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Testosterone replacement therapy and cardiovascular risk

Abstract

Testosterone is the main male sex hormone and is essential for the maintenance of male secondary sexual characteristics and fertility. Androgen deficiency in young men owing to organic disease of the hypothalamus, pituitary gland or testes has been treated with testosterone replacement for decades without reports of increased cardiovascular events. In the past decade, the number of testosterone prescriptions issued for middle-aged or older men with either age-related or obesity-related decline in serum testosterone levels has increased exponentially even though these conditions are not approved indications for testosterone therapy. Some retrospective studies and randomized trials have suggested that testosterone replacement therapy increases the risk of cardiovascular disease, which has led the FDA to release a warning statement about the potential cardiovascular risks of testosterone replacement therapy. However, no trials of testosterone replacement therapy published to date were designed or adequately powered to assess cardiovascular events; therefore, the cardiovascular safety of this therapy remains unclear. In this Review, we provide an overview of epidemiological data on the association between serum levels of endogenous testosterone and cardiovascular disease, prescription database studies on the risk of cardiovascular disease in men receiving testosterone therapy, randomized trials and meta-analyses evaluating testosterone replacement therapy and its association with cardiovascular events and mechanistic studies on the effects of testosterone on the cardiovascular system. Our aim is to help clinicians to make informed decisions when considering testosterone replacement therapy in their patients.

Key points

  • Population studies suggest that low serum levels of endogenous testosterone are a risk factor for cardiovascular events, although these studies cannot establish causality or exclude reverse causality, and some of these associations might result from residual confounding.

  • Although many retrospective studies show no association, some retrospective studies of prescription databases have shown a higher risk of cardiovascular events in men receiving testosterone, with the risk increasing early after treatment initiation.

  • Meta-analyses of randomized, controlled trials of testosterone replacement therapy report conflicting findings, probably because the included trials lacked power or the duration was too short to assess cardiovascular events.

  • The TRAVERSE trial, the first trial of testosterone therapy that is adequately powered to assess cardiovascular events, began in 2018, and its findings might take a decade to become available.

  • Until the results of the TRAVERSE trial are available, clinicians should individualize testosterone treatment after having an informed discussion with their patients about the risks and benefits of testosterone replacement therapy.

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Fig. 1: Time-to-event analysis of cardiovascular adverse events in the TOM trial.
Fig. 2: Effects of testosterone treatment on coronary artery plaques in clinical trials.
Fig. 3: Meta-analyses of clinical trials of testosterone replacement therapy.
Fig. 4: Cardiovascular targets and effects of testosterone.
Fig. 5: Molecular mechanisms of testosterone modulation of vascular tone.
Fig. 6: Effects of testosterone on cardiac electrophysiology.

References

  1. 1.

    Basaria, S. Male hypogonadism. Lancet 383, 1250–1263 (2014).

    CAS  PubMed  Google Scholar 

  2. 2.

    Bhasin, S. et al. Testosterone therapy in men with hypogonadism: an Endocrine Society Clinical Practice Guideline. J. Clin. Endocrinol. Metab. 103, 1715–1744 (2018).

    PubMed  Google Scholar 

  3. 3.

    Wu, F. C. et al. Hypothalamic-pituitary-testicular axis disruptions in older men are differentially linked to age and modifiable risk factors: the European Male Aging Study. J. Clin. Endocrinol. Metab. 93, 2737–2745 (2008).

    CAS  PubMed  Google Scholar 

  4. 4.

    Bhasin, S. et al. Reference ranges for testosterone in men generated using liquid chromatography tandem mass spectrometry in a community-based sample of healthy nonobese young men in the Framingham Heart Study and applied to three geographically distinct cohorts. J. Clin. Endocrinol. Metab. 96, 2430–2439 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  5. 5.

    Harman, S. M. et al. Longitudinal effects of aging on serum total and free testosterone levels in healthy men. Baltimore Longitudinal Study of Aging. J. Clin. Endocrinol. Metab. 86, 724–731 (2001).

    CAS  PubMed  Google Scholar 

  6. 6.

    Feldman, H. A. et al. Age trends in the level of serum testosterone and other hormones in middle-aged men: longitudinal results from the Massachusetts male aging study. J. Clin. Endocrinol. Metab. 87, 589–598 (2002).

    CAS  PubMed  Google Scholar 

  7. 7.

    Wu, F. C. et al. Identification of late-onset hypogonadism in middle-aged and elderly men. N. Engl. J. Med. 363, 123–135 (2010).

    CAS  PubMed  Google Scholar 

  8. 8.

    Snyder, P. J. et al. Effects of testosterone treatment in older men. N. Engl. J. Med. 374, 611–624 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  9. 9.

    Handelsman, D. J. Global trends in testosterone prescribing, 2000-2011: expanding the spectrum of prescription drug misuse. Med. J. Aust. 199, 548–551 (2013).

    PubMed  Google Scholar 

  10. 10.

    Baillargeon, J., Urban, R. J., Ottenbacher, K. J., Pierson, K. S. & Goodwin, J. S. Trends in androgen prescribing in the United States, 2001 to 2011. JAMA. Intern. Med. 173, 1465–1466 (2013).

    Google Scholar 

  11. 11.

    Nguyen, C. P. et al. Testosterone and “age-related hypogonadism” — FDA concerns. N. Engl. J. Med. 373, 689–691 (2015).

    PubMed  Google Scholar 

  12. 12.

    Layton, J. B. et al. Testosterone lab testing and initiation in the United Kingdom and the United States, 2000 to 2011. J. Clin. Endocrinol. Metab. 99, 835–842 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  13. 13.

    Handelsman, D. J. Testosterone and male aging: faltering hope for rejuvenation. JAMA 317, 699–701 (2017).

    PubMed  Google Scholar 

  14. 14.

    Baillargeon, J., Kuo, Y. F., Westra, J. R., Urban, R. J. & Goodwin, J. S. Testosterone Prescribing in the United States, 2002–2016. JAMA 320, 200–202 (2018).

    PubMed  PubMed Central  Google Scholar 

  15. 15.

    Yeap, B. B. et al. Lower testosterone levels predict incident stroke and transient ischemic attack in older men. J. Clin. Endocrinol. Metab. 94, 2353–2359 (2009).

    CAS  PubMed  Google Scholar 

  16. 16.

    Ohlsson, C. et al. High serum testosterone is associated with reduced risk of cardiovascular events in elderly men. The MrOS (Osteoporotic Fractures in Men) study in Sweden. J. Am. Coll. Cardiol. 58, 1674–1681 (2011).

    CAS  PubMed  Google Scholar 

  17. 17.

    Soisson, V. et al. A J-shaped association between plasma testosterone and risk of ischemic arterial event in elderly men: the French 3C cohort study. Maturitas 75, 282–288 (2013).

    CAS  PubMed  Google Scholar 

  18. 18.

    Yeap, B. B. et al. 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, 4565–4573 (2014).

    CAS  PubMed  Google Scholar 

  19. 19.

    Khaw, K. T. et al. 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).

    CAS  PubMed  Google Scholar 

  20. 20.

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

    CAS  PubMed  Google Scholar 

  21. 21.

    Haring, R. et al. 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, 1494–1501 (2010).

    CAS  PubMed  Google Scholar 

  22. 22.

    Vigen, R. et al. Association of testosterone therapy with mortality, myocardial infarction, and stroke in men with low testosterone levels. JAMA 310, 1829–1836 (2013).

    CAS  PubMed  Google Scholar 

  23. 23.

    Finkle, W. D. et al. Increased risk of non-fatal myocardial infarction following testosterone therapy prescription in men. PLOS ONE 9, e85805 (2014).

    PubMed  PubMed Central  Google Scholar 

  24. 24.

    Etminan, M., Skeldon, S. C., Goldenberg, S. L., Carleton, B. & Brophy, J. M. Testosterone therapy and risk of myocardial infarction: a pharmacoepidemiologic study. Pharmacotherapy 35, 72–78 (2015).

    CAS  PubMed  Google Scholar 

  25. 25.

    Martinez, C. et al. Testosterone treatment and risk of venous thromboembolism: population based case-control study. BMJ 355, i5968 (2016).

    PubMed  PubMed Central  Google Scholar 

  26. 26.

    Baillargeon, J. et al. Risk of venous thromboembolism in men receiving testosterone therapy. Mayo Clin. Proc. 90, 1038–1045 (2015).

    CAS  PubMed  Google Scholar 

  27. 27.

    Li, H., Benoit, K., Wang, W. & Motsko, S. Association between use of exogenous testosterone therapy and risk of venous thrombotic events among exogenous testosterone treated and untreated men with hypogonadism. J. Urol. 195, 1065–1072 (2016).

    CAS  PubMed  Google Scholar 

  28. 28.

    Sharma, R. et al. Association between testosterone replacement therapy and the incidence of DVT and pulmonary embolism: a retrospective cohort study of the Veterans Administration Database. Chest 150, 563–571 (2016).

    PubMed  Google Scholar 

  29. 29.

