Role of the N, N′-dimethylbiguanide metformin in the treatment of female prepuberal BALB/c mice hyperandrogenized with dehydroepiandrosterone

Abstract

The present study investigated the role of the N, N{ 0 }-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 1 T lymphocyte population and increased the percentage of the CD8 1 T lymphocyte population from both ovarian tissue and retroperitoneal lymph nodes. However, when metformin was administered together with DHEA, the percentages of CD4 1 and CD8 1 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-a) levels when compared with controls; however, when metformin was administered together with DHEA, serum TNF-a 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.

Dehydroepiandrosterone improves the ovarian reserve of women with diminished ovarian reserve and is a potential regulator of the immune response in the ovaries

“…DHEA restores the cell-mediated immune response of pro-inflammatory cytokines (IL-1, IL-6, TNF-α, and IL-18). Mice treated with DHEA exhibited increased production of cytokines such as serum TNF-α, IL-6, IL12p70, and IFN-γ (82,83). DHEA supplementation also increases vascular cell adhesion molecule 1 (VCAM-1) and intercellular cell adhesion molecule 1 (ICAM-1) in the granulosa cell layer of cysts and the theca cell layer of all follicles and cysts when DHEA androgenization induces the formation of cysts (83).…”

“…Extrathymic (DP) CD4+/ CD8+ T cells positively correlated with circulating levels of TNF-α and with the cortisol/DHEAs ratio (87). Flow cytometry showed that DHEA treatment in mice significantly increased the CD4+ lymphocyte population and decreased the CD8+ lymphocyte population, thus modulating the CD4+/CD8+ lymphocyte balance in both ovarian tissue and retroperitoneal lymph nodes (82). This may be due to the selective T lymphocyte infiltration of ovarian tissue (88).…”

Effect of DHEA and metformin on corpus luteum in mice

“…The dose of DHEA injected was that previously used by Lee et al (1991Lee et al ( , 1998, Henmi et al (2001), Luchetti et al (2004), Sander et al (2005Sander et al ( , 2006, Elia et al (2006) and Solano et al (2006) and ensure a hyperandrogenized status. The dose of metformin administered was ensured to that used in the treatment of women with PCOS.…”

Rodent models of polycystic ovary syndrome

“…Postnatal treatment of mice [47,48] and rats [44][45][46] with DHEA for 20 consecutive days resulted in all or most females exhibiting follicular cysts with a thin granulosa cell layer and anovulation. Ovaries exhibited an increase in fat and stroma tissues and increased numbers of atretic follicles [48,49], hyperandrogenism, and altered ovarian steroidogenesis with elevated serum levels of androgens [44,48,50], estrogens, P, and prostaglandin [44,47,49,50].…”

“…Ovaries exhibited an increase in fat and stroma tissues and increased numbers of atretic follicles [48,49], hyperandrogenism, and altered ovarian steroidogenesis with elevated serum levels of androgens [44,48,50], estrogens, P, and prostaglandin [44,47,49,50]. In one study, LH levels were elevated while follicle-stimulating hormone (FSH) levels did not change [44], but in other studies, LH and FSH levels were both decreased [46] or unchanged [50].…”