Effects of metformin administration on plasma gonadotropin levels in women with infertility, with an in vitro study of the direct effects on the pituitary gonadotrophs

Changes in LH and FSH levels were evaluated before and after metformin administration. In all 25 patients, plasma LH levels were significantly reduced after 3 months of metformin administration (500–1,500 mg/day). When patients were classified into a PCOS group (n = 12) or a non-PCOS group (n = 13), the reduction in LH levels only remained significant in the PCOS group. Plasma FSH levels were unchanged following metformin treatment when all patients were considered collectively and when patients were classified based on PCOS. LH/FSH ratio was significantly reduced only in the PCOS group. To examine the direct effect of metformin on gonadotropin-secreting cells, gonadotroph cell line, LβT2 was used for in vitro studies. Treatment of LβT2 cells with metformin modified neither the LHβ nor the FSHβ subunit promoter activity. The GnRH-induced LHβ promoter activity was not modulated in the presence of metformin. In contrast, GnRH-induced FSHβ promoter activity was significantly potentiated in the presence of metformin. Our results suggest that metformin does indeed modulate the basal level of LH and the LH/FSH ratio, albeit indirectly, particularly in the patients with PCOS. Additionally our results suggest that metformin does directly regulate FSH gene expression.