The effects of rosiglitazone and metformin on oxidative stress and homocysteine levels in lean patients with polycystic ovary syndrome

Murat Yilmaz 2 Neslihan Bukan 1 Gksun Ayvaz 0 Ayhan Karako 0 Fsun Trner 0 Nuri akir 0 Metin Arslan 0 0 Endocrinology and Metabolism, Faculty of Medicine, Gazi University , Ankara , Turkey 1 Departments of Biochemistry 2 Department of Endocrinology and Metabolism, Faculty of Medicine, Kirikkale University , 71100 Kirikkale BACKGOUND: Oxidative stress and hyperhomocysteinaemia are risk factors for cardiovascular diseases. The aim of this study was to assess the effects of rosiglitazone and metformin on cardiovascular disease risk factors such as insulin resistance, oxidative stress and homocysteine levels in lean patients with polycystic ovary syndrome (PCOS). MEHODS: Fifty lean patients (BMI <25 kg/m2) with PCOS and 35 healthy subjects were included this study. Serum homocysteine, sex steroids, fasting insulin, fasting glucose and lipid levels were measured. Total antioxidant status (TAS; combines concentrations of individual antioxidants) and malonyldialdehyde concentration (MDA) were determined. Insulin resistance was evaluated by using the homeostasis model insulin resistance index (HOMA-IR), quantitative insulin sensitivity check index (QUICKI), Area under the curve insulin (AUCI) and the insulin sensitivity index (ISI). Patients were divided into two groups. One group was treated with metformin (n = 25) and the other received rosiglitazone (n = 25) for 12 weeks. All measurements were repeated at the end of 12 weeks. RESULTS: Compared with healthy women, those with PCOS had significantly elevated serum MDA, homocysteine, HOMA-IR, AUCI and lipoprotein a levels, and significantly decreased serum TAS, QUICKI and ISI. Serum free testosterone levels showed a significant positive correlation with MDA, AUCI and HOMA-IR, and a negative correlation with TAS, ISI and QUICKI in PCOS patients. HOMA-IR and AUCI significantly decreased, while QUICKI and ISI significantly increased after treatment in both groups. Serum TAS level increased and serum MDA level decreased after the rosiglitazone treatment, but these parameters did not change after the metformin treatment. Serum homocysteine and lipid levels did not change in either group, while serum androgen levels and LH/FSH ratio significantly decreased after the treatment period in only the rosiglitazone-treated group. CONCLUSION: Elevated insulin resistance, oxidative stress and plasma homocysteine levels and changes in serum lipid profile (risk factors for cardiovascular disease) were observed in lean PCOS patients. Rosiglitazone seemed to decrease elevated oxidative stress when compared with metformin treatment in lean PCOS patients. Introduction Polycystic ovary syndrome (PCOS) is one of the most common endocrinopathies in women, affecting 510% of the population (Frank, 1995). PCOS is a heterogeneous disorder characterized by menstrual irregularities, clinical and/or biochemical hyperandrogenism, and hyperinsulinaemia secondary to reduced insulin sensitivity (Homburg, 2003). Approximately half of all women with PCOS are overweight or obese. Independently of the presence of obesity, these women are frequently insulinresistant and therefore they have hyperinsulinaemia, which may play a pathogenic role in the disease (Dunaif et al., 1989; Dunaif, 1997). Insulin resistance and the resulting hyperinsulinaemia lead patients to a cluster of long-term metabolic disorders, including impaired glucose tolerance, type 2 diabetes mellitus (DM) (Ehrmann et al., 1999) and cardiovascular disease (CVD) (Guzick, 1996; Legro, 2003). Oxidative stress means an imbalance between the production of reactive oxygen species and the antioxidant defence system, which buffers the oxidative damage. Oxidative stress is implicated in the pathogenesis of several diseases, such as atherosclerosis, DM and carcinogenesis (Betteridge et al., 2000). Oxidative stress also impairs insulin action, as has been demonstrated in type 2 diabetics, and this impairment might be due to several factors, such as membrane fluidity alterations, decreased availability of nitric oxide and increased intracellular calcium content (Caimi et al., 2003). Serum total antioxidant status (TAS) combines the concentrations of individual antioxidants, such as vitamin C and E, -carotene and thiol groups, and also their synergists. TAS is sensitive to the changes in plasma antioxidant levels and degrees of oxidative stress (Garibaldi et al., 2001). Malonyldialdehyde (MDA) is a marker of lipid peroxidation and increases in oxidative stress states (Knight et al., 1987; Betteridge, 2000). Recent studies have documented increased oxidative stress in patients with PCOS (Sabuncu et al., 2001; Fenki et al., 2003), which may increase the risk of CVD in such patients. Homocysteine (Hcy) is an intermediate product formed during the breakdown of the amino acid methionine, and may undergo remethylation to methionine or trans-sulphuration to cystathione and cysteine. Elevated serum levels of Hcy, called hyperhomocysteinaemia, have adverse effects on the cardiovascular system (Fonseca et al., 1999). Elevated plasma Hcy levels are considered to be an independent risk factor for CVD (Clarke et al., 1991). In recent studies, serum Hcy concentrations were found to be elevated in PCOS women, suggesting that an alteration in Hcy metabolism may play a role in the increased cardiovascular risk associated with PCOS (Loverro et al., 2002; Randeva et al., 2002; Vrbikova et al., 2002; Schachter et al., 2003; Wijeyaratne et al., 2004). Experimental and clinical evidence suggest indirectly that moderate hyperhomocysteinaemia may predispose affected individuals to endothelial dysfunction through a mechanism that involves the generation of reactive oxygen species (Kanani et al., 1999). Hyperhomocysteinaemia-induced oxidative stress may occur as a consequence of either decreased expression and activity of key antioxidant enzymes or increased enzymatic generation of superoxide anions (Eberhardt et al., 2000; Lentz et al., 2000; Faraci, 2003; Loscalzo, 2003; Ungvari et al., 2003). Use of oral anti-hyperglycaemic drugs, predominantly metformin and thiazolidinediones, have been shown to improve insulin sensitivity and ovarian function of women with PCOS. Metformin inhibits hepatic glucose production and enhances peripheral tissue sensitivity to insulin, resulting in a decrease in insulin secretion (Bailey and Turner, 1996). In women with PCOS, many studies have demonstrated the efficacy of metformin in improving menstrual cycle pattern, ovulation and pregnancy outcomes (Morin-Papunen et al., 1998; Unluhizarci et al., 1999; La Marca et al., 2000; Moghetti et al., 2000; Kocak et al., 2002; Baillargeon et al., 2004; Hoeger, et al., 2004). Rosiglitazone, an agonist of peroxisome proliferatoractivating receptor- (PPAR-), increases the uptake and utility of glucose in the periphery and decreases hepatic gluconeogenesis (Goldstein, 1999). Most of the studies have shown that rosiglitazone reduces plasma androgen levels, with co (...truncated)