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Testosterone, myocardial function, and mortality

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Abstract

The cardiovascular system is particularly sensitive to androgens, but some controversies exist regarding the effect of testosterone on the heart. While among anabolic abusers, cases of sudden cardiac death have been described, recently it was reported that low serum level of testosterone was correlated with increased risk of cardiovascular diseases (CVD) and mortality rate. This review aims to evaluate the effect of testosterone on myocardial tissue function, coronary artery disease (CAD), and death. Low testosterone level is associated with increased incidence of CAD and mortality. Testosterone administration in hypogonadal elderly men and women has a positive effect on cardiovascular function and improved clinical outcomes and survival time. Although at supraphysiologic doses, androgen may have a toxic effect, and at physiological levels, testosterone is safe and exerts a beneficial effect on myocardial function including mechanisms at cellular and mitochondrial level. The interaction with free testosterone and estradiol should be considered. Further studies are necessary to better understand the interaction mechanisms for an optimal androgen therapy in CVD.

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References

  1. Calof OM, Singh AB, Lee ML, Kenny AM, Urban RJ, Tenover JL, Bhasin S (2005) Adverse events associated with testosterone replacement in middle-aged and older men: a meta-analysis of randomized, placebo-controlled trials. J Gerontol A Biol Sci Med Sci 60(11):1451–1457

    Article  PubMed  Google Scholar 

  2. Haddad RM, Kennedy CC, Caples SM, Tracz MJ, Bolona ER, Sideras K, Uraga MV, Erwin PJ, Montori VM (2007) Testosterone and cardiovascular risk in men: a systematic review and meta-analysis of randomized placebo-controlled trials. Mayo Clin Proc 82(1):29–39. https://doi.org/10.4065/82.1.29

    Article  PubMed  CAS  Google Scholar 

  3. Fernandez-Balsells MM, Murad MH, Lane M, Lampropulos JF, Albuquerque F, Mullan RJ, Agrwal N, Elamin MB, Gallegos-Orozco JF, Wang AT, Erwin PJ, Bhasin S, Montori VM (2010) Clinical review 1: adverse effects of testosterone therapy in adult men: a systematic review and meta-analysis. J Clin Endocrinol Metab 95(6):2560–2575. https://doi.org/10.1210/jc.2009-2575

    Article  PubMed  CAS  Google Scholar 

  4. Huie MJ (1994) An acute myocardial infarction occurring in an anabolic steroid user. Med Sci Sports Exerc 26(4):408–413

    Article  PubMed  CAS  Google Scholar 

  5. Wysoczanski M, Rachko M, Bergmann SR (2008) Acute myocardial infarction in a young man using anabolic steroids. Angiology 59(3):376–378. https://doi.org/10.1177/0003319707304883

    Article  PubMed  Google Scholar 

  6. Stergiopoulos K, Brennan JJ, Mathews R, Setaro JF, Kort S (2008) Anabolic steroids, acute myocardial infarction and polycythemia: a case report and review of the literature. Vasc Health Risk Manag 4(6):1475–1480

    Article  PubMed  PubMed Central  Google Scholar 

  7. Kennedy C (1993) Myocardial infarction in association with misuse of anabolic steroids. Ulster Med J 62(2):174–176

    PubMed  PubMed Central  CAS  Google Scholar 

  8. McNutt RA, Ferenchick GS, Kirlin PC, Hamlin NJ (1988) Acute myocardial infarction in a 22-year-old world class weight lifter using anabolic steroids. Am J Cardiol 62(1):164

    Article  PubMed  CAS  Google Scholar 

  9. Bowman S (1990) Anabolic steroids and infarction. Bmj 300(6726):750

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  10. Goldstein DR, Dobbs T, Krull B, Plumb VJ (1998) Clenbuterol and anabolic steroids: a previously unreported cause of myocardial infarction with normal coronary arteriograms. South Med J 91(8):780–784

    Article  PubMed  CAS  Google Scholar 

  11. Fisher M, Appleby M, Rittoo D, Cotter L (1996) Myocardial infarction with extensive intracoronary thrombus induced by anabolic steroids. Br J Clin Pract 50(4):222–223

    PubMed  CAS  Google Scholar 

  12. Kennedy MC, Lawrence C (1993) Anabolic steroid abuse and cardiac death. Med J Aust 158(5):346–348

    PubMed  CAS  Google Scholar 

  13. Weidemann W, Hanke H (2002) Cardiovascular effects of androgens. Cardiovasc Drug Rev 20(3):175–198

    Article  PubMed  CAS  Google Scholar 

  14. Sullivan ML, Martinez CM, Gennis P, Gallagher EJ (1998) The cardiac toxicity of anabolic steroids. Prog Cardiovasc Dis 41(1):1–15

    Article  PubMed  CAS  Google Scholar 

  15. Parssinen M, Seppala T (2002) Steroid use and long-term health risks in former athletes. Sports Med 32(2):83–94

    Article  PubMed  Google Scholar 

  16. Wilson JD (1988) Androgen abuse by athletes. Endocr Rev 9(2):181–199. https://doi.org/10.1210/edrv-9-2-181

    Article  PubMed  CAS  Google Scholar 

  17. Yesalis CE, Kennedy NJ, Kopstein AN, Bahrke MS (1993) Anabolic-androgenic steroid use in the United States. JAMA 270(10):1217–1221

    Article  PubMed  CAS  Google Scholar 

  18. Araujo AB, O’Donnell AB, Brambilla DJ, Simpson WB, Longcope C, Matsumoto AM, McKinlay JB (2004) Prevalence and incidence of androgen deficiency in middle-aged and older men: estimates from the Massachusetts Male aging study. J Clin Endocrinol Metab 89(12):5920–5926. https://doi.org/10.1210/jc.2003-031719

    Article  PubMed  CAS  Google Scholar 

  19. Travison TG, Araujo AB, Kupelian V, O’Donnell AB, McKinlay JB (2007) The relative contributions of aging, health, and lifestyle factors to serum testosterone decline in men. J Clin Endocrinol Metab 92(2):549–555. https://doi.org/10.1210/jc.2006-1859

    Article  PubMed  CAS  Google Scholar 

  20. Cunningham GO, Michael YL (2004) Concepts guiding the study of the impact of the built environment on physical activity for older adults: a review of the literature. Am J Health Promot 18(6):435–443

    Article  PubMed  PubMed Central  Google Scholar 

  21. Araujo AB, Esche GR, Kupelian V, O’Donnell AB, Travison TG, Williams RE, Clark RV, McKinlay JB (2007) Prevalence of symptomatic androgen deficiency in men. J Clin Endocrinol Metab 92(11):4241–4247. https://doi.org/10.1210/jc.2007-1245

    Article  PubMed  CAS  Google Scholar 

  22. Bassil N, Alkaade S, Morley JE (2009) The benefits and risks of testosterone replacement therapy: a review. Ther Clin Risk Manag 5(3):427–448

    PubMed  PubMed Central  CAS  Google Scholar 

  23. Gan EH, Pattman S, Pearce S, Quinton R (2012) Many men are receiving unnecessary testosterone prescriptions. BMJ 345:e5469. https://doi.org/10.1136/bmj.e5469

    Article  PubMed  Google Scholar 

  24. Altieri P, Barisione C, Lazzarini E, Garuti A, Bezante GP, Canepa M, Spallarossa P, Tocchetti CG, Bollini S, Brunelli C, Ameri P (2016) Testosterone antagonizes doxorubicin-induced senescence of cardiomyocytes. J Am Heart Assoc 8(5):1-13. https://doi.org/10.1161/JAHA.115.002383

  25. Borst SE, Quindry JC, Yarrow JF, Conover CF, Powers SK (2010) Testosterone administration induces protection against global myocardial ischemia. Horm Metab Res 42(2):122–129. https://doi.org/10.1055/s-0029-1241843

    Article  PubMed  CAS  Google Scholar 

  26. Pongkan W, Chattipakorn SC, Chattipakorn N (2015) Roles of testosterone replacement in cardiac ischemia-reperfusion injury. J Cardiovasc Pharmacol Ther. 21(1):27–43. ​https://doi.org/10.1177/1074248415587977

  27. Yang J, Wang F, Sun W, Dong Y, Li M, Fu L (2016) Testosterone replacement modulates cardiac metabolic remodeling after myocardial infarction by upregulating PPARalpha. PPAR Res 2016:4518754. https://doi.org/10.1155/2016/4518754

