receptor site
(22). These GnRH antagonists produce a competitive blockade of GnRH
receptors, preventing stimulation by endogenous GnRH and causing an
immediate fall in gonadotropin and sex steroid secretion (23). The clinical
effect is observed within 24 to 72 hours. Moreover, antagonists may not function
solely as competitive inhibitors; evidence suggests they may also produce
downregulation of GnRH receptors, further contributing to the loss of
gonadotropin activity (24).
Structure—Agonists and Antagonists
As a peptide hormone, GnRH is degraded by enzymatic cleavage of bonds
between its amino acids. Pharmacologic alterations of the structure of GnRH led
to the creation of agonists and antagonists (Fig. 7-4). The primary sites of
enzymatic cleavage are between amino acids 5 and 6, 6 and 7, and 9 and 10.
Substitution of the position-6 amino acid glycine with large bulky amino acid
analogues makes degradation more difficult and creates a form of GnRH with a
relatively long half-life. Substitution at the carboxyl terminus produces a form of
GnRH with increased receptor affinity. The resulting high affinity and slow
degradation produces a molecule that mimics continuous exposure to native
GnRH (20). Thus, as with constant GnRH exposure, downregulation occurs.
GnRH agonists are widely used to treat disorders that are dependent on ovarian
292hormones (21). They are used to control ovulation induction cycles and treat
precocious puberty, ovarian hyperandrogenism, leiomyomas, endometriosis, and
hormonally dependent cancers. The development of GnRH antagonists proved
more difficult because a molecule was needed that maintained the binding and
degradation resistance of agonists but failed to activate the receptor. Early
attempts involved modification of amino acids 1 and 2, as well as those
previously utilized for agonists. Commercial antagonists have structural
modifications at amino acids 1, 2, 3, 6, 8, and 10. The treatment spectrum is
expected to be similar to that of GnRH agonists, but with a more rapid onset of
action.
Nonpeptide, small molecule structures with high affinity for the GnRH receptor
were developed (25). These compounds demonstrated the ability to suppress the
reproductive axis in a dose-related manner via oral administration, unlike the
parenteral approach required with traditional peptide analogues (26). Investigation
may elucidate an expanded therapeutic role for these antagonists.
Endogenous Opioids and Effects on GnRH
The endogenous opioids are three related families of naturally occurring
substances produced in the CNS that represent the natural ligands for the opioid
receptors (27–29). There are three major classes of endogenous opioids, each
derived from precursor molecules:
1. Endorphins are named for their endogenous morphine-like activity. These
substances are produced in the hypothalamus from the precursor
proopiomelanocortin (POMC) and have diverse activities, including regulation
of temperature, appetite, mood, and behavior (30).
2. Enkephalins are the most widely distributed opioid peptides in the brain, and
they function primarily in regulation of the autonomic nervous system.
Proenkephalin A is the precursor for the two enkephalins of primary
importance: methionine–enkephalin and leucine–enkephalin.
3. Dynorphins are endogenous opioids produced from the precursor
proenkephalin B that serve a function similar to that of the endorphins,
producing behavioral effects and exhibiting a high analgesic potency.
The endogenous opioids play a significant role in the regulation of
hypothalamic–pituitary function. Endorphins appear to inhibit GnRH
release within the hypothalamus, resulting in inhibition of gonadotropin
secretion (31). Ovarian sex steroids can increase the secretion of central
endorphins, further depressing gonadotropin levels (32).
Endorphin levels vary significantly throughout the menstrual cycle, with
293peak levels in the luteal phase and a nadir during menses (33). This inherent
variability, although helping to regulate gonadotropin levels, may contribute to
cycle-specific symptoms experienced by ovulatory women. For example, the
dysphoria experienced by some women in the premenstrual phase of the cycle
may be related to a withdrawal of endogenous opiates (34). This theory is
bolstered by the finding that inhibition of opiate withdrawal by naltrexone
alleviates many premenstrual symptoms (35).
Pituitary Hormone Secretion
Anterior Pituitary
The anterior pituitary is responsible for the secretion of the major hormonereleasing factors—FSH, LH, TSH, and ACTH—and GH and prolactin. Each
hormone is released by a specific pituitary cell type.
Gonadotropins
The gonadotropins FSH and LH are produced by the anterior pituitary
gonadotroph cells and are responsible for ovarian follicular stimulation.
Structurally, there is great similarity between FSH and LH (Fig. 7-6). They
are glycoproteins that share identical α subunits and differ only in the structure of
their β subunits, which confer receptor specificity (36,37). The synthesis of the β
subunits is the rate-regulating step in gonadotropin biosynthesis (38). TSH and
placental hCG share identical α subunits with the gonadotropins. There are
several forms of each gonadotropin, which differ in carbohydrate content as a
result of posttranslation modification. The degree of modification varies with
steroid levels and is an important regulator of gonadotropin bioactivity.
Prolactin
Prolactin, a 198-amino-acid polypeptide secreted by the anterior pituitary
lactotroph, is the primary trophic factor responsible for the synthesis of milk
by the breast (39). Several forms of this hormone, which are named according to
their size and bioactivity, are normally secreted (40). Prolactin gene transcription
is principally stimulated by estrogen; other hormones promoting transcription are
TRH and a variety of growth factors.
