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. This chapter is concerned with preparation of the female body for pregnancy, and Chapter 83 presents the physiology of pregnancy and childbirth.

Physiologic Anatomy of the Female Sexual Organs

Figures 82-1 and 82-2 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.

Figure 82-1., The female reproductive organs.

Figure 82-2., Internal structures of the uterus, ovary, and a uterine tube.

Oogenesis and Follicular Development in the Ovaries

A developing egg (oocyte) differentiates into a mature egg (ovum) through a series of steps called oogenesis ( Figure 82-3 ). During early embryonic development, primordial germ cells from the dorsal endoderm of the yolk sac migrate along the mesentery of the hindgut to the outer surface of the ovary, which is covered by a germinal epithelium, derived embryologically from the epithelium of the germinal ridges. During this migration, the germ cells divide repeatedly. Once these primordial germ cells reach the germinal epithelium, they migrate into the substance of the ovarian cortex and become oogonia or primordial ova .

Figure 82-3., Oogenesis and follicle development.

Each primordial 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; these epithelioid-like cells are then called granulosa cells . The ovum surrounded by a single layer of granulosa cells is called a primordial follicle . At this stage, the ovum is still immature and is called a primary oocyte , requiring two more cell divisions before it can be fertilized by a sperm.

The oogonia in the embryonic ovary complete mitotic replication, and the first stage of meiosis starts by the fifth month of fetal development. The germ cell mitosis then ceases and no additional oocytes are formed. At birth the ovary contains about 1 to 2 million primary oocytes.

The first stage of meiosis starts during fetal development but is arrested in the late stage of prophase I until puberty, which usually occurs between ages 10 and 14 in females. The first meiotic division of the oocyte is completed after puberty. Each oocyte divides into two cells, a large ovum (secondary oocyte) and a small first polar body . Each of these cells contains 23 duplicated chromosomes. The first polar body may or may not undergo a second meiotic division and then disintegrates. The ovum undergoes a second meiotic division, and after the sister chromatids separate, there is a pause in meiosis. If the ovum is fertilized, the final step in meiosis occurs and the sister chromatids in the ovum go to separate cells.

When the ovary releases the ovum (ovulation), and if the ovum is fertilized, the final meiosis occurs. Half of the sister chromatids remain in the fertilized ovum, and the other half are released in a second polar body, which then disintegrates.

At puberty, only about 300,000 oocytes remain in the ovaries, and only a small percentage of these oocytes become mature. The many thousands of oocytes that do not mature degenerate. During all the reproductive years of adult life, between about 13 and 46 years of age on average, only 400 to 500 of the primordial follicles develop enough to expel their ova, one each month; the remainder degenerate (i.e., become atretic ). At the end of reproductive capability (at menopause ), only a few primordial follicles remain in the ovaries, and even these follicles degenerate soon thereafter.

Female Hormonal System

The female hormonal system, like that of the male hormonal system, consists of three hierarchies of hormones, as follows:

1.
A hypothalamic releasing hormone, called 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 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 82-4 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).

Figure 82-4., 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 males.

Monthly Ovarian Cycle and Function of Gonadotropic Hormones

The normal reproductive years of the female are characterized by monthly rhythmic changes in the rates of secretion of the female hormones and corresponding physical changes in the ovaries and other sexual organs. This rhythmic 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.

The female sexual cycle has two significant results. 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, which are secreted by the anterior pituitary gland. Both FSH and LH are small glycoproteins that have molecular weights of about 30,000. 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 the 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. During each month of the female sexual cycle, there is a cyclical increase and decrease of FSH and LH, as shown in the bottom of Figure 82-4 . 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’ secretion rates 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 formation of protein kinase and multiple phosphorylations of key enzymes that stimulate sex hormone synthesis, as explained in Chapter 75 .

Ovarian Follicle Growth—The Follicular Phase of the Ovarian Cycle

Figure 82-5 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 factor that 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.

Figure 82-5., 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, which increases in diameter 2-fold to 3-fold. That stage is followed by 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 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. The theca 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, which lasts 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 82-5 .

The early growth of the primary follicle up to the antral stage is stimulated mainly by FSH alone. Greatly accelerated growth then occurs, leading to still larger follicles called vesicular follicles. This accelerated growth is caused by the following mechanisms:

1.
Estrogen is secreted into the follicle and causes the granulosa cells to form increasing numbers of FSH receptors, which 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.

Once the antral follicles begin to grow, their growth occurs almost explosively. The ovum also enlarges in diameter another 3-fold to 4-fold, 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, and the remaining 5 to 11 developing follicles involute (a process called atresia ).

The cause of the atresia is unclear, 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, which 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.

A Surge of Luteinizing Hormone 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 ovulation stage.

About 2 days before ovulation, 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 estrogen secretion 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 82-6 provides 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 (i.e., the capsule of the follicle) begins to release proteolytic enzymes from lysosomes. These enzymes 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. At the same time, prostaglandins (local hormones that cause vasodilation) are secreted into the follicular tissues.

Figure 82-6., The postulated mechanism of ovulation.

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—The 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 82-5 . 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 (with 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 corpus luteum normally grows to about 1.5 centimeters in diameter, reaching this stage of development 7 to 8 days after ovulation. Then the corpus luteum 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, the corpus albicans is replaced by connective tissue and over months is absorbed.

Luteinizing Function of Luteinizing Hormone

The change of granulosa and theca interna cells into lutein cells depends 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 factor 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 Luteinizing Hormone

The corpus luteum is a highly secretory organ, secreting large amounts of 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 go through a sequence of (1) proliferation, (2) enlargement, and (3) secretion, followed by (4) degeneration. All this occurs in about 12 days. As discussed in Chapter 83 , 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 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 FSH secretion by the anterior pituitary gland. Low blood concentrations of 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 estrogen, progesterone, and inhibin secretion 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 progesterone and estrogen secretion at this time also leads to menstruation by the uterus, which will be explained later.

Summary

About every 28 days, gonadotropic hormones from the anterior pituitary gland cause 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, estrogen is mainly secreted.

After ovulation, the secretory cells of the ovulating follicle develop into a corpus luteum that secretes large quantities of 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 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 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 development of most secondary sexual characteristics of females. 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 women, estrogens are secreted in significant quantities only by the ovaries, although minute amounts are also secreted by the adrenal cortices. During pregnancy, large quantities of estrogens are also secreted by the placenta, as discussed in Chapter 83 .

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 82-7 . The principal estrogen secreted by the ovaries is β-estradiol. Small amounts of estrone are also secreted, but most of this is formed in 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.

Figure 82-7., Synthesis of the principal female hormones. The chemical structures of the precursor hormones, including progesterone, are shown in Figure 78-2 .

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, 17α-hydroxyprogesterone, are secreted along with progesterone and have essentially the same effects. Yet, for practical purposes, progesterone is usually considered to be the only important progestin.

In nonpregnant females, progesterone is usually secreted in significant amounts only during the latter half of each ovarian cycle, when it is secreted by the corpus luteum.

As discussed in Chapter 83 , 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 82-7 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 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 82-8 ).

Figure 82-8., 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.

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