    Shores, M. M., Smith, N. L., Forsberg, C. W., Anawalt, B. D. & Matsumoto, A. M. Testosterone treatment and mortality in men with low testosterone levels. J. Clin. Endocrinol. Metab. 97, 2050–2058 (2012).

    CAS  PubMed  Google Scholar 

  30. 30.

    Muraleedharan, V., Marsh, H., Kapoor, D., Channer, K. S. & Jones, T. H. Testosterone deficiency is associated with increased risk of mortality and testosterone replacement improves survival in men with type 2 diabetes. Eur. J. Endocrinol. 169, 725–733 (2013).

    CAS  PubMed  Google Scholar 

  31. 31.

    Baillargeon, J. et al. Risk of myocardial infarction in older men receiving testosterone therapy. Ann. Pharmacother. 48, 1138–1144 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  32. 32.

    Sharma, R. et al. Normalization of testosterone level is associated with reduced incidence of myocardial infarction and mortality in men. Eur. Heart J. 36, 2706–2715 (2015).

    PubMed  Google Scholar 

  33. 33.

    Tan, R. S., Cook, K. R. & Reilly, W. G. Myocardial infarction and stroke risk in young healthy men treated with injectable testosterone. Int. J. Endocrinol. 2015, 970750 (2015).

    PubMed  PubMed Central  Google Scholar 

  34. 34.

    Anderson, J. L. et al. Impact of testosterone replacement therapy on myocardial infarction, stroke, and death in men with low testosterone concentrations in an integrated health care system. Am. J. Cardiol. 117, 794–799 (2016).

    CAS  PubMed  Google Scholar 

  35. 35.

    Wallis, C. J. et al. Survival and cardiovascular events in men treated with testosterone replacement therapy: an intention-to-treat observational cohort study. Lancet Diabetes Endocrinol. 4, 498–506 (2016).

    CAS  PubMed  Google Scholar 

  36. 36.

    Oni, O. A. et al. Normalization of testosterone levels after testosterone replacement therapy is not associated with reduced myocardial infarction in smokers. Mayo Clin. Proc. Innov. Qual. Outcomes 1, 57–66 (2017).

    PubMed  PubMed Central  Google Scholar 

  37. 37.

    Cheetham, T. C. et al. Association of testosterone replacement with cardiovascular outcomes among men with androgen deficiency. JAMA Intern. Med. 177, 491–499 (2017).

    PubMed  Google Scholar 

  38. 38.

    Sharma, R. et al. Normalization of testosterone levels after testosterone replacement therapy is associated with decreased incidence of atrial fibrillation. J. Am. Heart Assoc. 6, e004880 (2017).

    PubMed  PubMed Central  Google Scholar 

  39. 39.

    Basaria, S. et al. Adverse events associated with testosterone administration. N. Engl. J. Med. 363, 109–122 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  40. 40.

    Xu, L., Freeman, G., Cowling, B. J. & Schooling, C. M. Testosterone therapy and cardiovascular events among men: a systematic review and meta-analysis of placebo-controlled randomized trials. BMC Med. 11, 108 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  41. 41.

    US National Library of Medicine. ClinicalTrials.gov http://www.clinicaltrials.gov/ct2/show/NCT03518034 (2019).

  42. 42.

    Wang, C., Catlin, D. H., Demers, L. M., Starcevic, B. & Swerdloff, R. S. Measurement of total serum testosterone in adult men: comparison of current laboratory methods versus liquid chromatography-tandem mass spectrometry. J. Clin. Endocrinol. Metab. 89, 534–543 (2004).

    CAS  PubMed  Google Scholar 

  43. 43.

    Sikaris, K. et al. Reproductive hormone reference intervals for healthy fertile young men: evaluation of automated platform assays. J. Clin. Endocrinol. Metab. 90, 5928–5936 (2005).

    CAS  PubMed  Google Scholar 

  44. 44.

    Handelsman, D. J. & Wartofsky, L. Requirement for mass spectrometry sex steroid assays in the Journal of Clinical Endocrinology and Metabolism. J. Clin. Endocrinol. Metab. 98, 3971–3973 (2013).

    CAS  PubMed  Google Scholar 

  45. 45.

    Shores, M. M. et al. Testosterone and dihydrotestosterone and incident ischaemic stroke in men in the Cardiovascular Health Study. Clin. Endocrinol. 81, 746–753 (2014).

    CAS  Google Scholar 

  46. 46.

    Srinath, R., Gottesman, R. F., Hill Golden, S., Carson, K. A. & Dobs, A. Association between endogenous testosterone and cerebrovascular disease in the ARIC Study (Atherosclerosis Risk in Communities). Stroke 47, 2682–2688 (2016).

    CAS  PubMed  Google Scholar 

  47. 47.

    Magnani, J. W. et al. Association of sex hormones, aging, and atrial fibrillation in men: the Framingham Heart Study. Circ. Arrhythm. Electrophysiol. 7, 307–312 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  48. 48.

    Rosenberg, M. A. et al. Serum androgens and risk of atrial fibrillation in older men: the Cardiovascular Health Study. Clin. Cardiol. 41, 830–836 (2018).

    PubMed  PubMed Central  Google Scholar 

  49. 49.

    Zeller, T. et al. Low testosterone levels are predictive for incident atrial fibrillation and ischaemic stroke in men, but protective in women — results from the FINRISK study. Eur. J. Prev. Cardiol. 25, 1133–1139 (2018).

    Google Scholar 

  50. 50.

    Ruige, J. B., Mahmoud, A. M., De Bacquer, D. & Kaufman, J. M. Endogenous testosterone and cardiovascular disease in healthy men: a meta-analysis. Heart 97, 870–875 (2011).

    CAS  PubMed  Google Scholar 

  51. 51.

    Haring, R. et al. Mendelian randomization suggests non-causal associations of testosterone with cardiometabolic risk factors and mortality. Andrology 1, 17–23 (2013).

    CAS  PubMed  Google Scholar 

  52. 52.

    Shores, M. M., Matsumoto, A. M., Sloan, K. L. & Kivlahan, D. R. Low serum testosterone and mortality in male veterans. Arch. Intern. Med. 166, 1660–1665 (2006).

    CAS  PubMed  Google Scholar 

  53. 53.

    Tivesten, A. et al. Low serum testosterone and estradiol predict mortality in elderly men. J. Clin. Endocrinol. Metab. 94, 2482–2488 (2009).

    CAS  PubMed  Google Scholar 

  54. 54.

    Vikan, T., Schirmer, H., Njolstad, I. & Svartberg, J. Endogenous sex hormones and the prospective association with cardiovascular disease and mortality in men: the Tromso Study. Eur. J. Endocrinol. 161, 435–442 (2009).

    CAS  PubMed  Google Scholar 

  55. 55.

    Malkin, C. J. et al. Low serum testosterone and increased mortality in men with coronary heart disease. Heart 96, 1821–1825 (2010).

    CAS  PubMed  Google Scholar 

  56. 56.

    Menke, A. et al. Sex steroid hormone concentrations and risk of death in US men. Am. J. Epidemiol. 171, 583–592 (2010).

    PubMed  PubMed Central  Google Scholar 

  57. 57.

    Hyde, Z. et al. Low free testosterone predicts mortality from cardiovascular disease but not other causes: the Health in Men Study. J. Clin. Endocrinol. Metab. 97, 179–189 (2012).

    CAS  PubMed  Google Scholar 

  58. 58.

    Yeap, B. B. et al. 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, E9–E18 (2014).

    PubMed  Google Scholar 

  59. 59.

    Araujo, A. B. et al. Sex steroids and all-cause and cause-specific mortality in men. Arch. Intern. Med. 167, 1252–1260 (2007).

    CAS  PubMed  Google Scholar 

  60. 60.

    Szulc, P., Claustrat, B. & Delmas, P. D. Serum concentrations of 17beta-E2 and 25-hydroxycholecalciferol (25OHD) in relation to all-cause mortality in older men—the MINOS study. Clin. Endocrinol. 71, 594–602 (2009).

    CAS  Google Scholar 

  61. 61.

    Haring, R. et al. 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, 629–634 (2013).

    CAS  Google Scholar 

  62. 62.

    Shores, M. M. et al. Testosterone, dihydrotestosterone, and incident cardiovascular disease and mortality in the cardiovascular health study. J. Clin. Endocrinol. Metab. 99, 2061–2068 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  63. 63.

    Chan, Y. X. et al. Neutral associations of testosterone, dihydrotestosterone and estradiol with fatal and non-fatal cardiovascular events, and mortality in men aged 17–97 years. Clin. Endocrinol. 85, 575–582 (2016).

    CAS  Google Scholar 

  64. 64.

    Araujo, A. B. et al. Clinical review: Endogenous testosterone and mortality in men: a systematic review and meta-analysis. J. Clin. Endocrinol. Metab. 96, 3007–3019 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  65. 65.

    Keating, N. L., O’Malley, A. J. & Smith, M. R. Diabetes and cardiovascular disease during androgen deprivation therapy for prostate cancer. J. Clin. Oncol. 24, 4448–4456 (2006).

