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Endogenous estrogen levels are associated with endothelial function in males independently of lipid levels

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Abstract

Estrogens and androgens may play an important role in vascular health in both sexes. The aim of this study was to examine the relation of endogenous sex hormone levels with early markers of atherosclerosis in a cohort of apparently healthy males. 124 males (age 46.25 ± 9.56) attending a preventive medicine program were examined for unrecognised features of the metabolic syndrome. Flow-mediated dilatation (FMD) and intima-media thickness (IMT) of the common carotid artery were evaluated. Obesity parameters were recorded; estradiol, testosterone, SHBG, free testosterone, insulin, as well as glucose and lipid levels were measured. FMD was positively correlated with estradiol (r = 0.201, P = 0.041) and negatively with total cholesterol (r = −0.205, P = 0.022), low density lipoproteins (r = −0.232, P = 0.009), and triglyceride levels (r = −0.179, P = 0.046). In multivariate analysis, the association of FMD with estrogen was independent of BMI and lipid levels. No significant association between FMD and testosterone levels was found. Subjects with an increased mean IMT (>0.73 mm, i.e., >3rd tertile) had lower levels of free (P = 0.021) and bioavailable (P = 0.016) testosterone. In multivariate logistic regression analysis, this association was no longer significant when age or cholesterol levels were considered. Endogenous estrogen levels are associated with FMD, independently of age and lipid levels, showing a protective effect in middle-age male subjects. Circulating androgens are associated, although not independently, with structural changes such as the IMT of carotid artery; this effect is possibly influenced by lipid levels and age.

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References

  1. K. Saltiki, M. Alevizaki, Coronary heart disease in postmenopausal women; the role of endogenous estrogens and their receptors. Hormones (Athens) 6, 9–24 (2007)

    Google Scholar 

  2. P.Y. Liu, A.K. Death, D.J. Handelsman, Androgens and cardiovascular disease. Endocr. Rev. 24, 313–340 (2003)

    Article  CAS  PubMed  Google Scholar 

  3. K. Sudhir, P.A. Komesaroff, Clinical review 110: cardiovascular actions of estrogens in men. J. Clin. Endocrinol. Metab. 84, 3411–3415 (1999)

    Article  CAS  PubMed  Google Scholar 

  4. K. Kublickiene, L. Luksha, Gender and the endothelium. Pharmacol. Rep. 60, 49–60 (2008)

    CAS  PubMed  Google Scholar 

  5. M.E. Mendelsohn, Genomic and nongenomic effects of estrogen in the vasculature. Am. J. Cardiol. 90, 3F–6F (2002)

    Article  CAS  PubMed  Google Scholar 

  6. J. Case, C.A. Davison, Estrogen alters relative contributions of nitric oxide and cyclooxygenase products to endothelium-dependent vasodilation. J. Pharmacol. Exp. Ther. 291, 524–530 (1999)

    CAS  PubMed  Google Scholar 

  7. R. Lew, P. Komesaroff, M. Williams, T. Dawood, K. Sudhir, Endogenous estrogens influence endothelial function in young men. Circ. Res. 93, 1127–1133 (2003)

    Article  CAS  PubMed  Google Scholar 

  8. E. Barrett-Connor, Clinical review 162: cardiovascular endocrinology 3—an epidemiologist looks at hormones and heart disease in women. J. Clin. Endocrinol. Metab. 88, 4031–4042 (2003)

    Article  CAS  PubMed  Google Scholar 

  9. B. Zegura, I. Keber, M. Sebestjen, E. Borko, Orally and transdermally replaced estradiol improves endothelial function equally in middle-aged women after surgical menopause. Am. J. Obstet. Gynecol. 188, 1291–1296 (2003)

    Article  CAS  PubMed  Google Scholar 

  10. K. Sudhir, T.M. Chou, K. Chatterjee, E.P. Smith, T.C. Williams, J.P. Kane, M.J. Malloy, K.S. Korach, G.M. Rubanyi, Premature coronary artery disease associated with a disruptive mutation in the estrogen receptor gene in a man. Circulation 96, 3774–3777 (1997)

    CAS  PubMed  Google Scholar 

  11. K. Sudhir, T.M. Chou, L.M. Messina, S.J. Hutchison, K.S. Korach, K. Chatterjee, G.M. Rubanyi, Endothelial dysfunction in a man with disruptive mutation in oestrogen-receptor gene. Lancet 349, 1146–1147 (1997)

    Article  CAS  PubMed  Google Scholar 

  12. P.Y. Liu, R.C. Christian, M. Ruan, V.M. Miller, L.A. Fitzpatrick, Correlating androgen and estrogen steroid receptor expression with coronary calcification and atherosclerosis in men without known coronary artery disease. J. Clin. Endocrinol. Metab. 90, 1041–1046 (2005)

