Physiology 5th Ed.

FEMALE REPRODUCTIVE PHYSIOLOGY

The female gonads are the ovaries, which, together with the uterus and the fallopian tubes, constitute the female reproductive tract. The ovaries, analogous to the testes in the male, have two functions: oogenesis and secretion of the female sex steroid hormones, progesterone and estrogen. Each adult ovary is attached to the uterus by ligaments, and running through these ligaments are the ovarian arteries, veins, lymphatic vessels, and nerves.

The ovary has three zones. The cortex is the outer and largest zone. It is lined by germinal epithelium and contains all of the oocytes, each of which is enclosed in a follicle. The ovarian follicles are also responsible for steroid hormone synthesis. The medulla is the middle zone and is a mixture of cell types. The hilum is the inner zone, through which blood vessels and lymphatics pass.

The ovarian steroid hormones have both paracrine and endocrine functions. Locally, within the ovaries, the ovarian steroid hormones act to support the development of the ova. Systemically, the ovarian steroid hormones act on a variety of target tissues including uterus, breast, and bone.

The functional unit of the ovaries is the single ovarian follicle, which comprises one germ cell surrounded by endocrine cells. When fully developed, the ovarian follicle serves several critical roles: It will provide nutrients for the developing oocyte; release the oocyte at the proper time (ovulation); prepare the vagina and fallopian tubes to aid in fertilization of the egg by a sperm; prepare the lining of the uterus for implantation of the fertilized egg; and, in the event of fertilization, maintain steroid hormone production for the fetus until the placenta can assume this role.

Oogenesis

In the developing ovaries, primordial germ cells produce oogonia by mitotic divisions until gestational weeks 20 to 24. At that time, there are approximately 7 million oogonia. Beginning at gestational weeks 8 to 9, some of these oogonia enter the prophase of meiosis and become primary oocytes. The meiotic process continues until approximately 6 months after birth, at which point all oogonia have become oocytes. The oocytes remain in a state of suspended prophase; the first meiotic division will not be completed until ovulation occurs many years later. Simultaneously, there is attrition of oocytes. At birth, only 2 million oocytes remain; by puberty, only 400,000 oocytes remain; by menopause (which marks the end of the reproductive period), few, if any, oocytes remain. Whereas males continuously produce spermatogonia and spermatocytes, females do not produce new oogonia and function from a declining pool of oocytes.

The development of ovarian follicles occurs in the following stages, which are illustrated in Figure 10-7:

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Figure 10–7 Development of the oocyte from a primordial follicle. If fertilization occurs, the corpus luteum secretes steroid hormones and supports the developing zygote. If no fertilization occurs, the corpus luteum regresses and becomes the corpus albicans.

1.          First stage. The first stage of follicular development parallels prophase of the oocyte. Thus, the first stage of the ovarian follicle lasts many years. The shortest duration for the first stage is approximately 13 years (the approximate age at first ovulation); the longest duration is 50 years (the approximate age at menopause). As the primary oocyte grows, the granulosa cells proliferate and nurture the oocyte with nutrients and steroid hormones. During this stage, the primordial follicle develops into a primary follicle, theca interna cells develop, and granulosa cells begin to secrete fluid. No follicle progresses beyond this first stage in prepubertal ovaries.

2.          Second stage. The second stage of follicular development occurs much more rapidly than the first stage. This stage takes place over a period of 70 to 85 days and is present only during the reproductive period. During each menstrual cycle, a few follicles enter this sequence. A fluid containing steroid hormones, mucopolysaccharides, proteins, and FSH accumulates in a central area of the follicle called the antrum. The steroid hormones reach the antrum by direct secretion from granulosa cells. The granulosa and theca cells continue to grow. At the end of the second stage, the follicle is called a graafian follicleand has an average diameter of 2 to 5 mm.

3.          Third stage. The third and final stage of follicular development is the most rapid, occurring 5 to 7 days after menses (menses marks the end of the previous cycle). A single graafian follicle achieves dominance over its cohorts, and the cohorts regress. Within 48 hours, the dominant follicle grows to 20 mm in diameter. On day 14 of a 28-day menstrual cycle, ovulation occurs and the dominant follicle ruptures and releases its oocyte into the peritoneal cavity. At this time, the first meiotic division is completed and the resulting secondary oocyte enters the nearby fallopian tube, where it begins the second meiotic division. In the fallopian tube, if fertilization by a sperm occurs, the second meiotic division is completed, producing the haploid ovum with 23 chromosomes.

