Guyton and Hall Textbook of Medical Physiology, 12th Ed

CHAPTER 81

Female Physiology Before Pregnancy and Female Hormones

imageFemale 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. This chapter is concerned with preparation of the female body for pregnancy, and Chapter 82 presents the physiology of pregnancy and childbirth.

Physiologic Anatomy of the Female Sexual Organs

Figures 81-1 and 81-2 show the principal organs of the human female reproductive tract, including the ovaries, fallopian tubes (also called uterine 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.

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Figure 81-1 Female reproductive organs.

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Figure 81-2 Internal structures of the uterus, ovary, and a uterine tube.

(Redrawn from Guyton AC: Physiology of the Human Body, 6th ed. Philadelphia: Saunders College Publishing, 1984.)

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 ovadifferentiate 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 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 secreted at drastically differing rates during different parts of the female monthly sexual 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).

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Figure 81-3 Approximate plasma concentrations of the gonadotropins and ovarian hormones during the normal female sexual cycle. FSH, follicle-stimulating hormone; LH, luteinizing hormone.

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 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, as explained in Chapter 74.

Ovarian Follicle Growth—”Follicular” Phase of the Ovarian Cycle

Figure 81-4 shows the progressive stages of follicular growth in the ovaries. When a female child is born, each ovum is surrounded by a single layer of granulosa cells; the ovum, with this granulosa cell sheath, is called a primordial follicle, as shown in the figure. Throughout childhood, the granulosa cells are believed to provide nourishment for the ovum and to secrete an oocyte maturation-inhibiting factorthat keeps the ovum suspended in its primordial state in the prophase stage of meiotic division. Then, after puberty, when FSH and LH from the anterior pituitary gland begin to be secreted in significant quantities, the ovaries, together with some of the follicles within them, begin to grow.

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Figure 81-4 Stages of follicular growth in the ovary, also showing formation of the corpus luteum.

The first stage of follicular growth is moderate enlargement of the ovum itself, which increases in diameter twofold to threefold. Then follows growth of additional layers of granulosa cells in some of the follicles; these follicles are known as primary follicles.

Development of Antral and Vesicular Follicles

During the first few days of each monthly female sexual cycle, the concentrations of both FSH and LH secreted by the anterior pituitary gland increase slightly to moderately, with the increase in FSH slightly greater than that of LH and preceding it by a few days. These hormones, especially FSH, cause accelerated growth of 6 to 12 primary follicles each month. The initial effect is rapid proliferation of the granulosa cells, giving rise to many more layers of these cells. In addition, spindle cells derived from the ovary interstitium collect in several layers outside the granulosa cells, giving rise to a second mass of cells called the theca. This is divided into two layers. In the theca interna,the cells take on epithelioid characteristics similar to those of the granulosa cells and develop the ability to secrete additional steroid sex hormones (estrogen and progesterone). The outer layer, the theca externa, develops into a highly vascular connective tissue capsule that becomes the capsule of the developing follicle.

After the early proliferative phase of growth, lasting for a few days, the mass of granulosa cells secretes a follicular fluid that contains a high concentration of estrogen, one of the important female sex hormones (discussed later). Accumulation of this fluid causes an antrum to appear within the mass of granulosa cells, as shown in Figure 81-4.

The early growth of the primary follicle up to the antral stage is stimulated mainly by FSH alone. Then greatly accelerated growth occurs, leading to still larger follicles called vesicular follicles. This accelerated growth is caused by the following: (1) Estrogen is secreted into the follicle and causes the granulosa cells to form increasing numbers of FSH receptors; this causes a positive feedback effect because it makes the granulosa cells even more sensitive to FSH. (2) The pituitary FSH and the estrogens combine to promote LH receptors on the original granulosa cells, thus allowing LH stimulation to occur in addition to FSH stimulation and creating an even more rapid increase in follicular secretion. (3) The increasing estrogens from the follicle plus the increasing LH from the anterior pituitary gland act together to cause proliferation of the follicular thecal cells and increase their secretion as well.

Once the antral follicles begin to grow, their growth occurs almost explosively. The ovum itself also enlarges in diameter another threefold to fourfold, giving a total ovum diameter increase up to 10-fold, or a mass increase of 1000-fold. As the follicle enlarges, the ovum remains embedded in a mass of granulosa cells located at one pole of the follicle.

Only One Follicle Fully Matures Each Month, and the Remainder Undergo Atresia

After a week or more of growth—but before ovulation occurs—one of the follicles begins to outgrow all the others; the remaining 5 to 11 developing follicles involute (a process called atresia), and these follicles are said to become atretic.

