Modulation of oestrogenic effects by progesterone antagonists in the rat uterus

Antiprogestins can modulate oestrogenic effects in various oestrogen-dependent tissues, dependent on species, tissue, dose and duration of treatment. Enhanced oestrogenic responses to mifepristone and onapristone occur in vitro and in vivo. However, the antiprogestins mifepristone, onapristone, and ZK 137 316 can block the ability of oestradiol to increase endometrial growth in non-human primates. Our purposes were firstly, to decide whether mifepristone and onapristone had direct oestrogenic activity in vitro and in the uterus of spayed and immature rats, and secondly, to discover whether antiprogestins exhibit inhibitory effects on oestrogen action in the uterus in spayed, oestrogen-substituted rats. In transactivation assays, mifepristone induced oestrogenic response, whereas onapristone had only marginal effects on reporter gene transcription. In immature rats, onapristone and mifepristone markedly increased uterine weights, and onapristone, but not mifepristone significantly enhanced endometrial luminal epithelial height, a sensitive oestrogen parameter. Conversely, in spayed and adrenalectomized rats, neither onapristone nor mifepristone changed uterine weights or endometrial morphology, indicating that their effects in immature rats were indirect. In spayed, oestrogen-substituted rats, antiprogestins did not block oestradiol-stimulated endometrial growth and luminal and glandular epithelium were stimulated more after antiprogestin plus oestrogen, than after oestradiol alone. All compounds induced compaction of the uterine stroma. In spayed rats, onapristone and some other 13alpha-configured (type 1) antagonists (ZK 135 569, ZK 131 535) reduced oestradiol-stimulated myometrial proliferation and induced an overall uterine weight reduction in animals treated with oestrogen and antiprogestins, in comparison with oestradiol-treated controls. 13beta- configured (type II) antagonists, including mifepristone, lilopristone and ZK 112 993, were not effective. In the uteri of spayed rats, onapristone was also found to enhance the oestradiol-stimulatory effect on expression of the oestrogen-dependent proto-oncogene, c-fos. In conclusion, antiprogestins do not inhibit, but rather enhance, oestrogen-induced uterine glandular and luminal epithelium in spayed rats, contrary to their effects in primates. The rat model is unsuitable to study endometrial antiproliferative effects of antiprogestins in primate uteri.