The residual elements of the ruptured primary follicle form the corpus luteum. The corpus luteum is composed primarily of granulosa cells but also of theca cells, capillaries, and fibroblasts. The corpus luteum synthesizes and secretes steroid hormones, which are necessary for implantation and maintenance of the zygote should fertilization occur. If fertilization does occur, the corpus luteum will secrete steroid hormones until the placenta assumes this role, later in pregnancy. If fertilization does not occur, the corpus luteum regresses during the next 14 days (the second half of the menstrual cycle) and is replaced by a scar called the corpus albicans.

Synthesis and Secretion of Estrogen and Progesterone

The ovarian steroid hormones, progesterone and 17β-estradiol, are synthesized by the ovarian follicles through the combined functions of the granulosa cells and the theca cells (Fig. 10-8). Virtually all steps in the biosynthetic pathway are the same as those discussed previously for the adrenal cortex and the testes. Recall that the adrenal cortex produces all intermediates up to the level of androstenedione, but because it lacks the enzyme 17β-hydroxysteroid dehydrogenase, it does not produce testosterone. Recall also that the testes, having 17β-hydroxysteroid dehydrogenase, produce testosterone as their major hormonal product. In the ovaries, all steps in the biosynthetic pathway are present including aromatase, which converts testosterone to 17β-estradiol, the major ovarian estrogen.

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Figure 10–8 Biosynthetic pathway for progesterone and 17β-estradiol in the ovaries. Luteinizing hormone (LH) stimulates cholesterol desmolase in theca cells. Follicle-stimulating hormone (FSH) stimulates aromatase in granulosa cells.

Progesterone and 17β-estradiol are synthesized as follows: Theca cells synthesize and secrete progesterone. Theca cells also synthesize androstenedione; this androstenedione diffuses from the theca cells to the nearby granulosa cells, which contain 17β-hydroxysteroid dehydrogenase and aromatase. In the granulosa cells, androstenedione is converted to testosterone and testosterone is then converted to 17β-estradiol. FSH and LH each have roles in the biosynthetic process. LH stimulates cholesterol desmolase in the theca cells, the first step in the biosynthetic pathway (parallel to its role in the testes). FSHstimulates aromatase in the granulosa cells, the last step in the synthesis of 17β-estradiol.

Regulation of the Ovaries

As noted, the ovaries have two functions: oogenesis and secretion of the female sex steroid hormones. Both functions are controlled by the hypothalamic-pituitary axis. As in the testes, the hypothalamic hormone is GnRH and the anterior pituitary hormones are FSH and LH.

GnRH

Like testicular function in the male, ovarian function in the female is driven by pulsatile activity of the hypothalamic-pituitary axis. GnRH is delivered directly to the anterior lobe of the pituitary in high concentration, where it stimulates pulsatile secretion of FSH and LH. FSH and LH then act on the ovaries to stimulate follicular development and ovulation and to stimulate the synthesis of the female sex steroid hormones.

FSH and LH

To understand the hypothalamic-pituitary control of the ovaries, it is necessary to appreciate its cyclic behavior. Every 28 days a sequence of follicular development, ovulation, and formation and degeneration of a corpus luteum is repeated in the menstrual cycle. The first 14 days of the menstrual cycle involve follicular development and are called the follicular phase. The last 14 days of the menstrual cycle are dominated by the corpus luteum and are called the luteal phase. At the midpoint of the cycle, between the follicular and luteal phases, ovulation occurs.

The actions of FSH and LH on follicular development and on ovulation are explained as follows:

image FSH. The granulosa cells are the only ovarian cells with FSH receptors. Initial actions of FSH stimulate the growth of granulosa cells in primary follicles and stimulate estradiol synthesis. The locally produced estradiol then supports the trophic effect of FSH on follicular cells. Thus, the two effects of FSH on the granulosa cells are mutually reinforcing: more cells, more estradiol, more cells.

image LH. Ovulation is initiated by LH. Just prior to ovulation, the concentration of LH in blood rises sharply and induces rupture of the dominant follicle, releasing the oocyte. LH also stimulates formation of the corpus luteum, a process called luteinization, and maintains steroid hormone production by the corpus luteum during the luteal phase of the menstrual cycle.

