Connie Alford, MD
Sahadat Nurudeen, MD
This chapter is concerned with the function of the female reproductive system from birth, through puberty and adulthood, and finally to menopause.
After birth, the gonads are quiescent until they are activated by gonadotropins from the pituitary to bring about the final maturation of the reproductive system. This period of final maturation is known as adolescence. It is often called puberty, although strictly defined, puberty is the period when the endocrine and gametogenic functions of the gonads first develop to the point where reproduction is possible.
After sexual maturity, there are regular periodic changes of the adult female reproductive system, each in preparation for pregnancy. The cyclic changes are primarily divided into the ovarian and uterine cycle, though changes can also be seen in the uterine cervix, vagina, and breasts. Control of the cycle is exerted through the regulation of hypothalamic, pituitary, and ovarian hormones.
With advancing age, these cycles become irregular and eventually cease in the period known as menopause. The ovarian follicles are less responsive to central regulation, and there is an acute decrease in estrogen levels, which may lead to vasomotor symptoms, labile mood, and many changes in the female reproductive tract.
PUBERTY
The age at the time of puberty is variable. In Europe and the United States, it has been declining at the rate of 1–3 months per decade for more than 175 years. In the United States in recent years, puberty has generally been occurring between the ages of 8 and 13 in girls and 9 and 14 in boys depending on ethnic background.
Another event that occurs in humans at the time of puberty is an increase in the secretion of adrenal androgens (Fig. 4–1). The onset of this increase is called adrenarche. It typically happens in males and females before the onset of puberty occurring at age 8–10 years in girls and 10–12 years in boys. Dehydroepiandrosterone (DHEA) values peak at about 25 years of age and are slightly higher in boys. They then decline slowly to low values after the age of 60.
Figure 4–1. Change in serum dehydroepiandrosterone sulfate (DHEAS) with age. The middle line is the mean, and the dashed lines identify ±1.96 standard deviations. (Reproduced with permission from Smith MR, Rudd BT, Shirley A, et al. A radioimmunoassay for the estimation of serum dehydroepiandrosterone sulfate in normal and pathological sera. Clin Chim Acta 1975;65:5.)
The increase in adrenal androgen secretion at adrenarche occurs without any changes in the secretion of cortisol or adrenocorticotropic hormone (ACTH). Adrenarche is probably due to a rise in the lyase activity of a 17α-hydroxylase. Thereafter, there is a gradual decline in this activity as plasma adrenal androgen secretion declines to low levels in old age.
In girls, the first event of puberty is thelarche, the development of breasts. The breasts develop under the influence of the ovarian hormones estradiol and progesterone, with estradiol primarily responsible for the growth of ducts and progesterone primarily responsible for the growth of lobules and alveoli. Thelarche is then followed by pubarche, the development of axillary and pubic hair. The adrenal androgens contribute significantly to the growth of axillary and pubic hair. Finally there is menarche, the first menstrual period. The initial periods are generally anovulatory with regular ovulation beginning about 1 year later.
The sequence of changes that occur at puberty in girls is summarized in Figure 4–2.
Figure 4–2. Sequence of events at adolescence in girls. A: Stage 1: Preadolescent; elevation of breast papillae only. Stage 2: Breast bud stage (may occur between ages 8 and 13); elevation of breasts and papillae as small mounds, with enlargement of areolar diameter. Stage 3: Enlargement and elevation of breasts and areolas with no separation of contours. Stage 4: Areolas and papillae project from breast to form a secondary mound. Stage 5: Mature; projection of papillae only, with recession of areolas into general contour of breast. B: Stage 1: Preadolescent; no pubic hair. Stage 2: Sparse growth along labia of long, slightly pigmented, downy hair that is straight or slightly curled (may occur between ages 8 and 14). Stage 3: Darker, coarser, more curled hair growing sparsely over pubic area. Stage 4: Resembles adult in type but covers smaller area. Stage 5: Adult in quantity and type. (Redrawn, with permission, from Tanner JM. Growth at Adolescence. 2nd ed. New York, NY: Blackwell; 1962.)
Control of the Onset of Puberty
In general, many factors can influence the timing of the initiation of puberty including general health, genetic influences, nutrition, and exercise. However, a neural mechanism is thought to be predominantly responsible for the onset of puberty. It depends on normal functioning of the hypothalamic-pituitary-gonadal axis. In children, the gonads can be stimulated by gonadotropins, the pituitary contains gonadotropins, and the hypothalamus contains gonadotropin-releasing hormone (GnRH). However, the gonadotropins are not secreted. In immature monkeys, normal menstrual cycles can be brought on by pulsatile injection of GnRH, and the cycles persist as long as the pulsatile injection is continued. In addition, GnRH is secreted in a pulsatile fashion in adults. Thus, it seems clear that during the period from birth to puberty, a neural mechanism is operating to prevent the normal pulsatile release of GnRH. The nature of the mechanism inhibiting the GnRH pulse generator is unknown. Several theories have been suggested about this mechanism, including a recent study involving humans and mice, providing evidence that GPR54, a gene for a G protein–coupled receptor, is involved in the regulation of the processing or secretion of GnRH by the hypothalamus.
Relation to Leptin
It has been argued for some time that normally a critical body weight must be reached for puberty to occur. Thus, for example, young women who engage in strenuous athletics lose weight and stop menstruating. The same is seen in girls with anorexia nervosa. If these girls start to eat and gain weight, they menstruate again, ie, they “go back through puberty.” It now appears that leptin, the satiety-producing hormone secreted by fat cells, may be the link between body weight and puberty. Leptin treatment has been shown to induce precocious puberty in immature female mice. However, more recent studies have suggested leptin to have a more permissive role for the onset of puberty rather than being a trigger. Observations of recombinant leptin administration in older, but not younger, children with leptin deficiency resulted in increased gonadotropin pulsatility. The role of leptin in the control of pubarche remains to be determined.
Sexual Precocity
Sexual precocity is pubertal development occurring before the age of 8 years in girls, and before the age of 9 years in boys. The major causes of precocious sexual development in humans are listed in Table 4–1. Early development of secondary sexual characteristics without gametogenesis is caused by abnormal exposure of immature males to androgen or females to estrogen. This syndrome should be called precocious pseudopuberty to distinguish it from true precocious puberty due to an early, but otherwise normal pubertal pattern of gonadotropin secretion from the pituitary (Fig. 4–3).
Table 4–1. Classification of the causes of precocious sexual development in humans.
Figure 4–3. Constitutional precocious puberty in a 3½-year-old girl. The patient developed pubic hair and started to menstruate at the age of 17 months.
In 1 large series of cases, precocious puberty was the most frequent endocrine symptom of hypothalamic disease. It is interesting that in experimental animals and humans, lesions of the ventral hypothalamus near the infundibulum cause precocious puberty. The effect of the lesions may be due to an interruption of neural pathways that produce inhibition of the GnRH pulse generator or a local release of factors causing premature activation of the GnRH pulse generator. Pineal tumors are sometimes associated with precocious puberty, but there is evidence that these tumors are related only when there is secondary damage to the hypothalamus. Precocity due to this and other forms of hypothalamic damage probably occurs with equal frequency in both sexes, although the constitutional form of precocious puberty is more common in girls. In addition, it has now been proven that precocious gametogenesis and steroidogenesis can occur without the pubertal pattern of gonadotropin secretion (gonadotropin-independent precocity). At least in some cases of the condition, the sensitivity of luteinizing hormone (LH) receptors to gonadotropins is increased because of an activating mutation in the G protein that couples receptors to adenylyl cyclase.
Recent observational studies have proposed a link between low birth weight, increased weight gain during childhood, changes in insulin sensitivity, and subsequent hormonal changes, such as early pubarche. Although the association remains speculative, these studies suggest a programmed adaptation to improved postnatal nutritional status triggering a pathway of rapid growth and secondary sexual development.
