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INTRODUCTION

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Estrogens and progestins are endogenous hormones that produce numerous 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 biosynthesis, biotransformation, and disposition of estrogens and progestins are well established. Two well-characterized receptors are present for each hormone, and there is evidence that the receptors mediate biological actions in both the unliganded and steroid hormone-liganded states.

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The therapeutic use of estrogens and progestins largely reflects extensions of their physiological activities. The most common uses of these agents are menopausal hormone therapy and contraception in women, but the specific compounds and dosages used in these two settings differ substantially. Estrogen- and progesterone-receptor antagonists also are available. The main uses of anti-estrogens are 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 anti-progestins has been for medical abortion, but other uses are theoretically possible.

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A number of naturally occurring and synthetic environmental chemicals mimic, antagonize, or otherwise affect the actions of estrogens in experimental test systems. The precise effect of these agents on humans is unknown, but this is an area of active investigation. Cancer chemotherapeutic strategies based on blockade of estrogen- and/or progesterone-receptor functions are considered in further detail in Chapter 63. Complementary therapeutic strategies based on suppression of gonadotropin secretion by long-acting gonadotropin-releasing hormone agonists are also discussed in Chapter 63.

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History. The hormonal nature of the ovarian control of the female reproductive system was firmly established in 1900 by Knauer when he found that ovarian transplants prevented the symptoms of gonadectomy, and by Halban, who showed that normal sexual development and function occurred when glands were transplanted. In 1923, Allen and Doisy devised a bioassay for ovarian extracts based on the vaginal smear of the rat. Frank and associates in 1925 detected an active sex principle in the blood of sows in estrus, and Loewe and Lange discovered in 1926 that a female sex hormone varied in the urine of women throughout the menstrual cycle. The excretion of estrogen in the urine during pregnancy also was reported by Zondek in 1928 and enabled Butenandt and Doisy in 1929 to crystallize an active substance.

Early investigations indicated that the ovary secretes two substances. Beard had postulated in 1897 that the corpus luteum serves a necessary function during pregnancy, and Fraenkel showed in 1903 that destruction of the corpora lutea in pregnant rabbits caused abortion. Several groups then isolated progesterone from mammalian corpora lutea in the 1930s.

In the early 1960s, pioneering studies by Jensen and colleagues suggested the presence of intracellular receptors for estrogens in target tissues. This ...

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