Negative and Positive Feedback

In females, the hypothalamic-pituitary axis is controlled by both negative and positive feedback, depending on the phase of the menstrual cycle (Fig. 10-9).

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Figure 10–9 Control of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) secretion in females during the menstrual cycle. The follicular and luteal phases are characterized by negative feedback of estradiol and progesterone, respectively, on the anterior pituitary. Midcycle is characterized by positive feedback of estradiol on the anterior pituitary. GnRH, Gonadotropin-releasing hormone.

image In the follicular phase of the menstrual cycle, FSH and LH stimulate synthesis and secretion of estradiol by follicular cells. One of the actions of estradiol is negative feedback on the anterior pituitary cells to inhibit further secretion of FSH and LH. Thus, the follicular phase is dominated by negative feedback effects of estradiol.

image At midcycle, the pattern changes. Estradiol levels rise sharply as a result of the proliferation of follicular cells and the stimulation of estradiol synthesis that occurred during the follicular phase. When a critical level of estradiol is reached (of at least 200 picograms per milliliter of plasma), estradiol has a positive feedback effect on the anterior pituitary, by upregulating GnRH receptors in the anterior pituitary, thus causing further secretion of FSH and LH. This burst of hormone secretion by the anterior pituitary, called the ovulatory surge of FSH and LH, then triggers ovulation of the mature oocyte.

image In the luteal phase of the menstrual cycle, the major hormonal secretion of the ovaries is progesterone. One of the actions of progesterone is negative feedback on the anterior pituitary to inhibit secretion of FSH and LH. Thus, the luteal phase is dominated by negative feedback effects of progesterone.

image Inhibin is produced by ovarian granulosa cells. As in the testes, it inhibits FSH secretion from the anterior pituitary.

image Activin is also produced by ovarian granulosa cells and stimulates FSH secretion.

Actions of Estrogen and Progesterone

The physiologic actions of estrogen and progesterone are summarized in Tables 10-2 and 10-3. In general, the two ovarian steroid hormones function in a coordinated fashion to support reproductive activity of the female including development of the ovum, development and maintenance of the corpus luteum to sustain a fertilized ovum, maintenance of pregnancy, and preparation of the breasts for lactation.

Table 10–2 Actions of Estrogens on Target Tissues

Maturation and maintenance of uterus, fallopian tubes, cervix, and vagina

Responsible at puberty for the development of female secondary sex characteristics

Requisite for development of the breasts

Responsible for proliferation and development of ovarian granulosa cells

Up-regulation of estrogen, progesterone, and LH receptors

Negative and positive feedback effects on FSH and LH secretion

Maintenance of pregnancy

Lowering of uterine threshold to contractile stimuli

Stimulation of prolactin secretion

Blocking the action of prolactin on the breast

Decreasing LDL cholesterol

Anti-osteoporosis

FSH, Follicle-stimulating hormone; LDL, low-density lipoproteins; LH, luteinizing hormone.

Table 10–3 Actions of Progesterone on Target Tissues

Maintenance of secretory activity of uterus during luteal phase

Development of the breasts

Negative feedback effects on FSH and LH secretion

Maintenance of pregnancy

Raising uterine threshold to contractile stimuli during pregnancy

FSH, Follicle-stimulating hormone; LH, luteinizing hormone.

Usually, estrogen and progesterone complement or enhance each other’s actions in the female reproductive tract. Occasionally, they antagonize or modulate each other’s actions. Over the course of the menstrual cycle, estrogen secretion by the ovaries precedes progesterone secretion, preparing the target tissues to respond to progesterone. An example of this “preparation” is seen in the up-regulation of progesterone receptors by estrogen in several target tissues. Without estrogen and its up-regulatory action, progesterone has little biologic activity. Conversely, progesterone down-regulates estrogen receptors in some target tissues, decreasing their responsiveness to estrogen.

Development of the Female Reproductive Tract

At puberty, the ovaries, driven by pulsatile secretion of FSH and LH, begin to secrete estrogen. In turn, estrogen promotes the growth and development of the female reproductive tract: the uterus, fallopian tubes, cervix, and vagina. Progesterone is also active in these tissues, usually increasing their secretory activity. Thus, in the uterus, estrogen causes cell proliferation, cell growth, and increased contractility; progesterone increases secretory activity and decreases contractility. In the fallopian tubes, estrogen stimulates ciliary activity and contractility, aiding in the movement of sperm toward the uterus; progesterone increases secretory activity and decreases contractility. In the vagina, estrogen stimulates proliferation of epithelial cells; progesterone stimulates differentiation but inhibits proliferation of epithelial cells.

