Differential associations of oral estradiol and conjugated equine estrogen with hemostatic biomarkers

J Thromb Haemost. 2014 Jun;12(6):879-86. doi: 10.1111/jth.12560.


Background: The risk of venous thrombosis (VT) associated with oral hormone therapy (HT) may differ by type of estrogen compound.

Objective: To compare the thrombotic profile of women using oral conjugated equine estrogens (CEE) with that of women using oral estradiol (E2).

Methods: In postmenopausal, female, health maintenance organization (HMO) members with no history of VT, we measured thrombin generation, levels of factor VII activity, antithrombin activity and total protein S antigen. Mean levels of hemostasis biomarkers were cross-sectionally compared by use and type of estrogen using multiple linear regressions. The type of estrogen used was determined primarily by the HMO formulary, which changed its preferred estrogen from CEE to E2 during the study period.

Results: The sample included 92 E2 users and 48 CEE users, with a mean age of 64.1 years and mean BMI of 29.1 kg m(-2) . Twenty-seven per cent of HT contained medroxyprogesterone acetate. Compared with E2 users, CEE users had greater thrombin generation peak values and endogenous thrombin potential, and lower total protein S (multivariate adjusted differences of 49.8 nm (95% CI, 21.0, 78.6), 175.0 nm × Min (95% CI, 54.4, 295.7) and -13.4% (95% CI, -19.8, -6.9), respectively). Factor VII and antithrombin levels were not different between E2 and CEE users. Results were similar in subgroups of users of unopposed HT, opposed HT, low-dose estrogen and standard dose estrogen.

Conclusion: The hemostatic profile of women using CEE is more prothrombotic than that of women using E2. These findings provide further evidence for a different thrombotic risk for oral CEE and oral E2.

Keywords: estradiol; estrogen replacement therapy; estrogens; hemostasis; thromboembolism; venous thrombosis.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural

MeSH terms

  • Administration, Oral
  • Aged
  • Antithrombins / metabolism
  • Biomarkers / blood
  • Cross-Sectional Studies
  • Estradiol / administration & dosage*
  • Estradiol / adverse effects
  • Estrogen Replacement Therapy* / adverse effects
  • Estrogens, Conjugated (USP) / administration & dosage*
  • Estrogens, Conjugated (USP) / adverse effects
  • Factor VII / metabolism
  • Female
  • Hemostasis / drug effects*
  • Humans
  • Middle Aged
  • Postmenopause
  • Protein S / metabolism
  • Risk Factors
  • Thrombin / metabolism
  • Venous Thrombosis / blood
  • Venous Thrombosis / chemically induced


  • Antithrombins
  • Biomarkers
  • Estrogens, Conjugated (USP)
  • Protein S
  • Estradiol
  • Factor VII
  • Thrombin