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Low testosterone is common in men with coronary heart disease and negatively impacts survival

Image : Man clutching his chest

Low serum testosterone and increased mortality in men with coronary heart disease. Malkin CJ, Pugh PJ, Morris PD, et al. Heart 2010;96(22):1821-1825.

A total of 930 men (mean age 61 years) were followed in a prospective cohort study for a mean of 6.9 years to determine the prevalence of testosterone deficiency and to investigate the effect of serum testosterone levels on survival in men with confirmed coronary disease.1 The cohort was a consecutive series of men referred to a tertiary cardiothoracic centre for diagnostic coronary angiography between June 2000 and June 2002. Significant coronary artery disease was defined as 70% or greater stenosis in any epicardial coronary artery or 50% or greater stenosis of the main stem of the left coronary artery.

Key Points

The nested case-control study showed:

  • 20.9% of men had biochemical testosterone deficiency defined as bioavailable testosterone <2.6 nmol/L, 16.91% using testosterone <8.1 nmol/L and 24% using either1
  • There was excess mortality in testosterone-deficient men; 21% versus 12% in those with testosterone levels in the normal range (>2.6 nmol/L), p=0.002 (Figure 1)1
  • Low serum testosterone was one of only four variables found to influence the time to all-cause mortality in multivariate analysis (hazard ratio [HR] 2.27)1
  • The other variables significantly influencing time to all-cause mortality were presence of left ventricular dysfunction (HR 3.85), aspirin therapy (HR 0.63) and β-blocker therapy (HR 0.45)1
  • Low bioavailable testosterone more than doubled adjusted all-cause and vascular mortality (HR 2.2, p<0.0001 for all-cause mortality and HR 2.2, p=0.007 for vascular mortality) compared with those with normal levels of testosterone1
  • Overall, serum total testosterone was inversely associated with mortality (HR 0.96), with a baseline level of <15.1 nmol/L associated with an all-cause HR of 1.86 and vascular mortality with a HR of 2.5.1

What is known

The risk for men of dying from coronary disease is double that for women, even after controlling for cardiovascular risk factors.2 Although there has been an assumption that testosterone has harmful effects on the cardiovascular system, there is little evidence that endogenous testosterone increases cardiovascular risk and the role of testosterone status and testosterone replacement therapy on male health remains controversial.3It is well established that high doses of exogenous anabolic steroids have a deleterious effect on cardiac disease.4 However, high levels of endogenous testosterone within the normal range appear not to be detrimental, and there is increasing evidence that low testosterone levels in men are associated with increased cardiovascular risk resulting from a more adverse cardiometabolic profile.5,6 Furthermore, testosterone replacement therapy improves insulin resistance, glycaemic control, central obesity, lean body mass, hypercholesterolaemia and pro-inflammatory cytokines associated with diabetes, atherosclerosis and the metabolic syndrome.7-9

There is accumulating evidence that low testosterone levels are associated with an increase in all-cause and cardiovascular mortality.10-13 However, this study is the first to examine the effects of low testosterone in men with established cardiovascular disease.

What this study adds

This is the first epidemiological study to demonstrate that low testosterone is a marker of early mortality in men with vascular disease, who have been excluded in previous follow-up studies of testosterone. In an editorial accompanying the study, Drs Ronald Ma and Peter Tong note that the study contributes to the emerging picture suggesting that reduced testosterone levels in men may be associated with increased cardiovascular risk, and suggest that testosterone measurements may have a place in the evaluation of cardiovascular risk in male patients, although issues to be resolved include the variability of testosterone concentrations, the influence of acute or chronic concomitant illness, the accuracy and reliability of current assays and whether to measure sex-hormone binding globulin, total or free testosterone.14

This study shows that testosterone deficiency is common in patients with coronary disease and has a considerable negative impact on survival. The authors conclude that a prospective outcome trial of testosterone replacement on mortality in men with low testosterone is the next logical step, targeting high-risk populations such as men with cardiac disease or diabetes, who have the most to gain from the potentially beneficial effects.1

Figure 1: Excess mortality after a mean follow-up of 6.9 years in men with confirmed coronary disease and low serum testosterone levels.1

Figure 1: Excess mortality after a mean follow-up of 6.9 years in men with confirmed coronary disease and low serum testosterone levels.

References

1. Malkin CJ, Pugh PJ, Morris PD, et al. Low serum testosterone and increased mortality in men with coronary heart disease. Heart 2010;96(22):1821-1825.
2. Njolstad I, Arnesen E, Lund-Larsen PG. Smoking, serum lipids, blood pressure, and sex differences in myocardial infarction. A 12-year follow-up of the Finnmark Study. Circulation 1996;93(3):450-456.
3. Haddad RM, Kennedy CC, Caples SM, et al. Testosterone and cardiovascular risk in men: a systematic review and meta-analysis of randomized placebo-controlled trials. Mayo Clin Proc 2007;82(1):29-39.
4. Bagatell CJ, Bremner WJ. Androgens in men–uses and abuses. N Engl J Med 1996;334(11):707-714.
5. Jones RD, Nettleship JE, Kapoor D, et al. Testosterone and atherosclerosis in aging men: purported association and clinical implications. Am J Cardiovasc Drugs 2005;5(3):141-154.
6. Kapoor D, Aldred H, Clark S, et al. Clinical and biochemical assessment of hypogonadism in men with type 2 diabetes: correlations with bioavailable testosterone and visceral adiposity. Diabetes Care 2007;30(4):911-917.
7. Kapoor D, Goodwin E, Channer KS, et al. Testosterone replacement therapy improves insulin resistance, glycaemic control, visceral adiposity and hypercholesterolaemia in hypogonadal men with type 2 diabetes. Eur J Endocrinol 2006;154(6):899-906.
8. Malkin CJ, Pugh PJ, Jones RD, et al. The effect of testosterone replacement on endogenous inflammatory cytokines and lipid profiles in hypogonadal men. J Clin Endocrinol Metab 2004;89(7):3313-3318.
9. Heufelder AE, Saad F, Bunck MC, et al. Fifty-two-week treatment with diet and exercise plus transdermal testosterone reverses the metabolic syndrome and improves glycemic control in men with newly diagnosed type 2 diabetes and subnormal plasma testosterone. J Androl 2009;30(6):726-733.
10. Shores MM, Moceri VM, Gruenewald DA, et al. Low testosterone is associated with decreased function and increased mortality risk: a preliminary study of men in a geriatric rehabilitation unit. J Am Geriatr Soc 2004;52(12):2077-2081.
11. Khaw KT, Dowsett M, Folkerd E, 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 2007;116(23):2694-2701.
12. Shores MM, Matsumoto AM, Sloan KL, et al. Low serum testosterone and mortality in male veterans. Arch Intern Med 2006;166(15):1660-1665.
13. Laughlin GA, Barrett-Connor E, Bergstrom J. Low serum testosterone and mortality in older men. J Clin Endocrinol Metab 2008;93(1):68-75.
14. Ma RC, Tong PC. Testosterone levels and cardiovascular disease. Heart 2010;96(22):1787-1788.

 

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Last updated: 2018
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