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Article: Francesco Orio, Jr, Stefano Palomba, Teresa Cascella, Biagio De Simone, Francesco Manguso, Silvia Savastano, Tiziana Russo, Achille Tolino, Fulvio Zullo, Gaetano Lombardi, Ricardo Azziz, and Annamaria Colao Improvement in endothelial structure and function after metformin treatment in young normal-weight women with polycystic ovary syndrome: results of a six-month study J Clin Endocrinol Metab 2005; 0: jc.2005-0965v1 [Abstract]

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Re: Does Metformin Treatment Really Improve Arterial Structure in Women with Polycystic Ovarian Synd

Francesco Orio, Stefano Palomba, Francesco Manguso, Annamaria Colao   (14 December 2005)

Does Metformin Treatment Really Improve Arterial Structure in Women with Polycystic Ovarian Syndrome

Sophia Zoungas, Helena Teede   (30 November 2005)

Re: Does Metformin Treatment Really Improve Arterial Structure in Women with Polycystic Ovarian Synd 14 December 2005
Francesco Orio, MD,PhD Department of Molecular and Clinical Endocrinology and Oncology,Federico II University,Naples,Italy, Stefano Palomba, Francesco Manguso, Annamaria Colao Send letter to journal: Re: Re: Does Metformin Treatment Really Improve Arterial Structure in Women with Polycystic Ovarian Synd francescoorio{at}virgilio.it Francesco Orio, et al.	We thank Zoungas et al. for their interest in our paper (1) and constructive comments. We have demonstrated a noticeable reduction of the intima-media thickness (IMT) in young women with PCOS. These data are difficult to compare to those of current literature in the field (2-4). In fact, our study population included young women without major or even stable medical conditions, while other published data came from patients of both sexes aged from 31 to 75 years with a history of myocardial infarction or unstable angina (2), from patients of both sexes suffering from type 2 diabetes (3, 4), or from patients aged about 60 years (3). Our finding could be explained by this distinct study population. The beneficial effect of metformin on IMT may be explained by a modulation of reactive oxygen species generation (5) and by a reduction of systemic methylglycoxal concentration (6). While a possible confounding factor in our results could have been vessel dilatation, no significant difference in carotid artery lumen diameter was observed before and after metformin administration (6.55ą0.62 vs 6.45ą0.89, mmąSD; P=0.5). We do not agree that our study was underpowered because we obtained significant statistical differences with important clinical implications. The absence of a pre-study sample size calculation was due to the absence of data available in literature on the effects of metformin in PCOS patients. Nonetheless, our study seems strong enough, as demonstrated from the post-study power analysis on IMT or FMD with a 1-beta of >95% for each. Finally, we agree with Zoungas et al. that the lack of a control group is a limitation of our study design, but this point was already acknowledged in the discussion section of our paper (1). References 1. Orio F Jr, Palomba S, Cascella T, De Simone B, Manguso F, Savastano S, Russo T, Tolino A, Zullo F, Lombardi G, Azziz R, Colao A 2005 Improvement in endothelial structure and function after metformin treatment in young normal-weight women with polycystic ovary syndrome: results of a 6-month study. J Clin Endocrinol Metab 90: 6072-6076. Epub 2005 Aug 23 2. MacMahon S, Sharpe N, Gamble G, Hart H, Scott J, Simes J, White H 1998 Effects of lowering average of below-average cholesterol levels on the progression of carotid atherosclerosis: results of the LIPID Atherosclerosis Substudy. LIPID Trial Research Group. Circulation 97:1784- 1790 3. Katakami N, Yamasaki Y, Hayaishi-Okano R, Ohtoshi K, Kaneto H, Matsuhisa M, Kosugi K, Hori M. 2004 Metformin or gliclazide, rather than glibenclamide, attenuate progression of carotid intima-media thickness in subjects with type 2 diabetes. Diabetologia 47:1906-1913 4. Matsumoto K, Sera Y, Abe Y, Tominaga T, Yeki Y, Miyake S 2004 Metformin attenuates progression of carotid arterial wall thickness in patients with type 2 diabetes. Diabetes Res Clin Pract 64:225-228 5. Bonnefont-Rouseelot D, Raji B, Walrand S, Gardes-Albert M, Jore D, Legrand A, Peynet J, Vasson MP 2003 An intracellular modulation of free radical production could contribute to the beneficial effects of metformin towards oxidative stress. Metabolism 52:586-589 6. Thornalley PJ 1996 Pharmacology of methylglycoxal: formation, modification of proteins and nucleic acids, and enzymatic detoxification-a role in pathogenesis and antiproliferative chemotherapy. Gen Pharmacol 27:565-573