294FIGURE 7-6 The structural similarity between follicle-stimulating hormone (FSH),
luteinizing hormone (LH), and thyroid-stimulating hormone (TSH). The α subunits are
identical, and the β subunits differ.
Prolactin secretion is under tonic inhibitory control by the hypothalamic
secretion of dopamine (41). Therefore, disease states characterized by decreased
dopamine secretion or any condition that interrupts transport of dopamine down
the infundibular stalk to the pituitary gland will result in increased synthesis of
prolactin. In this respect, prolactin is unique in comparison with all other pituitary
hormones: It is predominantly under tonic inhibition, and release of control
produces an increase in secretion. Clinically, increased prolactin levels are
associated with amenorrhea and galactorrhea, and hyperprolactinemia
should be suspected in any individual with symptoms of either of these
conditions.
Although prolactin appears to be primarily under inhibitory control,
many stimuli can elicit its release, including breast manipulation, drugs,
stress, exercise, and certain foods. Hormones that may stimulate prolactin
release include TRH, vasopressin, γ-aminobutyric acid (GABA), dopamine, β-
endorphin, vasoactive intestinal peptide (VIP), epidermal growth factor (EGF),
angiotensin II, estrogens, and possibly GnRH (42–46). The relative contributions
of these substances under normal conditions remain to be determined.
Thyroid-Stimulating Hormone, Adrenocorticotropic Hormone, and Growth Hormone
The other hormones produced by the anterior pituitary are TSH, ACTH,
and GH. TSH is secreted by the pituitary thyrotrophs in response to TRH.
As with GnRH, TRH is synthesized primarily in the arcuate nucleus of the
hypothalamus and is secreted into the portal circulation for transport to the
pituitary. In addition to stimulating TSH release, TRH is a major stimulus for the
295release of prolactin. TSH stimulates release of T3 and T4 from the thyroid gland,
which in turn has a negative feedback effect on pituitary TSH secretion.
Abnormalities of thyroid secretion (hyper- and hypothyroidism) are frequently
associated with ovulatory dysfunction as a result of diverse actions on the
hypothalamic–pituitary–ovarian axis (47).
Adrenocorticotrophic hormone is secreted by the anterior pituitary in
response to another hypothalamic-releasing factor, CRH, and stimulates the
release of adrenal glucocorticoids. Unlike the other anterior pituitary products,
ACTH secretion has a diurnal variation with an early morning peak and a late
evening nadir. As with the other pituitary hormones, ACTH secretion is
negatively regulated by feedback from its primary end product, which in this case
is cortisol.
The anterior pituitary hormone that is secreted in the greatest absolute
amount is GH. It is secreted in response to the hypothalamic-releasing factor,
GHRH, and by thyroid hormone and glucocorticoids. This hormone is secreted in
a pulsatile fashion but with peak release occurring during sleep. In addition to its
vital role in the stimulation of linear growth, GH plays a diverse role in
physiologic homeostasis. The hormone plays a role in bone mitogenesis, CNS
function (improved memory, cognition, and mood), body composition, breast
development, and cardiovascular function. It also affects insulin regulation and
acts anabolically. GH appears to have a role in the regulation of ovarian function,
although the degree to which it serves this role in normal physiology is unclear
(48).
Posterior Pituitary
Structure and Function
The posterior pituitary (neurohypophysis) is composed exclusively of neural
tissue and is a direct extension of the hypothalamus. It lies directly adjacent to
the adenohypophysis but is embryologically distinct, derived from an
invagination of neuroectodermal tissue in the third ventricle. Axons in the
posterior pituitary originate from neurons with cell bodies in two distinct regions
of the hypothalamus, the supraoptic and paraventricular nuclei, named for their
anatomic relationship to the optic chiasm and the third ventricle. Together these
two nuclei compose the hypothalamic magnocellular system. These neurons can
secrete their synthetic products directly from axonal boutons into the general
circulation to act as hormones. This is the mechanism of secretion of the
hormones of the posterior pituitary, oxytocin and arginine vasopressin (AVP).
Although this is the primary mode of release for these hormones, numerous other
secondary pathways were identified, including secretion into the portal
296circulation, intrahypothalamic secretion, and secretion into other regions of the
CNS (49).
In addition to the established functions of oxytocin and vasopressin, several
other diverse roles were suggested in animal models. These functions include
modulation of sexual activity and appetite, learning and memory consolidation,
temperature regulation, and regulation of maternal behaviors (50). In the human,
these neuropeptides were linked to social attachment (51–53). Receptor variants
for these two molecules were linked to the spectrum of autistic disorders,
suggesting that proper function of these two neuropeptides with their receptors is
required for positive group interactive behavior. This relationship is strengthened
by a strong association between altruistic behavior and the length of the AVP-1a
receptor promoter region (52,54). Complex human behaviors may be partially
governed by a relatively simple neuropeptide system. Continuing investigation
should help elucidate this physiology and potential therapeutic interventions.
