Female Physiology Before Pregnancy and Female Hormones

Female reproductive functions can be divided into two major phases: (1) preparation of the female body for conception and pregnancy, and (2) the period of pregnancy itself.

Physiologic Anatomy of the Female Sexual Organs Figures 81–1 and 81–2 show the principal organs of the human female reproductive tract, the most important of which are the ovaries, fallopian tubes, uterus, and vagina. Reproduction begins with the development of ova in the ovaries. In the middle of each monthly sexual cycle, a single ovum is expelled from an ovarian follicle into the abdominal cavity near the open fimbriated ends of the two fallopian tubes. This ovum then passes through one of the fallopian tubes into the uterus; if it has been fertilized by a sperm, it implants in the uterus, where it develops into a fetus, a placenta, and fetal membranes—and eventually into a baby. During fetal life, the outer surface of the ovary is covered by a germinal epithelium, which embryologically is derived from the epithelium of the germinal ridges. As the female fetus develops, primordial ova differentiate from this germinal epithelium and migrate into the substance of the ovarian cortex. Each ovum then collects around it a layer of spindle cells from the ovarian stroma (the supporting tissue of the ovary) and causes them to take on epithelioid characteristics; they are then called granulosa cells. The ovum surrounded by a single layer of granulosa cells is called a primordial follicle. The ovum itself at this stage is still immature, requiring two more cell divisions before it can be fertilized by a sperm. At this time, the ovum is called a primary oocyte. During all the reproductive years of adult life, between about 13 and 46 years of age, 400 to 500 of the primordial follicles develop enough to expel their ova—one each month; the remainder degenerate (become atretic). At the end of reproductive capability (at menopause), only a few primordial follicles remain in the ovaries, and even these degenerate soon thereafter. Female Hormonal System The female hormonal system, like that of the male, consists of three hierarchies of hormones, as follows: 1. A hypothalamic releasing hormone, gonadotropin-releasing hormone (GnRH) 2. The anterior pituitary sex hormones, follicle-stimulating hormone (FSH) and luteinizing hormone (LH), both of which are secreted in response to the release of GnRH from the hypothalamus 3. The ovarian hormones, estrogen and progesterone, which are secreted by the ovaries in response to the two female sex hormones from the anterior pituitary gland These various hormones are not secreted in constant amounts throughout the female monthly sexual cycle; they are secreted at drastically differing rates during different parts of the cycle. Figure 81–3 shows the approximate changing concentrations of the anterior pituitary gonadotropic hormones FSH and LH (bottom two curves) and of the ovarian hormones estradiol (estrogen) and progesterone (top two curves). The amount of GnRH released from the hypothalamus increases and decreases much less drastically during the monthly sexual cycle. It is secreted in short pulses averaging once every 90 minutes, as occurs in the male. Monthly Ovarian Cycle; Function of the Gonadotropic Hormones The normal reproductive years of the female are characterized by monthly rhythmical changes in the rates of secretion of the female hormones and corresponding physical changes in the ovaries and other sexual organs. This rhythmical pattern is called the female monthly sexual cycle (or, less accurately, the menstrual cycle). The duration of the cycle averages 28 days. It may be as short as 20 days or as long as 45 days in some women, although abnormal cycle length is frequently associated with decreased fertility. There are two significant results of the female sexual cycle. First, only a single ovum is normally released from the ovaries each month, so that normally only a single fetus will begin to grow at a time. Second, the uterine endometrium is prepared in advance for implantation of the fertilized ovum at the required time of the month. Gonadotropic Hormones and Their Effects on the Ovaries The ovarian changes that occur during the sexual cycle depend completely on the gonadotropic hormones FSH and LH, secreted by the anterior pituitary gland. In the absence of these hormones, the ovaries remain inactive, which is the case throughout childhood, when almost no pituitary gonadotropic hormones are secreted. At age 9 to 12 years, the pituitary begins to secrete progressively more FSH and LH, which leads to onset of normal monthly sexual cycles beginning between the ages of 11 and 15 years. This period of change is called puberty, and the time of the first menstrual cycle is called menarche. Both FSH and LH are small glycoproteins having molecular weights of about 30,000.

