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.

In our study of 596 men hospitalized in the last 3 years for deep venous thrombosis-pulmonary emboli (DVT-PE), we determined the prevalence of exogenous testosterone (T) use with subsequent development of DVT-PE. Of the 596 men, 110 were now dead, 97 had cancer thought to cause DVT-PE, 250 could not be contacted, leaving 139, of whom 7 had taken T before and at the time of their admissions, 1.2% of the total cohort, a conservative estimate of the prevalence of T-associated DVT-PE. In all, 5 of the 7 DVT-PE events occurred within 3 months of initiation of T, with mean and median intervals between initiation of T and hospitalization with DVT-PE 6.7 and 2 months. Of the 7 men treated with exogenous T, all 5 men who had evaluation of thrombophilia-hypofibrinolysis were found to have previously undiagnosed familial or acquired thrombophilia or hypofibrinolysis, suggesting a thrombotic interaction between exogenous T and thrombophilia-hypofibrinolysis.