TREATMENT WITH A PROGESTERONE ANTAGONIST ZK 98.299 DELAYS ENDOMETRIAL DEVELOPMENT WITHOUT BLOCKING OVULATION IN BONNET MONKEYS

The effects of an antiprogestin ZK 98.299 (onapristone) on serum levels of estradiol and progesterone, and on the endometrial morphology were studied in adult bonnet monkeys. Twelve animals having menstrual cycles of normal duration (24 to 30 days) were randomly distributed into 4 equal groups. The animals in Group 1 were treated (s.c.) with the vehicle (benzyl benzoate : castor oil, 1:10), and in Groups 2, 3 and 4 with 5 mg, 10 mg, or 20 mg ZK 98.299 once-a-week, respectively. Treatment was initiated on day 1 of the menstrual cycle and each animal in Groups 1, 2 and 3 was treated for two consecutive cycles. Since the treatment cycle length of animals in Group 4 was considerably prolonged, they were treated for one menstrual cycle only. Endometrial biopsy was taken around day 20 of the second treatment cycle of first three groups and around day 50 of the 4th group of animals. Treatment with vehicle or 5 mg ZK 98.299 had no significant effect on the menstrual cycle length. Treatment with 10 mg dose had no effect in two animals and prolonged the cycle length in one, whereas, further increase in the dose to 20 mg prolonged the cycle length in all the animals. The duration of menses was generally reduced. Treatment with vehicle or different doses of ZK 98.299 had no effect on ovulation. In animals treated with 5 or 10 mg dose, the pattern of mid cycle rise in serum estradiol levels and progesterone levels during the luteal phase of both treatment cycles were comparable to those of vehicle-treated animals and were suggestive of normal ovulatory cycles. On the other hand, in animals treated with the higher dose (20 mg/week), progesterone levels during the luteal phase were significantly reduced and were indicative of luteal insufficiency. The hormonal data during the treatment period of this group of animals was suggestive of two distinct ovarian cycles indicating that the menstrual bleeding during the treatment period was probably very scanty. Treatment with ZK 98.299 impaired the endometrial development in a dose-dependent manner. In vehicle-treated animals, the endometrium had large and tortous glands with secretions. Treatment with ZK 98.299 caused atrophic changes in the glands as well as in the stroma. The height of the epithelial cells was markedly decreased and they became small and inactive. This study, therefore, suggests that treatment with low doses of antiprogestin ZK 98.299 at weekly intervals does not block folliculogenesis or ovulation, but has an inhibitory effect on the endometrium. This study opens up a possibility of development of antiprogestins as a contraceptive agent.