    CAS  PubMed  Google Scholar 

  66. 66.

    Azoulay, L. et al. Androgen-deprivation therapy and the risk of stroke in patients with prostate cancer. Eur. Urol. 60, 1244–1250 (2011).

    CAS  PubMed  Google Scholar 

  67. 67.

    Keating, N. L., O’Malley, A. J., Freedland, S. J. & Smith, M. R. Diabetes and cardiovascular disease during androgen deprivation therapy: observational study of veterans with prostate cancer. J. Natl Cancer Inst. 102, 39–46 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  68. 68.

    Martin-Merino, E., Johansson, S., Morris, T. & Garcia Rodriguez, L. A. 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, 1061–1077 (2011).

    PubMed  Google Scholar 

  69. 69.

    Hu, J. C. et al. Androgen-deprivation therapy for nonmetastatic prostate cancer is associated with an increased risk of peripheral arterial disease and venous thromboembolism. Eur. Urol. 61, 1119–1128 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  70. 70.

    Maggi, M. et al. Testosterone treatment is not associated with increased risk of adverse cardiovascular events: results from the Registry of Hypogonadism in Men (RHYME). Int. J. Clin. Pract. 70, 843–852 (2016).

    CAS  PubMed  Google Scholar 

  71. 71.

    Layton, J. B. et al. Comparative safety of testosterone dosage forms. JAMA Intern. Med. 175, 1187–1196 (2015).

    PubMed  PubMed Central  Google Scholar 

  72. 72.

    Basaria, S. Need for standardising adverse event reporting in testosterone trials. Evid. Based Med. 19, 32–33 (2014).

    PubMed  Google Scholar 

  73. 73.

    Gluud, C. The Copenhagen Study Group for Liver Diseases. Testosterone treatment of men with alcoholic cirrhosis: a double-blind study. The Copenhagen Study Group for Liver Diseases. Hepatology 6, 807–813 (1986).

    Google Scholar 

  74. 74.

    Basaria, S. et al. Risk factors associated with cardiovascular events during testosterone administration in older men with mobility limitation. J. Gerontol. A 68, 153–160 (2013).

    CAS  Google Scholar 

  75. 75.

    Newman, A. B. et al. Association of long-distance corridor walk performance with mortality, cardiovascular disease, mobility limitation, and disability. JAMA 295, 2018–2026 (2006).

    CAS  PubMed  Google Scholar 

  76. 76.

    Newman, A. B. et al. Associations of subclinical cardiovascular disease with frailty. J. Gerontol. A 56, M158–M166 (2001).

    CAS  Google Scholar 

  77. 77.

    Basaria, S. et al. 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, 570–581 (2015).

    CAS  PubMed  Google Scholar 

  78. 78.

    Resnick, S. M. et al. Testosterone treatment and cognitive function in older men with low testosterone and age-associated memory impairment. JAMA 317, 717–727 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  79. 79.

    Budoff, M. J. et al. Testosterone treatment and coronary artery plaque volume in older men with low testosterone. JAMA 317, 708–716 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  80. 80.

    Roy, C. N. et al. Association of testosterone levels with anemia in older men: a controlled clinical trial. JAMA Intern. Med. 177, 480–490 (2017).

    PubMed  PubMed Central  Google Scholar 

  81. 81.

    Snyder, P. J. et al. Effect of testosterone treatment on volumetric bone density and strength in older men with low testosterone: a controlled clinical trial. JAMA Intern. Med. 177, 471–479 (2017).

    PubMed  PubMed Central  Google Scholar 

  82. 82.

    Meriggiola, M. C. et al. A combined regimen of cyproterone acetate and testosterone enanthate as a potentially highly effective male contraceptive. J. Clin. Endocrinol. Metab. 81, 3018–3023 (1996).

    CAS  PubMed  Google Scholar 

  83. 83.

    Bebb, R. A. et al. Combined administration of levonorgestrel and testosterone induces more rapid and effective suppression of spermatogenesis than testosterone alone: a promising male contraceptive approach. J. Clin. Endocrinol. Metab. 81, 757–762 (1996).

    CAS  PubMed  Google Scholar 

  84. 84.

    Meriggiola, M. C., Bremner, W. J., Costantino, A., Di Cintio, G. & Flamigni, C. Low dose of cyproterone acetate and testosterone enanthate for contraception in men. Hum. Reprod. 13, 1225–1229 (1998).

    CAS  PubMed  Google Scholar 

  85. 85.

    Zhang, G. Y., Gu, Y. Q., Wang, X. H., Cui, Y. G. & Bremner, W. J. A clinical trial of injectable testosterone undecanoate as a potential male contraceptive in normal Chinese men. J. Clin. Endocrinol. Metab. 84, 3642–3647 (1999).

    CAS  PubMed  Google Scholar 

  86. 86.

    Anawalt, B. D., Bebb, R. A., Bremner, W. J. & Matsumoto, A. M. A lower dosage levonorgestrel and testosterone combination effectively suppresses spermatogenesis and circulating gonadotropin levels with fewer metabolic effects than higher dosage combinations. J. Androl. 20, 407–414 (1999).

    CAS  PubMed  Google Scholar 

  87. 87.

    Wu, F. C., Balasubramanian, R., Mulders, T. M. & Coelingh-Bennink, H. J. Oral progestogen combined with testosterone as a potential male contraceptive: additive effects between desogestrel and testosterone enanthate in suppression of spermatogenesis, pituitary-testicular axis, and lipid metabolism. J. Clin. Endocrinol. Metab. 84, 112–122 (1999).

    CAS  PubMed  Google Scholar 

  88. 88.

    Anawalt, B. D. et al. Desogestrel plus testosterone effectively suppresses spermatogenesis but also causes modest weight gain and high-density lipoprotein suppression. Fertil. Steril. 74, 707–714 (2000).

    CAS  PubMed  Google Scholar 

  89. 89.

    Meriggiola, M. C., Costantino, A., Bremner, W. J. & Morselli-Labate, A. M. Higher testosterone dose impairs sperm suppression induced by a combined androgen-progestin regimen. J. Androl. 23, 684–690 (2002).

    CAS  PubMed  Google Scholar 

  90. 90.

    Gu, Y. Q. et al. A multicenter contraceptive efficacy study of injectable testosterone undecanoate in healthy Chinese men. J. Clin. Endocrinol. Metab. 88, 562–568 (2003).

    CAS  PubMed  Google Scholar 

  91. 91.

    Meriggiola, M. C. et al. Testosterone undecanoate maintains spermatogenic suppression induced by cyproterone acetate plus testosterone undecanoate in normal men. J. Clin. Endocrinol. Metab. 88, 5818–5826 (2003).

    CAS  PubMed  Google Scholar 

  92. 92.

    Herbst, K. L., Anawalt, B. D., Amory, J. K., Matsumoto, A. M. & Bremner, W. J. The male contraceptive regimen of testosterone and levonorgestrel significantly increases lean mass in healthy young men in 4 weeks, but attenuates a decrease in fat mass induced by testosterone alone. J. Clin. Endocrinol. Metab. 88, 1167–1173 (2003).

    CAS  PubMed  Google Scholar 

  93. 93.

    Gu, Y. Q. et al. Male hormonal contraception: effects of injections of testosterone undecanoate and depot medroxyprogesterone acetate at eight-week intervals in chinese men. J. Clin. Endocrinol. Metab. 89, 2254–2262 (2004).

    CAS  PubMed  Google Scholar 

  94. 94.

    Anawalt, B. D. et al. Intramuscular testosterone enanthate plus very low dosage oral levonorgestrel suppresses spermatogenesis without causing weight gain in normal young men: a randomized clinical trial. J. Androl. 26, 405–413 (2005).

    CAS  PubMed  Google Scholar 

  95. 95.

    Meriggiola, M. C. et al. Norethisterone enanthate plus testosterone undecanoate for male contraception: effects of various injection intervals on spermatogenesis, reproductive hormones, testis, and prostate. J. Clin. Endocrinol. Metab. 90, 2005–2014 (2005).

    CAS  PubMed  Google Scholar 

  96. 96.

    Qoubaitary, A. et al. Pharmacokinetics of testosterone undecanoate injected alone or in combination with norethisterone enanthate in healthy men. J. Androl. 27, 853–867 (2006).

    CAS  PubMed  Google Scholar 

  97. 97.

    Wang, C. et al. Transient scrotal hyperthermia and levonorgestrel enhance testosterone-induced spermatogenesis suppression in men through increased germ cell apoptosis. J. Clin. Endocrinol. Metab. 92, 3292–3304 (2007).

    CAS  PubMed  Google Scholar 

  98. 98.

    Gu, Y. et al. Multicenter contraceptive efficacy trial of injectable testosterone undecanoate in Chinese men. J. Clin. Endocrinol. Metab. 94, 1910–1915 (2009).

    CAS  PubMed  Google Scholar 

  99. 99.

    Nieschlag, E. et al. Hormonal male contraception in men with normal and subnormal semen parameters. Int. J. Androl. 34, 556–567 (2011).

