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The Female Reproductive System
The female reproductive system functions to (1) produce haploid gametes— ova, (2) facilitate syngamy —or fertilization—between an ovum and a spermatozoon, (3) supply a site for implantation of the embryo (if syngamy occurs) and the establishment of pregnancy, (4) provide for the physical environment and nutritional needs of the developing fetus and its timely birth, and (5) nurture the neonate.
The system consists of the gonads (the ovaries), the fallopian tubes, the uterus and cervix, the vagina ( Fig. 55-1 A ), the external genitalia, and the mammary glands, and is controlled by hormones produced in the hypothalamus, pituitary, and ovaries. The principal female sex hormones are estrogens (mainly estradiol) and progesterone, which are produced by the ovaries in a cyclic manner and regulate the growth and function of the female sex accessory structures and the development of secondary sexual characteristics. Function of the female reproductive system is ultimately regulated by hormones produced by the hypothalamic-pituitary-gonadal axis under the control of higher brain centers. The system involves finely tuned neuroendocrine feedback interactions between hormones produced by the hypothalamus and anterior pituitary and hormones produced by the ovaries. The result is the cyclic production of gametes and the preparation of the sex accessory organs for the establishment of pregnancy.
Anatomy of the female internal genitalia and accessory sex organs.
Female reproductive organs include the ovaries and accessory sex organs
The ovaries lie on the sides of the pelvic cavity (see Fig. 55-1 A ). Covered by a layer of mesothelial cells, each ovary consists of an inner medulla and an outer cortex. The cortex of the ovary in a mature female contains developing follicles and corpora lutea in various stages of development (see Fig. 55-1 B ). These elements are interspersed throughout the stroma, which includes connective tissue, interstitial cells, and blood vessels. The medulla comprises large blood vessels and other stromal elements.
The female sex accessory organs include the fallopian tubes, the uterus, the vagina, and the external genitalia. The fallopian tubes provide a pathway for the transport of ova from the ovary to the uterus. The distal end of the fallopian tube expands as the infundibulum, which ends in multiple fimbriae. The fimbriae and the rest of the fallopian tubes are lined with epithelial cells, most of which have cilia that beat toward the uterus. The activity of these cilia and the contractions of the wall of the fallopian tube, particularly around the time of ovulation, facilitate transport of the ovum. Interspersed with ciliated cells are peg cells that secrete fluid and nutrients supporting the ovum and spermatozoa as well as the zygote that may result as fertilization occurs in the fallopian tubes.
The uterus is a complex, pear-shaped, muscular organ that is suspended by a series of supporting ligaments. It is composed of a fundus, a corpus, and a narrow caudal portion called the cervix. The external surface of the uterus is covered by serosa, whereas the interior, or endometrium, of the uterus consists of complex glandular tissue and stroma. The bulk of the uterine wall consists of specialized smooth muscle, myometrium, that lies between the endometrium and the uterine serosa. The uterus is continuous with the vagina via the cervical canal. The cervix is composed of dense fibrous connective tissue and smooth-muscle cells. Glands lining the cervical canal produce a sugar-rich secretion, the viscosity of which is conditioned by estrogen and progesterone.
The human vagina is ~10 cm in length and is a single, expandable tube. The vagina is lined by stratified epithelium and is surrounded by a thin muscular layer. During development, the lower end of the vagina is covered by the membranous hymen, which is partially perforated during fetal life. In some instances, the hymen remains continuous. The external genitalia include the clitoris, the labia majora, and the labia minora, as well as the accessory secretory glands (including the glands of Bartholin), which open into the vestibule. The clitoris is an erectile organ that is homologous to the penis (see p. 1091 ) and mirrors the cavernous ends of the glans penis.
The breasts can also be considered as part of the female reproductive system. Breast development (thelarche) begins at puberty in response to ovarian steroid hormones. The ductal epithelium of the breast is sensitive to ovarian steroids and especially during pregnancy becomes activated to produce milk (lactation) that will sustain the newborn infant.
