EFFECTS OF THE PROGESTERONE ANTAGONISTS ONAPRISTONE (ZK-98-299) AND ZK-136-799 ON SURGICALLY INDUCED ENDOMETRIOSIS IN INTACT RATS

The effects of the progesterone antagonists (antiprogestins) onapristo ne (ZK 98 299) and ZK 136 799 on surgically induced endometriosis were studied in intact female rats, Endometriosis was induced by transplan ting homologous endometrium to the parietal peritoneum of the abdomina l wall (location A) and to the mesentery of the small intestine (locat ion B). The animals were treated daily for 4 weeks at doses of 0.4 and 2.0 mg onapristone or ZK 136;799. The growth of the endometriosis-lik e foci was measured with a calliper during both pre- and post-treatmen t laparotomy, Both antiprogestins exerted inhibitory effects on the gr owth of the endometriosis-like foci in terms of complete remission. A 40 and 50% remission:df endometriosis was observed at each location af ter the administration of 2.0 mg onapristone, whereas 50 and 63% (loca tion A) and 50 and 75% (location B) remissions were found after the ad ministration of 0.4 and 2.0 mg of ZK 136 799 respectively. ZK 136 799 was also more potent than onapristone in growth inhibition (85 versus 48% for location B) in animals with persistent endometriosis, Growth i nhibition of the endometriosis-like foci was confirmed by histology an d immunohistochemical staining of the proliferating cell nuclear antig en, The antiprogestins caused a reduction in glandular and luminal epi thelial cells in the ectopic endometrium. Both antiprogestins tended t o cause a decrease in uterine weight. Unlike the inhibitory effects in the ectopic endometrium, both onapristone and ZK 136 799 exhibited so me stimulatory effects on the epithelial cells within the eutopic endo metrium. Serum 17 beta-oestradiol concentrations did not vary signific antly among the different treatment groups. No antiglucocorticoid effe ct of the antiprogestins was observed at either dose. This study indic ates that the antiprogestins onapristone and ZK-136 799 exhibit antipr oliferative effects in the ectopic but not;he eutopic endometrium via mechanisms which remain to be established, The better efficacy of ZK 1 36 799 is more likely caused by its higher antiprogestagenic activity than its partial androgenic activity. These findings may be a further indication of the future potential of antiprogestins such as onapristo ne and ZK 136 799 in the treatment of endometriosis.