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Endocrine Care: Gerald B. Phillips Is Atherosclerotic Cardiovascular Disease an Endocrinological Disorder? The Estrogen-Androgen Paradox J Clin Endocrinol Metab 2005; 90: 2708-2711 [Abstract] [Full text] [PDF]

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Response to Letter to the Editor

Gerald B. Phillips   (4 November 2005)

Letter to the Editor

Maria Alevizaki, Adriana Cimponeriu, Christos Papamichael, and John P. Lekakis   (3 October 2005)

Response to Letter to the Editor 4 November 2005
Gerald B. Phillips, MD Columbia University College of Physicians and Surgeons Send letter to journal: Re: Response to Letter to the Editor gbp1{at}columbia.edu Gerald B. Phillips	I thank Dr. Alevizaki and colleagues for their comments on my paper (1). I agree that the assessment of androgen receptor (AR) function could help to resolve inconsistencies in the complex relationship between sex hormones and cardiovascular disease (CVD). In their study in men of the AR polymorphism that depends on the number of glutamine (encoded by CAG) repeats, where the number of CAG repeats appears to be inversely associated with androgen sensitivity, they report (as appears to be stated correctly under "Results") that significant coronary artery disease (CAD) "was present in 86% of the lowest quartile of repeats and 68% of the highest quartile (P=0.04)" (2). Thus, if the number of CAG repeats reflects androgen sensitivity, men with higher androgen sensitivity had a significantly higher prevalence of CAD than men with lower androgen sensitivity. As a result, Alevizaki et al. suggest that testosterone in men might promote CAD (2), opposite to what we and others have hypothesized (1). They also suggest that less androgen sensitivity is associated with a compensatory increase in plasma testosterone level (although they did not find this). While an increase in testosterone level with less CAD would be consistent with our findings and those of others (1), it would appear to lead to the bizarre conclusion that in the male population, the testosterone level, which is positively associated with signs of maleness, would inversely reflect testosterone action. For example, longer CAG repeats in men have been reported to be associated with greater fat-free mass, as well as a higher testosterone level (3). Does that mean that greater muscle mass is associated with lower testosterone action? Furthermore, in assessing the relationship of CAG repeats to CVD risk, Zitzmann et al. point out that longer CAG repeats in men relate favorably to endothelial function and HDL-C, and unfavorably to fat mass and insulin sensitivity (4). Finally, the only other study, apparently, on CAG repeats and CVD did not find a relationship between number of repeats and either CAD or myocardial infarction (5). Because studies relating this AR polymorphism to testosterone level, CVD, and CVD risk factors appear to be sparse and contradictory, I believe that additional studies will be needed in order to determine how important a role this polymorphism plays in the relationship of sex hormones and CVD. References 1. Phillips GB 2005 Is atherosclerotic cardiovascular disease an endocrinological disorder? The estrogen-androgen paradox. J Clin Endocrinol Metab 90:2708-2711 2. Alevizaki M, Cimponeriu AT, Garofallaki M, Sarika H-L, Alevizaki CC, Papamichael C, Philippou G, Anastasiou EA, Lekakis JP, Mavrikakis M 2003 The androgen receptor gene CAG polymorphism is associated with the severity of coronary artery disease in men. Clin Endocrinol 59:749-755 3. Walsh S, Zmuda JM, Cauley JA, Shea PR, Metter EJ, Hurley BF, Ferrell RE, Roth SM 2005 Androgen receptor CG repeat polymorphism is associated with fat-free mass in men. J Appl Physiol 98:132-137 4. Zitzmann M, Gromoll J, von Eckardstein A, Nieschlag E 2003 The CAG repeat polymorphism in the androgen receptor gene modulates body fat mass and serum concentrations of leptin and insulin in men. Diabetologia 46:31- 39 5. Hersberger M, Muntwyler J, Funke H, Marti-Jaun J, Schulte H, Assmann G, Luscher TF, von Eckardstein A 2005 The CAG repeat polymorphism in the androgen receptor gene is associated with HDL-cholesterol but not with coronary atherosclerosis or myocardial infarction. Clin Chem 51:1110- 1115
Letter to the Editor 3 October 2005
Maria Alevizaki, MD Athens University School of Medicine, Adriana Cimponeriu, Christos Papamichael, and John P. Lekakis Send letter to journal: Re: Letter to the Editor mani{at}otenet.gr Maria Alevizaki, et al.	We have read with interest the paper by GB Phillips in the May issue of the Journal of Clinical Endocrinology and Metabolism earlier this year (1) dealing with the different effects of sex steroids on cardiovascular risk. The paper focuses more on what the experiments of nature taught us in the rare paradigms of estrogen deficient men either due to estrogen receptor mutation and estrogen resistance or to aromatase deficiency. However, we have recently shown (2) that in more common population samples, such as in men undergoing coronary angiography, the androgen receptor may also be associated with the severity of cardiovascular disease (CAD) in this particular group of subjects: we have thus shown that men carrying the androgen receptor variant associated with reduced sensitivity to androgens (upper quartile of polyglutamine track in the transactivation domain) had less severe coronary artery disease. It thus appears that the sensitivity to androgens may be an important factor involved in the clinical expression of cardiovascular disease in men; this may in fact be indirectly influencing the estradiol levels as higher testosterone is probably needed for the “less sensitive” receptor to maintain the feedback balance of the hypothalamic-pituitary-testicular axis. Indeed in our study we also found higher estrogen levels in men carrying the less sensitive receptor probably due to increased substrate available for peripheral conversion; so, the final effect is obviously more complex and estrogen may again be involved. The androgen receptor polyglutamine polymorphism appears to modulate androgen effects on cardiovascular risk factors such as endothelial function and HDL levels even in younger male individuals in the general population (3). Furthermore, obesity and insulin sensitivity, also important for CAD in men, appear to be associated with the type of receptor and thus the sensitivity to androgens (2,4). These observations may offer an explanation for the lack of consistent association between circulating sex steroid hormone levels and CAD in men. Differences in sensitivity to androgens may thus be one of the factors involved in the complex puzzle which constitutes the “estrogen – androgen paradox” suggested in the paper by GB Phillips and atherosclerotic cardiovascular disease may thus indeed be an endocrinological disorder. 1. Phillips GB. Is atherosclerotic cardiovascular disease an endocrinological disorder? The estrogen-androgen paradox. J Clin Endocrinol Metab 2005 90:2708-2711 2. Alevizaki, M, Cimponeriu A, Garofallaki M, Sarika H-L, Alevizaki CC, Papamichael C, Philippou G, Anastasiou E, Lekakis J, Mavrikakis M. 2003 The Androgen Receptor CAG polymorphism is associated with the severity of coronary artery disease in men. Clin Endocrinol 59:749-755 3. Zitzmann M, Brune M, Kornmann B, Gromoll J, von Eckardstein S, von Eckardstein A, E Nieschlag E 2001. The CAG repeat polymorphism in the AR gene affects high density lipoprotein cholesterol and arterial vasoreactivity. J Clin Endocr Metab. 86: 4867-4873 4. Zitzmann M, Gromol J, von Eckardstein A, Nieschlag E 2003 The CAG repeat polymorphism in the androgen receptor gene modulates body fat mass and serum concentrations of leptin and insulin in men. Diabetologia 46:31- 39