The TTrials are a coordinated group of seven trials examining the effects of testosterone gel compared with a placebo gel. Data from the three main trials—Sexual Function Trial, Physical Function Trial, and Vitality Trial—were included in the present study.
“The results of the TTrials show for the first time that testosterone treatment of older men who have unequivocally low testosterone levels does have some benefit,” said lead author and principal investigator Peter J. Snyder, MD, Professor of Medicine and Medical Director of the Penn Pituitary Center at the University of Pennsylvania. “However, decisions about testosterone treatment for these men also will depend on the results of the other four trials—Cognitive Function, Bone, Cardiovascular, and Anemia—and the risks of testosterone treatment.”
A total of 790 men ages 65 years and older participated in one or more of the three double-blind, placebo-controlled trials. At baseline, the men had serum testosterone concentrations <275 ng/dL and symptoms suggestive of hypoandrogenism. Exclusion criteria were a history of prostate cancer, risk of all prostate cancer of more than 35% or of high-grade prostate cancer of more than 7%, conditions linked to hypogonadism, use of medications that alter the 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–Fatigue scale).
The participants were randomized to testosterone gel or placebo for 1 year. Testosterone was initiated at 5g daily and was titrated with the goal of achieving a concentration within the normal range for young men (ages 19 to 40 years). A majority of participants (91%) maintained a mean testosterone concentration above the lower limit of the normal range for young men from month 3 through month 12.
Improvements in Sexual Function, Physical Function, and Mood Found
Testosterone also improved all aspects of sexual function, including sexual activity, sexual desire, and the ability to get an erection (P<0.001 for each measure). Testosterone treatment did not significantly improve distance walked in six 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). The treatment did not improve energy but did improve mood and depressive symptoms.
Adverse events—including heart attack, stroke, other cardiovascular events and prostate conditions—were similar in the testosterone and placebo groups across the three trials. However, the number of men in the TTrials was too small to draw conclusions about the risk of testosterone treatment, which the researchers noted would require a larger and longer trial.
Geoffrey Hackett, MD
Consultant in Sexual Medicine
Good Hope Hospital
Sutton Coldfield, UK
The TTrials showed highly significant improvement in sexual function, with improvement in 6-minute walking distance, functional performance, mood, vitality, and depression. These multiple small improvements may add up to considerable benefits in older men that will likely reduce frailty and increase independence. Other studies of testosterone treatment showed improved insulin resistance, weight loss, and possibly improved bone mineral density, adding to the potential benefits of this therapy.
This study should increase confidence to initiate testosterone in older men after a proper diagnosis of hypogonadism has been made. Multiple medications would be required to achieve similar benefits found in these trials with the corresponding risk of side effects.
Optimal treatment of sexual dysfunction in elderly hypogonadal men usually requires testosterone replacement and ED-specific therapy. Strangely, the authors and editorial accompanying this paper suggest that phosphodiesterase-5 inhibitors (PDE5Is) might have shown equivalent effect on sexual function, but any experienced physician treating sexual dysfunction in older men will confirm that both testosterone therapy and PDE5Is will be required to raise a baseline erectile function score of 7 to a normal score of 26 or above.
The licensing studies on PDE5Is excluded men with untreated hypogonadism due to predicted low response. The one trial quoted to support their case was from Spitzer et al involving men aged 40-70 years, which found that sildenafil actually increased testosterone to a level seen with testosterone replacement, a finding not endorsed by other studies. The only treatment to have consistently improved erectile function in hypogonadal men is testosterone. Testosterone therapy also increases the response to PDE5Is, as demonstrated in multiple studies. Men in the TTrials were over 65 years of age, so extrapolation from Spitzer et al is highly questionable.
There were 3 deaths in the testosterone cohort versus 7 in the placebo cohort, although this study was not powered or of sufficient duration to assess cardiovascular and all-cause mortality. In line with recent expert opinion, there were no concerns related to the prostate.
Strengths and Weaknesses of the Trials
This is the largest randomized controlled trial of testosterone replacement in older men, conducted with a rigorous protocol. A huge population was screened to find the 790 men in the study, and there is inadequate explanation about this. Might this be a very highly selected group, not reflective of the general population?
In addition, apart from 30% having diabetes, medications are not discussed. Are we expected to believe that no men were taking a PDE5I during the 12 months?
Furthermore, the division into 3 separate studies—sexual function, vitality, and physical function is confusing and reduces cohort size. The authors describe non-significance, but this becomes significant when the 3 trials are merged. In their conclusions, the authors seem to state findings based on the smaller cohorts whereas significant results were obtained from the larger group.
March 10, 2016
Snyder PJ, Bhasin S, Cunningham GR, et al. Effects of testosterone treatment in older men. N Engl J Med. 2016;374(7):611-624.