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Objective To assess the risk of venous thromboembolism in women using hormone replacement therapy by study design, characteristics of the therapy and venous thromboembolism, and clinical background. Design Systematic review and meta-analysis. Data sources Medline. Studies reviewed Eight observational studies and nine randomised controlled trials. Inclusion criteria Studies on hormone replacement therapy that reported venous thromboembolism. Review measures Homogeneity between studies was analysed using χ 2 and I 2 statistics. Overall risk of venous thromboembolism was assessed from a fixed effects or random effects model. Results Meta-analysis of observational studies showed that oral oestrogen but not transdermal oestrogen increased the risk of venous thromboembolism. Compared with non-users of oestrogen, the odds ratio of first time venous thromboembolism in current users of oral oestrogen was 2.5 (95% confidence interval 1.9 to 3.4) and in current users of transdermal oestrogen was 1.2 (0.9 to 1.7). Past users of oral oestrogen had a similar risk of venous thromboembolism to never users. The risk of venous thromboembolism in women using oral oestrogen was higher in the first year of treatment (4.0, 2.9 to 5.7) compared with treatment for more than one year (2

Postmenopausal hormone replacement therapy is associated with a reduction in the incidence of coronary heart disease. However, inconclusive results have been reported with respect to the risk of stroke, and recent studies consistently showed an increased risk of venous thromboembolism in postmenopausal women using oral estrogen. There are surprisingly few interventional studies to assess the true effects of estrogen-progestin regimens on blood coagulation and fibrinolysis, and the impact of the route of estrogen administration on hemostasis has not been well documented. Therefore, we investigated the effects of oral and transdermal estradiol/progesterone replacement therapy on hemostatic variables. Forty-five healthy postmenopausal women, aged 45 to 64 years, were assigned randomly to one of the three following groups: cyclic oral or transdermal estradiol, both combined with progesterone, or no hormonal treatment. Hemostatic variables were assayed at baseline and after a 6-month period. Pairwise differences in the mean change between the three groups were compared using nonparametric tests. Oral but not transdermal estradiol regimen significantly increased the mean value of prothrombin activation peptide (F1 + 2) and decreased mean antithrombin activity compared with no treatment. Differences in fragment F1 + 2 levels between active treatments were significant. The oral estrogen group was associated with a significant decrease in both mean tissue-type plasminogen (t-PA) concentration and plasminogen activator inhibitor (PAI-1) activity and a significant rise in global fibrinolytic capacity (GFC) compared with the two other groups. A transdermal estrogen regimen had no significant effect on PAI-1, t-PA, and GFC levels. There were no significant changes in mean values of fibrinogen, factor VII, von Willebrand factor, protein C, fibrin D-dimer, and plasminogen between and within the three groups. We conclude that oral estrogen/progesterone replacement therapy may result in coagulation activation and increased fibrinolytic potential, whereas opposed transdermal estrogen appears without any substantial effects on hemostasis. Whereas these results may account for an increased risk of venous thromboembolism in users of oral postmenopausal estrogen, they emphasize the potential importance of the route of estrogen administration in prescribing hormone replacement therapy to postmenopausal women, especially to those at high risk of thrombotic disease.

