Beyond T-Trials, T4DM and TRAVERSE: the next large testosterone randomized controlled trial.

Evidence of Leydig cell impairment emerges in men above the age of 70 years.

• This represents an age-related decline in testosterone production capacity.
• This finding is relevant to understanding the physiological basis for testosterone deficiency in older men.
• The impairment is at the level of the Leydig cells, which are responsible for testosterone synthesis in the testes.

Lower testosterone concentrations are associated with increased risk of diabetes and incident dementia in men.

• Lower testosterone is associated with diabetes risk as well as risk of incident dementia.
• These associations are based on observational findings in ageing men.
• These associations do not establish causality without support from randomized controlled trials.

An individual participant data meta-analysis identified testosterone thresholds below which risks of all-cause mortality and cardiovascular deaths in men increased.

• Below a threshold of 7.4 nmol/L, risk of all-cause mortality in men increased.
• Below a threshold of 5.3 nmol/L, risk of cardiovascular deaths in men increased.
• These thresholds were identified through an individual participant data meta-analysis.

The T4DM randomized controlled trial showed that testosterone treatment prevented or reverted type 2 diabetes in men at high risk.

• T4DM stands for Testosterone for the Prevention of Type 2 Diabetes Mellitus.
• T4DM was a multicentre RCT.
• The trial targeted men at high risk of type 2 diabetes.
• T4DM also confirmed findings from the T-Trials that testosterone improved sexual function, and bone microarchitecture and density.

The TRAVERSE trial demonstrated cardiovascular and prostate safety of testosterone treatment in men with or at risk of cardiovascular disease.

• TRAVERSE stands for Testosterone Replacement Therapy for Assessment of Long-term Vascular Events and Efficacy Response in Hypogonadal Men.
• TRAVERSE was designed as a cardiovascular safety trial.
• The trial enrolled men with or at risk of cardiovascular disease.
• Cardiovascular safety and prostate safety were both demonstrated in the testosterone-treated group.

In the TRAVERSE trial, testosterone-treated men had a higher risk of clinical bone fractures but not major osteoporotic fractures.

• This finding was in contrast to T-Trials data suggesting testosterone improved bone microarchitecture and density.
• The elevated fracture risk was specific to clinical bone fractures, not major osteoporotic fractures.
• This discrepancy between bone density improvements and fracture outcomes represents an unresolved finding from TRAVERSE.

Men with disorders of the hypothalamic-pituitary-testicular (HPT) axis causing androgen deficiency warrant consideration for testosterone therapy, while men with an intact HPT axis require high-quality RCT justification for testosterone treatment.

• A distinction is drawn between classical hypogonadism (HPT axis disorder) and age-related testosterone decline with intact HPT axis.
• In men with an intact HPT axis, testosterone treatment is characterized as '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.

The authors conclude there is scope for another large testosterone RCT to investigate whether testosterone treatment might extend disability-free survival in older men.

• The proposed outcome of interest is disability-free survival specifically in older men.
• The review identifies gaps remaining after T-Trials, T4DM, and TRAVERSE that would justify a further large trial.
• The authors frame such a trial as necessary to address the question of broader clinical benefit beyond cardiometabolic disease prevention.