Reproductive function in the human female is cyclic
In some species (e.g., rabbits), female reproductive function, and specifically ovulation (the liberation of fertilizable oocytes), is triggered by mating. However, in most species, the female reproductive system functions in a cyclic manner. In some of these species with cyclic function (e.g., sheep, cattle, horses), females are receptive to males only around the time of ovulation, which maximizes the chances of fertilization and pregnancy. This receptive behavior is known as estrus, and the animals are said to have seasonal estrus cycles, whereby the ovaries are active only at a certain time of the year. Such cyclic reproductive function in females enhances reproductive efficiency by coordinating gamete production with environmental (in seasonal species) and physiological changes that attract males and prepare the reproductive tract for sperm and ovum transport, fertilization, implantation, and pregnancy. In a small subset of species (e.g., humans, baboons, apes), ovulation occurs in monthly cycles—known as menstrual cycles —that are associated with regular episodes of uterine bleeding termed menstruation.
Hypothalamic-Pituitary-Gonadal Axis and Control of the Menstrual Cycle
The human menstrual cycle coordinates changes in both the ovary and endometrium
The human menstrual cycle involves rhythmic changes in two organs: the ovary and the uterus ( Fig. 55-2 ). Although menstrual cycles are generally regular during the reproductive years, the length of the menstrual cycle may be highly variable because of disturbances in neuroendocrine function. Starting with the first day of the menses on day 0, the average menstrual cycle lasts 28 days. However, considerable variation occurs during both the early reproductive years and the premenopausal period, primarily because of the increased frequency of anovulatory cycles ( Box 55-1 ).
Box 55-1
Effect of Energy Stores on Female Fertility
Activity of the hypothalamic GnRH neurons in females is very sensitive to environmental and physiological conditions, as is particularly obvious in species with a seasonal estrus. The evolutionary rationale for this environmental sensitivity is that reproduction is most efficient when resources are available to sustain a pregnancy and nurture the newborn. In addition, pregnancy confers a survival risk to females.
Leptin is produced by adipocytes and its levels in the circulation reflect the amount of energy stores (see pp. 1001–1002 ). Because leptin promotes the production and release of GnRH by hypothalamic neurons, leptin signals the brain that fat stores are sufficient to support human female reproductive function. Indeed, increased leptin levels are associated with the onset of puberty in both sexes, and normal levels of leptin are needed to maintain menstrual cycles and normal female reproductive function. Low levels of leptin—due to starvation, anorexia, or strenuous exercise—are associated with amenorrhea (cessation of menstrual cycles). Thus, signals to the neuroendocrine reproductive axis are permissive for reproduction if fuel reserves are adequate, but inhibit the system if reserves are low. The practical consequence is to help ensure that reproduction occurs when the female has sufficient energy reserves to sustain a pregnancy and nurture an infant.
The ovarian cycle includes four key events: (1) folliculogenesis, (2) ovulation, (3) formation of the corpus luteum, and (4) death (atresia) of the corpus luteum. Temporally, the ovarian cycle includes two major phases: the follicular and luteal phases. The follicular phase begins soon after the corpus luteum degenerates, lasts 12 to 14 days, and ends at ovulation. The luteal phase begins at ovulation, lasts 12 to 14 days, and ends when the corpus luteum degenerates.
Steroid hormones produced by the ovaries during the follicular and luteal phases induce changes in the endometrial lining of the uterus that constitute the endometrial cycle. The endometrial cycle consists of three key events: (1) menstruation, (2) endometrial growth and proliferation, and (3) differentiation of the endometrial epithelium into a glandular secretory phenotype. The endometrial cycle is divided into menses, the proliferative phase and the secretory phase (see Fig. 55-2 ).
Ovarian and endometrial events are integrated into a single sequence as follows.
Follicular/Proliferative Phase
The follicular/proliferative phase begins with the initiation of menstruation and averages ~14 days. The follicular phase of the ovarian cycle varies more in duration than any other phase of the cycle. During this time, follicle-stimulating hormone (FSH) and luteinizing hormone (LH) stimulate the growth of a cohort of follicles, all of which (even those destined for atresia) produce estradiol. Consequently, circulating estradiol levels gradually increase during the follicular phase. Because estradiol stimulates rapid growth of the endometrium, this period is the proliferative phase of the endometrial cycle. Eventually, a single large, dominant preovulatory follicle develops in one of the ovaries. This follicle becomes the principal source of estradiol as the follicular phase progresses.
