Oral, but Not Transdermal, Administration of Estrogens Lowers Tissue-Type Plasminogen Activator Levels in Humans Without Affecting Endothelial Synthesis

Abstract

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) 17␤-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 (nϭ15) or transdermal 17␤-estradiol (nϭ15); 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 17␤-estradiol plus CA, nor oral CA, nor parenteral testosterone lowered plasma tPA and plasminogen activator inhibitor-1 (PϽ0.001 for both). tPA release during venous occlusion was not affected by oral ethinyl estradiol plus CA in males (Pϭ0.52) or by parenteral testosterone in females (Pϭ0.89). 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 Ⅲ sex hormones Ⅲ venous occlusion Ⅲ endothelium Ⅲ estrogen E strogens and testosterone are administered for a growing number of indications, including oral contraception and hormone replacement therapy in premenopausal and postmenopausal women and androgen substitution therapy in aging men. Their effects on the fibrinolytic system are still incompletely understood. Administration of estrogens via the oral route decreases tissue-type plasminogen activator (tPA) and plasminogen activator inhibitor-1 (PAI-1) levels in males 1-3 and females. 4 -9 By contrast, transdermal administration of estrogens in females is not associated with decreases in tPA and PAI-1 antigen levels. [7][8][9] Because most studies focused on changes in plasma levels, it is not clear whether the decrease in tPA levels after oral administration of estrogens reflects an increase in tPA clearance, a decrease in its synthesis, or both. Because tPA is synthesized and released by the vascular endothelium 10 -15 and because the continuous deposition and dissolution of fibrin along the vessel wall would be directly and locally affected if endothelial synthesis of tPA changed, the difference between the 2 possibilities is of some clinical importance.Circulating tPA, either in the free form or complexed with PAI-1, is rapi...

Comparative Effects of Estrogen and Angiotensin-Converting Enzyme Inhibition on Plasminogen Activator Inhibitor-1 in Healthy Postmenopausal Women

“…Estrogen significantly reduced PAI-1 in this study, even though it was administered transdermally, in contrast to several other studies. 7,33 Also, the authors observed that PAI-1 4G/5G genotype affected baseline PAI-1 antigen concentrations in women with CAD but not in healthy postmenopausal women; the effect of PAI-1 4G/5G genotype on the fibrinolytic response to transdermal estrogen in healthy women was not reported in this study. On the other hand, the finding that PAI-1 4G/5G genotype influenced the PAI-1 response to ACE inhibition is compatible with a prior study demonstrating that the PAI-1 4G/5G locus modulates the effect of activation of the RAAS by salt depletion on PAI-1 antigen concentrations.…”

“…31 The finding that both CEE and ACE inhibition decrease PAI-1 even though the drugs exert different effects on the RAAS may indicate that they lower PAI-1 through different mechanisms. Clinical studies indicating that oral but not transdermal HRT reduces PAI-1 7,33 suggest that estrogen lowers circulating PAI-1 concentrations primarily by suppressing hepatic PAI-1 production or enhancing hepatic clearance. In vitro, estrogen suppresses PAI-1 expression through an ER ␤-receptor dependent mechanism (Vaughan DE, unpublished data, 1999).…”

Angiotensin-Converting Enzyme Inhibition Increases Basal Vascular Tissue Plasminogen Activator Release in Women But Not in Men

“…21,22 Estrogen has been shown to decrease ACE activity, 23 to upregulate BK receptors 24,25 and to increase t-PA synthesis in some 26,27 but not all studies. 28,29 To exclude an effect of gender or menopausal status on BK degradation during ACE inhibition, we measured both ACE activity and kinin concentrations and found that differences in BK degradation cannot account for differences in basal or BK-stimulated t-PA release during ACE inhibition.…”

“…21,22 Estrogen has been shown to decrease ACE activity, 23 to upregulate BK receptors 24,25 and to increase t-PA synthesis in some 26,27 but not all studies. 28,29 To exclude an effect of gender or menopausal status on BK degradation during ACE inhibition, we measured both ACE activity and kinin concentrations and found that differences in BK degradation cannot account for differences in basal or BK-stimulated t-PA release during ACE inhibition.To determine whether gender or menopausal status influenced sensitivity to BK at the receptor or post-receptor level we compared dose-response curves for the effect of exogenous BK on FBF and t-PA release in the presence and absence of ACE inhibitor. The observation that gender did not affect the BK dose-vasodilation response curve during ACE inhibition suggests that gender and hormonal status influence BK-stimulated t-PA release at a point downstream to the B 2 receptor.…”

Cardiovascular disease in transsexual persons treated with cross-sex hormones: reversal of the traditional sex difference in cardiovascular disease pattern

“…One study showed that oral ethinyl estradiol treatment of MtoF (compared with transdermal 17b-estradiol) was associated with adverse changes in activated protein C resistance and plasma levels of protein S and C, while testosterone had antithrombotic effects in FtoM (44). The other study found that administration of oral ethinyl estradiol, but not transdermal 17b-estradiol, lowered tissue-type plasminogen activator levels in humans without affecting endothelial synthesis (47). The third study found that both oral ethinyl estradiol and transdermal 17b-estradiol lowered plasma total homocysteine in MtoF (39,48).…”