Mansfield, R., Galea, R., Brincat, M., Hole, D., & Mason, H. (2003). Metformin has direct effects on human ovarian steroidogenesis. Fertility and Sterility, 79(4), 956-962. https://doi.org/10.1016/s0015-0282(02)04925-7
Mansfield R, Galea R, Brincat M, Hole D, Mason H. Metformin has direct effects on human ovarian steroidogenesis. Fertil Steril. 2003;79(4):956-962. doi:10.1016/s0015-0282(02)04925-7
Mansfield, Rebecca, et al. "Metformin has direct effects on human ovarian steroidogenesis." Fertility and Sterility, vol. 79, no. 4, 2003, pp. 956-962.
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Metformin lowers androgen production in cultured human ovarian cells
In ovarian cells from women who had their ovaries removed, metformin lowered androgen output from cultured theca cells. In granulosa cells grown in culture, it also reduced hormone-stimulated estradiol and progesterone output. Effects were clearest with insulin present.
Key Findings
Theca cells made 0%–40% less androstenedione (A) with metformin.
With insulin added, metformin reduced A in step with the dose, while progesterone (P) rose by a similar amount. The authors report the combined P rise was not significant.
In granulosa cells (GCs), metformin reduced P and estradiol (E2) output driven by gonadotropin and by insulin, by 25%–50%, in step with the dose.
Metformin alone had a variable effect on GCs. P and E2 were both significantly inhibited (range 0%–30%).
GC number at the end of the experiment did not change significantly, judged by MTT assay.
Interpretation
The study is an in vitro experiment. Researchers grew ovarian cells for 48 hours and measured the hormones released. Cells from normal and polycystic ovaries showed no obvious difference in response, so the data were pooled. The authors state they had insufficient data in the two groups to draw firm conclusions. Effects appeared at concentrations the authors suggest may be at or below the physiological range.
RRM Context
PCOS (also called PMOS, Polyendocrine Metabolic Ovarian Syndrome) involves excess ovarian androgen. The authors note that affected women are often insulin resistant. Restorative reproductive medicine looks for the mechanisms that drive a condition. Here those are androgen output from theca cells and the insulin signal that stimulates it. The paper reports that metformin acts directly on ovarian cells in culture.
Our editorial summary of this paper, not the article's abstract.
Abstract
Objective
To investigate the possibility of direct effects of metformin on ovarian steroidogenesis.
Design
Cultured ovarian cells.
Setting
Academic research environment.
Patients
Women undergoing bilateral salpingoophorectomy for benign gynecological disease.
Main Outcome Measures
Estradiol and P were measured in granulosa cell (GC) conditioned medium and androstenedione (A) and P in theca conditioned medium.
Results
The effect of addition of metformin alone to GCs was variable, but significant inhibition of both P and E2 was seen (range 0%-30%). Metformin dose-dependently inhibited gonadotrophin and insulin-stimulated P and E2 production (range 25%-50%). In theca, metformin inhibited A production (0%-40%) with no effect on P. In the presence of insulin, A was inhibited dose-dependently and P increased by a similar magnitude.
Conclusions
These results demonstrate a direct effect of metformin on ovarian steroidogenesis. The inhibitory effects on androgen production in particular would be beneficial in polycystic ovary syndrome (PCOS).
