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 high rates of underlying familial and acquired thrombophilia who received testosterone therapy.4-7 Notably, two of these studies included women.4,6 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. It has been reported in another study that testosterone replacement therapy interacts with thrombophilia to increase the risk of venous thromboembolism.8 However, the June 2014 FDA warning was based on post-marketing surveillance of reports of venous thromboembolism in men without polycythemia.9
Development of venous thromboembolism is biologically plausible, given that testosterone therapy increases hematocrit with associated increased blood viscosity4,5, platelet aggregation5,10, and the risk of developing polycythemia.4,5,10,11 Testosterone therapy also increases circulating levels of estrogens4,12 that may play a role in thrombotic events.13 Because testosterone is converted by aromatization to estradiol, it may be prothrombotic by the same mechanism as estrogen-based therapies. However, there is also evidence that testosterone therapy may have protective endothelial effects.14-17 In line with this, two large population-based studies reported that endogenous testosterone levels are not associated with venous thromboembolism.18,19
What this study adds
This case-control study by Baillargeon et al. used administrative health data from the Clinformatics Data Mart (CDM; OptumInsight), a database of 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.
The strengths of the study by Baillargeon et al. are the large representative sample, matching based on sociodemographic and disease risk factors, simultaneous adjustment for potentially confounding medical conditions and medications, and assessment of multiple exposure windows.3
This large general population-based comparative analysis of testosterone and venous thromboembolism risk addresses a public health issue that has concerned many patients and physicians. 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, as well as for practicing physicians.