Venous Thrombosis and Changes of Hemostatic Variables during Cross-Sex Hormone Treatment in Transsexual People

• Published in: The journal of clinical endocrinology and metabolism Vol. 88; no. 12; pp. 5723 - 5729
• Main Authors: Toorians, A. W. F. T., Thomassen, M. C. L. G. D., Zweegman, S., Magdeleyns, E. J. P., Tans, G., Gooren, L. J. G., Rosing, J.
• Format: Journal Article
• Language: English
• Published: Bethesda, MD Endocrine Society 01-12-2003; Copyright by The Endocrine Society
• Subjects: Activated Protein C Resistance; Adult; Androgen Antagonists - therapeutic use; Androgens - therapeutic use; Biological and medical sciences; Blood and lymphatic vessels; Cardiology. Vascular system; Cyproterone Acetate - therapeutic use; Diseases of the peripheral vessels. Diseases of the vena cava. Miscellaneous; Drug Therapy, Combination; Estradiol - adverse effects; Estrogens - adverse effects; Ethinyl Estradiol - adverse effects; Female; Gonadal Steroid Hormones - adverse effects; Gonadal Steroid Hormones - therapeutic use; Hemostasis - drug effects; Hormones - blood; Hormones. Endocrine system; Humans; Male; Medical sciences; Pharmacology. Drug treatments; Sex Characteristics; Testosterone - therapeutic use; Transsexualism - blood; Transsexualism - drug therapy; Transsexualism - physiopathology; Venous Thrombosis - chemically induced; Venous Thrombosis - prevention & control; Antineoplastic agent; Human; Drug combination; Transsexualism; Hemostatic; Pathophysiology; Toxicity; Coagulation; 17β-Estradiol; Antiandrogen; Cardiovascular disease; Protein C; Antihormone; Cyproterone; Venous disease; Treatment; Secondary effect; Prothrombin; Protein S; Venous thrombosis; Hormone replacement therapy
• ISSN: 0021-972X; 1945-7197
• DOI: 10.1210/jc.2003-030520

The incidence of venous thrombosis associated with estrogen treatment in male-to-female (M→F) transsexuals is considerably higher with administration of oral ethinyl estradiol (EE) than with transdermal (td) 17-β-estradiol (E2).
To find an explanation for the different thrombotic risks of oral EE and td E2 use, we compared the effects of treatment of M→F transsexuals with cyproterone acetate (CPA) only, and with CPA in combination with td E2, oral EE, or oral E2 on a number of hemostatic variables [activated protein C (APC) resistance and plasma levels of protein S, protein C, and prothombin], all of which are documented risk factors for venous thrombosis. APC resistance was determined by quantification of the effect of APC on the amount of thrombin generated during tissue factor-initiated coagulation; plasma levels of total and free protein S were determined by standard ELISA; and levels of prothrombin and protein C were determined with functional assays after complete activation of the zymogens with specific snake venom proteases.
CPA-only, td-E2+CPA, or oral-E2+CPA treatment produced rather small effects on hemostatic variables, whereas oral EE treatment resulted in a large increase in APC resistance from 1.2 ± 0.8 to 4.1 ± 1 (P < 0.001), a moderate increase in plasma protein C (9%; P = 0.012), and a large decrease in both total and free plasma protein S (30%; P < 0.005). The large differential effect of oral EE and oral E2 indicates that the prothrombotic effect of EE is due to its molecular structure rather than to a first-pass liver effect (which they share). Moreover, these differences may explain why M→F transsexuals treated with oral EE are exposed to a higher thrombotic risk than transsexuals treated with td E2. Testosterone administration to female-to-male transsexuals had an antithrombotic effect.