Risk of Blood Clots in Men Receiving Testosterone Therapy

Risk of Blood Clots in Men Receiving Testosterone Therapy

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 clot formation (venous thromboembolism) has been suggested to be one main risk with testosterone replacement 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 replacement therapy and venous thromboembolism have been reported. Here we report the results of a recent case-control study – published July 20, 2015 - that 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 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.4-7 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 thickness4,5, and the risk of developing polycythemia.4,5,8,9 Testosterone therapy also increases circulating levels of estrogens4,10 that may play a role in thrombotic events.11 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 protective vascular effects.12-15 In line with this, two large population-based studies reported that endogenous testosterone levels are not associated with venous thromboembolism.16,17

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.

References

1. Testosterone products: FDA/CDER statementdrisk of venous blood clots. US Food and Drug Administration website. http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm402054.htm Published June 20, 2014. Accessed July 26, 2015.
2. Summary safety review - testosterone replacement products - cardiovascular risk. Health Canada website. http://www.hc-sc.gc.ca/dhp-mps/medeff/reviews-examens/testosterone-eng.php Published July 15, 2014. Accessed July 26, 2015.
3. Baillargeon J, Urban RJ, Morgentaler A, et al. Risk of Venous Thromboembolism in Men Receiving Testosterone Therapy. Mayo Clin. Proc. 2015;July 15 [Epub ahead of print].
4. Glueck CJ, Wang P. Testosterone therapy, thrombosis, thrombophilia, cardiovascular events. Metabolism. 2014;63(8):989-994.
5. Glueck CJ, Richardson-Royer C, Schultz R, et al. Testosterone therapy, thrombophilia-hypofibrinolysis, and hospitalization for deep venous thrombosis-pulmonary embolus: an exploratory, hypothesis-generating study. Clinical and applied thrombosis/hemostasis : official journal of the International Academy of Clinical and Applied Thrombosis/Hemostasis. 2014;20(3):244-249.
6. Glueck CJ, Bowe D, Valdez A, Wang P. Thrombosis in three postmenopausal women receiving testosterone therapy for low libido. Womens Health (Lond Engl). 2013;9(4):405-410.
7. Glueck CJ, Goldenberg N, Budhani S, et al. Thrombotic events after starting exogenous testosterone in men with previously undiagnosed familial thrombophilia. Translational research : the journal of laboratory and clinical medicine. 2011;158(4):225-234.
8. Fernandez-Balsells MM, Murad MH, Lane 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):2560-2575.
9. Ajayi AA, Mathur R, Halushka PV. Testosterone increases human platelet thromboxane A2 receptor density and aggregation responses. Circulation. 1995;91(11):2742-2747.
10. Swerdloff RS, Wang C. Three-year follow-up of androgen treatment in hypogonadal men: preliminary report with testosterone gel. The aging male : the official journal of the International Society for the Study of the Aging Male. 2003;6(3):207-211.
11. Hoibraaten E, Qvigstad E, Andersen TO, Mowinckel MC, Sandset PM. 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):775-781.
12. Heufelder AE, Saad F, Bunck MC, Gooren L. 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):726-733.
13. Saad F. Androgen therapy in men with testosterone deficiency: can testosterone reduce the risk of cardiovascular disease? Diabetes. Metab. Res. Rev. 2012;28 Suppl 2:52-59.
14. Castela A, Vendeira P, Costa C. Testosterone, endothelial health, and erectile function. ISRN endocrinology. 2011;2011:839149.
15. Kelly DM, Jones TH. Testosterone: a vascular hormone in health and disease. J. Endocrinol. 2013;217(3):R47-71.
16. Holmegard HN, Nordestgaard BG, Schnohr P, Tybjaerg-Hansen A, Benn M. Endogenous sex hormones and risk of venous thromboembolism in women and men. Journal of thrombosis and haemostasis : JTH. 2014;12(3):297-305.
17. Svartberg J, Braekkan SK, Laughlin GA, Hansen JB. Endogenous sex hormone levels in men are not associated with risk of venous thromboembolism: the Tromso study. Eur. J. Endocrinol. 2009;160(5):833-838.
Last updated: 2017
G.GM.MH.04.2015.0334