Postmenopausal hormone replacement therapy is associated with a reduction in the incidence of coronary heart disease. However, inconclusive results have been reported with respect to the risk of stroke, and recent studies consistently showed an increased risk of venous thromboembolism in postmenopausal women using oral estrogen. There are surprisingly few interventional studies to assess the true effects of estrogen-progestin regimens on blood coagulation and fibrinolysis, and the impact of the route of estrogen administration on hemostasis has not been well documented. Therefore, we investigated the effects of oral and transdermal estradiol/progesterone replacement therapy on hemostatic variables. Forty-five healthy postmenopausal women, aged 45 to 64 years, were assigned randomly to one of the three following groups: cyclic oral or transdermal estradiol, both combined with progesterone, or no hormonal treatment. Hemostatic variables were assayed at baseline and after a 6-month period. Pairwise differences in the mean change between the three groups were compared using nonparametric tests. Oral but not transdermal estradiol regimen significantly increased the mean value of prothrombin activation peptide (F1 + 2) and decreased mean antithrombin activity compared with no treatment. Differences in fragment F1 + 2 levels between active treatments were significant. The oral estrogen group was associated with a significant decrease in both mean tissue-type plasminogen (t-PA) concentration and plasminogen activator inhibitor (PAI-1) activity and a significant rise in global fibrinolytic capacity (GFC) compared with the two other groups. A transdermal estrogen regimen had no significant effect on PAI-1, t-PA, and GFC levels. There were no significant changes in mean values of fibrinogen, factor VII, von Willebrand factor, protein C, fibrin D-dimer, and plasminogen between and within the three groups. We conclude that oral estrogen/progesterone replacement therapy may result in coagulation activation and increased fibrinolytic potential, whereas opposed transdermal estrogen appears without any substantial effects on hemostasis. Whereas these results may account for an increased risk of venous thromboembolism in users of oral postmenopausal estrogen, they emphasize the potential importance of the route of estrogen administration in prescribing hormone replacement therapy to postmenopausal women, especially to those at high risk of thrombotic disease.

Objective-Activated protein C (APC) resistance not related to the factor V Leiden mutation is a risk factor for venous thrombosis. Oral estrogen replacement therapy (ERT) has been reported to induce APC resistance. Little is known about the effect of transdermal estrogen. Methods and Results-We enrolled 196 postmenopausal women who were randomly allocated to receive either 1 mg 17␤-estradiol orally (nϭ63) or 50 g 17␤-estradiol transdermally per day (nϭ68), both associated with 100 mg progesterone daily or placebo (nϭ65) for 6 months. An activated partial thromboplastin time (APTT)-based test and the effect of APC on thrombin potential (ETP) were used. Oral ERT induced an ETP-based APC resistance compared with both placebo (Pϭ0.006) and transdermal ERT (PϽ0.001), but there was no significant effect of transdermal ERT compared with placebo (Pϭ0.191). There was no significant effect of ERT on the APTT-based APC sensitivity ratio. Prothrombin fragment 1ϩ2 plasma levels were significantly higher after 6 months of treatment in women allocated to oral ERT compared with those on placebo and transdermal ERT and were positively and significantly correlated with changes in ETP-based APC sensitivity ratio. Conclusions-Our data show that oral, unlike transdermal, estrogen induces APC resistance and activates blood coagulation. These results emphasize the importance of the route of estrogen administration. Key Words: hormone replacement therapy Ⅲ APC resistance Ⅲ blood coagulation Ⅲ randomized trial Ⅲ factor V S everal observational studies [1][2][3][4][5][6][7] found that oral estrogen replacement therapy (ERT) was associated with a 2-fold increased risk of venous thromboembolism (VTE). This finding was confirmed in 2 randomized clinical trials. 8,9 Furthermore, consistent data provided evidence that oral ERT resulted in coagulation activation. 10 -14 However, studies investigating the effect of transdermal estrogen on the thrombotic process are scarce. 3,15 Activated protein C (APC) resistance has recently emerged as a risk factor for venous thrombosis. 16,17 In most cases, this defect is related to the presence of the R506Q mutation in factor V (FV) Leiden. 18 However, an APC-resistant phenotype detected in the absence of FV Leiden is also an independent risk factor for venous thrombosis. 19 Observational studies 20 -22 and 1 randomized trial 23 showed that oral ERT could induce an acquired APC resistance. Little is known about the effect of transdermal ERT on APC resistance. Therefore, we conducted a randomized, placebocontrolled trial that investigated the effect of both oral and transdermal estrogen/progesterone regimens on the anticoagulant response to APC and on coagulation activation. Methods Study Design and SettingThis study was a randomized, double-blind, placebo-controlled, parallel-group trial that took place at the Hôpital de la Cavale Blanche, Brest, France, between September 1999 and August 2001. Participants were followed up by regular visits, at randomization (baseline), and after 6 months. A medical revi...