Antiproliferative effects of progesterone antagonists and progesterone receptor modulators on the endometrium

Progesterone antagonists (PAs, antiprogestins) can modulate estrogenic effe cts in various estrogen-dependent tissues. These modulatory effects are com plex and depend on species, tissue, type of compound, dose, and duration of treatment. In non-human primates, PAs, including mifepristone, ZK 137 316 and ZK 230 211, inhibit endometrial proliferation and induce amenorrhea. Wh en administered chronically at relatively low doses, these compounds block the mitotic activity of endometrial epithelium and induce stromal compactio n in a dose-dependent manner in both spayed and intact monkeys at high estr adiol concentrations. These effects were accompanied by an atrophy of spira l arteries, The antiproliferative effects were endometrium-specific, since the estrogenic effects in the oviduct and vagina were not inhibited by PBs. Similar endometrial antiproliferative effects were also found after treatm ent with the progesterone receptor modulator (PRM), mesoprogestin J1042. Th e endometrial antiproliferative effects of PAs, particularly within the end ometrial glands, were also observed in spayed rabbits. In spayed rats, howe ver, the PAs did not inhibit, but rather enhanced, various estrogen respons es, including endometrial proliferation, pointing to species-specific diffe rences. In conclusion, our studies indicate that both pure PAs and PRMs sel ectively inhibit estrogen-dependent endometrial proliferation in the primat e endometrium without affecting estrogenic response in other estrogen-depen dent tissues or inducing unscheduled bleeding. Our studies indicate that th e spiral arteries, which are unique to the primate endometrium, are the pri mary targets that are damaged or inhibited by PAs and PRMs. The damage to t hese unique vessels may underlay the paradoxical, endometrium-specific, ant iproliferative effects of these compounds. Hence, the properties of PAs and PRMs (mesoprogestins) open up new applications in gynecological therapy an d hormone replacement therapy. (C) 2000 Elsevier Science Inc. All rights re served.