on July 17, 2003
Published online before print July 17, 2003, doi: 10.1161/01.ATV.0000087141.05044.1F
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Submitted on October 14, 2002
Accepted on March 6, 2003
Differential Effects of Oral and Transdermal Estrogen/Progesterone Regimens on Sensitivity to Activated Protein C Among Postmenopausal Women. A Randomized Trial
Emmanuel Oger *;
From Département de Médecine Interne (E.O., K.L., D.M.), Laboratoire d'Hématologie (M-T.B., J-F.A.), Service d'Endocrinologie (N.R., V.K.), and Service de Gynécologie (M.C.), Hôpital de la Cavale Blanche, Brest; Laboratoire d'Hématologie INSERM U428 (M.A-G., M.A.), Hôpital Européen Georges Pompidou, Paris; and INSERM U258 (P-Y.S.), Villejuif, France.
* To whom correspondence should be addressed. E-mail: emmanual.oger{at}southernhealth.org.au.
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 (n=63) or 50 µg 17-estradiol transdermally per day (n=68), both associated with 100 mg progesterone daily or placebo (n=65) 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 (P=0.006) and transdermal ERT (P<0.001), but there was no significant effect of transdermal ERT compared with placebo (P=0.191). There was no significant effect of ERT on the APTT-based APC sensitivity ratio. Prothrombin fragment 1+2 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 • APC resistance • blood coagulation • randomized trial • factor V
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