Thromboembolic Risk and Testosterone Replacement Therapy: Debunking Myths and Clarifying Evidence with Recent Systematic Reviews and Meta-Analyses

Abstract

Objectives: To critically evaluate the relationship between testosterone replacement therapy (TRT) and thromboembolic events, addressing concerns raised by older studies while focusing on recent robust evidence. This review analyzes the methodological limitations of earlier studies and presents new, high-quality evidence that refutes these claims. Additionally, we assess the implications of different TRT formulations, patient-specific risk factors, and long-term coagulation effects.

Methods: A systematic review and meta-analysis were conducted, analyzing randomized controlled trials (RCTs) and cohort studies from 2000 to August 2024. The search strategy included PubMed, Embase, and the Cochrane Library, using combinations of terms such as “testosterone replacement therapy,” “thromboembolism,” “cardiovascular events,” “venous thromboembolism (VTE),” “deep vein thrombosis (DVT),” and “pulmonary embolism (PE).” Both earlier studies suggesting increased risk and newer studies refuting these concerns were included. Study quality was assessed using standardized risk of bias tools. Heterogeneity across studies was evaluated using the I² statistic, with subgroup analyses based on TRT formulations, follow-up duration, and patient age.

Findings: Recent meta-analyses and large-scale cohort studies demonstrate that TRT does not significantly increase the risk of thromboembolic events. The pooled relative risk (RR) for major adverse cardiovascular events (MACE) was 1.08 (95% CI: 0.89–1.31, p = 0.46), indicating no statistically significant increase in thromboembolic risk. Sensitivity analyses confirmed the robustness of these findings, and no significant differences were observed between TRT formulations (injections, gels, transdermal patches). However, a wide confidence interval suggests that a clinically relevant increased risk cannot be entirely ruled out, warranting careful patient selection and monitoring. The inconsistencies in previous studies are addressed, considering selection bias, short follow-up periods, heterogeneity in study designs, and lack of adjustment for confounders such as obesity, smoking, and pre-existing cardiovascular disease.

Conclusion: When prescribed appropriately and monitored regularly, TRT does not significantly elevate thromboembolic or cardiovascular risk. Earlier concerns about an increased risk of thromboembolic events were based on studies with methodological limitations, including biased patient selection and inadequate control for confounding variables. However, long-term data on the effects of TRT on thrombin generation and coagulation profiles remain limited, and further research is warranted. Clinicians should feel confident prescribing TRT in hypogonadal men, provided that individualized patient assessments, hematocrit monitoring, and cardiovascular risk evaluations are conducted.