. "B11. Primate Models for the Study of Antiprogestins in Reproductive Medicine." Clinical Applications of Mifepristone (RU486) and Other Antiprogestins: Assessing the Science and Recommending a Research Agenda. Washington, DC: The National Academies Press, 1993.
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Clinical Applications of Mifepristone (RU 486) and other Antiprogestins: Assessing the Science and Recommending a Research Agenda
findings will be reported publicly soon. A Chinese version of mifepristone is also being produced for abortifacient use in that country.
PART II: NONCOMPETITIVE ANTIESTROGENIC ACTIVITY OF PROGESTERONE ANTAGONISTS
That some progesterone antagonists express other biological activities, besides being antiprogestins, was revealed by the antiglucocorticoid functions of mifepristone (Healy et al., 1983, 1985). More recently, we reported that mifepristone has a noncompetitive antiestrogenic activity that blocks estrogen-induced endometrial proliferation in primates (van Uem et al., 1989). This action of the antiprogestin was later found to be dose dependent in the presence of physiologic estradiol (Wolf et al., 1989b). Paradoxically, we found that mifepristone elevates the concentration of estrogen receptors in monkey endometrium, yet the mitogenic (proliferative) impact of estrogen on endometrial growth was negated (Neulen et al., 1990).
These observations are consistent with other monkey and human data that may substantiate this antiproliferative activity of mifepristone on primate endometrium (Kettel et al., 1991; Murphy et al., 1991; Batista et al., 1992). Apparently, other progesterone antagonists may also possess this property. For example, Chwalisz and coworkers recently reported that onapristone curtails endometrial growth (Chwalisz et al., 1991). Based on this report, we wonder how general this activity may be among a wider spectrum of antiprogestin compounds.
Below, some basic biological studies are summarized that suggest potential therapeutic uses of the antiproliferative activity of antiprogestins on uterine tissues.
Initial Evidence of Noncompetitive Antiestrogenic Activity of Mifepristone
In previous studies, mifepristone administration arrested spontaneous folliculogenesis (van Uem et al., 1989). To investigate the central versus peripheral effects of mifepristone on the ovarian/menstrual cycle, including endometrial proliferation, mifepristone was administered daily [10 mg/kg per day, intramuscular (IM)] from menstrual cycle day 3 or 7 to day 25 in six normal adult cynomolgus monkeys receiving human menopausal gonadotropin (hMG) treatment [37.5 IU (international units) per day] from days 3 to 8. Mifepristone administration with hMG/human chorionic gonadotropin (hCG) therapy did not inhibit ovarian response, as evidenced by steroidogenesis and ovulation. Nine of 23 oocytes retrieved by lavage or follicular aspiration at laparotomy after ovulation induction were morphologically classified as mature