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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2003;23:1671.)
© 2003 American Heart Association, Inc.

Thrombosis

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

A Randomized Trial

Emmanuel Oger; Martine Alhenc-Gelas; Karine Lacut; Marie-Thérèse Blouch; Nathalie Roudaut; Véronique Kerlan; Michel Collet; Jean-François Abgrall; Martine Aiach; Pierre-Yves Scarabin; Dominique Mottier for the SARAH Investigators

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.

Reprint requests to Dr Emmanuel Oger, Department of Vascular Science and Medicine, Dandenong Hospital, David Street, Dandenong, Victoria 3175, Australia. 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 17ß-estradiol orally (n=63) or 50 µg 17ß-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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