    CAS  PubMed  Google Scholar 

  100. 100.

    Behre, H. M. et al. Efficacy and safety of an injectable combination hormonal contraceptive for men. J. Clin. Endocrinol. Metab. 101, 4779–4788 (2016).

    CAS  PubMed  Google Scholar 

  101. 101.

    Gonzalo, I. T. et al. Levonorgestrel implants (Norplant II) for male contraception clinical trials: combination with transdermal and injectable testosterone. J. Clin. Endocrinol. Metab. 87, 3562–3572 (2002).

    CAS  PubMed  Google Scholar 

  102. 102.

    Handelsman, D. J., Conway, A. J., Howe, C. J., Turner, L. & Mackey, M. A. Establishing the minimum effective dose and additive effects of depot progestin in suppression of human spermatogenesis by a testosterone depot. J. Clin. Endocrinol. Metab. 81, 4113–4121 (1996).

    CAS  PubMed  Google Scholar 

  103. 103.

    Kinniburgh, D., Anderson, R. A. & Baird, D. T. Suppression of spermatogenesis with desogestrel and testosterone pellets is not enhanced by addition of finasteride. J. Androl. 22, 88–95 (2001).

    CAS  PubMed  Google Scholar 

  104. 104.

    Anderson, R. A. et al. Investigation of hormonal male contraception in African men: suppression of spermatogenesis by oral desogestrel with depot testosterone. Hum. Reprod. 17, 2869–2877 (2002).

    CAS  PubMed  Google Scholar 

  105. 105.

    Kinniburgh, D. et al. Oral desogestrel with testosterone pellets induces consistent suppression of spermatogenesis to azoospermia in both Caucasian and Chinese men. Hum. Reprod. 17, 1490–1501 (2002).

    CAS  PubMed  Google Scholar 

  106. 106.

    Anderson, R. A., Kinniburgh, D. & Baird, D. T. Suppression of spermatogenesis by etonogestrel implants with depot testosterone: potential for long-acting male contraception. J. Clin. Endocrinol. Metab. 87, 3640–3649 (2002).

    CAS  PubMed  Google Scholar 

  107. 107.

    Turner, L. et al. Contraceptive efficacy of a depot progestin and androgen combination in men. J. Clin. Endocrinol. Metab. 88, 4659–4667 (2003).

    CAS  PubMed  Google Scholar 

  108. 108.

    Brady, B. M. et al. Depot testosterone with etonogestrel implants result in induction of azoospermia in all men for long-term contraception. Hum. Reprod. 19, 2658–2667 (2004).

    CAS  PubMed  Google Scholar 

  109. 109.

    Wang, C. et al. Levonorgestrel implants enhanced the suppression of spermatogenesis by testosterone implants: comparison between Chinese and non-Chinese men. J. Clin. Endocrinol. Metab. 91, 460–470 (2006).

    CAS  PubMed  Google Scholar 

  110. 110.

    Walton, M. J., Kumar, N., Baird, D. T., Ludlow, H. & Anderson, R. A. 7alpha-methyl-19-nortestosterone (MENT) versus testosterone in combination with etonogestrel implants for spermatogenic suppression in healthy men. J. Androl. 28, 679–688 (2007).

    CAS  PubMed  Google Scholar 

  111. 111.

    Page, S. T. et al. Testosterone gel combined with depomedroxyprogesterone acetate is an effective male hormonal contraceptive regimen and is not enhanced by the addition of a GnRH antagonist. J. Clin. Endocrinol. Metab. 91, 4374–4380 (2006).

    CAS  PubMed  Google Scholar 

  112. 112.

    Mahabadi, V. et al. Combined transdermal testosterone gel and the progestin nestorone suppresses serum gonadotropins in men. J. Clin. Endocrinol. Metab. 94, 2313–2320 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  113. 113.

    Ilani, N. et al. A new combination of testosterone and nestorone transdermal gels for male hormonal contraception. J. Clin. Endocrinol. Metab. 97, 3476–3486 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  114. 114.

    Calof, O. M. et al. Adverse events associated with testosterone replacement in middle-aged and older men: a meta-analysis of randomized, placebo-controlled trials. J. Gerontol. A 60, 1451–1457 (2005).

    Google Scholar 

  115. 115.

    Haddad, R. M. et al. Testosterone and cardiovascular risk in men: a systematic review and meta-analysis of randomized placebo-controlled trials. Mayo Clin. Proc. 82, 29–39 (2007).

    CAS  PubMed  Google Scholar 

  116. 116.

    Fernandez-Balsells, M. M. et al. Clinical review 1: Adverse effects of testosterone therapy in adult men: a systematic review and meta-analysis. J. Clin. Endocrinol. Metab. 95, 2560–2575 (2010).

    CAS  PubMed  Google Scholar 

  117. 117.

    Albert, S. G. & Morley, J. E. Testosterone therapy, association with age, initiation and mode of therapy with cardiovascular events: a systematic review. Clin. Endocrinol. 85, 436–443 (2016).

    CAS  Google Scholar 

  118. 118.

    Alexander, G. C., Iyer, G., Lucas, E., Lin, D. & Singh, S. Cardiovascular risks of exogenous testosterone use among men: a systematic review and meta-analysis. Am. J. Med. 130, 293–305 (2017).

    CAS  PubMed  Google Scholar 

  119. 119.

    Corona, G. et al. Testosterone and cardiovascular risk: meta-analysis of interventional studies. J. Sex. Med. 15, 820–838 (2018).

    PubMed  Google Scholar 

  120. 120.

    Tunstall-Pedoe, H. et al. Contribution of trends in survival and coronary-event rates to changes in coronary heart disease mortality: 10-year results from 37 WHO MONICA project populations. Monitoring trends and determinants in cardiovascular disease. Lancet 353, 1547–1557 (1999).

    CAS  PubMed  Google Scholar 

  121. 121.

    D’Agostino, R. B. Sr. et al. General cardiovascular risk profile for use in primary care: the Framingham Heart Study. Circulation 117, 743–753 (2008).

    PubMed  Google Scholar 

  122. 122.

    Kappert, K. et al. Impact of sex on cardiovascular outcome in patients at high cardiovascular risk: analysis of the Telmisartan Randomized Assessment Study in ACE-Intolerant Subjects With Cardiovascular Disease (TRANSCEND) and the Ongoing Telmisartan Alone and in Combination With Ramipril Global End Point Trial (ONTARGET). Circulation 126, 934–941 (2012).

    PubMed  Google Scholar 

  123. 123.

    Kalin, M. F. & Zumoff, B. Sex hormones and coronary disease: a review of the clinical studies. Steroids 55, 330–352 (1990).

    CAS  PubMed  Google Scholar 

  124. 124.

    Alexandersen, P., Haarbo, J., Byrjalsen, I., Lawaetz, H. & Christiansen, C. Natural androgens inhibit male atherosclerosis: a study in castrated, cholesterol-fed rabbits. Circ. Res. 84, 813–819 (1999).

    CAS  PubMed  Google Scholar 

  125. 125.

    Qiu, Y. et al. Dihydrotestosterone suppresses foam cell formation and attenuates atherosclerosis development. Endocrinology 151, 3307–3316 (2010).

    CAS  PubMed  Google Scholar 

  126. 126.

    Larsen, B. A., Nordestgaard, B. G., Stender, S. & Kjeldsen, K. Effect of testosterone on atherogenesis in cholesterol-fed rabbits with similar plasma cholesterol levels. Atherosclerosis 99, 79–86 (1993).

    CAS  PubMed  Google Scholar 

  127. 127.

    Li, S., Li, X. & Li, Y. Regulation of atherosclerotic plaque growth and stability by testosterone and its receptor via influence of inflammatory reaction. Vascul. Pharmacol. 49, 14–18 (2008).

    CAS  PubMed  Google Scholar 

  128. 128.

    Nettleship, J. E., Jones, T. H., Channer, K. S. & Jones, R. D. 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, 2427–2434 (2007).

    CAS  PubMed  Google Scholar 

  129. 129.

    Bourghardt, J. et al. Androgen receptor-dependent and independent atheroprotection by testosterone in male mice. Endocrinology 151, 5428–5437 (2010).

    CAS  PubMed  Google Scholar 

  130. 130.

    Nathan, L. et al. Testosterone inhibits early atherogenesis by conversion to estradiol: critical role of aromatase. Proc. Natl Acad. Sci. USA 98, 3589–3593 (2001).

    CAS  PubMed  Google Scholar 

  131. 131.

    Kelly, D. M., Sellers, D. J., Woodroofe, M. N., Jones, T. H. & Channer, K. S. Effect of testosterone on inflammatory markers in the development of early atherogenesis in the testicular-feminized mouse model. Endocr. Res. 38, 125–138 (2012).

    PubMed  Google Scholar 

  132. 132.

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

    CAS  PubMed  Google Scholar 

  133. 133.