Menstrual Cycle

Over the course of the menstrual cycle, estrogen and progesterone are responsible for the changes that occur in the endometrium, cervix, and vagina and are responsible for feedback regulation of FSH and LH secretion by the anterior pituitary.

Based on a “typical” 28-day cycle, the follicular phase of the menstrual cycle is the 14-day period preceding ovulation. This phase, which is also called the proliferative phase, is dominated by estrogen. 17β-Estradiol, whose secretion increases markedly during this phase, has significant effects on the endometrial lining of the uterus, preparing it for the possibility of accepting a fertilized ovum: Estradiol stimulates growth of the endometrium, growth of glands and stroma, and elongation of the spiral arteries, which supply the endometrium. Estradiol also causes the cervical mucus to become copious, watery, and elastic. When spread on a glass slide, cervical mucus from the follicular phase produces a pattern known as “ferning.” This characteristic of cervical mucus has physiologic significance: Channels form in the watery mucus, creating openings in the cervix through which sperm can be propelled.

The luteal phase of a 28-day menstrual cycle is the 14-day period following ovulation. This phase also is called the secretory phase and is dominated by progesterone. Proliferation of the endometrium slows, and its thickness decreases. The uterine glands become more tortuous, accumulate glycogen in vacuoles, and increase their mucus secretions. The stroma of the endometrium becomes edematous. The spiral arteries elongate more and become coiled. Progesterone secretion decreases the quantity of cervical mucus, which then becomes thick and nonelastic and does not “fern” on a slide. (Because the opportunity for fertilization has passed, the cervical mucus need not be penetrable by sperm.)

Breasts

Development of adult breasts is absolutely dependent on estrogen. The breasts, or mammary glands, are composed of lobular ducts lined by a milk-secreting epithelium. Small ducts converge and empty into larger ducts that converge at the nipple. These glandular structures are embedded in adipose tissue. At puberty, with the onset of estrogen secretion, the lobular ducts grow and the area around the nipple, the areola, enlarges. Estrogen also increases the amount of adipose tissue, giving the breasts their characteristic female shape. Progesterone collaborates with estrogen by stimulating secretory activity in the mammary ducts.

Pregnancy

The highest levels of estrogen and progesterone occur during pregnancy, synthesized in early pregnancy by the corpus luteum and in mid-to-late pregnancy by the placenta. Both estrogen and progesterone have multiple roles in pregnancy. Estrogen stimulates growth of the myometrium, growth of the ductal system of the breasts, prolactin secretion, and enlargement of the external genitalia. Progesterone maintains the endometrial lining of the uterus and increases the uterine threshold to contractile stimuli, thus preserving the pregnancy until the fetus is ready to be delivered.

Other Actions of Estrogen and Progesterone

In addition to those actions previously discussed, estrogen contributes to the pubertal growth spurt, closure of the epiphyses at the end of the growth spurt, and the deposition of subcutaneous fat (i.e., female fat distribution). Progesterone has a mild thermogenic action, which increases basal body temperature during the luteal phase of the menstrual cycle. This increase in basal body temperature during the luteal phase is the basis for the “rhythm” method of contraception, in which the increase in temperature can be used retrospectively to determine the time of ovulation.

Events of the Menstrual Cycle

The menstrual cycle recurs approximately every 28 days over the reproductive period of the female: from puberty until menopause. The events of the cycle include development of an ovarian follicle and its oocyte, ovulation, preparation of the reproductive tract to receive the fertilized ovum, and shedding of the endometrial lining if fertilization does not occur. The cycle length can vary from 21 to 35 days, but the average length is 28 days. The variability in cycle length is attributable to variability in the duration of the follicular phase; the luteal phase is constant. The hormonal changes and events of a 28-day menstrual cycle are illustrated in Figure 10-10 and described in the following steps. By convention, day 0 marks the onset of menses from the previous cycle.

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Figure 10–10 Events of the menstrual cycle. Days of the cycle are counted from the onset of menses from the previous cycle. Ovulation occurs on day 14 of a 28-day cycle. FSH, Follicle-stimulating hormone; LH, luteinizing hormone.

