In a retrospective observational cohort study testosterone therapy was associated with decreased mortality in men with low testosterone levels compared with no testosterone treatment

Testosterone Treatment and Mortality in Men with Low Testosterone Levels. Shores MM, Smith NL, Forsberg CW, et al. Testosterone. J Clin Endocrinol Metab 2012; 97(6): 2050-2058.

This observational, retrospective cohort study based on a clinical database that included seven Veteran Affairs medical centres in the US was the first to examine the association between testosterone treatment and mortality in men with low testosterone levels.1 Mortality was compared in testosterone-treated compared with untreated hypogonadal men, using appropriate statistical models adjusted for age, diabetes and coronary heart disease. Testosterone formulations included intramuscular injections (88.6%), patch (9.1%) or gel (2.3%). The cohort included 1031 men aged >40 (mean 62) years with low total testosterone levels ≤8.7 nmol/L (250 ng/dL) at study entry, no history of prostate cancer, who were assessed in 2001–2002 and followed-up until the end of 2005 (mean follow-up time 40.5 months).1

Mean body mass index (BMI) was 32.0 kg/m2, and mean total testosterone level was 6.3 nmol/L (181 ng/dL). There was a high degree of medical comorbidity in the cohort; a mean of 6.7 pharmacologically-treated medical conditions, including diabetes (38%), sexual dysfunction (36%) and coronary heart disease (21%). There was an association between lower testosterone levels and higher medical comorbidity (p=0.037).

Key Points1

  • Testosterone replacement therapy was started in 39% of men (398/1031) during routine clinical care
  • After a mean follow-up of 40.5 months, overall mortality in testosterone-treated men was 10.3%, compared with 20.7% for untreated men (p<0.001)
  • The mortality rate was 3.4 deaths/100 person-years in testosterone-treated men, compared with 5.7/100 person years in untreated men
  • Analysis showed that testosterone-treated men had longer a survival time than untreated men (p=0.029) (Figure 1)
  • Testosterone-treated men had a 39% reduction in mortality risk [hazard risk (HR) 0.61; 95% confidence interval 0.42–0.88, p=0.008] compared with untreated men when data were adjusted for age, treatment site, BMI, baseline testosterone level, overall medical morbidity, hospitalisation, and for the presence of coronary heart disease and diabetes mellitus
  • Testosterone treatment continued to be associated with decreased mortality in secondary analyses and after sensitivity analysis
  • Although there was no significant effect modification by age, diabetes or cardiovascular disease, testosterone treatment appeared to be associated with greater mortality reduction in younger men (age <60 years), diabetic men and men without coronary heart disease
  • During the study, 1.6% of testosterone-treated men and 2.0% of untreated men were diagnosed with incident prostate cancer (p=0.68).

What is known

Low testosterone levels, common in older men, are associated with a range of adverse outcomes, including diabetes, obesity, cardiovascular events, loss of muscle mass and strength, osteoporosis and diminished libido.2,3 It has been reported that there is an (approximately two-fold) increase in mortality in men with low testosterone, compared with men with normal testosterone levels,4 which has been confirmed by most,5-8 but not all9,10 other studies. The use of testosterone replacement therapy has increased markedly in recent years, particularly in the US.11 Therefore it is important to clarify the risks and benefits of testosterone treatment in the health of older men with low testosterone levels.

A number of studies have shown beneficial effects for testosterone treatment in older men, including improvements in muscle mass and strength and increased bone mineral density, insulin sensitivity and libido.12-15 Nevertheless, ongoing concerns about prostate cancer incidence or mortality linger, and there was a recent unexpected finding when a trial in frail, elderly men was discontinued after a greater occurrence of cardiovascular events in testosterone-treated men.16 However, another study in a similar population of frail elderly men found no increased cardiovascular risk,14 and a systematic review and meta-analysis found no increased cardiovascular risks with testosterone treatment.17

