Is clinical prescription of testosterone therapy associated with short-term risk of venous thromboembolism in men with and without hypogonadism?

In this case-crossover study comparing 6-month testosterone use for 39,622 men who had a venous thromboembolism with testosterone use 6 to 12 months before the venous thromboembolism, use of testosterone therapy in the 6-month case period was associated with an increased risk of venous thromboembolism among men with and without hypogonadism.

The findings suggest that testosterone therapy is associated with increased short-term risk of venous thrombo-embolism among all men prescribed the therapy

The clinical indication for testosterone therapy is primarily to treat hypogonadism, a condition in which serum testosterone levels in men decrease below a specific threshold, resulting in sexual dysfunction, altered bone metabolism and body composition, and potential emotional dysregulation. Although testosterone levels may decrease with age, external causes of clinical hypogonadism include genetic diseases or complications from surgery, infection, and medications. Testosterone prescriptions among men increased more than 300% from 2001 to 20135,6; the increase is thought to be caused by testosterone therapy being prescribed for common symptoms, such as low libido and fat redistribution, associated with ageing, obesity, and diabetes and not necessarily with clinical hypogonadism. This increase in prescription rate was more pronounced among men aged 18 to 45 years than among older men. In 2014, the US Food and Drug Administration released a warning about testosterone therapy and the potential risk of heart attack and stroke; since then, testosterone therapy prescriptions have decreased and eventually plateaued. Recent trends estimate that, in the United States, 2.3 million men older than 30 years (3.2%) were prescribed testosterone therapy in 2013 and that this trend decreased to approximately 1.15 million men (1.6%) in 2016. Evidence suggests that testosterone therapy is still being prescribed to men without hypogonadism.

Venous thromboembolism (VTE), consisting of deep vein thrombosis and pulmonary embolism, is a common condition in the United States, with more than 1 million individuals experiencing a VTE annually. Baseline testosterone levels are not associated with increase in VTE risk. However, exogenous testosterone therapy may increase endogenous hematocrit levels, which can increase blood viscosity, platelet accumulation, and thromboxane A2 concentrations for up to 6 months and could subsequently increase risk of blood clot formation and subsequent VTE events. Testosterone therapy is most commonly administered via transdermal gels, patches, or intramuscular routes, each having their own rate of absorption and prescription strengths that potentially affect cardiovascular pathophysiologic factors. Pathophysiologic research suggests that exogenous testosterone therapy could increase VTE risk, but the 2 largest observational studies evaluating this association reached conflicting conclusions. Furthermore, these studies were underpowered to examine testosterone therapy use within important clinical subgroups, such as by clinical hypogonadism status, age, route of testosterone therapy exposure, and duration of testosterone therapy use.

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