New Research Links Testosterone to Risk of Dangerous Blood Clots

One of the many documented dangers of testosterone products (see table below) is an increased risk of developing blood clots in large veins, most often in the legs. These clots can break off, move to the lungs and block blood vessels there, which can be fatal. Such blood clots collectively are known as venous thromboembolism.

Testosterone Products Available in the U.S.*

*All of these products are Limited Use.

In 2014, the Food and Drug Administration (FDA) required manufacturers of all approved testosterone products to include a general warning on the product labeling about the risk of developing venous blood clots.[1] The warning states that there have been reports of venous blood clots in patients using testosterone products and that the drugs should be discontinued in patients suspected of having such adverse events.[2]

Since the FDA’s action in 2014, studies evaluating the risk of blood clots with testosterone use have yielded conflicting results. One study that analyzed data from three small randomized clinical trials of testosterone found a nearly sixfold increased risk of venous blood clots in subjects receiving testosterone compared to control subjects.[3] In contrast, two observational studies of patients using testosterone found no increased risk.[4],[5] Importantly, neither of these observational studies examined the timing and duration of testosterone use, which could have masked an increased risk of blood clots soon after the start of treatment.[6]

A well-designed observational study published in November 2016 in the British medical journal BMJ was the first to examine the effect of timing and duration of testosterone treatment on the risk of venous blood clots. The study demonstrated that patients using testosterone products had a significantly increased risk of venous blood clots during the first six months of therapy, but that risk subsequently tapered off.

The BMJ study[7]

Using a database of detailed electronic medical and pharmacy records available for more than 98 percent of people living in the UK, the researchers identified all men ages 20-89 from January 2001 to May 2013. Out of a population of 2.9 million men in the database, the researchers found 19,246 who had a confirmed new diagnosis of venous blood clots during the study period. Of these, 44 percent had been diagnosed with clots in large veins and 56 percent with clots in the lungs.

The researchers then compared these 19,246 patients to more than 900,000 control patients who had not been diagnosed with venous blood clots. These control patients were similar to the venous blood clot patients in terms of age, underlying medical conditions and numerous factors known to increase the risk of thromboembolism. The researchers then assessed the use of testosterone products in both patient groups, taking into account the duration of use and the reasons for using testosterone.

The researchers found that current use of testosterone overall was associated with a 25 percent increase in the risk of venous blood clots compared to no testosterone use, but this finding was not statistically significant. The period of greatest risk was the first six months of testosterone use, when there was a statistically significant 63 percent increase in the risk of venous blood clots compared to patients not using testosterone. This translated to an estimated 10 additional cases of venous blood clots for every 10,000 patients treated with testosterone per year.

Using mathematical modeling, the researchers estimated that the risk of venous blood clots peaked at about three months after starting testosterone and then declined gradually thereafter, reaching the same level as prior to treatment within two years.

Of note, a 2014 study similarly found that there was an increased risk of heart attacks during the first three months after starting testosterone therapy.[8]

The exact mechanism by which testosterone drugs increase the risk of venous blood clots — and heart attacks — is unknown. However, testosterone treatment has been shown to increase red blood cell counts,[9],[10] blood viscosity,[11] and the tendency of platelets to stick together,[12] all of which could predispose patients to venous thromboembolism and heart attacks.

References

[1] Food and Drug Administration. FDA adding general warning to testosterone products about potential for venous blood clots. June 19, 2014. http://www.fda.gov/Drugs/DrugSafety/ucm401746.htm? source=govdelivery&utm_medium=email&utm_source=govdelivery. Accessed January 15, 2017.

[2] AbbVie. Label: ANDROGEL (testosterone gel). October 2016. https://dailymed.nlm.nih.gov/dailymed/getFile.cfm?setid=8677ba5b-8374- 46cb-854c-403972e9ddf3&type=pdf&name=8677ba5b-8374-46cb-854c-403972e9ddf3. Accessed January 15, 2017.

[3] Xu L, Schooling CM. Differential risks in men and women for first and recurrent venous thrombosis: The role of genes and environment: Comment. J Thromb Haemost. 2015;13(5):884-886.

[4] Sharma R, Oni OA, Chen G, et al. Association between testosterone replacement therapy and the incidence of DVT and pulmonary embolism: A retrospective cohort study of the Veterans Administration Database. Chest. 2016;150(3):563-571.

[5] 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.

[6] Martinez C, Suissa S, Rietbrock S, et al. Testosterone treatment and risk of venous thromboembolism: Population based case-control study. BMJ. 2016 Nov 30;355:i5968.

[7] Ibid.

[8] Finkle WD, Greenland S, Ridgeway GK, et al. Increased risks of non-fatal myocardial infarction following testosterone therapy prescription in men. PLoS ONE 9(1): e85805.

[9] Fernandez-Balsells MM, Murad MH, Lane M, et al. Adverse effects of testosterone therapy in adult men: a systematic review and meta- analysis. J Clin Endocrinol Metab. 2010;95(6):256-2575.

[10] AbbVie. Label: ANDROGEL (Testosterone gel). October 2016. https://dailymed.nlm.nih.gov/dailymed/getFile.cfm? setid=8677ba5b-8374-46cb-854c-403972e9ddf3&type=pdf&name=8677ba5b-8374-46cb- 854c-403972e9ddf3. Accessed January 15, 2017.

[11] Panin LE, Mokrushnikov PV, Kunitsyn VG, Zaitsev BN. Interaction mechanism of anabolic steroid hormones with structural components of erythrocyte membranes. J Phys Chem B. 2011;115(50):14969-14979.

[12] Ajayi AA, Mathur R, Halushka PV. Testosterone increases human platelet thromboxane A2 receptor density and aggregation responses. Circulation. 1995;91(11):2742-2747.