During each month of the female sexual cycle, there is a cyclical increase and decrease of both FSH and LH, as shown in the bottom of Figure 81–3. These cyclical variations cause cyclical ovarian changes, which are explained in the following sections. Both FSH and LH stimulate their ovarian target cells by combining with highly specific FSH and LH receptors in the ovarian target cell membranes. In turn, the activated receptors increase the cells’ rates of secretion and usually the growth and proliferation of the cells as well. Almost all these stimulatory effects result from activation of the cyclic adenosine monophosphate second messenger system in the cell cytoplasm, which causes the formation of protein kinase and multiple phosphorylations of key enzymes that stimulate sex hormone synthesis.

Surge of LH Is Necessary for Ovulation. LH is necessary for final follicular growth and ovulation. Without this hormone, even when large quantities of FSH are available, the follicle will not progress to the stage of ovulation. About 2 days before ovulation (for reasons that are not completely understood but are discussed in more detail later in the chapter), the rate of secretion of LH by the anterior pituitary gland increases markedly, rising 6- to 10-fold and peaking about 16 hours before ovulation. FSH also increases about 2-fold to 3-fold at the same time, and the FSH and LH act synergistically to cause rapid swelling of the follicle during the last few days before ovulation. The LH also has a specific effect on the granulosa and theca cells, converting them mainly to progesterone-secreting cells. Therefore, the rate of secretion of estrogen begins to fall about 1 day before ovulation, while increasing amounts of progesterone begin to be secreted. It is in this environment of (1) rapid growth of the follicle, (2) diminishing estrogen secretion after a prolonged phase of excessive estrogen secretion, and (3) initiation of secretion of progesterone that ovulation occurs. Without the initial preovulatory surge of LH, ovulation will not take place. Initiation of Ovulation. Figure 81–5 gives a schema for the initiation of ovulation, showing the role of the large quantity of LH secreted by the anterior pituitary gland. This LH causes rapid secretion of follicular steroid hormones that contain progesterone. Within a few hours, two events occur, both of which are necessary for ovulation: (1) The theca externa (the capsule of the follicle) begins to release proteolytic enzymes from lysosomes, and these cause dissolution of the follicular capsular wall and consequent weakening of the wall, resulting in further swelling of the entire follicle and degeneration of the stigma. (2) Simultaneously, there is rapid growth of new blood vessels into the follicle wall, and at the same time, prostaglandins (local hormones that cause vasodilation) are secreted into the follicular tissues. These two effects cause plasma transudation into the follicle, which contributes to follicle swelling. Finally, the combination of follicle swelling and simultaneous degeneration of the stigma causes follicle rupture, with discharge of the ovum. Corpus Luteum—“Luteal” Phase of the Ovarian Cycle During the first few hours after expulsion of the ovum from the follicle, the remaining granulosa and theca interna cells change rapidly into lutein cells. They enlarge in diameter two or more times and become filled with lipid inclusions that give them a yellowish appearance.This process is called luteinization, and the total mass of cells together is called the corpus luteum, which is shown in Figure 81–4. A well-developed vascular supply also grows into the corpus luteum. The granulosa cells in the corpus luteum develop extensive intracellular smooth endoplasmic reticula that form large amounts of the female sex hormones progesterone and estrogen (more progesterone than estrogen). The theca cells form mainly the androgens androstenedione and testosterone rather than female sex hormones. However, most of these hormones are also converted by the granulosa cells into the female hormones. In the normal female, the corpus luteum grows to about 1.5 centimeters in diameter, reaching this stage of development 7 to 8 days after ovulation. Then it begins to involute and eventually loses its secretory function as well as its yellowish, lipid characteristic about 12 days after ovulation, becoming the corpus albicans; during the ensuing few weeks, this is replaced by connective tissue and over months is absorbed. Luteinizing Function of LH. The change of granulosa and theca interna cells into lutein cells is dependent mainly on LH secreted by the anterior pituitary gland. In fact, this function gives LH its name—“luteinizing,” for “yellowing.” Luteinization also depends on extrusion of the ovum from the follicle. A yet uncharacterized local hormone in the follicular fluid, called luteinization-inhibiting factor, seems to hold the luteinization process