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  28. Xiao FY, Nheu L, Komesaroff P, Ling S (2015) Testosterone protects cardiac myocytes from superoxide injury via NF-kappaB signalling pathways. Life Sci 133:45–52. https://doi.org/10.1016/j.lfs.2015.05.009

    Article  PubMed  CAS  Google Scholar 

  29. Manning BD, Cantley LC (2007) AKT/PKB signaling: navigating downstream. Cell 129(7):1261–1274. https://doi.org/10.1016/j.cell.2007.06.009

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  30. Perkins ND (2007) Integrating cell-signalling pathways with NF-kappaB and IKK function. Nat Rev Mol Cell Biol 8(1):49–62. https://doi.org/10.1038/nrm2083

    Article  PubMed  CAS  Google Scholar 

  31. Witayavanitkul N, Woranush W, Bupha-Intr T, Wattanapermpool J (2013) Testosterone regulates cardiac contractile activation by modulating SERCA but not NCX activity. Am J Physiol Heart Circ Physiol 304(3):H465–H472. https://doi.org/10.1152/ajpheart.00555.2012

    Article  PubMed  CAS  Google Scholar 

  32. Tsang S, Wong SS, Wu S, Kravtsov GM, Wong TM (2009) Testosterone-augmented contractile responses to alpha1- and beta1-adrenoceptor stimulation are associated with increased activities of RyR, SERCA, and NCX in the heart. Am J Physiol Cell Physiol 296(4):C766–C782. https://doi.org/10.1152/ajpcell.00193.2008

    Article  PubMed  CAS  Google Scholar 

  33. Dutta D, Calvani R, Bernabei R, Leeuwenburgh C, Marzetti E (2012) Contribution of impaired mitochondrial autophagy to cardiac aging: mechanisms and therapeutic opportunities. Circ Res 110(8):1125–1138. https://doi.org/10.1161/CIRCRESAHA.111.246108

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  34. Wang F, Yang J, Sun J, Dong Y, Zhao H, Shi H, Fu L (2015) Testosterone replacement attenuates mitochondrial damage in a rat model of myocardial infarction. J Endocrinol 225(2):101–111. https://doi.org/10.1530/JOE-14-0638

    Article  PubMed  CAS  Google Scholar 

  35. Usui T, Kajita K, Kajita T, Mori I, Hanamoto T, Ikeda T, Okada H, Taguchi K, Kitada Y, Morita H, Sasaki T, Kitamura T, Sato T, Kojima I, Ishizuka T (2014) Elevated mitochondrial biogenesis in skeletal muscle is associated with testosterone-induced body weight loss in male mice. FEBS Lett 588(10):1935–1941. https://doi.org/10.1016/j.febslet.2014.03.051

    Article  PubMed  CAS  Google Scholar 

  36. Ikeda Y, Aihara K, Akaike M, Sato T, Ishikawa K, Ise T, Yagi S, Iwase T, Ueda Y, Yoshida S, Azuma H, Walsh K, Tamaki T, Kato S, Matsumoto T (2010) Androgen receptor counteracts doxorubicin-induced cardiotoxicity in male mice. Mol Endocrinol 24(7):1338–1348. https://doi.org/10.1210/me.2009-0402

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  37. Skogastierna C, Hotzen M, Rane A, Ekstrom L (2014) A supraphysiological dose of testosterone induces nitric oxide production and oxidative stress. Eur J Prev Cardiol 21(8):1049–1054. https://doi.org/10.1177/2047487313481755

    Article  PubMed  Google Scholar 

  38. Victor VM, Rocha M, Banuls C, Rovira-Llopis S, Gomez M, Hernandez-Mijares A (2014) Mitochondrial impairment and oxidative stress in leukocytes after testosterone administration to female-to-male transsexuals. J Sex Med 11(2):454–461. https://doi.org/10.1111/jsm.12376

    Article  PubMed  CAS  Google Scholar 

  39. Hanke H, Lenz C, Hess B, Spindler KD, Weidemann W (2001) Effect of testosterone on plaque development and androgen receptor expression in the arterial vessel wall. Circulation 103(10):1382–1385

    Article  PubMed  CAS  Google Scholar 

  40. Fujimoto R, Morimoto I, Morita E, Sugimoto H, Ito Y, Eto S (1994) Androgen receptors, 5 alpha-reductase activity and androgen-dependent proliferation of vascular smooth muscle cells. J Steroid Biochem Mol Biol 50(3–4):169–174

    Article  PubMed  CAS  Google Scholar 

  41. Marsh JD, Lehmann MH, Ritchie RH, Gwathmey JK, Green GE, Schiebinger RJ (1998) Androgen receptors mediate hypertrophy in cardiac myocytes. Circulation 98(3):256–261

    Article  PubMed  CAS  Google Scholar 

  42. Ikeda Y, Aihara K, Sato T, Akaike M, Yoshizumi M, Suzaki Y, Izawa Y, Fujimura M, Hashizume S, Kato M, Yagi S, Tamaki T, Kawano H, Matsumoto T, Azuma H, Kato S, Matsumoto T (2005) Androgen receptor gene knockout male mice exhibit impaired cardiac growth and exacerbation of angiotensin II-induced cardiac fibrosis. J Biol Chem 280(33):29661–29666. https://doi.org/10.1074/jbc.M411694200

    Article  PubMed  CAS  Google Scholar 

  43. Ikeda Y, Aihara K, Yoshida S, Sato T, Yagi S, Iwase T, Sumitomo Y, Ise T, Ishikawa K, Azuma H, Akaike M, Kato S, Matsumoto T (2009) Androgen-androgen receptor system protects against angiotensin II-induced vascular remodeling. Endocrinology 150(6):2857–2864. https://doi.org/10.1210/en.2008-1254

    Article  PubMed  CAS  Google Scholar 

  44. Liu K, Shen C, Chen X (2015) Expression of androgen receptor in coronary artery in the cases of sudden coronary death. Int J Clin Exp Pathol 8(4):3742–3747

    PubMed  PubMed Central  CAS  Google Scholar 

  45. Svartberg J, von Muhlen D, Mathiesen E, Joakimsen O, Bonaa KH, Stensland-Bugge E (2006) Low testosterone levels are associated with carotid atherosclerosis in men. J Intern Med 259(6):576–582. https://doi.org/10.1111/j.1365-2796.2006.01637.x

    Article  PubMed  CAS  Google Scholar 

  46. Sieveking DP, Lim P, Chow RW, Dunn LL, Bao S, McGrath KC, Heather AK, Handelsman DJ, Celermajer DS, Ng MK (2010) A sex-specific role for androgens in angiogenesis. J Exp Med 207(2):345–352. https://doi.org/10.1084/jem.20091924

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  47. Grohe C, Kahlert S, Lobbert K, Vetter H (1998) Expression of oestrogen receptor alpha and beta in rat heart: role of local oestrogen synthesis. J Endocrinol 156(2):R1–R7

    Article  PubMed  CAS  Google Scholar 

  48. Karas RH, Patterson BL, Mendelsohn ME (1994) Human vascular smooth muscle cells contain functional estrogen receptor. Circulation 89(5):1943–1950

    Article  PubMed  CAS  Google Scholar 

  49. Losordo DW, Kearney M, Kim EA, Jekanowski J, Isner JM (1994) Variable expression of the estrogen receptor in normal and atherosclerotic coronary arteries of premenopausal women. Circulation 89(4):1501–1510

    Article  PubMed  CAS  Google Scholar 

  50. Hodges YK, Tung L, Yan XD, Graham JD, Horwitz KB, Horwitz LD (2000) Estrogen receptors alpha and beta: prevalence of estrogen receptor beta mRNA in human vascular smooth muscle and transcriptional effects. Circulation 101(15):1792–1798

    Article  PubMed  CAS  Google Scholar 

  51. Mendelsohn ME, Karas RH (1999) The protective effects of estrogen on the cardiovascular system. N Engl J Med 340(23):1801–1811. https://doi.org/10.1056/NEJM199906103402306

    Article  PubMed  CAS  Google Scholar 

  52. Bell JR, Mellor KM, Wollermann AC, Ip WT, Reichelt ME, Meachem SJ, Simpson ER, Delbridge LM (2011) Aromatase deficiency confers paradoxical postischemic cardioprotection. Endocrinology 152(12):4937–4947. https://doi.org/10.1210/en.2011-1212

