Clomiphene and tamoxifen inhibit progesterone synthesis in granulosa cells: comparison with estradiol.
The actions of clomiphene, tamoxifen, and 17 beta-estradiol were studied in an isolated avian granulosa cell system during short term incubations. A dose-dependent inhibition of ovine LH-enhanced progesterone production was observed for all three compounds, with an IC50 of 3 X 10(-6) M and maximal inhibition (95%) at 5 X 10(-5) M. A similar inhibition was found when cells were stimulated by either 8-bromo-cAMP or forskolin. Neither clomiphene nor tamoxifen had an inhibitory effect on the conversion of pregnenolone to progesterone, a step that was blocked by 17 beta-estradiol and isoxazole , a known inhibitor of 3 beta-hydroxysteroid dehydrogenase. On the other hand, cells exposed to clomiphene failed to use [6-3H]25-hydroxycholesterol, while estradiol significantly increased the conversion of labeled substrate to pregnenolone at the expense of progesterone (30% vs. 7% of the total radioactivity). By comparison, in control cells, progesterone represented the major metabolite with 36% of the total radioactivity; pregnenolone had only 2.8%. The results demonstrate that these triphenylethylene compounds, which are used clinically as antiestrogens, inhibit steroidogenesis at a step before pregnenolone formation, probably at the site of the cholesterol side-chain cleavage enzyme complex, while 17 beta-estradiol inhibits 3 beta-hydroxysteroid dehydrogenase.
D015056:1-Methyl-3-isobutylxanthine / Q000494:pharmacology; D015124:8-Bromo Cyclic Adenosine Monophosphate / Q000494:pharmacology; D000818:Animals; D002645:Chickens; D002996:Clomiphene / Q000494:pharmacology*; D005576:Colforsin; D004224:Diterpenes / Q000494:pharmacology; D004958:Estradiol / Q000494:pharmacology*; D005260:Female; D006107:Granulosa Cells / Q000187:drug effects / Q000378:metabolism*; D007700:Kinetics; D011374:Progesterone / Q000096:biosynthesis*; D013629:Tamoxifen / Q000494:pharmacology*
D004224:Diterpenes; D013629:Tamoxifen; D005576:Colforsin; D002996:Clomiphene; D015124:8-Bromo Cyclic Adenosine Monophosphate; D011374:Progesterone; D004958:Estradiol; D015056:1-Methyl-3-isobutylxanthine