An editorial notes that in 2003, an Institute of Medicine panel in US reviewed the evidence that testosterone supplementation is beneficial and considered it unsubstantial and recommended a series of clinical trials to critically evaluate supplementation for several clinical indications. The T-Trials, a series of 7 linked, rigorously designed and well-executed studies, were performed to address these recommendations. The findings from 3 of these studies (in men with symptoms related to sexual function, vigor, and physical performance) were recently published. The results of 2 more studies (addressing effects on bone and anaemia) are reported in this issue of JAMA Internal Medicine. The editorial suggests that together, the T-Trials represent the most definitive assessments of the potential short-term advantages of testosterone replacement in older men, but stresses they were not intended to address the equally critical issue of whether there are important long-term adverse effects. Another study also published in this issue of JAMA Internal Medicine reports the association of testosterone supplementation with cardiovascular events in a large, retrospective cohort study.
An RCT published in JAMA reported that in older men with symptomatic hypogonadism, treatment with testosterone gel for 1 year vs. placebo was linked to significantly greater increase in coronary artery noncalcified plaque volume, the clinical implications of which remains to be determined. An editorial commenting on this and another study looking at impact on cognitive function, states that the findings from subtrials of the TTrials do not materially change the unfavorable balance of safety and efficacy to initiate testosterone treatment for age-related hypogonadism. It suggests that for clinicians prescribing off-label testosterone, these cardiovascular findings make it incumbent to strengthen warnings of adverse cardiovascular risk and also support the FDA decision in September 2015 to tighten cardiovascular safety warnings about off-label testosterone prescribing and mandated that testosterone manufacturers undertake longer-term safety and efficacy trials for off-label use of testosterone for aging men. It notes that testosterone overprescribing has been propelled not only by direct-to-consumer advertising, but also with the complicity of some professional organizations and physicians supporting the redefinition of the term hypogonadism to minimise the fundamental distinction between pathological hypogonadism and age-related, low circulating testosterone. It acknowledges that testosterone and synthetic androgens have valuable medical applications but a key lesson is that such novel indications should be established by efficacy and safety studies and not preceded by wide-scale, off-label adoption. The editorial in JAMA concludes that for now, the hopes for testosterone-led rejuvenation for older men are dimmed and disappointed if not yet finally dashed based on the results of the current studies.