Ovulation
As we will see below, for most of the follicular phase, estradiol exerts negative feedback on gonadotropin secretion at the level of the hypothalamus and pituitary. However, toward the end of the follicular phase (day 12 to 13), when estradiol levels are maximal, the effect of estradiol on the hypothalamus and pituitary switches from negative to positive feedback. The result is a large transient surge in LH and a small increase in FSH secretion by the gonadotrophs. The LH surge causes the dominant follicle to rupture and releases its oocyte—ovulation.
Luteal/Secretory Phase
After release of the ovum, the remnants of the dominant follicle transform into a corpus luteum, which is why the second half of the ovarian cycle is called the luteal phase. Luteal cells produce progesterone and small amounts of estradiol, which together stimulate the endometrium to develop secretory glands—hence the term secretory phase of the endometrial cycle. If embryo implantation does not occur by day 20 to 22 of the cycle (i.e., midway through the luteal phase), the corpus luteum begins to degenerate and its production of progesterone and estradiol rapidly declines. The mechanisms that control the life span of the corpus luteum during a nonfertile cycle are not fully understood. If pregnancy is established, human chorionic gonadotropin (hCG) produced by the placenta maintains the corpus luteum. As a result, the corpus luteum maintains support for the endometrium, and menstruation does not occur.
Menses
In the absence of pregnancy, withdrawal of progesterone (and estrogen) due to the demise of the corpus luteum leads to degeneration and shedding of the superficial part of the endometrium known as the functional layer. Degeneration of the functional layer is due to necrosis caused by the constriction of blood vessels that supply the endometrium. The necrotic tissue then sloughs away from the uterus and, in conjunction with blood from the underlying vessels and other uterine fluids, is shed as menstrual discharge (i.e., the period). Menstruation usually last 4 to 6 days. The first day of the menses (i.e., the first day of the endometrial cycle) is also the first day of the ovarian cycle. Rebuilding of the functional layer resumes when estrogen levels rise as a result of follicle growth during the new follicular phase.
The hypothalamic-pituitary-ovarian axis drives the menstrual cycle
Neurons in the hypothalamus synthesize, store, and release gonadotropin-releasing hormone (GnRH). Long portal vessels carry the GnRH to the anterior pituitary, where the hormone binds to receptors on the surface of gonadotrophs. The results are the synthesis and release of both FSH and LH from the gonadotrophs ( Fig. 55-3 ). These trophic hormones, LH and FSH, stimulate the ovary to synthesize and secrete the sex steroids estrogens and progestins as well as to produce mature gametes. The ovaries also produce peptides called inhibins and activins. Together, these ovarian steroids and peptides exert both negative and positive feedback on both the hypothalamus and the anterior pituitary. This complex interaction is unique among the endocrine systems of the body in that it generates a monthly pattern of hormone fluctuations. Because the cyclic secretion of estrogens and progestins primarily controls endometrial maturation, menstruation reflects these cyclic changes in hormone secretion.
Neurons in the hypothalamus release GnRH in a pulsatile fashion
A finely tuned neuroendocrine feedback between hormones produced by the brain and ovaries controls the menstrual cycle. As noted on pages 1092–1094 , the process begins in the arcuate nucleus and the preoptic area of the hypothalamus, where neurons synthesize GnRH and transport it to their nerve terminals in the median eminence for storage and subsequent release. Higher centers in the brain trigger the release of GnRH near portal vessels, which carry GnRH to the gonadotrophs in the anterior pituitary. Before puberty, the GnRH neurons are quiescent and thus the reproductive system is inactive. 