The cause of the atresia is unknown, but it has been postulated to be the following: The large amounts of estrogen from the most rapidly growing follicle act on the hypothalamus to depress further enhancement of FSH secretion by the anterior pituitary gland, in this way blocking further growth of the less well developed follicles. Therefore, the largest follicle continues to grow because of its intrinsic positive feedback effects, while all the other follicles stop growing and actually involute.

This process of atresia is important because it normally allows only one of the follicles to grow large enough each month to ovulate; this usually prevents more than one child from developing with each pregnancy. The single follicle reaches a diameter of 1 to 1.5 centimeters at the time of ovulation and is called the mature follicle.

Ovulation

Ovulation in a woman who has a normal 28-day female sexual cycle occurs 14 days after the onset of menstruation. Shortly before ovulation the protruding outer wall of the follicle swells rapidly, and a small area in the center of the follicular capsule, called the stigma, protrudes like a nipple. In another 30 minutes or so, fluid begins to ooze from the follicle through the stigma, and about 2 minutes later, the stigma ruptures widely, allowing a more viscous fluid, which has occupied the central portion of the follicle, to evaginate outward. This viscous fluid carries with it the ovum surrounded by a mass of several thousand small granulosa cells, called the corona radiata.

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 twofold to threefold 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.

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Figure 81-5 Postulated mechanism of ovulation.

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 during the luteal phase). 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 enzyme aromatase in the granulosa cells into estrogens, the female hormones.

The corpus luteum normally 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 and 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, as explained later.

Summary

About every 28 days, gonadotropic hormones from the anterior pituitary gland cause about 8 to 12 new follicles to begin to grow in the ovaries. One of these follicles finally becomes “mature” and ovulates on the 14th day of the cycle. During growth of the follicles, mainly estrogen is secreted.

After ovulation, the secretory cells of the ovulating follicle develop into a corpus luteum that secretes large quantities of both the major female hormones, progesterone and estrogen. After another 2 weeks, the corpus luteum degenerates, whereupon the ovarian hormones estrogen and progesterone decrease greatly and menstruation begins. A new ovarian cycle then follows.

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: β-estradiol, estrone, and estriol, the formulas for which are shown in Figure 81-6. The principal estrogen secreted by the ovaries is β-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.

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Figure 81-6 Synthesis of the principal female hormones.The chemical structures of the precursor hormones, including progesterone, are shown in Figure 77-2.

The estrogenic potency of β-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 β-estradiol is usually many times that of the other two together. For this reason, β-estradiol 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-α-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 androgens (testosterone and androstenedione) are synthesized first; then, during the follicular phase of the ovarian cycle, before these two initial hormones can leave the ovaries, almost all the androgens and much of the progesterone are converted into estrogens by the enzyme aromatase in the granulosa cells. Because the theca cells lack the aromatase, they cannot convert androgens to estrogens. However, androgens diffuse out of the theca cells into the adjacent granulosa cells, where they are converted to estrogens by aromatase, the activity of which is stimulated by FSH (Figure 81-7).

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Figure 81-7 Interaction of follicular theca and granulosa cells for production of estrogens. The theca cells, under the control of luteinizing hormone (LH), produce androgens that diffuse into the granulosa cells. In mature follicles, follicle stimulating hormone (FSH) acts on granulosa cells to stimulate aromatase activity, which converts the androgens to estrogens. AC, adenylate cyclase; ATP, adenosine triphosphate; cAMP, cyclic adenosine monophosphate; LDL, low-density lipoproteins.

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 percent 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. As discussed in Chapter 79, at least part of this effect is due to stimulation of osteoprotegerin, also called osteoclastogenesis inhibitory factor, a cytokine that inhibits bone resorption.

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, many postmenopausal women are treated prophylactically with estrogen replacement to prevent the osteoporotic effects.

Estrogens Slightly Increase 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 much more powerful than that caused by estrogens.

Estrogens Increase 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.

Estrogens Have Little Effect 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

Progesterone Promotes Secretory Changes in 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.

Progesterone Promotes Development of 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 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 81-8.

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Figure 81-8 Phases of endometrial growth and menstruation during each monthly female sexual cycle.

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 re-epithelialized within 4 to 7 days after the beginning of menstruation.

Then, during the next week and a half, 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.