Oxytocin
Oxytocin is a 9-amino-acid peptide primarily produced by the
paraventricular nucleus of the hypothalamus (Fig. 7-7). The primary function
of this hormone in humans is the stimulation of two specific types of muscular
contractions (Fig. 7-8). The first type, uterine muscular contraction, occurs during
parturition. The second type of muscular contraction regulated by oxytocin is
breast lactiferous duct myoepithelial contractions, which occur during the milk
letdown reflex. Oxytocin release may be stimulated by suckling, triggered by a
signal from nipple stimulation transmitted via thoracic nerves to the spinal cord
and then to the hypothalamus, where oxytocin is released in an episodic fashion
(48). Oxytocin release may be triggered by olfactory, auditory, and visual clues,
and may play a role in the conditioned reflex in nursing animals. Stimulation of
the cervix and vagina can cause significant release of oxytocin, which may trigger
reflex ovulation (the Ferguson reflex) in some species.
FIGURE 7-7 Oxytocin and arginine vasopressin (AVP) are 9-amino-acid peptides
produced by the hypothalamus. They differ in only two amino acids.
297FIGURE 7-8 Oxytocin stimulates muscular contractions of the uterus during parturition
and the breast lactiferous duct during the milk letdown reflex. Arginine vasopressin (AVP)
regulates circulating blood volume, pressure, and osmolality.
Arginine Vasopressin
Also known as antidiuretic hormone (ADH), AVP is the second major
secretory product of the posterior pituitary (Fig. 7-7). It is synthesized
primarily by neurons with cell bodies in the supraoptic nuclei (Fig. 7-8). Its major
298function is the regulation of circulating blood volume, pressure, and osmolality
(55). Specific receptors throughout the body can trigger the release of AVP.
Osmoreceptors located in the hypothalamus sense changes in blood osmolality
from a mean of 285 mOsm/kg. Baroreceptors sense changes in blood pressure
caused by alterations in blood volume and are peripherally located in the walls of
the left atrium, carotid sinus, and aortic arch (56). These receptors can respond to
changes in blood volume of more than 10%. In response to decreases in blood
pressure or volume, AVP is released and causes arteriolar vasoconstriction and
renal free–water conservation. This leads to a decrease in blood osmolality and an
increase in blood pressure. Activation of the renal renin–angiotensin system can
also activate AVP release.
MENSTRUAL CYCLE PHYSIOLOGY
[3] In the normal menstrual cycle, orderly cyclic hormone production and
parallel proliferation of the uterine lining prepare for implantation of the
embryo. Disorders of the menstrual cycle and, likewise, disorders of
menstrual physiology, may lead to various pathologic states, including
infertility, recurrent miscarriage, and malignancy.
Normal Menstrual Cycle
The normal human menstrual cycle can be divided into two segments: the
ovarian cycle and the uterine cycle, based on the organ under examination.
The ovarian cycle may be further divided into follicular and luteal phases,
whereas the uterine cycle is divided into corresponding proliferative and
secretory phases (Fig. 7-9). The phases of the ovarian cycle are characterized
as follows:
1. Follicular phase—hormonal feedback promotes the orderly development
of a single dominant follicle, which should be mature at midcycle and
prepared for ovulation. The average length of the human follicular phase
ranges from 10 to 14 days, and variability in this length is responsible for
most variations in total cycle length.
2. Luteal phase—the time from ovulation to the onset of menses has an
average length of 14 days.
A normal menstrual cycle lasts from 21 to 35 days, with 2 to 6 days of flow
and an average blood loss of 20 to 60 mL. However, studies of large numbers
of women with normal menstrual cycles showed that approximately twothirds of adult women have cycles lasting 21 to 35 days (57). The extremes of
299reproductive life (after menarche and perimenopause) are characterized by a
higher percentage of anovulatory or irregularly timed cycles (58,59).
Hormonal Variations
The relative pattern of ovarian, uterine, and hormonal variation along the
normal menstrual cycle is shown in Figure 7-9.
1. At the beginning of each monthly menstrual cycle, levels of gonadal
steroids are low and have been decreasing since the end of the luteal phase
of the previous cycle.
2. With the demise of the corpus luteum, FSH levels begin to rise, and a
cohort of growing follicles is recruited. These follicles each secrete
increasing levels of estrogen as they grow in the follicular phase. The
increase in estrogen is the stimulus for uterine endometrial proliferation.
3. Rising estrogen levels provide negative feedback on pituitary FSH
secretion, which begins to wane by the midpoint of the follicular phase. In
addition, the growing follicles produce inhibin B, which suppresses FSH
secretion by the pituitary. Conversely, LH initially decreases in response
to rising estradiol levels, but late in the follicular phase the LH level is
increased dramatically (biphasic response).
4. At the end of the follicular phase (just before ovulation), FSH-induced LH
receptors are present on granulosa cells and, with LH stimulation,
modulate the secretion of progesterone. Progesterone secretion is
responsible for the FSH midcycle surge.
5. After a sufficient degree of estrogenic stimulation, the pituitary LH surge
is triggered, which is the proximate cause of ovulation that occurs 24 to 36
hours later. Ovulation heralds the transition to the luteal–secretory phase.
6. The estrogen level decreases through the early luteal phase from just
before ovulation until the midluteal phase, when it begins to rise again as
a result of corpus luteum secretion. Similarly, inhibin A is secreted by the
corpus luteum.
7. Progesterone levels rise precipitously after ovulation and can be used as a
presumptive sign that ovulation has occurred.
8. Progesterone, estrogen, and inhibin A act centrally to suppress
gonadotropin secretion and new follicular growth. These hormones
remain elevated through the lifespan of the corpus luteum and wane with
its demise, thereby setting the stage for the next cycle.