N55-1 After puberty, activity of the neurons increases, triggering release of GnRH in rhythmic pulses, about once per hour. Because the half-life of GnRH in blood is only 2 to 4 minutes, these hourly bursts of GnRH cause clearly discernible oscillations in GnRH levels in portal blood, leading to hourly surges in release of the gonadotropins LH and FSH. Early in the follicular phase of the cycle, when the gonadotrophs are not very GnRH sensitive, each burst of GnRH elicits only a small rise in LH ( Fig. 55-4 A ). Later in the follicular phase, when the gonadotrophs in the anterior pituitary become much more sensitive to the GnRH in the portal blood, each burst of GnRH triggers a much larger release of LH (see Fig. 55-4 B ). N55-2
N55-1
Fetal Gonadotropin-Releasing Hormone
GnRH is present in the hypothalamus at 14 to 16 weeks' gestation, and its target, the gonadotropin-containing cells (gonadotrophs), are present in the anterior pituitary gland as early as 10 weeks' gestation. The hypothalamic-pituitary system is functionally competent by ~23 weeks' gestation, at which time fetal tissues release GnRH.
N55-2
Control of Pulsing of Gonadotropin-Releasing Hormone Neurons
Although the mechanisms controlling the hourly pulses of GnRH remain unclear, the pulse generator for GnRH is thought to be located in the arcuate nucleus of the medial basal hypothalamus, where one group of GnRH neurons resides. GnRH neurons isolated from the rodent hypothalamus secrete GnRH in vitro in a rhythmic manner, with a frequency of approximately one pulse per hour. Those studies show that GnRH neurons have intrinsic pulsatile GnRH secretory activity and that the GnRH pulse generator resides within the GnRH neurons. In vivo studies show that bursts of nerve impulses from neurons in the arcuate nucleus correspond in time with the pulsatile release of GnRH from the hypothalamus and with the episodic release of LH from the anterior pituitary. These data suggest that a built-in system within the hypothalamus, and specifically the arcuate nucleus, controls the pulsatile discharge of GnRH from nerve terminals. Although the pulse generator is thought to be intrinsic to cells in the arcuate nucleus, it is significantly influenced by neurons from higher brain centers, predominantly in the cortex, that impact on the GnRH-secreting cells. Inhibitory and excitatory signals affect the pulse frequency of GnRH neurons. In general, kisspeptin neurons and glutamate neurons increase GnRH secretion frequency, whereas GABA neurons inhibit GnRH secretion and repress kisspeptin neurons. This GABA pathway is the main mechanism that keeps GnRH secretion relatively low during the juvenile prepubertal period.
At puberty, GnRH secretion and pulse frequency increase, mainly due to increased activity of kisspeptin neurons and reduction in tonic GABA inhibition. Decreased GABA activity also is thought to enhance the stimulation of kisspeptin neurons by glutamatergic signaling through N -methyl- d -aspartate (NMDA) receptors. Thus, the GnRH pulse-generating mechanism is intrinsic to the hypothalamic GnRH neurons, whose rhythmic activity is modulated by GABAergic, kisspeptinergic, and glutamatergic neurons from higher centers in the cortex. The modulation of GnRH pulse frequency via specific neurotransmitters in response to integration by higher brain centers is key to the control of puberty onset and cyclic reproductive function.
The frequency of GnRH release, N55-3 and thus LH release, determines the specific response of the gonad. Pulses spaced 60 to 90 minutes apart upregulate the GnRH receptors on the gonadotrophs, thus stimulating release of gonadotropins and activating the ovaries. However, continuous administration of GnRH (or an analog) causes downregulation of the GnRH receptors, which suppresses gonadotropin release and gonadal function ( Box 55-2 ).
Box 55-2
Therapeutic Uses of GnRH
Continuous administration of GnRH leads to downregulation (suppression) of gonadotropin secretion, whereas pulsatile release of GnRH causes upregulation (stimulation) of FSH and LH secretion. Clinical problems requiring upregulation of gonadotropin secretion, which leads to stimulation of the gonads, are therefore best treated by a pulsatile mode of GnRH administration. In contrast, when the patient requires gonadal inhibition, a continuous mode of administration is necessary.