Secretory Phase (Progestational Phase) of the Endometrial Cycle, Occurring After Ovulation

During most of the latter half of the monthly cycle, after ovulation has occurred, progesterone and estrogen together are secreted in large quantities by the corpus luteum. The estrogens cause slight additional cellular proliferation in the endometrium during this phase of the cycle, whereas progesterone causes marked swelling and secretory development of the endometrium. The glands increase in tortuosity; an excess of secretory substances accumulates in the glandular epithelial cells. Also, the cytoplasm of the stromal cells increases; lipid and glycogen deposits increase greatly in the stromal cells; and the blood supply to the endometrium further increases in proportion to the developing secretory activity, with the blood vessels becoming highly tortuous. At the peak of the secretory phase, about 1 week after ovulation, the endometrium has a thickness of 5 to 6 millimeters.

The whole purpose of all these endometrial changes is to produce a highly secretory endometrium that contains large amounts of stored nutrients to provide appropriate conditions for implantation of a fertilized ovum during the latter half of the monthly cycle. From the time a fertilized ovum enters the uterine cavity from the fallopian tube (which occurs 3 to 4 days after ovulation) until the time the ovum implants (7 to 9 days after ovulation), the uterine secretions, called “uterine milk,” provide nutrition for the early dividing ovum. Then, once the ovum implants in the endometrium, the trophoblastic cells on the surface of the implanting ovum (in the blastocyst stage) begin to digest the endometrium and absorb the endometrial stored substances, thus making great quantities of nutrients available to the early implanting embryo.

Menstruation

If the ovum is not fertilized, about 2 days before the end of the monthly cycle, the corpus luteum in the ovary suddenly involutes and the ovarian hormones (estrogens and progesterone) decrease to low levels of secretion, as shown in Figure 81-3. Menstruation follows.

Menstruation is caused by the reduction of estrogens and progesterone, especially progesterone, at the end of the monthly ovarian cycle. The first effect is decreased stimulation of the endometrial cells by these two hormones, followed rapidly by involution of the endometrium itself to about 65 percent of its previous thickness. Then, during the 24 hours preceding the onset of menstruation, the tortuous blood vessels leading to the mucosal layers of the endometrium become vasospastic, presumably because of some effect of involution, such as release of a vasoconstrictor material—possibly one of the vasoconstrictor types of prostaglandins that are present in abundance at this time.

The vasospasm, the decrease in nutrients to the endometrium, and the loss of hormonal stimulation initiate necrosis in the endometrium, especially of the blood vessels. As a result, blood at first seeps into the vascular layer of the endometrium and the hemorrhagic areas grow rapidly over a period of 24 to 36 hours. Gradually, the necrotic outer layers of the endometrium separate from the uterus at the sites of the hemorrhages until, about 48 hours after the onset of menstruation, all the superficial layers of the endometrium have desquamated. The mass of desquamated tissue and blood in the uterine cavity, plus contractile effects of prostaglandins or other substances in the decaying desquamate, all acting together, initiate uterine contractions that expel the uterine contents.

During normal menstruation, approximately 40 milliliters of blood and an additional 35 milliliters of serous fluid are lost. The menstrual fluid is normally nonclotting because a fibrinolysin is released along with the necrotic endometrial material. If excessive bleeding occurs from the uterine surface, the quantity of fibrinolysin may not be sufficient to prevent clotting. The presence of clots during menstruation is often clinical evidence of uterine pathology.

Within 4 to 7 days after menstruation starts, the loss of blood ceases because, by this time, the endometrium has become re-epithelialized.

Leukorrhea During Menstruation

During menstruation, tremendous numbers of leukocytes are released along with the necrotic material and blood. It is probable that some substance liberated by the endometrial necrosis causes this outflow of leukocytes. As a result of these leukocytes and possibly other factors, the uterus is highly resistant to infection during menstruation, even though the endometrial surfaces are denuded. This is of extreme protective value.

Regulation of the Female Monthly Rhythm—Interplay Between the Ovarian and Hypothalamic-Pituitary Hormones

Now that we have presented the major cyclical changes that occur during the monthly female sexual cycle, we can attempt to explain the basic rhythmical mechanism that causes the cyclical variations.

The Hypothalamus Secretes GnRH, Which Causes the Anterior Pituitary Gland to Secrete LH and FSH

As pointed out in Chapter 74, secretion of most of the anterior pituitary hormones is controlled by “releasing hormones” formed in the hypothalamus and then transported to the anterior pituitary gland by way of the hypothalamic-hypophysial portal system. In the case of the gonadotropins, one releasing hormone, GnRH, is important. This hormone has been purified and has been found to be a decapeptide with the following formula:

image

Intermittent, Pulsatile Secretion of GnRH by the Hypothalamus Stimulates Pulsatile Release of LH from the Anterior Pituitary Gland

The hypothalamus does not secrete GnRH continuously but instead secretes it in pulses lasting 5 to 25 minutes that occur every 1 to 2 hours. The lower curve in Figure 81-9 shows the electrical pulsatile signals in the hypothalamus that cause the hypothalamic pulsatile output of GnRH.

