Chronic treatment of female rhesus monkeys with low doses of the antiprogestin ZK 137 316: establishment of a regimen that permits normal menstrual cyclicity

Large doses of antiprogestin typically disrupt menstrual cyclicity. Achronic low-dose regimen of the potent new antiprogestin ZK 137 316, whichpermits continued menstrual cyclicity but alters gonadal- reproductivetract activity, was established. Rhesus monkeys received vehicle (n = 6) or0.01 (n = 8), 0.03 (n = 8) or 0.1 (n = 5) mg ZK 137 316/kg body weightdaily for five menstrual cycles (C-1 to C-5). Oestradiol, progesterone andgonadotrophin profiles were normal during cycles involving vehicle and 0.01and 0.03 mg ZK 137 316/kg body weight. In the 0.1 mg/kg group, mid-cycleoestradiol and gonadotrophin surges, and subsequent progesteroneproduction, were absent in C-3 and C-5. Ovarian cyclicity was accompaniedby timely menstruation in the vehicle and 0.01 mg/kg groups. By C-3, halfthe animals in the 0.03 mg/kg group and all animals in the 0.1 mg/kg groupwere amenorrhoeic. A corpus luteum was noted during the mid-luteal phase ofC-5 in the vehicle, 0.01 mg/kg and 0.03 mg/kg groups. Large antral andcystic follicles were evident in the 0.1 mg/kg group. Thus, a dailytreatment with 0.01 mg/kg ZK 136317 permitted normal menstrual cyclicity inmacaques. While the daily administration of 0.03 mg/kg ZK 136 317 allowedovarian cyclicity, menstruation was disrupted in some animals. Increasingthe dose to 0.1 mg/kg antagonized pituitary function and resulted inanovulation and amenorrhoea. A chronic low-dose regimen of theantiprogestin ZK 137 316, which permits normal ovarian/menstrual cyclicity,has potential as a contraceptive in women.