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.
An editorial notes that this is likely the largest well-controlled study of cognitive effects of testosterone in male aging, but the findings are not surprising because, among placebo-controlled studies, only a single small study ever indicated otherwise and a longer (3 years) but smaller study also had negative findings. It adds that these convincing, unequivocal findings affirm that testosterone treatment does not improve cognitive function in older men. Nevertheless, this does not preclude other possible psychological (e.g. mood-elevating) effects of testosterone.
Another study in the same issue of JAMA reports on findings of the TTrials cardiovascular trial involving a subset of 138 men with low testosterone who completed computed tomographic (CT) evaluation of coronary artery plaque volume before and after 12 months of testosterone treatment or placebo treatment. Compared with placebo, testosterone treatment was associated with a significantly greater increase in noncalcified and total plaque volume, but not in calcified plaque. No major cardiovascular events occurred in either treatment group, although the study was not designed to detect such events.
Further reports from 2 other substudies of the TTrials were recently published in JAMA Internal Medicine. One study demonstrated that testosterone treatment increased hemoglobin levels among men with anemia, and speculated that low testosterone levels could be considered as a possible cause of unexplained mild anemia in older men, whereas the other study showed that testosterone treatment increased bone mineral density and estimated bone strength. The editorial stresses that even though these findings may represent useful and beneficial effects, they are not indications to initiate testosterone treatment.
According to an editorial, 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 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.