    Hatakeyama, H. et al. Testosterone inhibits tumor necrosis factor-alpha-induced vascular cell adhesion molecule-1 expression in human aortic endothelial cells. FEBS Lett. 530, 129–132 (2002).

    CAS  PubMed  Google Scholar 

  134. 134.

    Mukherjee, T. K., Dinh, H., Chaudhuri, G. & Nathan, L. Testosterone attenuates expression of vascular cell adhesion molecule-1 by conversion to estradiol by aromatase in endothelial cells: implications in atherosclerosis. Proc. Natl Acad. Sci. USA 99, 4055–4060 (2002).

    CAS  PubMed  Google Scholar 

  135. 135.

    Cybulsky, M. I. & Gimbrone, M. A. Jr. Endothelial expression of a mononuclear leukocyte adhesion molecule during atherogenesis. Science 251, 788–791 (1991).

    CAS  PubMed  Google Scholar 

  136. 136.

    O’Brien, K. D. et al. Vascular cell adhesion molecule-1 is expressed in human coronary atherosclerotic plaques. Implications for the mode of progression of advanced coronary atherosclerosis. J. Clin. Invest. 92, 945–951 (1993).

    PubMed  PubMed Central  Google Scholar 

  137. 137.

    Cybulsky, M. I. et al. A major role for VCAM-1, but not ICAM-1, in early atherosclerosis. J. Clin. Invest. 107, 1255–1262 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  138. 138.

    McCrohon, J. A., Jessup, W., Handelsman, D. J. & Celermajer, D. S. Androgen exposure increases human monocyte adhesion to vascular endothelium and endothelial cell expression of vascular cell adhesion molecule-1. Circulation 99, 2317–2322 (1999).

    CAS  PubMed  Google Scholar 

  139. 139.

    Son, B. K. et al. Androgen receptor-dependent transactivation of growth arrest-specific gene 6 mediates inhibitory effects of testosterone on vascular calcification. J. Biol. Chem. 285, 7537–7544 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  140. 140.

    Son, B. K. et al. Statins protect human aortic smooth muscle cells from inorganic phosphate-induced calcification by restoring Gas6-Axl survival pathway. Circul. Res. 98, 1024–1031 (2006).

    CAS  Google Scholar 

  141. 141.

    Son, B. K. et al. Gas6/Axl-PI3K/Akt pathway plays a central role in the effect of statins on inorganic phosphate-induced calcification of vascular smooth muscle cells. Eur. J. Pharmacol. 556, 1–8 (2007).

    CAS  PubMed  Google Scholar 

  142. 142.

    Zhu, D. et al. Ablation of the androgen receptor from vascular smooth muscle cells demonstrates a role for testosterone in vascular calcification. Sci. Rep. 6, 24807 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  143. 143.

    Langer, C. et al. Testosterone up-regulates scavenger receptor BI and stimulates cholesterol efflux from macrophages. Biochem. Biophys. Res. Commun. 296, 1051–1057 (2002).

    CAS  PubMed  Google Scholar 

  144. 144.

    Moverare-Skrtic, S. et al. Dihydrotestosterone treatment results in obesity and altered lipid metabolism in orchidectomized mice. Obesity 14, 662–672 (2006).

    CAS  PubMed  Google Scholar 

  145. 145.

    Herbst, K. L., Amory, J. K., Brunzell, J. D., Chansky, H. A. & Bremner, W. J. Testosterone administration to men increases hepatic lipase activity and decreases HDL and LDL size in 3 wk. Am. J. Physiol. Endocrinol. Metab. 284, E1112–E1118 (2003).

    CAS  PubMed  Google Scholar 

  146. 146.

    Tan, K. C., Shiu, S. W., Pang, R. W. & Kung, A. W. Effects of testosterone replacement on HDL subfractions and apolipoprotein A-I containing lipoproteins. Clin. Endocrinol. 48, 187–194 (1998).

    CAS  Google Scholar 

  147. 147.

    Khera, A. V. et al. Cholesterol efflux capacity, high-density lipoprotein function, and atherosclerosis. N. Engl. J. Med. 364, 127–135 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  148. 148.

    Rubinow, K. B. et al. Testosterone replacement in hypogonadal men alters the HDL proteome but not HDL cholesterol efflux capacity. J. Lipid Res. 53, 1376–1383 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  149. 149.

    Rubinow, K. B., Vaisar, T., Chao, J. H., Heinecke, J. W. & Page, S. T. Sex steroids mediate discrete effects on HDL cholesterol efflux capacity and particle concentration in healthy men. J. Clin. Lipidol. 12, 1072–1082 (2018).

    PubMed  PubMed Central  Google Scholar 

  150. 150.

    Shahidi, N. T. Androgens and erythropoiesis. N. Engl. J. Med. 289, 72–80 (1973).

    CAS  PubMed  Google Scholar 

  151. 151.

    Shahani, S., Braga-Basaria, M., Maggio, M. & Basaria, S. Androgens and erythropoiesis: past and present. J. Endocrinol. Invest. 32, 704–716 (2009).

    CAS  PubMed  Google Scholar 

  152. 152.

    Bachman, E. et al. Testosterone induces erythrocytosis via increased erythropoietin and suppressed hepcidin: evidence for a new erythropoietin/hemoglobin set point. J. Gerontol. A 69, 725–735 (2014).

    CAS  Google Scholar 

  153. 153.

    Gagliano-Juca, T. et al. Mechanisms responsible for reduced erythropoiesis during androgen deprivation therapy in men with prostate cancer. Am. J. Physiol. Endocrinol. Metab. 315, E1185–E1193 (2018).

    CAS  PubMed  Google Scholar 

  154. 154.

    Guo, W. et al. The effects of short-term and long-term testosterone supplementation on blood viscosity and erythrocyte deformability in healthy adult mice. Endocrinology 156, 1623–1629 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  155. 155.

    Zhao, C., Moon du, G. & Park, J. K. Effect of testosterone undecanoate on hematological profiles, blood lipid and viscosity and plasma testosterone level in castrated rabbits. Can. Urol. Assoc. J. 7, E221–E225 (2013).

    PubMed  PubMed Central  Google Scholar 

  156. 156.

    Reinhart, W. H. The optimum hematocrit. Clin. Hemorheol. Microcircul. 64, 575–585 (2016).

    CAS  Google Scholar 

  157. 157.

    Eugster, M. & Reinhart, W. H. The influence of the haematocrit on primary haemostasis in vitro. Thromb. Haemostasis 94, 1213–1218 (2005).

    CAS  Google Scholar 

  158. 158.

    Ajayi, A. A., Mathur, R. & Halushka, P. V. Testosterone increases human platelet thromboxane A2 receptor density and aggregation responses. Circulation 91, 2742–2747 (1995).

    CAS  PubMed  Google Scholar 

  159. 159.

    Ajayi, A. A. & Halushka, P. V. Castration reduces platelet thromboxane A2 receptor density and aggregability. QJM 98, 349–356 (2005).

    CAS  PubMed  Google Scholar 

  160. 160.

    Yue, P., Chatterjee, K., Beale, C., Poole-Wilson, P. A. & Collins, P. Testosterone relaxes rabbit coronary arteries and aorta. Circulation 91, 1154–1160 (1995).

    CAS  PubMed  Google Scholar 

  161. 161.

    Deenadayalu, V. P., White, R. E., Stallone, J. N., Gao, X. & Garcia, A. J. Testosterone relaxes coronary arteries by opening the large-conductance, calcium-activated potassium channel. Am. J. Physiol. Heart Circ. Physiol. 281, H1720–H1727 (2001).

    CAS  PubMed  Google Scholar 

  162. 162.

    Tep-areenan, P., Kendall, D. A. & Randall, M. D. Testosterone-induced vasorelaxation in the rat mesenteric arterial bed is mediated predominantly via potassium channels. Br. J. Pharmacol. 135, 735–740 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  163. 163.

    Chou, T. M. et al. Testosterone induces dilation of canine coronary conductance and resistance arteries in vivo. Circulation 94, 2614–2619 (1996).

    CAS  PubMed  Google Scholar 

  164. 164.

    Perusquia, M., Greenway, C. D., Perkins, L. M. & Stallone, J. N. Systemic hypotensive effects of testosterone are androgen structure-specific and neuronal nitric oxide synthase-dependent. Am. J. Physiol. Regul. Integr. Comp. Physiol. 309, R189–R195 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  165. 165.

    Bachetti, T. et al. Co-expression and modulation of neuronal and endothelial nitric oxide synthase in human endothelial cells. J. Mol. Cell. Cardiol. 37, 939–945 (2004).

    CAS  PubMed  Google Scholar 

  166. 166.

    Molinari, C. et al. The effect of testosterone on regional blood flow in prepubertal anaesthetized pigs. J. Physiol. 543, 365–372 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  167. 167.

    Scragg, J. L., Jones, R. D., Channer, K. S., Jones, T. H. & Peers, C. Testosterone is a potent inhibitor of L-type Ca(2+) channels. Biochem. Biophys. Res. Commun. 318, 503–506 (2004).

    CAS  PubMed  Google Scholar 

  168. 168.

