Effects of the Progesterone Antagonists Onapristone (ZK 98 299) and ZK 136 799 on Surgically Induced Endometriosis in Intact Rats

Abstract

The effects of the progesterone antagonists (antiprogestins) onapristone (ZK 98 299) and ZK 136 799 on surgically induced endometriosis were studied in intact female rats. Endometriosis was induced by transplanting homologous endometrium to the parietal peritoneum of the abdominal wall (location A) and to the mesentery of the small intestine (location 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-like foci was measured with a calliper during both pre- and post-treatment laparotomy. Both antiprogestins exerted inhibitory effects on the growth of the endometriosis-like foci in terms of complete remission. A 40 and 50% remission of endometriosis was observed at each location after the administration of 2.0 mg onapristone, whereas 50 and 63% (location A) and 50 and 75% (location B) remissions were found after the administration 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 inhibition of the endometriosis-like foci was confirmed by histology and immunohistochemical staining of the proliferating cell nuclear antigen. The antiprogestins caused a reduction in glandular and luminal epithelial cells in the ectopic endometrium. Both antiprogestins tended to cause a decrease in uterine weight. Unlike the inhibitory effects in the ectopic endometrium, both onapristone and ZK 136 799 exhibited some stimulatory effects on the epithelial cells within the eutopic endometrium. Serum 17 beta-oestradiol concentrations did not vary significantly among the different treatment groups. No antiglucocorticoid effect of the antiprogestins was observed at either dose. This study indicates that the antiprogestins onapristone and ZK 136 799 exhibit antiproliferative effects in the ectopic but not the eutopic endometrium via mechanisms which remain to be established. The better efficacy of ZK 136 799 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 onapristone and ZK 136 799 in the treatment of endometriosis.