Lower testosterone concentrations have been associated with poorer health outcomes in ageing men, but proving causality and demonstrating potential for therapeutic benefit requires randomized clinical trials (RCTs). This review discusses recent observational findings and results of major testosterone RCTs, to explore the need for another, larger trial. Evidence of Leydig cell impairment emerges in men above the age of 70 years. Lower testosterone is associated with diabetes risk, and also risk of incident dementia. An individual participant data meta-analysis found that below thresholds of testosterone of 7.4 nmol/L and 5.3 nmol/l respectively, risks of all-cause mortality and cardiovascular deaths in men increased. Testosterone for the Prevention of Type 2 Diabetes Mellitus (T4DM), a multicentre RCT, showed that testosterone treatment prevented or reverted type 2 diabetes in men at high risk. Testosterone Replacement Therapy for Assessment of Long-term Vascular Events and Efficacy Response in Hypogonadal Men (TRAVERSE), a cardiovascular safety trial, demonstrated cardiovascular and prostate safety of testosterone treatment in men with or at risk of cardiovascular disease. T4DM confirmed findings from the Testosterone Trials (T-Trials) that testosterone improved sexual function, and bone microarchitecture and density. However, in TRAVERSE, testosterone-treated men had a higher risk of clinical bone fractures, but not major osteoporotic fractures. Men with disorders of the hypothalamic-pituitary-testicular (HPT) axis causing androgen deficiency warrant consideration for testosterone therapy. In men with an intact HPT axis, testosterone treatment is a pharmacological intervention which requires justification from high quality RCT data. Currently, there is insufficient evidence to justify wider use of testosterone for prevention of cardiometabolic disease. However, there is scope for another large testosterone RCT to investigate whether testosterone treatment might, in older men, extend disability-free survival.
Read full abstract