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

Abstract

Intrauterine devices (IUDs) that release progestins are highly effective contraceptives, but they induce breakthrough bleeding that some women find unacceptable. Because progesterone (P) antagonists (AP) are known to suppress the endometrium, induce amenorrhea, and inhibit fertility, AP IUDs may provide an effective contraceptive that also controls endometrial bleeding. Here we assessed the effects of empty (blank) vs AP-releasing (ZK 230 211) IUDs 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, progesterone withdrawal bleeding was prevented and estradiol-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 estradiol on endometrial proliferation as previously shown for systemic treatment with APs. Therefore, AP IUDs may provide novel contraceptive devices with minimal breakthrough bleeding.

Selective progesterone receptor modulators in reproductive medicine: pharmacology, clinical efficacy and safety

“…Some studies have suggested that SPRMs may be able to control uterine bleeding via a direct effect on endometrial blood vessels (45,72,108,109), as amenorrhea in patients receiving SPRMs does not appear to depend on inhibition of ovulation in all cases (45,72). The mechanism of the amenorrhea observed after SPRM treatment is still poorly understood (110).…”

Early effects of high concentrations of progesterone and Mifepristone A gene expression study of endometrial cancer cells (Ishikawa)

“…Activation of mitogenactivated protein kinase has also been investigated [19,20]. In a therapeutic setting a new anti-progestin impregnated intrauterine device, showing to superior compared to the levonorgestrelimpregnated IUD in reducing breakthrough bleedings, also induced mucosal atrophy [21]. Mifepristone and other steroid receptor antagonists are assumed to be more potent than predicted by simple competition for progesterone binding and Mifepristone effectively antagonizes progesterone activation of the receptor at concentrations much less than sub-stoichiometric with the agonist [12].…”

Contraceptive applications of progesterone receptor modulators

“…Administration of the PRM ZK 230 211 using an intrauterine system (IUS) has been tested in primates 52 and in women 53 . The effects of a ZK 230 211-releasing IUS on bleeding patterns and endometrial growth in ovariectomized, artificially cycled macaques 52 has been compared to those of a blank device.…”