The Effects of Transdermal Estradiol and Oral Conjugated Estrogens on Haemostasis Variables

Abstract

SummaryThe effects of oral and transdermal administration of estrogen replacement therapy (ERT) have been fairly well investigated regarding lipoprotein and carbohydrate metabolism, while the effects of different modes of estrogen administration on the haemostatic system have been less well studied.To delineate and compare the effects of perorally administered conjugated estrogens (CE) and transdermally administered estradiol (E2) in doses needed for hormone replacement therapy (HRT) on haemostasis parameters, 23 postmenopausal women were engaged in a study with an open cross-over design. The doses compared (0.625 mg CE and 50 μg E2/24h) are the lowest which, with few exceptions, eliminate climacteric symptoms. Both CE and E2 increased factor VII:C, factor VII:Ag, and the prothrombin fragment1+2. The increase in factor VII:Ag, however, was significantly higher after treatment with CE. These changes were all towards a state of hypercoagulability. Furthermore, CE decreased plasminogen activator inhibitor (PAI) and the thrombin-antithrombin complexes (TAT), as well as antithrombin (ATIII).

Effect of Estrogen-Progestin Hormonal Replacement Therapy on Blood Coagulation and Fibrinolysis in Postmenopausal Women

“…They reached statistical significance only in patients receiving transdermal 17beta-estradiol plus MP at T 3 ; that is, in patients with no AT-III reduction. This is in contrast with the findings of Kroon 27 and Caine, 29 who observed high F1+2 levels in women receiving oral CEE, though this phenomenon was not seen in those receiving transdermal 17beta-estradiol. As we observed for AT-III and F1+2 levels, they were always within the normal range, suggesting that the elevation is not clinically relevant.…”

“…[27][28][29][30] Some authors observed AT-III reduction with ethinyl estradiol [31][32][33] and with estradiol valerate. 32,33 On the other hand, AT-III reduction during HT with oral CEE was not observed by others, but this may be due to methodology.…”

Postmenopausal Hormone Replacement Therapy Increases Coagulation Activity and Fibrinolysis

“…Elevated levels of F1ϩ2 have also been reported with estrogen alone. An open crossover study showed a 25% increase after 6 weeks of treatment with 0.625 mg conjugated equine estrogen (CEE), 14 and a randomized crossover study involving treatment for 3 months with CEE (either 0.625 or 1.25 mg) demonstrated a 40% and 98% increase in F1ϩ2, respectively. 13 On the other hand, results of placebo-controlled trials of combined estrogen and progestin therapy have been inconsistent.…”

“…8,10,11 Thrombosis results from inappropriate initiation and propagation of the hemostatic response and may occur as a result of activation of coagulation or inhibition of fibrinolysis. 12 That estrogen has a complex effect on the mechanisms underlying thrombosis is suggested by clinical studies indicating that although it produces a dose-dependent increase in plasma markers of thrombin and fibrin generation, 13,14 it also decreases plasma fibrinolytic inhibitory activity 14 -18 by decreasing levels of plasminogen activator inhibitor-1 (PAI-1). 14,16 -18 However, there is considerable uncertainty regarding the effects of combined HRT with estrogen and progestin on coagulation and fibrinolytic processes.…”

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

“…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.…”