Differential Effects of Oral and Transdermal Estrogen/Progesterone Regimens on Sensitivity to Activated Protein C Among Postmenopausal Women

Abstract

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...

Hormone Therapy and Venous Thromboembolism Among Postmenopausal Women

“…29 In addition, 2 randomized controlled trials have shown that oral but not transdermal estrogen, both combined with micronized progesterone, induced an activated protein C resistance. 30,31 Thus, hemostatic data, together with the results of the ESTHER study, suggest that transdermal estrogen combined with micronized progesterone is safe with respect to VTE risk. Similarly, recent data showing that chlormadinone acetate, a pregnane derivative, has little or no effect on blood coagulation and fibrinolysis 32 are consistent with the absence of increased VTE risk among postmenopausal women using transdermal estrogen combined with pregnane derivatives.…”

Prothrombotic Mutations, Hormone Therapy, and Venous Thromboembolism Among Postmenopausal Women

“…13 In addition, an acquired resistance to activated protein C has been demonstrated in users of oral estrogen, 14 but 2 randomized trials recently indicated that these results did not apply to users of transdermal estrogen. 15,16 Thus, oral estrogen may impair the balance between procoagulant factors and antithrombotic mechanisms, whereas transdermal estrogen appears to have little or no effect on hemostasis.…”

Pharmacology of Hormone Replacement Therapy in Menopause

“…An explanation for the distinct VTE risk profile following the two routes of administration involves the first-pass effect of oestrogen. This was shown to affect the synthesis of various oestrogen-dependent hepatic serum factors (Kuhl, 2005), including coagulation and fibrinolysis factors, resulting in blood coagulation activation (Scarabin et al, 1997;Vehkavaara et al, 2001), increased thrombin generation or induction of resistance to activated protein C (Hemelaar et al, 2006;Oger et al, 2003). However, the precise mechanisms by which these changes occur are still unclear.…”