    Article  PubMed  CAS  Google Scholar 

  53. Kararigas G, Nguyen BT, Jarry H (2014) Estrogen modulates cardiac growth through an estrogen receptor alpha-dependent mechanism in healthy ovariectomized mice. Mol Cell Endocrinol 382(2):909–914. https://doi.org/10.1016/j.mce.2013.11.011

    Article  PubMed  CAS  Google Scholar 

  54. Babiker FA, Lips DJ, Delvaux E, Zandberg P, Janssen BJ, Prinzen F, van Eys G, Grohe C, Doevendans PA (2007) Oestrogen modulates cardiac ischaemic remodelling through oestrogen receptor-specific mechanisms. Acta Physiol (Oxford) 189(1):23–31. https://doi.org/10.1111/j.1748-1716.2006.01633.x

    Article  CAS  Google Scholar 

  55. Pugach EK, Blenck CL, Dragavon JM, Langer SJ, Leinwand LA (2016) Estrogen receptor profiling and activity in cardiac myocytes. Mol Cell Endocrinol 431:62–70. https://doi.org/10.1016/j.mce.2016.05.004

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  56. Schuster I, Mahmoodzadeh S, Dworatzek E, Jaisser F, Messaoudi S, Morano I, Regitz-Zagrosek V (2016) Cardiomyocyte-specific overexpression of oestrogen receptor beta improves survival and cardiac function after myocardial infarction in female and male mice. Clin Sci (Lond) 130(5):365–376. https://doi.org/10.1042/CS20150609

    Article  CAS  Google Scholar 

  57. Weinberg EO, Thienelt CD, Katz SE, Bartunek J, Tajima M, Rohrbach S, Douglas PS, Lorell BH (1999) Gender differences in molecular remodeling in pressure overload hypertrophy. J Am Coll Cardiol 34(1):264–273

    Article  PubMed  CAS  Google Scholar 

  58. Cavasin MA, Sankey SS, Yu AL, Menon S, Yang XP (2003) Estrogen and testosterone have opposing effects on chronic cardiac remodeling and function in mice with myocardial infarction. Am J Phys Heart Circ Phys 284(5):H1560–H1569. https://doi.org/10.1152/ajpheart.01087.2002

    Article  CAS  Google Scholar 

  59. Malhotra A, Buttrick P, Scheuer J (1990) Effects of sex hormones on development of physiological and pathological cardiac hypertrophy in male and female rats. Am J Phys 259(3 Pt 2):H866–H871

    CAS  Google Scholar 

  60. Pham TV, Rosen MR (2002) Sex, hormones, and repolarization. Cardiovasc Res 53(3):740–751

    Article  PubMed  CAS  Google Scholar 

  61. Morita H, Wu J, Zipes DP (2008) The QT syndromes: long and short. Lancet 372(9640):750–763. https://doi.org/10.1016/S0140-6736(08)61307-0

    Article  PubMed  CAS  Google Scholar 

  62. Surawicz B, Parikh SR (2003) Differences between ventricular repolarization in men and women: description, mechanism and implications. Ann Noninvasive Electrocardiol 8(4):333–340

    Article  PubMed  Google Scholar 

  63. Charbit B, Christin-Maitre S, Demolis JL, Soustre E, Young J, Funck-Brentano C (2009) Effects of testosterone on ventricular repolarization in hypogonadic men. Am J Cardiol 103(6):887–890. https://doi.org/10.1016/j.amjcard.2008.11.041

    Article  PubMed  CAS  Google Scholar 

  64. Rautaharju PM, Zhou SH, Wong S, Calhoun HP, Berenson GS, Prineas R, Davignon A (1992) Sex differences in the evolution of the electrocardiographic QT interval with age. Can J Cardiol 8(7):690–695

    PubMed  CAS  Google Scholar 

  65. Pecori Giraldi F, Toja PM, Filippini B, Michailidis J, Scacchi M, Stramba Badiale M, Cavagnini F (2010) Increased prevalence of prolonged QT interval in males with primary or secondary hypogonadism: a pilot study. Int J Androl 33(1):e132–e138. https://doi.org/10.1111/j.1365-2605.2009.00985.x

    Article  PubMed  CAS  Google Scholar 

  66. Pecori Giraldi F, Manzoni G, Michailidis J, Scacchi M, Stramba-Badiale M, Cavagnini F (2011) High prevalence of prolonged QT interval in obese hypogonadal males. Obesity (Silver Spring) 19(10):2015–2018. https://doi.org/10.1038/oby.2011.33

    Article  CAS  Google Scholar 

  67. Bidoggia H, Maciel JP, Capalozza N, Mosca S, Blaksley EJ, Valverde E, Bertran G, Arini P, Biagetti MO, Quinteiro RA (2000) Sex differences on the electrocardiographic pattern of cardiac repolarization: possible role of testosterone. Am Heart J 140(4):678–683. https://doi.org/10.1067/mhj.2000.109918

    Article  PubMed  CAS  Google Scholar 

  68. Lubart E, Yarovoy A, Gal G, Krakover R, Leibovitz A (2015) QT interval length in elderly prostatic cancer patients on anti-testosterone treatment. Isr Med Assoc J 17(6):356–359

    PubMed  Google Scholar 

  69. Cheng J (2006) Evidences of the gender-related differences in cardiac repolarization and the underlying mechanisms in different animal species and human. Fundam Clin Pharmacol 20(1):1–8. https://doi.org/10.1111/j.1472-8206.2005.00384.x

    Article  PubMed  CAS  Google Scholar 

  70. Malkin CJ, Morris PD, Pugh PJ, English KM, Channer KS (2003) Effect of testosterone therapy on QT dispersion in men with heart failure. Am J Cardiol 92(10):1241–1243

    Article  PubMed  CAS  Google Scholar 

  71. van Noord C, Dorr M, Sturkenboom MC, Straus SM, Reffelmann T, Felix SB, Hofman A, Kors JA, Haring R, de Jong FH, Nauck M, Uitterlinden AG, Wallaschofski H, Witteman JC, Volzke H, Stricker BH (2010) The association of serum testosterone levels and ventricular repolarization. Eur J Epidemiol 25(1):21–28. https://doi.org/10.1007/s10654-009-9406-z

    Article  PubMed  CAS  Google Scholar 

  72. Bai CX, Kurokawa J, Tamagawa M, Nakaya H, Furukawa T (2005) Nontranscriptional regulation of cardiac repolarization currents by testosterone. Circulation 112(12):1701–1710. https://doi.org/10.1161/CIRCULATIONAHA.104.523217

    Article  PubMed  CAS  Google Scholar 

  73. Kurokawa J, Furukawa T (2013) Non-genomic action of sex steroid hormones and cardiac repolarization. Biol Pharm Bull 36(1):8–12

    Article  PubMed  CAS  Google Scholar 

  74. Fulop L, Banyasz T, Szabo G, Toth IB, Biro T, Lorincz I, Balogh A, Peto K, Miko I, Nanasi PP (2006) Effects of sex hormones on ECG parameters and expression of cardiac ion channels in dogs. Acta Physiol 188(3–4):163–171. https://doi.org/10.1111/j.1748-1716.2006.01618.x

    Article  CAS  Google Scholar 

  75. James AF, Choisy SC, Hancox JC (2007) Recent advances in understanding sex differences in cardiac repolarization. Prog Biophys Mol Biol 94(3):265–319. https://doi.org/10.1016/j.pbiomolbio.2005.05.010

    Article  PubMed  Google Scholar 

  76. Bigi MA, Aslani A, Aslani A (2009) Short qt interval: a novel predictor of androgen abuse in strength trained athletes. Ann Noninvasive Electrocardiol 14(1):35–39. https://doi.org/10.1111/j.1542-474X.2008.00271.x

    Article  PubMed  Google Scholar 

  77. Nettleship JE, Jones TH, Channer KS, Jones RD (2007) Physiological testosterone replacement therapy attenuates fatty streak formation and improves high-density lipoprotein cholesterol in the Tfm mouse: an effect that is independent of the classic androgen receptor. Circulation 116(21):2427–2434. https://doi.org/10.1161/CIRCULATIONAHA.107.708768

