The effects of metformin on uterine tissue of hyperandrogenized BALB/c mice.

The present study investigated the role of the N, N'-dimethylbiguanide metformin (50 mg/kg body weight in 0.05 ml water, given orally with a canulla) in preventing the adverse effects generated by hyperandrogenism on uterine function. Daily injection of dehydroepiandrosterone (DHEA: 6 mg/100 g body weight in 0.1 ml oil) for 20 consecutive days induces polycystic ovaries in BALB/c mice. In this model we found that DHEA produced alterations on uterine histology closely related to the development of pre-cancerous structures concomitantly with increased incidence of uterine apoptosis. The injection of DHEA induced a pro-inflammatory status since uterine prostaglandin (PG) F2 alpha levels and cyclooxygenase 2 were increased although PGE levels were decreased. Furthermore, DHEA promoted a pro-oxidant status since it increased nitric oxide synthase (NOS) activity and decreased superoxide dismutase and catalase activities and the antioxidant metabolite glutathione levels. DHEA also regulated the percentages of CD4+ and CD8+ T lymphocyte that infiltrate uterine tissue. When metformin was administered together with DHEA uterine histology and apoptosis did not differ when compared with controls. Therefore, metformin prevented the pro-inflammatory and pro-oxidative status generated by DHEA and restores the ratios of CD4+ and CD8+ T cells to those observed in controls. We conclude that metformin is able to restore either directly or indirectly uterine function by preventing some inflammatory and oxidative alterations produced by hyperandrogenism.