Delayed or Absent Puberty
The normal variation in the age at which adolescent changes occur is so wide that puberty cannot be considered to be pathologically delayed until the absence of secondary sexual development by age 14 in girls or until the failure of menarche by the age of 17. Failure of maturation due to panhypopituitarism is associated with dwarfing and evidence of other endocrine abnormalities. Patients with the XO chromosomal pattern and gonadal dysgenesis are also dwarfed. In some individuals, puberty is delayed and menarche does not occur (primary amenorrhea), even though the gonads are present and other endocrine functions are normal.
REPRODUCTIVE FUNCTION AFTER SEXUAL MATURITY
Menstrual Cycle
The anatomy of the reproductive system of adult women is described in Chapter 1. Unlike the reproductive system of men, this system shows regular cyclic changes that teleologically may be regarded as periodic preparation for fertilization and pregnancy. In primates, the cycle is a menstrual cycle, and its most conspicuous feature is the cyclic vaginal bleeding that occurs with shedding of the uterine mucosa (menstruation). The length of the cycle is notoriously variable, but the average figure is 28 days from the start of one menstrual period to the start of the next. By common usage, the days of the cycle are identified by number, starting with the first day of menstruation.
Ovarian Cycle
From the time of birth, there are many primordial follicles under the ovarian capsule. Each contains an immature ovum (Fig. 4–4). At the start of each cycle, several of these follicles enlarge and a cavity forms around the ovum (antrum formation). This cavity is filled with follicular fluid. In humans, 1 of the follicles in 1 ovary starts to grow rapidly on about the sixth day and becomes the dominant follicle. The others regress, forming atretic follicles. It is not known how 1 follicle is singled out for development during this follicular phase of the menstrual cycle, but it seems to be related to the follicle’s ability to produce estrogen, which is necessary for final maturation. The secretion of estrogen, in animal models, has been demonstrated even before the dominant follicle has emerged as morphologically dominant. Theoretically, depending on the position of the follicle to the blood supply, there is a gradient of exposure to different amounts of hormones, growth factors, and other signaling molecules. Therefore, the follicle most responsive to follicle-stimulating hormone (FSH) is likely to be the first to produce estradiol.
The structure of a mature ovarian follicle (graafian follicle) is shown in Figure 4–4. The cells of the theca interna of the follicle are the primary source of circulating estrogens. The follicular fluid has a high estrogen content, and much of this estrogen comes from the granulosa cells.
Figure 4–4. Diagram of a mammalian ovary, showing the sequential development of a follicle, formation of a corpus luteum, and, in the center, follicular atresia. A section of the wall of a mature follicle is enlarged at the upper right. The interstitial cell mass is not prominent in primates.
At about the 14th day of the cycle, the distended follicle ruptures, and the ovum is extruded into the abdominal cavity. This is the process of ovulation. The ovum is picked up by the fimbriated ends of the uterine tubes (oviducts) and transported to the uterus. Unless fertilization occurs, the ovum degenerates or passes on through the uterus and out of the vagina.
The follicle that ruptures at the time of ovulation promptly fills with blood, forming what is sometimes called a corpus hemorrhagicum. Minor bleeding from the follicle into the abdominal cavity may cause peritoneal irritation and fleeting lower abdominal pain (“mittelschmerz”). The granulosa and theca cells of the follicle lining promptly begin to proliferate, and the clotted blood is rapidly replaced with yellowish, lipid-rich luteal cells, forming the corpus luteum. This is the luteal phase of the menstrual cycle, during which the luteal cells secrete estrogen and progesterone. Growth of the corpus luteum depends on its developing an adequate blood supply. There is evidence that vascular endothelial growth factor (VEGF) is essential for this process through regulation by the transcription factor, HIF-1α, under hypoxic conditions or by gonadotropin-stimulated conditions. If pregnancy occurs, the corpus luteum persists, and there are usually no more menstrual cycles until after delivery. If there is no pregnancy, the corpus luteum begins to degenerate about 4 days before the next menses (day 24 of the cycle) and is eventually replaced by fibrous tissue, forming a corpus albicans.
In humans, no new ova are formed after birth. During fetal development, the ovaries contain over 7 million germ cells; however, many undergo involution before birth, and others are lost after birth. At the time of birth, there are approximately 2 million primordial follicles containing ova, but approximately 50% of these are atretic. The remaining million ova undergo the first meiotic division at this time and arrest in prophase until adulthood. Atresia continues during development, and the number of ova in both the ovaries at the time of puberty is less than 300,000 (Fig. 4–5). Normally, only 1 of these ova per cycle (or about 400–500 in the course of a normal reproductive life) is stimulated to mature; the remainder degenerate. Just before ovulation, the first meiotic division is completed. One of the daughter cells, the secondary oocyte, receives most of the cytoplasm, while the other, the first polar body, fragments and disappears. The secondary oocyte immediately begins the second meiotic division, but this division stops at metaphase and is completed only when a sperm penetrates the oocyte. At that time, the second polar body is cast off, and the fertilized ovum proceeds to form a new individual.
Figure 4–5. Number of primordial follicles per ovary in women at various ages. 
premenopausal women (regular menses); 
perimenopausal women (irregular menses for at least 1 year); 
postmenopausal women (no menses for at least 1 year). Note that the vertical scale is a log scale and that the values are from 1 rather than 2 ovaries. (Reproduced, with permission, from Richardson SJ, Senikas V, Nelson JF. Follicular depletion during the menopausal transition: evidence for accelerated loss and ultimate exhaustion. J Clin Endocrinol Metab 1987;65:1231.)
Uterine Cycle
The events that occur in the uterus during the menstrual cycle terminate with the menstrual flow. By the end of each menstrual period, all but the deep layer of the endometrium has sloughed. Under the influence of estrogen secreted from the developing follicles, the endometrium regenerates from the deep layer and increases rapidly in thickness during the period from the fifth to 16th days of the menstrual cycle. As the thickness increases, the uterine glands are drawn out so that they lengthen (Fig. 4–6), but they do not become convoluted or secrete to any degree. These endometrial changes are called proliferative, and this part of the menstrual cycle is sometimes called the proliferative phase. It is also called the preovulatory or follicular phase of the cycle. After ovulation, the endometrium becomes more highly vascularized and slightly edematous under the influence of estrogen and progesterone from the corpus luteum. The glands become coiled and tortuous (Fig. 4–6), and they begin to secrete clear fluid. Consequently, this phase of the cycle is called the secretory or luteal phase. Late in the luteal phase, the endometrium, like the anterior pituitary, produces prolactin. The function of this endometrial prolactin has yet to be determined, though it has been suggested that prolactin may play a role in implantation.
Figure 4–6. Changes in the endometrium during the menstrual cycle. (Reproduced, with permission, from Ganong WF. Review of Medical Physiology. 22nd ed. New York, NY: McGraw-Hill; 2005.)
The endometrium is supplied by 2 types of arteries. The superficial two-thirds of the endometrium, the stratum functionale, is shed during menstruation and is supplied by the long, coiled spiral arteries. The deep layer, which is not shed, is called the stratum basale and is supplied by short, straight basilar arteries.
When the corpus luteum regresses, hormonal support for the endometrium is withdrawn, causing vascular spasms in the spiral artery, ultimately leading to endometrial ischemia. The endometrium becomes thinner, which adds to the coiling of the spiral arteries. Leukocyte infiltration into the endometrial stroma initiates the breakdown of the extracellular matrix in the functionalis layer. Foci of necrosis appear in the endometrium and walls of the spiral arteries, which coalesce and lead to spotty hemorrhages that become confluent and ultimately produce menstrual flow.
Spiral artery vasospasm serves to limit blood loss during menstruation and probably is produced by locally released prostaglandins. There are large quantities of prostaglandins in the secretory endometrium and in menstrual blood. Infusions of prostaglandin F2a (PGF2a) produce endometrial necrosis and bleeding. One theory of the onset of menstruation holds that in necrotic endometrial cells, lysosomal membranes break down and release proteolytic enzymes that foster the formation of prostaglandins from cellular phospholipids while promoting further local tissue destruction.