    Article  PubMed  CAS  Google Scholar 

  78. Chung SD, Chen YK, Wu FJ, Lin HC (2012) Hormone therapy for prostate cancer and the risk of stroke: a 5-year follow-up study. BJU Int 109(7):1001–1005. https://doi.org/10.1111/j.1464-410X.2011.10459.x

    Article  PubMed  CAS  Google Scholar 

  79. Martin-Merino E, Johansson S, Morris T, Garcia Rodriguez LA (2011) Androgen deprivation therapy and the risk of coronary heart disease and heart failure in patients with prostate cancer: a nested case-control study in UK primary care. Drug Saf 34(11):1061–1077. https://doi.org/10.2165/11594540-000000000-00000

    Article  PubMed  Google Scholar 

  80. Nguyen CT, Aaronson A, Morrissey RP, Agarwal M, Willix RD, Schwarz ER (2011) Myths and truths of growth hormone and testosterone therapy in heart failure. Expert Rev Cardiovasc Ther 9(6):711–720. https://doi.org/10.1586/erc.11.25

    Article  PubMed  CAS  Google Scholar 

  81. Collier A, Ghosh S, McGlynn B, Hollins G (2012) Prostate cancer, androgen deprivation therapy, obesity, the metabolic syndrome, type 2 diabetes, and cardiovascular disease: a review. Am J Clin Oncol 35(5):504–509. https://doi.org/10.1097/COC.0b013e318201a406

    Article  PubMed  Google Scholar 

  82. Tsai HK, D’Amico AV, Sadetsky N, Chen MH, Carroll PR (2007) Androgen deprivation therapy for localized prostate cancer and the risk of cardiovascular mortality. J Natl Cancer Inst 99(20):1516–1524. https://doi.org/10.1093/jnci/djm168

    Article  PubMed  Google Scholar 

  83. Huang F (2018) Is a previously or currently reduced testosterone level in male patients with type 2 diabetes mellitus a risk factor for the development of coronary artery disease? A Systematic Review and Meta-analysis. Diabetes Ther 9(3):1061-1072.​ https://doi.org/10.1007/s13300-018-0415-3

  84. Budoff MJ, Ellenberg SS, Lewis CE, Mohler ER 3rd, Wenger NK, Bhasin S, Barrett-Connor E, Swerdloff RS, Stephens-Shields A, Cauley JA, Crandall JP, Cunningham GR, Ensrud KE, Gill TM, Matsumoto AM, Molitch ME, Nakanishi R, Nezarat N, Matsumoto S, Hou X, Basaria S, Diem SJ, Wang C, Cifelli D, Snyder PJ (2017) Testosterone treatment and coronary artery plaque volume in older men with low testosterone. JAMA 317(7):708–716. https://doi.org/10.1001/jama.2016.21043

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  85. Abd Alamir M, Ellenberg SS, Swerdloff RS, Wenger NK, Mohler ER 3rd, Lewis CE, Barrett-Conner E, Nakanishi R, Darabian S, Alani A, Matsumoto S, Nezarat N, Snyder PJ, Budoff MJ (2016) The Cardiovascular trial of the testosterone trials: rationale, design, and baseline data of a clinical trial using computed tomographic imaging to assess the progression of coronary atherosclerosis. Coron Artery Dis 27(2):95–103. https://doi.org/10.1097/MCA.0000000000000321

    Article  PubMed  Google Scholar 

  86. Chan YX, Knuiman MW, Hung J, Divitini ML, Handelsman DJ, Beilby JP, McQuillan B, Yeap BB (2015) Testosterone, dihydrotestosterone and estradiol are differentially associated with carotid intima-media thickness and the presence of carotid plaque in men with and without coronary artery disease. Endocr J 62(9):777–786. https://doi.org/10.1507/endocrj.EJ15-0196

    Article  PubMed  CAS  Google Scholar 

  87. Khazai B, Golden SH, Colangelo LA, Swerdloff R, Wang C, Honoris L, Gapstur SM, Ouyang P, Cushman M, Li D, Kopp P, Vaidya D, Liu K, Dobs A, Budoff M (2016) Association of endogenous testosterone with subclinical atherosclerosis in men: the multi-ethnic study of atherosclerosis. Clin Endocrinol 84(5):700–707. https://doi.org/10.1111/cen.12997

    Article  CAS  Google Scholar 

  88. Basaria S, Harman SM, Travison TG, Hodis H, Tsitouras P, Budoff M, Pencina KM, Vita J, Dzekov C, Mazer NA, Coviello AD, Knapp PE, Hally K, Pinjic E, Yan M, Storer TW, Bhasin S (2015) Effects of testosterone administration for 3 years on subclinical atherosclerosis progression in older men with low or low-normal testosterone levels: a randomized clinical trial. JAMA 314(6):570–581. https://doi.org/10.1001/jama.2015.8881

    Article  PubMed  CAS  Google Scholar 

  89. Srinath R, Hill Golden S, Carson KA, Dobs A (2015) Endogenous testosterone and its relationship to preclinical and clinical measures of cardiovascular disease in the atherosclerosis risk in communities study. J Clin Endocrinol Metab 100(4):1602–1608. https://doi.org/10.1210/jc.2014-3934

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  90. Ouyang P, Vaidya D, Dobs A, Golden SH, Szklo M, Heckbert SR, Kopp P, Gapstur SM (2009) Sex hormone levels and subclinical atherosclerosis in postmenopausal women: the Multi-ethnic study of atherosclerosis. Atherosclerosis 204(1):255–261. https://doi.org/10.1016/j.atherosclerosis.2008.08.037

    Article  PubMed  CAS  Google Scholar 

  91. Vikan T, Johnsen SH, Schirmer H, Njolstad I, Svartberg J (2009) Endogenous testosterone and the prospective association with carotid atherosclerosis in men: the Tromso study. Eur J Epidemiol 24(6):289–295. https://doi.org/10.1007/s10654-009-9322-2

    Article  PubMed  CAS  Google Scholar 

  92. Soisson V, Brailly-Tabard S, Empana JP, Feart C, Ryan J, Bertrand M, Guiochon-Mantel A, Scarabin PY (2012) Low plasma testosterone and elevated carotid intima-media thickness: importance of low-grade inflammation in elderly men. Atherosclerosis 223(1):244–249. https://doi.org/10.1016/j.atherosclerosis.2012.05.009

    Article  PubMed  CAS  Google Scholar 

  93. Yeap BB, Alfonso H, Chubb SA, Handelsman DJ, Hankey GJ, Golledge J, Flicker L, Norman PE (2013) Lower plasma testosterone or dihydrotestosterone, but not estradiol, is associated with symptoms of intermittent claudication in older men. Clin Endocrinol 79(5):725–732. https://doi.org/10.1111/cen.12208

    Article  CAS  Google Scholar 

  94. Li L, Guo CY, Jia EZ, Zhu TB, Wang LS, Cao KJ, Ma WZ, Yang ZJ (2012) Testosterone is negatively associated with the severity of coronary atherosclerosis in men. Asian J Androl 14(6):875–878. https://doi.org/10.1038/aja.2012.95

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  95. Hu X, Rui L, Zhu T, Xia H, Yang X, Wang X, Liu H, Lu Z, Jiang H (2011) Low testosterone level in middle-aged male patients with coronary artery disease. Eur J Intern Med 22(6):e133–e136. https://doi.org/10.1016/j.ejim.2011.08.016

    Article  PubMed  CAS  Google Scholar 

  96. Phillips GB, Pinkernell BH, Jing TY (1994) The association of hypotestosteronemia with coronary artery disease in men. Arterioscler Thromb 14(5):701–706

    Article  PubMed  CAS  Google Scholar 

  97. Debing E, Peeters E, Duquet W, Poppe K, Velkeniers B, Van Den Brande P (2008) Men with atherosclerotic stenosis of the carotid artery have lower testosterone levels compared with controls. Int Angiol 27(2):135–141

    PubMed  CAS  Google Scholar 

  98. Brand JS, van der Schouw YT (2010) Testosterone, SHBG and cardiovascular health in postmenopausal women. Int J Impot Res 22(2):91–104. https://doi.org/10.1038/ijir.2009.64

    Article  PubMed  CAS  Google Scholar 

  99. Pierpoint T, McKeigue PM, Isaacs AJ, Wild SH, Jacobs HS (1998) Mortality of women with polycystic ovary syndrome at long-term follow-up. J Clin Epidemiol 51(7):581–586

