METFORMIN IS ABLE TO RESTORE OVARIAN CYCLICITY IN HYPERANDROGENIZED MICE: ROL OF OXIDATIVE BALANCE

VALERIA SANDER; LILIA PIEHL; GRACIELA FACORRO; EMILIO RUBEN DE CELIS; ALICIA BEATRIZ MOTTA

Miami, Florida, USA

Congreso; INTER-AMERICAN SOCIETY OF HYPERTENSION XVIITH SCIENTIFIC SESSIONS; 2007

INTER-AMERICAN SOCIETY OF HYPERTENSION XVIITH SCIENTIFIC SESSIONS

Polycystic ovary syndrome (PCOS), which is characterized by hyperandrogenism, is associated with multiple cardiovascular risk factors, such as hypertension, obesity, insulin resistance and menstrual irregularity. In previous studies we have demonstrated that the hyperandrogenization with dehydroepiandrosterone (DHEA) modified the ovarian steroidogenesis and the estral cycle in prepuberal Balb/c mice. Treatment with metfmormin (Met), an insulin-sensitizing drug, was able to restore these parameters. In view that reactive oxygen species (ROS) are involved in corpus luteum regression; the aim of the present study was to evaluate the effects of DHEA and Met on the oxidative balance during luteolysis.  Prepuberal Balb/c mice were injected i.p with equine chorionic gonadotropin  (eCG:10UI/mouse,day 0) to induce ovulation and formation of corpora lutea that remain functional for 11 days. Mice were treated 24 y 48 hours before euthanasia (day 11): DHEA(sc, 60mg/kg), Met(oral 50mg/kg), DHEA+Met y  control vehicle (Veh), n=10 animals/treatment-assay. In ovarian tissue superoxide dismutase (SOD) and catalase(CAT) activities were studied, the DMPO/°OH  adduct was evaluated by electronic spin resonance (ESR), lipoperoxidation index (LPO) and glutathione formation (GSH) were measured. Serum progesterone (P4) and ovarian prostaglandin F-2alfa(PGF-2a) were quantified by radioimmunoassay (RIA). SOD was increased in DHEA and DHEA+Met(p<0.01), whereas Met was similar related to Veh (130+30; 170+20; 67+6 and 63+16 USOD/mg prot). CAT activity was significantly higher in DHEA and Met(p<0.05) and wasn’t significantly different in DHEA+Met in comparison to Veh(0.19+0.02; 0.18+0.02; 0.17+0.02 and 0.11+0.01  pmol CAT/mg prot). The intensity of DMPO/°OH adduct fell (p<0.01) in DHEA and Met, on the contrary, DHEA+Met didn’t differ from Veh (60+10; 62+9; 71+5 and 110+20 AU of intensity of DMPO/°OH adduct /micrograme prot). Neither DHEA nor DHEA+Met modified LPO, only Met reduced it (p<0.01) regarding to Veh (0.440+0.08; 0.57+0.09; 0.29+0.06 and 0.7+0.1 nm malonialdehyde /mg tissue). GSH was augmented only in Met(p<0.01), in contrast to DHEA and DHEA+Met that didn’t differ from Veh (3+0.2; 2+0.2; 2+0.2 y 2+0.1  umol GSH/mg tissue). P4 levels were increased only in DHEA(p<0.05), DHEA+Met and Met were similar to Veh (1200+200; 700+100; 800+100 vs 600+200 pg P4 /ml serum ). PGF-2a was diminished(p<0.05) in DHEA, while DHEA+Met and Met were alike Veh (110+10; 130+10; 155+7 vs. 170+30 pg PGF-2a/mg tissue). The hyperandrogenization increased P4 secretion and diminished the formation of superoxide, hydrogen peroxide and hydroxyl radicals during corpus luteum regression. These facts lead to a PGF-2a diminution, which would avoid the normal ovarian cyclicity. Metformin treatment given together with DHEA (DHEA+Met group) was found capable of reverting these effects, excepting SOD activity, which remained augmented. Thus, the administration of metformin to target ovarian cycle irregularities might be useful to eliminate this cardiovascular risk factor.