in check until after ovulation. Secretion by the Corpus Luteum: An Additional Function of LH. The corpus luteum is a highly secretory organ, secreting large amounts of both progesterone and estrogen. Once LH (mainly that secreted during the ovulatory surge) has acted on the granulosa and theca cells to cause luteinization, the newly formed lutein cells seem to be programmed to go through a preordained sequence of (1) proliferation, (2) enlargement, and (3) secretion, followed by (4) degeneration.All this occurs in about 12 days. We shall see in the discussion of pregnancy in Chapter 82 that another hormone with almost exactly the same properties as LH, chorionic gonadotropin, which is secreted by the placenta, can act on the corpus luteum to prolong its life—usually maintaining it for at least the first 2 to 4 months of pregnancy. Involution of the Corpus Luteum and Onset of the Next Ovarian Cycle. Estrogen in particular and progesterone to a lesser extent, secreted by the corpus luteum during the luteal phase of the ovarian cycle, have strong feedback effects on the anterior pituitary gland to maintain low secretory rates of both FSH and LH. In addition, the lutein cells secrete small amounts of the hormone inhibin, the same as the inhibin secreted by the Sertoli cells of the male testes. This hormone inhibits secretion by the anterior pituitary gland, especially FSH secretion. Low blood concentrations of both FSH and LH result, and loss of these hormones finally causes the corpus luteum to degenerate completely, a process called involution of the corpus luteum. Final involution normally occurs at the end of almost exactly 12 days of corpus luteum life, which is around the 26th day of the normal female sexual cycle, 2 days before menstruation begins. At this time, the sudden cessation of secretion of estrogen, progesterone, and inhibin by the corpus luteum removes the feedback inhibition of the anterior pituitary gland, allowing it to begin secreting increasing amounts of FSH and LH again. FSH and LH initiate the growth of new follicles, beginning a new ovarian cycle. The paucity of secretion of progesterone and estrogen at this time also leads to menstruation by the uterus.

Functions of the Ovarian Hormones—Estradiol and Progesterone The two types of ovarian sex hormones are the estrogens and the progestins. By far the most important of the estrogens is the hormone estradiol, and by far the most important progestin is progesterone. The estrogens mainly promote proliferation and growth of specific cells in the body that are responsible for the development of most secondary sexual characteristics of the female. The progestins function mainly to prepare the uterus for pregnancy and the breasts for lactation. Chemistry of the Sex Hormones Estrogens. In the normal nonpregnant female, estrogens are secreted in significant quantities only by the ovaries, although minute amounts are also secreted by the adrenal cortices. During pregnancy, tremendous quantities of estrogens are also secreted by the placenta, as discussed in Chapter 82. Only three estrogens are present in significant quantities in the plasma of the human female: b-estradiol, estrone, and estriol, the formulas for which are shown in Figure 81–6. The principal estrogen secreted by the ovaries is b-estradiol. Small amounts of estrone are also secreted, but most of this is formed in the peripheral tissues from androgens secreted by the adrenal cortices and by ovarian thecal cells. Estriol is a weak estrogen; it is an oxidative product derived from both estradiol and estrone, with the conversion occurring mainly in the liver. The estrogenic potency of b-estradiol is 12 times that of estrone and 80 times that of estriol. Considering these relative potencies, one can see that the total estrogenic effect of b-estradiol is usually many times that of the other two together. For this reason, bestradiol is considered the major estrogen, although the estrogenic effects of estrone are not negligible. Progestins. By far the most important of the progestins is progesterone. However, small amounts of another progestin, 17-a-hydroxyprogesterone, are secreted along with progesterone and have essentially the same effects. Yet, for practical purposes, it is usually reasonable to consider progesterone the only important progestin. In the normal nonpregnant female, progesterone is secreted in significant amounts only during the latter half of each ovarian cycle, when it is secreted by the corpus luteum. As we shall see in Chapter 82, large amounts of progesterone are also secreted by the placenta during pregnancy, especially after the fourth month of gestation. Synthesis of the Estrogens and Progestins. Note from the chemical formulas of the estrogens and progesterone in Figure 81–6 that they are all steroids. They are synthesized in the ovaries mainly from cholesterol derived from the blood but also to a slight extent from acetyl coenzyme A, multiple