300FIGURE 7-9 The menstrual cycle. The top panel shows the cyclic changes of folliclestimulating hormone (FSH), luteinizing hormone (LH), estradiol (E2), and progesterone (P)
relative to the time of ovulation. The bottom panel correlates the ovarian cycle in the
follicular and luteal phases and the endometrial cycle in the proliferative and secretory
phases.
Uterus
Cyclic Changes of the Endometrium
In 1950, Noyes, Hertig, and Rock described the cyclic histologic changes in the
301adult human endometrium (Fig. 7-10) (60). These changes proceed in an orderly
fashion in response to cyclic hormonal production by the ovaries (Fig. 7-9).
Histologic cycling of the endometrium can best be viewed in two parts: the
endometrial glands and the surrounding stroma. The superficial two-thirds of
the endometrium is the zone that proliferates and is ultimately shed with
each cycle if pregnancy does not occur. This cycling portion of the
endometrium is known as the decidua functionalis and is composed of a
deeply situated intermediate zone (stratum spongiosum) and a superficial
compact zone (stratum compactum). The decidua basalis is the deepest
region of the endometrium. It does not undergo significant monthly
proliferation but, instead, is the source of endometrial regeneration after
each menses (61).
302FIGURE 7-10 The number of oocytes in the ovary before and after birth and through
menopause.
The existence of endometrial stem cells was assumed but difficult to document.
Researchers found a small population of human epithelial and stromal cells that
possess clonogenicity, suggesting that they represent the putative endometrial
stem cells (62). Further evidence of the existence of such cells, and their source,
was provided by another study that showed endometrial glandular epithelial cells,
obtained from endometrial biopsies of women undergoing bone marrow
transplants, express the HLA type of the donor bone marrow (63). This finding
suggests that endometrial stem cells exist, reside in bone marrow, and migrate to
the basalis of the endometrium. Furthermore, the timing of the appearance of
these cells following the transplant was as long as several years. This experiment
has been duplicated using autologous bone marrow–derived stem cells and
placing them in the spiral arterioles of patients with intrauterine synechiae (64).
Animal models suggest this approach may be of value in regenerating damaged or
absent endometrium (65,66). It is likely that this treatment will prove to be of
clinical importance in patients with difficult to treat Asherman syndrome.
Proliferative Phase
[4] By convention, the first day of vaginal bleeding is called day 1 of the
menstrual cycle. After menses, the decidua basalis is composed of primordial
glands and dense scant stroma in its location adjacent to the myometrium.
The proliferative phase is characterized by progressive mitotic growth of the
decidua functionalis in preparation for implantation of the embryo in
response to rising circulating levels of estrogen (67). At the beginning of the
proliferative phase, the endometrium is relatively thin (1 to 2 mm). The
predominant change seen during this time is evolution of the initially
straight, narrow, and short endometrial glands into longer, tortuous
structures (68). Histologically, these proliferating glands have multiple
mitotic cells, and their organization changes from a low columnar pattern in
the early proliferative period to a pseudostratified pattern before ovulation.
Throughout this time, the stroma is a dense compact layer, and vascular
structures are infrequently seen.
Secretory Phase
In the typical 28-day cycle, ovulation occurs on cycle day 14. Within 48 to 72
hours following ovulation, the onset of progesterone secretion produces a
shift in histologic appearance of the endometrium to the secretory phase, so
named for the clear presence of eosinophilic protein-rich secretory products
303in the glandular lumen. In contrast to the proliferative phase, the secretory
phase of the menstrual cycle is characterized by the cellular effects of
progesterone in addition to estrogen. In general, progesterone’s effects are
antagonistic to those of estrogen, and there is a progressive decrease in the
endometrial cell’s estrogen receptor concentration. As a result, during the
latter half of the cycle, estrogen-induced DNA synthesis and cellular mitosis
are antagonized (67).
During the secretory phase, the endometrial glands form characteristic
periodic acid–Schiff positive–staining, glycogen-containing vacuoles. These
vacuoles initially appear subnuclearly and progress toward the glandular
lumen (Fig. 7-10) (60). The nuclei can be seen in the midportion of the cells
and ultimately undergo apocrine secretion into the glandular lumen, often by
cycle day 19 or 20. At postovulatory day 6 or 7, secretory activity of the
glands is generally maximal, and the endometrium is optimally prepared for
implantation of the blastocyst.
The stroma of the secretory phase remains unchanged histologically until
approximately the 7th postovulatory day, when there is a progressive
increase in edema. Coincident with maximal stromal edema in the late
secretory phase, the spiral arteries become clearly visible and progressively
lengthen and coil during the remainder of the secretory phase. By around
day 24, an eosinophilic-staining pattern, known as cuffing, is visible in the
perivascular stroma. Eosinophilia progresses to form islands in the stroma
followed by areas of confluence. This staining pattern of the edematous
stroma is termed pseudodecidual because of its similarity to the pattern that
occurs in pregnancy. Approximately 2 days before menses, there is a
dramatic increase in the number of polymorphonuclear lymphocytes that
migrate from the vascular system. This leukocytic infiltration heralds the
collapse of the endometrial stroma and the onset of the menstrual flow.
Menses
In the absence of implantation, glandular secretion ceases and an irregular
breakdown of the decidua functionalis occurs. The resultant shedding of this
layer of the endometrium is termed menses. The destruction of the corpus
luteum and its production of estrogen and progesterone is the presumed
cause of the shedding. With withdrawal of sex steroids, there is a profound
spiral artery vascular spasm that ultimately leads to endometrial ischemia.
