INHIBITION OF STEROIDOGENESIS BY LUTEAL CELLS OF EARLY-PREGNANCY IN THE RAT IN RESPONSE TO IN-VITRO ADMINISTRATION OF A GONADOTROPIN-RELEASING-HORMONE AGONIST

Previous studies from this laboratory have demonstrated that the admin istration of a gonadotropin-releasing hormone agonist (GnRH-Ag) in viv o in early or mid-pregnancy to rats induces antifertility effects by s uppressing the luteal production of progesterone (P-4) within 24 h wit h a concomitant increase in luteal lipid droplets and decreases in the luteal cytochrome P450 side chain cleavage (P450scc) enzyme and its m RNA content. These observations suggest a direct inhibitory effect of GnRH-Ag on the corpus luteum. Here we demonstrate a suppressive effect of GnRH-Ag in vitro on the basal P-4, pregnenolone (P-5) and 20 alpha -dihydroprogesterone (20 alpha-DHP) production by luteal cells obtaine d during early pregnancy in rats. We further studied its effect on two key enzymes, namely P450scc and 3 beta-hydroxysteroid dehydrogenase ( 3 beta-HSD), which participate in the conversion of cholesterol to P-5 and conversion of P-5 to P-4, respectively. We observed that two dose s of GnRH-Ag, 10(-4) and 10(-7) M, suppress the basal P-4 production i n vitro after 12 h of incubation by luteal cells; P-4 remained suppres sed after 48 h of incubation. Basal P-5 production was also suppressed after luteal cells were incubated for 12 h with 10(-4) and 10(-7) M G nRH-Ag, but incubation for 48 h with GnRH-Ag failed to alter P-5 produ ction by these cells. 20 alpha-DHP production was suppressed after inc ubating the luteal cells with both doses of GnRH-Ag for 12 h. GnRH-Ag inhibited P450scc activity after 12 h of incubation and 3 beta-HSD pro tein content at all time periods measured. These results suggest that GnRH exerts a direct inhibitory effect on luteal steroidogenesis. This inhibition is due to its suppressive effect on P450scc and/or 3 beta- HSD and not due to an increase in P-4 metabolites.