Testosterone Replacement Therapy and Mortality in Older Men

While US testosterone prescriptions have tripled in the last decade with lower trends in Europe, debate continues over the risks, benefits and appropriate use of testosterone replacement therapy (TRT). Several authors blame advertising and the availability of more convenient formulations, whilst others have pointed out that the routine testing of men with erectile dysfunction (ED) (a significant marker of cardiovascular risk) and those with diabetes would inevitably increase the diagnosis of hypogonadism and lead to an increase in totally appropriate prescribing. They commented that this was merely an appropriate correction of previous under-diagnosis and under-treatment in line with evidence based guidelines. It is unlikely that persuasive advertising or convenient formulations could grow a market over such a sustained period if the treatment was not effective. Urologists and primary care physicians are the most frequent initiators of TRT usually for ED. Benefits are clearly established for sexual function, increase in lean muscle mass and strength, mood and cognitive function, with a possible reduction in frailty and osteoporosis. There remains no evidence that TRT is associated with increased risk of prostate cancer or symptomatic benign prostatic hyperplasia, yet the decision to initiate and continue therapy is often decided by urologists. The cardiovascular issues associated with TRT have been clarified by recent studies showing that therapy associated with clear increases in serum testosterone levels to the normal range is associated with reduced all-cause mortality. Studies reporting to show increased risk have been subject to flawed designs with inadequate baseline diagnosis and follow-up testing. Effectively, they have compared non-treated patients with under-treated or non-compliant subjects involving a range of different therapy regimes. Recent evidence suggests long-acting injections may be associated with decreased cardiovascular risk, but the transdermal route may be associated with potentially relatively greater risk because of conversion to dihydrotestosterone by the effect of 5-alpha reductase in skin. The multiple effects of TRT may add up to a considerable benefit to the patient that might be underestimated by the physician primarily concerned with his own specialty. In a response to concerns about the possible risks associated with inappropriate prescribing expressed by Public Citizen, the Food and Drug Administration (FDA) published a complete refutation of all the concerns, only to issue a subsequent bulletin of concern over inappropriate use, whilst confirming the benefits in treating men with established testosterone deficiency. No additional evidence was provided for this apparent change of opinion, but longer term safety data on testosterone products were strongly suggested. In contrast, the European Medicines Agency (EMA), in November 2014, concluded that “there is no consistent evidence of increased cardiovascular risk with testosterone products”. This paper explores the most recent evidence surrounding the benefits and risks associated with TRT.