Metformin directly inhibits androgen production in human thecal cells

Objective: To examine the direct effect of metformin on thecal cell androgen production. Setting: Basic science research laboratory, University of Texas Southwestern, Dallas, Texas. Intervention(s): Human ovarian theca-like tumor cells were treated with various concentrations of metformin in the presence and absence of forskolin for 48 hours. Main Outcome Measure(s): Media were collected, and radioimmunoassay (RIA) for progesterone, 17α-hydroxyprogesterone (17OHP), androstenedione, and testosterone was performed. The effect of metformin on the expression of various enzymes involved in theca cell steroidogenesis was examined. Result(s): Metformin (50 μM and 200 μM) significantly inhibited androstenedione production from both forskolin-stimulated and unstimulated theca cells. Testosterone production was also significantly inhibited in forskolin-treated cells in the presence of 200 μM of metformin-treated compared with forskolin-only-treated cells. Western blot analysis revealed that metformin significantly inhibited the expression of steroidogenic acute regulatory (StAR) protein and 17α-hydroxylase (CYP17) expression in cells stimulated with forskolin compared with forskolin treatment alone. There was no significant change in either 3β-hydroxysteroid dehydrogenase (3βHSD) or cholesterol side-chain cleavage (CYP11A1) protein expression. Northern analysis revealed a significant decrease in the expression of CYP17 mRNA in forskolin-stimulated cells treated with metformin (200 μM) compared with forskolin-only-treated cells, however, there was no significant change in steroidogenic acute regulatory protein mRNA expression. Conclusion(s): Our results suggest that metformin may have a direct effect on thecal cells' androgen production.