From the point of view of endometrial function, the proliferative phase of the menstrual cycle represents the restoration of the epithelium from the preceding menstruation, while the secretory phase represents the preparation of the uterus for implantation of the fertilized ovum. The length of the secretory phase is remarkably constant, about 14 days. The variations seen in the length of the menstrual cycle are mostly due to variations in the length of the proliferative phase. When fertilization fails to occur during the secretory phase, the endometrium is shed, and a new cycle begins.
Normal Menstruation
Menstrual blood is predominantly arterial, with only 25% of the blood being of venous origin. It contains tissue debris, prostaglandins, and relatively large amounts of fibrinolysin from the endometrial tissue. The fibrinolysin lyses clots, so menstrual blood does not normally contain clots unless the flow is excessive.
The usual duration of the menstrual cycle is 3–5 days, but flow as short as 1 day and as long as 8 days can occur in normal women. The average amount of blood loss is 30 mL but normally may range from slight spotting to 80 mL. Loss of more than 80 mL is abnormal. Obviously, the amount of flow can be affected by various factors, including not only the thickness of the endometrium, but also the medications and diseases that affect clotting mechanisms. After menstruation, the endometrium regenerates from the stratum basale.
Anovulatory Cycles
In some instances, ovulation fails to occur during the menstrual cycle. Such anovulatory cycles are common for the first 12–18 months after menarche and again before the onset of menopause. When ovulation does not occur, no corpus luteum is formed, and the effects of progesterone on the endometrium are absent. Estrogens continue to cause growth, however, and the proliferative endometrium becomes thick enough to break down and begin to slough. The time it takes for bleeding to occur is variable, but it usually occurs less than 28 days from the last menstrual period. The flow is also variable and ranges from scanty to relatively profuse.
Cyclic Changes in the Uterine Cervix
Although it is contiguous with the body of the uterus, the cervix of the uterus is different in a number of ways. The mucosa of the uterine cervix does not undergo cyclic desquamation, but there are regular changes in the cervical mucus. Estrogen makes the mucus much thinner and more alkaline, changes that promote the survival and transport of sperm. Progesterone makes it thick, tenacious, and cellular. The mucus is thinnest at the time of ovulation, and its elasticity, or spinnbarkeit, increases so that by midcycle a drop can be stretched into a long, thin thread that may be 8–12 cm or more in length. In addition, it dries in an arborizing, fernlike pattern when a thin layer is spread on a slide (Fig. 4–7). After ovulation and during pregnancy, it becomes thick and fails to form the fern pattern.
Figure 4–7. Patterns formed when cervical mucus is smeared on a slide, permitted to dry, and examined under the microscope. Progesterone makes the mucus thick and cellular. In the smear from a patient who failed to ovulate (bottom), there is no progesterone to inhibit the estrogen-induced fern pattern. (Reproduced, with permission, from Barrett KE. Ganong’s Review of Medical Physiology. 23rd ed. New York, NY: McGraw-Hill; 2010.)
Vaginal Cycle
Under the influence of estrogens, the vaginal epithelium becomes cornified, and these cornified epithelial cells can be identified in a vaginal smear. Under the influence of progesterone, a thick mucus is secreted, and the epithelium proliferates and becomes infiltrated with leukocytes. The cyclic changes in the vaginal smear in rats are particularly well known. The changes in humans and other species are similar but unfortunately not so clear-cut. However, the increase in cornified epithelial cells is apparent when a vaginal smear from an adult woman in the follicular phase of the menstrual cycle is compared, for example, with a smear taken from a prepubescent female.
Cyclic Changes in the Breasts
Although lactation normally does not occur until the end of pregnancy, there are cyclic changes in the breasts during the menstrual cycle. Estrogens cause proliferation of mammary ducts, whereas progesterone causes growth of lobules and alveoli (see Actions of Progesterone). The breast swelling, tenderness, and pain experienced by many women during the 10 days preceding menstruation probably are due to distention of the ducts, hyperemia, and edema of the interstitial tissue of the breasts. All of these changes regress, along with the symptoms, during menstruation.
Cyclic Changes in Other Body Functions
In addition to cyclic breast swelling and tenderness, there is usually a small increase in body temperature during the luteal phase of the menstrual cycle. This change in body temperature (see Indicators of Ovulation) probably is due to the thermogenic effect of progesterone.
Changes During Sexual Intercourse
During sexual excitation, the vaginal walls become moist as a result of transudation of fluid through the mucus membrane. A lubricating mucus is secreted by the vestibular glands. The upper part of the vagina is sensitive to stretch, while tactile stimulation from the labia minora and clitoris adds to the sexual excitement. The stimuli are reinforced by tactile stimuli from the breasts and, as in men, by visual, auditory, and olfactory stimuli. Eventually, the crescendo or climax known as orgasm may be reached. During orgasm, there are autonomically mediated rhythmic contractions of the vaginal wall. Impulses also travel via the pudendal nerves and produce rhythmic contractions of the bulbocavernosus and ischiocavernosus muscles. The vaginal contractions may aid in the transport of spermatozoa but are not essential for it, as fertilization of the ovum is not dependent on orgasm.
Indicators of Ovulation
Knowing when during the menstrual cycle ovulation occurs is important in increasing fertility or, conversely, in contraception. A convenient, but retrospective, indicator of the time of ovulation is a rise in the basal body temperature (Fig. 4–8). Accurate temperatures can be obtained by using a thermometer that is able to measure temperature precisely between 96 and 100°F. The woman should take her temperature orally, vaginally, or rectally in the morning before getting out of bed. The cause of temperature change at the time of ovulation is unknown but probably is due to the increase in progesterone secretion, as progesterone is thermogenic. A rise in urinary LH occurs during the rise in circulating LH that causes ovulation. This increase can be measured and used as another indicator of ovulation. Kits using dipsticks or simple color tests for detection of urinary LH are available for home use.
Ovulation normally occurs about 9 hours after the peak of the LH surge at midcycle (Fig. 4–8). The ovum lives approximately 72 hours after it is extruded from the follicle but probably is fertilizable for less than half this time. In a study of the relationship of isolated intercourse to pregnancy, 36% of women had a detected pregnancy following intercourse on the day of ovulation, but with intercourse on days after ovulation, the percentage was zero. Isolated intercourse of the first and second days before ovulation led to pregnancy in about 36% of the women. A few pregnancies resulted from isolated intercourse on day 3, 4, or 5 before ovulation, although the percentage was much lower, ie, 8% on day 5 before ovulation. Thus, some sperm can survive in the female genital tract and produce fertilization for up to 120 hours before ovulation, but the most fertile period is clearly the 48 hours before ovulation. However, for those interested in the “rhythm method” of contraception, if should be noted that there are rare but documented cases of pregnancy resulting from isolated coitus on every day of the cycle.
Figure 4–8. Basal body temperature and plasma hormone concentrations (mean ± standard error) during the normal human menstrual cycle. Values are aligned with respect to the day of the midcycle luteinizing hormone (LH) peak. FSH, follicle-stimulating hormone. (Reproduced, with permission, from Barrett KE. Ganong’s Review of Medical Physiology. 23rd ed. New York, NY: McGraw-Hill; 2010.)
OVARIAN HORMONES
Chemistry, Biosynthesis, & Metabolism of Estrogens
The naturally occurring estrogens are 17β-estradiol, estrone, and estriol (Fig. 4–9). They are C18 steroids, ie, they do not have an angular methyl group attached to the 10 position or a Δ4-3-keto configuration in the A ring. They are secreted primarily by the granulosa and thecal cells of the ovarian follicles, the corpus luteum, and the placenta. The biosynthetic pathway involves their aromatization from androgens. Aromatase (CYP19) is the enzyme that catalyzes the conversion of androstenedione to estrone (Fig. 4–9). It also catalyzes the conversion of testosterone to estradiol.
