Many steroidal and nonsteroidal compounds possess estrogenic activity (Table 57—1 and Figure 57—1). The most potent endogenous estrogen is 17fi-estradiol, followed by estrone and estriol. The phenolic A ring is the principal structural feature responsible for selective, high-affinity binding to the estrogen receptors (ERs). Ethinyl substitutions at C17 increase oral potency by inhibiting first-pass hepatic metabolism.
Nonsteroidal compounds with estrogenic or antiestrogenic activity—including flavones, isoflavones (e.g., genistein), and coumestan derivatives—occur in plants and fungi. Synthetic agents—including pesticides (e.g., p,p'-DDT), plasticizers (e.g., bisphenol A), and other industrial chemicals (e.g., polychlorinated biphenyls)—also have hormonal or antihormonal activity. While their affinity is relatively weak, their large number, bioaccumulation, and persistence in the environment raise concerns about their potential toxicity in humans and wildlife.
Steroidal estrogens arise from androstenedione or testosterone (Figure 57—1) by aromatiza-tion of the A ring, a reaction catalyzed by aromatase (CYP19), an enzyme found in ovarian granulosa cells, testicular Sertoli and Leydig cells, adipose stroma, placental syncytiotrophoblast, preimplantation blastocysts, bone, various brain regions, and other tissues. Ovaries are the principal source of circulating estrogen in premenopausal women. Gonadotropins, acting via receptors that couple to the G-adenylyl cyclase—cyclic AMP pathway, increase the activities of aromatase and the cholesterol side-chain cleavage enzyme. The ovary contains the type I isoform of 17fi-hydroxysteroid dehydrogenase, which favors the production of testosterone and estradiol from androstenedione and estrone, respectively. In the liver, the type II isoform oxidizes circulating estradiol to estrone, which then is converted to estriol (Figure 57—1). These estrogens are excreted in the urine along with their glucuronide and sulfate conjugates. In postmenopausal women, the principal source of circulating estrogen is adipose tissue stroma, where estrone is synthesized from dehydroepiandrosterone (DHEA) secreted by the adrenals. In men, the testes produce estrogens but extragonadal aromatization of circulating androstenedione and DHEA accounts for most circulating estrogens.
Local production of estrogens by the aromatization of androgens may play a causal role in the development or progression of diseases such as breast cancer. Estrogens also may be produced from androgens by CYP19 in the central nervous system (CNS) and other tissues and exert local effects near their production site (e.g., in bone they increase bone mineral density).
Physiological and Pharmacological Actions developmental actions Estrogens in girls cause growth and development of the vagina, uterus, and fallopian tubes, and contribute to breast enlargement, molding the body contours, shaping the skeleton, and causing the pubertal growth spurt of the long bones and epiphyseal closure. Growth of axillary and pubic hair, pigmentation of the genital region, and the regional pigmentation of the nipples and areolae that occur after the first trimester of pregnancy are also estro-genic actions.
Estrogens also play developmental roles in males. In boys, estrogen deficiency diminishes the pubertal growth spurt and delays skeletal maturation and epiphyseal closure so that linear growth continues into adulthood. Estrogen deficiency in men leads to elevated gonadotropins, macro-orchidism, and increased testosterone levels and also may affect carbohydrate and lipid metabolism and fertility.
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