molecules of which can combine to form the appropriate steroid nucleus. During synthesis, mainly progesterone and the male sex hormone testosterone are synthesized first; then, during the follicular phase of the ovarian cycle, before these two initial hormones can leave the ovaries, almost all the testosterone and much of the progesterone are converted into estrogens by the granulosa cells. During the luteal phase of the cycle, far too much progesterone is formed for all of it to be converted, which accounts for the large secretion of progesterone into the circulating blood at this time. Also, about one fifteenth as much testosterone is secreted into the plasma of the female by the ovaries as is secreted into the plasma of the male by the testes. Estrogens and Progesterone Are Transported in the Blood Bound to Plasma Proteins. Both estrogens and progesterone are transported in the blood bound mainly with plasma albumin and with specific estrogen- and progesterone-binding globulins.The binding between these hormones and the plasma proteins is loose enough that they are rapidly released to the tissues over a period of 30 minutes or so. Functions of the Liver in Estrogen Degradation. The liver conjugates the estrogens to form glucuronides and sulfates, and about one fifth of these conjugated products is excreted in the bile; most of the remainder is excreted in the urine. Also, the liver converts the potent estrogens estradiol and estrone into the almost totally impotent estrogen estriol. Therefore, diminished liver function actually increases the activity of estrogens in the body, sometimes causing hyperestrinism. Fate of Progesterone. Within a few minutes after secretion, almost all the progesterone is degraded to other steroids that have no progestational effect.As with the estrogens, the liver is especially important for this metabolic degradation. The major end product of progesterone degradation is pregnanediol. About 10 per cent of the original progesterone is excreted in the urine in this form. Therefore, one can estimate the rate of progesterone formation in the body from the rate of this excretion. Functions of the Estrogens— Their Effects on the Primary and Secondary Female Sex Characteristics A primary function of the estrogens is to cause cellular proliferation and growth of the tissues of the sex organs and other tissues related to reproduction. Effect of Estrogens on the Uterus and External Female Sex Organs. During childhood, estrogens are secreted only in minute quantities, but at puberty, the quantity secreted in the female under the influence of the pituitary gonadotropic hormones increases 20-fold or more. At this time, the female sex organs change from those of a child to those of an adult. The ovaries, fallopian tubes, uterus, and vagina all increase several times in size. Also, the external genitalia enlarge, with deposition of fat in the mons pubis and labia majora and enlargement of the labia minora. In addition, estrogens change the vaginal epithelium from a cuboidal into a stratified type, which is considerably more resistant to trauma and infection than is the prepubertal cuboidal cell epithelium. Vaginal infections in children can often be cured by the administration of estrogens simply because of the resulting increased resistance of the vaginal epithelium. During the first few years after puberty, the size of the uterus increases twofold to threefold, but more important than the increase in uterus size are the changes that take place in the uterine endometrium under the influence of estrogens. Estrogens cause marked proliferation of the endometrial stroma and greatly increased development of the endometrial glands, which will later aid in providing nutrition to the implanted ovum. These effects are discussed later in the chapter in connection with the endometrial cycle. Effect of Estrogens on the Fallopian Tubes. The estrogens’ effect on the mucosal lining of the fallopian tubes is similar to that on the uterine endometrium.They cause the glandular tissues of this lining to proliferate; especially important, they cause the number of ciliated epithelial cells that line the fallopian tubes to increase. Also, activity of the cilia is considerably enhanced. These cilia always beat toward the uterus, which helps propel the fertilized ovum in that direction. Effect of Estrogens on the Breasts. The primordial breasts of females and males are exactly alike. In fact, under the influence of appropriate hormones, the masculine breast during the first 2 decades of life can develop sufficiently to produce milk in the same manner as the female breast. Estrogens cause (1) development of the stromal tissues of the breasts, (2) growth of an extensive ductile system, and (3) deposition of fat in the breasts. The lobules and alveoli of the breast develop to a slight extent under the influence of estrogens alone, but it is progesterone and prolactin that cause the ultimate determinative