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Chapter 22 Reproductive Development & Function of the Female Reproductive System Introduction In most species of mammals, the multiple differences between the male and the female depend primarily on a single chromosome (the Y chromosome) and a single pair of endocrine structures, namely the testes i...

Chapter 22 Reproductive Development & Function of the Female Reproductive System Introduction In most species of mammals, the multiple differences between the male and the female depend primarily on a single chromosome (the Y chromosome) and a single pair of endocrine structures, namely the testes in the male and the ovaries in the female. The differentiation of the primitive gonads into testes or ovaries in utero is genetically determined in humans, but the formation of male genitalia depends on the presence of a functional, secreting testis; in the absence of testicular tissue, development is female. Evidence indicates that male sexual behavior and, in some species, the male pattern of gonadotropin secretion are due to the action of male hormones on the brain in early development. After birth, the gonads remain quiescent until adolescence, when they are activated by gonadotropins from the anterior pituitary. Hormones secreted by the gonads at this time cause the appearance of features typical of the adult male or female and the onset of the sexual cycle in the female. In human females. ovarian function regresses after a number of years and sexual cycles cease (the menopause). In males, gonadal function slowly declines with advancing age, but the ability to produce viable gametes persists. In both sexes, the gonads have a dual function: 1. the production of germ cells (gametogenesis) 2. the secretion of sex hormones. The androgens are steroid sex hormones that are masculinizing in their action; the estrogens are those that are feminizing. Both types of hormones are normally secreted in both sexes. The ovaries secrete large amounts of estrogens and small amounts of androgens, a pattern that is reversed in males. Androgens are secreted from the adrenal cortex in both sexes the androgens are converted to estrogens in fat and other extragonadal and extraadrenal tissues. The ovaries also secrete progesterone, a steroid that has special functions in preparing the uterus for pregnancy. Particularly during pregnancy, the ovaries secrete the polypeptide hormone relaxin, which loosens the ligaments of the pubic symphysis and softens the cervix, facilitating delivery of the fetus. In both sexes, the gonads secrete other polypeptides, including inhibin B, a polypeptide that inhibits follicle-stimulating hormone (FSH) secretion. The secretory and gametogenic functions of the gonads are both dependent on the secretion of the anterior pituitary gonadotropins, FSH, and luteinizing hormone (LH). The sex hormones and inhibin B feed back to inhibit gonadotropin secretion. In males, gonadotropin secretion is noncyclic; but in postpubertal females an orderly, sequential secretion of gonadotropins is necessary for the occurrence of menstruation, pregnancy, and lactation. SEX DIFFERENTIATION and DEVELOPMENT The Sex Chromosomes Sex is determined genetically by two chromosomes, called the sex chromosomes, to distinguish them from the somatic chromosomes (autosomes). In humans and many other mammals, the sex chromosomes are called X and Y. The Y chromosome is necessary and sufficient for the production of testes, and the testis-determining gene product is called SRY (for sex-determining region of the Y chromosome). SRY is a DNA-binding regulatory protein. It bends the DNA and acts as a transcription factor that initiates transcription of a cascade of genes necessary for testicular differentiation, including the gene for müllerian inhibiting substance (MIS). The gene for SRY is located near the tip of the short arm of the human Y chromosome. Diploid male cells contain an X and a Y chromosome (XY pattern), whereas female cells contain two X chromosomes (XX pattern). As a consequence of meiosis during gametogenesis, each normal ovum contains a single X chromosome, but half of the normal sperm contain an X chromosome and half contain a Y chromosome (Figure 22–1). When a sperm containing a Y chromosome fertilizes an ovum, an XY pattern results and the zygote develops into a genetic male. When fertilization occurs with an X-containing sperm, an XX pattern and a genetic female results. In the two-stage meiotic division in the female, only one cell survives as the mature ovum. In the male, the meiotic division results in the formation of four sperms, two containing the X and two the Y chromosome. Fertilization thus produces a male zygote with 22 pairs of autosomes plus an X and a Y or a female zygote with 22 pairs of autosomes and two X chromosomes. Development of the Gonads On each side of the embryo a condensation of tissue near the adrenal gland. The gonad develops a cortex and a medulla. Until the sixth week of