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

The effects of an antiprogestin ZK 98.299 (onapristone) on serum level s of estradiol and progesterone, and on the endometrial morphology wer e studied in adult bonnet monkeys. Twelve animals having menstrual cyc les 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 ve hicle (benzyl benzoate : castor oil, 1:10), and in Groups 2, 3 and 4 w ith 5 mg, 10 mg, or 20 mg ZK 98.299 once-a-week, respectively. Treatme nt was initiated on day 1 of the menstrual cycle and each animal in Gr oups 1, 2 and 3 was treated for two consecutive cycles. Since the trea tment cycle length of animals in Group 4 was considerably prolonged, t hey were treated for one menstrual cycle only. Endometrial biopsy was taken around day 20 of the second treatment cycle of first three group s and around day 50 of the 4th group of animals. Treatment with vehicl e or 5 mg ZK 98.299 had no significant effect on the menstrual cycle l ength. Treatment with 10 mg dose had no effect in two animals and prol onged the cycle length in one, whereas, further increase in the dose t o 20 mg prolonged the cycle length in all the animals. The duration of menses was generally reduced. Treatment with vehicle or different dos es 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 cyc les were comparable to those of vehicle-treated animals and were sugge stive of normal ovulatory cycles. On the other hand, in animals treate d with the higher dose (20 mg/week), progesterone levels during the lu teal phase were significantly reduced and were indicative of luteal in sufficiency. The hormonal data during the treatment period of this gro up 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 develop ment in a dose-dependent manner. In vehicle-treated animals, the endom etrium 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 b ecame small and inactive. This study, therefore, suggests that treatme nt 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 o f antiprogestins as a contraceptive agent.