FEATURED NEW INVESTIGATOR Testosterone, thrombophilia, thrombosis JOEL FREEDMAN, CHARLES J. GLUECK, MARLOE PRINCE, RASHID RIAZ, and PING WANG CINCINNATI, OHIO We screened previously undiagnosed thrombophilia (V Leiden–prothrombin muta- tions, Factors VIII and XI, homocysteine, and antiphospholipid antibody [APL] syndrome) in 15 men and 2 women with venous thromboembolism (VTE) or osteonecrosis 7 months (median) after starting testosterone therapy (TT), gel (30–50 mg/d), intramuscular (100–400 mg/wk), or human chorionic gonadotropin (HCG) (6000 IU/wk). Thrombophilia was studied in 2 healthy control groups without thrombosis (97 normal controls, 31 subjects on TT) and in a third control group (n 5 22) with VTE, not on TT. Of the 17 cases, 76% had $1 thrombophilia vs 19% of 97 normal controls (P , 0.0001), vs 29% of 31 TT controls (P 5 0.002). Cases differed from normal controls by Factor V Leiden (12% vs 0%, P 5 0.021), by high Factor VIII (.150%) (24% vs 7%, P 5 0.058), by high homocysteine (29% vs 5%, P 5 0.007), and from both normal and TT controls for APL syndrome (18% vs 2%, P 5 0.023, vs 0%, P 5 0.04). Despite adequate anticoagulation with TT continued after the first deep venous thrombosis–pulmonary embolus (DVT-PE), 1 man sustained 3 DVT-PEs 5, 8, and 11 months later and a second man had 2 DVT-PEs 1 and 2 months later. Of the 10 cases with serum T measured on TT, 6 (60%) had supranormal T (.800 ng/ dL) and of 9 with estradiol measured on TT, 7 (78%) had supranormal levels (.42.6 pg/mL). TT interacts with thrombophilia leading to thrombosis. TT continuation in thrombophilic men is contraindicated because of recurrent thrombi despite anti- coagulation. Screening for thrombophilia before starting TT should identify subjects at high risk for VTE with an adverse the risk to benefit ratio for TT. (Translational Research 2015;165:537–548) Abbreviations: APL ¼ antiphospholipid antibody; DVT ¼ deep venous thrombosis; E2 ¼ estradiol; FV ¼ Factor V; HRT ¼ hormone replacement therapy; ON ¼ osteonecrosis; PE ¼ pulmonary embolus; PTG ¼ prothrombin gene mutation; T ¼ testosterone; TT ¼ testosterone therapy; VTE ¼ venous thromboembolism INTRODUCTION A ndrogen use in men aged $40 has increased more than 3-fold from 0.81% in 2001 to 2.91% in 2011. 1 The broad use of testosterone therapy (TT) may have major public health ramifica- tions, given recent reports of thrombotic 2-7 and cardiovascular disease (CVD) events 8-10 associated with TT. Despite lessons learned about venous thromboembolism (VTE) and CVD associated with sex-hormone therapy in postmenopausal women from Joel Freedman, MD, is a third year resident in Internal Medicine at the Jewish Hospital Internal Medicine Residency Program. His article is based on a presentation given at the Combined Annual Meeting of the Central Society for Clinical and Translational Research and the Midwestern Section American Federation for Medical Research, held in Chicago, Ill, on April 2014. From the Jewish Hospital Internal Medicine Residency Program, Cincinnati, Ohio; Cholesterol, Metabolism, and Thrombosis Center, Jewish Hospital of Cincinnati, Cincinnati, Ohio. Submitted for publication September 30, 2014; revision submitted December 16, 2014; accepted for publication December 17, 2014. Reprint requests: Charles J. Glueck, Cholesterol, Metabolism, and Thrombosis Center, Suite 430, 2135 Dana Avenue, Cincinnati, OH 45207; e-mail: sonar16@gmail.com. 1931-5244/$ - see front matter Ó 2015 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.trsl.2014.12.003 537