A Safer Menopausal Estrogen?

Large clinical trials have shown that oral postmenopausal estrogen treatment does not provide overall clinical benefit in chronic disease prevention,1,2 and current recommendations suggest that it be prescribed for only short durations for relief of menopausal symptoms. Because these drugs provide effective relief of menopausal symptoms, and venous thrombosis is the most common adverse vascular outcome of treatment, a better understanding of the venous safety of alternative forms of hormones than those widely studied is needed. In this issue of Atherosclerosis, Thrombosis, and Vascular Biology, results from the E3N cohort study relating route of administration of postmenopausal hormones to the risk of idiopathic venous thrombosis are presented.3 The investigators ascertained use of postmenopausal hormone treatment at 2-year intervals in 80 308 postmenopausal women without a history of cancer or prior thrombosis. Women were followed on average for 10.1 years, between 1992 and 2005. Participants were primarily teachers living in France. Hormone use status was evaluated in relation to the risk of developing venous thrombosis. During follow up, 549 women experienced idiopathic venous thrombosis, 415 with deep vein thrombosis and 134 with pulmonary embolism. The 329 women who experienced a provoked venous thrombosis were censored from the analysis at the time of their event. The rationale for this was to avoid “diluting” the impact of hormone treatment on thrombosis risk. Women experiencing other types of venous thrombosis, such as upper extremity, superficial thrombophlebitis, or retinal vein thrombosis were not considered cases. The major finding of this study was that oral, but not transdermal estradiol, was associated with risk of venous thrombosis. Adjusting for other risk factors, use of oral estradiol was associated with a 1.7-fold increased risk of venous thrombosis (95% confidence interval [CI], 1.1 to 2.8), whereas the risk estimate for transdermal estradiol was 1.1 (95% CI, 0.8 to 1.8). The authors further assessed the progestagen type used in relation to venous thrombosis risk. Among micronized progesterone, pregnane derivatives, norpregnane derivatives, and nortestosterone derivatives, only the use of norpregnane derivatives (nomegestrol acetate and promegestone), compared to no progestagen, was associated with increased risk of venous thrombosis when used with transdermal estrogen. The authors conclude that transdermal estrogen may be safe from the standpoint of venous thrombosis unless administered with norpregnane progestagens, agents used in Europe and not the United States.