    Jones, R. D., English, K. M., Jones, T. H. & Channer, K. S. Testosterone-induced coronary vasodilatation occurs via a non-genomic mechanism: evidence of a direct calcium antagonism action. Clin. Sci. 107, 149–158 (2004).

    CAS  PubMed  Google Scholar 

  169. 169.

    Yu, J. et al. Androgen receptor-dependent activation of endothelial nitric oxide synthase in vascular endothelial cells: role of phosphatidylinositol 3-kinase/akt pathway. Endocrinology 151, 1822–1828 (2010).

    CAS  PubMed  Google Scholar 

  170. 170.

    Campelo, A. E., Cutini, P. H. & Massheimer, V. L. Cellular actions of testosterone in vascular cells: mechanism independent of aromatization to estradiol. Steroids 77, 1033–1040 (2012).

    CAS  PubMed  Google Scholar 

  171. 171.

    Ruamyod, K., Watanapa, W. B. & Shayakul, C. Testosterone rapidly increases Ca2+-activated K+ currents causing hyperpolarization in human coronary artery endothelial cells. J. Steroid Biochem. Mol. Biol. 168, 118–126 (2017).

    CAS  PubMed  Google Scholar 

  172. 172.

    Ellison, K. E., Ingelfinger, J. R., Pivor, M. & Dzau, V. J. Androgen regulation of rat renal angiotensinogen messenger RNA expression. J. Clin. Invest. 83, 1941–1945 (1989).

    CAS  PubMed  PubMed Central  Google Scholar 

  173. 173.

    Quan, A. et al. Androgens augment proximal tubule transport. Am. J. Physiol. Renal Physiol. 287, F452–F459 (2004).

    CAS  PubMed  Google Scholar 

  174. 174.

    Mackovic, M., Zimolo, Z., Burckhardt, G. & Sabolic, I. Isolation of renal brush-border membrane vesicles by a low-speed centrifugation; effect of sex hormones on Na+-H+ exchange in rat and mouse kidney. Biochim. Biophys. Acta 862, 141–152 (1986).

    CAS  PubMed  Google Scholar 

  175. 175.

    Loh, S. Y., Giribabu, N. & Salleh, N. Sub-chronic testosterone treatment increases the levels of epithelial sodium channel (ENaC)-alpha, beta and gamma in the kidney of orchidectomized adult male Sprague-Dawley rats. PeerJ 4, e2145 (2016).

    PubMed  PubMed Central  Google Scholar 

  176. 176.

    Herak-Kramberger, C. M. et al. Sex-dependent expression of water channel AQP1 along the rat nephron. Am. J. Physiol. Renal Physiol. 308, F809–F821 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  177. 177.

    Bidoggia, H. et al. Sex differences on the electrocardiographic pattern of cardiac repolarization: possible role of testosterone. Am. Heart J. 140, 678–683 (2000).

    CAS  PubMed  Google Scholar 

  178. 178.

    Bai, C. X., Kurokawa, J., Tamagawa, M., Nakaya, H. & Furukawa, T. Nontranscriptional regulation of cardiac repolarization currents by testosterone. Circulation 112, 1701–1710 (2005).

    CAS  PubMed  Google Scholar 

  179. 179.

    Er, F. et al. Impact of testosterone on cardiac L-type calcium channels and Ca2+ sparks: acute actions antagonize chronic effects. Cell Calcium 41, 467–477 (2007).

    CAS  PubMed  Google Scholar 

  180. 180.

    Ridley, J. M., Shuba, Y. M., James, A. F. & Hancox, J. C. Modulation by testosterone of an endogenous hERG potassium channel current. J. Physiol. Pharmacol. 59, 395–407 (2008).

    CAS  PubMed  Google Scholar 

  181. 181.

    Golden, K. L., Marsh, J. D., Jiang, Y. & Moulden, J. Acute actions of testosterone on contractile function of isolated rat ventricular myocytes. Eur. J. Endocrinol. 152, 479–483 (2005).

    CAS  PubMed  Google Scholar 

  182. 182.

    Curl, C. L., Delbridge, L. M., Canny, B. J. & Wendt, I. R. Testosterone modulates cardiomyocyte Ca(2+) handling and contractile function. Physiol. Res. 58, 293–297 (2009).

    CAS  PubMed  Google Scholar 

  183. 183.

    Golden, K. L., Marsh, J. D., Jiang, Y., Brown, T. & Moulden, J. Gonadectomy of adult male rats reduces contractility of isolated cardiac myocytes. Am. J. Physiol. Endocrinol. Metab. 285, E449–E453 (2003).

    CAS  PubMed  Google Scholar 

  184. 184.

    Tsang, S., Wong, S. S., Wu, S., Kravtsov, G. M. & Wong, T. M. 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, C766–C782 (2009).

    CAS  PubMed  Google Scholar 

  185. 185.

    Eleawa, S. M. et al. Effect of testosterone replacement therapy on cardiac performance and oxidative stress in orchidectomized rats. Acta Physiol. 209, 136–147 (2013).

    CAS  Google Scholar 

  186. 186.

    Witayavanitkul, N., Woranush, W., Bupha-Intr, T. & Wattanapermpool, J. Testosterone regulates cardiac contractile activation by modulating SERCA but not NCX activity. Am. J. Physiol. Heart Circ. Physiol. 304, H465–H472 (2013).

    CAS  PubMed  Google Scholar 

  187. 187.

    Jaffe, M. D. Effect of testosterone cypionate on postexercise ST segment depression. Br. Heart J. 39, 1217–1222 (1977).

    CAS  PubMed  PubMed Central  Google Scholar 

  188. 188.

    Webb, C. M., McNeill, J. G., Hayward, C. S., de Zeigler, D. & Collins, P. Effects of testosterone on coronary vasomotor regulation in men with coronary heart disease. Circulation 100, 1690–1696 (1999).

    CAS  PubMed  Google Scholar 

  189. 189.

    English, K. M., Steeds, R. P., Jones, T. H., Diver, M. J. & Channer, K. S. Low-dose transdermal testosterone therapy improves angina threshold in men with chronic stable angina: a randomized, double-blind, placebo-controlled study. Circulation 102, 1906–1911 (2000).

    CAS  PubMed  Google Scholar 

  190. 190.

    Mathur, A. et al. Long-term benefits of testosterone replacement therapy on angina threshold and atheroma in men. Eur. J. Endocrinol. 161, 443–449 (2009).

    CAS  PubMed  Google Scholar 

  191. 191.

    Webb, C. M. et al. Effects of oral testosterone treatment on myocardial perfusion and vascular function in men with low plasma testosterone and coronary heart disease. Am. J. Cardiol. 101, 618–624 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  192. 192.

    Smith, J. C. et al. The effects of induced hypogonadism on arterial stiffness, body composition, and metabolic parameters in males with prostate cancer. J. Clin. Endocrinol. Metab. 86, 4261–4267 (2001).

    CAS  PubMed  Google Scholar 

  193. 193.

    Dockery, F., Bulpitt, C. J., Agarwal, S., Vernon, C. & Rajkumar, C. Effect of androgen suppression compared with androgen receptor blockade on arterial stiffness in men with prostate cancer. J. Androl. 30, 410–415 (2009).

    CAS  PubMed  Google Scholar 

  194. 194.

    Johannsson, G., Gibney, J., Wolthers, T., Leung, K. C. & Ho, K. K. Independent and combined effects of testosterone and growth hormone on extracellular water in hypopituitary men. J. Clin. Endocrinol. Metab. 90, 3989–3994 (2005).

    CAS  PubMed  Google Scholar 

  195. 195.

    Stramba-Badiale, M., Spagnolo, D., Bosi, G. & Schwartz, P. J. Are gender differences in QTc present at birth? MISNES Investigators. Multicenter Italian Study on Neonatal Electrocardiography and Sudden Infant Death Syndrome. Am. J. Cardiol. 75, 1277–1278 (1995).

    CAS  PubMed  Google Scholar 

  196. 196.

    Alimurung, M. M., Joseph, L. G., Craige, E. & Massell, B. F. The Q-T interval in normal infants and children. Circulation 1, 1329–1337 (1950).

    CAS  PubMed  Google Scholar 

  197. 197.

    Rautaharju, P. M. et al. Sex differences in the evolution of the electrocardiographic QT interval with age. Can. J. Cardiol. 8, 690–695 (1992).

    CAS  PubMed  Google Scholar 

  198. 198.

    Zhang, Y. et al. Sex-steroid hormones and electrocardiographic QT-interval duration: findings from the third National Health and Nutrition Examination Survey and the Multi-Ethnic Study of Atherosclerosis. Am. J. Epidemiol. 174, 403–411 (2011).

    PubMed  PubMed Central  Google Scholar 

  199. 199.

    Junttila, M. J. et al. Relationship between testosterone level and early repolarization on 12-lead electrocardiograms in men. J. Am. Coll. Cardiol. 62, 1633–1634 (2013).

    CAS  PubMed  Google Scholar 

  200. 200.