Simultaneously, there is a breakdown of lysosomes and a release of
proteolytic enzymes, which further promote local tissue destruction. This
layer of endometrium is shed, leaving the decidua basalis as the source of
subsequent endometrial growth. Prostaglandins are produced throughout
304the menstrual cycle and are at their highest concentration during menses
(66). Prostaglandin F2α (PGF2α) is a potent vasoconstrictor, causing further
arteriolar vasospasm and endometrial ischemia. PGF2α produces
myometrial contractions that decrease local uterine wall blood flow and may
serve to expel physically the sloughing endometrial tissue from the uterus.
Dating the Endometrium
The changes seen in secretory endometrium relative to the LH surge were thought
to allow the assessment of the “normalcy” of endometrial development. Since
1950, it was felt that by knowing when a patient ovulated, it was possible to
obtain a sample of endometrium by endometrial biopsy and determine whether
the state of the endometrium corresponds to the appropriate time of the cycle.
Traditional thinking held that any discrepancy of more than 2 days between
chronologic and histologic date indicated a pathologic condition termed luteal
phase defect; this abnormality was linked to infertility (via implantation failure)
and early pregnancy loss (69).
Evidence suggests a lack of utility for the endometrial biopsy as a
diagnostic test for either infertility or early pregnancy loss (59). In a
randomized, observational study of regularly cycling, fertile women, it was found
that endometrial dating by hematoxylin and eosin staining is far less accurate and
precise than originally claimed and does not provide a valid method for the
diagnosis of luteal phase defect (70). Furthermore, a large prospective,
multicenter trial sponsored by the National Institutes of Health showed that
histologic dating of the endometrium does not discriminate between fertile and
infertile women (71). Thus, after half a century of using this test in the evaluation
of the subfertile couple, it became clear that the traditional endometrial biopsy has
no role in the routine evaluation of infertility or early pregnancy loss.
Given the lack of histologic efficacy in evaluating the receptivity of the
endometrium, investigation turned to the use of molecular and genetic markers.
Cyclin E and p27 were found to be credible markers to discern endometrial
receptivity (72,73). Microarray technology has been utilized to link gene
expression to functionally receptive endometrium, with promising results (74,75).
Ovarian Follicular Development
The number of oocytes peaks in the fetus at 6 to 7 million by 20 weeks of
gestation (Fig. 7-10) (76). Simultaneously (and peaking at the 5th month of
gestation), atresia of the oogonia occurs, rapidly followed by follicular atresia. At
birth, only 1 to 2 million oocytes remain in the ovaries, and at puberty, only
300,000 of the original 6 to 7 million oocytes are available for ovulation
305(76,77). Of these, only 400 to 500 will ultimately be released during ovulation.
By the time of menopause, the ovary will be composed primarily of dense stromal
tissue with only rare interspersed oocytes remaining.
A central dogma of reproductive biology is that in postnatal mammalian
females there is no capacity for oocyte production. Because oocytes enter the
diplotene resting stage of meiosis in the fetus and persist in this stage until
ovulation, much of the DNA, proteins, and messenger RNA (mRNA) necessary
for development of the preimplantation embryo is synthesized by this stage. At
the diplotene stage, a single layer of 8 to 10 granulosa cells surrounds the oogonia
to form the primordial follicle. The oogonia that fail to become properly
surrounded by granulosa cells undergo atresia (78). The remainder proceeds with
follicular development. Thus, most oocytes are lost during fetal development, and
the remaining follicles are steadily “used up” throughout the intervening years
until menopause.
Evidence has begun to challenge this theory. Studies in the mouse showed that
production of oocytes and corresponding folliculogenesis can occur well into
adult life (79). The reservoir of germline stem cells responsible for this oocyte
development appears to reside in the bone marrow (80). While stem cells have
been found in the human adult ovary (81,82), it is not clear if these cells are true
ovarian germline stem cells and if they play a physiologic role within the ovary
regarding follicular development (82,83).
Meiotic Arrest of Oocyte and Resumption
Meiosis (the germ cell process of reduction division) is divided into four
phases: prophase, metaphase, anaphase, and telophase. The prophase of
meiosis I is further divided into five stages: leptotene, zygotene, pachytene,
diplotene, and diakinesis.
Oogonia differ from spermatogonia in that only one final daughter cell
(oocyte) forms from each precursor cell, with the excess genetic material
discarded in two polar bodies. When the developing oogonia begin to enter
meiotic prophase I, they are known as primary oocytes (84). This process
begins at roughly 8 weeks of gestation. Only those oogonia that enter meiosis will
survive the wave of atresia that sweeps the fetal ovary before birth. The oocytes
arrested in prophase (in the late diplotene or “dictyate” stage) will remain thus
until the time of ovulation, when the process of meiosis resumes. The mechanism
for this mitotic stasis is believed to be an oocyte maturation inhibitor (OMI)
produced by granulosa cells (85). Granulosa-derived cAMP seems to be
implicated in inhibiting germinal vesicle breakdown and meiosis resumption (86).