Figure 4–9. Biosynthesis and metabolism of estrogens. (Reproduced, with permission, from Barrett KE. Ganong’s Review of Medical Physiology. 23rd ed. New York, NY: McGraw-Hill; 2010.)
Theca interna cells have many LH receptors, and LH acts on them via cyclic adenosine 3′,5′-monophosphate (cAMP) to increase conversion of cholesterol to androstenedione. Some of the androstenedione is converted to estradiol, which enters the circulation. The theca interna cells also supply androstenedione to granulosa cells. The granulosa cells only make estradiol when provided with androgens (Fig. 4–10), and they secrete the estradiol that they produce into the follicular fluid. They have many FSH receptors, and FSH facilitates the secretion of estradiol by acting via cAMP to increase the aromatase activity in these cells. Mature granulosa cells also acquire LH receptors, and LH stimulates estradiol production.
Figure 4–10. Interactions between theca and granulosa cells in estradiol synthesis and secretion. (Reproduced, with permission, from Barrett KE. Ganong’s Review of Medical Physiology. 23rd ed. New York, NY: McGraw-Hill; 2010.)
The stromal tissue of the ovary also has the potential to produce androgens and estrogens. However, it probably does so in insignificant amounts in normal premenopausal women. 17β-Estradiol, the major secreted estrogen, is in equilibrium in the circulation with estrone. Estrone is further metabolized to estriol (Fig. 4–9), probably mainly in the liver. Estradiol is the most potent estrogen of the three, and estriol is the least potent.
Two percent of the circulating estradiol is free. The remainder is bound to protein: 60% to albumin and 38% to the same gonadal steroid-binding globulin (GBG) that binds testosterone (Table 4–2).
Table 4–2. Distribution of gonadal steroids and cortisol in plasma.
In the liver, estrogens are oxidized or converted to glucuronide and sulfate conjugates. Appreciable amounts are secreted in the bile and reabsorbed in the bloodstream (enterohepatic circulation). There are at least 10 different metabolites of estradiol in human urine.
Secretion of Estrogens
The concentration of estradiol in plasma during the menstrual cycle is shown in Figure 4–8. Almost all of the estrogen comes from the ovary. There are 2 peaks of secretion: one just before ovulation and one during the midluteal phase. The estradiol secretion rate is 36 μg/d (133 nmol/d) in the early follicular phase, 380 μg/d just before ovulation, and 250 μg/d during the midluteal phase (Table 4–3). After menopause, estrogen secretion declines to low levels. For comparison, the estradiol production rate in men is about 50 μg/d (184 nmol/d).
Table 4–3. Twenty-four–hour production rates of sex steroids in women at different stages of the menstrual cycle.
Effects on Female Genitalia
Estrogens facilitate the growth of the ovarian follicles and increase the motility of the uterine tubes. Their role in the cyclic changes in the endometrium, cervix, and vagina is discussed earlier. They increase uterine blood flow and have important effects on the smooth muscle of the uterus. In immature and ovariectomized females, the uterus is small and the myometrium atrophic and inactive. Estrogens increase the amount of uterine muscle and its content of contractile proteins. Under the influence of estrogens, the myometrium becomes more active and excitable, and action potentials in the individual muscle fibers are increased. The “estrogen-dominated” uterus is also more sensitive to oxytocin.
Prolonged treatment with estrogens causes endometrial hypertrophy. When estrogen therapy is discontinued, there is some sloughing and withdrawal bleeding. Some “breakthrough” bleeding may also occur during prolonged treatment with estrogens.
Effects on Endocrine Organs
Estrogens decrease FSH secretion. In some circumstances, estrogens inhibit LH secretion (negative feedback); in others, they increase LH secretion (positive feedback). Estrogens also increase the size of the pituitary. Women are sometimes given large doses of estrogens for 4–6 days to prevent conception during the fertile period (postcoital or “morning-after” contraception). In this instance, pregnancy probably is prevented by interference with implantation of the fertilized ovum rather than by changes in gonadotropin secretion.
Estrogens cause increased secretion of angiotensinogen and thyroid-binding globulin. They also cause epiphyseal closure in humans. In livestock, they exert an important protein anabolic effect, possibly by stimulating the secretion of androgens from the adrenal; estrogens have been used commercially to increase the weight of domestic animals.
Effects on the Central Nervous System
Estrogens are responsible for estrus behavior in animals, and they may increase libido in humans. They apparently exert this action by a direct effect on certain neurons in the hypothalamus (Fig. 4–11).
Figure 4–11. Loci where implantations of estrogen in the hypothalamus affect ovarian weight and sexual behavior in rats, projected on a sagittal section of the hypothalamus. The implants that stimulate sex behavior are located in the suprachiasmatic area above the optic chiasm, whereas ovarian atrophy is produced by implants in the arcuate nucleus and surrounding ventral hypothalamus just above the pituitary stalk. MB, mamillary body. (Reproduced, with permission, from Barrett KE. Ganong’s Review of Medical Physiology. 23rd ed. New York, NY: McGraw-Hill; 2010.)
Estrogens increase the proliferation of dendrites on neurons and the number of synaptic knobs in rats. In humans, they have been reported to slow the progression of Alzheimer’s disease, but this role of estrogen remains controversial.
Effects on the Breasts
Estrogens produce duct growth in the breasts and are largely responsible for breast enlargement at puberty in girls. Breast enlargement that occurs when estrogen-containing skin creams are applied locally is primarily due to systemic absorption of the estrogen, although a slight local effect is also produced. Estrogens are responsible for the pigmentation of the areolas. Pigmentation usually becomes more intense during the first pregnancy than it does at puberty.
Effects on Female Secondary Sex Characteristics
The body changes that develop in girls at puberty—in addition to enlargement of the breasts, uterus, and vagina—are due in part to estrogens, which are the “feminizing hormones,” and in part simply to the absence of testicular androgens. Women have narrow shoulders, broad hips, thighs that converge, and arms that diverge (wide carrying angle). This body configuration, plus the female distribution of fat in the breasts and buttocks, is also seen in castrated males. In women, the larynx retains its prepubertal proportions, and the voice is high-pitched. There is less body hair and more scalp hair, and the pubic hair generally has a characteristic flattop pattern (female escutcheon). Growth of pubic and axillary hair in the female is due primarily to androgens rather than estrogens, although estrogen treatment may cause some hair growth. The androgens are produced by the adrenal cortex and, to a lesser extent, by the ovaries.
Other Actions of Estrogens
Normal women retain salt and water and gain weight just before menstruation. Estrogens can cause some degree of salt and water retention. However, aldosterone secretion is slightly elevated in the luteal phase, and this also contributes to premenstrual fluid retention.
Estrogens make sebaceous gland secretions more fluid and thus counter the effect of testosterone and inhibit formation of comedones (“blackheads”) and acne. The liver palms, spider angiomas, and slight breast enlargement seen in advanced liver disease are due to increased circulating estrogens. The increase appears to be due to decreased hepatic metabolism of androstenedione, making more of this androgen available for conversion to estrogens.
Estrogens have a significant plasma cholesterol-lowering action. They produce vasodilatation and inhibit vascular smooth muscle proliferation, possibly by increasing the local production of nitric oxide (NO). Estrogen has also been shown to prevent expression of factors important in the initiation of atherosclerosis. These actions may account for the low incidence of myocardial infarction and other complications of atherosclerotic-vascular disease in premenopausal women. There is considerable evidence that small doses of estrogen may reduce the incidence of cardiovascular disease after menopause. However, some recently published data do not support this conclusion, and additional research is needed. Large doses of oral estrogen also promote thrombosis, apparently because the high concentrations of estrogen that reach the liver in the portal blood alter hepatic production of clotting factors.