    Article  CAS  PubMed  Google Scholar 

  13. P.A. Komesaroff, C.V. Black, R.A. Westerman, A novel, nongenomic action of estrogen on the cardiovascular system. J. Clin. Endocrinol. Metab. 83, 2313–2316 (1998)

    Article  CAS  PubMed  Google Scholar 

  14. M.A. Sader, R.J. McCredie, K.A. Griffiths, S.M. Wishart, D.J. Handelsman, D.S. Celermajer, Oestradiol improves arterial endothelial function in healthy men receiving testosterone. Clin. Endocrinol. (Oxf.) 54, 175–181 (2001)

    Article  CAS  Google Scholar 

  15. G. New, K.L. Timmins, S.J. Duffy, B.T. Tran, R.C. O’Brien, R.W. Harper, I.T. Meredith, Long-term estrogen therapy improves vascular function in male to female transsexuals. J. Am. Coll. Cardiol. 29, 1437–1444 (1997)

    Article  CAS  PubMed  Google Scholar 

  16. J.A. McCrohon, W.A. Walters, J.T. Robinson, R.J. McCredie, L. Turner, M.R. Adams, D.J. Handelsman, D.S. Celermajer, Arterial reactivity is enhanced in genetic males taking high dose estrogens. J. Am. Coll. Cardiol. 29, 1432–1436 (1997)

    Article  CAS  PubMed  Google Scholar 

  17. P.A. Komesaroff, M. Fullerton, M.D. Esler, A. Dart, G. Jennings, K. Sudhir, Low-dose estrogen supplementation improves vascular function in hypogonadal men. Hypertension 38, 1011–1016 (2001)

    Article  CAS  PubMed  Google Scholar 

  18. P. Collins, G.M. Rosano, P.M. Sarrel, L. Ulrich, S. Adamopoulos, C.M. Beale, J.G. McNeill, P.A. Poole-Wilson, 17 beta-estradiol attenuates acetylcholine-induced coronary arterial constriction in women but not men with coronary heart disease. Circulation 92, 24–30 (1995)

    CAS  PubMed  Google Scholar 

  19. G. New, S.J. Duffy, K.L. Berry, R.W. Harper, I.T. Meredith, Acute administration of 17beta-oestradiol does not improve endothelium-dependent vasodilatation in young men. Clin. Sci. (Lond.) 97, 225–232 (1999)

    Article  CAS  Google Scholar 

  20. G.M. Rubanyi, A.D. Freay, K. Kauser, D. Sukovich, G. Burton, D.B. Lubahn, J.F. Couse, S.W. Curtis, K.S. Korach, Vascular estrogen receptors and endothelium-derived nitric oxide production in the mouse aorta. Gender difference and effect of estrogen receptor gene disruption. J. Clin. Invest. 99, 2429–2437 (1997)

    Article  CAS  PubMed  Google Scholar 

  21. A.W. van den Beld, M.L. Bots, J.A. Janssen, H.A. Pols, S.W. Lamberts, D.E. Grobbee, Endogenous hormones and carotid atherosclerosis in elderly men. Am. J. Epidemiol. 157, 25–31 (2003)

    Article  PubMed  Google Scholar 

  22. M. Muller, A.W. van den Beld, M.L. Bots, D.E. Grobbee, S.W. Lamberts, Y.T. van der Schouw, Endogenous sex hormones and progression of carotid atherosclerosis in elderly men. Circulation 109, 2074–2079 (2004)

    Article  CAS  PubMed  Google Scholar 

  23. J. Svartberg, D. von Muhlen, E. Mathiesen, O. Joakimsen, K.H. Bonaa, E. Stensland-Bugge, Low testosterone levels are associated with carotid atherosclerosis in men. J. Intern. Med. 259, 576–582 (2006)

    Article  CAS  PubMed  Google Scholar 

  24. M. Zitzmann, M. Brune, B. Kornmann, J. Gromoll, S. von Eckardstein, A. von Eckardstein, E. Nieschlag, The CAG repeat polymorphism in the AR gene affects high density lipoprotein cholesterol and arterial vasoreactivity. J. Clin. Endocrinol. Metab. 86, 4867–4873 (2001)

    Article  CAS  PubMed  Google Scholar 

  25. J. Makinen, M.J. Jarvisalo, P. Pollanen, A. Perheentupa, K. Irjala, M. Koskenvuo, J. Makinen, I. Huhtaniemi, O.T. Raitakari, Increased carotid atherosclerosis in andropausal middle-aged men. J. Am. Coll. Cardiol. 45, 1603–1608 (2005)

