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The present study investigated the role of the N, N{'}-dimethylbiguanide metformin (50 mg/100 g body weight in 0.05 ml water, given orally with a canulla) in the prevention of endocrine and immune disorders provoked by the hyperandrogenization with dehydroepiandrosterone (DHEA) in prepuberal BALB/c mice. The treatment with DHEA (6 mg/100 g body weight in 0.1 ml oil) for 20 consecutive days, recreates a mouse model that resembles some aspects of the human polycystic ovary syndrome (PCOS). The treatment with DHEA did not modify either body mass index (BMI) or blood glucose levels, but did increase fasting insulin levels when compared with controls. Markers of ovarian function - serum estradiol (E), progesterone (P) and ovarian prostaglandin E (PGE) - were evaluated. The treatment with DHEA increased serum E and P levels while ovarian PGE diminished. When metformin was administered together with DHEA, serum insulin, E and P levels, and ovarian PGE values did not differ when compared with controls. Using flow cytometry assays we found that the treatment with DHEA diminished the percentage of the CD4 + T lymphocyte population and increased the percentage of the CD8 + T lymphocyte population from both ovarian tissue and retroperitoneal lymph nodes. However, when metformin was administered together with DHEA, the percentages of CD4 + and CD8 + T lymphocyte populations from both ovarian tissue and retroperitoneal lymph nodes were similar to those observed in controls. Finally, when DHEA was administered alone it increased the serum tumor necrosis factor-alpha (TNF-alpha ) levels when compared with controls; however, when metformin was administered together with DHEA, serum TNF-alpha levels were similar to controls. These results indicate that metformin is able, directly or indirectly, to avoid the endocrine and immune alterations produced when mice are hyperandrogenized with DHEA.

Corpus luteum regression has been described in terms of: (i) functional luteolysis - a reversible decline in serum progesterone concentration; and (ii) structural luteolysis - irreversible morphological changes and tissue remodelling events within the cellular membrane. In rats, PGF(2alpha) and interleukin 1beta (IL-1beta) are involved in structural luteolysis, PGF(2alpha) by increasing ovarian lipid peroxidation, and IL-1beta by reducing progesterone and increasing PGF(2alpha) concentrations. The aim of the present report was to determine whether by an early action IL-1beta is able to regulate functional luteolysis. Thus, ovarian explants from rats at the mid-stage of corpus luteum development were incubated during short periods with either 15 or 25 ng IL-1beta ml(-1). At 15 ng ml(-1), IL-1beta inhibited progesterone after 4 and 8 h of culture without affecting PGF(2alpha) production, and a longer incubation (21 h) was needed to increase PGF(2alpha) production. In contrast, IL-1beta enhanced PGF(2alpha) concentrations at 8 h only at the higher dose (25 ng ml(-1)). The observed reduction in progesterone synthesis at the lower dose of IL-1beta before the increase in PGF(2alpha) concentrations led to the hypothesis that IL-1beta regulates functional luteolysis (progesterone diminution) before it affects structural luteolysis (PGF(2alpha) increase). The fact that the early IL-1beta action was described at 4 h but no effects on inducible nitric oxide synthase and inducible cyclooxygenase expression were found before this time led to the suggestion that these inductions were not necessary for the early IL-1beta action described.