Medical Physiology, 3rd Edition

Ovarian Steroids

Starting from cholesterol, the ovary synthesizes estradiol, the major estrogen, and progesterone, the major progestin

Estrogens in female humans are derived from the ovary and the adrenal gland and from peripheral conversion of androgens in adipose tissue. In a nonpregnant woman, estradiol, the primary circulating estrogen, is secreted principally by the ovary. The precursor for the biosynthesis of the ovarian steroids, as it is for all other steroid hormones produced elsewhere in the body, is cholesterol. Cholesterol is a 27-carbon sterol that is both ingested in the diet and synthesized in the liver from acetate (see p. 968). Ovarian cells can synthesize their own cholesterol de novo. Alternatively, cholesterol can enter cells in the form of low-density lipoprotein (LDL) cholesterol and bind to LDL receptors.

As shown in Figure 55-8 , a P-450 enzymeimage N54-4 (see Table 50-2) known as the side-chain-cleavage enzyme (or 20,22-desmolase) catalyzes the conversion of cholesterol to pregnenolone. This reaction is the rate-limiting step in estrogen production. Ovarian cells then convert pregnenolone to progestins and estrogens. The initial steps of estrogen biosynthesis from pregnenolone follow the same steps as synthesis of the two so-called adrenal androgens dehydroepiandrosterone (DHEA) and androstenedione, both of which have 19 carbon atoms. We discuss these steps in connection with both substances (see Figs. 50-2 and 54-6). The Leydig cells in the testis can use either of two pathways to convert these weak androgens to testosterone. Cells in the ovaries are different because, as shown in Figure 55-9 , they have a P-450 aromatase (P-450arom) that can convert androstenedione to estrone and testosterone to estradiol. This aromatization also results in loss of the 19-methyl group (thus, the estrogens have only 18 carbons), as well as conversion of the ketone at position 3 to a hydroxyl in the A ring of the androgen precursor. Once formed, estrone can be converted into the more powerful estrogen estradiol, and vice versa, by 17β-hydroxysteroid dehydrogenase (17β-HSD). Finally, the liver can convert both estradiol and estrone into the weak estrogen estriol.

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FIGURE 55-8 Biosynthesis of the ovarian steroids. This scheme summarizes the synthesis of the progestins and estrogens from cholesterol. The individual enzymes are shown in the horizontal and vertical boxes; they are located in either the smooth endoplasmic reticulum (SER) or the mitochondria. The side-chain-cleavage enzyme that produces pregnenolone is also known as 20,22-desmolase. The chemical groups modified by each enzyme are highlighted in the reaction product. The ovary differs from the testis in having aromatase, which converts androgens to estrogens. Certain of these pathways are shared in the biosynthesis of the glucocorticoids and mineralocorticoids (see Fig. 50-2) as well as androgens (see Fig. 54-6).

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FIGURE 55-9 Two-cell, two-gonadotropin model. During the follicular phase, the major product of the follicle is estradiol, whereas during the luteal phase, the major products of the corpus luteum are the progestins, although estradiol synthesis is still substantial. In the follicular phase, LH primes the theca cell to convert cholesterol to androstenedione. Because the theca cell lacks aromatase, it cannot generate estradiol from this androstenedione. Instead, the androstenedione diffuses to the granulosa cell, whose aromatase activity has been stimulated by FSH. The aromatase converts the androstenedione to estradiol. In the luteal phase, the vascularization of the corpus luteum makes LDL available to the granulosa-lutein cells. Thus, both the theca-lutein and the granulosa-lutein cells can produce progesterone, the major product of the corpus luteum. For production of 17α-hydroxyprogesterone (17α-OH progesterone), some of the progesterone diffuses into the theca-lutein cell, which has the 17α-hydroxylase activity needed for converting the progesterone to 17α-hydroxyprogesterone. The theca-lutein cell can also generate androstenedione, which diffuses into the granulosa-lutein cell for estradiol synthesis. AC, adenylyl cyclase.

The two major progestins, progesterone and 17α-hydroxyprogesterone, are formed even earlier in the biosynthetic pathway than the adrenal androgens. Functionally, progesterone is the more important progestin, and it has higher circulating levels (Box 55-3 ).

Box 55-3

The Birth Control Pill

Hormonal contraception is the most commonly used method of contraception in the United States; ~30% of sexually active women take the oral contraceptive pill (OCP).

Types of Oral Contraceptives

Numerous combination (i.e., estrogen and progestin) oral contraceptives and progestin-only pills are available. The estrogens and progestins used in OCPs have varying potencies. In the United States, two estrogen compounds are approved for oral contraceptive use: ethinyl estradiol and mestranol. The progestins used in OCPs are modified steroids in which the methyl at position 19 (see Fig. 55-8) is removed; these progestins include norethindrone, norgestrel, norethynodrel, norethindrone acetate, and ethynodiol diacetate. A new generation of progestins—including gestodene and norgestimate—have reduced androgenic effects.