Mechanism of Action
The 2 principal types of nuclear estrogen receptors are estrogen receptor-α (ER-α), which is encoded by a gene on chromosome 6, and estrogen receptor-β (ER-β), which is encoded by a gene on chromosome 14. Both are members of the nuclear receptor superfamily, which includes receptors for many different steroids. After binding estrogen, the nuclear receptors dimerize and bind to DNA, altering its transcription (Fig. 4–12). Some tissues contain one type or the other, but there is also overlap, with some tissues containing both ER-α and ER-β. ER-α is found primarily in the uterus, kidneys, liver, and heart; whereas ER-β is found primarily in the ovaries, prostate, lung, gastrointestinal tract, hemopoietic system, and central nervous system. The receptors also form heterodimers, with ER-α binding to ER-β. Male and female mice in which the gene for ER-α has been knocked out are sterile, develop osteoporosis, and continue to grow because their epiphyses do not close. ER-β female knockouts are infertile, but ER-β male knockouts are fertile even though they have hyperplastic prostates and loss of fat. Thus, the actions of the estrogen receptors are complex, multiple, and varied. However, this is not surprising because it is now known that both receptors exist in various isoforms and, like thyroid receptors, can bind to various activating and stimulating factors.
Figure 4–12. Mechanism of action of steroid hormones. The estrogen, progestin, androgen, glucocorticoid, mineralocorticoid, and 1,25-dihydroxycholecalciferol receptors have different molecular weights, but all have a ligand-binding domain and a DNA-binding domain that is exposed when the ligand binds. The receptor– hormone complex then binds to DNA, producing increased or decreased transcription. H, hormone; R, receptor. (Reproduced, with permission, from Ganong WF. Review of Medical Physiology. 22nd ed. New York, NY: McGraw-Hill; 2005.)
Most of the actions of estrogens are genomic, ie, mediated by actions of the nucleus. However, some effects are so rapid that it is difficult to believe they are mediated via increased expression of mRNAs. These include effects on neuronal discharge in the brain and possibly feedback effects on gonadotropin secretion. Their existence has led to the hypothesis that, in addition to genomic actions, there are nongenomic effects of estrogens that are presumably mediated by membrane receptors. Similar rapid effects of progesterone, testosterone, and aldosterone may also be produced by membrane receptors.
Synthetic Estrogen
The ethinyl derivative of estradiol (Fig. 4–13) is a potent estrogen. Unlike naturally occurring estrogens, it is relatively active when given orally because it has an ethinyl group in position 17, which makes it resistant to hepatic metabolism. Naturally occurring hormones have low activity when given orally because the portal venous drainage of the intestine carries them to the liver, where they are largely inactivated before they can reach the general circulation. Some nonsteroidal substances and a few compounds found in plants have estrogenic activity. Plant estrogens rarely affect humans but may cause undesirable effects in farm animals. Diethylstilbestrol (Fig. 4–13) and a number of related compounds are strongly estrogenic, possible because they are converted to steroid-like ring structures in the body.
Figure 4–13. Synthetic estrogens. (Reproduced, with permission, from Ganong WF. Review of Medical Physiology. 22nd ed. New York, NY: McGraw-Hill; 2005.)
Estradiol reduces the hot flashes and other symptoms of the menopause, and it prevents the development of osteoporosis. It may reduce the initiation and progression of atherosclerosis and the incidence of myocardial infarctions. However, it also stimulates the growth of the endometrium and the breast, and it can lead to cancer of the uterus and possibly the breast. Therefore, there has been an active search for “tailor-made” estrogens that have the bone and cardiovascular effects of estradiol but lack its growth-stimulating effects on the uterus and the breast. Two of the selective estrogen receptor modulators (SERMs), tamoxifen and raloxifene, show promise in this regard. Neither combats the symptoms of menopause, but both have the bone-preserving effects of estradiol. They may also have cardioprotective effects, but the clinical relevance of these effects has not been established. In addition, tamoxifen does not stimulate the breast, and raloxifene does not stimulate the breast or uterus. The clinical uses of the 2 drugs are discussed elsewhere in this book.
Chemistry, Biosynthesis, & Metabolism of Progesterone
Progesterone (Fig. 4–14) is a C21 steroid secreted in large amounts by the corpus luteum and the placenta. It is an important intermediate in steroid biosynthesis in all tissues that secrete steroid hormones, and small amounts enter the circulation from the testes and adrenal cortex. The 20α- and 20β-hydroxy derivatives of progesterone are formed in the corpus luteum. About 2% of the progesterone in the circulation is free (Table 4–2), whereas 80% is bound to albumin and 18% is bound to corticosteroid-binding globulin. Progesterone has a short half-life and is converted in the liver to pregnanediol, which is conjugated to glucuronic acid and excreted in the urine (Fig. 4–14).
Figure 4–14. Biosynthesis of progesterone and major pathway for its metabolism. Other metabolites are also formed. (Reproduced, with permission, from Barrett KE. Ganong’s Review of Medical Physiology. 23rd ed. New York, NY: McGraw-Hill; 2010.)
Secretion of Progesterone
The plasma progesterone level in women during the follicular phase of the menstrual cycle is approximately 0.9 ng/mL (3 nmol/L), whereas the level in men is approximately 0.3 ng/mL (1 nmol/L). The difference is due to secretion of small amounts of progesterone by cells in the ovarian follicle. During the luteal phase, the large amounts secreted by the corpus luteum cause ovarian secretion to increase about 20-fold. The result is an increase in plasma progesterone to a peak value of approximately 18 ng/mL (60 nmol/L) (Fig. 4–8).
The stimulating effect of LH on progesterone secretion by the corpus luteum is due to activation of adenylyl cyclase and involves a subsequent step that is dependent on protein synthesis.
Actions of Progesterone
The principal target organs of progesterone are the uterus, the breasts, and the brain. Progesterone is responsible for the progestational changes in the endometrium and the cyclic changes in the cervix and vagina described earlier. It has antiestrogenic effects on the myometrial cells, decreasing their excitability, their sensitivity to oxytocin, and their spontaneous electrical activity, while increasing their membrane potential. Progesterone decreases the number of estrogen receptors in the endometrium and increases the rate of conversion of 17β-estradiol to less active estrogens.
In the breast, progesterone stimulates the development of lobules and alveoli. It induces differentiation of estrogen-prepared ductal tissue and supports the secretory function of the breast during lactation.
The feedback effects of progesterone are complex and are exerted at both the hypothalamic and the pituitary level. Large doses of progesterone inhibit LH secretion and potentiate the inhibitory effects of estrogens, preventing ovulation.
Progesterone is thermogenic and probably is responsible for the rise in basal body temperature at the time of ovulation (Fig. 4–8). Progesterone stimulates respiration, and the fact that alveolar partial pressure of carbon dioxide (Pco2) in women during the luteal phase of the menstrual cycle is lower than that in men is attributed to the action of secreted progesterone. In pregnancy, alveolar Pco2 falls as progesterone secretion rises.
Large doses of progesterone produce natriuresis, probably by blocking the action of aldosterone on the kidney. The hormone does not have significant anabolic effect.
Mechanism of Action
The effects of progesterone, like those of other steroids, are brought about by an action on DNA to initiate synthesis of new mRNA. The progesterone receptor is bound to a heat shock protein in the absence of the steroid, and progesterone binding releases the heat shock protein, exposing the DNA-binding domain of the receptor. The synthetic steroid mifepristone (RU-486) binds to the receptor but does not release the heat shock protein, and it blocks the binding of progesterone. As the maintenance of early pregnancy depends on the stimulatory effect of progesterone on endometrial growth and its inhibition of uterine contractility, mifepristone causes absorption. In some countries, mifepristone combined with a prostaglandin is used to produce elective abortions.
Two isoforms of the progesterone receptor are produced by differential processing from a single gene on chromosome 11. Progesterone receptor A (PRA) is a truncated form that when activated is capable of inhibiting some of the actions of progesterone receptor B (PRB). A third isoform has been identified in humans, PRC, which is thought to modulate the transcriptional activity of PRA and PRB. However, although the physiologic significance of the existence of the isoforms remains to be determined, it has been suggested that they have distinct tissue-specific responses to progesterone.