growth and function of these structures. In summary, the estrogens initiate growth of the breasts and of the milk-producing apparatus. They are also responsible for the characteristic growth and external appearance of the mature female breast. However, they do not complete the job of converting the breasts into milk-producing organs. Effect of Estrogens on the Skeleton. Estrogens inhibit osteoclastic activity in the bones and therefore stimulate bone growth. At puberty, when the female enters her reproductive years, her growth in height becomes rapid for several years. However, estrogens have another potent effect on skeletal growth: They cause uniting of the epiphyses with the shafts of the long bones. This effect of estrogen in the female is much stronger than the similar effect of testosterone in the male. As a result, growth of the female usually ceases several years earlier than growth of the male.A female eunuch who is devoid of estrogen production usually grows several inches taller than a normal mature female because her epiphyses do not unite at the normal time. Osteoporosis of the Bones Caused by Estrogen Deficiency in Old Age. After menopause, almost no estrogens are secreted by the ovaries. This estrogen deficiency leads to (1) increased osteoclastic activity in the bones, (2) decreased bone matrix, and (3) decreased deposition of bone calcium and phosphate. In some women, this effect is extremely severe, and the resulting condition is osteoporosis, described in Chapter 79. Because this can greatly weaken the bones and lead to bone fracture, especially fracture of the vertebrae, a large share of postmenopausal women are treated prophylactically with estrogen replacement to prevent the osteoporotic effects. Effect of Estrogens on Protein Deposition. Estrogens cause a slight increase in total body protein, which is evidenced by a slight positive nitrogen balance when estrogens are administered. This mainly results from the growth-promoting effect of estrogen on the sexual organs, the bones, and a few other tissues of the body. The enhanced protein deposition caused by testosterone is much more general and many times as powerful as that caused by estrogens. Effect of Estrogens on Body Metabolism and Fat Deposition. Estrogens increase the whole-body metabolic rate slightly, but only about one third as much as the increase caused by the male sex hormone testosterone. They also cause deposition of increased quantities of fat in the subcutaneous tissues. As a result, the percentage of body fat in the female body is considerably greater than that in the male body, which contains more protein. In addition to deposition of fat in the breasts and subcutaneous tissues, estrogens cause the deposition of fat in the buttocks and thighs, which is characteristic of the feminine figure. Effect of Estrogens on Hair Distribution. Estrogens do not greatly affect hair distribution. However, hair does develop in the pubic region and in the axillae after puberty. Androgens formed in increased quantities by the female adrenal glands after puberty are mainly responsible for this. Effect of Estrogens on the Skin. Estrogens cause the skin to develop a texture that is soft and usually smooth, but even so, the skin of a woman is thicker than that of a child or a castrated female. Also, estrogens cause the skin to become more vascular; this is often associated with increased warmth of the skin and also promotes greater bleeding of cut surfaces than is observed in men. Effect of Estrogens on Electrolyte Balance. The chemical similarity of estrogenic hormones to adrenocortical hormones has been pointed out. Estrogens, like aldosterone and some other adrenocortical hormones, cause sodium and water retention by the kidney tubules.This effect of estrogens is normally slight and rarely of significance, but during pregnancy, the tremendous formation of estrogens by the placenta may contribute to body fluid retention, as discussed in Chapter 82. Functions of Progesterone Effect of Progesterone on the Uterus. By far the most important function of progesterone is to promote secretory changes in the uterine endometrium during the latter half of the monthly female sexual cycle, thus preparing the uterus for implantation of the fertilized ovum. This function is discussed later in connection with the endometrial cycle of the uterus. In addition to this effect on the endometrium, progesterone decreases the frequency and intensity of uterine contractions, thereby helping to prevent expulsion of the implanted ovum. Effect of Progesterone on the Fallopian Tubes. Progesterone also promotes increased secretion by the mucosal lining of the fallopian tubes. These secretions are necessary for nutrition of the fertilized, dividing ovum as it traverses the fallopian tube before implantation. Effect of Progesterone on the Breasts. Progesterone promotes development of the lobules and alveoli of the breasts, causing the alveolar cells to