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Why is understanding the relationship of testosterone to cardiovascular risk so important?

1 School of Medicine, University of Western Australia, Perth, Western Australia 6009, Australia
2 Department of Endocrinology and Diabetes, Fiona Stanley Hospital, Perth, Western Australia 6150, Australia
3 Department of Medicine, University of Washington School of Medicine, Seattle, Washington 98195, United States

Date of Submission04-Dec-2017
Date of Acceptance05-Dec-2017
Date of Web Publication06-Feb-2018

Correspondence Address:
Bu B Yeap,
School of Medicine, University of Western Australia, Perth, Western Australia 6009, Australia; Department of Endocrinology and Diabetes, Fiona Stanley Hospital, Perth, Western Australia 6150, Australia

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Source of Support: None, Conflict of Interest: None

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How to cite this URL:
Yeap BB, Anawalt BD. Why is understanding the relationship of testosterone to cardiovascular risk so important?. Asian J Androl [Epub ahead of print] [cited 2018 Feb 18]. Available from:

Bu B Yeap, Bradley D Anawalt
Co.Guest Editors for this special issue.

Epidemiological studies hint at a beneficial influence of endogenous circulating testosterone (T), or its metabolite dihydrotestosterone (DHT), such that men with lower concentrations of T or DHT appear to have poorer health outcomes including frailty, diabetes, cardiovascular disease, and mortality.[1] Small interventional studies of T have shown favorable effects on surrogate outcome measures, but a large randomized controlled trial (RCT) with the prespecified outcome of cardiovascular events has not been performed and would be logistically demanding.[2] In the absence of such a definitive RCT, there is a controversy about the cardiovascular risks of T-therapy fuelled by contradictory findings from retrospective analyses of insurance databases of men prescribed T.[3],[4],[5] The US Testosterone Trials (T-Trials) are the largest published RCTs of T-therapy in older men with symptoms or signs of hypogonadism and circulating T <9.54 nmol l−1 at baseline.[6] The T-Trials showed a modest benefit of T-therapy over a 12-month period on sexual function, a significant benefit in bone density and for anemia and neutral effect on cognition.[7],[8],[9] The T-Trials cardiovascular sub-study was designed to determine the effects of T in these older men, and there was a statistically significant difference in the increase in noncalcified plaque volume in the T-treated group compared to placebo, but it is difficult to interpret these results due to differences in baseline coronary plaque burden (>50% difference) between the treatment and placebo arms of the subset involved.[10] Therefore, there continues to be ongoing uncertainty over the effect of T-therapy on the cardiovascular system in men.

Resolution of the uncertainty of the effects of T-therapy on the male cardiovascular system is important from two perspectives. First, men who are androgen deficient due to diseases of the hypothalamus, pituitary, and testes should be considered for T-replacement therapy.[11] In these men who have hypogonadism due to pathology of the gonadal axis, it is essential to inform and advise them of potential benefits and possible risks of treatment.[12] Second, there has been a marked increase in T prescribing worldwide over the past decades, despite the prevalence of pathological hypogonadism remaining relatively stable.[13],[14] In men who do not have hypothalamic, pituitary, or testicular disease, who are typically older with other medical comorbidities and circulating T that would be regarded as low in younger men, the question arises as to the justification for T treatment and whether potential harms might outweigh anticipated benefits.[15] Understanding the extent and the limitations of the existing evidence base would help health practitioners counsel men receiving T treatment for medical indications, may discourage its misuse in men where a medical indication is not clear, and will provide a foundation for future research.

In this Special Issue of the Asian Journal of Andrology, authors from around the world provide reviews of the available evidence of the cardiovascular effects of T on men. These reviews cover epidemiological studies of T and the incidence of cardiovascular events[16] and mortality risk,[17] RCTs representing mechanistic studies of T and the cardiovascular system,[18] T RCTs reporting cardiovascular adverse events,[19] and retrospective reviews of T prescription databases.[20] These are accompanied by commentaries on the implications for Andrology in the regional context[21] and globally for studies of male hormonal contraception.[22] Taken together, the content of this Special Issue addresses a pressing debate that affects the care we provide to men with androgen deficiency and future research to preserve health in the expanding population of older men in our communities.