    Article  PubMed  CAS  Google Scholar 

  100. Bernini GP, Sgro M, Moretti A, Argenio GF, Barlascini CO, Cristofani R, Salvetti A (1999) Endogenous androgens and carotid intimal-medial thickness in women. J Clin Endocrinol Metab 84(6):2008–2012. https://doi.org/10.1210/jcem.84.6.5824

    Article  PubMed  CAS  Google Scholar 

  101. Debing E, Peeters E, Duquet W, Poppe K, Velkeniers B, Van den Brande P (2007) Endogenous sex hormone levels in postmenopausal women undergoing carotid artery endarterectomy. Eur J Endocrinol 156(6):687–693. https://doi.org/10.1530/EJE-06-0702

    Article  PubMed  CAS  Google Scholar 

  102. Rexrode KM, Manson JE, Lee IM, Ridker PM, Sluss PM, Cook NR, Buring JE (2003) Sex hormone levels and risk of cardiovascular events in postmenopausal women. Circulation 108(14):1688–1693. https://doi.org/10.1161/01.CIR.0000091114.36254.F3

    Article  PubMed  CAS  Google Scholar 

  103. Meun C, Franco OH, Dhana K, Jaspers L, Muka T, Louwers Y, Ikram MA, Fauser B, Kavousi M, Laven JSE (2018) High androgens in postmenopausal women and the risk for atherosclerosis and cardiovascular disease: the Rotterdam study. J Clin Endocrinol Metab 103(4):1622-1630. https://doi.org/10.1210/jc.2017-02421

  104. Rosano GM, Spoletini I, Vitale C (2017) Cardiovascular disease in women, is it different to men? The role of sex hormones. Climacteric 20(2):125–128. https://doi.org/10.1080/13697137.2017.1291780

    Article  PubMed  CAS  Google Scholar 

  105. Rosano GM, Leonardo F, Pagnotta P, Pelliccia F, Panina G, Cerquetani E, della Monica PL, Bonfigli B, Volpe M, Chierchia SL (1999) Acute anti-ischemic effect of testosterone in men with coronary artery disease. Circulation 99(13):1666–1670

    Article  PubMed  CAS  Google Scholar 

  106. White CM, Ferraro-Borgida MJ, Moyna NM, McGill CC, Ahlberg AW, Thompson PD, Chow MS, Heller GV (1998) The pharmacokinetics of intravenous testosterone in elderly men with coronary artery disease. J Clin Pharmacol 38(9):792–797

    PubMed  CAS  Google Scholar 

  107. Webb CM, Adamson DL, de Zeigler D, Collins P (1999) Effect of acute testosterone on myocardial ischemia in men with coronary artery disease. Am J Cardiol 83(3):437–439 A439

    Article  PubMed  CAS  Google Scholar 

  108. Thompson PD, Ahlberg AW, Moyna NM, Duncan B, Ferraro-Borgida M, White CM, McGill CC, Heller GV (2002) Effect of intravenous testosterone on myocardial ischemia in men with coronary artery disease. Am Heart J 143(2):249–256

    Article  PubMed  CAS  Google Scholar 

  109. Jaffe MD (1977) Effect of testosterone cypionate on postexercise ST segment depression. Br Heart J 39(11):1217–1222

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  110. English KM, Steeds RP, Jones TH, Diver MJ, Channer KS (2000) Low-dose transdermal testosterone therapy improves angina threshold in men with chronic stable angina: a randomized, double-blind, placebo-controlled study. Circulation 102(16):1906–1911

    Article  PubMed  CAS  Google Scholar 

  111. Mathur A, Malkin C, Saeed B, Muthusamy R, Jones TH, Channer K (2009) Long-term benefits of testosterone replacement therapy on angina threshold and atheroma in men. Eur J Endocrinol 161(3):443–449. https://doi.org/10.1530/EJE-09-0092

    Article  PubMed  CAS  Google Scholar 

  112. Wu SZ, Weng XZ (1993) Therapeutic effects of an androgenic preparation on myocardial ischemia and cardiac function in 62 elderly male coronary heart disease patients. Chin Med J 106(6):415–418

    PubMed  CAS  Google Scholar 

  113. Molinari C, Battaglia A, Grossini E, Mary DA, Vassanelli C, Vacca G (2002) The effect of testosterone on regional blood flow in prepubertal anaesthetized pigs. J Physiol 543(Pt 1):365–372

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  114. Perusquia M, Greenway CD, Perkins LM, Stallone JN (2015) Systemic hypotensive effects of testosterone are androgen structure-specific and neuronal nitric oxide synthase-dependent. Am J Physiol Regul Integr Comp Physiol 309(2):R189–R195. https://doi.org/10.1152/ajpregu.00110.2015

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  115. English KM, Jones RD, Jones TH, Morice AH, Channer KS (2000) Aging reduces the responsiveness of coronary arteries from male Wistar rats to the vasodilatory action of testosterone. Clin Sci 99(1):77–82

    Article  PubMed  CAS  Google Scholar 

  116. Mozaffarian D, Benjamin EJ, Go AS, Arnett DK, Blaha MJ, Cushman M, de Ferranti S, Despres JP, Fullerton HJ, Howard VJ, Huffman MD, Judd SE, Kissela BM, Lackland DT, Lichtman JH, Lisabeth LD, Liu S, Mackey RH, Matchar DB, McGuire DK, Mohler ER 3rd, Moy CS, Muntner P, Mussolino ME, Nasir K, Neumar RW, Nichol G, Palaniappan L, Pandey DK, Reeves MJ, Rodriguez CJ, Sorlie PD, Stein J, Towfighi A, Turan TN, Virani SS, Willey JZ, Woo D, Yeh RW, Turner MB, American Heart Association Statistics C, Stroke Statistics S (2015) Heart disease and stroke statistics—2015 update: a report from the American heart association. Circulation 131(4):e29–e322. https://doi.org/10.1161/CIR.0000000000000152

  117. Moriyama Y, Yasue H, Yoshimura M, Mizuno Y, Nishiyama K, Tsunoda R, Kawano H, Kugiyama K, Ogawa H, Saito Y, Nakao K (2000) The plasma levels of dehydroepiandrosterone sulfate are decreased in patients with chronic heart failure in proportion to the severity. J Clin Endocrinol Metab 85(5):1834–1840. https://doi.org/10.1210/jcem.85.5.6568

    Article  PubMed  CAS  Google Scholar 

  118. Jankowska EA, Biel B, Majda J, Szklarska A, Lopuszanska M, Medras M, Anker SD, Banasiak W, Poole-Wilson PA, Ponikowski P (2006) Anabolic deficiency in men with chronic heart failure: prevalence and detrimental impact on survival. Circulation 114(17):1829–1837. https://doi.org/10.1161/CIRCULATIONAHA.106.649426

    Article  PubMed  CAS  Google Scholar 

  119. Kontoleon PE, Anastasiou-Nana MI, Papapetrou PD, Alexopoulos G, Ktenas V, Rapti AC, Tsagalou EP, Nanas JN (2003) Hormonal profile in patients with congestive heart failure. Int J Cardiol 87(2–3):179–183

    Article  PubMed  Google Scholar 

  120. Pugh PJ, Jones RD, West JN, Jones TH, Channer KS (2004) Testosterone treatment for men with chronic heart failure. Heart 90(4):446–447

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  121. Caminiti G, Volterrani M, Iellamo F, Marazzi G, Massaro R, Miceli M, Mammi C, Piepoli M, Fini M, Rosano GM (2009) Effect of long-acting testosterone treatment on functional exercise capacity, skeletal muscle performance, insulin resistance, and baroreflex sensitivity in elderly patients with chronic heart failure a double-blind, placebo-controlled, randomized study. J Am Coll Cardiol 54(10):919–927. https://doi.org/10.1016/j.jacc.2009.04.078

    Article  PubMed  CAS  Google Scholar 

  122. Malkin CJ, Pugh PJ, West JN, van Beek EJ, Jones TH, Channer KS (2006) Testosterone therapy in men with moderate severity heart failure: a double-blind randomized placebo controlled trial. Eur Heart J 27(1):57–64. https://doi.org/10.1093/eurheartj/ehi443