An example of a disease requiring pulsatile GnRH administration is Kallmann syndrome. Disordered migration of GnRH cells during embryologic development causes Kallmann syndrome, which in adults results in hypogonadotropic hypogonadism and anosmia (loss of sense of smell). Normally, primordial GnRH cells originate in the nasal placode during embryologic development. These primitive cells then migrate through the forebrain to the diencephalon, where they become specific neuronal groups within the medial basal hypothalamus and preoptic area. In certain individuals, both male and female, proper migration of GnRH cells fails to occur. Females with Kallmann syndrome generally have amenorrhea (no menstrual cycles). However, the pituitary and gonads of these individuals can function properly when appropriately stimulated. Thus, females treated with exogenous gonadotropins or GnRH analogs— pulsatile administration with a programmed infusion pump—can have normal folliculogenesis, ovulation, and pregnancy.
An example of a disease requiring continuous GnRH administration to downregulate gonadal function is endometriosis. Endometriosis is a common condition caused by the aberrant presence of endometrial tissue outside the uterine cavity. This tissue responds to estrogens during the menstrual cycle and is a source of pain and other problems, including infertility. In patients with endometriosis, continuous administration of GnRH analogs inhibits replenishment of the receptor for GnRH in the gonadotrophs in the anterior pituitary. As a result, insufficient numbers of GnRH receptors are available for optimum GnRH action; this deficiency diminishes gonadotropin secretion and produces relative hypoestrogenism. Because estrogen stimulates the endometrium, continuous administration of GnRH or GnRH analogs causes involution and diminution of endometriotic tissue.
Leiomyomas (smooth-muscle tumors) of the uterus (also called uterine fibroids) are also estrogen dependent. When estrogen levels are decreased, the proliferation of these lesions is decreased. Therefore, leiomyomas of the uterus can also be effectively treated by continuous administration of GnRH analogs.
N55-3
Frequency versus Amplitude of Hypothalamic Releasing Hormones
For GnRH release, it appears that the important factor for signaling is the frequency of the GnRH pulses. On the other hand, in the case of corticotropin-releasing hormone (CRH; see pp. 1023–1025 ), it appears that amplitude is the primary factor in controlling adrenocorticotropic hormone (ACTH) release. Thus, depending on the target of the releasing hormone, either frequency or amplitude can be dominant.
In addition to the hourly rhythm of GnRH secretion, a monthly rhythm of GnRH secretion also occurs in females of reproductive age. A massive increase in GnRH secretion by neurons in the preoptic area at midcycle is, in part, responsible for the LH surge, which, as we will see below (see p. 1116 ), leads to ovulation.
GnRH stimulates gonadotrophs in the anterior pituitary to secrete FSH and LH
GnRH enters the anterior pituitary through the portal system and binds to GnRH receptors on the surface of the gonadotroph, thus initiating a series of cellular events that result in the synthesis and secretion of gonadotropins. As discussed for the male on pages 1094–1095 , occupation of the G protein–coupled GnRH receptor ( GnRHR ) N55-4 leads to the formation of inositol 1,4,5-trisphosphate (IP 3 ) and diacylglycerol (DAG; see p. 58 ). The IP 3 causes an increase in [Ca 2+ ] i , triggering exocytosis and gonadotropin release ( Fig. 55-5 ). In addition, the DAG stimulates protein kinase C, which indirectly leads to increases in gene transcription. The net effect is an increase in synthesis of the gonadotropins FSH and LH, which are in the same family as thyroid-stimulating hormone (TSH or thyrotropin; see pp. 1014–1016 ) and hCG (see p. 1139 ). N55-5
N55-4
Gonadotropin-Releasing Hormone Receptor
The GnRH receptor (GnRHR) is internalized and partially degraded in the lysosomes. However, a portion of the GnRHR is shuttled back to the cell surface. Return of the GnRHR to the cell membrane is referred to as receptor replenishment and is related to the upregulation of receptor activity discussed above in the text. The mechanism through which GnRH receptor replenishment occurs remains unclear.
N55-5
The TSH-FSH-LH-hCG Family of Glycoprotein Hormones
FSH and LH are in the same family as TSH (see p. 1014 ) and hCG (see p. 1139 ). All four are glycoprotein hormones with α and β chains. The α chains of all four of these hormones are identical; in humans, they have 92 amino acids and a molecular weight of ~20 kDa. The β chains are unique and confer the specificity of the hormones.
