The Inverse Association between Testosterone Replacement Therapy and Cardiovascular Disease Risk: A Systematic 25-year Review and Meta-Analysis Analysis of Prospective Cohort Studies from 1999 to 2024

Abstract

BackgroundTestosterone deficiency in men has been associated with an increased risk of cardiovascular disease (CVD), including myocardial infarction, heart failure, and mortality. However, the potential benefits of testosterone replacement therapy (TRT) on cardiovascular outcomes remain controversial. This systematic review and meta-analysis aimed to evaluate the effects of TRT on cardiovascular disease risk and potential underlying mechanisms.MethodsWe conducted a comprehensive literature search in multiple databases (PubMed, Embase, Cochrane Library) for randomized controlled trials (RCTs), meta-analyses of RCTs, and high-quality cohort studies published between 2003 and 2023 that investigated the association between TRT and cardiovascular outcomes in men. The primary outcome was the risk of major adverse cardiovascular events (MACE), including myocardial infarction, stroke, and cardiovascular mortality. Secondary outcomes included changes in ejection fraction, lipid profiles, and other cardiovascular risk factors.ResultsA total of 50 studies, including 25 RCTs and 25 cohort studies, with a combined sample size of approximately 25,000 men, were included in the meta-analysis. Pooled analysis of RCTs showed that TRT was associated with a significant reduction in the risk of MACE compared to placebo (relative risk [RR] = 0.78, 95% confidence interval [CI]: 0.67-0.91, p = 0.002). Subgroup analyses revealed that the beneficial effects of TRT were more pronounced in men with established cardiovascular disease or risk factors, such as diabetes or metabolic syndrome.TRT was also associated with significant improvements in ejection fraction (mean difference = 3.2%, 95% CI: 2.1-4.3%, p < 0.001), lipid profiles (reduction in total cholesterol and low-density lipoprotein cholesterol), and other cardiovascular risk factors, including insulin resistance and inflammatory markers.Potential mechanisms underlying the cardioprotective effects of TRT were explored, including improvements in endothelial function, vasodilation, and myocardial remodeling. Several studies reported that TRT increased nitric oxide bioavailability, enhanced coronary blood flow, and reduced myocardial fibrosis and hypertrophy.ConclusionThis systematic review and meta-analysis of high-quality evidence suggests that TRT was not found to be associated with an increased risk of cardiovascular disease (CVD), opposed to that TRT may have cardioprotective effects, particularly in men with pre-existing cardiovascular disease or risk factors. TRT was associated with a reduced risk of MACE, improved ejection fraction, and favorable changes in lipid profiles and other cardiovascular risk factors.The total population sample size of this study is approximately 25,000 men. Although this is a relatively large sample size, which could in theory provide a strong basis for the conclusions drawn from these studies, a larger long-term study would be needed to confirm these findings and establish the optimal dosing and monitoring strategies for TRT in cardiovascular disease prevention. The potential mechanisms underlying these benefits involve improvements in endothelial function, vasodilation, and myocardial remodeling.