The effects of metformin on uterine tissue of hyperandrogenized BALB/c mice.
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.
Elia
Evelin Mariel
EM
Laboratorio de Fisio-patología Ovárica, Centro de Estudios Farmacológicos y Botánicos (CEFYBO), UBA-CONICET, BuenosAires, Argentina.
Belgorosky
Denise
D
Faut
Mónica
M
Vighi
Susana
S
Pustovrh
Carolina
C
Luigi
Devoto
D
Motta
Alicia Beatriz
AB
D000818:Animals; D015153:Blotting, Western; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000378:metabolism; D002374:Catalase / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000378:metabolism; D003687:Dehydroepiandrosterone / Q000494:pharmacology; D015237:Dinoprost / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D005434:Flow Cytometry; D066298:In Vitro Techniques; D008687:Metformin / Q000494:pharmacology*; D051379:Mice; D008807:Mice, Inbred BALB C; D019001:Nitric Oxide Synthase / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D011085:Polycystic Ovary Syndrome / Q000139:chemically induced / Q000517:prevention & control*; D011863:Radioimmunoassay; D013482:Superoxide Dismutase / Q000378:metabolism; D014599:Uterus / Q000187:drug effects* / Q000378:metabolism
D003687:Dehydroepiandrosterone; D008687:Metformin; D015237:Dinoprost; D002374:Catalase; D019001:Nitric Oxide Synthase; D051546:Cyclooxygenase 2; D013482:Superoxide Dismutase