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Chapter: Medical Physiology: Female Physiology Before Pregnancy and Female Hormones

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Functions of the Ovarian Hormones-Estradiol and Progesterone

The two types of ovarian sex hormones are the estro-gens and the progestins.

Functions of the Ovarian Hormones-Estradiol and Progesterone

The two types of ovarian sex hormones are the estro-gens and the progestins. By far the most important ofthe estrogens is the hormone estradiol, and by far the most important progestin is progesterone. The estro-gens mainly promote proliferation and growth of spe-cific 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 normalnonpregnantfemale, estro-gens 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.

Only three estrogens are present in significant quan-tities in the plasma of the human female: b-estradiol,estrone, and estriol, the formulas for which are shownin Figure 81–6. The principal estrogen secreted by the ovaries is b-estradiol. Small amounts of estrone are also secreted, but most of this is formed in the peripheral tissues from androgens secreted by the adrenal cortices and by ovarian thecal cells. Estriol is a weak estrogen; it is an oxidative product derived from both estradiol and estrone, with the conversion occurring mainly in the liver.

The estrogenic potency of b-estradiol is 12 times that of estrone and 80 times that of estriol. Consider-ing these relative potencies, one can see that the total estrogenic effect of b-estradiol is usually many times that of the other two together. For this reason, b-estradiol is considered the major estrogen, although the estrogenic effects of estrone are not negligible.

Progestins. By far the most important of the progestinsis progesterone. However, small amounts of another progestin, 17-a-hydroxyprogesterone, are secreted along with progesterone and have essentially the same effects. Yet, for practical purposes, it is usually reason-able 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, 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 thechemical formulas of the estrogens and progesterone in Figure 81–6 that they are all steroids. They are synthesized in the ovaries mainly from cholesterol derived from the blood but also to a slight extent from acetyl coenzyme A, multiple molecules of which can combine to form the appropriate steroid nucleus.

During synthesis, mainly progesterone and the male sex hormone testosterone are synthesized first; then, during the follicular phase of the ovarian cycle, before these two initial hormones can leave the ovaries, almost all the testosterone and much of the proges-terone are converted into estrogens by the granulosa cells. During the luteal phase of the cycle, far too much progesterone is formed for all of it to be converted, which accounts for the large secretion of progesterone into the circulating blood at this time. Also, about one fifteenth as much testosterone is secreted into the plasma of the female by the ovaries as is secreted into the plasma of the male by the testes.

Estrogens and Progesterone Are Transported in the Blood Bound to Plasma Proteins. Both estrogens and progesteroneare transported in the blood bound mainly with plasma albumin and with specific estrogen- and prog-esterone-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 liverconjugates the estrogens to form glucuronides and sul-fates, 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, dimin-ished liver function actually increases the activity of estrogens in the body, sometimes causing hyperestrinism.

Fate of Progesterone. Within a few minutes after secre-tion, almost all the progesterone is degraded to other steroids that have no progestational effect. As with the estrogens, the liver is especially important for this metabolic degradation.

The major end product of progesterone degradation is pregnanediol. About 10 per cent of the original prog-esterone is excreted in the urine in this form. There-fore, 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 cellu-lar 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 onlyin 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, fal-lopian 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 consid-erably more resistant to trauma and infection than is the prepubertal cuboidal cell epithelium. Vaginal infections in children can often be cured by the admin-istration 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 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 causethe 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 breastsof 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 inhibitosteoclastic activity in the bones and therefore stimu-late bone growth. At puberty, when the female enters her reproductive years, her growth in height becomes rapid for several years. However, estrogens have another potent effect on skeletal growth: They cause uniting of the epiphyses with the shafts of the long bones. This effect of estrogen in the female is much stronger than the similar effect of testosterone in the male. As a result, growth of the female usually ceases several years earlier than growth of the male. A female eunuch who is devoid of estrogen production usually grows several inches taller than a normal mature female because her epiphyses do not unite at the normal time.

OsteoporosisoftheBonesCausedbyEstrogen Deficiency in Old Age. After menopause, almost noestrogens 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. Because this can greatly weaken the bones and lead to bone fracture, especially fracture of the vertebrae, a large share of postmenopausal women are treated prophylactically with estrogen replacement to prevent the osteoporotic effects.

Effect of Estrogens on Protein Deposition. Estrogens causea slight increase in total body protein, which is evi-denced 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 testos-terone is much more general and many times as pow-erful as that caused by estrogens.

Effect of Estrogens on Body Metabolism and Fat Deposition.

Estrogens increase the whole-body metabolic rate slightly, but only about one third as much as the increase caused by the male sex hormone testosterone. They also cause deposition of increased quantities of fat in the subcutaneous tissues. As a result, the per-centage of body fat in the female body is considerably greater than that in the male body, which contains more protein. In addition to deposition of fat in the breasts and subcutaneous tissues, estrogens cause the deposition of fat in the buttocks and thighs, which is characteristic of the feminine figure.

Effect of Estrogens on Hair Distribution. Estrogens do notgreatly 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 skinto 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 associ-ated with increased warmth of the skin and also pro-motes greater bleeding of cut surfaces than is observed in men.

Effect of Estrogens on Electrolyte Balance. The chemicalsimilarity of estrogenic hormones to adrenocortical hormones has been pointed out. Estrogens, like aldos-terone and some other adrenocortical hormones, cause sodium and water retention by the kidney tubules.This effect of estrogens is normally slight and rarely of sig-nificance, but during pregnancy, the tremendous for-mation of estrogens by the placenta may contribute to body fluid retention.

Functions of Progesterone

Effect of Progesterone on the Uterus. By far the mostimportant function of progesterone is to promotesecretory changes in the uterine endometriumduringthe 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. Progesteronealso promotes increased secretion by the mucosal lining of the fallopian tubes. These secretions are necessary for nutrition of the fertilized, dividing ovum as it traverses the fallopian tube before implantation.

Effect of Progesterone on the Breasts. Progesteronepromotes 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; milk is secreted only after the prepared breast is further stimulated by pro-lactin from the anterior pituitary gland.

Progesterone also causes the breasts to swell. Part of this swelling is due to the secretory development in the lobules and alveoli, but part also results from increased fluid in the subcutaneous tissue.

Monthly Endometrial Cycle and Menstruation

Associated with the monthly cyclical production of estrogens and progesterone by the ovaries is an endometrial cycle in the lining of the uterus that oper-ates through the following stages: (1) proliferation of the uterine endometrium; (2) development of secre-tory changes in the endometrium; and (3) desqua-mation of the endometrium, which is known as menstruation. The various phases of this endometrialcycle are shown in Figure 81–7.

Proliferative Phase (Estrogen Phase) of the Endometrial Cycle, Occurring Before Ovulation. At the beginning of eachmonthly 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 ofestrogens, secreted in increasing quantities by theovary 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—that is, before ovulation occurs—the endometrium increases greatly in thickness, owing to increasing numbers of stromal cells and to progressive growth of the endome-trial glands and new blood vessels into the endo-metrium. At the time of ovulation, the endometrium is 3 to 5 millimeters thick.

The endometrial glands, especially those of the cer-vical 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 latterhalf 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 accu-mulates in the glandular epithelial cells. Also, the cyto-plasm 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 con-tains 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 daysbefore 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 estro-gens 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 per cent 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 vasoconstric-tor 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 hemor-rhagic 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 clot-ting.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 menstrua-tion, tremendous numbers of leukocytes are released along with the necrotic material and blood. It is prob-able 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 men-struation, even though the endometrial surfaces are denuded. This is of extreme protective value.

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