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Objective: Oral estrogen therapy increases venous thromboembolism risk among postmenopausal women. Although recent data showed transdermal estrogens may be safe with respect to thrombotic risk, the impact of the route of estrogen administration and concomitant progestogens is not fully established., Methods and Results: We used data from the E3N French prospective cohort of women born between 1925 and 1950 and biennially followed by questionnaires from 1990. Study population consisted of 80 308 postmenopausal women (average follow-up: 10.1 years) including 549 documented idiopathic first venous thromboembolism. Hazard ratios (HR) and 95% confidence intervals (CI) were estimated using Cox proportional models. Compared to never-users, past-users of hormone therapy had no increased thrombotic risk (HR=1.1; 95% CI: 0.8 to 1.5). Oral not transdermal estrogens were associated with increased thrombotic risk (HR=1.7; 95% CI: 1.1 to 2.8 and HR=1.1; 95% CI: 0.8 to 1.8; homogeneity: P=0.01). The thrombotic risk significantly differed by concomitant progestogens type (homogeneity: P<0.01): there was no significant association with progesterone, pregnanes, and nortestosterones (HR=0.9; 95% CI: 0.6 to 1.5, HR=1.3; 95% CI: 0.9 to 2.0 and HR=1.4; 95% CI: 0.7 to 2.4). However, norpregnanes were associated with increased thrombotic risk (HR=1.8; 95% CI: 1.2 to 2.7)., Conclusions: In this large study, we found that route of estrogen administration and concomitant progestogens type are 2 important determinants of thrombotic risk among postmenopausal women using hormone therapy. Transdermal estrogens alone or combined with progesterone might be safe with respect to thrombotic risk.

Background: Oral estrogen therapy increases the risk of venous thromboembolism (VTE) in postmenopausal women. Transdermal estrogen may be safer. However, currently available data have limited the ability to investigate the wide variety of types of progestogen., Methods and Results: We performed a multicenter case-control study of VTE among postmenopausal women 45 to 70 years of age between 1999 and 2005 in France. We recruited 271 consecutive cases with a first documented episode of idiopathic VTE (208 hospital cases, 63 outpatient cases) and 610 controls (426 hospital controls, 184 community controls) matched for center, age, and admission date. After adjustment for potential confounding factors, odds ratios (ORs) for VTE in current users of oral and transdermal estrogen compared with nonusers were 4.2 (95% CI, 1.5 to 11.6) and 0.9 (95% CI, 0.4 to 2.1), respectively. There was no significant association of VTE with micronized progesterone and pregnane derivatives (OR, 0.7; 95% CI, 0.3 to 1.9 and OR, 0.9; 95% CI, 0.4 to 2.3, respectively). In contrast, norpregnane derivatives were associated with a 4-fold-increased VTE risk (OR, 3.9; 95% CI, 1.5 to 10.0)., Conclusions: Oral but not transdermal estrogen is associated with an increased VTE risk. In addition, our data suggest that norpregnane derivatives may be thrombogenic, whereas micronized progesterone and pregnane derivatives appear safe with respect to thrombotic risk. If confirmed, these findings could benefit women in the management of their menopausal symptoms with respect to the VTE risk associated with oral estrogen and use of progestogens.

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.