development, these structures are identical in both sexes. In genetic males, the medulla develops during the seventh and eighth weeks into a testis, and the cortex regresses. Leydig and Sertoli cells appear, and testosterone and MIS are secreted. The MIS causes regression of mullerian duct. In genetic females, the cortex develops into an ovary and the medulla regresses. the müllerian duct system then develops into uterine tubes (oviducts) and a uterus. The embryonic ovary does not secrete hormones. Hormonal treatment of the mother has no effect on gonadal (as opposed to ductal and genital) differentiation in humans. PUBERTY A burst of testosterone secretion occurs in male fetuses before birth. In the neonatal period there is another burst, with unknown function, but thereafter the Leydig cells become quiescent. There follows in all mammals a period in which the gonads of both sexes are quiescent until they are activated by gonadotropins from the pituitary to bring about the final maturation of the reproductive system. (Figure 22–8) This period of final maturation is known as adolescence. It is often also called puberty, although puberty, strictly defined, is the period when the endocrine and gametogenic functions of the gonads have first developed to the point where reproduction is possible. In girls, the first event is thelarche, the development of breasts, followed by pubarche, the development of axillary and pubic hair, and then by menarche, the first menstrual period. Initial menstrual periods are generally anovulatory, and regular ovulation appears about a year later. In contrast to the situation in adulthood, removal of the gonads during the period from soon after birth to puberty causes only a small increase in gonadotropin secretion, so gonadotropin secretion is not being held in check by the gonadal hormones. In children between the ages of 7 and 10, a slow increase in estrogen and androgen secretion precedes the more rapid rise in the early teens. The age at the time of puberty is variable. puberty generally occurs between the ages of 8 and 13 in girls and 9 and 14 in boys. Another event that occurs in humans at the time of puberty is an increase in the secretion of adrenal androgens. The onset of this increase is called adrenarche. It occurs at age 8–10 years in girls and age 10–12 years in boys. (DHEA) values peak at about age 25 in women and slightly later than that in men. They then decline slowly to low values in old age. The rise appears to be due to an increase in the activity of 17α-hydroxylase. Control of the Onset of Puberty The gonads of children can be stimulated by gonadotropins; their pituitaries contain gonadotropins and their hypothalami contain gonadotropin-releasing Dehydroepiandrosterone hormone (GnRH). Thus, it seems clear that pulsatile secretion of GnRH brings on puberty. 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. However, one or more genes produce products that stimulate secretion of GnRH, and inhibition of these genes before puberty is an interesting possibility MENOPAUSE The human ovaries become unresponsive to gonadotropins with advancing age, and their function declines, so that sexual cycles disappear (menopause). This unresponsiveness is associated with and probably caused by decline in the number of primordial follicles, which becomes precipitous at the time of menopause. 1. The ovaries no longer secrete progesterone and 17β-estradiol in appreciable quantities, and estrogen is formed only in small amounts by aromatization of androstenedione in peripheral tissues. 2. The uterus and the vagina gradually become atrophic. 3. As the negative feedback effect of estrogens and progesterone is reduced, secretion of FSH is increased, and plasma FSH increases to high levels, LH levels are moderately high. In women, a period called perimenopause precedes menopause and can last up to 10 years. During perimenopause FSH levels will increase before an increase in LH is observed due to a decrease in estrogen, progesterone, and inhibins and the menses become irregular. This usually occurs between the ages of 45 and 55. The average age at onset of the menopause is 52 years. The loss of ovarian function causes many symptoms such as sensations of warmth spreading from the trunk to the face (hot flushes; also called hot flashes) and night sweats. In addition, the onset of menopause increases the risk of many diseases such as osteoporosis, ischemic heart disease, and renal disease. Hot flushes are said to occur in 75% of menopausal women and may continue intermittently for as long as 40 years. They also occur when early menopause is produced by bilateral ovariectomy, and they are prevented by estrogen treatment. Their cause is unknown. However, they coincide with surges of LH secretion. LH is secreted in episodic bursts at intervals of 30–60 min 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, because they can continue after removal of the pituitary. Instead, it appears that some estrogen-sensitive event in