To the Editor:
We would like to thank Dr. Pamuk et al. for their fine article (1). In this study, they found that there were no significant differences in asymmetric dimethylarginine (ADMA) levels and intima media thickness (IMT) in polycystic ovary syndrome (PCOS) group compared with controls. In addition, there was no relationship between ADMA and IMT in the study.
ADMA is an endogenous competitive inhibitor of nitric oxide synthase (NOS) (2). The enzyme dimethylaminohydrolase (DDAH) hydrolyzes ADMA to L-citruline and methylamine (3). It has been proposed that DDAH regulates NOS activity by controlling the concentration of ADMA (4). There is a close relationship between homocysteine and ADMA since homocysteine inhibits the activity of DDAH in endothelial cells, causing the accumulation of ADMA and the inhibition of NOS (5). Studies also demonstrated that ADMA levels increase in patients with hyperhomocysteinemia (6). In this study, the authors found that homocysteine levels were higher in PCOS, but there was no significant difference in ADMA between the groups. The authors reported that they did not find any correlation between ADMA and homocysteine. However, these important findings were stated only in discussion section. It would be appropriate if they showed these results statistically in results section.
Although it has been reported that there is also a close relationship between ADMA and insulin resistance (6), no association was found between insulin resistance and ADMA. The number or the percentage of insulin resistant patients that was assessed by homeostatic model of insulin resistance (HOMAR) of this population was important. The results might be different statistically if percentage of insulin resistant group was higher or lower that was not defined in the text.
The title of the page indicates that they studied ADMA and IMT in obese PCOS patients. The definition of obesity was not made in the study. Furthermore when we look at Table 1 we see that BMI ranges from 23.9 to 34.4 in PCOS group and 23.1 to 33.8 in control group. The title of the manuscript is not suitable for the study, because nonobese patients were also included.
Although the aims of the study were to evaluate whether there were any correlations between ADMA, IMT and metabolic parameters, the authors also investigated the relationship between HOMAR and some parameters such as age, BMI, total cholesterol, free testosterone and DHEAS that was not the purpose of the study.
Fatma Ferda Verit, MD
Mehmet Vural, MD
Department of Obstetrics and Gynecology
Harran University, Faculty of Medicine
1. Pamuk BO, Torun AN, Kulaksizoglu M, Ertugrul D, Ciftci O, Kulaksizoglu S, et al. Asymmetric dimethylarginine levels and carotid intima-media thickness in obese patients with polycystic ovary syndrome and their relationship with metabolic parameters. Fertil Steril. 2008 Dec 22. [Epub ahead of print]
2. Vallance P, Leone A, Calver A, Collier J, Moncada S. Accumulation of an endogenous inhibitor of nitric oxide synthesis in renal failure. Lancet 1992;339:572–5.
3. Ogawa T, Kimoto M, Sasaoka K. Purification and properties of a new enzyme, NG-dimethylarginine dimethylaminohydrolase, from rat kidney. J Biol Chem 1989; 264:10205–9.
4. Selley ML. Homocysteine increases the production of asymmetric dimethylarginine in cultured neurons. J Neurosci Res. 2004;77(1):90-3.
5. Stuhlinger MC, Tsao PS, Her J-H, Kimoto M, Balint RF, Cooke JP. Homocysteine impairs the nitric oxide synthase pathway: role of asymmetric dimethylarginine. Circulation 2001; 104:2569 –75.
6. Heutling D, Schulz H, Nickel I, Kleinstein J, Kaltwasser P, Westphal S, et al. Asymmetrical dimethylarginine, inflammatory and metabolic parameters in women with polycystic ovary syndrome before and after metformin treatment. J Clin Endocrinol Metab 2008; 93(1):34-6.
Published online in Fertility and Sterility doi:10.1016/j.fertnstert.2009.04.016
The Authors Respond:
Drs. Verit and Vural have raised several concerns regarding our manuscript which were associated with asymmetric dimethyl arginine (ADMA) and intima-media thickness (IMT) levels in polycystic ovary syndrome (PCOS). Among their suggestions and concerns was that the body mass index (BMI) issue should be taken into consideration. In this study, we accepted obesity as BMI>27 kg/m2 as previously adopted by many authors. Unfortunately, there were two subjects in PCOS group and one subject in conrol group that had normal BMIs. However, this situation could have no significant effect on ADMA or IMT levels, as the mean and median BMI levels were over 27 kg/m2.
Furthermore, if this discrepancy had affected ADMA or IMT levels, it would probably have caused unexpected findings in other parameters such as homocysteine, fasting insulin levels and CRP, but it did not. We think that the authors’ other concerns regarding the presentation of our data or our preferences for the editing of the manuscript are subjective and did not have significant scientific contribution to the issue.
Baris Onder Pamuk, M.D.
Division of Endocrinology and Metabolism
Department of Internal Medicine,
Baskent University, School of Medicine
Published online in Fertility and Sterility doi:10.1016/j.fertnstert.2009.04.015