This project is part of an IRPG proposal whose overall goal is to bring together clinical and laboratory scientists to develop a novel contraceptive strategy based upon the anit-progestins. The IRPG, which consists of 3 interlocking projects, is based on the hypothesis supported by preliminary studies in several species that low doses of anti- progestin permit ovarian cyclicity, yet alter the function of the hypothalamus-pituitary-ovary-reproductive tract to prevent pregnancy initiation. Experiments in the current project will utilize adult, female rhesus monkeys to (1) characterize long-acting parental forms of anti- progestin and establish optimal routes and low doses that do not induce premature menses, (2) determine if chronic exposure to low-dose anit- progestin impairs the function of the ovary/reproductive tract without causing amenorrhea or irregular cyclicity, significant toxic effects or irreversible changes in reproductive capacity, and (3) test low-dose regimens of anti-progestin in cycling monkeys for protection against pregnancy. Research will initially concentrate on testing depot formulations, such as pellets for subcutaneous implantation and microspheres for intramuscular injection, for output capacity, release kinetics and duration, local and systemic toxicity, and dose-related ability to induce premature menses. Then vehicle and selected dose of anti-progestin will administered to normal cycling monkeys for 4 months. Circulating levels of ovarian steroids, pituitary gonadotropins and anti- progestin, lengths of follicular and luteal phases and menstrual cycle, as well as direct indices of ovulation and uterine maturation will be compared between treatment groups and within groups as a function of treatment interval. Next vehicle or a dose(s) of anti-progestin will be administered to female monkeys caged with male (paired housing: 1 male + 1 female) throughout the breeding season. Early pregnancy will be confirmed by ultrasonography, with the number and percent of fertile animals/group analyzed for each ensuing cycle. Fetal wastage, gestation length, and fetal weight at delivery will be compared between groups. Monkeys chronically exposed to anti-progestin (and their offspring, if any) will be used for toxicologic evaluation of tissues. Additional monkeys receiving an anti-fertility dose of anti-progestin will be treated with vehicle in the following breeding season to assess reversibility of action. Development of practical delivery system for low-dose anti-progestins that result in safe, effective contraception in rhesus monkeys while retaining menstrual cyclicity will support the step- wide plan to consider this method for controlling fertility in women.