the hypothalamus initiates both the release of LH and the episode of flushing. Although the function of the testes tends to decline slowly with advancing age, the evidence is unclear whether there is a “male menopause” (andropause) similar to that occurring in women THE FEMALE REPRODUCTIVE SYSTEM THE MENSTRUAL CYCLE (MC) The reproductive system of women shows regular cyclic changes that teleologically may be regarded as periodic preparations for fertilization and pregnancy. In humans and other primates, the cycle is a menstrual cycle, and its most conspicuous feature is the periodic vaginal bleeding that occurs with the shedding of the uterine mucosa (menstruation). The length of the cycle is notoriously variable in women, but an 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 1.The follicular phase : From the time of birth, there are many primordial follicles under the ovarian capsule. Each contains an immature ovum. 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. grow rapidly on about the 6th day and becomes the dominant follicle, while the others regress, forming atretic follicles. The atretic process involves apoptosis. It is uncertain how one follicle is selected to be the dominant follicle in this follicular phase of the menstrual cycle, but it seems to be related to the ability of the follicle to secrete the estrogen inside it that is needed for final maturation. The structure of a maturing ovarian (graafian) follicle is shown in (Figure 22–11). The primary source of circulating estrogen is the granulosa cells of the ovaries; however, the cells of the theca interna of the follicle are necessary for the production of estrogen as they secrete androgens that are aromatized to estrogen by the granulosa cells. 2.The ovulatory phase: 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). It is transported to the uterus and, unless fertilization occurs, out through the vagina. 3.The luteal phase: 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, lipidrich luteal cells, forming the corpus luteum. This initiates 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, and there is evidence that vascular endothelial growth factor (VEGF) is essential for this process. If pregnancy occurs, the corpus luteum persists and usually there are no more periods until after delivery. If pregnancy does not occur, the corpus luteum begins to degenerate about 4 days before the next menses (24th day of the cycle) and is eventually replaced by scar tissue, forming a corpus albicans. The ovarian cycle in other mammals is similar, except that in many species more than one follicle ovulates and multiple births are the rule. Corpora lutea form in some sub-mammalian species but not in others. In humans, no new ova are formed after birth. During fetal development, the ovaries contain over 7 million primordial follicles. However, many undergo (involution) before birth and others are lost after birth. atresia At the time of birth, there are 2 million ova. Atresia continues during development, and the number of ova in both of the ovaries at the time of puberty is less than 300,000. Only one of these ova per cycle (or about 500 in the course of a normal reproductive life) normally reaches maturity; the remainder degenerate. Just before ovulation. Uterine Cycle : At the end of menstruation, all but the deep layers of the endometrium have sloughed. A new endometrium then regrows under the influence of estrogens from the developing follicle. The endometrium increases rapidly in thickness from the 5th to the 14th days of the menstrual cycle. As the thickness increases, the uterine glands are drawn out so that they lengthen (Figure 22–12), 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 and they begin to secrete a clear fluid. Consequently, this phase of the cycle is called the secretory or luteal phase. When the corpus luteum regresses, hormonal support for the endometrium is withdrawn. The endometrium becomes thinner, which adds to the coiling of the spiral arteries. Foci of necrosis appear in the endometrium, and these coalesce. In addition, spasm and degeneration of the walls of the spiral arteries take place, leading to spotty hemorrhages that become confluent and produce the menstrual flow. The vasospasm is probably produced by locally released prostaglandins. Large quantities of prostaglandins are present in the secretory endometrium and in menstrual blood, From the point of view of endometrial function, the proliferative phase of the menstrual cycle represents restoration of the epithelium from the preceding menstruation, and the secretory phase represents preparation of the uterus for implantation of the fertilized ovum. The length of the secretory phase is remarkably constant at about 14 days, and the variations seen in the length of the menstrual cycle are due for the most part 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 starts. 