  References Top

Yeap BB, Araujo AB, Wittert GA. Do low testosterone levels contribute to ill-health during male ageing? Crit Rev Clin Lab Sci 2012; 49: 168–82.  Back to cited text no. 1
Onasanya O, Iyer G, Lucas E, Lin D, Singh S, et al. Association between exogenous testosterone and cardiovascular events: an overview of systematic reviews. Lancet Diabetes Endocrinol 2016; 4: 943–56.  Back to cited text no. 2
Vigen R, O'Donnell CI, Baron AE, Grunwald GK, Maddox TM, et al. Association of testosterone therapy with mortality, myocardial infarction, and stroke in men with low testosterone levels. JAMA 2013; 310: 1829–36. Erratum published in JAMA 2014; 311: 967.  Back to cited text no. 3
Sharma R, Oni OA, Gupta K, Chen G, Sharma M, et al. Normalization of testosterone level is associated with reduced incidence of myocardial infarction and mortality in men. Eur Heart J 2015; 36: 2706–15.  Back to cited text no. 4
Cheetham TC, An JJ, Jacobsen SJ, Niu F, Sidney S, et al. Association of testosterone replacement with cardiovascular outcomes among men with androgen deficiency. JAMA Intern Med 2017; 177: 491–9.  Back to cited text no. 5
Snyder PJ, Bhasin S, Cunningham GR, Matsumoto AM, Stephens-Shields AJ, et al. Effects of testosterone treatment in older men. N Engl J Med 2016; 374: 611–24.  Back to cited text no. 6
Resnick SM, Matsumoto AM, Stephens-Shields AJ, Ellenberg SS, Gill TM, et al. Testosterone treatment and cognitive function in older men with low testosterone and age-associated memory impairment. JAMA 2017; 317: 717–27.  Back to cited text no. 7
Snyder PJ, Kopperdahl DL, Stephens-Shields AJ, Ellenberg SS, Cauley JA, 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 2017; 177: 471–9.  Back to cited text no. 8
Roy CN, Snyder PJ, Stephens-Shields AJ, Artz AS, Bhasin S, et al. Association of testosterone levels with anemia in older men: a controlled clinical trial. JAMA Intern Med 2017; 177: 480–90.  Back to cited text no. 9
Budoff MJ, Ellenberg SS, Lewis CE, Mohler ER, Wenger NK, et al. Testosterone treatment and coronary artery plaque volume in older men with low testosterone. JAMA 2017; 317: 708–16.  Back to cited text no. 10
Yeap BB, Grossmann M, McLachlan RI, Handelsman DJ, Wittert GA, et al. Endocrine Society of Australia position statement on male hypogonadism (part 1): assessment and indications for testosterone therapy. Med J Aust 2016; 205: 173–8.  Back to cited text no. 11
Yeap BB, Grossmann M, McLachlan RI, Handelsman DJ, Wittert GA, et al. Endocrine Society of Australia position statement on male hypogonadism (part 2): treatment and therapeutic considerations. Med J Aust 2016; 205: 228–31.  Back to cited text no. 12
Handelsman DJ. Global trends in testosterone prescribing, 2000–2011: expanding the spectrum of prescription drug misuse. Med J Aust 2013; 199: 548–51.  Back to cited text no. 13
Layton JB, Li D, Meier CR, Sharpless JL, Stumer T, et al. Testosterone lab testing and initiation in the United Kingdom and the United States 2000–2011. J Clin Endocrinol Metab 2014; 99: 835–42.  Back to cited text no. 14
Swerdloff R, Anawalt BD. Clinical decisions: testosterone-replacement therapy. New Engl J Med 2014; 371: 2032–4.  Back to cited text no. 15
Yeap BB. Testosterone and its metabolites: differential associations with cardiovascular and cerebrovascular events in men. Asian J Androl 2018; 20: 109–14.  Back to cited text no. 16
Meyer EJ, Wittert G. Endogenous testosterone and mortality risk. Asian J Androl 2018; 20: 115–9.  Back to cited text no. 17
Jones TH, Kelly DM. Randomized controlled trials – mechanistic studies of testosterone and the cardiovascular system. Asian J Androl 2018; 20: 120–30.  Back to cited text no. 18
Gagliano-Juca T, Basaria S. Trials of testosterone replacement reporting cardiovascular adverse events. Asian J Androl 2018; 20: 131–7.  Back to cited text no. 19
Shores MM. Testosterone treatment and cardiovascular events in analyses of prescription databases. Asian J Androl 2018; 20: 138–44.  Back to cited text no. 20
An Q, Gu YQ. Testosterone replacement therapy: dilemmas and challenges in China and Asia. Asian J Androl 2018; 20: 149–51.  Back to cited text no. 21
Zitzmann M. Would male hormonal contraceptives affect cardiovascular risk? Asian J Androl 2018; 20: 145–8.  Back to cited text no. 22


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