    Article  PubMed  Google Scholar 

  26. D.S. Celermajer, K.E. Sorensen, V.M. Gooch, D.J. Spiegelhalter, O.I. Miller, I.D. Sullivan, J.K. Lloyd, J.E. Deanfield, Non-invasive detection of endothelial dysfunction in children and adults at risk of atherosclerosis. Lancet 340, 1111–1115 (1992)

    Article  CAS  PubMed  Google Scholar 

  27. R. Joannides, W.E. Haefeli, L. Linder, V. Richard, E.H. Bakkali, C. Thuillez, T.F. Luscher, Nitric oxide is responsible for flow-dependent dilatation of human peripheral conduit arteries in vivo. Circulation 91, 1314–1319 (1995)

    CAS  PubMed  Google Scholar 

  28. A. Simon, J. Gariepy, G. Chironi, J.L. Megnien, J. Levenson, Intima-media thickness: a new tool for diagnosis and treatment of cardiovascular risk. J. Hypertens. 20, 159–169 (2002)

    Article  CAS  PubMed  Google Scholar 

  29. K.S. Stamatelopoulos, J.P. Lekakis, G. Vamvakou, P. Katsichti, A. Protogerou, I. Revela, K. Karatzi, M. Alevizaki, N. Zakopoulos, C.M. Papamichael, The relative impact of different measures of adiposity on markers of early atherosclerosis. Int. J. Cardiol. 119, 139–146 (2007)

    Article  PubMed  Google Scholar 

  30. A. Vermeulen, L. Verdonck, J.M. Kaufman, A critical evaluation of simple methods for the estimation of free testosterone in serum. J. Clin. Endocrinol. Metab. 84, 3666–3672 (1999)

    Article  CAS  PubMed  Google Scholar 

  31. E.N. Karatzis, I. Ikonomidis, G.D. Vamvakou, T.G. Papaioannou, A.D. Protogerou, I. Andreadou, P.T. Voidonikola, K.N. Karatzi, C.M. Papamichael, J.P. Lekakis, Long-term prognostic role of flow-mediated dilatation of the brachial artery after acute coronary syndromes without ST elevation. Am. J. Cardiol. 98, 1424–1428 (2006)

    Article  PubMed  Google Scholar 

  32. P.T. Voidonikola, K.S. Stamatelopoulos, M. Alevizaki, G.E. Kollias, N.A. Zakopoulos, J.P. Lekakis, E. Anastasiou, M.J. Theodorakis, A.G. Pittas, C.M. Papamichael, The association between glycemia and endothelial function in nondiabetic individuals: the importance of body weight. Obesity (Silver Spring) 16, 2658–2662 (2008)

    Article  CAS  Google Scholar 

  33. A. Vermeulen, J.M. Kaufman, S. Goemaere, I. van Pottelberg, Estradiol in elderly men. Aging Male 5, 98–102 (2002)

    CAS  PubMed  Google Scholar 

  34. P.A. Komesaroff, R. Murray, C. Rajkumar, M.D. Esler, G.L. Jennings, A.M. Dart, J.W. Funder, K. Sudhir, Aromatase inhibition alters vascular reactivity and arterial compliance in men: a possible vascular role for endogenous sex hormones in males. Aust. N. Z. J. Med. 29, 265–267 (1999)

    CAS  PubMed  Google Scholar 

  35. I.T. Huhtaniemi, S.R. Pye, K.L. Limer, W. Thomson, T.W. O’Neill, H. Platt, D. Payne, S.L. John, M. Jiang, S. Boonen et al., Increased estrogen rather than decreased androgen action is associated with longer androgen receptor CAG repeats. J. Clin. Endocrinol. Metab. 94, 277–284 (2009)

    Article  CAS  PubMed  Google Scholar 

  36. M. Alevizaki, A.T. Cimponeriu, M. Garofallaki, H.L. Sarika, C.C. Alevizaki, C. Papamichael, G. Philippou, E.A. Anastasiou, J.P. Lekakis, M. Mavrikakis, The androgen receptor gene CAG polymorphism is associated with the severity of coronary artery disease in men. Clin. Endocrinol. (Oxf). 59, 749–755 (2003)

    Article  CAS  Google Scholar 

  37. J. Arnlov, M.J. Pencina, S. Amin, B.H. Nam, E.J. Benjamin, J.M. Murabito, T.J. Wang, P.E. Knapp, R.B. D’Agostino Sr., S. Bhasin et al., Endogenous sex hormones and cardiovascular disease incidence in men. Ann. Intern. Med. 145, 176–184 (2006)

