gestins and the antiestrogen, tamoxifen, in inducing abortion. This was not seen in one study in women (Van Look and von Hertzen, Appendix B12). However, the study in women may not have been expected to demonstrate synergy due to the drug regimens tested. The concentration of mifepristone used in the human study was a maximal, or near maximal, dose. By definition, synergism could not be demonstrated under these circumstances, and lower (submaximal) doses would have to be utilized to evaluate the potential synergistic action properly.
Cook of Research Triangle Institute (RTI) presented information at the Institute of Medicine workshop on a new RTI compound that has a basic structure similar to other antiprogestins, but exhibits agonist rather than antagonist effects in the rabbit. Chwalisz of Schering AG pointed out that the rabbit progesterone receptor was anomalous and many antiprogestins that exhibit antagonist effects in other animals often exhibit agonist effects in rabbits. Therefore, the rabbit does not appear to be a good model for evaluating antiprogestins for potential application in humans.
Most of the control systems that govern reproductive function in the higher primates are fundamentally different from those in other mammals. This holds true for the control of ovulation, the recognition and maintenance of pregnancy, and the initiation of labor. The rhesus monkey has been a good model for the human in the context of neuroendocrine control of the menstrual cycle and ovulation; however, it differs markedly in the control of pregnancy. Progesterone metabolism is totally different from that in the human. In the rhesus monkey, progesterone is not converted to pregnanediol, and its concentration during pregnancy does not rise much above luteal phase except in the last few days before parturition (Neill et al., 1969). In this regard, the rhesus monkey behaves like sheep, cow, and other ungulates.
Despite the differences described above, Hodgen (Appendix B11), in reviewing the primate model for the study of antiprogestins, suggested that data from macaques (both rhesus and cynomolgus monkeys) and humans are quite similar. His comparisons focused on the noncompetitive antiestrogenic activity of progesterone antagonists, the dose-dependent blockade by mifepristone of the proliferative action of estradiol on the endometrium, and the elevation of estrogen receptors in the endometrium induced by mifepristone (Hodgen, Appendix B11). Some differences between primates and humans, however, have been noted. For example, Spitz and coworkers (1993; and Danforth et al., 1989) found that intermittent mifepristone was more effective at inhibiting ovulation in the monkey than in women. Furthermore, Frydman and coworkers (1991) found mifepristone to be more effective at inducing labor in women at the end of the third trimester than had been previously reported in monkeys.