Substances that mimic the action of progesterone are sometimes called progestational agents, gestagens, or progestins. They are used along with synthetic estrogens as oral contraceptive agents.
RELAXIN
Relaxin is a polypeptide hormone that is secreted by the corpus luteum in women and by the prostate in men. During pregnancy, it relaxes the pubic symphysis and other pelvic joints while softening and dilating the uterine cervix, thus facilitating delivery. It also inhibits uterine contractions and may play a role in the development of the mammary glands. In nonpregnant women, relaxin is found in the corpus luteum and the endometrium during the secretory but not the proliferative phase of the menstrual cycle. Its function in non-pregnant women is unknown, but it is postulated that relaxin may play a role in follicular development, ovulation, and/or implantation. There is currently no evidence that endogenous relaxin contributes to reproductive processes in any species.
In most species, there is only 1 relaxin gene, but in humans there are 2 genes on chromosome 9 that code for 2 structurally different polypeptides with relaxin activity. However, only 1 of these genes is active in the ovary and the prostate. The structure of the polypeptide produced in these 2 tissues is shown in Figure 4–15.
Figure 4–15. Structure of human luteal and prostatic relaxin. Note the A and B chains are connected by disulfide bridges. Pca, pyroglutamic acid residue at N-terminal of A chain. (Modified and reproduced, with permission, from Winslow JW Shih A, Bourell JH, et al. Human seminal relaxin is a product of the same gene as human luteal relaxin. Endocrinology 1992;130:2660.)
INHIBINS & ACTIVINS
Both the ovaries and testes produce polypeptides called inhibins that inhibit FSH secretion. There are 2 inhibins, and they are formed from 3 polypeptide subunits: a glycosylated α subunit with a molecular weight of 18,000, and 2 nonglycosylated β subunits, βA and βB, each with a molecular weight of 14,000. The subunits are formed from precursor proteins (Fig. 4–16). The α subunit combines with βA to form a heterodimer and with βB to form another heterodimer, with the subunits linked by disulfide bonds. Both αβA (inhibin A) and αβB (inhibin B) inhibit FSH secretion by a direct action on the pituitary, although it now appears that inhibin B is the FSH-regulating hormone in adults. Inhibins are produced by Sertoli cells in males and by granulosa cells in females.
Figure 4–16. Inhibin precursor proteins and the various inhibins and activins that are formed from them. SS, disulfide bonds. (Reproduced, with permission, from Ganong WF. Review of Medical Physiology. 22nd ed. New York, NY: McGraw-Hill; 2005.)
The heterodimer, βAβB, and the homodimers, βAβA and βBβB, stimulate rather than inhibit FSH secretion and consequently are called activins. Their function in reproduction is unsettled. However, the inhibins and activins are members of the transforming growth factor-β superfamily of dimeric growth factors. Also included in this superfamily is the müllerian inhibitory substance (MIS), which is important in embryonic development of the gonads. Two activin receptors have been cloned, and both appear to be serine kinases. Inhibins and activins are found not only in the gonads, but also in the brain and many other tissues. In the bone marrow, activins are involved in the development of white blood cells. In embryonic life, activins are involved in the formation of mesoderm. All mice with a targeted deletion of the α-inhibin gene initially grew in a normal fashion but then developed gonadal stromal tumors, thus elucidating the role of the α-inhibin gene as a tumor suppressor gene.
In plasma, α2-macroglobulin binds activins and inhibins. In tissues, activins bind to a family of 4 glycoproteins called follistatins. Binding of the activins inactivates their biologic activity, which may involve regulation of FSH production from gonadotropes in the anterior pituitary. However, the relation of follistatins to inhibin and their physiologic function remain unsettled.
PITUITARY HORMONES
Ovarian secretion depends on the action of hormones secreted by the anterior pituitary gland. The anterior pituitary gland secretes 6 established hormones: ACTH, growth hormone, thyroid-stimulating hormone (TSH), FSH, LH, and prolactin (Fig. 4–17). It also secretes 1 putative hormone: β-lipotrophic hormone (β-LPH).
Figure 4–17. Anterior pituitary hormones. In women, follicle-stimulating hormone (FSH) and luteinizing hormone (LH) act in sequence on the ovary to produce growth of the ovarian follicle, which secretes estrogen, then ovulation, followed by formation and maintenance of the corpus luteum, which secretes estrogen and progesterone. In men, FSH and LH control the functions of the testes. Prolactin stimulates lactation. β-LPH, β-lipotropic hormone; ACTH, adrenocorticotropic hormone; TSH, thyroid-stimulating hormone. (Reproduced, with permission, from Ganong WF. Review of Medical Physiology. 22nd ed. New York, NY: McGraw-Hill; 2005.)
The posterior pituitary differs from the anterior pituitary in that its hormones, oxytocin and arginine vasopressin, are secreted by neurons directly into the systemic circulation.
GONADOTROPINS
The gonadotropins, FSH and LH, act in concert to regulate the cyclic secretion of the ovarian hormones. They are glycoproteins made up of α and β subunits. The α subunits have the same amino acid composition as the α subunits in the glycoproteins, TSH and human chorionic gonadotropin (hCG). The specificity of these 4 glyco-protein hormones is imparted by the different structures of their β subunits. The carbohydrates in the gonadotropin molecules increase the potency of the hormones by markedly slowing their metabolism. The half-life of human FSH is about 170 minutes; the half-life of LH is about 60 minutes.
The receptors for FSH and LH are serpentine receptors coupled to adenylyl cyclase through GS. In addition, each has an extended, glycosylated extracellular domain.
HYPOTHALAMIC HORMONES
Secretion of the anterior pituitary hormones is regulated by the hypothalamic hypophysiotropic hormones. These substances are produced by neurons and enter the portal hypophysial vessels (Fig. 4–18), a special group of blood vessels that transmit substances directly from the hypothalamus to the anterior pituitary gland. The actions of these hormones are summarized in Figure 4–19. The structures of 6 established hypophysiotropic hormones are known (Fig. 4–20). No single prolactin-releasing hormone has been isolated and identified. However, several polypeptides that are found in the hypothalamus can increase prolactin secretion, and 1 or more of these may stimulate prolactin secretion under physiologic conditions.
Figure 4–18. Secretion of hypothalamic hormones. The hormones of the posterior lobe (PL) are released into the general circulation from the endings of supraoptic and paraventricular neurons, whereas hypophysiotropic hormones are secreted into the portal hypophysial circulation from the endings of arcuate and other hypothalamic neurons. AL, anterior lobe; MB, mamillary bodies; OC, optic chiasm. (Reproduced, with permission, from Ganong WF. Review of Medical Physiology. 22nd ed. New York, NY: McGraw-Hill; 2005.)
Figure 4–19. Effects of hypophysiotropic hormones on the secretion of anterior pituitary hormones. β-LPH, β-lipotropic hormone; ACTH, adrenocorticotropic hormone; CRH, corticotropin-releasing hormone; FSH, follicle-stimulating hormone; GIH, growth-inhibiting hormone; GnRH, gonadotropin-releasing hormone; GRH, growth hormone-releasing hormone; LH, luteinizing hormone; PIH, prolactin-inhibiting hormone; PRH, prolactin-releasing hormone; TRH, thyroid-releasing hormone; TSH, thyroid-stimulating hormone. (Reproduced, with permission, from Ganong WF. Review of Medical Physiology. 22nd ed. New York, NY: McGraw-Hill; 2005.)
Figure 4–20. Structures of hypophysiotropic hormones in humans. The structure of somatostatin shown is the tetradecapeptide (somatostatin 14). In addition, preprosomatostatin is the source of an N-terminal extended polypeptide containing 28 amino acid residues (somatostatin 28). Both forms are found in many tissues. CRH, corticotropin-releasing hormone; GnRH, gonadotropin-releasing hormone; GRH, growth hormone-releasing hormone; PIH, prolactin-inhibiting hormone; TRH, thyroid-releasing hormone. (Reproduced, with permission, from Ganong WF. Review of Medical Physiology. 22nd ed. New York, NY: McGraw-Hill; 2005.)
