The antiovulatory potential of progesterone antagonists correlates with a down-regulation of progesterone receptors in the hypothalamus, pituitary and ovaries

These studies analyze the regulation of progesterone receptors(PRs) in cent ral and peripheral tissues with the aim of further understanding mechanisti cally the inhibition of ovulation by progesterone antagonists (PA). Therefo re, it was of interest to investigate the influence of the progesterone rec eptor antagonist, Onapristone (ON), on PRs in the ovary, pituitary (PT), an d hypothalamus (HYP), since ON effectively inhibits ovulation in rats. For this study PMSG/hCG-primed immature and adult female rats were treated with ON. Immunohistochemistry was used for the detection of PRs. Progesterone ( P-4) and estradiol (E-2) levels were determined by RIA. PR expression in th e ovaries of immature rats was not detectable until after hCG administratio n. In these animals, ON caused a reduction in the staining intensity of PR in the tertiary follicles at the time when the preovulatory P-4-surge was i nhibited (6 h post hCG). Adult rats treated for 15 days with ON showed a de creased PR expression in PT and HYP. At this time (proestrus, 7 p. m.) the P-4 and E-2 levels are significantly lowered. These results suggest that after treatment with ON the expression of PR is reduced in the ovary, PT and HYP The regulation of PR in the ovary seems to be less dependent on estrogens than on LH. Thus, it is conceivable that th e reduced PR expression after ON treatment may be a result of decreased LH sensitivity in the ovary. In the pituitary and hypothalamus, PR expression is stimulated by estrogens and progesterone, and therefore the fall in the P-4 and E-2 levels in ON-treated animals may be responsible for the reduced PR expression in PT and HYP, and may contribute to the antiovulatory effec t of ON. We therefore conclude that the mechanism of the antiovulatory pote ncy of progesterone antagonists is based on a reduced preovulatory P-4-prod uction and PR expression in the ovary and also on the down-regulation of PR in the anterior pituitary and hypothalamus.