CLINICAL STUDY Metformin administration improves endothelial function in women with polycystic ovary syndrome E Diamanti-Kandarakis, K Alexandraki, A Protogerou 1 , C Piperi 2 , C Papamichael 1 , A Aessopos, J Lekakis 1 and M Mavrikakis 1 Laiko Hospital, Medical School, University of Athens, Endocrine Section, First Department of Medicine, Athens, Greece, 1 Alexandra University Hospital, Medical School, University of Athens, Vascular Laboratory, Department of Clinical Therapeutic, Athens, Greece and 2 Laboratory of Biological Chemistry, University of Athens Medical School, Athens, Greece (Correspondence should be addressed to E Diamanti-Kandarakis, Athens University School of Medicine, Laiko, General Hospital, 1A Zefyrou str, Athens 14578, Greece; Email: akandara@otenet.gr) Abstract Objective: The aim of this study was to investigate the endothelial status in young women with poly- cystic ovary syndrome (PCOS), using a simple and easily reproducible hemodynamic method com- bined with a biological marker and to evaluate the effect of metformin treatment on these parameters. Design: Descriptive clinical trial. Methods: Forty young women, 20 with PCOS and 20 normal women of similar age and body mass index were studied. Metformin (1700 mg daily) was administered for 6 months to the PCOS group. The endothelium status and the metabolic and hormonal profile were studied in both groups, as well as after metformin, by flow-mediated dilatation (FMD) on the brachial artery and by measure- ments of plasma endothelin-1 (ET-1) levels. Results: FMD was impaired in the PCOS group when compared with controls (3.24^0.71% vs 8.81^1.07% respectively, P , 0.0001), but this difference normalized after metformin treatment (PCOS post-metformin vs controls: 8.17^1.26 vs 8.81^1.07%, P ¼ 0.70) since the values significantly improved after metformin treatment (PCOS pre-metformin vs PCOS post-metformin : 3.24^0.71 vs 8.17^1.26%, P ¼ 0.003). ET-1 levels were significantly higher in the PCOS women compared with the control group (7.23^0.50 vs 4.99^0.69 fmol/l, P ¼ 0.01), they improved significantly after metformin treatment (PCOS pre-metformin vs PCOS post-metformin : 7.23^0.50 vs 3.57^0.60 fmol/l, P , 0.0001) and their difference compared with the control group was reversed (PCOS post-metformin vs controls: 3.57^0.60 vs 4.99^0.69 fmol/l, P ¼ 0.13). Metformin administration improved hyper- androgenemia. However, in this study, mathematical methods used to assess insulin resistance failed to show any detected alteration after treatment with metformin. Conclusions: PCOS women were found to exhibit endothelial dysfunction compared with controls, which was reversed 6 months after metformin administration. European Journal of Endocrinology 152 749–756 Introduction Polycystic ovary syndrome (PCOS), affecting 4–7% of women of reproductive age (1, 2), bears a risk for devel- opment of cardiovascular disease and type 2 diabetes (T2D) (3–9). The major surrogate markers for cardio- vascular risk factors identified in PCOS are coronary calcifications assessed by electron beam computed tom- ography (EBCT), carotid intima media thickness by ultrasound and arterial stiffness by recording pulse wave velocity (PWV) across the brachial artery (10 – 12). Furthermore, endothelial dysfunction has been investigated by different methods in women with PCOS with contradictory results (13–16). Endothelial dysfunction is defined as a change in concentration of the chemical messengers (like endothelin-1 (ET-1)) produced by endothelium and/or as a blunting of the nitric oxide (NO)-dependent vaso- dilator response to hyperemia (17). Additionally, the disruption of the balance between the endothelial pro- duction of protective vasoactive molecules such as NO and the generation of deleterious substances, such as ET-1, may participate in the mechanisms of the ather- osclerotic process (17, 18). Insulin resistance may be linked to endothelial dysfunction by a number of mech- anisms, including disturbances of subcellular signaling pathways common to both insulin action and NO pro- duction or other potential unifying links such as oxi- dant stress, ET-1, the renin–angiotensin system and the secretion of hormones and cytokines by adipose tissue (18). Different approaches have been used to assess endo- thelial integrity (13–16). Paradisi et al. (14) found that obese, insulin-resistant women with PCOS exhibit European Journal of Endocrinology (2005) 152 749–756 ISSN 0804-4643 q 2005 Society of the European Journal of Endocrinology DOI: 10.1530/eje.1.01910 Online version via www.eje-online.org