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Clinical Applications of Mifepristone (RU 486) and other Antiprogestins: Assessing the Science and Recommending a Research Agenda 1 Introduction BACKGROUND AND HISTORICAL PERSPECTIVES The human ovarian cycle is controlled by the gonadotropic hormones (the luteinizing hormone—LH—and the follicle-stimulating hormone—FSH) secreted by the pituitary gland, which are, in turn, under the control of a neuropeptide (gonadotropin-releasing hormone, GnRH) produced by the brain. The gonadotropic hormones direct follicular development, ovulation, the formation of the corpus luteum, and the secretion of estrogen and progesterone (the female sex hormones). These ovarian steroid hormones, in turn, inhibit the production of the gonadotropic hormones (negative feedback). If estrogen and progesterone are given in sufficient quantities they can completely block gonadotropin secretion, thereby arresting gonadal function. Historically, this observation is the physiological basis for the development of oral contraceptives that contain varying proportions of analogues of these ovarian steroids. Although it is now known that the estrogenic and progestational constituents of oral contraceptives may control fertility in many ways other than the inhibition of follicular development and ovulation, the fact remains that many details of their molecular actions are not yet clear. The desirability of finding precisely defined targets for the interruption of the reproductive process, with unambiguously understood consequences, has remained an elusive goal that continues to occupy the attention of many in the scientific and medical communities, and to a certain extent in the pharmaceutical industry (IOM, 1990). The discovery that hormones bind to specific receptors before acting on their target cells provided new opportunities for circumscribed
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Clinical Applications of Mifepristone (RU 486) and other Antiprogestins: Assessing the Science and Recommending a Research Agenda 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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Clinical Applications of Mifepristone (RU 486) and other Antiprogestins: Assessing the Science and Recommending a Research Agenda TABLE 1.1 Selected Antiprogestins: Name and in Vivo Testing Generic Name Company Company Code Name In Vivo Data Available Mifepristone Roussel-Uclaf RU 486 Human, monkey, sheep, rabbit, dog, rat, mouse Onapristone Schering AG ZK 98 299 Human, monkey, guinea pig, rabbit, rat, mouse Lilopristone Schering AG ZK 98 734 Human, monkey, guinea pig, rabbit, rat, mouse None Schering AG ZK 112 993 Monkey, guinea pig, rabbit, rat, mouse None Organon ORG 31710, 31806 Monkey, rabbit, rat None Research Triangle Institute HRP 2000 Rabbit related to one particular antiprogestin, mifepristone (RU 486, manufactured by Roussel-Uclaf, a French pharmaceutical company), there is published information on other antiprogestins as well. More than 400 compounds with possible antiprogestin activity have been synthesized. The main antiprogestins that have been studied to date, however, are listed in Table 1.1. None of the antiprogestins are "pure" antiprogestins, having marked antiglucocorticoid properties as well, especially at higher doses. In addition, mifepristone and onapristone, and perhaps other antiprogestins, have as yet poorly understood antiestrogenic activity and, in some circumstances, progesterone-like actions. Mifepristone also appears to antagonize gonadotropin secretion directly at the level of the pituitary gland, an effect that, curiously, is reversed by the addition of progesterone. Furthermore, mifepristone has been reported to block ovulation and progesterone production directly at the ovarian level. While these non-antiprogestational actions of mifepristone may not have particular relevance to its current application as an abortifacient or post-coital contraceptive, they do emphasize the hazard of using mifepristone, or other antiprogestins with mixed activity, as probes in attempts to study the mode and mechanisms of action of progesterone. Less studied than mifepristone are other antiprogestational compounds, produced primarily by Schering AG and Organon. Some of these are claimed to have greatly diminished antiglucocorticoid activity relative to mifepristone and to differ from mifepristone in not blocking ovulation in monkeys, while preventing pregnancy (Baulieu, Appendix B1; Van Look and von Hertzen, Appendix B12). It is not clear at present how extensively, if at all, these compounds will be subjected to clinical trials. For the future, a large number of new antiprogestins are known to be under development by Roussel-Uclaf, Schering, Organon, Research
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Clinical Applications of Mifepristone (RU 486) and other Antiprogestins: Assessing the Science and Recommending a Research Agenda Triangle Institute, and others, and these efforts may yield compounds with greater specificities as antiprogestins, with the goal of eventually obtaining a "pure" antiprogestin. The mechanisms of action and the structure/function relationships of antiprogestational and antiglucocorticoid compounds are discussed at length in papers included in Appendix B (Baulieu, Appendix B1; Weigel, Appendix B2). THE IOM REPORT During spring, 1993, the IOM convened an expert committee to assess current knowledge about the clinical uses of antiprogestins and to develop recommendations for research on antiprogestins in the United States. Political controversy has focused public attention on the use of antiprogestins to induce miscarriage; this committee, however, was specifically charged with considering the full spectrum of clinical applications of antiprogestins, not just their use for medical abortion. The seven-member committee held a two-day invitational workshop in Washington, D.C., to hear from leading researchers in this field. Speakers were asked to prepare papers (1) highlighting the current state of the science, focusing on clinical and animal studies including their own research and cell studies as they are pertinent, and (2) identifying important and promising areas for future research. These papers are included in Appendix B. The speakers presented summaries of their papers during the workshop. After reading each paper and participating in the workshop (which included lively discussion among speakers, committee, and observers), the committee developed its conclusions and recommendations that appear in this report. In this report the committee considers current information and research needed to advance knowledge about the following clinical applications of antiprogestins: intermittent or continuous use to alter the reproductive cycle (contraceptive use); use for post-coital contraception; inducing missed menses; pregnancy termination during the first trimester; pregnancy termination and cervical ripening during the second trimester; labor induction in late pregnancy; use as a therapy for endometriosis and uterine leiomyomas; and uses in breast cancer and meningioma therapy. In addition, uses of these compounds that take advantage of the antiglucocorticoid properties of the antiprogestins were considered. CROSS-CUTTING RECOMMENDATIONS Each chapter contains specific recommendations pertinent to that issue. The committee also had three recommendations that seemed to be cross-cutting issues for all the applications considered:
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Clinical Applications of Mifepristone (RU 486) and other Antiprogestins: Assessing the Science and Recommending a Research Agenda Recommendation No. 1. Research is needed to define the basic mechanisms and modes of action of mifepristone (RU 486) and other antiprogestins in order to understand the effects that have already been demonstrated and to develop compounds with more specific antiprogestin activity. Recommendation No. 2. Because antiprogestins as a class have clear potential for preventive and therapeutic applications in human health beyond those that have already been documented, the committee strongly recommends additional clinical testing of mifepristone and of newer antiprogestins as they are developed. Recommendation No. 3. Because some uses of antiprogestins may require long-term administration, the committee recommends studies to evaluate the potential toxicity, maintenance of efficacy, and development of drug resistance for antiprogestins used over longer periods of time. REFERENCES Institute of Medicine (IOM). Developing New Contraceptives. Mastroianni, L., Jr., Donaldson, P.J., and Kane, T.T., eds. Washington, D.C.: National Academy Press, 1990. Jensen, E.V., and Jacobson, H.I. Basic guides to the mechanism of estrogen action. Pp. 387–414 in Recent Progress in Hormone Research. Vol. XVIII. Pincus, G., ed. New York and London: Academic Press, 1962. Segal, S.J., and Thompson, C.R. Inhibition of estradiol induced pituitary hypertrophy in rats. Proceedings of the Society for Experimental Biology and Medicine 93:270–273, 1956.
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