In the female, the rhythm of GnRH secretion influences the relative rates of expression of genes encoding the synthesis of the α, β FSH , and β LH subunits of FSH and LH. GnRH pulsatility also determines the dimerization of the α and β FSH subunits, or α and β LH , as well as their glycosylation. Differential secretion of FSH and LH is also affected by several other hormonal mediators, including ovarian steroids, inhibins, and activins. The role of these agents is discussed in the section on feedback control of the hypothalamic-pituitary-ovarian axis. Thus, depending on the specific hormonal milieu produced by different physiological circumstances, the gonadotroph produces and secretes the α and β subunits of FSH and LH at different rates. The secretion of LH and FSH is further modulated by neuropeptides, amino acids such as aspartate, neuropeptide Y, corticotropin-releasing hormone (CRH), and endogenous opioids.
Before ovulation, the LH and FSH act on cells of the developing follicles. The theca cells (see p. 1117 ) of the follicle have LH receptors, whereas the granulosa cells (see p. 1117 ) have both LH and FSH receptors. After ovulation, LH acts on the cells of the corpus luteum. Both the LH and the FSH receptors are coupled through Gα s to adenylyl cyclase (see p. 53 ), which catalyzes the conversion of ATP to cAMP. cAMP stimulates protein kinase A, which increases the expression of genes whose products enhance cell division or the production of peptide and steroid hormones.
The ovarian steroids (estrogens and progestins) feed back on the hypothalamic-pituitary axis
As summarized in Figure 55-3 , the ovarian steroids—primarily estradiol and progesterone—exert both negative and positive feedback on the hypothalamic-pituitary axis. Whether the feedback is negative or positive depends on both the concentration of the gonadal steroids and the duration of the exposure to these steroids (i.e., the time in the menstrual cycle). In addition, the ovarian peptides—the inhibins and activins—also feed back on the anterior pituitary.
Negative Feedback by Ovarian Steroids
Throughout most of the menstrual cycle, the estradiol and progesterone that are produced by the ovary feed back negatively on both the hypothalamus and the gonadotrophs of the anterior pituitary. The net effect is reduced release of both LH and FSH. Estradiol exerts negative feedback at both low and high concentrations, whereas progesterone is effective only at high concentrations.
Although estradiol inhibits the GnRH neurons in the arcuate nucleus and preoptic area of the hypothalamus, this inhibition is not direct. Rather, estradiol stimulates interneurons that inhibit the GnRH neurons. In the arcuate nucleus, these inhibitory neurons exert their inhibition via opiates. However, in the preoptic area, the inhibitory neurons exert their inhibitory effect via gamma-aminobutyric acid (GABA), a classic inhibitory neurotransmitter (see p. 309 ).
Positive Feedback by Ovarian Steroids
Although ovarian steroids feed back negatively on the hypothalamic-pituitary axis during most of the menstrual cycle, they have the opposite effect at the end of the follicular phase. Levels of estradiol rise gradually during the first half the follicular phase of the ovarian cycle and then increase steeply during the second half ( Fig. 55-6 ). After the estradiol levels reach a certain threshold for a minimum of 2 days—and perhaps because of the accelerated rate of estradiol secretion—the hypothalamic-pituitary axis reverses its sensitivity to estrogens. That is, estradiol now exerts positive feedback on the axis. One manifestation of this positive feedback is that estradiol increases the sensitivity of the gonadotrophs in the anterior pituitary gland to GnRH. As discussed in the next section, this switch to positive feedback promotes the LH surge. Indeed, pituitary cells that are cultured in the absence of estradiol have suboptimal responses to GnRH. Once high levels of estradiol have properly conditioned the gonadotrophs, rising levels of progesterone during the late follicular phase also produce a positive-feedback response and thus facilitate the LH surge.
Ovaries produce peptide hormones—inhibins, activins, and follistatins—that modulate FSH secretion
Inhibins, activins, and follistatins are gonadal peptide hormones, originally identified in follicular fluid, that selectively affect the production and secretion of FSH but do not affect LH. Inhibins inhibit FSH production by gonadotrophs, activins activate FSH production, and follistatins inhibit FSH production by binding to and thereby inhibiting activins.
