Prothrombotic mutations, hormone therapy, and venous thromboembolism among postmenopausal women: impact of the route of estrogen administration

Circulation. 2005 Nov 29;112(22):3495-500. doi: 10.1161/CIRCULATIONAHA.105.565556. Epub 2005 Nov 21.


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.

Publication types

  • Multicenter Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Case-Control Studies
  • Drug Administration Routes
  • Estrogens / administration & dosage*
  • Estrogens / adverse effects
  • Factor V
  • Female
  • Hormone Replacement Therapy / adverse effects*
  • Humans
  • Middle Aged
  • Mutation*
  • Mutation, Missense
  • Postmenopause / physiology*
  • Prothrombin / genetics
  • Risk Factors
  • Thromboembolism / epidemiology
  • Thromboembolism / etiology
  • Thrombophilia / genetics*
  • Venous Thrombosis / epidemiology
  • Venous Thrombosis / etiology*


  • Estrogens
  • factor V Leiden
  • Factor V
  • Prothrombin