Direct effect of Metformin on granulosa cells: widening the uses of this drug in Polycystic Ovary Syndrome.

DI PIETRO MARIANA; PASCUALI NATALIA; ABRAMOVICH DALHIA; IRUSTA GRISELDA; PARBORELL, FERNANDA; SCOTTI LEOPOLDINA; TESONE, MARTA

Congreso; Reunión Anual de la Sociedad Argentina de Investigacion Clinica; 2016

Polycystic Ovary Syndrome (PCOS) is a frequentpathology that affects more than 5% of women of reproductive age. Its symptomsare heterogeneous and range from chronic anovulation, oligo- or amenorrhea andhyperandrogenism to obesity and insulin resistance. In addition, PCOS ischaracterized by abnormalities in angiogenesis and alteration in the levels ofangiogenic factors.Metformin has been introduced in the treatmentof PCOS to manage insulin resistance and hyperglycemia. Besides its metaboliceffects, metformin has been shown to improve ovulation, pregnancy and livebirth rates in PCOS patients. Metformin mechanism of action on the ovary is notknown and a direct effect of this drug on follicular cells cannot be discarded.Metformin can get into the cell by passive diffusion or through the OrganicCation Transporters (OCTs). Hypothesis: Metformin can act directly ongranulosa cells modulating angiogenic factor synthesis. Methods: Granulosa cells were isolated fromDES-treated prepubertal Sprague Dawley rat ovaries. Cells were seeded ontoplastic plates precoatedwith rat tail collagen with 10% bovine fetal serum.After 24, medium was replaced by serum-free medium and the cells werestimulated with different concentrations of metformin (0; 0.01 and 0.1 mM). Results: Metformin increased the levels ofphospho-AMPK and decreased the levels of VEGF in granulosa cells. Furthermore,we demonstrated for the first time the presence of OCT2 and OCT3 in granulosacells. Conclusion: Our results suggest that metformin actsdirectly on granulosa cells modulating their function and angiogenic factorsysthesis. This drug could be getting into the cell through its transportersOCT2 and OCT3. The study of metformin mechanism of action will allow therevision of its indication and uses, leading to a direct benefit to patientstrying to conceive.