Attia, G. R., Rainey, W. E., & Carr, B. R. (2001). Metformin directly inhibits androgen production in human thecal cells. Fertility and Sterility, 76(3), 517-524. https://doi.org/10.1016/s0015-0282(01)01975-6
Attia GR, Rainey WE, Carr BR. Metformin directly inhibits androgen production in human thecal cells. Fertil Steril. 2001;76(3):517-524. doi:10.1016/s0015-0282(01)01975-6
Attia, George R., et al. "Metformin directly inhibits androgen production in human thecal cells." Fertility and Sterility, vol. 76, no. 3, 2001, pp. 517-524.
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The University of Texas Southwestern Medical Center05byvp690
Division of Reproductive Endocrinology, Department of Obstetrics and Gynecology, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75235-9032, USA.
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RRM Academy Synopsis
Metformin lowered androgen production in cultured human thecal cells
Metformin lowered androgen production in cultured human ovarian thecal cells. Researchers treated a human thecal-like tumor cell line with metformin for 48 hours. They measured steroid output and proteins involved in making steroids. The authors suggest metformin may act on the cells directly.
Key Findings
Metformin alone lowered androstenedione, an androgen, by 40% at the lower concentration and 65% at the higher concentration, compared with untreated cells.
In cells stimulated with forskolin, which raised steroid output, metformin lowered androstenedione by 25% and 50% and testosterone by 10% and 40%. The testosterone drop was significant only at the higher concentration.
Combined output of androstenedione, 17-hydroxyprogesterone and progesterone in forskolin-stimulated cells fell by 17% and 35% at the two concentrations.
CYP17 messenger RNA in forskolin-stimulated cells fell by 44% and 65%. On Western blot in forskolin-stimulated cells, CYP17 protein and StAR protein fell, while StAR messenger RNA showed no significant change.
Metformin alone raised progesterone output by 30% at the higher concentration and left testosterone output unchanged compared with untreated cells.
Interpretation
This laboratory study treated human ovarian thecal cells with metformin for 48 hours. The cells came from a thecal-like tumor line. The authors state the cells keep many traits of normal thecal cells. Androstenedione fell more than 17-hydroxyprogesterone in the treated cells. The authors say this points to metformin blocking the lyase step of the CYP17 enzyme. The authors note that blood levels after oral metformin run lower than both doses tested here. The findings support further study of this direct effect in women with PMOS.
RRM Context
Women with polyendocrine metabolic ovarian syndrome (PMOS), formerly polycystic ovary syndrome (PCOS), have excess androgens. Restorative reproductive medicine looks for the cause of that excess. The paper cites reports that weight loss or an insulin-lowering drug cut baseline androgen levels in these women. The authors say the cell results could partly explain the lower levels in women treated with metformin.
Our editorial summary of this paper, not the article's abstract.
Abstract
Objective
To examine the direct effect of metformin on thecal cell androgen production.
Setting
Basic science research laboratory, University of Texas Southwestern, Dallas, Texas.
Interventions
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 Measures
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.
Results
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.
Conclusions
Our results suggest that metformin may have a direct effect on thecal cells' androgen production.
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