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Figure 81-9 Upper curve: Pulsatile change in luteinizing hormone (LH) in the peripheral circulation of a pentobarbital-anesthetized ovariectomized rhesus monkey. Lower curve: Minute-by-minute recording of multi-unit electrical activity (MUA) in the mediobasal hypothalamus.

(Data from Wilson RC, Kesner JS, Kaufman JM, et al: Central electrophysiologic correlates of pulsatile luteinizing hormone secretion. Neuroendocrinology 39:256, 1984.)

It is intriguing that when GnRH is infused continuously so that it is available all the time rather than in pulses, its ability to cause the release of LH and FSH by the anterior pituitary gland is lost. Therefore, for reasons unknown, the pulsatile nature of GnRH release is essential to its function.

The pulsatile release of GnRH also causes intermittent output of LH secretion about every 90 minutes. This is shown by the upper curve in Figure 81-9.

Hypothalamic Centers for Release of GnRH

The neuronal activity that causes pulsatile release of GnRH occurs primarily in the mediobasal hypothalamus, especially in the arcuate nuclei of this area. Therefore, it is believed that these arcuate nuclei control most female sexual activity, although neurons located in the preoptic area of the anterior hypothalamus also secrete GnRH in moderate amounts. Multiple neuronal centers in the higher brain’s “limbic” system (the system for psychic control) transmit signals into the arcuate nuclei to modify both the intensity of GnRH release and the frequency of the pulses, thus providing a partial explanation of why psychic factors often modify female sexual function.

Negative Feedback Effects of Estrogen and Progesterone to Decrease LH and FSH Secretion

Estrogen in small amounts has a strong effect to inhibit the production of both LH and FSH. Also, when progesterone is available, the inhibitory effect of estrogen is multiplied, even though progesterone by itself has little effect (Figure 81-10).

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Figure 81-10 Feedback regulation of the hypothalamic-pituitary-ovarian axis in females. Stimulatory effects are shown by ⊕ and negative feedback inhibitory effects are shown by -. Estrogens and progestins exert both negative and positive feedback effects on the anterior pituitary and hypothalamus depending on the stage of the ovarian cycle. Inhibin has a negative feedback effect on the anterior pituitary. FSH, follicle-stimulating hormone; GnRH, gonadotropin-releasing hormone; LH, luteinizing hormone.

These feedback effects seem to operate mainly on the anterior pituitary gland directly, but they also operate to a lesser extent on the hypothalamus to decrease secretion of GnRH, especially by altering the frequency of the GnRH pulses.

Inhibin from the Corpus Luteum Inhibits FSH and LH Secretion

In addition to the feedback effects of estrogen and progesterone, other hormones seem to be involved, especially inhibin, which is secreted along with the steroid sex hormones by the granulosa cells of the ovarian corpus luteum in the same way that Sertoli cells secrete inhibin in the male testes (see Figure 81-10). This hormone has the same effect in the female as in the male—inhibiting the secretion of FSH and, to a lesser extent, LH by the anterior pituitary gland. Therefore, it is believed that inhibin might be especially important in causing the decrease in secretion of FSH and LH at the end of the monthly female sexual cycle.

Positive Feedback Effect of Estrogen Before Ovulation—The Preovulatory LH Surge

For reasons not completely understood, the anterior pituitary gland secretes greatly increased amounts of LH for 1 to 2 days beginning 24 to 48 hours before ovulation. This effect is demonstrated in Figure 81-3. The figure shows a much smaller preovulatory surge of FSH as well.

Experiments have shown that infusion of estrogen into a female above a critical rate for 2 to 3 days during the latter part of the first half of the ovarian cycle will cause rapidly accelerating growth of the ovarian follicles, as well as rapidly accelerating secretion of ovarian estrogens. During this period, secretions of both FSH and LH by the anterior pituitary gland are at first slightly suppressed. Then secretion of LH increases abruptly sixfold to eightfold, and secretion of FSH increases about twofold. The greatly increased secretion of LH causes ovulation to occur.

