Risk of venous thromboembolism in men receiving testosterone therapy

July 2015

STUDY: Baillargeon J, Urban RJ, Morgentaler A, et al. Risk of Venous Thromboembolism in Men Receiving Testosterone Therapy. Mayo Clin Proc. 2015;90(8):1038-1045.

Venous thromboembolism has been suggested to be one main risk with testosterone therapy. In 2014, both the US Food and Drug Administration (FDA)1 and Health Canada2 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 therapy and venous thromboembolism have been reported. In this editorial we report the results of a recent case-control study by Baillargeon et al., which specifically examined the risk of venous thromboembolism associated with testosterone therapy in middle-aged and older men.3

KEY POINTS

  • 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 spontaneous reporting in post-marketing surveillance.
  • Testosterone may have both prothrombotic and protective endothelial 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 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 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 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.

References

  • Testosterone products: FDA/CDER statementdrisk of venous blood clots. US Food and Drug Administration website (accessed July 26, 2015) Return to content
  • Summary safety review - testosterone replacement products - cardiovascular risk. Health Canada website. https://hpr-rps.hres.ca/reg-content/summary-safety-review-detail.php?linkID=SSR00058 Published July 15, 2014. Accessed July 26, 2015. Return to content
  • Baillargeon, J., et al., Risk of Venous Thromboembolism in Men Receiving Testosterone Therapy. Mayo Clin Proc, 2015. July 15 [Epub ahead of print]. Return to content
  • Glueck, C.J. and P. Wang, Testosterone therapy, thrombosis, thrombophilia, cardiovascular events. Metabolism, 2014. 63(8): p. 989-94. Return to content
  • Glueck, C.J., et al., Testosterone therapy, thrombophilia-hypofibrinolysis, and hospitalization for deep venous thrombosis-pulmonary embolus: an exploratory, hypothesis-generating study. Clin Appl Thromb Hemost, 2014. 20(3): p. 244-9. Return to content
  • Glueck, C.J., et al., Thrombosis in three postmenopausal women receiving testosterone therapy for low libido. Womens Health (Lond Engl), 2013. 9(4): p. 405-10. Return to content
  • Glueck, C.J., et al., Thrombotic events after starting exogenous testosterone in men with previously undiagnosed familial thrombophilia. Transl Res, 2011. 158(4): p. 225-34. Return to content
  • Freedman, J., et al., Testosterone, thrombophilia, thrombosis. Transl Res, 2015. 165(5): p. 537-48. Return to content
  • LeWine, H., FDA warns about blood clot risk with testosterone products. Harvard Health Publications website. Published June 24, 2014. Accessed July 27, 2015. Return to content
  • Fernandez-Balsells, M.M., et al., Clinical review 1: Adverse effects of testosterone therapy in adult men: a systematic review and meta-analysis. J Clin Endocrinol Metab, 2010. 95(6): p. 2560−75. Return to content
  • Ajayi, A.A., R. Mathur, and P.V. Halushka, Testosterone increases human platelet thromboxane A2 receptor density and aggregation responses. Circulation, 1995. 91(11): p. 2742-7. Return to content
  • Swerdloff, R.S. and C. Wang, Three-year follow-up of androgen treatment in hypogonadal men: preliminary report with testosterone gel. Aging Male, 2003. 6(3): p. 207-11. Return to content
  • Hoibraaten, E., et al., The effects of hormone replacement therapy (HRT) on hemostatic variables in women with previous venous thromboembolism--results from a randomized, double-blind, clinical trial. Thromb Haemost, 2001. 85(5): p. 775-81. Return to content
  • Heufelder, A.E., et al., Fifty-two-week treatment with diet and exercise plus transdermal testosterone reverses the metabolic syndrome and improves glycemic control in men with newly diagnosed type 2 diabetes and subnormal plasma testosterone. J Androl, 2009. 30(6): p. 726-33. Return to content
  • Saad, F., Androgen therapy in men with testosterone deficiency: can testosterone reduce the risk of cardiovascular disease? Diabetes Metab Res Rev, 2012. 28 Suppl 2: p. 52-9. Return to content
  • Castela, A., P. Vendeira, and C. Costa, Testosterone, endothelial health, and erectile function. ISRN Endocrinol, 2011. 2011: p. 839149. Return to content
  • Kelly, D.M. and T.H. Jones, Testosterone: a vascular hormone in health and disease. J Endocrinol, 2013. 217(3): p. R47-71. Return to content
  • Holmegard, H.N., et al., Endogenous sex hormones and risk of venous thromboembolism in women and men. J Thromb Haemost, 2014. 12(3): p. 297-305. Return to content
  • Svartberg, J., et al., Endogenous sex hormone levels in men are not associated with risk of venous thromboembolism: the Tromso study. Eur J Endocrinol, 2009. 160(5): p. 833-8. Return to content