The woman takes the OCPs daily for 21 days out of the 28-day cycle; she takes no pill, a placebo, or an iron pill during days 22 to 28. No medication is usually given during this fourth week to allow withdrawal bleeding to occur. Three regimens of contraceptive steroid administration are used:

1. Monophasic or fixed-combination OCPs. The pills taken for the first 21 days of the cycle are identical.

2. Multiphasic or varying-dose OCPs. The pills contain two or three different amounts of the same estrogen and progestin, the dosages of which vary at specific intervals during the 21-day medication period. Multiphasic OCPs generally maintain a low dose of estrogen throughout the cycle, combined with varying amounts of progestin. The rationale for this type of formulation is that the woman takes a lower total dose of steroid but is not at increased risk of breakthrough endometrial bleeding.

3. Progestin-only OCPs (“minipill”). These estrogen-free pills are taken daily for 3 weeks of a 4-week cycle. This regimen may be associated with irregular, low-grade breakthrough endometrial bleeding. The progestin-only OCP is a good option for nursing mothers as well as women for whom estrogens are contraindicated (e.g., those with thromboembolic disease, a history of cerebrovascular incidents, or hypertension).

Biological Action of Oral Contraceptives

The contraceptive effectiveness of OCPs accrues from several actions. Like natural ovarian steroids, contraceptive steroids feed back both directly at the level of the hypothalamus (decreasing secretion of GnRH) and at the level of the gonadotrophs in the anterior pituitary (see Fig. 55-3). The net effect is suppressed secretion of the gonadotropins FSH and LH. The low FSH levels are insufficient to stimulate normal folliculogenesis; the low LH levels obviate the LH surge and therefore inhibit ovulation. However, in the commonly used doses, contraceptive steroids do not completely abolish either gonadotropin secretion or ovarian function.

The progestin component of the OCP causes the cervical mucus to thicken and become viscid and scant. These actions inhibit sperm penetration into the uterus. The progestins also impair the motility of the uterus and oviducts and therefore decrease transport of both ova and sperm to the normal site of fertilization in the distal fallopian tube (see p. 1129). Progestins also produce changes in the endometrium that are not conducive for implantation of the embryo. These changes include decreased glandular production of glycogen and thus diminished energy for the blastocyst to survive in the uterus.

Progestin-only OCPs do not effectively inhibit ovulation, as do the combination pills. However, they do produce other actions, as noted above: mucus thickening, reduced motility, and impaired implantation. Because they are inconsistent inhibitors of ovulation, the progestin-only OCPs have a substantially higher failure rate than does the combined type of OCPs.

Side effects of the compounds in OCPs are those associated with estrogens and progestins and include nausea, edema, headaches, and weight gain. Specific side effects of progestins include depression, mastodynia, acne, and hirsutism. Many of the side effects associated with the progestin component of the pill, particularly acne and hirsutism, are the result of the androgenic actions of the progestins used. The potential benefits of the newer progestins include decreased androgenic effects, such as increased sex hormone–binding globulin, improved glucose tolerance (see p. 1038), and increased high-density and decreased low-density lipoprotein cholesterol (see Table 46-4). The clinical impact of these changes remains to be determined. Table 55-1 lists the major benefits and risks of OCPs.

TABLE 55-1

Benefits and Risks of Oral Contraceptives

Oral Contraceptives Decrease the Risk of

Ovarian cancer

Endometrial cancer

Ovarian retention cysts

Ectopic pregnancy

Pelvic inflammatory disease

Benign breast disease

Oral Contraceptives Increase the Risk of

Benign liver tumors

Cholelithiasis (gallstones)

Hypertension

Heart attack

Stroke

Deep vein thrombosis

Pulmonary embolus

Estrogen biosynthesis requires two ovarian cells and two gonadotropins, whereas progestin synthesis requires only a single cell

A unique aspect of estradiol synthesis in the ovary is that it requires the contribution of two distinct cell types: the theca and granulosa cells within the follicle and the theca-lutein and granulosa-lutein cells within the corpus luteum (see Fig. 55-9).

The superficial theca cells and theca-lutein cells can take up cholesterol and produce DHEA and androstenedione (see Fig. 55-8), but they do not have the aromatase necessary for estrogen production. The deeper granulosa cells and granulosa-lutein cells have the aromatase, but they lack the 17α-hydroxylase and 17,20-desmolase (which are the same protein) necessary for making DHEA and androstenedione. Another difference between the two cell types is that, in the follicle, the superficial theca cell is near blood vessels, which supply LDL cholesterol. The granulosa cell, conversely, is far from blood vessels and, instead, is surrounded by LDL-deficient follicular fluid. Thus, in the follicular stage, the granulosa cells obtain most of their cholesterol by de novo synthesis. However, after formation of the corpus luteum, the accompanying vascularization makes it possible for the granulosa-lutein cell to take up LDL cholesterol from the blood and to thus synthesize large amounts of progesterone. A final difference between the two cell types is that theca cells have LH receptors, whereas granulosa cells have both LH and FSH receptors.

