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(Circulation. 2005;112:3495-3500.)
© 2005 American Heart Association, Inc.

Vascular Medicine

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

Impact of the Route of Estrogen Administration

Céline Straczek, PhD; Emmanuel Oger, MD, PhD; Marianne Beau Yon de Jonage-Canonico, PhD; Geneviève Plu-Bureau, MD, PhD; Jacqueline Conard, PhD; Guy Meyer, MD; Martine Alhenc-Gelas, PhD; Hervé Lévesque, MD; Nathalie Trillot, MD; Marie-Thérèse Barrellier, MD; Denis Wahl, MD, PhD; Joseph Emmerich, MD, PhD; Pierre-Yves Scarabin, MD, MSc, for the Estrogen and Thromboembolism Risk (ESTHER) Study Group

From INSERM, Cardiovascular Epidemiology Unit, Villejuif (C.S., M.B.Y.d.J.-C., G.P.-B., P.-Y.S.); Département de Médecine Interne, Hôpital de la Cavale Blanche, Brest (E.O.); Service d’Hématologie Biologique, Hôpital Hôtel-Dieu, Paris (G.P.-B., J.C.); Université Paris-Descartes, Faculté de Médecine, and Assistance Publique–Hôpitaux de Paris (G.M.) and Service d’Hématologie Biologique A (M.A.-G.), Hôpital Européen Georges Pompidou, Paris; Département de Médecine Interne, CHU Rouen, Rouen (H.L.); Institut d’Hématologie–Transfusion, CHRU, Lille (N.T.); Service d’Explorations Fonctionnelles, CHU Côte de Nacre, Caen (M.-T.B.); Unité de Médecine Interne Thromboses Maladies Vasculaires, CHU de Nancy, Hôpital de Brabois, and INSERM U734, Faculté de Médecine de Nancy, Université Henri Poincaré, Nancy (D.W.); and University Paris Descartes, INSERM U428, and Service de Médecine Vasculaire–HTA, Hôpital Européen Georges Pompidou, Paris (J.E.), France.

Correspondence to P.-Y. Scarabin, INSERM, Cardiovascular Epidemiology Unit U258, 16 Ave Paul Vaillant-Couturier, 94807 Villejuif Cedex France. E-mail scarabin{at}vjf.inserm.fr

Received May 31, 2005; revision received September 6, 2005; accepted September 14, 2005.

Background— Oral estrogen increases the risk of venous thromboembolism (VTE) in postmenopausal women, particularly in those with a prothrombotic mutation. Transdermal estrogen may be safe with respect to VTE. We investigated the impact of the route of estrogen administration on the association between a prothrombotic mutation (factor V Leiden or prothrombin G20210A mutation) and VTE risk.

Methods and Results— We performed a multicenter case-control study of VTE among postmenopausal women who were enrolled in 1999 through 2004 at 7 clinical centers in France. We recruited 235 consecutive patients with a first documented episode of idiopathic VTE and 554 controls. Factor V Leiden was associated with a 3.4-fold–increased risk of VTE (95% confidence interval [CI], 2.0 to 5.8), and a prothrombin mutation was associated with a 4.8-fold–increased risk of VTE (95% CI, 2.5 to 9.4). Oral but not transdermal estrogen was associated with an increased risk of VTE (odds ratio [OR], 4.3; 95% CI, 2.6 to 7.2; and OR, 1.2; 95% CI, 0.8 to 1.7, respectively). After adjustment for potential confounding factors, the combination of either factor V Leiden or prothrombin G20210A mutation and oral estrogen gave a 25-fold–increased risk of VTE compared with nonusers without mutation (95% CI, 6.9 to 95.0). However, the risk for women with prothrombotic mutation using transdermal estrogen was similar to that of women with a mutation who were not using estrogen (OR, 4.4; 95% CI, 2.0 to 9.9; and OR, 4.1; 95% CI, 2.3 to 7.4, respectively).

Conclusions— In contrast to oral estrogen, transdermal estrogen does not confer additional risk on women who carry a prothrombotic mutation. The safety of transdermal estrogen has to be confirmed in randomized trials.

Key Words: embolism • epidemiology • genetics • hormones • thrombosis

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