contraceptive strategies. The notion that competition with the active hormone for its receptor by an inert or less active compound was anticipated by Segal and Thompson (1956) some 40 years ago when they demonstrated that the weak estrogen estriol inhibited the stimulatory action of estradiol-17ß on the uterus of ovariectomized rats. The subsequent demonstration of the existence of estrogen receptors by Jensen and Jacobson (1962) in the late 1950s and the subsequent elucidation of the mechanisms of estrogen action led to the development of antiestrogenic compounds that block the effects of estradiol to varying degrees. Most of these, however, were not ''pure" antiestrogens in that they possessed estrogenic properties as well. One such compound is currently used to stimulate ovulation in women, and there is still some debate about whether it acts as an estrogen or as an antiestrogen in this context.

The discovery that in the absence of progesterone, pregnancy cannot be initiated or maintained provided the basis for a massive effort designed to interfere with the normal functioning of the corpus luteum, the source of progesterone, during the luteal phase of the menstrual cycle and during early pregnancy. Because in sheep and a number of other mammals the normal regression of the corpus luteum is caused by uterine prostaglandin production, a variety of these compounds were used without success in attempts to induce luteolysis in primates. The physiological demise of the corpus luteum in humans is occasioned by quite different mechanisms that remain to be fully elucidated.

This experience underlines the belated recognition that seemingly fundamental reproductive processes in different mammalian species such as ovulation, the recognition and maintenance of pregnancy, and the initiation of labor, are governed by a variety of different control systems and that findings in one species cannot be extrapolated to others and particularly cannot be extrapolated to humans without rigorous verification.

Finding an Antiprogestin

Although attempts to interfere with the production of progesterone in humans have been without success, the recognition that progesterone, like all other steroids, binds to specific receptors as the first step in its action provided a more precise target for blocking the action of progesterone and thus preventing pregnancy. Some compounds that bind to receptors stimulate activity (agonists); other compounds bind to the receptor and inhibit the action of the hormone (antagonists). Compounds that are antagonists of progesterone—antiprogestins—formed the central theme of the Institute of Medicine (IOM) project presented in this report. Although most of the data reviewed by the committee were



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