Metabolism Of Estrogens

The metabolism of natural estrogens has been reviewed in detail.37 The three primary estrogens in women are 17^-estradiol, estrone, and estriol (16a,17j6-estriol). Although 17^-estradiol is produced in the greatest amounts, it is quickly oxidized (see Fig. 25.12) to estrone, the estrogen found in highest concentration in the plasma. Estrone, in turn, is converted to estriol, the major estrogen found in human urine, by hydroxylation at C16 (to provide the 16a-hydroxyl) and reduction of the C17 ketone (17^-hydroxyl). Estradiol can also be directly converted to estriol. In the human placenta, the most abundant estrogen synthesized is estriol. In both pregnant and nonpregnant women, however, the three primary estrogens are also metabolized to small amounts of other derivatives (e.g., 2-hydroxyestrone, 2-methoxyestrone, 4-hydroxyestrone, and 16j6-hydroxy-17j6-estradiol). Only about 50% of therapeutically administered estrogens (and their various metabolites) are excreted in the urine during the first 24 hours. The remainder are excreted into the bile and reabsorbed; consequently, several days are required for complete excretion of a given dose.

Conjugation appears to be very important in estrogen transport and metabolism. Although the estrogens are unconjugated in the ovaries, significant amounts of conju

Ethinyl Estradiol Metabolism

Sodium Glucuronide of Estriol 2-Methoxyestrone

Figure 25.12 • Metabolites of 17ß-estradiol and estrone.

gated estrogens may predominate in the plasma and other tissues. Most of the conjugation takes place in the liver. The primary estrogen conjugates found in plasma and urine are glucuronides and sulfates. As sodium salts, they are quite water soluble. The sodium glucuronide of estriol and the sodium sulfate ester of estrone are shown in Figure 25.12.

BIOLOGICAL ACTIVITIES OF ESTROGENS12

In addition to having important roles in the menstrual cycle (described previously), the estrogens and, to a lesser extent, progesterone are largely responsible for the development of secondary sex characteristics in women at puberty. The estrogens cause a proliferation of the breast ductile system, and progesterone stimulates development of the alveolar system. The estrogens also stimulate the development of lipid and other tissues that contribute to breast shape and function. Pituitary hormones and other hormones are also involved. Fluid retention in the breasts during the later stages of the menstrual cycle is a common effect of the estrogens.

The estrogens directly stimulate the growth and development of the vagina, uterus, and fallopian tubes and, in combination with other hormones, play a primary role in sexual arousal and in producing the body contours of the mature woman. Pigmentation of the nipples and genital tissues and growth stimulation of pubic and underarm hair (possibly with the help of small amounts of testosterone) are other results of estrogen action.

The physiological changes at menopause emphasize the important roles of estrogens in a young woman. Breast and reproductive tissues atrophy, the skin loses some of its suppleness, coronary atherosclerosis and gout become potential health problems for the first time, and the bones begin to lose density because of decreased mineral content.

STRUCTURAL CLASSES: ESTROGENS

As shown in Figure 25.13, there are three structural classes of estrogens: steroidal estrogens, diethylstilbestrol and other synthetic compounds, and phytoestrogens (Each class is summarized in the sections that follow). The steroidal estrogens include the naturally occurring estrogens found in humans and other mammals, as well as semisynthetic derivatives of these compounds. Because of rapid metabolism, estradiol itself has poor oral bioavailability. The addition of a 17a-alkyl group to the estradiol structure blocks oxidation to estrone. Ethinyl estradiol is therefore very effective orally, whereas estradiol itself is not. Most of the therapeutically useful steroidal estrogens are produced semisynthetically from natural precursors such as diosgenin, a plant sterol.

Steroidal Estrogens—Conjugated Estrogens, Esterified Estrogens. Conjugated estrogens (sometimes called equine estrogens) are estradiol-related metabolites originally obtained from the urine of horses, especially pregnant mares. Premarin, the major conjugated estrogen product on the market, is a mixture of numerous components that is obtained from mare urine. Equine estrogens are largely mixtures of estrone sodium sulfate and equilin sodium sulfate. Little or no equilin and equilenin are produced in humans. The sulfate groups must be removed metabolically to release the active estrogens. Conjugated estrogens that derive exclusively from plant precursors are also on the market. Esterified estrogens are also mainly a combination of estrone sodium sulfate and equilin sodium sulfate, but in a different ratio to that in conjugated estrogens. The esterified estrogens are now prepared exclusively from plant sterols.

Diethylstilbestrol. At first glance, it might be surprising that synthetic nonsteroidal molecules such as diethylstilbes-trol (DES) could have the same activity as estradiol or other estrogens. DES can be viewed, however, as a form of estradiol with rings B and C open and a six-carbon ring D. The activity of DES analogs was explained in 1946.38 It was proposed that the distance between the two DES phenol OH groups was the same as the 3-OH to 17-OH distance of estradiol; therefore, they could both fit the same receptor. Medicinal chemists have shown the OH-to-OH distance to be actually 12.1 A in DES and 10.9 A in estradiol. In aqueous solution, however, estradiol has two water molecules that are hydrogen bonded to the 17-OH. If one of the two water mol ecules is included in the distance measurement, there is a perfect fit with the two OH groups of DES (Fig. 25.14). This suggests that water may have an important role for estradiol in its receptor site. It is now generally accepted that the estrogens must have a phenolic moiety for binding, but some investigators propose that the receptor may be flexible enough to accommodate varying distances between the two key hydrox-yls. This point about estrogens needing a phenolic ring for high-affinity binding to the ER is critical. Steroids with a phenolic A ring and related phenolic compounds lack high-affinity binding to the other steroid hormone receptors. Although DES was used for many years, it was discovered that the daughters of women who had taken DES during pregnancy (DES babies) had a high risk of vaginal, cervical, and uterine abnormalities, along with a low risk of vaginal clear cell ade-nocarcinoma.39 Because of the safety concerns associated with DES, it was completely removed from the U.S. market in the late 1990s. DES is still available as an estrogen for use in veterinary medicine, however.

Thinning Vaginal Wall Elderly
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