The cause of this abrupt surge in LH secretion is not known. However, several possible explanations are as follows: (1) It has been suggested that estrogen at this point in the cycle has a peculiar positive feedback effect of stimulating pituitary secretion of LH and, to a lesser extent, FSH (see Figure 81-10); this is in sharp contrast to its normal negative feedback effect that occurs during the remainder of the female monthly cycle. (2) The granulosa cells of the follicles begin to secrete small but increasing quantities of progesterone a day or so before the preovulatory LH surge, and it has been suggested that this might be the factor that stimulates the excess LH secretion.

Without this normal preovulatory surge of LH, ovulation will not occur.

Feedback Oscillation of the Hypothalamic-Pituitary-Ovarian System

Now, after discussing much of the known information about the interrelations of the different components of the female hormonal system, we can explain the feedback oscillation that controls the rhythm of the female sexual cycle. It seems to operate in approximately the following sequence of three events.

1. Postovulatory Secretion of the Ovarian Hormones, and Depression of the Pituitary Gonadotropins. The easiest part of the cycle to explain is the events that occur during the postovulatory phase—between ovulation and the beginning of menstruation. During this time, the corpus luteum secretes large quantities of progesterone and estrogen, as well as the hormone inhibin. All these hormones together have a combined negative feedback effect on the anterior pituitary gland and hypothalamus, causing the suppression of both FSH and LH secretion and decreasing them to their lowest levels about 3 to 4 days before the onset of menstruation. These effects are shown in Figure 81-3.

2. Follicular Growth Phase. Two to 3 days before menstruation, the corpus luteum has regressed to almost total involution and the secretion of estrogen, progesterone, and inhibin from the corpus luteum decreases to a low ebb. This releases the hypothalamus and anterior pituitary from the negative feedback effect of these hormones. Therefore, a day or so later, at about the time that menstruation begins, pituitary secretion of FSH begins to increase again, as much as twofold; then, several days after menstruation begins, LH secretion increases slightly as well. These hormones initiate new ovarian follicle growth and a progressive increase in the secretion of estrogen, reaching a peak estrogen secretion at about 12.5 to 13 days after the onset of the new female monthly sexual cycle.

During the first 11 to 12 days of this follicle growth, the rates of pituitary secretion of the gonadotropins FSH and LH decrease slightly because of the negative feedback effect, mainly of estrogen, on the anterior pituitary gland. Then there is a sudden, marked increase in the secretion of LH and, to a lesser extent, FSH. This is the preovulatory surge of LH and FSH, which is followed by ovulation.

3. Preovulatory Surge of LH and FSH Causes Ovulation. About 11½ to 12 days after the onset of the monthly cycle, the decline in secretion of FSH and LH comes to an abrupt halt. It is believed that the high level of estrogens at this time (or the beginning of progesterone secretion by the follicles) causes a positive feedback stimulatory effect on the anterior pituitary, as explained earlier, which leads to a terrific surge in the secretion of LH and, to a lesser extent, FSH. Whatever the cause of this preovulatory LH and FSH surge, the great excess of LH leads to both ovulation and subsequent development of and secretion by the corpus luteum. Thus, the hormonal system begins its new round of secretions until the next ovulation.

Anovulatory Cycles—Sexual Cycles at Puberty

If the preovulatory surge of LH is not of sufficient magnitude, ovulation will not occur and the cycle is said to be “anovulatory.” The phases of the sexual cycle continue, but they are altered in the following ways: First, lack of ovulation causes failure of development of the corpus luteum, so there is almost no secretion of progesterone during the latter portion of the cycle. Second, the cycle is shortened by several days but the rhythm continues. Therefore, it is likely that progesterone is not required for maintenance of the cycle itself, although it can alter its rhythm.

The first few cycles after the onset of puberty are usually anovulatory, as are the cycles occurring several months to years before menopause, presumably because the LH surge is not potent enough at these times to cause ovulation.

Puberty and Menarche

Puberty means the onset of adult sexual life, and menarche means the beginning of the cycle of menstruation. The period of puberty is caused by a gradual increase in gonadotropic hormone secretion by the pituitary, beginning in about the eighth year of life, as shown in Figure 81-11, and usually culminating in the onset of puberty and menstruation between ages 11 and 16 years in girls (average, 13 years).

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Figure 81-11 Total rates of secretion of gonadotropic hormones throughout the sexual lives of female and male human beings, showing an especially abrupt increase in gonadotropic hormones at menopause in the female.

