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 (E(2))-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 E(2) on endometrial proliferation, as previously shown for systemic treatment with APs. Therefore, AP IUDs may provide novel contraceptive devices with minimal breakthrough bleeding.

Assessment of menstruation in the vervet (Cercopithecus aethiops).

Vervet monkeys (Chlorocebus aethiops) are Old World nonhumans that display attenuated menstruation that requires detection by vaginal swab. The physiology underlying attenuated menstruation in this species has not been previously studied. To fill this gap, we evaluated endometrial cell proliferation, steroid receptor localization and expression of menstruation-associated matrix metalloproteinase (MMP) enzymes in vervets during natural and artificial menstrual cycles. The artificial cycles were induced by sequentially treating ovariectomized animals with estradiol (E(2)) and progesterone (P). Because menstrual flow is exceptionally light in this species, menses was detected by vaginal swab. We found that both natural and artificially cycled animals menstruated 3-5 days after the decline of P at the end of the cycle. As in other primates, P withdrawal at the end of artificial cycles triggered endometrial expression of MMPs, including MMP-1, 2, 3, 7, 10, 11, 13 and 26 transcripts. In both the natural and artificial menstrual cycle, menstrual sloughing was restricted to the upper one-fourth of the endometrium, and MMP-1 and 2 were strongly expressed by the stroma of the sloughing zone. MMP-7 was localized in the endometrial glands during late menses. As in macaques, epithelial cell proliferation was localized to the functionalis zone during the estrogen-dominated proliferative phase and to the basalis zone glands during the P-dominated secretory phase. Regulation of estrogen and progestin (or estradiol and progesterone) receptors was similar to that reported for macaques. Because strong similarities exist between the endometrium of vervets, macaques and women, we conclude that vervets can provide a useful animal model for studies on hormone regulation of menstruation.