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 endometrial tissue. The fibrinolysin lyses clots, so that menstrual blood does not normally contain clots unless the flow is excessive. The usual duration of the menstrual flow is 3–5 days but flows as short as 1 day and as long as 8 days can occur in normal women. The amount of blood lost may range normally from slight spotting to 80 mL; the average amount lost is 30 mL. Loss of more than 80 mL is abnormal. Obviously, the amount of flow can be affected by various factors, including the thickness of the endometrium, medication, and diseases that affect the clotting mechanism. Anovulatory Cycles anovulatory cycles are common for the first 12–18 months after menarche and again before the onset of the 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 begins to slough. The time it takes for bleeding to occur is variable, but it usually occurs in less than 28 days from the last menstrual period. The flow is also variable and ranges from scanty to relatively profuse. Indicators of Ovulation A convenient and reasonably reliable indicator of the time of ovulation is a change—usually a rise—in the basal body temperature (Figure 22–14). The rise starts 1–2 days after ovulation. Women interested in obtaining an accurate temperature chart should use a digital thermometer and take their temperatures (oral or rectal) in the morning before getting out of bed. The cause of the temperature change at the time of ovulation is probably the increase in progesterone secretion, since progesterone is thermogenic. A increase in LH secretion triggers ovulation, and ovulation normally occurs about 9 h after the peak of the LH surge at midcycle. The ovum lives for approximately 72 h after it is extruded from the follicle, but it is fertilizable for a much shorter time than this. the most fertile period is clearly the 48 h before ovulation. OVARIAN HORMONES Estrogens : The naturally occurring estrogens are 17β-estradiol, estrone, and estriol. They are steroids secreted primarily by the granulosa cells of the ovarian follicles, the corpus luteum, and the placenta. Their biosynthesis depends on the enzyme aromatase (CYP19), which converts testosterone to estradiol and androstenedione to estrone. The latter reaction also occurs in fat, liver, muscle, and the brain. Theca interna cells have many LH receptors, and LH acts via cAMP to increase conversion of cholesterol to androstenedione. The theca interna cells supply androstenedione to the granulosa cells. The granulosa cells make estradiol when provided with androgens and it appears that the estradiol they form in primates is secreted into the follicular fluid. Granulosa cells have many FSH receptors, and FSH facilitates their secretion of estradiol by acting via cAMP to increase their aromatase activity. Mature granulosa cells also acquire LH receptors, and LH also stimulates estradiol production. 2% of the circulating estradiol is free, and the remainder is bound to protein: 1. 60% to albumin 2. 38% to the same gonadal steroid-binding globulin (GBG) that binds testosterone. In the liver, estradiol, estrone, and estriol are converted to glucuronide and sulfate conjugates. All these compounds, along with other metabolites, are excreted in the urine. Appreciable amounts are secreted in the bile and reabsorbed into the bloodstream (enterohepatic circulation). Estrogens Secretion : estrogen comes from the ovary, and two peaks of secretion occur: 1. one just before ovulation 2. one during the midluteal phase. The estradiol secretion rate is 1. 36 μg/day (133 nmol/day) in the early follicular phase 2. 380 μg/day just before ovulation 3. 250 μg/day during the midluteal phase (After menopause, estrogen secretion declines to low levels. As noted previously, the estradiol production rate in men is about 50 μg/day (184 nmol/day). Effects on the Female Genitalia: Estrogens facilitate the growth of the ovarian follicles and increase the motility of the uterine tubes. They increase uterine blood flow and have important effects on the smooth muscle of the uterus. Under the influence of estrogens, the muscle becomes more active and excitable, and action potentials in the individual fibers become more frequent. The “estrogen-dominated” uterus is also more sensitive to oxytocin. Effects on Endocrine Organs: Estrogens decrease FSH secretion. Under some circumstances, they inhibit LH secretion (negative feedback); in other circumstances, they increase LH secretion (positive feedback). Women are sometimes given large doses of estrogens for 4–6 days to prevent conception after coitus during the fertile period (postcoital or “morning-after” contraception). However, in this instance, pregnancy is probably prevented by interference with implantation of the ovum rather than changes in gonadotropin secretion. Effects on the Breasts: Estrogens produce duct growth in the breasts and are largely responsible for breast enlargement at puberty in girls; they have been called the growth hormones of the breast. They are responsible for the pigmentation of the areolas, although pigmentation usually