    CAS  PubMed  Google Scholar 

  38. L.J. Gooren, E.J. Giltay, M.C. Bunck, Long-term treatment of transsexuals with cross-sex hormones: extensive personal experience. J. Clin. Endocrinol. Metab. 93, 19–25 (2008)

    Article  CAS  PubMed  Google Scholar 

  39. M. Muller, I. den Tonkelaar, J.H. Thijssen, D.E. Grobbee, Y.T. van der Schouw, Endogenous sex hormones in men aged 40–80 years. Eur. J. Endocrinol. 149, 583–589 (2003)

    Article  CAS  PubMed  Google Scholar 

  40. A. Tivesten, J. Hulthe, K. Wallenfeldt, J. Wikstrand, C. Ohlsson, B. Fagerberg, Circulating estradiol is an independent predictor of progression of carotid artery intima-media thickness in middle-aged men. J. Clin. Endocrinol. Metab. 91, 4433–4437 (2006)

    Article  CAS  PubMed  Google Scholar 

  41. A.E. Hak, J.C. Witteman, F.H. de Jong, M.I. Geerlings, A. Hofman, H.A. Pols, Low levels of endogenous androgens increase the risk of atherosclerosis in elderly men: the Rotterdam study. J. Clin. Endocrinol. Metab. 87, 3632–3639 (2002)

    Article  CAS  PubMed  Google Scholar 

  42. K.T. Khaw, M. Dowsett, E. Folkerd, S. Bingham, N. Wareham, R. Luben, A. Welch, N. Day, Endogenous testosterone and mortality due to all causes, cardiovascular disease, and cancer in men: European prospective investigation into cancer in Norfolk (EPIC-Norfolk) Prospective Population Study. Circulation 116, 2694–2701 (2007)

    Article  CAS  PubMed  Google Scholar 

  43. G.A. Laughlin, E. Barrett-Connor, J. Bergstrom, Low serum testosterone and mortality in older men. J. Clin. Endocrinol. Metab. 93, 68–75 (2008)

    Article  CAS  PubMed  Google Scholar 

  44. M. Zitzmann, M. Brune, E. Nieschlag, Vascular reactivity in hypogonadal men is reduced by androgen substitution. J. Clin. Endocrinol. Metab. 87, 5030–5037 (2002)

    Article  CAS  PubMed  Google Scholar 

  45. G. Bernini, D. Versari, A. Moretti, A. Virdis, L. Ghiadoni, M. Bardini, C. Taurino, D. Canale, S. Taddei, A. Salvetti, Vascular reactivity in congenital hypogonadal men before and after testosterone replacement therapy. J. Clin. Endocrinol. Metab. 91, 1691–1697 (2006)

    Article  CAS  PubMed  Google Scholar 

  46. S.M. Kang, Y. Jang, J.Y. Kim, N. Chung, S.Y. Cho, J.S. Chae, J.H. Lee, Effect of oral administration of testosterone on brachial arterial vasoreactivity in men with coronary artery disease. Am. J. Cardiol. 89, 862–864 (2002)

    Article  CAS  PubMed  Google Scholar 

  47. L. Nathan, W. Shi, H. Dinh, T.K. Mukherjee, X. Wang, A.J. Lusis, G. Chaudhuri, Testosterone inhibits early atherogenesis by conversion to estradiol: critical role of aromatase. Proc. Natl Acad. Sci. U.S.A. 98, 3589–3593 (2001)

    Article  CAS  PubMed  Google Scholar 

  48. H. Murakami, N. Harada, H. Sasano, Aromatase in atherosclerotic lesions of human aorta. J. Steroid. Biochem. Mol. Biol. 79, 67–74 (2001)

    Article  CAS  PubMed  Google Scholar 

  49. L.P. Ly, M. Jimenez, T.N. Zhuang, D.S. Celermajer, A.J. Conway, D.J. Handelsman, A double-blind, placebo-controlled, randomized clinical trial of transdermal dihydrotestosterone gel on muscular strength, mobility, and quality of life in older men with partial androgen deficiency. J. Clin. Endocrinol. Metab. 86, 4078–4088 (2001)

    Article  CAS  PubMed  Google Scholar 

  50. M. Kimura, K. Sudhir, M. Jones, E. Simpson, A.M. Jefferis, J.P. Chin-Dusting, Impaired acetylcholine-induced release of nitric oxide in the aorta of male aromatase-knockout mice: regulation of nitric oxide production by endogenous sex hormones in males. Circ. Res. 93, 1267–1271 (2003)

    Article  CAS  PubMed  Google Scholar 

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Saltiki, K., Papageorgiou, G., Voidonikola, P. et al. Endogenous estrogen levels are associated with endothelial function in males independently of lipid levels. Endocr 37, 329–335 (2010). https://doi.org/10.1007/s12020-010-9307-7

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