Introduction: Testosterone levels decrease as men age. The effects of testosterone therapy in older men are unclear. The Institute of Medicine issued a report in 2003 stating that insufficient evidence existed to support any beneficial effect of testosterone in older men, and recommending that a set of trials be conducted to determine the effects of testosterone therapy in older men with age-related low testosterone levels and clinical conditions that might be attributed to low testosterone levels. This report was the impetus for Testosterone Trials (TTrials), which are now the largest randomized controlled clinical trials to examine the efficacy of testosterone treatment in men ages ≥65 years with low testosterone levels.
Methods: A total of 790 men (ages ≥65 years) participated in one or more of the following three double-blind, placebo-controlled trials: Sexual Function Trial, Physical Function Trial, and Vitality Trial. At baseline, the men had serum testosterone concentrations <275 ng/dL and symptoms suggestive of hypoandrogenism. Exclusion criteria included a history of or increased risk for prostate cancer (risk of all prostate cancer >35% or of high-grade prostate cancer >7% on the Prostate Cancer Risk Calculator); conditions known to cause hypogonadism; use of medications that alter testosterone concentration; high cardiovascular risk; severe depression; and any other conditions that may affect interpretation of outcomes.
Men in the Sexual Function Trial had self-reported decreased libido (score ≤20 on the sexual-desire domain of the Derogatis Interview for Sexual Functioning in Men–II) and a partner willing to have intercourse twice a month. Men in the Physical Function Trial had self-reported difficulty walking or climbing stairs and a gait speed <1.2 m/second on a 6-minute walk test. Men in the Vitality Trial had self-reported low vitality (score <40 on the Functional Assessment of Chronic Illness Therapy (FACIT) Fatigue Scale).
The participants were randomized to testosterone gel or placebo for 1 year. Testosterone was initiated at 5 g daily and titrated with the goal of achieving a concentration within the normal range for younger men (ages 19 to 40 years). A majority of participants (91%) maintained a mean testosterone concentration above the lower limit of this goal normal range from months 3 through 12.
Results: Testosterone gel use was associated with significant improvements in all aspects of sexual function assessed, including sexual activity, sexual desire, and erectile function (P<0.001 for each measure). Testosterone treatment did not significantly improve distance walked in 6 minutes when only men enrolled in the physical function trial were considered, but did increase the proportion of men who had an increase of at least 50 m in the 6-minute walk test when all men in the TTrials were considered (20.5% in the testosterone group vs 12.6% of the placebo group, P=0.003).
Testosterone treatment did not improve energy, but small significant improvements were found in mood (according to PANAS positive and negative affect scores; P=0.04 and P<0.001) and severity of depressive symptoms on the PHQ-9 (P=0.004) in the testosterone group.
The two groups had a similar rate of adverse events—including heart attack, stroke, other cardiovascular events and prostate conditions—across the three trials.
Conclusion: Testosterone treatment significantly improved sexual function in men ≥65 years of age with low testosterone levels, and had small-to-moderate beneficial effects on some measures of physical ability, mood, and depression.
Snyder PJ, Bhasin S, Cunningham GR, et al. Effects of testosterone treatment in older men. N Engl J Med. 2016;374(7):611-624.
Commentary by Tamara L Wexler MD, PhD
Tamara L. Wexler, MD, PhD, is an endocrinologist specializing in neuroendocrinology and reproductive endocrinology. She is the Director of the NYU Langone Medical Center Pituitary Center in New York, NY, as well as an Attending in Medicine at Massachusetts General Hospital, Boston, MA.
As men age, they may experience changes in sexual function, energy, and physical strength. In addition, testosterone levels have been observed to decrease over time. Evidence regarding a causal relationship between testosterone levels and the above-noted symptoms has not been conclusively determined. The TTrials were designed to investigate the effect of testosterone replacement in a cohort of older men with low testosterone levels and symptoms consistent with hypogonadism.
