Published Online
on November 21, 2005

A more recent version of this article appeared on November 29, 2005

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Submitted on May 31, 2005
Revised on September 6, 2005
Accepted on September 14, 2005

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.

^* To whom correspondence should be addressed. E-mail: scarabin{at}vjf.inserm.fr.

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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