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

Departments of Endocrinology/Andrology (A.W.F.T.T., L.J.G.G.) and Haematology (S.Z.), Vrije Universiteit University Medical Center, 1007 MB Amsterdam, The Netherlands; and Department of Biochemistry (M.C.L.G.D.T., E.J.P.M., G.T., J.R.), Cardiovascular Research Institute Maastricht, Maastricht University, 6200 MD Maastricht, The Netherlands

Address all correspondence and requests for reprints to: Dr. L. J. G. Gooren, Department of Endocrinology/Andrology, Vrije Universiteit University Medical Center, P.O. Box 7057, 1007 MB Amsterdam, The Netherlands. E-mail: ljg.gooren{at}vumc.nl.

The incidence of venous thrombosis associated with estrogen treatment in male-to-female (MF) transsexuals is considerably higher with administration of oral ethinyl estradiol (EE) than with transdermal (td) 17-ß-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 MF 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 MF 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.

Abbreviations: APC, Activated protein C; CPA, cyproterone acetate; E₂, 17-ß-estradiol; EE, ethinyl estradiol; FM, female to male; MF, male to female; nAPCsr, normalized APC sensitivity ratio; OC, oral contraceptive; T, testosterone; td, transdermal(ly); VT, venous thrombosis.

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