Video: Menstrual cycle

1.          Follicular or proliferative phase. The follicular phase occurs from day 0 until day 14. During this period, a primordial follicle develops into a graafian follicle and neighboring follicles become atretic (degenerate or regress). After the neighboring follicles degenerate, the remaining follicle is called the dominant follicle. Early in the follicular phase, receptors for FSH and LH are up-regulated in ovarian theca and granulosa cells and the gonadotropins stimulate the synthesis of estradiol. The follicular phase is dominated by 17β-estradiol, whose levels steadily increase. The high levels of estradiol cause proliferation of the endometrial lining of the uterus and inhibit FSH and LH secretion by the anterior pituitary by negative feedback (see Fig. 10-9).

2.          Ovulation. Ovulation occurs on day 14 of a 28-day menstrual cycle. Regardless of cycle length, ovulation typically occurs 14 days prior to menses. For example, in a 35-day cycle, ovulation occurs on day 21, or 14 days before menses; in a 24-day cycle, ovulation occurs on day 10. Ovulation follows a burst of estradiol secretion at the end of the follicular phase: The burst of estradiol has a positive feedback effect on FSH and LH secretion by the anterior pituitary (called the FSH and LH surge). The FSH and LH surge then causes ovulation of the mature ovum. At ovulation, cervical mucus increases in quantity and becomes watery and more penetrable by sperm. Estradiol levels decrease just after ovulation, but they will increase again during the luteal phase.

3.          Luteal or secretory phase. The luteal phase occurs from days 14 to 28, ending with the onset of menses. During the luteal phase, the corpus luteum develops and begins synthesizing estradiol and progesterone. The high levels of progesterone during this phase stimulate secretory activity of the endometrium and increase its vascularity. Thus, in the follicular phase, estradiol causes the endometrial lining to proliferate; in the luteal phase, progesterone is preparing the endometrium to receive a fertilized ovum. Basal body temperature increases during the luteal phase because progesterone increases the hypothalamic temperature set-point. The cervical mucus becomes less abundant and thicker, and it is now “too late” for sperm to fertilize the ovum. Late in the luteal phase, if fertilization has not occurred, the corpus luteum regresses. With this regression, the luteal source of estradiol and progesterone is lost, and blood levels of the hormones decrease abruptly.

4.          Menses. Regression of the corpus luteum and the abrupt loss of estradiol and progesterone cause the endometrial lining and blood to be sloughed (menses or menstrual bleeding). Typically, menses lasts 4 to 5 days, corresponding to days 0 to 4 or 5 of the next menstrual cycle. During this time, primordial follicles for the next cycle are being recruited and are beginning to develop.

Pregnancy

If the ovum is fertilized by a sperm, the fertilized ovum begins to divide and will become the fetus. The period of development of the fetus is called pregnancy or gestation, which, in humans, lasts approximately 40 weeks.

During pregnancy, the levels of estrogen and progesterone increase steadily. Their functions include maintenance of the endometrium, development of the breasts for lactation after delivery, and suppression of the development of new ovarian follicles. In early pregnancy (the first trimester), the source of steroid hormones is the corpus luteum; in mid-to-late pregnancy (the second and third trimesters), the source is the placenta.

Events of Early Pregnancy

The events of early pregnancy are summarized in Table 10-4. The timetable is based on the number of days after ovulation and includes the following steps:

Table 10–4 Events of Early Pregnancy

 

Event

Days after Ovulation

Ovulation

0 day

Fertilization

1 day

Entrance of blastocyst into uterine cavity

4 days

Implantation

5 days

Formation of trophoblast and attachment to endometrium

6 days

Onset of trophoblast secretion of HCG

8 days

HCG “rescue” of corpus luteum

10 days

HCG, Human chorionic gonadotropin.

1.          Fertilization of the ovum takes place within 24 hours of ovulation, in a distal portion of the oviduct called the ampulla. Once a sperm penetrates the ovum, the second polar body is extruded and the fertilized ovum begins to divide. Four days after ovulation the fertilized ovum, the blastocyst, with approximately 100 cells, arrives in the uterine cavity.