Because of their unique physiological properties, neither the theca/theca-lutein cells nor the granulosa/granulosa-lutein cells can make estrogens by themselves. According to the two-cell, two-gonadotropin hypothesis, estrogen synthesis occurs in the following steps:

Step 1: LH stimulates the theca cell, through the adenylyl cyclase pathway, to increase its synthesis of LDL receptors and the side-chain-cleavage enzyme.

Step 2: Thus stimulated, the theca cell increases its synthesis of androstenedione.

Step 3: The androstenedione synthesized in the theca cells freely diffuses to the granulosa cells.

Step 4: FSH, also acting through the adenylyl cyclase pathway, stimulates the granulosa cell to produce aromatase.

Step 5: The aromatase converts androstenedione to estrone (see Fig. 55-8). 17β-HSD then converts the estrone to estradiol. Alternatively, 17β-HSD can first convert the same androstenedione to testosterone, and then the aromatase can convert this product to estradiol. By these pathways, theca-derived androgens are converted to estrogens in the granulosa cell.

Step 6: The estradiol diffuses into the blood vessels.

At low concentrations, the weak androgens produced by the theca cells are substrates for estrogen synthesis by the granulosa cells, in addition to enhancing the aromatase activity of granulosa cells. However, at high concentrations, conversion of androgens to estrogens is diminished. Instead, the weak androgens are preferentially converted by 5α-reductase (see Fig. 54-6) to more potent androgens, such as dihydrotestosterone, a substance that cannot be converted to estrogen. Furthermore, these 5α-reduced androgens inhibit aromatase activity. Thus, the net effect of a high-androgen environment in the follicle is to decrease estrogen production. These androgens also inhibit LH receptor formation on follicular cells.

In the luteal phase of the cycle, luteinization of the follicle substantially changes the biochemistry of the theca and granulosa cells. As part of the formation of the corpus luteum, blood vessels invade deep toward the granulosa-lutein cells. Recall that in the follicle, the granulosa cells had been surrounded by follicular fluid, which is poor in LDL cholesterol. The increased vascularity facilitates the delivery of LDL cholesterol to the granulosa-lutein cells. In addition, LH stimulates the granulosa-lutein cells to take up and process cholesterol—as it does the theca cells. The net effect is the increased progesterone biosynthesis that is characteristic of the midluteal phase. Indeed, the major products of the corpus luteum are progesterone and 17α-hydroxyprogesterone, although the corpus luteum also produces estradiol. As indicated in Figure 55-9, the granulosa-lutein cells cannot make either 17α-hydroxyprogesterone or estradiol directly because these cells lack the protein that has dual activity for 17α-hydroxylase and 17,20-desmolase (see Fig. 55-8). Thus, 17α-hydroxyprogesterone synthesis necessitates that progesterone first moves to the theca-lutein cell (see Fig. 55-9), which can convert progesterone to 17α-hydroxyprogesterone, as well as androstenedione. Furthermore, estradiol synthesis necessitates that androstenedione from the theca-lutein cell move to the granulosa-lutein cell for aromatization and formation of estradiol.

Estrogens stimulate cellular proliferation and growth of sex organs and other tissues related to reproduction

Most estrogens in blood plasma are bound to carrier proteins, as are testosterone and other steroid hormones. In the case of estradiol, 60% is bound to albumin and 38% to sex hormone–binding globulin (SHBG; see p. 1099)—also known as testosterone-binding globulin (TeBG). TeBG is doubly a misnomer because this protein binds estradiol and, moreover, its levels are twice as high in women as in men. At least one reason for the higher levels in women is that estrogens (including birth control pills) stimulate the synthesis of SHBG. Only 2% of total plasma estradiol circulates as the free hormone, which readily crosses cell membranes. The nuclear estrogen receptors ERα and ERβ function as dimers (αα, αβ, or ββ; see Table 3-6). When bound to estrogen, the ER dimer interacts with steroid response elements on chromatin and induces the transcription of specific genes. Over the next several hours, DNA synthesis increases, and the mitogenic action of estrogens becomes apparent. Estrogens almost exclusively affect particular target sex organs—including uterus and breasts—that have ERs.

In addition to acting through nuclear receptors, estrogens can also exert nongenomic actions (see p. 989) by binding to the G protein–coupled receptor GPR30.

The progestins, particularly progesterone, stimulate glandular secretion in reproductive tissue and promote the maturation of certain estrogen-stimulated tissue. One of the most prominent actions of progesterone, which binds to the dimeric progesterone receptor (PR; see Table 3-6), is the induction of secretory changes in the endometrium. In part because estrogens induce PR expression in endometrial cells, estrogens must condition the endometrium for progesterone to act effectively, as during the luteal phase. During the latter half of the menstrual cycle, progesterone induces final maturation of the uterine endometrium for reception and implantation of the fertilized ovum.

LESION

REFLEXOGENIC ERECTION

PSYCHOGENIC ERECTION

EFFECT ON EJACULATION

Upper motor neuron

Present

Absent

Significantly impaired

Lower motor neuron

Absent

Present

Less impaired