Oral, but not transdermal, estrogen use associated with increased risk of venous thromboembolism


Oral estrogen use in postmenopausal women may elevate the risk of venous thromboembolism (VTE); however, the use of transdermal estrogen does not appear to increase the risk of VTE.

Key Points

Oral estrogen use in postmenopausal women may elevate the risk of venous thromboembolism (VTE); however, the use of transdermal estrogen does not appear to increase the risk of VTE, according to the results of the Estrogen and Thromboembolism Risk (ESTHER) study. Additionally, the data suggest that norpregnane derivatives are thrombogenic, yet micronized progesterone and pregnane derivatives may be safe in terms of thrombotic risk.

This multicenter (8 hospitals) case-control trial in France assessed VTE in postmenopausal women, aged 45 to 70 years, from 1999 to 2005. A total of 271 case patients (208 hospital-based and 63 outpatient-based) with a first recorded occurrence of VTE were matched with 610 control patients (426 hospital-based, 184 community-based). Patients with a personal history of VTE, contraindication for hormone therapy, and/or a predisposing factor for VTE were excluded from the study.

All patients completed a questionnaire, which included information about types of estrogens and progestogens, dose, and treatment duration. Hormone therapy users were grouped by estrogen administration method and progestogen type.

There was no association between previous use of estrogen and risk of VTE (OR=1.1; 95% CI, 0.6–1.7). Overall, 26.0% of case patients and 29.9% of control patients used transdermal estrogen (OR=0.9; 95% CI, 0.4–2.1). Oral estrogen use was more prevalent among case patients (17.4%) than among control patients (6.5%) (OR= 4.0; 95% CI, 1.4–11.4). Most estrogen users were treated with 17 beta-estradiol. For transdermal estrogen use, the most common dose was ≤50 mcg/d. For oral estrogen use, the mean estradiol dose was 1.5 mg/d (range, 0.5–2 mg/d).

A total of 5.4% of case patients and 6.7% of control patients received estrogen only. Additionally, 7.4% of case patients and 10.4% of control patients received micronized progesterone (OR=0.7; 95% CI, 0.3–2.0). A total of 15.1% of case patients and 13.1% of control patients used pregnane derivatives (OR=0.9; 95% CI, 0.4–2.4). Norpregnane derivatives were the choice of 15.5% of case patients and 6.1% of control patients. The risk of VTE increased markedly in users of norpregnane derivatives compared with nonusers (OR=3.9; 95% CI, 1.5–10.2).

After adjustment for potential confounding factors, the odds ratios for VTE in current users of oral or transdermal estrogen compared with nonusers were 4.2 (95% CI, 1.5–11.6) and 0.9 (95% CI, 0.4–2.1), respectively. There was no significant relationship between VTE and micronized progesterone or pregnane derivatives (OR=0.7; 95% CI, 0.3–1.9 and OR=0.9; 95% CI, 0.4–2.3, respectively). Significantly, among users of norpregnane derivatives, there was a 4-fold elevated risk for VTE (OR=3.9; 95% CI, 1.5–10.0).

In an editorial on the ESTHER study, Kathryn M. Rexrode, MD, MPH, et al stated that the study provides significant data to support the theory that the type of hormone therapy and mode of delivery do affect outcomes. Cited strengths of the study include the number of carefully selected cases, a large population of transdermal estrogen users, and the variety of progestogen types assessed.


Canonico M, Oger E, Plu-Bureau G, et al; for the Estrogen and Thromboembolism Risk (ESTHER) Study Group. Hormone therapy and venous thromboembolism among postmenopausal women: Impact of the route of estrogen administration and progestogens: The ESTHER study. Circulation. 2007;115:840–845.

Rexrode KM, Manson JE. Are some types of hormone therapy safer than others? Lessons from the Estrogen and Thromboembolism Risk study. Circulation. 2007;115:820–822.

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