This inhibitor gains access to the oocyte via gap junctions connecting the oocyte
and its surrounding cumulus of granulosa. These intercellular channels are formed
306by proteins known as connexins. With the midcycle LH surge, the gap junctions
are disrupted, granulosa cells are no longer connected to the oocyte, and meiosis I
is allowed to resume.
Follicular Development
Follicular development, also known as folliculogenesis, is a dynamic process
that continues from menarche until menopause. The process is designed to
allow the monthly recruitment of a cohort of primordial follicles and,
ultimately, to release a single, mature, dominant follicle during ovulation
each month. Therefore, it is highly coordinated with oocyte maturation.
Folliculogenesis has been divided into different steps according to follicular
characteristics regarding the number and appearance of granulosa cells,
development of theca cells and formation of a fluid-filled structure known as
antrum. Preantral follicles include primordial, primary, and secondary follicles.
Antral follicles include tertiary and preovulatory follicles.
Primordial follicles are 0.03 to 0.05 mm in diameter structures formed by a
primary oocyte (arrested in prophase of meiosis I), surrounded by one layer of
flattened granulosa cells contained by the basal lamina.
Primary follicles are 0.1 mm follicles formed when granulosa cells are still a
one cell layer but acquire a cuboidal form. This is the first sign of follicular
recruitment. Protein synthesis and secretion form an extracellular matrix capsule
known as the zona pellucida, traversed by intercellular channels (gap unions) that
maintain active connections between granulosa cells and the oocyte. Granulosa
cells in the primary follicle develop FSH receptors, without endocrine effect as a
result of the absence of follicular vascularization and, therefore, nonexistent
exposure to circulating FSH.
Secondary follicles are 0.2 mm in size and develop several layers of cuboidal
granulosa cells with marked expression of FSH receptors. Stromal cell in contact
with the granulosa and basal lamina are differentiated into theca cells with LH
receptor expression. In the theca layer neoangiogenesis occurs, vascularizing the
follicle and exposing it to circulating FSH and LH.
Tertiary follicles are characterized by the formation of the antral cavity or
antrum, as a consequence of granulosa cell secretion intercellular accumulation.
Early tertiary follicles are 0.2 to 5 mm in size and at this point the theca layer is
divided into theca interna and theca externa, which forms a transition with the
ovarian stroma. Late tertiary follicles are 10 to 20 mm in size. Their large antral
cavity divides granulosa in several cell populations, the corona radiata in contact
with the oocyte, mural (membranous) granulosa in contact with the follicular wall
and the cumulus ophorus that appears as a stalk joining the corona radiata and the
mural granulosa.
307Preovulatory follicles are the final stage of follicular development and >20
mm in size, structures from which ovulation occurs. Late in this stage and before
ovulation, the primary oocyte completes meiosis I, becoming a secondary oocyte
arrested in metaphase of meiosis II. Late tertiary/preovulatory follicles are also
known as Graafian follicles.
Gonadotropin dependence in folliculogenesis is conditioned by the expression
of FSH and LH receptors in granulosa and theca cells, respectively, and by the
presence of follicular vascularization. Considerable expression of granulosa FSH
receptors and formation of vascularized theca layer occurs in the secondary
follicle. Consequently, follicular development is gonadotropin independent up to
the formation of secondary follicles or late preantral phase. Early antral follicle
development and its maturation process up to a preovulatory follicle is a
gonadotropin dependent phase.
Primordial Follicles
The initial recruitment and growth of the primordial follicles is gonadotropin
independent and affects a cohort over several months (87). The stimuli
responsible for the recruitment of a specific cohort of follicles in each cycle are
yet to be understood, but it seems to be under autocrine and paracrine control.
Interaction between oocyte and neighboring granulosa cells seems to be
fundamental for oocyte growth development, granulosa cell proliferation and the
resultant primordial follicle activation.
Maintenance of a population of dormant primordial follicles is the basis for
guaranteeing an oocyte supply throughout reproductive life (88). Whether
secretion of stimulating or inhibiting factors is involved in recruitment regulation
is being studied, although accelerated recruitment in isolated primordial follicles
cultured in vitro suggests inhibitory mechanisms can have a more important role
(89). Several factors have been implicated with an inhibitory effect over
primordial follicle activation, such as anti-mullerian hormone (AMH) (90),
phosphate and tensin homolog (PTEN) (91), tuberin/tuberous sclerosis complex
(TSC) (92), Forkhead boxL2 (Foxl2) (93), and Forkhead box O3 (FOXO3a) (94).
Their expression is responsible for preservation of primordial follicular dormancy
and depletion of these factors in knockout mice has been associated with
premature activation and early depletion of primordial follicles. On the other
hand, phosphotidylinositol-3-kinase signaling mediated by 3-phosphoinositide
dependent kinase-1 (PDK1), and mammalian target of rapamycin complex-1
(mTORC1), and S6 kinase-ribosomal protein (S6K1-rpS6), have been related to
primordial follicle activation and survival (95–98).
Preantral Follicle
308At the secondary follicle stage, after initial recruitment, FSH assumes control of
follicular differentiation and growth and allows a cohort of follicles to continue
differentiation. This process signals the shift from gonadotropin-independent to
gonadotropin-dependent growth. The decline in luteal phase estrogen,
progesterone, and inhibin A production by the now fading corpus luteum from the
previous cycle allows the increase in FSH that stimulates this follicular growth
(99).