The posterior pituitary hormones are produced in the cell bodies of neurons located in the supraoptic and paraventricular nuclei of the hypothalamus and transported down the axons of these neurons to their endings in the posterior lobe of the pituitary. The hormones are released from the endings into the circulation when action potentials pass down the axons and reach their endings. The structures of the hormones are shown in Figure 4–21.
Figure 4–21. Structures of arginine vasopressin and oxytocin. (Reproduced, with permission, from Ganong WF. Review of Medical Physiology. 22nd ed. New York, NY: McGraw-Hill; 2005.)
CONTROL OF OVARIAN FUNCTION
FSH from the pituitary is responsible for the early maturation of the ovarian follicles, while FSH and LH together are responsible for the final maturation. A burst of LH secretion (Fig. 4–8) triggers ovulation and the initial formation of the corpus luteum. There is also a smaller midcycle burst of FSH secretion, the significance of which is uncertain. LH stimulates the secretion of estrogen and progesterone from the corpus luteum.
Hypothalamic Components
The hypothalamus occupies a key role in the control of gonadotropin secretion. Hypothalamic control is exerted by GnRH secreted into the portal hypophysial vessels. GnRH stimulates the secretion of both FSH and LH. It is unlikely that there is an additional separate follicle-stimulating hormone-releasing hormone (FRH).
GnRH is normally secreted in episodic bursts (circhoral secretion). These bursts are essential for normal secretion of gonadotropins, which are also exerted in a pulsatile fashion (Fig. 4–22). If GnRH is administered by constant infusion, the number of GnRH receptors in the anterior pituitary decreases (downregulation) and LH secretion falls to low levels. However, if GnRH is administered episodically at a rate of 1 pulse per hour, LH secretion is stimulated. This is true even when endogenous GnRH secretion has been prevented by a lesion of the ventral hypothalamus.
Figure 4–22. Profertility and antifertility actions of gonadotropin-releasing hormone (GnRH) and its agonists. The normal secretion of GnRH is pulsatile, occurring at 30- to 60-minute intervals. This mode, which can be mimicked by timed injections, produces circhoral peaks of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) secretion and promotes fertility. If GnRH is administered by continuous infusion or if 1 of its long-acting synthetic agonists is injected, there is initial stimulation of the pituitary receptors. However, this stimulation lasts for only a few days and is followed by receptor downregulation with inhibition of gonadotropin secretion (antifertility effect). (Reproduced, with permission, from Conn PM, Crowley WF Jr. Gonadotropin-releasing hormone and its analogues. N Engl J Med 1991;324:93.)
It is clear that, not only is this episodic nature of secretion of GnRH an important phenomenon, but that fluctuations in the frequency and amplitude of these GnRH bursts are also important in generating the other hormonal changes that are responsible for the menstrual cycle. Frequency is increased by estrogens and decreased by progesterone and testosterone. The frequency increases late in the follicular phase of the cycle, culminating in the LH surge. During the secretory phase, the frequency decreases as a result of the action of progesterone, but when estrogen and progesterone secretion decrease at the end of the cycle, frequency once again increases.
At the time of the midcycle LH surge, the sensitivity of the gonadotropes to GnRH is greatly increased because of their exposure to GnRH pulses of the frequency that exist at this time. This self-priming effect of GnRH is important in producing a maximum LH response.
The nature and the exact location of the GnRH pulse generator in the hypothalamus are still unsettled. However, it is known that norepinephrine and possibly epinephrine increase GnRH pulse frequencies. Conversely, opioid peptides, such as the enkephalins and β-endorphin, reduce the frequency of GnRH pulses.
The downregulation of pituitary receptors and the consequent decrease in LH secretion produced by constantly elevated levels of GnRH has led to the use of long-acting GnRH agonists to inhibit LH secretion in precocious puberty, endometriosis, leiomyomas, and cancer of the prostate.
Feedback Effects
Changes in plasma levels of LH, FSH, sex steroids, and inhibin B during the menstrual cycle are shown in Figure 4–8, and their feedback relations are diagrammed in Figure 4–23. At the start of the follicular phase, the inhibin B level is low and the FSH level is modestly elevated, fostering follicular growth. LH secretion is held in check by the negative feedback effect of the rising plasma estrogen level. At 36–48 hours before ovulation, the estrogen feedback effect becomes positive, which initiates the burst of LH secretion (LH surge) that produces ovulation. Ovulation occurs about 9 hours after the LH peak. FSH secretion also peaks, despite a small rise in inhibin B level, probably because of the strong stimulation of gonadotropes by GnRH. During the luteal phase, secretion of LH and FSH is low because of the elevated levels of estrogen, progesterone, and inhibin B.
Figure 4–23. Feedback regulation of ovarian function. The cells of the theca interna provide androgens to the granulosa cells, and the thecal cells produce the circulating estrogens, which inhibit the secretion of luteinizing hormone (LH), gonadotropin-releasing hormone (GnRH), and follicle-stimulating hormone (FSH). Inhibin B from the granulosa cells also inhibits FSH secretion. LH regulates thecal cells, whereas the granulosa cells are regulated by both LH and FSH. The dashed arrows indicate inhibition, and the solid arrows indicate stimulation. (Reproduced, with permission, from Ganong WF. Review of Medical Physiology. 22nd ed. New York, NY: McGraw-Hill; 2005.)
It should be emphasized that a moderate, constant level of circulating estrogen exerts a negative feedback effect on LH secretion, whereas an elevated estrogen level exerts a positive feedback and stimulates LH secretion. It has been demonstrated in monkeys that there is also a minimum time that estrogen levels must be elevated to produce a positive feedback. When the circulating estrogen level was increased about 300% for 24 hours, only negative feedback was seen; but when it was increased about 300% for 36 hours or more, a brief decline in secretion was followed by a burst of LH secretion that resembled the midcycle surge. When circulating levels of progesterone were high, the positive feedback effect of estrogen was inhibited. There is evidence in primates that both the negative and the positive feedback effects of estrogen are exerted in the medio-basal hypothalamus via the ER-α receptors. The mechanism of the “switch” between negative and positive feedback remains unknown.
Control of Menstrual Cycle
In an important sense, regression of the corpus luteum (luteolysis) starting 3–4 days before menses is the key to the menstrual cycle. PGF2a appears to be a physiologic luteolysin, but this prostaglandin is only active when endothelial cells producing endothelin-1 (ET-1) are present. Therefore, it appears that, at least in some species, luteolysis is produced by the combined action of PGF2a and ET-1. In some domestic animals, oxytocin secreted by the corpus luteum appears to exert a local luteolytic effect, possibly by causing the release of prostaglandins. Once luteolysis begins, the estrogen and progesterone levels fall, followed by increased secretion of FSH and LH. A new crop of follicles develops, and then a single dominant follicle matures as a result of the action of FSH and LH. Near midcycle, there is a rise in estrogen secretion from the follicle. This rise augments the responsiveness of the pituitary to GnRH and triggers a burst of LH secretion. The resulting ovulation is followed by formation of a corpus luteum. There is a drop in estrogen secretion at first, but progesterone and estrogen levels then rise together, along with inhibin B. The elevated levels inhibit FSH and LH secretion for a while, but luteolysis again occurs and a new cycle begins.
Reflex Ovulation
Female cats, rabbits, mink, and certain other animals have long periods of estrus, or heat, during which they ovulate only after copulation. Such reflex ovulation is brought about by afferent impulses from the genitalia and the eyes, ears, and nose that converge on the ventral hypothalamus and provoke an ovulation-inducing release of LH from the pituitary. In species such as rats, monkeys, and humans, ovulation is a spontaneous periodic phenomenon, but afferent impulses converging on the hypothalamus can also exert effects. Ovulation can be delayed for 24 hours in rats by administering pentobarbital or other neurally active drugs 12 hours before the expected time of follicle rupture. In women, menstrual cycles may be markedly influenced by emotional stimuli.
