Effect of RU486 on ovarian progesterone production at pro-oestrus and during pregnancy: a possible dual regulation of the biosynthesis of progesterone

Changes in progesterone production were analysed after intrabursal ovarian administration of the antiprogesterone RU486, mifepristone, in rats at pro-oestrus and during pregnancy. RU486 was administered at 09:00–10:00 h and serum progesterone was measured 8 h after treatment, except for those on days 3 and 12 of pregnancy when the steroid was measured 4, 8 and 24 h later. RU486 stimulates progesterone production on the day of pro-oestrus and on days 3–5 and 15–20 of pregnancy. Conversely, treatment with the antiprogestagen inhibits progesterone production on days 7–14 of gestation. The inhibition (day 12) or stimulation (day 19) of progesterone production induced by RU486 could be correlated with the simultaneous inhibition or stimulation of 3β-hydroxysteroid dehydrogenase (3β-HSD) activity observed in corpora lutea. A similar effect on 3β-HSD activity in corpora lutea was obtained by intrabursal ovarian administration of a specific progesterone antibody, indicating that the effect of RU486 is exerted through its antiprogesterone action. On the day of pro-oestrus and during early pregnancy the intrabursal ovarian injection of RU486 did not modify serum prolactin and LH concentrations, demonstrating that the antiprogesterone did not have a central action. The stimulatory action of RU486 on progesterone production on days 3 and 5 of pregnancy shifted to an inhibitory effect on progesterone production on day 7. Oestradiol treatment on day 6 of pregnancy reversed the effect of RU486 on progesterone production on day 7, inducing a response similar to that obtained on days 3 and 5 of gestation. Tamoxifen treatment on days 14 and 15 prevented the stimulatory effect of RU486 on progesterone production observed on day 15 of pregnancy. These results indicated that RU486 is a useful tool to demonstrate a stimulatory and inhibitory direct effect of progesterone on ovarian steroidogenesis, exerted most probably at the corpus luteum, affecting its own biosynthesis. The inhibitory effect of progesterone seems to be oestrogen dependent. The existence of a particular intraovarian regulation of progesterone production in rats during pro-oestrus and pregnancy is suggested.