Simultaneously, theca cells in the stroma bordering the granulosa cells
proliferate. Both cell types function synergistically to produce estrogens that are
secreted into the systemic circulation. At this stage of development, each of the
seemingly identical cohort members must be either selected for dominance or
undergo atresia. It is likely that the follicle destined to ovulate was selected before
this point, although the mechanism for selection remains obscure.
Two-Cell, Two-Gonadotropin Theory
The fundamental tenet of follicular development is the two-cell, twogonadotropin theory (Fig. 7-11) (87,100,101). This theory states that there is
a subdivision and compartmentalization of steroid hormone synthesis
activity in the developing follicle. Most aromatase activity (for estrogen
production) is in the granulosa cells (102). Aromatase activity is enhanced by
FSH stimulation of specific receptors on these cells (103,104). Granulosa cells
lack several enzymes that occur earlier in the steroidogenic pathway and require
androgens as a substrate for aromatization. Androgens, in turn, are synthesized
primarily in response to stimulation by LH, and the theca cells possess most of
the LH receptors at this stage (103,104). Therefore, a synergistic relationship
must exist: LH stimulates the theca cells to produce androgens (primarily
androstenedione), which are transferred to the granulosa cells for FSH-stimulated
aromatization into estrogens. These locally produced estrogens create a
microenvironment within the follicle that is favorable for continued growth and
nutrition (105). FSH and local estrogens serve to further stimulate estrogen
production, FSH receptor synthesis and expression, and granulosa cell
proliferation and differentiation.
Androgens have two positive regulatory roles in follicular development.
Within the ovary, androgens promote granulose cell proliferation, aromatase
activity, and inhibit programmed death of these cells (106).
As the peripheral estrogen level rises, it negatively feeds back on the
pituitary and hypothalamus to decrease circulating FSH levels (107).
Increased ovarian production of inhibin B further decreases FSH production
at this point.
The falling FSH level that occurs with the progression of the follicular
309phase represents a threat to continued follicular growth. The resulting adverse
environment can be withstood only by follicles with a selective advantage for
binding the diminishing FSH molecules; that is, those with the greatest number of
FSH receptors. The dominant follicle, therefore, can be perceived as the one with
a richly estrogenic microenvironment and the most FSH receptors (108). Increase
in FSH receptors results from an increase in granulosa cell population, because
FSH receptor number is similar and constant in each granulosa cell (109,110). As
it grows and develops, the follicle continues to produce estrogen, which results in
further lowering of the circulating FSH and creates a more adverse environment
for competing follicles. This process continues until all members of the initial
cohort, with the exception of the single dominant follicle, have suffered atresia.
The stage is set for ovulation.
Chronic elevation of androgens suppresses hypothalamic–pituitary secretion of
FSH, a detriment to the development and maturation of a dominant follicle (106).
Clinically, androgen excess results in chronic anovulation, as is seen in polycystic
ovarian syndrome.
FIGURE 7-11 The two-cell, two-gonadotropin theory of follicular development in which
there is compartmentalization of steroid hormone synthesis in the developing follicle. LH,
luteinizing hormone; FSH, follicle-stimulating hormone.
Preovulatory Follicle
Preovulatory follicles are characterized by a fluid-filled antrum that is
311composed of plasma with granulosa cell secretions. The granulosa cells at this
point have further differentiated into a heterogeneous population. The oocyte
remains connected to the follicle by a stalk of specialized granulosa known as the
cumulus oophorus.
Rising estrogen levels have a negative feedback effect on FSH secretion.
Conversely, LH undergoes biphasic regulation by circulating estrogens. At
lower concentrations, estrogens inhibit LH secretion. At higher levels,
estrogen enhances LH release. This stimulation requires a sustained high level
of estrogen (>200 pg/mL) for more than 48 hours (111). When the rising estrogen
level produces positive feedback, a substantial surge in LH secretion occurs.
Concomitant to these events, the local estrogen–FSH interactions in the
dominant follicle induce LH receptors on the granulosa cells. Exposure to high
levels of LH results in a specific response by the dominant follicle—the result is
luteinization of the granulosa cells, production of progesterone, and initiation of
ovulation. Late follicular phase progesterone secretion is responsible for the FSH
midcycle surge that stimulates plasminogen activator, LH granulosa cell receptor
formation, and debilitates oocyte binding to the follicular wall (110). Ovulation
will occur in the single mature, or Graafian, follicle 10 to 12 hours after the LH
peak or 34 to 36 hours after the initial rise in midcycle LH (112–114).
The sex steroids are not the only gonadotropin regulators of follicular
development. Two related granulosa cell–derived peptides were identified that
play opposing roles in pituitary feedback (115). The first of these peptides,
inhibin, is secreted in two forms: inhibin A and inhibin B. Inhibin B is
secreted primarily in the follicular phase and is stimulated by FSH, whereas
inhibin A is mainly active in the luteal phase (116). Both forms of inhibin act to
inhibit FSH synthesis and release (117,118). The second peptide, activin,
stimulates FSH release from the pituitary gland and potentiates its action in the
ovary (119,120). It is likely that there are numerous other intraovarian regulators
similar to inhibin and activin, each of which may play a key role in promoting the
normal ovulatory process (121). Some of these include follistatin, insulin-like
growth factor-1 (ILGF-1), (EGF)/transforming growth factor-α (TGF-α), TGF-β1,
growth differentiation factor 9 (GDF-9) (122,123), fibroblast growth factor-β
(FGF-β), interleukin-1, tissue necrosis factor-α, OMI, and renin–angiotensin.
