By Seema Gupta, MD, MSPH
Clinical Assistant Professor, Department of Family and Community Health, Joan C. Edwards School of Medicine, Marshall University, Hunington, WV
Dr. Gupta reports no financial relationships relevant to this field of study.
SYNOPSIS: Testosterone replacement therapy showed no impact on subclinical atherosclerosis progression in recent study.
SOURCE: 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. JAMA 2015;314:570-581.
In recent years, there has been a dramatic rise in the use of testosterone therapy in healthy middle-aged and older men. In fact, the commercial sales of testosterone replacement therapy have increased substantially. Recent evidence demonstrates that from 2001 through 2011, androgen use among men ≥ 40 years of age increased more than three-fold, with topical gel demonstrating the highest rate of overall use and the highest rate of increase — more than five-fold.1 Clinical benefits of testosterone therapy in hypogonadal men include the restoration of libido and energy, increased muscle strength, and improvements in bone mineral density. Improvements in mood and cognition also may be observed. However, in older men with age-related declines in testosterone levels, a long-term replacement therapy regimen has not consistently demonstrated clinical benefit. Additionally, there may be risks associated with testosterone therapy in elderly men, including worsening of sleep apnea, gynecomastia, polycythemia, fluid retention, and acceleration of benign or malignant prostate disease. There is also a concern for an increase in the risk of cardiovascular disease associated with testosterone replacement therapy, although the evidence on the matter has been inconclusive. While evidence from a subgroup analysis of men ≥ 65 years of age did not demonstrate an increase in cardiovascular events associated with testosterone replacement, another randomized trial in older men with high prevalence of chronic disease ended early due to higher frequency of self-reported cardiovascular-related adverse events in men designated to the testosterone arm compared with the placebo arm.2,3 Testosterone levels have been negatively associated with common carotid artery intima-media thickness.
Basaria et al conducted a placebo-controlled, double-blind, parallel-group, randomized trial to determine the effect of testosterone administration on subclinical atherosclerosis progression in older men with low or low-normal testosterone levels. Researchers enrolled a total of 308 men (≥ 60 years of age) with low or low-normal testosterone levels (100-400 ng/dL, free testosterone < 50 pg/mL) at three U.S. centers between 2004 and 2009. One hundred fifty-six participants were randomized to receive 7.5 g of 1% testosterone and 152 were randomized to receive placebo gel packets daily for 3 years. The dose was adjusted to achieve testosterone levels between 500 and 900 ng/dL. Primary outcomes measured were the rate of change in distal right common carotid artery intima-media thickness and coronary artery calcium. Secondary outcomes included sexual function and health-related quality of life.
The researchers found that among older men (mean age 67.6 years) with low or low-normal testosterone levels, 3 years of testosterone gel administration did not result in a significant difference in the rates of change in either common carotid artery intima-media thickness or coronary artery calcium when compared with placebo. The rate of change in intima-media thickness was 0.010 mm/year in the placebo group and 0.012 mm/year in the testosterone group. The mean difference adjusted for age and trial site was 0.0002 mm/year (95% confidence interval [CI], −0.003 to 0.003; P = 0.89). The rate of change in the coronary artery calcium score was 41.4 Agatston units/year in the placebo group and 31.4 Agatston units/year in the testosterone group. The adjusted mean difference was -10.8 Agatston units/year (95% CI, -45.7 to 24.2; P = 0.54). Additionally, researchers found no improvement in the overall sexual function or health-related quality of life in the testosterone treatment group compared with placebo.
COMMENTARY
There is both good and bad news resulting from this well-done study. The good news is that testosterone replacement therapy showed no impact on subclinical atherosclerosis progression in older men with low to low-normal testosterone levels. Although this trial was not specifically designed to determine the effects of testosterone on cardiovascular disease events, it does suggest that the increase in cardiovascular events in previous studies may not be due to the atherosclerosis progression from testosterone treatment. Some previous epidemiological studies have reported the association of low testosterone levels with greater common carotid artery intima-media thickness as well as cardiovascular and all-cause mortality.4 Therefore, further research is needed to determine whether there may be a reverse causality association in which individuals at high risk for death or cardiovascular events may in fact have resultant lower testosterone levels. However, the study finding that testosterone administration did not significantly improve erectile or ejaculatory function, sexual desire, or health-related quality of life is significant. This contrasts with the efficacy of phosphodiesterase inhibitors in relation to sexual function and perhaps testosterone should not be prescribed for this purpose with the possible exception of clearly low testosterone levels.5 In summary, testosterone replacement should be restricted to symptomatic men with hypogonadism, which is evident by clinical symptoms and signs consistent with androgen deficiency and a subnormal morning serum testosterone concentration.
REFERENCES
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Baillargeon J, et al. Trends in androgen prescribing in the United States, 2001 to 2011. JAMA Intern Med 2013;173:1465-1466.
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Fernández-Balsells MM, et al. Clinical review 1: Adverse effects of testosterone therapy in adult men: A systematic review and meta-analysis. J Clin Endocrinol Metab 2010;95:2560-2575.
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Basaria S, et al. Adverse events associated with testosterone administration. N Engl J Med 2010 Jul 8;363:109-122.
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Bhasin S, et al. Testosterone therapy in men with androgen deficiency syndromes: An Endocrine Society clinical practice guideline. J Clin Endocrinol Metab 2010;95:2536-2559.
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Isidori AM, et al. Effects of testosterone on sexual function in men: Results of a meta-analysis. Clin Endocrinol (Oxf) 2005;63:381-394.
