Troglitazone inhibits progesterone production in porcine granulosa cells.
Troglitazone (a thiazolidinedione that improves insulin resistance) lowers elevated androgen concentrations in women with polycystic ovarian syndrome. In this study, we assessed the direct effects of troglitazone on steroidogenesis in porcine granulosa cells. Troglitazone inhibited progesterone production in a dose- and time-dependent manner (earliest effects at 4 h, maximum at 24 h) without affecting cell viability. Progesterone production was also inhibited by troglitazone in the presence of 25-hydroxycholesterol, indicating that the drug does not affect intracellular cholesterol transport. Troglitazone also inhibited FSH- and forskolin-stimulated progesterone secretion. The reduced progesterone production was accompanied by marked elevations of pregnenolone concentrations, suggesting inhibition of 3beta-hydroxysteroid dehydrogenase (3beta-HSD). The activity of 3beta-HSD in troglitazone-treated granulosa cells was decreased by more than 60%, compared with controls after 24 h. Troglitazone did not affect aromatase activity in porcine granulosa cells. In summary, troglitazone has direct effects on porcine granulosa cell steroidogenesis. The drug specifically inhibits 3beta-HSD activity, resulting in impaired progesterone production. The clinical relevance of this direct in vitro effect on steroidogenesis needs further investigation.
Gasic
S
S
Department of Internal Medicine, University of Texas Medical Branch, Galveston 77555-1060, USA.
Bodenburg
Y
Y
Nagamani
M
M
Green
A
A
Urban
R J
RJ
D015096:3-Hydroxysteroid Dehydrogenases / Q000378:metabolism; D000818:Animals; D002478:Cells, Cultured; D002839:Chromans / Q000494:pharmacology*; D005576:Colforsin / Q000494:pharmacology; D004958:Estradiol / Q000378:metabolism; D005260:Female; D005640:Follicle Stimulating Hormone / Q000494:pharmacology; D006107:Granulosa Cells / Q000187:drug effects* / Q000378:metabolism*; D011374:Progesterone / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D013256:Steroids / Q000096:biosynthesis; D013552:Swine; D013844:Thiazoles / Q000494:pharmacology*; D045162:Thiazolidinediones; D013997:Time Factors; D000077288:Troglitazone
D002839:Chromans; D013256:Steroids; D013844:Thiazoles; D045162:Thiazolidinediones; D005576:Colforsin; D011374:Progesterone; D004958:Estradiol; D005640:Follicle Stimulating Hormone; D015096:3-Hydroxysteroid Dehydrogenases; D000077288:Troglitazone