Inhibition of steroidogenesis by luteal cells of early pregnancy in the rat in response to in vitro administration of a gonadotropin- releasing hormone agonist

Abstract Previous studies from this laboratory have demonstrated that the administration of a gonadotropin- releasing hormone agonist (GnRH-Ag) in vivo in early or mid-pregnancy to rats induces antifertility effects by suppressing the luteal production of progesterone (P 4 ) within 24 h with a concomitant increse in luteal lipid droplets and decreses in the luteal cytochrome P 450 side chain cleavage ( P 450scc) enzyme and its mRNA 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 20α-dihydroprogesterone (20α-DHP) production by luteal cells obtained during early pregnancy in rats. We further studied its effect on two key enzymes, namely P 450scc and 3β-hydroxysteroid dehydrogenase (3β-HSD), which participate in the conversion of cholesterol to P 5 amd conversion of P 4 , respectively. We observed that two doses of GnRH-Ag, 10 −4 and 10 −7 M, suppress the basal P 4 production in vitro after 12 h of incubation by luteal cells; P 4 remained suppessed 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 GnRH-Ag, but incubation for 48 h with GnRH-Ag failed to alter P 5 production by these cells. 20α-DHP production was suppressed after incubating the luteal cells with both doses of GnRH-Ag for 12 h. GnRH-Ag inhibited P 450scc activity after 12 h of incubation and 3β-HSD protein 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 P 450scc and/or 3β-HSD and not due to an increase in P 4 metabolites.