Dehydroepiandrosterone and metformin modulate progesterone-induced blocking factor (PIBF), cyclooxygenase 2 (COX2) and cytokines in early pregnant mice

The present study examined the mechanism by which metformin (N,N′-dimethylbiguanide) prevents embryonic resorption induced in mice by dehydroepiandrosterone (DHEA). Treatment with DHEA (60 mg/kg, s.c. 24 and 48 h post-implantation) induces embryo resorption of early pregnant BALB/c mice while simultaneous treatment with metformin (240 mg/kg, oral 24 and 48 h post-implantation) prevents it. During pregnancy progesterone-induced blocking factor (PIBF) modulates prostaglandins (PGs) and cytokine production. These findings prompted us to investigate the effect of DHEA and metformin on both PIBF and cyclooxygenase 2 (COX2) expressions at the implantation sites, as well as cytokine production. PIBF and COX2 expression were detected by immunohistochemistry from DHEA and DHEA+ metformin treated 8 days-pregnant mice and serum cytokine levels of these animals were determined by ELISA. DHEA treatment both abolished PIBF expression and increased COX2 expression. Embryo resorption correlates with the lack of PIBF expression, diminished IL-6 levels and increased IL-2 concentration while metformin was able to reverse the effect of DHEA on both PIBF and COX2 expression and IL-6 levels. We concluded that hyperandrogenization induces embryo resorption in early pregnancy diminishing PIBF in implantation sites, having a pro-inflammatory effect. Metformin is able to prevent such effects.