becomes more intense during the first pregnancy than it does at puberty. Female Secondary Sex Characteristics: The body changes that develop in girls at puberty—in addition to enlargement of 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 and 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 seen also in castrate males. In women, the larynx retains its prepubertal proportions and the voice stays high-pitched. Women have less body hair and more scalp hair, and the pubic hair generally has a characteristic flat-topped pattern (female escutcheon). However, growth of pubic and axillary hair in both sexes is due primarily to androgens rather than estrogens. Mechanism of Action: There are two principal types of nuclear estrogen receptors: estrogen receptor α (ERα). After binding estrogen, they form homodimers and bind to DNA, altering its transcription. Some tissues contain one type or the other with some tissues containing both ERα and ERβ. ERα is found primarily in the uterus, kidneys, liver, and heart, ERβ is found primarily in the ovaries, prostate, lungs, gastrointestinal tract, hemopoietic system, and central nervous system (CNS). Most of the effects of estrogens are genomic, that is, due to actions on the nucleus, but some are so rapid that it is difficult to believe they are mediated via production of mRNAs. These include effects on neuronal discharge in the brain and, possibly, feedback effects on gonadotropin secretion. Progesterone Progesterone is a steroid secreted by the corpus luteum, the placenta, and (in small amounts) the follicle. It is an important intermediate in steroid biosynthesis in all tissues that secrete steroid hormones, and small mounts apparently enter the circulation from the testes and adrenal cortex. About 2% of the circulating progesterone is free 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. Secretion In men, the plasma progesterone level is approximately 0.3 ng/mL (1 nmol/L). In women, the level is approximately 0.9 ng/mL (3 nmol/L) during the follicular phase of the menstrual cycle. The difference is due to secretion of small amounts of progesterone by cells in the ovarian follicles; theca cells provide pregnenolone to the granulosa cells, which convert it to progesterone. Late in the follicular phase, progesterone secretion begins to increase. During the luteal phase, the corpus luteum produces large quantities of progesterone and plasma progesterone is markedly increased to a peak value of approximately 18 ng/mL (60 nmol/L). 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 The principal target organs of progesterone are the uterus, the breasts, and the brain. Progesterone is responsible for the 1. pregestational changes in the endometrium and the cyclical changes in the cervix and vagina 2. It has an antiestrogenic effect on the myometrial cells, decreasing their excitability, their sensitivity to oxytocin, and their spontaneous electrical activity while increasing their membrane potential. 3. decreases the number of estrogen receptors in the endometrium and increases the rate of conversion of 17β-estradiol to less active estrogens. 4. In the breast, progesterone stimulates the development of lobules and alveoli. 5. 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 pituitary levels. Large doses of progesterone inhibit LH secretion and potentiate the inhibitory effect of estrogens, preventing ovulation. Progesterone is thermogenic and is probably responsible for the rise in basal body temperature at the time of ovulation. It stimulates respiration, and the alveolar PCO2 Large doses of progesterone produce natriuresis, probably by blocking the action of aldosterone on the kidney. The hormone does not have a significant anabolic effect. Relaxin Relaxin is a polypeptide hormone that is produced in the corpus luteum, uterus, placenta, and mammary glands in women and in the prostate gland in men. During pregnancy, it relaxes the pubic symphysis and other pelvic joints and softens and dilates the uterine cervix. Thus, it facilitates 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 nonpregnant women is unknown. In men, it is found in semen, where it may help maintain sperm motility and aid in sperm penetration of the ovum. Feedback regulation of ovarian function During the early part of the follicular phase, inhibin B is low and FSH 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 h before ovulation, the estrogen feedback effect becomes positive, and this initiates the burst of LH secretion (LH surge) that produces ovulation. Ovulation occurs about 9 h after the LH peak. FSH secretion also peaks, despite a small rise in inhibin. probably because of the strong stimulation of gonadotropes by GnRH. During the luteal phase, the secretion of LH and FSH is low because of the elevated levels of estrogen, progesterone, and inhibin Figure 22–19. It should be emphasized that a moderate, constant level of circulating estrogen exerts a negative feedback effect on LH secretion, whereas