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Background Testosterone treatment is common in men, although risks for major cardiovascular events are unclear. Methods and Results A study was conducted in US male veterans, aged ≥40 years, with low serum testosterone and multiple medical comorbidities and without history of myocardial infarction, stroke, venous thromboembolism, prostate cancer, or testosterone treatment in the prior year. For the primary outcome, we examined if testosterone treatment was associated with a composite cardiovascular outcome (incident myocardial infarction, ischemic stroke, or venous thromboembolism). Testosterone use was modeled as intramuscular or transdermal and as current use, former use, and no use. Current testosterone users were compared with former users to reduce confounding by indication. The cohort consisted of 204 857 men with a mean (SD) age of 60.9 (9.9) years and 4.7 (3.5) chronic medical conditions. During follow‐up of 4.3 (2.8) years, 12 645 composite cardiovascular events occurred. In adjusted Cox regression analyses, current use of transdermal testosterone was not associated with risk for the composite cardiovascular outcome (hazard ratio [HR], 0.89; 95% CI, 0.76–1.05) in those without prevalent cardiovascular disease, and in those with prevalent cardiovascular disease was associated with lower risk (HR, 0.80; 95% CI, 0.70–0.91). In similar analyses, current use of intramuscular testosterone was not associated with risk for the composite cardiovascular outcome in men without or with prevalent cardiovascular disease (HR, 0.91; 95% CI, 0.80–1.04; HR, 0.98; 95% CI, 0.89–1.09, respectively). Conclusions In a large cohort of men without a history of myocardial infarction, stroke, or venous thromboembolism, testosterone treatment was not associated with increased risk for incident composite cardiovascular events.

Introduction This study aims to clarify the role(s) of endogenous sex hormones to influence health outcomes in men, specifically to define the associations of plasma testosterone with incidence of cardiovascular events, cancer, dementia and mortality risk, and to identify factors predicting testosterone concentrations. Data will be accrued from at least three Australian, two European and four North American population-based cohorts involving approximately 20 000 men.Methods and analysis Eligible studies include prospective cohort studies with baseline testosterone concentrations measured using mass spectrometry and 5 years of follow-up data on incident cardiovascular events, mortality, cancer diagnoses or deaths, new-onset dementia or decline in cognitive function recorded. Data for men, who were not taking androgens or drugs suppressing testosterone production, metabolism or action; and had no prior orchidectomy, are eligible. Systematic literature searches were conducted from 14 June 2019 to 31 December 2019, with no date range set for searches. Aggregate level data will be sought where individual participant data (IPD) are not available. One-stage IPD random-effects meta-analyses will be performed, using linear mixed models, generalised linear mixed models and either stratified or frailty-augmented Cox regression models. Heterogeneity in estimates from different studies will be quantified and bias investigated using funnel plots. Effect size estimates will be presented in forest plots and non-negligible heterogeneity and bias investigated using subgroup or meta-regression analyses.Ethics and dissemination Ethics approvals obtained for each of the participating cohorts state that participants have consented to have their data collected and used for research purposes. The Androgens In Men Study has been assessed as exempt from ethics review by the Human Ethics office at the University of Western Australia (file reference number RA/4/20/5014). Each of the component studies had obtained ethics approvals; please refer to respective component studies for details. Research findings will be disseminated to the scientific and broader community via the publication of four research articles, with each involving a separate set of IPD meta-analyses (articles will investigate different, distinct outcomes), at scientific conferences and meetings of relevant professional societies. Collaborating cohort studies will disseminate findings to study participants and local communities.PROSPERO registration number CRD42019139668.

Over the past decade, there has been a substantial increase in the number of men who are treated with testosterone. Despite this increase in the use of testosterone, the risks of adverse cardiovascular events are unclear as meta-analyses have reported conflicting findings and no clinical studies have been large enough or long enough to adequately assess for cardiovascular risks. The goal of this paper is to review large prescription database studies of testosterone treatment and adverse cardiovascular events and mortality with the aim of providing some guidance for clinicians and researchers in this controversial area.

PURPOSE:Testosterone treatment of men with low testosterone is common and, although relatively short-term, has raised concern regarding an increased risk of prostate cancer (CaP). We investigated the association between modest-duration testosterone treatment and incident aggressive CaP. MATERIALS AND METHODS:Retrospective inception cohort study of male Veterans aged 40 to 89 years with a laboratory-defined low testosterone measurement from 2002 to 2011 and recent prostate specific antigen (PSA) testing; excluding those with recent testosterone treatment, prostate or breast cancer, high PSA or prior prostate biopsy. Histologically-confirmed incident aggressive prostate cancer or any prostate cancer were the primary and secondary outcomes, respectively. RESULTS:Of the 147,593 men included, 58,617 were treated with testosterone. 313 aggressive CaPs were diagnosed, 190 among untreated men (incidence rate (IR) 0.57 per 1000 person years, 95% CI 0.49-0.65) and 123 among treated men (IR 0.58 per 1000 person years; 95% CI 0.48-0.69). After adjusting for age, race, hospitalization during year prior to cohort entry, geography, BMI, medical comorbidities, repeated testosterone and PSA testing, testosterone treatment was not associated with incident aggressive CaP (HR 0.89; 95% CI 0.70-1.13) or any CaP (HR 0.90; 95% CI 0.81-1.01). No association between cumulative testosterone dose or formulation and CaP was observed. CONCLUSIONS:Among men with low testosterone levels and normal PSA, testosterone treatment was not associated with an increased risk of aggressive or any CaP. The clinical risks and benefits of testosterone treatment can only be fully addressed by large, longer-term randomized controlled trials.