Reassurance about the safety, and likely benefit, of testosterone replacement therapy for men with hypogonadism

Fallara et al., 2022. Cardiovascular morbidity and mortality in men – findings from a meta-analysis on the time-related measure of risk of exogenous testosterone. Journal of Sexual Medicine
 

Testosterone replacement therapy for hypogonadal men is important for maintaining the health and quality of life of affected men. However, there has been some uncertainty about the potential harm of long-term testosterone replacement therapy because of reports suggesting an increase in cardiovascular risk.

The problem with the evidence relating to the safety of testosterone replacement therapy for hypogonadal men is that studies are small and underpowered, and most meta-analyses employ measures that do not consider a potential temporal effect of therapy on outcomes.

A new meta-analysis of 10 (mostly retrospective) studies, in which testosterone replacement therapy was compared to placebo or observation alone using time-related measures of risk (i.e. Hazard ratios), contains data about mortality and cardiovascular events from 179,631 subjects¹.

The meta-analysis finds no effect of testosterone replacement therapy on cardiovascular events (new-onset hypertension, myocardial infarction, heart failure, stroke or death from cardiovascular cause), thus demonstrating safety of the treatment for hypogonadal men.

Testosterone replacement therapy protected against all-cause mortality (pooled hazard ratio 0.70; 95% confidence interval 0.54-0.90, p<0.01). In a subset of men, for whom normalization of circulating testosterone levels was confirmed, a similar level of protection was observed (pooled hazard ratio 0.65; 95% confidence interval 0.44-0.97, p<0.01).

The results of this recent meta-analysis are consistent with observations that hypogonadism increases the risk of mortality in men.

The quality of meta-analyses is limited by that of their constituent studies. In this case, variations in definitions of hypogonadism, treatment modality (route, dose, duration) and the duration of follow-up are limitations. This current meta-analysis adds support to existing evidence that suggests the treatment is beneficial and safe for hypogonadal men.