    Article  PubMed  CAS  Google Scholar 

  123. Pugh PJ, Jones TH, Channer KS (2003) Acute haemodynamic effects of testosterone in men with chronic heart failure. Eur Heart J 24(10):909–915

    Article  PubMed  CAS  Google Scholar 

  124. Iellamo F, Volterrani M, Caminiti G, Karam R, Massaro R, Fini M, Collins P, Rosano GM (2010) Testosterone therapy in women with chronic heart failure: a pilot double-blind, randomized, placebo-controlled study. J Am Coll Cardiol 56(16):1310–1316. https://doi.org/10.1016/j.jacc.2010.03.090

    Article  PubMed  CAS  Google Scholar 

  125. Stout M, Tew GA, Doll H, Zwierska I, Woodroofe N, Channer KS, Saxton JM (2012) Testosterone therapy during exercise rehabilitation in male patients with chronic heart failure who have low testosterone status: a double-blind randomized controlled feasibility study. Am Heart J 164(6):893–901. https://doi.org/10.1016/j.ahj.2012.09.016

    Article  PubMed  CAS  Google Scholar 

  126. Mirdamadi A, Garakyaraghi M, Pourmoghaddas A, Bahmani A, Mahmoudi H, Gharipour M (2014) Beneficial effects of testosterone therapy on functional capacity, cardiovascular parameters, and quality of life in patients with congestive heart failure. Biomed Res Int 2014:392432. https://doi.org/10.1155/2014/392432

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  127. Jankowska EA, Filippatos G, Ponikowska B, Borodulin-Nadzieja L, Anker SD, Banasiak W, Poole-Wilson PA, Ponikowski P (2009) Reduction in circulating testosterone relates to exercise capacity in men with chronic heart failure. J Card Fail 15(5):442–450. https://doi.org/10.1016/j.cardfail.2008.12.011

    Article  PubMed  CAS  Google Scholar 

  128. Wehr E, Pilz S, Boehm BO, Marz W, Grammer T, Obermayer-Pietsch B (2011) Low free testosterone is associated with heart failure mortality in older men referred for coronary angiography. Eur J Heart Fail 13(5):482–488. https://doi.org/10.1093/eurjhf/hfr007

    Article  PubMed  CAS  Google Scholar 

  129. Toma M, McAlister FA, Coglianese EE, Vidi V, Vasaiwala S, Bakal JA, Armstrong PW, Ezekowitz JA (2012) Testosterone supplementation in heart failure: a meta-analysis. Circ Heart Fail 5(3):315–321. https://doi.org/10.1161/CIRCHEARTFAILURE.111.965632

    Article  PubMed  CAS  Google Scholar 

  130. Dos Santos MR, Sayegh AL, Bacurau AV, Arap MA, Brum PC, Pereira RM, Takayama L, Barretto AC, Negrao CE, Alves MJ (2016) Effect of exercise training and testosterone replacement on skeletal muscle wasting in patients with heart failure with testosterone deficiency. Mayo Clin Proc 91(5):575–586. https://doi.org/10.1016/j.mayocp.2016.02.014

    Article  PubMed  CAS  Google Scholar 

  131. Sun J, Fu L, Tang X, Han Y, Ma D, Cao J, Kang N, Ji H (2011) Testosterone modulation of cardiac beta-adrenergic signals in a rat model of heart failure. Gen Comp Endocrinol 172(3):518–525. https://doi.org/10.1016/j.ygcen.2011.04.019

    Article  PubMed  CAS  Google Scholar 

  132. Kelly DM, Jones TH (2014) Testosterone and cardiovascular risk in men. Front Horm Res 43:1–20. https://doi.org/10.1159/000360553

    Article  PubMed  Google Scholar 

  133. Wehr E, Pilz S, Boehm BO, Grammer TB, Marz W, Obermayer-Pietsch B (2011) Low free testosterone levels are associated with all-cause and cardiovascular mortality in postmenopausal diabetic women. Diabetes Care 34(8):1771–1777. https://doi.org/10.2337/dc11-0596

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  134. Haring R, Teng Z, Xanthakis V, Coviello A, Sullivan L, Bhasin S, Murabito JM, Wallaschofski H, Vasan RS (2013) Association of sex steroids, gonadotrophins, and their trajectories with clinical cardiovascular disease and all-cause mortality in elderly men from the Framingham heart study. Clin Endocrinol 78(4):629–634. https://doi.org/10.1111/cen.12013

    Article  CAS  Google Scholar 

  135. Khaw KT, Dowsett M, Folkerd E, Bingham S, Wareham N, Luben R, Welch A, Day N (2007) 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(23):2694–2701. https://doi.org/10.1161/CIRCULATIONAHA.107.719005

    Article  PubMed  CAS  Google Scholar 

  136. Laughlin GA, Barrett-Connor E, Bergstrom J (2008) Low serum testosterone and mortality in older men. J Clin Endocrinol Metab 93(1):68–75. https://doi.org/10.1210/jc.2007-1792

    Article  PubMed  CAS  Google Scholar 

  137. Tivesten A, Vandenput L, Labrie F, Karlsson MK, Ljunggren O, Mellstrom D, Ohlsson C (2009) Low serum testosterone and estradiol predict mortality in elderly men. J Clin Endocrinol Metab 94(7):2482–2488. https://doi.org/10.1210/jc.2008-2650

    Article  PubMed  CAS  Google Scholar 

  138. Araujo AB, Dixon JM, Suarez EA, Murad MH, Guey LT, Wittert GA (2011) Clinical review: endogenous testosterone and mortality in men: a systematic review and meta-analysis. J Clin Endocrinol Metab 96(10):3007–3019. https://doi.org/10.1210/jc.2011-1137

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  139. Corona G, Monami M, Boddi V, Cameron-Smith M, Fisher AD, de Vita G, Melani C, Balzi D, Sforza A, Forti G, Mannucci E, Maggi M (2010) Low testosterone is associated with an increased risk of MACE lethality in subjects with erectile dysfunction. J Sex Med 7(4 Pt 1):1557–1564. https://doi.org/10.1111/j.1743-6109.2009.01690.x

    Article  PubMed  CAS  Google Scholar 

  140. Malkin CJ, Pugh PJ, Morris PD, Asif S, Jones TH, Channer KS (2010) Low serum testosterone and increased mortality in men with coronary heart disease. Heart 96(22):1821–1825. https://doi.org/10.1136/hrt.2010.195412

    Article  PubMed  CAS  Google Scholar 

  141. Shores MM, Biggs ML, Arnold AM, Smith NL, Longstreth WT Jr, Kizer JR, Hirsch CH, Cappola AR, Matsumoto AM (2014) Testosterone, dihydrotestosterone, and incident cardiovascular disease and mortality in the cardiovascular health study. J Clin Endocrinol Metab 99(6):2061–2068. https://doi.org/10.1210/jc.2013-3576

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  142. Lehtonen A, Huupponen R, Tuomilehto J, Lavonius S, Arve S, Isoaho H, Huhtaniemi I, Tilvis R (2008) Serum testosterone but not leptin predicts mortality in elderly men. Age Ageing 37(4):461–464. https://doi.org/10.1093/ageing/afn048

    Article  PubMed  Google Scholar 

  143. Khurana KK, Navaneethan SD, Arrigain S, Schold JD, Nally JV Jr, Shoskes DA (2014) Serum testosterone levels and mortality in men with CKD stages 3-4. Am J Kidney Dis 64(3):367–374. https://doi.org/10.1053/j.ajkd.2014.03.010

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  144. Menke A, Guallar E, Rohrmann S, Nelson WG, Rifai N, Kanarek N, Feinleib M, Michos ED, Dobs A, Platz EA (2010) Sex steroid hormone concentrations and risk of death in US men. Am J Epidemiol 171(5):583–592. https://doi.org/10.1093/aje/kwp415

    Article  PubMed  Google Scholar 

  145. Militaru C, Donoiu I, Dracea O, Ionescu DD (2010) Serum testosterone and short-term mortality in men with acute myocardial infarction. Cardiol J 17(3):249–253

    PubMed  Google Scholar 

  146. Ohlsson C, Labrie F, Barrett-Connor E, Karlsson MK, Ljunggren O, Vandenput L, Mellstrom D, Tivesten A (2010) Low serum levels of dehydroepiandrosterone sulfate predict all-cause and cardiovascular mortality in elderly Swedish men. J Clin Endocrinol Metab 95(9):4406–4414. https://doi.org/10.1210/jc.2010-0760

