Testosterone Replacement Therapy in Men With Prostate Cancer on Active Surveillance: A Systematic Review of Oncological Safety

BACKGROUND: Up to 20% of men on active surveillance (AS) for prostate cancer (PCa) have symptomatic hypogonadism; the oncological safety of testosterone replacement therapy (TRT) in this population is uncertain. OBJECTIVES: To systematically evaluate the oncological safety of TRT in men with histologically confirmed PCa managed by AS. MATERIALS AND METHODS: PubMed, Embase, and CENTRAL were searched up to January 2026 (PRISMA 2020). Eligible studies enrolled men with PCa on AS receiving TRT for ≥ 12 months. Primary outcomes were biopsy progression, treatment conversion, metastasis, and PCa-specific mortality. Risk of bias was assessed using a modified Newcastle-Ottawa Scale. RESULTS: Seven observational studies (2011-2025; 295 TRT-treated men; 6826 non-TRT AS comparators; follow-up 2.3-6.1 years) were included. No PCa-specific deaths or metastatic events were reported among TRT recipients. The single controlled biopsy comparison showed comparable Gleason upgrading (10.7% TRT vs. 9.4% comparators; p = 0.732) and no significant difference in biopsy progression (32.1% vs. 44.7%; p = 0.280). The largest population-based study reported lower treatment conversion versus non-TRT AS controls (16.8% vs. 21.9%; adjusted HR 0.66, 95% CI 0.46-0.97), most plausibly reflecting selection bias. PSA remained stable despite two- to threefold testosterone increases and correlated poorly with histological progression. DISCUSSION: Short- to intermediate-term observational evidence does not demonstrate increased oncological risk with TRT in the predominantly low-risk populations studied. However, retrospective design, small samples, group imbalance, heterogeneous surveillance, and short follow-up relative to AS natural history substantially limit these findings. CONCLUSION: TRT may be cautiously considered in selected hypogonadal men on AS through shared decision-making; prospective studies with standardised surveillance and extended follow-up are required before broader recommendations.