INHIBITORY EFFECT OF MIFEPRISTONE (RU-486) ON OVULATION IN THE ISOLATED-PERFUSED RAT OVARY

The antigestagen mifepristone (RU 486) acts by blocking the progesterone receptor. Mifepristone has been used clinically for medical termination of pregnancy. It has recently also been shown that it can be used as an effective contraceptive agent in many species including the human. This contraceptive effect is acquired through prolonged exposure to mifepristone during the follicular phase and has been linked to disrupted folliculogenesis and inhibition of the LH surge. In the present study it is tested if mifepristone inhibits ovulation by a direct action on the ovary at the time of the LH surge. Preovulatory rat ovaries from immature Sprague-Dawley rats primed with 201U of equine CG were perfused in vitro for 20h in the presence of LH and 3-isobutyl-1-methylxanthine (IBMX) to induce ovulations. Mifepristone was added to study the effect on ovulation rate and ovarian steroidogenesis. Unstimulated control ovaries did not ovulate whereas addition of ovine LH (0.1 mu g/ml) and IBMX (0.2mM) resulted in 17.6 +/- 2.7 ovulations per treated ovary. Presence of mifepristone at 1 mu M did not significantly inhibit LH+IBMX-induced ovulation (13.0 +/- 1.2) whereas mifepristone at 50 mu M significantly (p<0.01) inhibited ovulation (2.8 +/- 1.4). When the latter dosage of mifepristone (50 mu M) was added 4h after LH+IBMX, no inhibitory effect was seen (17.2 +/- 3. 0). Progesterone and estradiol release was significantly increased by LH+IBMX over the control group. Presence of mifepristone at any tested dose or time of addition did not significantly change the LH+IBMX-stimulated steroid release. It is concluded that mifepristone inhibits ovulation in the rat at the ovarian level when present just before LH stimulation but not when administered 4h into the ovulatory process.