    Vicente, J., Johannesen, L., Galeotti, L. & Strauss, D. G. Mechanisms of sex and age differences in ventricular repolarization in humans. Am. Heart J. 168, 749–756 (2014).

    PubMed  Google Scholar 

  201. 201.

    Gagliano-Juca, T. et al. Effects of testosterone replacement on electrocardiographic parameters in men: findings from two randomized trials. J. Clin. Endocrinol. Metab. 102, 1478–1485 (2017).

    PubMed  Google Scholar 

  202. 202.

    Schwartz, J. B. et al. Effects of testosterone on the Q-T interval in older men and older women with chronic heart failure. Int. J. Androl. 34, e415–e421 (2011).

    CAS  PubMed  Google Scholar 

  203. 203.

    Gagliano-Juca, T. et al. Androgen deprivation therapy is associated with prolongation of QTc interval in men with prostate cancer. J. Endocr. Soc. 2, 485–496 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  204. 204.

    Zhang, Y. et al. Electrocardiographic QT interval and mortality: a meta-analysis. Epidemiology 22, 660–670 (2011).

    PubMed  PubMed Central  Google Scholar 

  205. 205.

    Noseworthy, P. A. et al. QT interval and long-term mortality risk in the Framingham Heart Study. Ann. Noninvasive Electrocardiol. 17, 340–348 (2012).

    PubMed  PubMed Central  Google Scholar 

  206. 206.

    Nielsen, J. B. et al. Risk prediction of cardiovascular death based on the QTc interval: evaluating age and gender differences in a large primary care population. Eur. Heart J. 35, 1335–1344 (2014).

    PubMed  PubMed Central  Google Scholar 

  207. 207.

    Salem, J. E. et al. Hypogonadism as a reversible cause of torsades de pointes in men. Circulation 138, 110–113 (2018).

    PubMed  PubMed Central  Google Scholar 

  208. 208.

    Buonanno, C. et al. Left ventricular function in men and women. Another difference between sexes. Eur. Heart J. 3, 525–528 (1982).

    CAS  PubMed  Google Scholar 

  209. 209.

    Hanley, P. C. et al. Gender-related differences in cardiac response to supine exercise assessed by radionuclide angiography. J. Am. Coll. Cardiol. 13, 624–629 (1989).

    CAS  PubMed  Google Scholar 

  210. 210.

    Merz, C. N., Moriel, M., Rozanski, A., Klein, J. & Berman, D. S. Gender-related differences in exercise ventricular function among healthy subjects and patients. Am. Heart J. 131, 704–709 (1996).

    CAS  PubMed  Google Scholar 

  211. 211.

    Traustadottir, T. et al. Long-term testosterone supplementation in older men attenuates age-related decline in aerobic capacity. J. Clin. Endocrinol. Metab. 103, 2861–2869 (2018).

    PubMed  PubMed Central  Google Scholar 

  212. 212.

    Storer, T. W. et al. Testosterone attenuates age-related fall in aerobic function in mobility limited older men with low testosterone. J. Clin. Endocrinol. Metab. 101, 2562–2569 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  213. 213.

    Pugh, P. J., Jones, T. H. & Channer, K. S. Acute haemodynamic effects of testosterone in men with chronic heart failure. Eur. Heart J. 24, 909–915 (2003).

    CAS  PubMed  Google Scholar 

  214. 214.

    Malkin, C. J. et al. Testosterone therapy in men with moderate severity heart failure: a double-blind randomized placebo controlled trial. Eur. Heart J. 27, 57–64 (2006).

    CAS  PubMed  Google Scholar 

  215. 215.

    Caminiti, G. et al. 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, 919–927 (2009).

    CAS  PubMed  Google Scholar 

  216. 216.

    Mortara, A. et al. Arterial baroreflex modulation of heart rate in chronic heart failure: clinical and hemodynamic correlates and prognostic implications. Circulation 96, 3450–3458 (1997).

    CAS  PubMed  Google Scholar 

  217. 217.

    Svartberg, J. et al. Low testosterone levels are associated with carotid atherosclerosis in men. J. Intern. Med. 259, 576–582 (2006).

    CAS  PubMed  Google Scholar 

  218. 218.

    Vikan, T., Johnsen, S. H., Schirmer, H., Njolstad, I. & Svartberg, J. Endogenous testosterone and the prospective association with carotid atherosclerosis in men: the Tromso study. Eur. J. Epidemiol. 24, 289–295 (2009).

    CAS  PubMed  Google Scholar 

  219. 219.

    Muller, M. et al. Endogenous sex hormones and progression of carotid atherosclerosis in elderly men. Circulation 109, 2074–2079 (2004).

    CAS  PubMed  Google Scholar 

  220. 220.

    Soisson, V. et al. Low plasma testosterone and elevated carotid intima-media thickness: importance of low-grade inflammation in elderly men. Atherosclerosis 223, 244–249 (2012).

    CAS  PubMed  Google Scholar 

  221. 221.

    Li, L. et al. Testosterone is negatively associated with the severity of coronary atherosclerosis in men. Asian J. Androl. 14, 875–878 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  222. 222.

    Park, B. J., Shim, J. Y., Lee, Y. J., Lee, J. H. & Lee, H. R. Inverse relationship between bioavailable testosterone and subclinical coronary artery calcification in non-obese Korean men. Asian J. Androl. 14, 612–615 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  223. 223.

    Travison, T. G. et al. Circulating sex steroids and vascular calcification in community-dwelling men: the Framingham Heart Study. J. Clin. Endocrinol. Metab. 101, 2160–2167 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  224. 224.

    Khazai, B. et al. Association of endogenous testosterone with subclinical atherosclerosis in men: the multi-ethnic study of atherosclerosis. Clin. Endocrinol. 84, 700–707 (2016).

    CAS  Google Scholar 

  225. 225.

    English, K. M. et al. Men with coronary artery disease have lower levels of androgens than men with normal coronary angiograms. Eur. Heart J. 21, 890–894 (2000).

    CAS  PubMed  Google Scholar 

  226. 226.

    Tivesten, A. et al. Low serum testosterone and high serum estradiol associate with lower extremity peripheral arterial disease in elderly men. The MrOS Study in Sweden. J. Am. Coll. Cardiol. 50, 1070–1076 (2007).

    CAS  PubMed  Google Scholar 

  227. 227.

    Makinen, J. I. et al. Endogenous testosterone and serum lipids in middle-aged men. Atherosclerosis 197, 688–693 (2008).

    CAS  PubMed  Google Scholar 

  228. 228.

    Haffner, S. M., Mykkanen, L., Valdez, R. A. & Katz, M. S. Relationship of sex hormones to lipids and lipoproteins in nondiabetic men. J. Clin. Endocrinol. Metab. 77, 1610–1615 (1993).

    CAS  PubMed  Google Scholar 

  229. 229.

    Zhang, N. et al. The relationship between endogenous testosterone and lipid profile in middle-aged and elderly Chinese men. Eur. J. Endocrinol. 170, 487–494 (2014).

    CAS  PubMed  Google Scholar 

  230. 230.

    Page, S. T. et al. Higher testosterone levels are associated with increased high-density lipoprotein cholesterol in men with cardiovascular disease: results from the Massachusetts Male Aging Study. Asian J. Androl. 10, 193–200 (2008).

    CAS  PubMed  Google Scholar 

  231. 231.

    Snyder, P. J. et al. Effect of transdermal testosterone treatment on serum lipid and apolipoprotein levels in men more than 65 years of age. Am. J. Med. 111, 255–260 (2001).

    CAS  PubMed  Google Scholar 

  232. 232.

    Whitsel, E. A., Boyko, E. J., Matsumoto, A. M., Anawalt, B. D. & Siscovick, D. S. Intramuscular testosterone esters and plasma lipids in hypogonadal men: a meta-analysis. Am. J. Med. 111, 261–269 (2001).

    CAS  PubMed  Google Scholar 

  233. 233.

    Mohler, E. R. 3rd et al. The effect of testosterone on cardiovacular biomarkers in the testosterone trials. J. Clin. Endocrinol. Metab. 103, 681–688 (2018).

    PubMed  Google Scholar 

  234. 234.

    Jones, T. H. et al. Testosterone replacement in hypogonadal men with type 2 diabetes and/or metabolic syndrome (the TIMES2 study). Diabetes Care 34, 828–837 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  235. 235.

    Muller, M., Grobbee, D. E., den Tonkelaar, I., Lamberts, S. W. & van der Schouw, Y. T. Endogenous sex hormones and metabolic syndrome in aging men. J. Clin. Endocrinol. Metab. 90, 2618–2623 (2005).

    CAS  PubMed  Google Scholar 

  236. 236.

    Ding, E. L., Song, Y., Malik, V. S. & Liu, S. Sex differences of endogenous sex hormones and risk of type 2 diabetes: a systematic review and meta-analysis. JAMA 295, 1288–1299 (2006).

    CAS  PubMed  Google Scholar 

  237. 237.

