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Candela Velazquez Studies of the Physiopathology of the Ovary Laboratory, Institute of Biology and Experimental Medicine (IBYME) - National Scientific and Technical Research Council (CONICET), Autonomous City of Buenos Aires, Argentina

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Mayra Bordaquievich Studies of the Physiopathology of the Ovary Laboratory, Institute of Biology and Experimental Medicine (IBYME) - National Scientific and Technical Research Council (CONICET), Autonomous City of Buenos Aires, Argentina

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Yamila Herrero Studies of the Physiopathology of the Ovary Laboratory, Institute of Biology and Experimental Medicine (IBYME) - National Scientific and Technical Research Council (CONICET), Autonomous City of Buenos Aires, Argentina

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Débora Juana Cohen Molecular Mechanisms of Fertilization Laboratory, Institute of Biology and Experimental Medicine (IBYME) - National Scientific and Technical Research Council (CONICET), Autonomous City of Buenos Aires, Argentina.

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María Silvia Bianchi Neuroendocrine Biochemistry Laboratory, Institute of Biology and Experimental Medicine (IBYME) - National Scientific and Technical Research Council (CONICET), Autonomous City of Buenos Aires, Argentina.

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Patricia Cuasnicu Molecular Mechanisms of Fertilization Laboratory, Institute of Biology and Experimental Medicine (IBYME) - National Scientific and Technical Research Council (CONICET), Autonomous City of Buenos Aires, Argentina.

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Katherine Prost Pedro Fiorito Hospital, Endocrinology area, Buenos Aires Province, Argentina.

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Natalia Pascuali Studies of the Physiopathology of the Ovary Laboratory, Institute of Biology and Experimental Medicine (IBYME) - National Scientific and Technical Research Council (CONICET), Autonomous City of Buenos Aires, Argentina
Department of Pathology, College of Medicine, University of Illinois at Chicago (UIC), Chicago, Illinois, USA

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Fernanda Parborell Studies of the Physiopathology of the Ovary Laboratory, Institute of Biology and Experimental Medicine (IBYME) - National Scientific and Technical Research Council (CONICET), Autonomous City of Buenos Aires, Argentina

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Dalhia Abramovich Studies of the Physiopathology of the Ovary Laboratory, Institute of Biology and Experimental Medicine (IBYME) - National Scientific and Technical Research Council (CONICET), Autonomous City of Buenos Aires, Argentina

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In brief

The hypoglycemic drug metformin has shown reproductive effects in women, although its mechanism of action is not fully understood. In this study, we demonstrate the direct effects of metformin on the ovary of healthy mice, with no alterations in fertility.

Abstract

Metformin is a hypoglycemic drug widely used in type-2 diabetes (T2D) patients. In recent years, this drug has been suggested as a treatment for gestational diabetes and recommended to women with ovarian hyperstimulation syndrome (PCOS) to increase the chances of pregnancy or avoid early miscarriages. However, the exact effects of metformin on the female reproductive tract in general, and on the ovary in particular, are still not completely understood. In this study, we analyzed the effect of metformin on fertility and ovarian physiology in healthy female mice. We found that this drug altered the estrous cycle, early follicular development, serum estradiol and progesterone levels, and ovarian steroidogenic enzyme expression. Moreover, ovarian angiogenesis was lower in metformin-treated animals compared with untreated ones, whereas natural or gonadotropin-induced fertilization rates remained unchanged. However, offspring of metformin-treated animals displayed decreased body weight at birth. In this work, we unraveled the main effects of metformin on the ovary, isolated from other conditions such as hyperglycemia and hyperandrogenism, which is essential for a better understanding of metformin’s mechanisms of action on reproduction and fertility.

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