Contraception
Methods commonly used to prevent conception, along with their failure rates, are listed in Table 4–4. Contraception is considered in detail in Chapter 58. It is briefly reviewed here because the techniques used are excellent examples of the practical application of the physiologic principles discussed in this chapter.
Table 4–4. Relative effectiveness of frequently used contraceptive methods.
Among the most extensively used contraceptives are estrogens and/or progestins in varying doses and combinations. They interfere with gonadotropic secretion or implantation, and in some cases, inhibit the union of sperm with ova.
Once conception has occurred, abortion can be produced by progesterone antagonists such as mifepristone.
Implantation of foreign bodies in the uterus causes changes in the duration of the sexual cycle in a number of mammalian species. In humans, such foreign bodies do not alter the menstrual cycle, but they act as effective contraceptive devices. The 2 intrauterine devices (IUDs) available in the United States are T-shaped devices that contain copper or progestin. There is production of a local, sterile, inflammatory reaction secondary to the presence of the foreign body in the uterine cavity, which is thought to act as a spermicide inhibiting sperm capacitation, penetration, and survival. The progestin IUD thickens cervical mucus and may cause endometrial alterations that prevent implantation.
Implants made up primarily of progestins are now being increasingly used in some parts of the world. The implants are inserted under the skin and remain effective for 3 years. The 2 primary mechanisms of action include inhibition of ovulation and restriction of sperm penetration through cervical mucus. They often produce amenorrhea but otherwise appear to be well tolerated. Spontaneous breakthrough bleeding is, however, a common side effect.
PROLACTIN
Chemistry of Prolactin
Prolactin is another anterior pituitary hormone that has important functions in reproduction and pregnancy. The human prolactin molecule contains 199 amino acid residues and 3 disulfide bridges (Fig. 4–24) and has considerable structural similarity to human growth hormone and human chorionic somatomammotropin (hCS). The half-life of prolactin, like that of growth hormone, is about 20 minutes. Structurally similar prolactins are secreted by the endometrium and by the placenta.
Figure 4–24. Structure of human prolactin. (Reproduced, with permission, from Bondy PK, Rosenberg LE. Metabolic Control and Disease. 8th ed. New York, NY: Saunders; 1980.)
Receptors
The human prolactin receptor resembles the growth hormone receptor. It is one of the superfamily of receptors that includes the growth hormone receptor and receptors for many cytokines and hematopoietic growth factors. It dimerizes and activates the JAK-STAT and other intracellular enzymes cascades.
Actions
Prolactin causes milk secretion from the breast after estrogen and progesterone priming. Its effect on the breast causes increased production of casein and lactalbumin. However, the action of the hormone is not exerted on the cell nucleus and is prevented by inhibitors of microtubules. Prolactin also inhibits the effects of gonadotropins, possibly by an action at the level of the ovary. Consequently, it is a “natural contraceptive” that spaces pregnancies by preventing ovulation in lactating women. The function of prolactin in normal males is unsettled, but excess prolactin in normal males causes impotence. An action of prolactin that has been used in the past as the basis for a bioassay to assess this hormone is stimulation of the growth and “secretion” of the crop sacs in pigeons and other birds. The paired crop sacs are outpouchings of the esophagus that form, by desquamation of their inner cell layers, a nutritious material (“milk”) that the birds feed to their young. However, prolactin, FSH, and LH are now regularly measured by radioimmunoassay.
Regulation of Prolactin Secretion
The normal plasma prolactin concentration is approximately 5 ng/mL in men and 8 ng/mL in women. Secretion is tonically inhibited by the hypothalamus, and a section of the pituitary stalk leads to an increase in circulating prolactin. Thus, the effect of the hypothalamic prolactin-inhibiting hormone (PIH), dopamine, is greater than the effect of the putative prolactin-releasing hormone. In humans, prolactin secretion is increased by stimulation of the nipple, exercise, and surgical or psychological stress (Table 4–5). The plasma prolactin level rises during sleep, with the rise starting after the onset of sleep and persisting throughout the sleep period. Secretion is increased during pregnancy, reaching a peak at the time of parturition. After delivery, the plasma concentration falls to nonpregnant levels in about 8 days. Suckling produces a prompt increase in secretion, but the magnitude of this rise gradually declines after a woman has been nursing for more than 3 months.
Table 4–5. Factors affecting the secretion of human prolactin and growth hormone.
L-Dopa decreases prolactin secretion by increasing formation of dopamine. Bromocriptine and other dopamine agonists inhibit secretion because they stimulate dopamine receptors. Chlorpromazine and related drugs that block dopamine receptors increase prolactin secretion. Thyroid-releasing hormone (TRH) stimulates the secretion of prolactin in addition to TSH, plus there are additional prolactin-releasing polypeptides in hypothalamic tissue. Estrogens produce a slowly developing increase in prolactin secretion as a result of a direct action on the lactotropes.
It has not been established that prolactin facilitates the secretion of dopamine in the median eminence. Thus, prolactin acts in the hypothalamus in a negative feedback fashion to inhibit its own secretion.
Hyperprolactinemia
Up to 70% of patients with chromophobe adenomas of the anterior pituitary have elevated plasma prolactin levels. In some instances, the elevation may be due to damage to the pituitary stalk, but in most cases, the tumor cells are actually secreting the hormone. The hyperprolactinemia may cause galactorrhea, but in many individuals, there are no demonstrable abnormalities. Indeed, most women with galactorrhea have normal prolactin levels; definite elevations are found in less than one-third of patients with this condition.
Another interesting observation is that 15–20% of women with secondary amenorrhea have elevated prolactin levels, and when prolactin secretion is reduced, normal menstrual cycles and fertility return. It appears that prolactin may produce amenorrhea by blocking the action of gonadotropins on the ovaries, but definitive proof of this hypothesis must await further research. The hypogonadism produced by prolactinomas is associated with osteoporosis due to estrogen deficiency.
Hyperprolactinemia in men is associated with impotence and hypogonadism that disappear when prolactin secretion is reduced.
MENOPAUSE
The human ovary gradually becomes unresponsive to gonadotropins with advancing age, and its function declines so that sexual cycles and menstruation disappear (menopause). This unresponsiveness is associated with and is probably caused by a decline in the number of primordial follicles (Fig. 4–5). The ovaries no longer secrete progesterone and 17β-estrodiol in appreciable quantities. Estrone is formed by aromatization of androstenedione in fat and other tissues, but the amounts are normally small. The uterus and vagina gradually become atrophic. As the negative feedback effect of the estrogens and progesterone is reduced, secretion of FSH and LH is increased, and plasma FSH and LH rise to high levels. Old female mice and rats have long periods of diestrus and increased levels of gonadotropin secretion, but a clear-cut “menopause” has apparently not been described in experimental animals.
In women, the menses usually become irregular and cease between the age of 45 and 55. The average age at onset of menopause has increased since the turn of the century and is currently about 51 years.
Sensation of warmth spreading from the trunk to the face (“hot flushes,” also called hot flashes), night sweats, and various mood fluctuations are common after ovarian function has ceased. Hot flushes are said to occur in 75% of menopausal women and may last as long as 40 years. They are prevented by administration of estrogen. These vasomotor symptoms are not always specific to menopause; they also occur in premenopausal women and men whose gonads are removed surgically or destroyed by disease. Thus, the vasomotor symptoms result from acute estrogen withdrawal. However, it has been demonstrated that they coincide with surges of LH secretion. LH is secreted in episodic bursts at intervals of 30–60 minutes or more (circhoral secretion), and in the absence of gonadal hormones, these bursts are large. Each hot flush begins with the start of a burst. However, LH itself is not responsible for the symptoms, as they can continue after removal of the pituitary. Instead, it appears that some event in the hypothalamus initiates both the release of LH and the episode of flushing. Menopause and the clinical management of patients with menopausal symptoms are discussed in more detail in Chapter 59.
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