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Mol. Hum. Reprod. Advance Access originally published online on June 29, 2006
Molecular Human Reproduction 2006 12(8):475-481; doi:10.1093/molehr/gal057
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© The Author 2006. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

The mechanisms involved in the action of metformin in regulating ovarian function in hyperandrogenized mice

E. Elia1, V. Sander1, C.G. Luchetti1, M.E. Solano1, G. Di Girolamo2, C. Gonzalez2 and A.B. Motta1,3

1Laboratorio de Fisio-patología Ovárica, Centro de Estudios Farmacológicos y Botánicos (CEFYBO), Facultad de Medicina (UBA), Consejo de Investigaciones Científicas y Tecnológicas (CONICET) and 2Departamento de Farmacología, Facultad de Medicina, Paraguay, Buenos Aires, Argentina

3 To whom correspondence should be addressed at: Laboratorio de Fisio-patología Ovárica, Centro de Estudios Farmacológicos y Botánicos (CEFYBO), Facultad de Medicina (UBA), Consejo de Investigaciones Científicas y Tecnológicas (CONICET), Paraguay 2155, (1121) Buenos Aires, Argentina. E-mail: aliciabmotta{at}yahoo.com.ar

The aim of this study was to investigate the mechanisms by which N,N'-dimethylbiguanide metformin (50 mg/100 g body weight (BW) in 0.05 ml of water, given orally with a cannula) prevents the ovarian disorders provoked by the hyperandrogenization with dehydroepiandrosterone (DHEA) in prepuberal BALB/c mice. The injection of DHEA (6 mg/100 g BW in 0.1 ml of oil) for 20 consecutive days re-creates a mouse model that resembles some aspects of the human polycystic ovary syndrome (PCOS). The treatment with DHEA increased ovarian oxidative stress because it enhanced lipid peroxidation (LPO) and diminished both catalase (CAT) activity and glutathione (GSH) content. Therefore, the treatment with DHEA diminished both ovarian nitric oxide synthase (NOS) activity and prostaglandin E (PGE) production. When metformin was administered together with DHEA, the ovarian GSH content, NOS activity and PGE production did not differ when compared with controls. However, metformin was not able to prevent the effect of DHEA on ovarian LPO or CAT activity. Finally, DHEA increased the ovarian protein expressions of inducible NOS (iNOS), inducible cyclooxygenase (COX2) and the phosphorylated AMP-depen-dent kinase {alpha} (AMPK-{alpha}) (Thr172). Metformin administered together with DHEA was able to prevent the increase of ovarian iNOS and COX2 expressions and to enhance the activation of phosphorylated AMPK-{alpha} expression.

Key words: AMP-dependent kinase {alpha}/cyclooxygenase/dehydroepiandrosterone/polycystic ovary syndrome


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[Abstract] [Full Text] [PDF]


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