Testosterone, Thrombophilia, and Thrombosis

Abstract

We describe thrombosis, deep venous thrombosis (DVT) pulmonary embolism (PE; n = 9) and hip-knee osteonecrosis (n = 5) that developed after testosterone therapy (median 11 months) in 14 previously healthy patients (13 men and 1 woman; 13 Caucasian and 1 African American), with no antecedent thrombosis and previously undiagnosed thrombophilia-hypofibrinolysis. Of the 14 patients, 3 were found to be factor V Leiden heterozygotes, 3 had high factor VIII, 3 had plasminogen activator inhibitor 1 4G4G homozygosity, 2 had high factor XI, 2 had high homocysteine, 1 had low antithrombin III, 1 had the lupus anticoagulant, 1 had high anticardiolipin antibody Immunoglobulin G, and 1 had no clotting abnormalities. In 4 men with thrombophilia, DVT-PE recurred when testosterone was continued despite therapeutic international normalized ratio on warfarin. In 60 men on testosterone, 20 (33%) had high estradiol (E2 >42.6 pg/mL). When exogenous testosterone is aromatized to E2, and E2-induced thrombophilia is superimposed on thrombophilia-hypofibrinolysis, thrombosis occurs. The DVT-PE and osteonecrosis after starting testosterone are associated with previously undiagnosed thrombophilia-hypofibrinolysis. Thrombophilia should be ruled out before administration of exogenous testosterone.

Testosterone, thrombophilia, thrombosis

“…In current study, congruent with our previous studies [2,4], despite adequate anticoagulation with coumadin, when exogenous T was continued after an initial DVTpulmonary embolism or osteonecrosis, three men had a second thrombotic event, and one had three pulmonary emboli, 3, 9, and 16 months after starting T. After an initial thrombotic event while taking T, in patients found to have thrombophilia-hypofibrinolysis, we believe that further T therapy is contraindicated, because of high likelihood of recurrent thrombi, even when adequate anticoagulation is maintained [2,4].…”

“…In 11 men who developed DVT-pulmonary embolismosteonecrosis or spinal cord infarction 3.5 months after starting T, eight were found to have previously undiagnosed major gene thrombophilia (factorV Leiden heterozygosity, prothrombin gene heterozygosity, high factor VIII, low antigenic protein S/antigenic factor VII) congruent with our previous reports [1][2][3][4]. High factor VIII was more common in the 11 men (36%) than in normal male controls (2%) (P ¼ 0.005), and more common than in T-controls (4%) (P ¼ 0.023).…”

“…Given an estimated population prevalence of thrombophilias of 18-28% [9][10][11], there is considerable opportunity for men and women given T therapy to also have familial and acquired thrombophilias, with resultant DVT-pulmonary embolism or osteonecrosis, as in our current and previous reports [1][2][3][4][5]. Given an estimated population prevalence of thrombophilias of 18-28% [9][10][11], there is considerable opportunity for men and women given T therapy to also have familial and acquired thrombophilias, with resultant DVT-pulmonary embolism or osteonecrosis, as in our current and previous reports [1][2][3][4][5].…”

“…Five of seven DVT-pulmonary embolism events occurred within 3 months of initiation of T [1]. Of the seven men treated with T, all five men who had evaluation of thrombophilia-hypofibrinolysis were found to have previously undiagnosed thrombophilia-hypofibrinolysis, suggesting a thrombotic interaction between exogenous T and thrombophilia-hypofibrinolysis [1][2][3][4]. Of 123 evaluable participants in an AndroGel trial [7], one (0.8%) of the participants had 'deep venous thrombosis deemed to be possibly related to T replacement.…”

“…When exogenous testosterone (T) is given to men and women with previously undiagnosed thrombophiliahypofibrinolysis, deep venous thrombosis (DVT), pulmonary embolism, and osteonecrosis can occur [1][2][3][4][5]. Pulmonary embolism is expensive to diagnose and treat ($8764/case) with a high case fatality rate (18%) [6], and approaches to reduce and/or prevent pulmonary embolism [1][2][3][4] are important, both medically and economically.…”