Venous thromboembolism is a blood clot that forms in a vein deep inside a part of the body; it mainly affects the large veins in the lower leg and thigh. Blood clots have been suggested to be one of the main risks of testosterone replacement therapy. In 2014, both the US Food and Drug Administration (FDA) and Health Canada implemented a requirement for manufacturers to add a warning about the potential risks of venous thromboembolism and deep vein thrombosis to the label of all testosterone products. However, to date no comparative studies examining an association between testosterone replacement therapy (TRT) and venous thromboembolism have been reported. I am analyzing the results of a recent study published in 2015 specifically examining the risk of venous thromboembolism associated with testosterone therapy in middle-aged and older men.
- In June 2014 FDA mandated a requirement for manufacturers to add a warning about potential risks of venous thromboembolism and deep vein thrombosis to the label of all testosterone products.
- The FDA warning was based on reporting in post-marketing surveillance.
- Testosterone may have both blood clot stimulating and protective vascular effects.
- Endogenous testosterone levels are not associated with venous thromboembolism.
- A comparative study that specifically evaluated a possible link between testosterone therapy and venous thromboembolism in the general population shows no increased risk.
What is known
Research on the association between testosterone and venous thromboembolism is conflicting. Venous thromboembolism has been reported in four studies on patients with thrombophilia (a condition where the blood has an increased tendency to form clots) who received testosterone therapy. Because all the individuals experiencing venous thromboembolism were found to have previously undiagnosed thrombophilia and because the studies did not include control groups of non-testosterone users with comparable rates of underlying thrombophilia, it is not possible to determine the extent to which venous thromboembolism was associated with testosterone use versus underlying thrombophilia, or the potential interaction between testosterone therapy and thrombophilia. Development of venous thromboembolism is biologically plausible, given that testosterone therapy increases hematocrit with associated increased blood thickness and the risk of developing polycythemia. Testosterone therapy has also been known to increase circulating levels of estrogens which may play a role in thrombotic events. Because testosterone partly is converted to estrogen, it may promote blood clot formation by the same mechanism as estrogen-based therapies. However, there is also evidence that testosterone therapy may have cardio protective effects. In line with this, two large population-based studies reported that endogenous testosterone levels are not associated with venous thromboembolism.
What this study adds
This new case-control study used administrative health data from one of the largest commercial health insurance programs in the US.3 Of 30,572 middle aged and older men, it was found that having filled a prescription for testosterone replacement therapy was not associated with an increased risk of venous thromboembolism. In addition, none of the specific routes of testosterone administration examined – topical, transdermal, or intramuscular – were associated with an increased risk of venous thromboembolism. However, it should be noted that this study excluded all men who had received anticoagulant or had a diagnosis of venous thromboembolism in the previous 12 months. While this may have reduced the number of incidences of venous thromboembolism, it does remove the confounding of pre-existing prothrombotic disease, and thus makes the results more applicable to the general population. This analysis of testosterone therapy and venous thromboembolism risk addresses a public health issue that has concerned many patients and doctors. The finding that middle-aged and older men receiving testosterone therapy do not have an increased risk of venous thromboembolism is reassuring for men with testosterone deficiency considering treatment.