    Article  PubMed  CAS  Google Scholar 

  147. Carrero JJ, Qureshi AR, Parini P, Arver S, Lindholm B, Barany P, Heimburger O, Stenvinkel P (2009) Low serum testosterone increases mortality risk among male dialysis patients. J Am Soc Nephrol 20(3):613–620. https://doi.org/10.1681/ASN.2008060664

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  148. Vikan T, Schirmer H, Njolstad I, Svartberg J (2009) Endogenous sex hormones and the prospective association with cardiovascular disease and mortality in men: the Tromso study. Eur J Endocrinol 161(3):435–442. https://doi.org/10.1530/EJE-09-0284

    Article  PubMed  CAS  Google Scholar 

  149. Araujo AB, Kupelian V, Page ST, Handelsman DJ, Bremner WJ, McKinlay JB (2007) Sex steroids and all-cause and cause-specific mortality in men. Arch Intern Med 167(12):1252–1260. https://doi.org/10.1001/archinte.167.12.1252

    Article  PubMed  CAS  Google Scholar 

  150. Ponikowska B, Jankowska EA, Maj J, Wegrzynowska-Teodorczyk K, Biel B, Reczuch K, Borodulin-Nadzieja L, Banasiak W, Ponikowski P (2010) Gonadal and adrenal androgen deficiencies as independent predictors of increased cardiovascular mortality in men with type II diabetes mellitus and stable coronary artery disease. Int J Cardiol 143(3):343–348. https://doi.org/10.1016/j.ijcard.2009.03.072

    Article  PubMed  Google Scholar 

  151. Hyde Z, Norman PE, Flicker L, Hankey GJ, Almeida OP, McCaul KA, Chubb SA, Yeap BB (2012) Low free testosterone predicts mortality from cardiovascular disease but not other causes: the Health in men study. J Clin Endocrinol Metab 97(1):179–189. https://doi.org/10.1210/jc.2011-1617

    Article  PubMed  CAS  Google Scholar 

  152. Holmboe SA, Vradi E, Jensen TK, Linneberg A, Husemoen LL, Scheike T, Skakkebaek NE, Juul A, Andersson AM (2015) the association of reproductive hormone levels and all-cause, cancer, and cardiovascular disease mortality in men. J Clin Endocrinol Metab 100(12):4472–4480. https://doi.org/10.1210/jc.2015-2460

    Article  PubMed  CAS  Google Scholar 

  153. Hsu B, Cumming RG, Naganathan V, Blyth FM, Le Couteur DG, Hirani V, Waite LM, Seibel MJ, Handelsman DJ (2016) Temporal changes in androgens and estrogens are associated with all-cause and cause-specific mortality in older men. J Clin Endocrinol Metab 101(5):2201–2210. https://doi.org/10.1210/jc.2016-1025

    Article  PubMed  CAS  Google Scholar 

  154. Muraleedharan V, Marsh H, Kapoor D, Channer KS, Jones TH (2013) Testosterone deficiency is associated with increased risk of mortality and testosterone replacement improves survival in men with type 2 diabetes. Eur J Endocrinol 169(6):725–733. https://doi.org/10.1530/EJE-13-0321

    Article  PubMed  CAS  Google Scholar 

  155. Pye SR, Huhtaniemi IT, Finn JD, Lee DM, O’Neill TW, Tajar A, Bartfai G, Boonen S, Casanueva FF, Forti G, Giwercman A, Han TS, Kula K, Lean ME, Pendleton N, Punab M, Rutter MK, Vanderschueren D, Wu FC, Group ES (2014) Late-onset hypogonadism and mortality in aging men. J Clin Endocrinol Metab 99(4):1357–1366. https://doi.org/10.1210/jc.2013-2052

    Article  PubMed  CAS  Google Scholar 

  156. Hamilton EJ, Davis WA, Makepeace A, Lim EM, Yeap BB, Peters KE, Davis TM (2016) Prevalence and prognosis of a low serum testosterone in men with type 2 diabetes: the fremantle diabetes study phase II. Clin Endocrinol 85(3):444–452. https://doi.org/10.1111/cen.13087

    Article  CAS  Google Scholar 

  157. Hackett G, Heald AH, Sinclair A, Jones PW, Strange RC, Ramachandran S (2016) Serum testosterone, testosterone replacement therapy and all-cause mortality in men with type 2 diabetes: retrospective consideration of the impact of PDE5 inhibitors and statins. Int J Clin Pract 70(3):244–253. https://doi.org/10.1111/ijcp.12779

    Article  PubMed  CAS  Google Scholar 

  158. Tint AN, Hoermann R, Wong H, Ekinci EI, MacIsaac RJ, Jerums G, Zajac JD, Grossmann M (2016) Association of sex hormone-binding globulin and free testosterone with mortality in men with type 2 diabetes mellitus. Eur J Endocrinol 174(1):59–68. https://doi.org/10.1530/EJE-15-0672

    Article  PubMed  CAS  Google Scholar 

  159. Daka B, Langer RD, Larsson CA, Rosen T, Jansson PA, Rastam L, Lindblad U (2015) Low concentrations of serum testosterone predict acute myocardial infarction in men with type 2 diabetes mellitus. BMC Endocr Disord 15:35. https://doi.org/10.1186/s12902-015-0034-1

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  160. Wu HY, Wang XF, Wang JH, Li JY (2011) Testosterone level and mortality in elderly men with systolic chronic heart failure. Asian J Androl 13(5):759–763. https://doi.org/10.1038/aja.2011.26

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  161. Shores MM, Smith NL, Forsberg CW, Anawalt BD, Matsumoto AM (2012) Testosterone treatment and mortality in men with low testosterone levels. J Clin Endocrinol Metab 97(6):2050–2058. https://doi.org/10.1210/jc.2011-2591

    Article  PubMed  CAS  Google Scholar 

  162. Yeap BB, Alfonso H, Chubb SA, Handelsman DJ, Hankey GJ, Almeida OP, Golledge J, Norman PE, Flicker L (2014) In older men an optimal plasma testosterone is associated with reduced all-cause mortality and higher dihydrotestosterone with reduced ischemic heart disease mortality, while estradiol levels do not predict mortality. J Clin Endocrinol Metab 99(1):E9–E18. https://doi.org/10.1210/jc.2013-3272

  163. Yoshihisa A, Suzuki S, Sato Y, Kanno Y, Abe S, Miyata M, Sato T, Oikawa M, Kobayashi A, Yamaki T, Kunii H, Nakazato K, Ishida T, Takeishi Y (2018) Relation of testosterone levels to mortality in men with heart failure. Am J Cardiol 121(11):1321-1327.​ https://doi.org/10.1016/j.amjcard.2018.01.052

  164. Haring R, Volzke H, Steveling A, Krebs A, Felix SB, Schofl C, Dorr M, Nauck M, Wallaschofski H (2010) Low serum testosterone levels are associated with increased risk of mortality in a population-based cohort of men aged 20-79. Eur Heart J 31(12):1494–1501. https://doi.org/10.1093/eurheartj/ehq009

    Article  PubMed  CAS  Google Scholar 

  165. Sharma R, Oni OA, Gupta K, Chen G, Sharma M, Dawn B, Sharma R, Parashara D, Savin VJ, Ambrose JA, Barua RS (2015) Normalization of testosterone level is associated with reduced incidence of myocardial infarction and mortality in men. Eur Heart J 36(40):2706–2715. https://doi.org/10.1093/eurheartj/ehv346

    Article  PubMed  Google Scholar 

  166. Shores MM, Matsumoto AM, Sloan KL, Kivlahan DR (2006) Low serum testosterone and mortality in male veterans. Arch Intern Med 166(15):1660–1665. https://doi.org/10.1001/archinte.166.15.1660

    Article  PubMed  CAS  Google Scholar 

  167. Maggio M, Lauretani F, Ceda GP, Bandinelli S, Ling SM, Metter EJ, Artoni A, Carassale L, Cazzato A, Ceresini G, Guralnik JM, Basaria S, Valenti G, Ferrucci L (2007) Relationship between low levels of anabolic hormones and 6-year mortality in older men: the aging in the Chianti area (InCHIANTI) study. Arch Intern Med 167(20):2249–2254. https://doi.org/10.1001/archinte.167.20.2249