In the female, as in the male, the infantile pituitary gland and ovaries are capable of full function if appropriately stimulated. However, as is also true in the male, and for reasons not understood, the hypothalamus does not secrete significant quantities of GnRH during childhood. Experiments have shown that the hypothalamus is capable of secreting this hormone, but the appropriate signal from some other area of brain to cause the secretion is lacking. Therefore, it is now believed that the onset of puberty is initiated by some maturation process that occurs elsewhere in the brain, perhaps somewhere in the limbic system.

Figure 81-12 shows (1) the increasing levels of estrogen secretion at puberty, (2) the cyclical variation during the monthly sexual cycle, (3) the further increase in estrogen secretion during the first few years of reproductive life, (4) the progressive decrease in estrogen secretion toward the end of reproductive life, and, finally, (5) almost no estrogen or progesterone secretion beyond menopause.

Menopause

At age 40 to 50 years, the sexual cycle usually becomes irregular and ovulation often fails to occur. After a few months to a few years, the cycle ceases altogether, as shown in Figure 81-12. The period during which the cycle ceases and the female sex hormones diminish to almost none is called menopause.

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Figure 81-12 Estrogen secretion throughout the sexual life of the female human being.

The cause of menopause is “burning out” of the ovaries. Throughout a woman’s reproductive life, about 400 of the primordial follicles grow into mature follicles and ovulate, and hundreds of thousands of ova degenerate. At about age 45 years, only a few primordial follicles remain to be stimulated by FSH and LH, and, as shown in Figure 81-12, the production of estrogens by the ovaries decreases as the number of primordial follicles approaches zero. When estrogen production falls below a critical value, the estrogens can no longer inhibit the production of the gonadotropins FSH and LH. Instead, as shown in Figure 81-11, the gonadotropins FSH and LH (mainly FSH) are produced after menopause in large and continuous quantities, but as the remaining primordial follicles become atretic, the production of estrogens by the ovaries falls virtually to zero.

At the time of menopause, a woman must readjust her life from one that has been physiologically stimulated by estrogen and progesterone production to one devoid of these hormones. The loss of estrogens often causes marked physiological changes in the function of the body, including (1) “hot flushes” characterized by extreme flushing of the skin, (2) psychic sensations of dyspnea, (3) irritability, (4) fatigue, (5) anxiety, and (6) decreased strength and calcification of bones throughout the body. These symptoms are of sufficient magnitude in about 15 percent of women to warrant treatment. If counseling fails, daily administration of estrogen in small quantities usually reverses the symptoms, and by gradually decreasing the dose, postmenopausal women can likely avoid severe symptoms.

Abnormalities of Secretion by the Ovaries

Hypogonadism-Reduced Secretion by the Ovaries

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.

Female Sexual Act

Stimulation of the Female Sexual Act

As is true in the male sexual act, successful performance of the female sexual act depends on both psychic stimulation and local sexual stimulation.

Thinking sexual thoughts can lead to female sexual desire, and this aids greatly in the performance of the female sexual act. Such desire is based on psychological and physiological drive, although sexual desire does increase in proportion to the level of sex hormones secreted. Desire also changes during the monthly sexual cycle, reaching a peak near the time of ovulation, probably because of the high levels of estrogen secretion during the preovulatory period.

Local sexual stimulation in women occurs in more or less the same manner as in men because massage and other types of stimulation of the vulva, vagina, and other perineal regions can create sexual sensations. The glans of the clitoris is especially sensitive for initiating sexual sensations.

As in the male, the sexual sensory signals are transmitted to the sacral segments of the spinal cord through the pudendal nerve and sacral plexus. Once these signals have entered the spinal cord, they are transmitted to the cerebrum. Also, local reflexes integrated in the sacral and lumbar spinal cord are at least partly responsible for some of the reactions in the female sexual organs.

Female Erection and Lubrication

Located around the introitus and extending into the clitoris is erectile tissue almost identical to the erectile tissue of the penis. This erectile tissue, like that of the penis, is controlled by the parasympathetic nerves that pass through the nervi erigentes from the sacral plexus to the external genitalia. In the early phases of sexual stimulation, parasympathetic signals dilate the arteries of the erectile tissue, probably resulting from release of acetylcholine, nitric oxide, and vasoactive intestinal polypeptide (VIP) at the nerve endings. This allows rapid accumulation of blood in the erectile tissue so that the introitus tightens around the penis; this aids the male greatly in his attainment of sufficient sexual stimulation for ejaculation to occur.