during the cycle, an elevated estrogen level exerts a positive feedback effect and stimulates LH secretion. but exactly how negative feedback is switched to positive feedback and then back to negative feedback in the luteal phase remains unknown. PREGNANCY: Fertilization & Implantation :In humans, fertilization of the ovum by the sperm usually occurs in the ampulla of the uterine tube. Fertilization involves (1) chemoattraction of the sperm to the ovum by substances produced by the ovum; (2) adherence to the zona pellucida, the membranous structure surrounding the ovum; (3) penetration of the zona pellucida and the acrosome reaction; and (4) adherence of the sperm head to the cell membrane of the ovum, with breakdown of the area of fusion and release of the sperm nucleus into the cytoplasm of the ovum (Figure 22–20). Millions of sperm are deposited in the vagina during intercourse. Eventually, 50–100 sperm reach the ovum, and many of them contact the zona pellucida. Sperm bind to a receptor in the zona, and this is followed by the acrosomal reaction, that is, the breakdown of the acrosome, the lysosome-like organelle on the head of the sperm. Various enzymes are released, including the trypsinlike protease acrosin. Acrosin facilitates but is not required for the penetration of the sperm through the zona pellucida. When one sperm reaches the membrane of the ovum, fusion to the ovum membrane is mediated by fertilin, a protein on the surface of the sperm head. The fusion provides the signal that initiates development. In addition, the fusion sets off a reduction in the membrane potential of the ovum that prevents polyspermy, the fertilization of the ovum by more than one sperm. This transient potential change is followed by a structural change in the zona pellucida that provides protection against polyspermy on a more long-term basis.The developing embryo, now called a blastocyst, moves down the tube into the uterus. This journey takes about 3 days, during which the blastocyst reaches the 8- or 16-cell stage. Once in contact with the endometrium, the blastocyst becomes surrounded by an outer layer of syncytiotrophoblast, a multi-nucleate mass with no discernible cell boundaries, and an inner layer of cytotrophoblast made up of individual cells. The syncytiotrophoblast erodes the endometrium, and the blastocyst burrows into it (implantation). The implantation site is usually on the dorsal wall of the uterus. A placenta then develops, and the trophoblast remains associated with it. Endocrine Changes In all mammals, the corpus luteum in the ovary at the time of fertilization fails to regress and instead enlarges in response to stimulation by gonadotropic hormones secreted by the placenta. The placental gonadotropin in humans is called human chorionic gonadotropin (hCG). The enlarged corpus luteum of pregnancy secretes estrogens, progesterone, and relaxin. Progesterone and relaxin help maintain pregnancy by inhibiting myometrial contractions; progesterone prevents prostaglandin production by the uterus, which stops contractions from occurring. In humans, the placenta produces sufficient estrogen and progesterone from maternal and fetal precursors to take over the function of the corpus luteum after the sixth week of pregnancy. The function of the corpus luteum begins to decline after 8 weeks of pregnancy, but it persists throughout pregnancy. hCG secretion decreases after an initial marked rise, but estrogen and progesterone secretion increase until just before parturition. Human Chorionic Gonadotropin hCG is a glycoprotein that contains galactose and hexosamine. It is produced by the syncytiotrophoblast. Like the pituitary glycoprotein hormones, it is made up of α and β subunits. hCG-α is identical to the α subunit of LH, FSH, and TSH. The molecular weight of hCG-α is 18,000, and that of hCG-β is 28,000. hCG is primarily luteinizing and luteotropic and has little FSH activity. It can be measured by radioimmunoassay and detected in the blood as early as 6 days after conception. Human Chorionic Somatomammotropin The syncytiotrophoblast also secretes large amounts of a protein hormone that is lactogenic and has a small amount of growth-stimulating activity. The structure of hCS is very similar to that of human growth hormone, and it appears that these two hormones and prolactin evolved from a common progenitor hormone. Large quantities of hCS are found in maternal blood, but very little reaches the fetus. Secretion of growth hormone from the maternal pituitary is not increased during pregnancy and may actually be decreased by hCS. However, hCS has most of the actions of growth hormone and apparently functions as a “maternal growth hormone of pregnancy” to bring about the nitrogen, potassium, and calcium retention, lipolysis, and decreased glucose utilization seen in this state. These latter two actions divert glucose to the fetus.. Low hCS levels are a sign of placental insufficiency. Parturition The duration of pregnancy in humans averages 270 days