CONTRACEPTION W/ MINI DOSE ANTIPROGESTIN IN RHESUS MONKEYS

我们最近确定持续使用低剂量

We recently determined that continual administration of low doses of the antiprogestin ZK 137 316 (Schering AG) to adult, female rhesus monkeys permits ovarian/menstrual cyclicity, but disrupts the growth and differentiation of the uterine endometrium. To determine if these (or other) changes in the reproductive tract are sufficient to prevent fertility (intrauterine pregnancy), female macaques (n=10/group) were treated daily with vehicle (controls), 0.01 or 0.03 mg ZK 137 316/kg body weight before and during 5 months of continual cohabitation with males of proven fertility. Mating behavior was confirmed by visual observation, and ejaculation occurred judged by the detection of sperm in the vagina. A cumulative pregnancy rate of 90% (9 of 10) was observed in controls. Of the animals receiving 0.01 mg/kg, 40% (4 of 10) conceived, with all conceptions occurring in the first 2 months of pairing. No pregnancies (0%, 0 of 10) occurred in the 0.03 mg/kg group. Although timely menstrual cyclicity occurred more frequently in the 0.01 mg/kg- than the 0.03 mg/kg-treated animals, ovarian cyclicity as judged from the observation of a corpus luteum on the ovaries was observed in both groups. Blood indices of circulating ions, liver function and blood cell constituents revealed no significant effects of chronic treatment. General toxicologic evaluation of major organs and tissues, either at a gross or microscopic level, did not identify any treatment-related changes. Thus, chronic administration of low dose antiprogestin prevents pregnancy in nonhuman primates, while permitting ovarian cyclicity and a high incidence of regular menstruation. Future studies are planned to determine the site(s) and mechanism(s) of contraceptive action of low-dose antiprogestin, e.g., in the uterus to prevent gamete transport or implantation. Also, experiments will examine whether the anti-fertility effects of ZK 137 316 are reversible. If so, this novel regimen of antiprogestin can be pursued as a potential contraceptive for women. RELEVANT PUBLICATIONS Zelinski-Wooten MB, Slayden OD, Chwalisz K, Hess DL, Brenner RM, Stouffer RL. Chronic treatment of female rhesus monkeys with low doses of the antiprogestin ZK 137 316 Establishment of a regimen that permits normal menstrual cyclicity. Hum Reprod, in press. Slayden OD, Zelinski-Wooten MB, Chwalisz K, Stouffer RL, Brenner RM. Chronic treatment of cycling rhesus monkeys with low doses of the antiprogestin ZK 137 316 Morphometric assessment of the uterus and oviduct. Hum Reprod, in press.