Cardiovascular and prostate cancer risk associated to testosterone replacement therapy - a systematic review and meta-analysis of 41 randomized controlled trials.

Testosterone therapy (TTh) is widely used to treat late-onset hypogonadism, aiming to improve quality of life and alleviate symptoms of testosterone deficiency. However, concerns remain regarding its potential association with major adverse cardiovascular events (MACE) and prostate cancer events (PCaE). This systematic review and meta-analysis, registered in PROSPERO (CRD42024603054) and conducted in accordance with PRISMA guidelines, evaluated the risk of MACE, PCaE, and clinically significant prostate cancer (CsPcE) associated with TTh in randomized controlled trials (RCTs). A comprehensive search of PubMed, ClinicalTrials.gov, and Cochrane Central identified 3794 records, of which 41 RCTs (n = 11,161) met inclusion criteria. Pooled odds ratios (OR) were estimated using Mantel-Haenszel or restricted maximum likelihood methods under fixed or random-effects models, based on heterogeneity. Meta-regression explored sources of heterogeneity and effect modifiers, and sensitivity analyses were performed using continuity correction for zero-event trials. TTh was not associated with a statistically significant increase in MACE (OR 0.83; 95% CI: 0.52-1.32; I² = 53.2%), PCaE (OR 0.88; 95% CI: 0.52-1.51; I² = 0.0%), or CsPcE (OR 1.13; 95% CI: 0.39-3.26; I² = 0.0%). Comorbidities contributed to heterogeneity in MACE outcomes. Current evidence supports the short- to mid-term safety of TTh, though long-term data remain necessary. Registry and the Registration No. of the study/trial: CRD42024603054.