Related Experiment Videos
Metformin directly inhibits androgen production in human thecal cells
G R Attia1, W E Rainey, B R Carr
1Division of Reproductive Endocrinology, Department of Obstetrics and Gynecology, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75235-9032, USA.
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, 17 alpha-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 microM and 200 microM) 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 microM 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 17 alpha-hydroxylase (CYP17) expression in cells stimulated with forskolin compared with forskolin treatment alone. There was no significant change in either 3beta-hydroxysteroid dehydrogenase (3 beta HSD) 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 microM) 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.
Insights
Metformin directly reduces androgen production in ovarian theca cells by inhibiting key enzymes like CYP17. This study investigates metformin's impact on steroidogenesis, suggesting a potential therapeutic role.
Area of Science:
- Reproductive Endocrinology
- Molecular Endocrinology
- Pharmacology
Background:
- Polycystic ovary syndrome (PCOS) is associated with hyperandrogenism, often treated with metformin.
- Thecal cells are the primary site of ovarian androgen production.
- The direct impact of metformin on thecal cell steroidogenesis requires further elucidation.
Purpose of the Study:
- To investigate the direct effect of metformin on androgen production by human ovarian theca-like cells.
- To determine metformin's influence on key steroidogenic enzymes and their gene expression in thecal cells.
Main Methods:
- Human ovarian theca-like tumor cells were cultured and treated with varying concentrations of metformin.
- Forskolin was used to stimulate steroidogenesis.
- Androgen levels (progesterone, 17OHP, androstenedione, testosterone) were measured via radioimmunoassay (RIA).
- Western blot and Northern analysis were employed to assess protein and mRNA expression of steroidogenic enzymes, including StAR and CYP17.
Main Results:
- Metformin significantly inhibited androstenedione production in both unstimulated and forskolin-stimulated theca cells.
- Testosterone production was significantly reduced in forskolin-stimulated cells treated with metformin.
- Metformin significantly decreased the expression of steroidogenic acute regulatory (StAR) protein and 17 alpha-hydroxylase (CYP17) protein and mRNA in forskolin-stimulated cells.
Conclusions:
- Metformin exerts a direct inhibitory effect on androgen production in ovarian theca cells.
- The mechanism involves the downregulation of StAR and CYP17 expression.
- These findings suggest a potential direct role for metformin in managing hyperandrogenism.