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Thrombosis |
Oral, but Not Transdermal, Administration of Estrogens Lowers Tissue-Type Plasminogen Activator Levels in Humans Without Affecting Endothelial Synthesis
From the Institute of Endocrinology, Reproduction and Metabolism (E.J.G., L.J.G.G.), the Department of Internal Medicine (C.D.A.S.), and the Institute for Cardiovascular Research (C.D.A.S.), University Hospital Vrije Universiteit, Amsterdam, and the Gaubius Laboratory (J.J.E., T.K.), The Netherlands Organization for Applied Research, Leiden, the Netherlands.
Correspondence to Dr Coen D.A. Stehouwer, MD, Department of Internal Medicine, University Hospital Vrije Universiteit, PO Box 7057, 1007 MB, Amsterdam, Netherlands. E-mail cda.stehouwer{at}azvu.nl
Abstract—Oral estrogen administration decreases plasma levels of tissue-type plasminogen activator (tPA), which may be explained by a decrease in endothelial tPA synthesis, an increase in its hepatic clearance, or both. In the present study, we determined (1) differences between oral (ie, via the liver) ethinyl estradiol and transdermal (ie, systemic) 17ß-estradiol administration on plasma antigen levels of tPA and plasminogen activator inhibitor type-1 before and after 4 months of hormone administration and (2) effects on endothelial tPA synthesis, by measuring the local increase in plasma tPA during venous occlusion of the upper extremity. Thirty transsexual males (median age 32 years, range 20 to 44 years ) were randomly assigned to either oral ethinyl estradiol (n=15) or transdermal 17ß-estradiol (n=15); both treatments included the antiandrogen cyproterone acetate (CA). Ten males were treated with CA alone. Seventeen transsexual females (median age 27 years, range 18 to 37 years) were treated with intramuscular testosterone esters. Only oral ethinyl estradiol plus CA but neither transdermal 17ß-estradiol plus CA, nor oral CA, nor parenteral testosterone lowered plasma tPA and plasminogen activator inhibitor-1 (P<0.001 for both). tPA release during venous occlusion was not affected by oral ethinyl estradiol plus CA in males (P=0.52) or by parenteral testosterone in females (P=0.89). These data are consistent with a previous observation, in rodents, that the decrease in tPA after oral estrogen administration can be explained by an increase in hepatic tPA clearance, leaving endothelial tPA synthesis unchanged, and suggest that these mechanisms also explain the decrease in tPA in humans.
Key Words: tissue-type plasminogen activator • sex hormones • venous occlusion • endothelium • estrogen
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