Estrogens and progestins are hormones that produce myriad physiological actions. In women, these include developmental effects, neuroendocrine actions involved in the control of ovulation, the cyclical preparation of the reproductive tract for fertilization and implantation, and major actions on mineral, carbohydrate, protein, and lipid metabolism. Estrogens also have important actions in males, including effects on bone, spermatogenesis, and behavior. The most common uses of these agents are menopausal hormone therapy and contraception in women, but the specific compounds and dosages used in these 2 settings differ substantially. Anti-estrogens are used in the treatment of hormone-responsive breast cancer and infertility. Selective estrogen receptor modulators (SERMs) that display tissue-selective agonist or antagonist activities are useful to prevent breast cancer and osteoporosis. The main use of antiprogestins has been for medical abortion.
Estrogens interact with 2 receptors of the nuclear receptor superfamily, termed estrogen receptors α (Erα) and β (ERβ). The most potent naturally occurring estrogen in humans, for both ERα- and ERβ-mediated actions, is 17β-estradiol, followed by estrone and estriol. Steroidal estrogens arise from androstenedione or testosterone (Figure 40–1) by a reaction catalyzed by aromatase (CYP19).
The biosynthetic pathway for estrogens.
The ovaries are the principal source of circulating estrogen in premenopausal women, with estradiol the main secretory product. Gonadotropins, acting via receptors that couple to the Gs-adenylyl cyclase–cyclic AMP pathway, increase the activities of aromatase and facilitate the transport of cholesterol (the precursor of all steroids) into the mitochondria of cells that synthesize steroids. In the ovary, type I 17β-hydroxysteroid dehydrogenase favors the production of testosterone and estradiol from androstenedione and estrone, respectively. In the liver, the type II enzyme favors oxidation of circulating estradiol to estrone, and both of these steroids are then converted to estriol (see Figure 40–1). All 3 of 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 secreted by the adrenals. In men, estrogens are produced by the testes, but extragonadal production by aromatization of circulating C19 steroids (e.g., androstenedione and dehydroepiandrosterone) accounts for most circulating estrogens. Local production of estrogens by aromatization of androgens may play a causal or promotional role in the development of certain diseases such as breast cancer. Estrogens also may be produced from androgens via aromatase in the central nervous system (CNS) and other tissues and exert local effects near their production site (e.g., in bone they affect bone mineral density).
Human urine during pregnancy is an abundant source of natural estrogens. Pregnant mare's urine is the source of conjugated equine estrogens, which have been widely used therapeutically for many years.