The Inverse Association between Testosterone Replacement Therapy and Cardiovascular Disease Risk: A Systematic 10 year Review and Meta-Analysis Analysis of Prospective Cohort Studies from 2003-2023

Abstract Background Testosterone deficiency in men has historically been associated with an increased risk of cardiovascular disease (CVD), including myocardial infarction, heart failure, and mortality. The potential benefits of testosterone replacement therapy (TRT) on cardiovascular outcomes remain controversial. This systematic review and meta-analysis aimed to investigate if there could be potential benefits of TRT on cardiovascular disease risk and, if so, uncover the underlying mechanisms. Methods A comprehensive literature search for Level A evidence in multiple databases (PubMed, Embase, Cochrane Library) was conducted, including randomized controlled trials (RCTs), systematic reviews, meta-analyses, cohort studies, review articles and experimental studies published between 1999 and 2024 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, side effects, and other cardiovascular risk factors. Results From 3,727 records identified using the selected criteria, a total of 51 studies were selected for the meta-analysis, comprising 4 RCTs, 9 cohort studies, 6 experimental studies, 23 review articles, 4 systematic reviews, and 5 meta-analyses, with a combined sample size of approximately 3,134,054 men. The findings from the meta-analysis suggests an 18% reduction in the risk of cardiovascular events among men receiving TRT compared to those receiving a placebo. TRT was found to be associated with significant improvements in ejection fraction, 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 include improvements in endothelial function, vasodilation, and myocardial remodeling. 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. Conclusion This systematic review and meta-analysis of high-quality evidence suggest that testosterone deficiency is associated with an increased risk of cardiovascular disease. Conversely, TRT is associated with a reduced risk of cardiovascular events, particularly in men with pre-existing cardiovascular disease or risk factors. TRT was linked to a reduced risk of MACE, improved ejection fraction, and favorable changes in lipid profiles and other cardiovascular risk factors. Despite the relatively large sample size, further long-term studies are needed to confirm these findings and establish optimal dosing and monitoring strategies for TRT in cardiovascular disease prevention.