Parasympathetic signals also pass to the bilateral Bartholin glands located beneath the labia minora and cause them to secrete mucus immediately inside the introitus. This mucus is responsible for much of the lubrication during sexual intercourse, although much is also provided by mucus secreted by the vaginal epithelium and a small amount from the male urethral glands. This lubrication is necessary during intercourse to establish a satisfactory massaging sensation rather than an irritative sensation, which may be provoked by a dry vagina. A massaging sensation constitutes the optimal stimulus for evoking the appropriate reflexes that culminate in both the male and female climaxes.

Female Orgasm

When local sexual stimulation reaches maximum intensity, and especially when the local sensations are supported by appropriate psychic conditioning signals from the cerebrum, reflexes are initiated that cause the female orgasm, also called the female climax. The female orgasm is analogous to emission and ejaculation in the male, and it may help promote fertilization of the ovum. Indeed, the human female is known to be somewhat more fertile when inseminated by normal sexual intercourse rather than by artificial methods, thus indicating an important function of the female orgasm. Possible reasons for this are as follows.

First, during the orgasm, the perineal muscles of the female contract rhythmically, which results from spinal cord reflexes similar to those that cause ejaculation in the male. It is possible that these reflexes increase uterine and fallopian tube motility during the orgasm, thus helping to transport the sperm upward through the uterus toward the ovum; information on this subject is scanty, however. Also, the orgasm seems to cause dilation of the cervical canal for up to 30 minutes, thus allowing easy transport of the sperm.

Second, in many lower animals, copulation causes the posterior pituitary gland to secrete oxytocin; this effect is probably mediated through the brain amygdaloid nuclei and then through the hypothalamus to the pituitary. The oxytocin causes increased rhythmical contractions of the uterus, which have been postulated to cause increased transport of the sperm. A few sperm have been shown to traverse the entire length of the fallopian tube in the cow in about 5 minutes, a rate at least 10 times as fast as that which the swimming motions of the sperm themselves could possibly achieve. Whether this occurs in the human female is unknown.

In addition to the possible effects of the orgasm on fertilization, the intense sexual sensations that develop during the orgasm also pass to the cerebrum and cause intense muscle tension throughout the body. But after culmination of the sexual act, this gives way during the succeeding minutes to a sense of satisfaction characterized by relaxed peacefulness, an effect called resolution.

Female Fertility

Fertile Period of Each Sexual Cycle

The ovum remains viable and capable of being fertilized after it is expelled from the ovary probably no longer than 24 hours. Therefore, sperm must be available soon after ovulation if fertilization is to take place. A few sperm can remain fertile in the female reproductive tract for up to 5 days. Therefore, for fertilization to take place, intercourse must occur sometime between 4 and 5 days before ovulation up to a few hours after ovulation. Thus, the period of female fertility during each month is short, about 4 to 5 days.

Rhythm Method of Contraception

One of the commonly practiced methods of contraception is to avoid intercourse near the time of ovulation. The difficulty with this method of contraception is predicting the exact time of ovulation. Yet the interval from ovulation until the next succeeding onset of menstruation is almost always between 13 and 15 days. Therefore, if the menstrual cycle is regular, with an exact periodicity of 28 days, ovulation usually occurs within 1 day of the 14th day of the cycle. If, in contrast, the periodicity of the cycle is 40 days, ovulation usually occurs within 1 day of the 26th day of the cycle. Finally, if the periodicity of the cycle is 21 days, ovulation usually occurs within 1 day of the seventh day of the cycle. Therefore, it is usually stated that avoidance of intercourse for 4 days before the calculated day of ovulation and 3 days afterward prevents conception. But such a method of contraception can be used only when the periodicity of the menstrual cycle is regular. The failure rate of this method of contraception, resulting in an unintentional pregnancy, may be as high as 20 to 25 percent per year.

Hormonal Suppression of Fertility—”The Pill.”

It has long been known that administration of either estrogen or progesterone, if given in appropriate quantities during the first half of the monthly cycle, can inhibit ovulation. The reason for this is that appropriate administration of either of these hormones can prevent the preovulatory surge of LH secretion by the pituitary gland, which is essential in causing ovulation.

Why the administration of estrogen or progesterone prevents the preovulatory surge of LH secretion is not fully understood. However, experimental work has suggested that immediately before the surge occurs, there is probably a sudden depression of estrogen secretion by the ovarian follicles, and this might be the necessary signal that causes the subsequent feedback effect on the anterior pituitary that leads to the LH surge. The administration of sex hormones (estrogens or progesterone) could prevent the initial ovarian hormonal depression that might be the initiating signal for ovulation.