Does Metformin Treatment Really Improve Arterial Structure in Women with Polycystic Ovarian Syndrome 30 November 2005
Sophia Zoungas, Endocrinologist Department of Medicine, Monash University, Dandenong Hospital, Dandenong, Victoria, Australia, Helena Teede Send letter to journal: Re: Does Metformin Treatment Really Improve Arterial Structure in Women with Polycystic Ovarian Syndrome sophia.zoungas{at}med.monash.edu.au Sophia Zoungas, et al.	We have read with great interest the paper by Orio et al. (1) published in a recent issue of the Journal of Clinical Endocrinology and Metabolism. In this study, a significant reduction in carotid artery IMT was reported after metformin treatment in 30 young women with polycystic ovarian syndrome. We wish to raise several concerns regarding the study design and findings, and suggest that these results be interpreted with caution. This study was limited by three factors: 1) a reported rate of regression of structural atherosclerotic disease in the vessel wall (IMT) that appears inconsistent with the previous literature and incompatible with the histopathology that this marker reflects; 2) small sample size; and 3) lack of a control group. Carotid artery IMT is a sensitive marker of subclinical atherosclerotic disease and correlates with cardiovascular risk factors, severity of coronary artery disease, and most importantly, with clinical cardiovascular events. Carotid IMT is generally believed to represent early intimal disease followed by plaque formation once >1mm. Measurement can, however, be influenced by vessel dilatation. The authors do not report carotid artery luminal diameter, so this has not been excluded as a potential explanation for the change in IMT. The issue of sample size is also important. In this study, IMT regression of 0.13 mm was noted after only 6 months of metformin treatment. In larger studies over longer periods, even statin therapy has not produced such dramatic effects (2). Given the histopathology of intimal and medial thickening, it is challenging to explain how such a rapid rate of change in IMT occurred. It is possible that factors such as wall oedema may have contributed. Especially with the forgoing limitations, study of a control group would have been critical. There are only two other small controlled studies reporting reduced progression, and not regression, of IMT with metformin therapy in patients with diabetes mellitus (3, 4). In conclusion, considering these limitations, the study by Orio et al. (1) should be interpreted with caution and needs to be corroborated by larger controlled studies. References 1. Orio F, Jr., Palomba S, Cascella T, De Simone B, Manguso F, Savastano S, Russo T, Tolino A, Zullo F, Lombardi G, Azziz R, Colao A. 2005 Improvement in endothelial structure and function after metformin treatment in young normal-weight women with polycystic ovary syndrome: results of a 6-month study. J Clin Endocrinol Metab 90:6072-6076 2. MacMahon S, Sharpe N, Gamble G, Hart H, Scott J, Simes J, White H. 1998 Effects of lowering average of below-average cholesterol levels on the progression of carotid atherosclerosis: results of the LIPID Atherosclerosis Substudy. LIPID Trial Research Group. Circulation 97:1784-1790 3. Katakami N, Yamasaki Y, Hayaishi-Okano R, Ohtoshi K, Kaneto H, Matsuhisa M, Kosugi K, Hori M. 2004 Metformin or gliclazide, rather than glibenclamide, attenuate progression of carotid intima-media thickness in subjects with type 2 diabetes. Diabetologia 47:1906-1913 4. Matsumoto K, Sera Y, Abe Y, Tominaga T, Yeki Y, Miyake S 2004 Metformin attenuates progression of carotid arterial wall thickness in patients with type 2 diabetes. Diabetes Res Clin Pract 64:225-228