The inhibins and the activins are glycoproteins that are members of the transforming growth factor-β (TGF-β) superfamily, which also includes antimüllerian hormone (AMH; see p. 1080 ). The inhibins and activins are dimers constructed from a related set of building blocks: a glycosylated 20-kDa α subunit and two nonglycosylated 12-kDa β subunits, one called β A and the other called β B ( Fig. 55-7 ). The inhibins are always composed of one α subunit and either a β A or a β B subunit; the α and β subunits are linked by disulfide bridges. The α-β A dimer is called inhibin A, whereas the α-β B dimer is called inhibin B. The activins, however, are composed of two β-type subunits. Thus, three kinds of activins are recognized: β A -β A , β B -β B , and the heterodimer β A -β B . Follistatin is an unrelated monomeric polypeptide that binds to activin with high affinity.
Negative Feedback by the Inhibins
FSH specifically stimulates the granulosa cells to produce inhibins. Estradiol also stimulates inhibin production through an intraovarian mechanism. Just before ovulation, after the granulosa cells acquire LH receptors, LH also stimulates the production of inhibin by granulosa cells. Inhibins are also produced by other tissues—including the pituitary, the brain, the adrenal gland, the kidney, the bone marrow, the corpus luteum, and the placenta. Nevertheless, the biological action of the inhibins is primarily confined to the reproductive system.
The inhibins inhibit FSH secretion by the gonadotrophs of the anterior pituitary (hence the name inhibin) in a classic negative-feedback arrangement. The initial action of inhibin appears to be beyond the Ca 2+ -mobilization step in FSH secretion. In cultured pituitary cells, even very small amounts of inhibin markedly reduce mRNA levels for both the α LH/FSH and the β FSH subunits. As a result, inhibins suppress FSH secretion. In contrast, inhibins have no effect on the mRNA levels of β LH . In addition to their actions on the anterior pituitary, the inhibins also have the intraovarian effect of decreasing androgen production, which can have secondary effects on intrafollicular estrogen production.
Positive Feedback by the Activins
The same tissues that produce the inhibins also produce the activins, which promote marked increases in β FSH mRNA and FSH release with no change in β LH formation. Activins augment GnRH production and release by hypothalamic neurons. However, the physiological role of activins in the female reproductive system is more complex than that of inhibins because multiple extragonadal tissues produce activin (and follistatin), which may affect the hypothalamic-pituitary-gonadal axis at many levels. Within the ovary, activins modulate folliculogenesis and steroid hormone production by the corpus luteum. Each of these effects is inhibited by inhibin and follistatin.
Activins bind to two types of cell-surface receptors (types I and II) that are serine/threonine kinases (see pp. 67–68 ). Upon ligand activation, the receptors couple to the SMAD second-messenger kinase cascade, which results in the modulation of transcription factors that affect the expression of a large variety of genes. Two cell-surface molecules that bind inhibin with high affinity antagonize the action of activin.
Modulation of gonadotropin secretion by positive and negative ovarian feedback produces the normal menstrual rhythm
In premenopausal women, the pulsatile release of GnRH from the hypothalamus, generally occurring every 60 to 90 minutes (see p. 1111 ), triggers a corresponding pulsatile release of LH and FSH from the gonadotrophs of the anterior pituitary. The gonadotropins induce the production and release of ovarian steroids, which in turn feed back on the hypothalamic-pituitary axis. This feedback loop is unusual because it elicits negative feedback on the hypothalamic-pituitary axis throughout most of the menstrual cycle but positive feedback immediately before ovulation.
Figure 55-6 illustrates the cyclic hormonal changes during the menstrual cycle. The time-averaged records of LH and FSH levels mask their hour-by-hour pulsatility. The follicular phase is characterized by a relatively high frequency of GnRH—and thus LH—pulses. Early in the follicular phase, when levels of estradiol are low but rising, the frequency of LH pulses remains unchanged, but their amplitude gradually increases with time. Figure 55-4 shows this increase in amplitude between the early and late follicular phases. Later in the follicular phase, the higher estradiol levels cause both the frequency and the amplitude of the LH pulses to increase gradually. During this time of high estradiol levels, the ovarian steroids are beginning to feed back positively on the hypothalamic-pituitary axis. Late in the follicular phase, the net effect of this increased frequency and amplitude of LH and FSH pulses is an increase in their time-averaged circulating levels (see Fig. 55-6 ).