2.          Implantation. The blastocyst floats freely in the uterine cavity for 1 day and then implants in the endometrium 5 days after ovulation. The receptivity of the endometrium to the fertilized ovum is critically dependent on a low estrogen/progesterone ratio and corresponds to the period of highest progesterone output by the corpus luteum. At the time of implantation, the blastocyst consists of an inner mass of cells, which will become the fetus, and an outer rim of cells called the trophoblast. The trophoblast invades the endometrium and forms an attachment to the maternal membranes. Thus, the trophoblast contributes the fetal portion of the placenta. At the point of implantation, under stimulation by progesterone, the endometrium differentiates into a specialized layer of decidual cells. Eventually, the decidua will envelop the entire conceptus. Trophoblastic cells proliferate and form the syncytiotrophoblast, whose function is to allow the blastocyst to penetrate deep into the endometrium.

3.          Secretion of HCG and “rescue” of the corpus luteum. The trophoblast, which will become the placenta, begins secreting human chorionic gonadotropin (HCG) approximately 8 days after ovulation. HCG, which has biologic activity similar to LH, is critical because it “informs” the corpus luteum that fertilization has occurred. The corpus luteum, now under the direction of HCG, continues to synthesize progesterone and estrogen, which maintain the endometrium for implantation. In other words, HCG from the trophoblast (placenta) “rescues” the corpus luteum from regression. (Without fertilization and the stimulation by HCG, the corpus luteum regresses 12 days after ovulation, at which point it stops producing steroid hormones, and menses occurs.) The high levels of estrogen and progesterone also suppress the development of the next cohort of ovarian follicles.

  Production of HCG increases dramatically during the first weeks of pregnancy. The pregnancy test is based on the excretion of large amounts of HCG in urine, which are measurable. HCG is detectable in maternal urine 9 days after ovulation, even before the next expected menses.

Hormones of Pregnancy

The duration of pregnancy is, by convention, counted from the date of the last menstrual period. Pregnancy lasts approximately 40 weeks from the onset of the last menstrual period, or 38 weeks from the date of the last ovulation. Pregnancy is divided into three trimesters, each of which corresponds to approximately 13 weeks. Hormone levels during pregnancy are depicted in Figure 10-11.

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Figure 10–11 Hormones of pregnancy. Number of weeks of pregnancy are counted from the onset of the last menses. HCG, Human chorionic gonadotropin.

image First trimester. HCG is produced by the trophoblast, beginning about 8 days after fertilization. As previously described, HCG “rescues” the corpus luteum from regression and, with an LH-like action, stimulates corpus luteal production of progesterone and estrogen. HCG levels are maximal at approximately gestational week 9 and then decline. Although HCG continues to be produced for the duration of pregnancy, its function beyond the first trimester is unclear.

image Second and third trimesters. During the second and third trimesters, the placenta, in concert with the mother and the fetus, assumes responsibility for production of steroid hormones. The pathways for the synthesis of progesterone and estrogen are shown in Figure 10-12.

image

Figure 10–12 Synthesis of progesterone (A) and estriol (B) during pregnancy. Progesterone is synthesized entirely by the placenta. Estriol synthesis requires the placenta, the fetal adrenal gland, and the fetal liver. DHEA, Dehydroepiandrosterone.

Progesterone is produced by the placenta as follows: Cholesterol enters the placenta from the maternal circulation. In the placenta, cholesterol is converted to pregnenolone, which then is converted to progesterone.

  Estriol, the major form of estrogen during pregnancy, is produced through a coordinated interplay of the mother and the placenta, and, importantly, requires the fetus. Again, cholesterol is supplied to the placenta from the maternal circulation and is converted to pregnenolone in the placenta. Pregnenolone then enters the fetal circulation and is converted to dehydroepiandrosterone-sulfate (DHEA-sulfate) in thefetal adrenal cortex. DHEA-sulfate is hydroxylated to 16-OH DHEA-sulfate in the fetal liver. 16-OH DHEA-sulfate then crosses back to the placenta, where a sulfatase enzyme removes sulfate and aromatase converts it to estriol.