We thank Drs Micheletti and Chevallier for their interest in our report. 1 First, we believe that odds ratios (ORs) and 95% confidence intervals (CIs) estimated from logistic regressions provide adequate information about significance and the size and direction of the effect of norpregnane derivatives. Because elevation in venous thromboembolism (VTE) risk is substantial (OR: 4) and significantly different from 1 (with the 95% CI not crossing 1), our results suggest a thrombogenic effect of norpregnanes, and the probability value (PϽ0.006) indicates that the probability of the result being due to chance is very small. Second, only the main effects of the route of estrogen administration and type of progestogens were estimated with a joint model ( Table 2 of the original article 1 ). Stratified analyses by route of estrogen administration and type of progestogens have also been performed. Among transdermal estrogen users, women received estrogen alone (10 cases and 35 controls; OR: 0.8, 95% CI: 0.4 to 1.8 after adjustment for obesity, family history of VTE, and varicose veins) or combined with either micronized progesterone (13 cases and 63 controls; OR: 0.6, 95% CI: 0.3 to 1.2), pregnane derivatives (16 cases and 51 controls; OR: 0.8, 95% CI: 0.4 to 1.6), or norpregnane derivatives (28 cases and 31 controls; OR: 3.1, 95% CI: 1.7 to 5.9). Among oral estrogen users, women received estrogen alone (4 cases and 5 controls) or combined with either micronized progesterone (6 cases and no controls), pregnane derivatives (23 cases and 28 controls), norpregnane derivatives (12 cases and 6 controls), or nortestosterone derivatives (12 cases and 7 controls). There was no significant difference in VTE risk between any of the progestogen subgroups among current users of oral estrogen (overall OR: 4.5, 95% CI: 2.6 to 7.5).Third, to allow for adequate numbers of subjects within subgroups, stratified analysis by time of exposure used the median of the distribution (5 years) as a cutoff point. Unlike oral estrogens, there was no significant interaction between the time of exposure to either transdermal estrogens or norpregnane derivatives and VTE risk. Therefore, differences in exposure time to hormone therapy cannot explain our results.Finally, although our results may be clinically relevant, we acknowledge that interpretation of data may have been biased by the inclusion of women with hyperestrogenic symptoms who were prescribed norpregnane derivatives. This prescription bias was emphasized in the Discussion section. Regarding the absence of thrombogenic mechanism underlying our results, Micheletti and Chevallier quote an inconclusive small trial 2 that failed to also show the well-known activation of blood coagulation among women using oral estrogens. In addition, relevant hemostatic tests such as plasmaactivated protein C sensitivity were not included as end points in this trial. Because relevant data are lacking, we are presently investigating the impact of norpregnanes on hemostasis among users of hormone therapy in the Stu...

Genetic variants of the beta fibrinogen gene are associated with an increased plasma level of fibrinogen, especially in smokers. The association with CAD appears to be the consequence of an increased risk of MI in subjects with severe CAD who carry the predisposing beta fibrinogen genotypes.

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. (Circulation.

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 (HRϭ1.1; 95% CI: 0.8 to 1.5). Oral not transdermal estrogens were associated with increased thrombotic risk (HRϭ1.7; 95% CI: 1.1 to 2.8 and HRϭ1.1; 95% CI: 0.8 to 1.8; homogeneity: Pϭ0.01). The thrombotic risk significantly differed by concomitant progestogens type (homogeneity: PϽ0.01): there was no significant association with progesterone, pregnanes, and nortestosterones (HRϭ0.9; 95% CI: 0.6 to 1.5, HRϭ1.3; 95% CI: 0.9 to 2.0 and HRϭ1.4; 95% CI: 0.7 to 2.4). However, norpregnanes were associated with increased thrombotic risk (HRϭ1.8; 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.

The prevalence of carotid atherosclerosis and of its risk factors was examined in 517 apparently healthy French women, aged 45-54 years. Early phases of carotid atherosclerosis were assessed by B-mode ultrasonography. An intimal-medial thickening was found in 30.4% of the women and atheromatous plaques in 8.7%. The prevalence rate of carotid atherosclerosis increased with age, smoking, and postmenopausal status. However, after adjustment for the effect of age, postmenopausal women did not have more atherosclerotic lesions than did premenopausal women. No significant associations were found between carotid atherosclerosis and triglyceride, apolipoprotein A-I, body mass index, blood glucose, fibrinogen, plasma viscosity, or hematocrit. The mean age-adjusted levels of total cholesterol, low density lipoprotein cholesterol, apolipoprotein B, and systolic and diastolic blood pressures significantly increased with the severity of carotid atherosclerosis, whereas high density lipoprotein cholesterol significantly decreased. Multiple regression analysis showed that age, smoking, high density lipoprotein cholesterol, low density lipoprotein cholesterol (or apolipoprotein B), and systolic (or diastolic) blood pressure were significantly and independently related to the severity of carotid atherosclerosis. In conclusion, the association of early carotid lesions with major cardiovascular risk factors suggests that carotid atherosclerosis may be used as a marker of the general atherosclerotic process. (Arteriosclerosis and Thrombosis 1991;ll:966-972)