    Chin, K. Y., Ima-Nirwana, S., Mohamed, I. N., Aminuddin, A. & Ngah, W. Z. Total testosterone and sex hormone-binding globulin are significantly associated with metabolic syndrome in middle-aged and elderly men. Exp. Clin. Endocrinol. Diabetes 121, 407–412 (2013).

    CAS  PubMed  Google Scholar 

  238. 238.

    Selvin, E. et al. Androgens and diabetes in men: results from the Third National Health and Nutrition Examination Survey (NHANES III). Diabetes Care 30, 234–238 (2007).

    CAS  PubMed  Google Scholar 

  239. 239.

    Yeap, B. B. et al. Lower serum testosterone is independently associated with insulin resistance in non-diabetic older men: the Health In Men Study. Eur. J. Endocrinol. 161, 591–598 (2009).

    CAS  PubMed  Google Scholar 

  240. 240.

    Vikan, T., Schirmer, H., Njolstad, I. & Svartberg, J. Low testosterone and sex hormone-binding globulin levels and high estradiol levels are independent predictors of type 2 diabetes in men. Eur. J. Endocrinol. 162, 747–754 (2010).

    CAS  PubMed  Google Scholar 

  241. 241.

    Yialamas, M. A. et al. Acute sex steroid withdrawal reduces insulin sensitivity in healthy men with idiopathic hypogonadotropic hypogonadism. J. Clin. Endocrinol. Metab. 92, 4254–4259 (2007).

    CAS  PubMed  Google Scholar 

  242. 242.

    Braga-Basaria, M. et al. Metabolic syndrome in men with prostate cancer undergoing long-term androgen-deprivation therapy. J. Clin. Oncol. 24, 3979–3983 (2006).

    PubMed  Google Scholar 

  243. 243.

    Tsai, H. T. et al. Risk of diabetes among patients receiving primary androgen deprivation therapy for clinically localized prostate cancer. J. Urol. 193, 1956–1962 (2015).

    CAS  PubMed  Google Scholar 

  244. 244.

    Shahani, S., Braga-Basaria, M. & Basaria, S. Androgen deprivation therapy in prostate cancer and metabolic risk for atherosclerosis. J. Clin. Endocrinol. Metab. 93, 2042–2049 (2008).

    CAS  PubMed  Google Scholar 

  245. 245.

    Basaria, S., Muller, D. C., Carducci, M. A., Egan, J. & Dobs, A. S. Hyperglycemia and insulin resistance in men with prostate carcinoma who receive androgen-deprivation therapy. Cancer 106, 581–588 (2006).

    CAS  PubMed  Google Scholar 

  246. 246.

    Gagliano-Juca, T. et al. Metabolic changes in androgen-deprived nondiabetic men with prostate cancer are not mediated by cytokines or aP2. J. Clin. Endocrinol. Metab. 103, 3900–3908 (2018).

    PubMed  Google Scholar 

  247. 247.

    Hsu, B. et al. Associations between circulating reproductive hormones and SHBG and prevalent and incident metabolic syndrome in community-dwelling older men: the Concord Health and Ageing in Men Project. J. Clin. Endocrinol. Metab. 99, E2686–E2691 (2014).

    CAS  PubMed  Google Scholar 

  248. 248.

    Antonio, L. et al. Associations between sex steroids and the development of metabolic syndrome: a longitudinal study in European men. J. Clin. Endocrinol. Metab. 100, 1396–1404 (2015).

    CAS  PubMed  Google Scholar 

  249. 249.

    Joyce, K. E. et al. Testosterone, dihydrotestosterone, sex hormone-binding globulin, and incident diabetes among older men: the Cardiovascular Health Study. J. Clin. Endocrinol. Metab. 102, 33–39 (2017).

    PubMed  Google Scholar 

  250. 250.

    Pitteloud, N. et al. Relationship between testosterone levels, insulin sensitivity, and mitochondrial function in men. Diabetes Care 28, 1636–1642 (2005).

    CAS  PubMed  Google Scholar 

  251. 251.

    Dhindsa, S. et al. Insulin resistance and inflammation in hypogonadotropic hypogonadism and their reduction after testosterone replacement in men with type 2 diabetes. Diabetes Care 39, 82–91 (2016).

    CAS  PubMed  Google Scholar 

  252. 252.

    Boyanov, M. A., Boneva, Z. & Christov, V. G. Testosterone supplementation in men with type 2 diabetes, visceral obesity and partial androgen deficiency. Aging Male 6, 1–7 (2003).

    CAS  PubMed  Google Scholar 

  253. 253.

    Huang, G. et al. Long-term testosterone administration on insulin sensitivity in older men with low or low-normal testosterone levels. J. Clin. Endocrinol. Metab. 103, 1678–1685 (2018).

    PubMed  PubMed Central  Google Scholar 

  254. 254.

    Gianatti, E. J. et al. Effect of testosterone treatment on glucose metabolism in men with type 2 diabetes: a randomized controlled trial. Diabetes Care 37, 2098–2107 (2014).

    CAS  PubMed  Google Scholar 

  255. 255.

    Willerson, J. T. & Ridker, P. M. Inflammation as a cardiovascular risk factor. Circulation 109, II2–10 (2004).

    PubMed  Google Scholar 

  256. 256.

    Ruparelia, N., Chai, J. T., Fisher, E. A. & Choudhury, R. P. Inflammatory processes in cardiovascular disease: a route to targeted therapies. Nat. Rev. Cardiol. 14, 133–144 (2017).

    CAS  PubMed  Google Scholar 

  257. 257.

    Ridker, P. M. Clinical application of C-reactive protein for cardiovascular disease detection and prevention. Circulation 107, 363–369 (2003).

    PubMed  Google Scholar 

  258. 258.

    Biasucci, L. M. et al. Increasing levels of interleukin (IL)-1Ra and IL-6 during the first 2 days of hospitalization in unstable angina are associated with increased risk of in-hospital coronary events. Circulation 99, 2079–2084 (1999).

    CAS  PubMed  Google Scholar 

  259. 259.

    Dunlay, S. M., Weston, S. A., Redfield, M. M., Killian, J. M. & Roger, V. L. Tumor necrosis factor-alpha and mortality in heart failure: a community study. Circulation 118, 625–631 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  260. 260.

    Pastuszak, A. W., Kohn, T. P., Estis, J. & Lipshultz, L. I. Low plasma testosterone is associated with elevated cardiovascular disease biomarkers. J. Sex. Med. 14, 1095–1103 (2017).

    PubMed  PubMed Central  Google Scholar 

  261. 261.

    Zhang, Y. et al. Endogenous sex hormones and C-reactive protein in healthy Chinese men. Clin. Endocrinol. 78, 60–66 (2013).

    CAS  Google Scholar 

  262. 262.

    Kaplan, S. A., Johnson-Levonas, A. O., Lin, J., Shah, A. K. & Meehan, A. G. Elevated high sensitivity C-reactive protein levels in aging men with low testosterone. Aging Male 13, 108–112 (2010).

    CAS  PubMed  Google Scholar 

  263. 263.

    Tsilidis, K. K. et al. Association between endogenous sex steroid hormones and inflammatory biomarkers in US men. Andrology 1, 919–928 (2013).

    CAS  PubMed  Google Scholar 

  264. 264.

    Haring, R. et al. Prospective inverse associations of sex hormone concentrations in men with biomarkers of inflammation and oxidative stress. J. Androl. 33, 944–950 (2012).

    CAS  PubMed  Google Scholar 

  265. 265.

    Maggio, M. et al. Correlation between testosterone and the inflammatory marker soluble interleukin-6 receptor in older men. J. Clin. Endocrinol. Metab. 91, 345–347 (2006).

    CAS  PubMed  Google Scholar 

  266. 266.

    Nakhai Pour, H. R., Grobbee, D. E., Muller, M. & van der Schouw, Y. T. Association of endogenous sex hormone with C-reactive protein levels in middle-aged and elderly men. Clin. Endocrinol. 66, 394–398 (2007).

    Google Scholar 

  267. 267.

    Malkin, C. J. et al. The effect of testosterone replacement on endogenous inflammatory cytokines and lipid profiles in hypogonadal men. J. Clin. Endocrinol. Metab. 89, 3313–3318 (2004).

    CAS  PubMed  Google Scholar 

  268. 268.

    Abriel, H. & Zaklyazminskaya, E. V. Cardiac channelopathies: genetic and molecular mechanisms. Gene 517, 1–11 (2013).

    CAS  PubMed  Google Scholar 

  269. 269.

    Arnlov, J. et al. Endogenous sex hormones and cardiovascular disease incidence in men. Ann. Intern. Med. 145, 176–184 (2006).

    CAS  PubMed  Google Scholar 

  270. 270.

    Abbott, R. D. et al. Serum estradiol and risk of stroke in elderly men. Neurology 68, 563–568 (2007).

    CAS  PubMed  Google Scholar 

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Gagliano-Jucá, T., Basaria, S. Testosterone replacement therapy and cardiovascular risk. Nat Rev Cardiol 16, 555–574 (2019). https://doi.org/10.1038/s41569-019-0211-4

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