proliferate, enlarge, and become secretory in nature. However, progesterone does not cause the alveoli to secrete milk; as discussed in Chapter 82, milk is secreted only after the prepared breast is further stimulated by prolactin from the anterior pituitary gland. Progesterone also causes the breasts to swell. Part of this swelling is due to the secretory development in the lobules and alveoli, but part also results from increased fluid in the subcutaneous tissue. Monthly Endometrial Cycle and Menstruation Associated with the monthly cyclical production of estrogens and progesterone by the ovaries is an endometrial cycle in the lining of the uterus that operates through the following stages: (1) proliferation of the uterine endometrium; (2) development of secretory changes in the endometrium; and (3) desquamation of the endometrium, which is known as menstruation. The various phases of this endometrial cycle are shown in Figure 81–7. Proliferative Phase (Estrogen Phase) of the Endometrial Cycle, Occurring Before Ovulation. At the beginning of each monthly cycle, most of the endometrium has been desquamated by menstruation. After menstruation, only a thin layer of endometrial stroma remains, and the only epithelial cells that are left are those located in the remaining deeper portions of the glands and crypts of the endometrium. Under the influence of estrogens, secreted in increasing quantities by the ovary during the first part of the monthly ovarian cycle, the stromal cells and the epithelial cells.

proliferate rapidly. The endometrial surface is reepithelialized within 4 to 7 days after the beginning of menstruation. Then, during the next week and a half—that is, before ovulation occurs—the endometrium increases greatly in thickness, owing to increasing numbers of stromal cells and to progressive growth of the endometrial glands and new blood vessels into the endometrium. At the time of ovulation, the endometrium is 3 to 5 millimeters thick. The endometrial glands, especially those of the cervical region, secrete a thin, stringy mucus. The mucus strings actually align themselves along the length of the cervical canal, forming channels that help guide sperm in the proper direction from the vagina into the uterus.

Abnormalities of Secretion by the Ovaries Hypogonadism. Less than normal secretion by the ovaries can result from poorly formed ovaries, lack of ovaries, or genetically abnormal ovaries that secrete the wrong hormones because of missing enzymes in the secretory cells. When ovaries are absent from birth or when they become nonfunctional before puberty, female eunuchism occurs. In this condition, the usual secondary sexual characteristics do not appear, and the sexual organs remain infantile. Especially characteristic of this condition is prolonged growth of the long bones because the epiphyses do not unite with the shafts as early as they do in a normal woman. Consequently, the female eunuch is essentially as tall as or perhaps even slightly taller than her male counterpart of similar genetic background. When the ovaries of a fully developed woman are removed, the sexual organs regress to some extent so that the uterus becomes almost infantile in size, the vagina becomes smaller, and the vaginal epithelium becomes thin and easily damaged. The breasts atrophy and become pendulous, and the pubic hair becomes thinner. The same changes occur in women after menopause. Irregularity of Menses, and Amenorrhea Caused by Hypogonadism. As pointed out in the preceding discussion of menopause, the quantity of estrogens produced by the ovaries must rise above a critical value in order to cause rhythmical sexual cycles. Consequently, in hypogonadism or when the gonads are secreting small quantities of estrogens as a result of other factors, such as hypothyroidism, the ovarian cycle often does not occur normally. Instead, several months may elapse between menstrual periods, or menstruation may cease altogether (amenorrhea). Prolonged ovarian cycles are frequently associated with failure of ovulation, presumably because of insufficient secretion of LH at the time of the preovulatory surge of LH, which is necessary for ovulation. Hypersecretion by the Ovaries. Extreme hypersecretion of ovarian hormones by the ovaries is a rare clinical entity, because excessive secretion of estrogens automatically decreases the production of gonadotropins by the pituitary, and this limits the production of ovarian hormones. Consequently, hypersecretion of feminizing hormones is usually recognized clinically only when a feminizing tumor develops. A rare granulosa cell tumor can develop in an ovary, occurring more often after menopause than before. These tumors secrete large quantities of estrogens, which exert the usual estrogenic effects, including hypertrophy of the uterine endometrium and irregular bleeding from this endometrium. In fact, bleeding is often the first and only indication that such a tumor exists.