Postmenopausal Hormone Therapy and Venous Thrombosis

Abstract & Commentary

Synopsis: Postmenopausal hormone therapy increases the risk of venous thrombosis, especially in overweight, older women.

Source: Cushman M, et al. JAMA. 2004;292: 1573-1580.

Results from the estrogen-progestin arm of the Women’s Health Initiative confirm (after central adjudication of the diagnoses) an increase in venous thrombosis associated with a standard dose of postmenopausal hormone therapy. The important observations include:

  • An overall two-fold increase in venous thrombosis, both deep vein thrombosis and pulmonary embolism
  • The risk was about four-fold higher in the first year of exposure, but remained elevated throughout followup. The test for trend was significant for a decreasing risk with increasing duration of use.
  • The risk was highest in overweight women and older women; thus, the highest risk was among the oldest, obese women.
  • Smoking and baseline use of statins or aspirin did not alter the results.
  • Among 6 genetic variants, only the presence of a mutation in factor V (the Leiden mutation) further increased the risk of venous thrombosis.

Comment by Leon Speroff, MD

In view of the fact that the increase in coronary heart disease reported in the canceled estrogen-progestin arm of the WHI was no longer statistically significant after central adjudication of diagnosis and the relative infrequency of strokes, venous thrombosis is the most common cardiovascular complication of postmenopausal hormone therapy. But the risk varies with the individual characteristics of each patient. In the youngest age group of women, ages 50-59, those who were of normal weight had an incidence of venous thrombosis that was slightly lower than that reported in the general population. It is possible that this population does not have an increased risk with hormone therapy.

The failure to observe a protective effect of statins or aspirin is contrary to the 50% reduction in venous thrombosis observed in the HERS trial.1

This is important because of the possibility that combined hormone therapy and statin/low-dose aspirin treatment may prevent the increased risk of venous thrombosis (although this has not been studied). In the WHI, only 16 of the 243 cases with venous thrombosis (6.6%) were statin users at baseline. This small number makes it difficult to be definitive. Furthermore, the preferred way to address this issue is a clinical trial with randomization to statins/aspirin.

Some practical recommendations:

1. It is worth considering methods to reduce the risk of venous thrombosis in overweight, older postmenopausal women. It has long been argued that the transdermal route of administration may be safer in regard to this risk, and evidence from a French case-control study and clinical trials measuring responses in activated protein C resistance indicates that this may be so. Combining a transdermal method with either statin treatment or low-dose aspirin deserves consideration.

2. In women with a previous episode of idiopathic venous thrombosis or with a close family history of venous thrombosis, I believe that it is reasonable to screen for the presence of an inherited disorder (the most effective method is referral to a hematologist). In the presence of an inherited disorder, consideration again should be given to the combination of a transdermal method with statin or low dose aspirin treatment.

3. Appropriate prophylactic anticoagulant treatment is indicated in hormone users anticipating immobility with hospitalization (especially if overweight and older), and hormone treatment should be discontinued at least 4 weeks prior to major surgery.


1. Herrington DM, et al. Circulation. 2002;105:2962.

Leon Speroff, MD, Professor of Obstetrics and Gynecology, Oregon Health Sciences University, Portland, is Editor for OB/GYN Clinical Alert.