Effects of metformin on mitochondrial function of leukocytes from polycystic ovary syndrome patients with insulin resistance Victor M Victor 1,2,3 , Susana Rovira-Llopis 1,2 , Celia Ban ˜ uls 1,2 , Noelia Diaz-Morales 1 , Raquel Castello ´ 1 , Rosa Falco ´n 1 , Marcelino Go ´ mez 1 , Milagros Rocha 1,2,3 and Antonio Herna ´ ndez-Mijares 1,2,4 1 Service of Endocrinology, University Hospital Doctor Peset, Foundation for the Promotion of Health and Biomedical Research in the Valencian Region (FISABIO), Avenida Gaspar Aguilar 90, 46017 Valencia, Spain, 2 Institute of Health Research INCLIVA, University of Valencia, Valencia, Spain, 3 CIBERehd – Department of Pharmacology and Physiology, University of Valencia, Valencia, Spain and 4 Department of Medicine, University of Valencia, Valencia, Spain Correspondence should be addressed to V M Victor or M Rocha or A Herna ´ ndez-Mijares Emails Victor.Victor@uv.es or Milagros.Rocha@uv.es or hernandez_antmij@gva.es Abstract Objective: Oxidative stress and mitochondrial dysfunction are implicated in polycystic ovary syndrome (PCOS). The present study assesses the effect of metformin treatment on mitochondrial function in polymorphonuclear cells from PCOS subjects. Additionally, we evaluate endocrine parameters and levels of interleukin 6 (IL6) and tumour necrosis factor alpha (TNFa). Design and methods: Our study population was comprised of 35 women of reproductive age diagnosed with PCOS and treated with metformin for 12 weeks, and their corresponding controls (nZ41), adjusted by age and BMI. We evaluated the alteration of endocrinological and anthropometrical parameters and androgen levels. Mitochondrial O 2 consumption (using a Clark-type O 2 electrode), membrane potential, mitochondrial mass, and levels of reactive oxygen species (ROS) and glutathione (GSH) (by means of fluorescence microscopy) were assessed in poymorphonuclear cells. H 2 O 2 was evaluated with the Amplex Red R H 2 O 2 /Peroxidase Assay kit. IL6 and TNFa were measured using the Luminex 200 flow analyser system. Results: Metformin had beneficial effects on patients by increasing mitochondrial O 2 consumption, membrane potential, mitochondrial mass and glutathione levels, and by decreasing levels of reactive oxygen species and H 2 O 2 . In addition, metformin reduced glucose, follicle-stimulating hormone, IL6 and TNFa levels and increased dehydroepiandrosterone sulfate levels. HOMA-IR and mitochondrial function biomarkers positively correlated with ROS production (rZ0.486, PZ0.025), GSH content (rZ0.710, PZ0.049) and H 2 O 2 (rZ0.837, PZ0.010), and negatively correlated with membrane potential (rZK0.829, PZ0.011) at baseline. These differences disappeared after metformin treatment. Conclusions: Our results demonstrate the beneficial effects of metformin treatment on mitochondrial function in leukocytes of PCOS patients. European Journal of Endocrinology (2015) 173, 683–691 Introduction Polycystic ovary syndrome (PCOS) is the most common endocrinopathy in reproductive aged women, affecting around 6–20% of said population (1, 2). It is a metabolic disorder characterised in a high percentage of cases by insulin resistance (IR) (3), which means that patients are at a high risk of developing type 2 diabetes (4) or metabolic syndrome (5). The cardiovascular and metabolic consequences of PCOS are varied, and so it is necessary to administer patients a multiple therapy. Metformin has been widely European Journal of Endocrinology Clinical study V M Victor and others Metformin and mitochondrial function in PCOS 173 :5 683–691 www.eje-online.org Ñ 2015 European Society of Endocrinology DOI: 10.1530/EJE-15-0572 Printed in Great Britain Published by Bioscientifica Ltd. Downloaded from Bioscientifica.com at 05/23/2020 06:04:20PM via free access