Effect of the progesterone antagonist mifepristone on the hypothalamo-hypophysial-ovarian axis in rats

Treatment of female rats for 3 weeks with the antigestagen 11 beta-(4-dimethylaminophenyl)-17 beta-hydroxy-17 alpha-(prop-1-ynyl)-estra- 4,9-dien-3-one (mifepristone) results in pituitary and ovarian enlargement. The present study dealt with the possible mechanism(s) of these responses. Ovarian enlargement appeared to be dependent upon prolactin. In the absence of prolactin, during combined treatment with mifepristone and the dopamine agonist 2-Br-alpha-ergokryptine, ovarian growth was significantly suppressed. It was unclear why persistent hyperprolactinaemia, due to treatment with mifepristone, resulted in persistence of functionally active corpora lutea despite intermittent ovulation, while persistent hyperprolactinaemia due to ectopic pituitary grafts did not. Pituitary enlargement appeared to be dependent upon the persistence of ovarian oestrogen secretion during the treatment period. Ovariectomy or lactation fully inhibited this response. Pituitary enlargement and prolactin secretion in ovariectomized rats in response to exogenous oestrogen (injections of oestradiol benzoate) were significantly enhanced by additional treatment with mifepristone. It is concluded that mifepristone facilitates the effect of oestrogen on pituitary lactotrophs, thereby enhancing pituitary growth. Ovarian enlargement during treatment with mifepristone may be specific for rats due to the luteotrophic action of prolactin in these animals. Pituitary enlargement due to facilitation of oestrogen-induced pituitary growth may become a focus of attention when this or similar antigestagenic drugs are being used for prolonged periods in clinical trials, e.g. for limiting steroid-sensitive tumour growth.