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  168. Hackett GI (2016) Testosterone replacement therapy and mortality in older men. Drug Saf 39(2):117–130. https://doi.org/10.1007/s40264-015-0348-y

    Article  PubMed  CAS  Google Scholar 

  169. Alexander GC, Iyer G, Lucas E, Lin D, Singh S (2017) Cardiovascular risks of exogenous testosterone use among men: a systematic review and meta-analysis. Am J Med 130(3):293–305. https://doi.org/10.1016/j.amjmed.2016.09.017

    Article  PubMed  CAS  Google Scholar 

  170. Nahrendorf M, Frantz S, Hu K, von zur Muhlen C, Tomaszewski M, Scheuermann H, Kaiser R, Jazbutyte V, Beer S, Bauer W, Neubauer S, Ertl G, Allolio B, Callies F (2003) Effect of testosterone on post-myocardial infarction remodeling and function. Cardiovasc Res 57(2):370–378

    Article  PubMed  CAS  Google Scholar 

  171. Tan RS, Cook KR, Reilly WG (2015) Myocardial infarction and stroke risk in young healthy men treated with injectable testosterone. Int J Endocrinol 2015:970750. https://doi.org/10.1155/2015/970750

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  172. Baillargeon J, Urban RJ, Kuo YF, Ottenbacher KJ, Raji MA, Du F, Lin YL, Goodwin JS (2014) Risk of myocardial infarction in older men receiving testosterone therapy. Ann Pharmacother 48(9):1138–1144. https://doi.org/10.1177/1060028014539918

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  173. Morgentaler A, Miner MM, Caliber M, Guay AT, Khera M, Traish AM (2015) Testosterone therapy and cardiovascular risk: advances and controversies. Mayo Clin Proc 90(2):224–251. https://doi.org/10.1016/j.mayocp.2014.10.011

    Article  PubMed  CAS  Google Scholar 

  174. Eisenberg ML, Li S, Herder D, Lamb DJ, Lipshultz LI (2015) Testosterone therapy and mortality risk. Int J Impot Res 27(2):46–48. https://doi.org/10.1038/ijir.2014.29

    Article  PubMed  CAS  Google Scholar 

  175. Yeap BB, Alfonso H, Chubb SA, Hankey GJ, Handelsman DJ, Golledge J, Almeida OP, Flicker L, Norman PE (2014) In older men, higher plasma testosterone or dihydrotestosterone is an independent predictor for reduced incidence of stroke but not myocardial infarction. J Clin Endocrinol Metab 99(12):4565–4573. https://doi.org/10.1210/jc.2014-2664

    Article  PubMed  CAS  Google Scholar 

  176. Xu L, Freeman G, Cowling BJ, Schooling CM (2013) Testosterone therapy and cardiovascular events among men: a systematic review and meta-analysis of placebo-controlled randomized trials. BMC Med 11:108. https://doi.org/10.1186/1741-7015-11-108

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  177. Finkle WD, Greenland S, Ridgeway GK, Adams JL, Frasco MA, Cook MB, Fraumeni JF Jr, Hoover RN (2014) Increased risk of non-fatal myocardial infarction following testosterone therapy prescription in men. PLoS One 9(1):e85805. https://doi.org/10.1371/journal.pone.0085805

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  178. Shores MM, Matsumoto AM (2014) Testosterone, aging and survival: biomarker or deficiency. Curr Opin Endocrinol Diabetes Obes 21(3):209–216. https://doi.org/10.1097/MED.0000000000000057

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  179. Schooling CM (2014) Testosterone and cardiovascular disease. Curr Opin Endocrinol Diabetes Obes 21(3):202–208. https://doi.org/10.1097/MED.0000000000000065

    Article  PubMed  CAS  Google Scholar 

  180. Vigen R, O’Donnell CI, Baron AE, Grunwald GK, Maddox TM, Bradley SM, Barqawi A, Woning G, Wierman ME, Plomondon ME, Rumsfeld JS, Ho PM (2013) Association of testosterone therapy with mortality, myocardial infarction, and stroke in men with low testosterone levels. JAMA 310(17):1829–1836. https://doi.org/10.1001/jama.2013.280386

    Article  PubMed  CAS  Google Scholar 

  181. Tam LM, Kim J, Blumenthal RS, Nasir K, Al-Mallah MH, Blaha MJ (2013) Absolute coronary artery calcium score is the best predictor of non-calcified plaque involvement in patients with low calcium scores (1-100). Atherosclerosis 230(1):76–79. https://doi.org/10.1016/j.atherosclerosis.2013.06.022

    Article  PubMed  CAS  Google Scholar 

  182. Lai J, Ge Y, Shao Y, Xuan T, Xia S, Li M (2015) Low serum testosterone level was associated with extensive coronary artery calcification in elderly male patients with stable coronary artery disease. Coron Artery Dis 26(5):437–441. https://doi.org/10.1097/MCA.0000000000000260

    Article  PubMed  Google Scholar 

  183. Park BJ, Shim JY, Lee YJ, Lee JH, Lee HR (2012) Inverse relationship between bioavailable testosterone and subclinical coronary artery calcification in non-obese Korean men. Asian J Androl 14(4):612–615. https://doi.org/10.1038/aja.2012.19

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  184. Ahmadi A, Stone GW, Leipsic J, Shaw LJ, Villines TC, Kern MJ, Hecht H, Erlinge D, Ben-Yehuda O, Maehara A, Arbustini E, Serruys P, Garcia-Garcia HM, Narula J (2016) Prognostic determinants of coronary atherosclerosis in stable ischemic heart disease: anatomy, physiology, or morphology? Circ Res 119(2):317–329. https://doi.org/10.1161/CIRCRESAHA.116.308952

    Article  PubMed  CAS  Google Scholar 

  185. Snyder PJ, Bhasin S, Cunningham GR, Matsumoto AM, Stephens-Shields AJ, Cauley JA, Gill TM, Barrett-Connor E, Swerdloff RS, Wang C, Ensrud KE, Lewis CE, Farrar JT, Cella D, Rosen RC, Pahor M, Crandall JP, Molitch ME, Cifelli D, Dougar D, Fluharty L, Resnick SM, Storer TW, Anton S, Basaria S, Diem SJ, Hou X, Mohler ER 3rd, Parsons JK, Wenger NK, Zeldow B, Landis JR, Ellenberg SS, Testosterone Trials I (2016) Effects of testosterone treatment in older men. N Engl J Med 374(7):611–624. https://doi.org/10.1056/NEJMoa1506119

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  186. Gianatti EJ, Hoermann R, Lam Q, Dupuis P, Zajac JD, Grossmann M (2015) Effect of testosterone treatment on cardiac biomarkers in a randomized controlled trial of men with type 2 diabetes. Clin Endocrinol 84(1):55-62. https://doi.org/10.1111/cen.12842

  187. Ruige JB, Ouwens DM, Kaufman JM (2013) Beneficial and adverse effects of testosterone on the cardiovascular system in men. J Clin Endocrinol Metab 98(11):4300–4310. https://doi.org/10.1210/jc.2013-1970

    Article  PubMed  CAS  Google Scholar 

  188. Pereira TV, Ioannidis JP (2011) Statistically significant meta-analyses of clinical trials have modest credibility and inflated effects. J Clin Epidemiol 64(10):1060–1069. https://doi.org/10.1016/j.jclinepi.2010.12.012

    Article  PubMed  Google Scholar 

  189. Maki-Nunes C, Toschi-Dias E, Cepeda FX, Rondon MU, Alves MJ, Fraga RF, Braga AM, Aguilar AM, Amaro AC, Drager LF, Lorenzi-Filho G, Negrao CE, Trombetta IC (2015) Diet and exercise improve chemoreflex sensitivity in patients with metabolic syndrome and obstructive sleep apnea. Obesity (Silver Spring) 23(8):1582–1590. https://doi.org/10.1002/oby.21126

    Article  CAS  Google Scholar 

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  1. Clinical Center Stella Maris, Laboratory of Physiology of Exercise, Strada Rovereta 42, 47891, Falciano, Republic of San Marino

    Vittorio Emanuele Bianchi

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Bianchi, V.E. Testosterone, myocardial function, and mortality. Heart Fail Rev 23, 773–788 (2018). https://doi.org/10.1007/s10741-018-9721-0

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