J Endocrinol Invest. 2026 Jun 27. doi: 10.1007/s40618-026-02945-w. Online ahead of print.
ABSTRACT
BACKGROUND: The cardiovascular safety of testosterone replacement therapy (TRT) in older men with hypogonadism has been debated for over a decade, largely on the basis of underpowered trials and conflicting observational data. The TRAVERSE trial, published in 2023, provided the first adequately powered, placebo-controlled evidence on this question.
OBJECTIVES: This review synthesises current evidence on the cardiovascular safety of TRT in older men, with particular attention to the interpretation of TRAVERSE findings, the clinical significance of non-MACE safety signals, and the practical management of organic versus functional hypogonadism.
METHODS: A systematic search of PubMed/MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials (CENTRAL) was conducted through March 2026. Approximately 450 articles were identified; 64 met the inclusion criteria and were selected for review. Evidence was appraised according to study design, with RCTs and meta-analyses weighted above observational data.
RESULTS: TRAVERSE demonstrated non-inferiority of TRT versus placebo for major adverse cardiovascular events (MACE) in men with confirmed hypogonadism and elevated cardiovascular risk (HR 0.96, 95% CI 0.78-1.17) [5]. Non-MACE signals – including atrial fibrillation (3.1% vs. 2.4%), pulmonary embolism (2.0% vs. 1.5%), and acute kidney injury (2.3% vs. 1.5%) – were numerically higher in the TRT arm but did not reach statistical significance within the trial. In contrast, large observational cohorts consistently report statistically significant associations between TRT and AF and VTE. Erythrocytosis was the most reproducible adverse effect (17.0% vs. 3.3%, p < 0.001). Functional hypogonadism secondary to obesity or metabolic syndrome responds to lifestyle intervention and GLP-1/GIP agonists, with testosterone normalisation in 81.4% at 6 months and 89.5% at 24 months after bariatric surgery [45].
CONCLUSIONS: TRT does not increase MACE risk in men with confirmed organic hypogonadism when titrated to physiological levels. Non-MACE signals warrant vigilance rather than contraindication. Metabolic optimisation should precede TRT in functional hypogonadism. Individualised monitoring and careful patient selection remain essential.
PMID:42364061 | DOI:10.1007/s40618-026-02945-w