The challenge in devising methods for the hormonal suppression of ovulation has been in developing appropriate combinations of estrogens and progestins that suppress ovulation but do not cause other, unwanted effects. For instance, too much of either hormone can cause abnormal menstrual bleeding patterns. However, use of certain synthetic progestins in place of progesterone, especially the 19-norsteroids, along with small amounts of estrogens usually prevents ovulation yet allows an almost normal pattern of menstruation. Therefore, almost all “pills” used for the control of fertility consist of some combination of synthetic estrogens and synthetic progestins. The main reason for using synthetic estrogens and progestins is that the natural hormones are almost entirely destroyed by the liver within a short time after they are absorbed from the gastrointestinal tract into the portal circulation. However, many of the synthetic hormones can resist this destructive propensity of the liver, thus allowing oral administration.

Two of the most commonly used synthetic estrogens are ethinyl estradiol and mestranol. Among the most commonly used progestins are norethindrone, norethynodrel, ethynodiol, and norgestrel. The drug is usually begun in the early stages of the monthly cycle and continued beyond the time that ovulation would normally occur. Then the drug is stopped, allowing menstruation to occur and a new cycle to begin.

The failure rate, resulting in an unintentional pregnancy, for hormonal suppression of fertility using various forms of the “pill” is about 8 to 9 percent per year.

Abnormal Conditions That Cause Female Sterility

About 5 to 10 percent of women are infertile. Occasionally, no abnormality can be discovered in the female genital organs, in which case it must be assumed that the infertility is due to either abnormal physiological function of the genital system or abnormal genetic development of the ova themselves.

The most common cause of female sterility is failure to ovulate. This can result from hyposecretion of gonadotropic hormones, in which case the intensity of the hormonal stimuli is simply insufficient to cause ovulation, or it can result from abnormal ovaries that do not allow ovulation. For instance, thick ovarian capsules occasionally exist on the outsides of the ovaries, making ovulation difficult.

Because of the high incidence of anovulation in sterile women, special methods are often used to determine whether ovulation occurs. These methods are based mainly on the effects of progesterone on the body because the normal increase in progesterone secretion usually does not occur during the latter half of anovulatory cycles. In the absence of progestational effects, the cycle can be assumed to be anovulatory.

One of these tests is simply to analyze the urine for a surge in pregnanediol, the end product of progesterone metabolism, during the latter half of the sexual cycle; the lack of this substance indicates failure of ovulation. Another common test is for the woman to chart her body temperature throughout the cycle. Secretion of progesterone during the latter half of the cycle raises the body temperature about 0.5°F, with the temperature rise coming abruptly at the time of ovulation. Such a temperature chart, showing the point of ovulation, is illustrated in Figure 81-13.

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Figure 81-13 Elevation in body temperature shortly after ovulation.

Lack of ovulation caused by hyposecretion of the pituitary gonadotropic hormones can sometimes be treated by appropriately timed administration of human chorionic gonadotropin, a hormone (discussed in Chapter 82) that is extracted from the human placenta. This hormone, although secreted by the placenta, has almost the same effects as LH and is therefore a powerful stimulator of ovulation. However, excess use of this hormone can cause ovulation from many follicles simultaneously; this results in multiple births, an effect that has caused as many as eight babies (stillborn in many cases) to be born to mothers treated for infertility with this hormone.

One of the most common causes of female sterility is endometriosis, a common condition in which endometrial tissue almost identical to that of the normal uterine endometrium grows and even menstruates in the pelvic cavity surrounding the uterus, fallopian tubes, and ovaries. Endometriosis causes fibrosis throughout the pelvis, and this fibrosis sometimes so enshrouds the ovaries that an ovum cannot be released into the abdominal cavity. Often, endometriosis occludes the fallopian tubes, either at the fimbriated ends or elsewhere along their extent.

Another common cause of female infertility is salpingitis, that is, inflammation of the fallopian tubes; this causes fibrosis in the tubes, thereby occluding them. In the past, such inflammation occurred mainly as a result of gonococcal infection. But with modern therapy, this is becoming a less prevalent cause of female infertility.

Still another cause of infertility is secretion of abnormal mucus by the uterine cervix. Ordinarily, at the time of ovulation, the hormonal environment of estrogen causes the secretion of mucus with special characteristics that allow rapid mobility of sperm into the uterus and actually guide the sperm up along mucous “threads.” Abnormalities of the cervix itself, such as low-grade infection or inflammation, or abnormal hormonal stimulation of the cervix, can lead to a viscous mucous plug that prevents fertilization.

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