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Mol. Hum. Reprod. Advance Access originally published online on May 29, 2009
Molecular Human Reproduction 2009 15(7):421-432; doi:10.1093/molehr/gap033
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© The Author 2009. 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 effects of metformin on uterine tissue of hyperandrogenized BALB/c mice

Evelin Mariel Elia1, Denise Belgorosky1, Mónica Faut1, Susana Vighi2, Carolina Pustovrh3, Devoto Luigi3 and Alicia Beatriz Motta1,4

1 Laboratorio de Fisio-patología Ovárica, Centro de Estudios Farmacológicos y Botánicos (CEFYBO), UBA-CONICET. Paraguay 2155, 1121, BuenosAires, Argentina 2Departamento de Patología, Hospital de Clínicas, Universidad de Buenos Aires (UBA), Buenos Aires, Argentina 3 Instituto de Investigaciones Materno Infantil (IDIMI), Santiago, Chile

4 Correspondence address. E-mail: aliciabmotta{at}yahoo.com.ar

The present study investigated the role of the N, N'-dimethylbiguanide metformin (50 mg/kg body weight in 0.05 ml water, given orally with a canulla) in preventing the adverse effects generated by hyperandrogenism on uterine function. Daily injection of dehydroepiandrosterone (DHEA: 6 mg/100 g body weight in 0.1 ml oil) for 20 consecutive days induces polycystic ovaries in BALB/c mice. In this model we found that DHEA produced alterations on uterine histology closely related to the development of pre-cancerous structures concomitantly with increased incidence of uterine apoptosis. The injection of DHEA induced a pro-inflammatory status since uterine prostaglandin (PG) F2 alpha levels and cyclooxygenase 2 were increased although PGE levels were decreased. Furthermore, DHEA promoted a pro-oxidant status since it increased nitric oxide synthase (NOS) activity and decreased superoxide dismutase and catalase activities and the antioxidant metabolite glutathione levels. DHEA also regulated the percentages of CD4+ and CD8+ T lymphocyte that infiltrate uterine tissue. When metformin was administered together with DHEA uterine histology and apoptosis did not differ when compared with controls. Therefore, metformin prevented the pro-inflammatory and pro-oxidative status generated by DHEA and restores the ratios of CD4+ and CD8+ T cells to those observed in controls. We conclude that metformin is able to restore either directly or indirectly uterine function by preventing some inflammatory and oxidative alterations produced by hyperandrogenism.

Key words: PCOS/Metformin/uterus/T lymphocytes/Prostaglandins

Submitted on January 12, 2009; resubmitted on April 24, 2009; accepted on May 11, 2009.


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