Parturition

Parturition, the delivery of the fetus, occurs approximately 40 weeks after the onset of the last menstrual period. The mechanism of parturition is unclear, although roles for estrogen, progesterone, cortisol, oxytocin, prostaglandins, relaxin, and catecholamines have been proposed. The following events occur near term and may contribute to parturition:

image Once the fetus reaches a critical size, distention of the uterus increases its contractility. Uncoordinated contractions, known as Braxton Hicks contractions, begin approximately 1 month before parturition.

image Near term, the fetal hypothalamic-pituitary-adrenal axis is activated and the fetal adrenal cortex produces significant amounts of cortisol. Cortisol increases the estrogen/progesterone ratio, which increases the sensitivity of the uterus to contractile stimuli. Recall that estrogen and progesterone have opposite effects on uterine contractility: Estrogen increases contractility, and progesterone decreases it.

image Estrogen stimulates (and progesterone inhibits) local production of the prostaglandins PGE2 and PGF2-α. Thus, the increasing estrogen/progesterone ratio stimulates local prostaglandin production. Prostaglandins increase the intracellular calcium concentration of uterine smooth muscle, thereby increasing its contractility.

image The role that oxytocin plays in normal parturition is puzzling. Oxytocin is a powerful stimulant of uterine contractions (indeed, it is used to induce labor). Evidence indicates that the uterine oxytocin receptors are up-regulated toward the end of gestation. It is also known that dilation of the cervix, as occurs during the progression of labor, stimulates oxytocin secretion. Yet maternal blood levels of oxytocindo not increase near term, leaving the physiologic role of oxytocin uncertain.

There are three stages of normal labor. In the first stage, uterine contractions originating at the fundus and sweeping downward move the head of the fetus toward the cervix and progressively widen and thin the cervix. In the second stage, the fetus is forced through the cervix and delivered through the vagina. In the third stage, the placenta separates from the uterine decidual tissue and is delivered. During this last stage, powerful contractions of the uterus also serve to constrict uterine blood vessels and limit postpartum bleeding. After delivery of the placenta, hormone concentrations return to their prepregnant levels, except for prolactin, whose levels remain high if the mother breast-feeds the infant (see Fig. 10-11).

Lactation

Throughout pregnancy, estrogen and progesterone stimulate the growth and development of the breasts, preparing them for lactation. Estrogen also stimulates prolactin secretion by the anterior pituitary, and prolactin levels steadily increase over the course of pregnancy (see Fig. 10-11). However, although prolactin levels are high during pregnancy, lactation does not occur because estrogen and progesterone block the action of prolactin on the breast. After parturition, when estrogen and progesterone levels fall precipitously, their inhibitory effects on the breast are removed and lactation can proceed. As described inChapter 9, lactation is maintained by suckling, which stimulates the secretion of both oxytocin and prolactin.

As long as lactation continues, there is suppression of ovulation because prolactin inhibits GnRH secretion by the hypothalamus and FSH and LH secretion by the anterior pituitary. Although not 100% effective, breast-feeding is a de facto method of contraception and family spacing in some regions of the world.

Hormonal Contraception

Oral contraceptives contain combinations of estrogen and progesterone or progesterone alone. The combination preparations exert contraceptive effects primarily through negative feedback effects on the anterior pituitary (i.e., by inhibiting FSH and LH secretion, they prevent ovulation). The combination preparations also reduce fertility by changing the character of the cervical mucus so that it is hostile to penetration by sperm and by decreasing the motility of the fallopian tubes. The contraceptive effect of progesterone alone is based primarily on its effects on cervical mucus and tubal motility.

Higher-dose preparations of estrogen and progesterone inhibit ovulation and may interfere with implantation; these preparations can be used as postcoital contraceptives, or "morning after" pills.

Menopause

Menopause is the cessation of menstrual cycles in women, and it occurs at approximately 50 years of age. For several years preceding menopause, anovulatory cycles (menstrual cycles in which ovulation does not occur) become more common and the number of functioning ovarian follicles decreases. Accordingly, estrogen secretion gradually declines and eventually ceases. Because of the decreased level of estrogen, there is reduced negative feedback on the anterior pituitary and, accordingly, increased secretion and pulsatility of FSH and LH at menopause.

The symptoms of menopause are caused by the loss of the ovarian source of estrogen and include thinning of the vaginal epithelium, decreased vaginal secretions, decreased breast mass, accelerated bone loss, vascular instability (“hot flashes”), and emotional lability. (Because estrogen can be produced from androgenic precursors in adipose tissue, obese women tend to be less symptomatic than nonobese women.)Estrogen replacement therapy is aimed at replacing the ovarian source of estrogen, thus minimizing or preventing the symptoms of menopause.