Results Of the UK Biobank participants, 13 691 had thromboembolism (6208 men, 7483 women), 1688 had heart failure (1186, 502), and 12 882 had myocardial infarction (10 136, 2746). In men, endogenous testosterone genetically predicted by variants in the JMJD1C gene region was positively associated with thromboembolism (odds ratio per unit increase in log transformed testosterone (nmol/L) 2.09, 95% confidence interval 1.27 to 3.46) and heart failure (7.81, 2.56 to 23.8), but not myocardial infarction (1.17, 0.78 to 1.75). Associations were less obvious in women. In the validation study, genetically predicted testosterone (based on JMJD1C gene region variants) was positively associated with myocardial infarction (1.37, 1.03 to 1.82). No excess heterogeneity was observed among genetic variants in their associations with the outcomes. However, testosterone genetically predicted by potentially pleiotropic variants in the SHBG gene region had no association with the outcomes.

Introduction

Testosterone sales increased 12-fold globally from 2000 to 2011,1 with noticeable increases in North America.1 In the United States, older men have probably been targeted in addition to men requiring medically indicated treatment for low testosterone levels.12 Testosterone replacement therapy (TRT) prescriptions in the US decreased by 50% between 2013 and 2016,3 but remain well above the levels needed to treat pathological hypogonadism.4 Since the 1970s, use of anabolic steroids has spread from athletes to the general population,5 with a lifetime prevalence rate of 6.4% for men.6

Observational studies of the association of measured endogenous testosterone with overall and specific cardiovascular diseases, including thromboembolism,789 myocardial infarction,10 and heart failure,11 are difficult to interpret.12131415 These studies are inherently open to confounding by obesity and ill health, which could reduce testosterone1617 and are well established causes of cardiovascular diseases.1819 Therefore, it is unclear from observational studies whether testosterone has a role or is an indicator of poor general health,17 particularly because testosterone might be affected by some cardioprotective treatments.20 Pharmacoepidemiology studies of drugs are open to subtle time related biases, such as immortal time bias,21 which are not always taken into consideration in studies of TRT.22 Studies of TRT using self comparisons to avoid confounding and time related biases have suggested that TRT could increase myocardial infarction23 and possibly cardiovascular events.24 Randomised placebo controlled trials of TRT are limited in size and scale. Therefore, systematic reviews and meta-analyses of randomised controlled trials are usually too small to be definitive overall or for any specific types of cardiovascular disease,25 although adverse effects of TRT on thromboembolism have been found.26 Recent Endocrine Society clinical practice guidelines recommend against TRT in men with stroke, myocardial infarction, or thrombophilia.27 To our knowledge, the new TRAVERSE trial (study to evaluate the effect of TRT on the incidence of major adverse cardiovascular events and efficacy measures in men with hypogonadism; clinicaltrials.gov, NCT03518034) is the first TRT trial with adequate power to assess cardiovascular events. The trial is designed to evaluate major adverse cardiac events (non-fatal myocardial infarction, non-fatal stroke, or death due to cardiovascular causes) in 6000 men over five years; it is unlikely to provide definitive evidence about specific cardiovascular diseases and will take several years to complete.

When the role of TRT is hotly debated but experimental evidence is limited, mendelian randomisation using genetic variants as instrumental variables can support causal inferences about the effects of modifiable risk factors.282930 Mendelian randomisation is less susceptible to confounding than traditional observational studies because genetic variants are randomly allocated at conception. Therefore, mendelian randomisation is at the interface of experimental and observational studies,30 and can be used to obtain evidence in support of a potential causal effect or of potential targets of interventions.30 However, mendelian randomisation studies give the effects of lifetime exposures and so the numerical effect estimates provide a guide rather than the exact level of an intervention required.30 A previous adequately powered mendelian randomisation study found preliminary evidence that endogenous testosterone is detrimental for ischaemic heart disease and ischaemic stroke, especially in men.31 To clarify the role of testosterone in other types of cardiovascular disease, which might have different causes,32 we assessed the effect of endogenous testosterone on additional cardiovascular conditions in the UK Biobank participants: thromboembolism because of evidence from randomised controlled trials and specific warnings by the US Food and Drug Administration and Health Canada,333435 heart failure because it can be a sequela of heart attack; and myocardial infarction for specificity. We validated our findings, when possible, using publicly available consortiums. We also considered whether the associations of genetic predictors of endogenous testosterone with the cardiovascular diseases studied varied by sex because men have higher levels of endogenous testosterone than women.