What this study adds

This retrospective observational cohort study showed that testosterone replacement therapy significantly decreased mortality in the cohort of men with low total testosterone levels and a high level of chronic medical morbidity.1

The limitations of observational study design mean that these results should be viewed cautiously. However, despite these and other potential study limitations, the study had a number of significant strengths. The study was the first to specifically examine the association between testosterone treatment and mortality in middle-aged and older men with low testosterone levels, and the threshold for inclusion in the study required clearly low testosterone levels, increasing the likelihood that men in the study had symptomatic and clinically significant androgen deficiency. This is also one of the first large studies to examine testosterone treatment in men with high medical morbidity. Such men may be more susceptible to harm or benefit from testosterone treatment.

While the results cannot be interpreted as demonstrating beneficial effects of testosterone treatment or establishing a causal relationship between testosterone treatment and reduced mortality, they should stimulate further investigation of the effects of testosterone treatment on the health of older men. The gold standard to examine any such causal relationship would be a large-scale, randomized, double blind, placebo-controlled trial.

Figure 1: Unadjusted Kaplan-Meier survival curves showing that testosterone-treated men had a longer survival time than untreated men

References

1. Shores MM, Smith NL, Forsberg CW, et al. Testosterone Treatment and Mortality in Men with Low Testosterone Levels. J Clin Endocrinol Metab 2012; 97(6): 2050-2058.
2. Matsumoto AM. Andropause: clinical implications of the decline in serum testosterone levels with aging in men. J Gerontol A Biol Sci Med Sci 2002;57(2):M76-99.
3. Travison TG, Araujo AB, Kupelian V, et al. The relative contributions of aging, health, and lifestyle factors to serum testosterone decline in men. J Clin Endocrinol Metab 2007;92(2):549-555.
4. Shores MM, Matsumoto AM, Sloan KL, et al. Low serum testosterone and mortality in male veterans. Arch Intern Med 2006;166(15):1660-1665.
5. 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.
6. Laughlin GA, Barrett-Connor E, Bergstrom J. Low serum testosterone and mortality in older men. J Clin Endocrinol Metab 2008;93(1):68-75.
7. Lehtonen A, Huupponen R, Tuomilehto J, et al. Serum testosterone but not leptin predicts mortality in elderly men. Age Ageing 2008;37(4):461-464.
8. Tivesten A, Vandenput L, Labrie F, et al. Low serum testosterone and estradiol predict mortality in elderly men. J Clin Endocrinol Metab 2009;94(7):2482-2488.
9. Araujo AB, Kupelian V, Page ST, et al. Sex steroids and all-cause and cause-specific mortality in men. Arch Intern Med 2007;167(12):1252-1260.
10. Cummings-Vaughn LA, Malmstrom TK, Morley JE, et al. Testosterone is not associated with mortality in older African-American males. Aging Male 2011;14(2):132-140.
11. US Food and Drug Administration 2009. Postmarket Reviews. Available from: http://fda.gov
12. Caminiti G, Volterrani M, Iellamo F, 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 2009;54(10):919-927.
13. Malkin CJ, Jones TH, Channer KS. The effect of testosterone on insulin sensitivity in men with heart failure. Eur J Heart Fail 2007;9(1):44-50.
14. Srinivas-Shankar U, Roberts SA, Connolly MJ, et al. Effects of testosterone on muscle strength, physical function, body composition, and quality of life in intermediate-frail and frail elderly men: a randomized, double-blind, placebo-controlled study. J Clin Endocrinol Metab 2010;95(2):639-650.
15. Wang C, Cunningham G, Dobs A, et al. Long-term testosterone gel (AndroGel) treatment maintains beneficial effects on sexual function and mood, lean and fat mass, and bone mineral density in hypogonadal men. J Clin Endocrinol Metab 2004;89(5):2085-2098.
16. Basaria S, Coviello AD, Travison TG, et al. Adverse events associated with testosterone administration. N Engl J Med 2010;363(2):109-122.
17. 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.

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Last updated: 2018
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