(with limited edits by Henry I. Bussey, Pharm.D.)
Editor’s Note #1: Charles J. Glueck, MD of the Jewish Hospital in Cincinnatti has shared with ClotCare his work on the relationship of testosterone supplementation and venous thrombosis and osteonecrosis (clotcare.org/testosterone_factor_v_clot_risk.aspx and clotcare.org/dvt_pe_testosterone_women.aspx ). He has provided us with an update on this topic. Dr. Glueck also offers his services at no cost to ClotCare users who have experienced blood clots while using a testosterone supplement. You may contact him at email@example.com or firstname.lastname@example.org
Venous thromboembolism (VTE) includes blood clots in the legs (known as deep vein thrombosis or DVT) and blood clots in the lungs (known as pulmonary embolism or PE). Whether testosterone supplementation therapy (TT) increases the risk of VTE, heart attack, and/or stroke remains at least somewhat controversial. Earlier work (cited above in the editor’s note #1) has suggested that TT, when administered to individuals with conditions that predispose them to clotting, does indeed carry a substantial risk of VTE. The information reviewed below provides further support for this position.
Martinez and colleagues recently examined the relationship of TT and VTE in a population-based case-control study of 9,215 patients with confirmed VTE (DVT and PE) compared to 909,530 age matched controls from a source population of more than 2.22 million men.1 Three testosterone exposure groups were identified: (1) current TT treatment (subdivided further by those with a duration
In our study of 67 men with VTE events while on TT, like Martinez and associates, we observed a peak VTE event rate at 3 months, with 60% of thrombotic events occurring within the first 8 months after starting TT.2, 3 The peak of VTE events around 3 months 1 and subsequent decline may reflect the early depletion of susceptible patients with familial or acquired thrombophilia-hypofibrinolysis4 where TT interacts with procoagulants to produce VTE. 3 Such “depletion” of susceptible patients from the group over time would leave a pro-coagulant-winnowed residual group with progressively fewer and fewer susceptible individuals over time. Such an effect would yield fewer and fewer VTE events over time. In other words, those individuals at risk of clotting with TT tend to have their VTE events early in the course of therapy and are removed from the pool of study patients so that the continued follow-up of the remaining patients may not show a significant risk of VTE. This effect may explain why cardiovascular events – but not VTE events – were increased with TT by injection in the study described in the editor’s note #2 below.5
Editor’s Note #2: TT may be administered by injection, topical gel, or topical patch. The injectable form is thought to provide higher peak levels of testosterone while the topical preparations provide lower but more sustained concentrations. To assess the safety of these formulations, Layton and colleagues performed a retrospective study of 544,115 TT users. Among this very large group of TT users, 37.4% received injections, 6.9% used the patch, and 55.8% used the gel formulation.5 It is important to note that there was not a non-TT control group. The risks (reported as hazard ratios and 95% confidence intervals – or CI) were higher for those receiving TT by injection. When compared to those receiving gel TT, the injectable group had hazard ratios of 1.26 (CI 1.18 – 1.35) for cardiovascular events (ie, heart attack, stroke, and angina), 1.16 (CI 1.13 – 1.19) for hospitalizations, and 1.34 (CI 1.15 – 1.56) for death. The hazard ratio for VTE, however, was not increased (0.92, CI 0.76 – 1.11). The event rates in the small portion of patients who used the patch, were virtually identical to the rates seen with gel use. Although the retrospective nature of this very large study weakens the findings, one might well conclude that the gel or patch may be safer forms of TT. It is important to note, however, that efficacy was not evaluated in this study and that one cannot draw any conclusions about the safety of these agents vs. no TT from this study.
- Martinez C, Suissa S, Rietbrock S, Katholing A, Freedman B, Cohen AT, et al. Testosterone treatment and risk of venous thromboembolism: population based case-control study. BMJ. 2016; 355: i5968.
- Glueck CJ, Lee K, Prince M, Jetty V, Shah P, Wang P. Four Thrombotic Events Over 5 Years, Two Pulmonary Emboli and Two Deep Venous Thrombosis, When Testosterone-HCG Therapy Was Continued Despite Concurrent Anticoagulation in a 55-Year-Old Man With Lupus Anticoagulant. J Investig Med High Impact Case Rep. 2016; 4(3): 2324709616661833.
- Glueck CJ, Prince M, Patel N, Patel J, Shah P, Mehta N, et al. Thrombophilia in 67 Patients With Thrombotic Events After Starting Testosterone Therapy. Clin Appl Thromb Hemost. 2016; 22(6): 548-53.
- Miettinen OS, Caro JJ. Principles of nonexperimental assessment of excess risk, with special reference to adverse drug reactions. J Clin Epidemiol. 1989; 42(4): 325-31.
- Layton JB, Meier CR, Sharpless JL, et al. Comparative Safety of Testosterone Dosage Forms. JAMA Intern Med. 2015:175(7):1187-96