Testosterone replacement therapy and vascular thromboembolic events: a systematic review and meta-analysis

Abstract

To evaluate the relationship between testosterone replacement therapy (TRT) and arterial and/or venous thrombosis in patients with pre-treatment total testosterone (TT) <12 nmol l−1, we performed a meta-analysis following the Population Intervention Comparison Outcome model. Population: men with TT <12 nmol l−1 or clear mention of hypogonadism in the inclusion criteria of patients; intervention: TRT; comparison: placebo or no therapy; outcomes: arterial thrombotic events (stroke, myocardial infarction [MI], upper limbs, and lower limbs), VTE (deep vein thrombosis [DVT], portal vein thrombosis, splenic thrombosis, and pulmonary embolism), and mortality. A total of 2423 abstracts were assessed for eligibility. Twenty-four studies, including 14 randomized controlled trials (RCTs), were finally included, with a total of 4027 and 310 288 hypotestosteronemic male patients, from RCTs and from observational studies, respectively. Based on RCT-derived data, TRT did not influence the risk of arterial thrombosis (odds ratio [OR] = 1.27, 95% confidence interval [CI]: 0.47–3.43, P = 0.64), stroke (OR = 1.34, 95% CI: 0.09–18.97, P = 0.83), MI (OR = 0.51, 95% CI: 0.11–2.31, P = 0.39), VTE (OR = 1.42, 95% CI: 0.22–9.03, P = 0.71), pulmonary embolism (OR = 1.38, 95% CI: 0.27–7.04, P = 0.70), and mortality (OR = 0.70, 95% CI: 0.20–2.38, P = 0.56). Meanwhile, when only observational studies are considered, a significant reduction in the risk of developing arterial thrombotic events, MI, venous thromboembolism, and mortality was observed. The risk for DVT remains uncertain, due to the paucity of RCT-based data. TRT in men with TT <12 nmol l−1 is safe from the risk of adverse cardiovascular events. Further studies specifically assessing the risk of DVT in men on TRT are needed.

Testosterone Therapy as an Isolated Risk Factor for Venous Thrombosis: A Case Report

“…Prior research from the 1990s has shown that androgens can increase the human platelet thromboxane A2 receptor density and formation [ 6 ]. In January 2014, the Food and Drug Administration issued a warning regarding the use of TRT due to the increased risk of stroke and myocardial infarction [ 7 , 8 ]. The Harvard Medical School issued a statement directly citing an increased risk for blood clots when using testosterone replacement therapy for low levels [ 8 ].…”

“…More recent studies using meta-analysis on men with low testosterone levels who used TRT found that the observational data did not show a correlation; however, the review showed a need for more research as the analysis showed a lack of randomized controlled data [ 7 ]. Most recently, the TRAVERSE trial showed that TRT in men with hypogonadism with preexisting cardiovascular risk was non-inferior to a placebo [ 13 ].…”

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

“…In men with type 2 diabetes and hypogonadism TRT resulted in a decrease in left ventricular mass and improvement in diastolic function [25] . The potential mechanisms underlying these effects on myocardial remodeling may involve the modulation of various signaling pathways, including the RAAS, transforming growth factor-beta (TGF-β), and matrix metalloproteinases (MMPs) [22,24], leading to a reduction in angiotensin II levels and subsequent improvements in endothelial function, vasodilation, and myocardial remodeling [22,23].…”

“…• No Increased Risk: Multiple studies, including systematic reviews and meta-analyses, concluded that TRT was not linked to an increased risk of thromboembolic events ( [25,31]).…”

“…Strengths and Limitations: This systematic review and meta-analysis has several strengths, including the comprehensive literature search, the inclusion of high-quality evidence from RCTs and cohort studies, and the large combined sample size of approximately 3,134,054 participants . Additionally, the assessment of potential mechanisms underlying the cardioprotective effects of TRT provides valuable insights into the underlying biological processes [16][17][18][19][20][21][24][25][26].…”