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 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 (P4) within 24h with a concomitant increase in luteal lipid droplets and decreases in the luteal cytochrome P450 side chain cleavage (P450scc) 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 P4, pregnenolone (P5) and 20 alpha-dihydroprogesterone (20 alpha-DHP) production by luteal cells obtained 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 P5 and conversion of P5 to P4, respectively. We observed that two doses of GnRH-Ag, 10(-4) and 10-7 M, suppress the basal P4 production in vitro after 12 h of incubation by luteal cells; P4 remained suppressed after 48 h of incubation. Basal P5 production was also suppressed after luteal cells were incubated for 12 h with 10(-4) M and 10(-7) M GnRH-Ag, but incubation for 48 h with GnRH-Ag failed to alter P5 production by these cells. 20 alpha-DHP production was suppressed after incubating 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 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 P450scc and/or 3 beta-HSD and not due to an increase in P4 metabolites.
Srivastava
R K
RK
Department of Physiology, Morehouse School of Medicine, Atlanta, GA 30310-1495.
Luu-The
V
V
Marrone
B L
BL
Harris-Hooker
S
S
Sridaran
R
R
D004092:20-alpha-Dihydroprogesterone / Q000096:biosynthesis*; D015096:3-Hydroxysteroid Dehydrogenases / Q000037:antagonists & inhibitors; D000818:Animals; D002478:Cells, Cultured; D065607:Cytochrome P-450 Enzyme Inhibitors; D005260:Female; D007987:Gonadotropin-Releasing Hormone / Q000031:analogs & derivatives* / Q000494:pharmacology; D008184:Luteal Cells / Q000187:drug effects / Q000378:metabolism*; D011247:Pregnancy; D011284:Pregnenolone / Q000096:biosynthesis*; D011374:Progesterone / Q000096:biosynthesis*; D051381:Rats; D017207:Rats, Sprague-Dawley
D065607:Cytochrome P-450 Enzyme Inhibitors; D004092:20-alpha-Dihydroprogesterone; D007987:Gonadotropin-Releasing Hormone; D011374:Progesterone; D011284:Pregnenolone; D015096:3-Hydroxysteroid Dehydrogenases; C030741:lutrelin acetate