RU-486 (RU), a synthetic steroid with antiprogesterone receptor activity, was used to study the role of progesterone in the normal menstrual cycle of rhesus monkeys. The drug, at dosages of 2, 4, or 12 mg/kg, was administered as a single im injection during the luteal phase (days 5-8) in 16 experiments in 8 monkeys. RU had acute effects on the endometrium, as it induced menstruation within 3 days in spite of persistant progesterone elevations, thereby shortening the cycle length by about 5 days. Long term effects on menstrual cyclicity were also found with the higher RU doses. The intermenstrual interval after RU treatment increased from 31.8 +/- 2.4 (+/- SE) days after a 2 mg/kg dose of RU to 82.4 +/- 6.8 days after a 12 mg/kg dose of RU, with a control cycle length of 29.4 +/- 0.7 days. This prolonged interval was related to a delay in the completion of the follicular maturation process and, therefore, a delay in ovulation, as judged by estrogen and progesterone concentrations. Subsequent menstrual cycles were regular and ovulatory. Our results suggest that RU binds to the endometrial progesterone receptor, thereby inducing premature menstruation in the presence of elevated progesterone levels. RU also exerts long term effects on the hypothalamo-hypophyseal axis, since it significantly alters menstrual cyclicity.