The Sexual Function, Physical Vitality, and Vitality Trials results were published on February 17 in the New England Journal of Medicine. The cohort enrolled in the TTrials is carefully delineated: community-dwelling men age ≥65 years; two early-morning low testosterone levels (average <275 ng/dL); self-reported sexual dysfunction, decreased vitality and/or mobility. Enrollment in specific trials—the Sexual Function Trial (n=470), Vitality Trial (n=474), and Physical Function Trial (n=390)—was based on further criteria. We describe the cohort, baseline characteristics and study metrics in full earlier in this EndoScan.
Seven-hundred-and-five (705) of the 790 men enrolled completed 1 year of the study. Snyder and colleagues found that increasing testosterone levels in hypogonadal men ≥65 for one year, using testosterone gel, was associated with improvements in sexual desire and activity, erectile function, and to a lesser degree in mood, but not in vitality (no lessening of fatigue) nor walking distance in the Physical Activity cohort alone, though there was a statistically significant difference among all TTrial participants."
An association between libido and testosterone has been described in population studies and clinical trials, but effects may vary depending on age group, and baseline health and degree of hypogonadism.1-3 One meta-analysis (of 41 studies, 29 of which compared testosterone to placebo) found that testosterone replacement in hypogonadal but not eugonadal men improved sexual parameters.4 Another meta-analysis of 17 RCTs concluded that testosterone replacement improved libido, sexual activity, and some erectile dysfunction in men with baseline low or low-normal T levels, but not normal T levels.5 The effect was not always sustained over time.5 One single-arm study of 32 men with documented hypogonadism found that libido was improved for at least 6 months, but improvements in erectile function and sexual satisfaction were shorter-lived.6 It is this very lack of clarity in terms of the impact of testosterone replacement in older men with specifically defined hypogonadism that led to the TTrials.
It is interesting to note that walking distance or vitality as measured by 6-minute walking distance or Functional Assessment of Chronic Illness Therapy (FACIT) Fatigue Scale, did not change significantly with testosterone increases, but the treated group did report subjective improvements in both areas. Prior studies have shown an improvement in physical parameters with testosterone replacement, but benefits are not always sustained over time.2,7,8
While no increase in cardiovascular events was noted, the study was not powered to address risks. The results of testosterone replacement across the full complement of TTrials—which also include studies of cardiovascular health, cognitive function, anemia, and bone—remain eagerly anticipated.
1. Travison TG, Morley JE, Araujo AB, et al. The relationship between libido and testosterone levels in aging men. J Clin Endocrinol Metab. 2006;91(7):2509-2513.
2. Page S, Amory J, Bowman F, et al. Exogenous testosterone (T) alone or with finasteride increases physical performance, grip strength, and lean body mass in older men with low serum T. J Clinc Endocrinol Metab. 2004;90:1502-1510.
3. Zitzmann M, Mattern A, Hanisch J, et al. IPASS: a study on the tolerability and effectiveness of injectable testosterone undecanoate for the treatment of male hypogonadism in a worldwide sample of 1,438 men. J Sex Med. 2013;10(2):579-588.
4. Corona G, Isidori AM, Buvat J, et al. Testosterone supplementation and sexual function: a meta-analysis study. J Sex Med. 2014;11(6):1577-1592.
5. Isidori AM, Giannetta E, Gianfrilli D, et al. Effects of testosterone on sexual function in men: results of a meta-analysis. Clin Endocrinol (Oxf). 2005;63(4):381-394.
6. Mulhall JP, Valenzuela R, Avid N, et al. Effect of testosterone supplementation on sexual function in hypogonadal men with erectile dysfunction. Urology. 2004;63(2):348-352; discussion 352-353.
7. 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;95:639-650.
8. O'Connell MD, Roberts SA. Srinivas-Shankar U, et al. Do the effects of testosterone on muscle strength, physical function, body composition, and quality of life persist six months after treatment in intermediate-frail and frail elderly men? J Clin Endocrinol Metab. 2011;96(2):454-458.