Chronic progesterone antagonist-estradiol therapy suppresses breakthrough bleeding and endometrial proliferation in a menopausal macaque model

Background: Clinicians routinely prescribe progestins along with estrogens during menopausal hormone therapy (HT) to block estrogen-dependent endometrial proliferation. Breakthrough bleeding (BTB) can negate the utility of this treatment. Because progestin antagonists also inhibit estrogen-dependent endometrial proliferation in women and macaques, we used a menopausal macaque model to determine whether a potent progestin antagonist (ZK 230 211, Schering AG; ZK) combined with estrogen would provide a novel mode of HT. Method: Ovariectomized rhesus macaques were treated for 5 months with either estradiol (E₂) alone, E₂ + progesterone (two doses) or E₂ + ZK (0.01, 0.05 or 0.25 mg/kg). Results: In the E₂ + progesterone groups, progesterone suppressed endometrial proliferation and induced a thick decidualized endometrium. In the E₂ + ZK 230 211 groups, all doses of ZK blocked endometrial proliferation and induced endometrial atrophy. In all ZK-treated groups, the atrophied endometrium contained some dilated glands lined by an inactive, flattened, non-mitotic epithelium. BTB was much lower in the E₂ + ZK groups (17 days of spotting, all groups) than in the E₂ and E₂ + progesterone groups (155 bleeding days, all groups). ZK suppressed E₂ effects in the cervix, but not in the vagina, oviduct or mammary glands. All serum chemistry and lipid profiles were normal. Conclusion: The ability of ZK to block estrogen-dependent endometrial proliferation, induce endometrial atrophy and suppress BTB in a menopausal macaque model indicates that progestin antagonists may provide a novel mode of HT.