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.
A second editorial considers that this study contained an ethical error in that participants with haemoglobin levels <10.0 g/dL at baseline were excluded from the trial and referred to their primary care providers for evaluation of anaemia, whereas the 126 (16%) with mild anemia (10.0 to 12.7 g/dL) were not told of this condition. It highlights that clinical researchers have an ethical and legal responsibility not only to minimise harms to participants caused by study interventions but also to disclose to participants valid individual results that would lead to changes in their clinical care. It suggests that the researchers were in a unique position to give participants an opportunity to identify causes of anemia for which timely treatment might improve outcomes.
According to an editorial in JAMA, 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. 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.
In September 2015 the FDA also mandated that testosterone manufacturers undertake longer-term safety and efficacy trials for off-label use of testosterone for aging men. The editorial 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.