Anti-mullerian hormone, produced exclusively by granulosa cells of growing
primary and preantral follicles, is the most accurate reflection of ovarian reserve
and seems to influence the dominant follicle selection by decreasing FSH
sensitivity at receptor level, thus inhibiting the initial selection of preantral and
small antral follicles (124–126).
Ovulation
312The midcycle LH surge is responsible for a dramatic increase in local
concentrations of prostaglandins and proteolytic enzymes in the follicular
wall (127). These substances progressively weaken the follicular wall, allowing
the formation of a bleb-like superficial follicular protrusion known as the stigma
and ultimately the wall’s perforation. Ovulation most likely represents a slow
extrusion of the oocyte through this opening in the follicle rather than a rupture of
the follicular structure (128). Direct measurements of intrafollicular pressures
were recorded and failed to demonstrate an explosive event.
Luteal Phase
Structure of Corpus Luteum
After ovulation, the remaining follicular shell is transformed into the
primary regulator of the luteal phase: the corpus luteum. Membranous
granulosa cells remaining in the follicle begin to take up lipids and the
characteristic yellow lutein pigment for which the structure is named. These cells
are active secretory structures that produce progesterone, which supports the
endometrium of the luteal phase. In addition, estrogen and inhibin A are produced
in significant quantities. Unlike the process that occurs in the developing follicle,
the basement membrane of the corpus luteum degenerates to allow proliferating
blood vessels to invade the granulosa-luteal cells in response to secretion of
angiogenic factors such as vascular endothelial growth factor (129). This
angiogenic response allows large amounts of luteal hormones to enter the
systemic circulation.
Hormonal Function and Regulation
The hormonal changes of the luteal phase are characterized by a series of
negative feedback interactions designed to lead to regression of the corpus
luteum if pregnancy does not occur. Corpus luteum steroids (estradiol and
progesterone) provide negative central feedback and cause a decrease in FSH
and LH secretion. Continued secretion of both steroids will decrease the
stimuli for subsequent follicular recruitment. Similarly, luteal secretion of
inhibin potentiates FSH withdrawal. In the ovary, local production of
progesterone inhibits the further development and recruitment of additional
follicles.
Continued corpus luteum function depends on continued LH production.
In the absence of this stimulation, the corpus luteum will invariably regress after
12 to 16 days and form the scar-like corpora albicans (130). The exact
mechanism of luteolysis is unclear and most likely involves local paracrine
factors. In the absence of pregnancy, the corpus luteum regresses, and estrogen
and progesterone levels wane. This removes central inhibition on gonadotropin
313secretion and allows FSH and LH levels to rise and recruit another cohort of
follicles.
If pregnancy does occur, placental hCG will mimic LH action and
continually stimulate the corpus luteum to secrete progesterone. Successful
implantation results in hormonal support to allow continued maintenance of the
corpus luteum and the endometrium. Evidence from patients undergoing oocyte
donation cycles demonstrated that continued luteal function is essential for
continuation of the pregnancy until approximately 5 weeks of gestation, when
sufficient progesterone is produced by the developing placenta (131). This switch
in the source of regulatory progesterone production is referred to as the luteal–
placental shift.
Summary of Menstrual Cycle Regulation
Following is a summary of the regulation of the menstrual cycle:
1. GnRH is produced in the arcuate nucleus of the hypothalamus and
secreted in a pulsatile fashion into the portal circulation, where it travels
to the anterior pituitary.
2. Ovarian follicular development moves from a period of gonadotropin
independence to a phase of FSH dependence.
3. As the corpus luteum of the previous cycle fades, luteal production of
progesterone and inhibin A decreases, allowing FSH levels to rise.
4. In response to FSH stimulus, the follicles grow, differentiate, and secrete
increasing amounts of estrogen and inhibin B.
5. Estrogen stimulates growth and differentiation of the functional layer of
the endometrium, which prepares for implantation. Estrogens work with
FSH in stimulating follicular development.
6. The two-cell, two-gonadotropin theory dictates that with LH stimulation,
the ovarian theca cells will produce androgens that are converted by the
granulosa cells into estrogens under the stimulus of FSH.
7. Rising estrogen and inhibin levels negatively feedback on the pituitary
gland and hypothalamus and decrease the secretion of FSH.
8. The one follicle destined to ovulate each cycle is called the dominant
follicle. It has relatively more FSH receptors and produces a larger
concentration of estrogens than the follicles that will undergo atresia. It is
able to continue to grow despite falling FSH levels.
9. Sustained high estrogen levels cause a surge in pituitary LH secretion that
triggers ovulation, progesterone production, and the shift to the secretory,
or luteal, phase.
10. Luteal function is dependent on the presence of LH. The corpus luteum
314secretes estrogen, progesterone, and inhibin A, which serve to maintain
gonadotropin suppression. Without continued LH secretion, the corpus
luteum will regress after 12 to 16 days. The resulting loss of progesterone
secretion results in menstruation.
11. If pregnancy occurs, the embryo secretes hCG, which mimics the action of LH
by sustaining the corpus luteum. The corpus luteum continues to secrete
progesterone and supports the secretory endometrium, allowing the pregnancy
to continue to develop.
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