from fertilization (284 days from the first day of the menstrual period preceding conception). Irregular uterine contractions increase in frequency in the last month of pregnancy.The difference between the body of the uterus and the cervix becomes evident at the time of delivery. The cervix, which is firm in the nonpregnant state and throughout pregnancy until near the time of delivery, softens and dilates, while the body of the uterus contracts and expels the fetus. There is still considerable uncertainty about the mechanisms responsible for the onset of labor. One factor is the increase in circulating estrogens produced by increased circulating DHEAS. This makes the uterus more excitable, increases the number of gap junctions between myometrial cells, and causes production of more prostaglandins, which in turn cause uterine contractions. In humans, CRH secretion by the fetal hypothalamus increases and is supplemented by increased placental production of CRH. This increases circulating adrenocorticotropic hormone (ACTH) in the fetus, and the resulting increase in cortisol hastens the maturation of the respiratory system. Thus, in a sense, the fetus picks the time to be born by increasing CRH secretion. The number of oxytocin receptors in the myometrium and the decidua (the endometrium of pregnancy) increases more than 100-fold during pregnancy and reaches a peak during early labor. Estrogens increase the number of oxytocin receptors, and uterine distension late in pregnancy may also increase their formation. Once labor is started, the uterine contractions dilate the cervix, and this dilation in turn sets up signals in afferent nerves that increase oxytocin secretion (Figure 22–22). The plasma oxytocin level rises and more oxytocin becomes available to act on the uterus. Thus, a positive feedback loop is established that aids delivery and terminates on expulsion of the products of conception. Oxytocin increases uterine contractions in two ways: (1) It acts directly on uterine smooth muscle cells to make them contract and (2) it stimulates the formation of prostaglandins in the decidua. The prostaglandins enhance the oxytocininduced contractions. During labor, spinal reflexes and voluntary contractions of the abdominal muscles (“bearing down”) also aid in delivery. LACTATION Development of the Breasts : In general, estrogens are primarily responsible for proliferation of the mammary ducts and progesterone for the development of the lobules. During pregnancy, prolactin levels increase steadily until term, and levels of estrogens and progesterone are elevated as well, producing full lobuloalveolar development. Secretion & Ejection of Milk: prolactin cause the formation of milk droplets and their secretion into the ducts. Oxytocin causes contraction of the myoepithelial cells lining the duct walls, with consequent ejection of the milk through the nipple in addition on the placenta secret human chorionic somatomammotropin (hcs) which has mild lactogenic properties. Initiation of Lactation after Delivery: The breasts enlarge during pregnancy in response to high circulating levels of estrogens, progesterone, prolactin, and possibly hCG. Some milk is secreted into the ducts as early as the 5th month, but the amounts are small compared with the surge of milk secretion that follows delivery. In most animals, milk is secreted within an hour after delivery, but in women it takes 1–3 days for the milk to “come in.”After expulsion of the placenta at parturition, the levels of circulating estrogens and progesterone abruptly decline. The drop in circulating estrogen initiates lactation. Prolactin and estrogen synergize in producing breast growth, but estrogen antagonizes the milk-producing effect of prolactin on the breast. Indeed, in women who do not wish to breastfeed their babies, estrogens may be administered to stop lactation. Suckling not only evokes reflex oxytocin release and milk ejection, it also maintains and augments the secretion of milk because of the stimulation of prolactin secretion it produces. The first fluid secreted is the colostrum with contain the same conc. Of protein and lactose but no fat as in milk. Effect of Lactation on Menstrual Cycles Women who do not breastfeed their infants usually have their first menstrual period 6 weeks after delivery. However, women who breastfeed regularly have amenorrhea for 25– 30 weeks. Breastfeeding stimulates prolactin secretion, and evidence suggests that prolactin inhibits GnRH secretion, inhibits the action of GnRH on the pituitary, and antagonizes the action of gonadotropins on the ovaries. Ovulation is inhibited, and the ovaries are inactive, so estrogen and progesterone output falls to low levels. Consequently, only 5–10% of women become pregnant again during the suckling period, and breastfeeding has long been known to be an important, if only partly effective, method of birth control. Furthermore, almost 50% of the cycles in the first 6 months after resumption of menses are anovulatory.