The LH surge is an abrupt and dramatic rise in the LH level that occurs around the 13th to 14th day of the follicular phase in the average woman. The LH surge peaks ~12 hours after its initiation and lasts for ~48 hours. The peak concentration of LH during the surge is ~3-fold greater than the concentration before the surge (see Fig. 55-6 ). The LH surge is superimposed on the smaller FSH surge. Positive feedback of estrogens, progestins, and activins on the hypothalamic-pituitary axis is involved in the induction of this LH surge. The primary trigger of the gonadotropin surge is a rise in estradiol to very high threshold levels just before the LH surge. The rise in estrogen levels has two effects. First, the accelerated rate of increase in estradiol levels in the preovulatory phase sensitizes the gonadotrophs in the anterior pituitary to GnRH pulses (see Fig. 55-4 ). Second, the increasing estrogen levels also modulate hypothalamic neuronal activity and induce a GnRH surge, presumably through GnRH neurons in the preoptic area of the hypothalamus. Thus, the powerful positive -feedback action of estradiol induces the midcycle surge of LH and, to a lesser extent, FSH. Gradually rising levels of the activins—secreted by granulosa cells—also act in a positive-feedback manner to contribute to the FSH surge. In addition, gradually increasing levels of LH trigger the preovulatory follicle to increase its secretion of progesterone. These increasing—but still “low”—levels of progesterone also have a positive-feedback effect on the hypothalamic-pituitary axis that is synergistic with the positive-feedback effect of the estrogens. Thus, although progesterone is not the primary trigger for the LH surge, it augments the effects of estradiol.
The gonadotropin surge causes ovulation and luteinization. The ovarian follicle ruptures, probably because of weakening of the follicular wall, and expels the oocyte and with it the surrounding cumulus and corona cells. This process is known as ovulation, and it is discussed in more detail in Chapter 56 . As discussed below, a physiological change— luteinization —in the granulosa cells of the follicle causes these cells to secrete progesterone rather than estradiol. The granulosa and theca cells undergo structural changes that transform them into luteal cells, a process known as luteinization. The pulsatile rhythm of GnRH release and gonadotropin secretion is maintained throughout the gonadotropin surge.
As the luteal phase of the menstrual cycle begins, circulating levels of LH and FSH rapidly decrease (see Fig. 55-6 ). This fall-off in gonadotropin levels reflects negative feedback by three ovarian hormones—estradiol, progesterone, and inhibin. Moreover, as gonadotropin levels fall, the levels of ovarian steroids also fall. Thus, immediately after ovulation we see more or less concurrent decreases in the levels of both gonadotropins and ovarian hormones.
Later, during the luteal phase, the luteal cells of the corpus luteum gradually increase their synthesis of estradiol, progesterone, and inhibin (see Fig. 55-6 ). The rise in the concentration of these hormones causes—in typical negative-feedback fashion—the continued decrease of gonadotropin levels midway through the luteal phase. One of the mechanisms of this negative feedback is the effect of progesterone on the hypothalamic-pituitary axis. Recall that at the peak of the LH surge, both the frequency and the amplitude of LH pulses are high. Progesterone levels rise, and high levels stimulate inhibitory opioidergic interneurons in the hypothalamus, which inhibits the GnRH neurons. This inhibition decreases the frequency of LH pulses, although the amplitude remains rather high.
By ~48 hours before onset of the menses, the pulsatile rhythm of LH secretion has decreased to one pulse every 3 to 4 hours. As a result, circulating levels of LH slowly fall during the luteal phase. During the late luteal phase, the gradual demise of the corpus luteum leads to decreases in the levels of progesterone, estradiol, and inhibin (see Fig. 55-6 ). After the onset of menstruation, the hypothalamic-pituitary axis returns to a follicular-phase pattern of LH secretion (i.e., a gradual increase in the frequency of GnRH pulses).
Ovarian Steroids
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