Antiprogestin-releasing intrauterine devices: a novel approach to endometrial contraception

Intrauterine devices (IUDs) that release progestins are highly effective contraceptives, but they induce breakthrough bleeding that some women find unacceptable. Because progesterone (P) antagonists [antiprogestins (APs)] are known to suppress the endometrium, induce amenorrhea and inhibit fertility, AP-releasing IUDs (AP-IUDs) may provide an effective contraceptive that also controls endometrial bleeding. Here, we assessed the effects of empty (blank) vs. AP-IUDs (ZK 230 211) on bleeding patterns and endometrial growth in ovariectomized, artificially cycled macaques. The AP-IUDs (but not the blank controls) induced extended, frank menstruation when inserted during the late luteal phase, an indication of local AP action. Over time, endometrial glandular and arterial proliferation were inhibited, steroid receptors were elevated, spiral arteries showed degenerative changes, P withdrawal bleeding was prevented, and estradiol (E₂)-dependent proliferation was suppressed by the AP-IUDs. In sum, AP-IUDs suppressed the effects of P on endometrial progestational development and blocked the effects of E₂ on endometrial proliferation, as previously shown for systemic treatment with APs. Therefore, AP IUDs may provide novel contraceptive devices with minimal breakthrough bleeding.