Estrogen and Venous Thrombosis: Route, Type, and Dose Matter!

JoAnn E. Manson, MD, DrPH


February 01, 2019

Hello. This is Dr JoAnn Manson, professor of medicine at Harvard Medical School and Brigham and Women's Hospital in Boston, Massachusetts. I'd like to talk with you about a recent report in the BMJ[1] on menopausal hormone therapy and risk for venous thromboembolism (VTE), which provides further evidence that transdermal estrogen does not increase this risk. We've known for a long time that oral hormone therapy is associated with increased risk for VTE, and several observational studies have suggested that these risks may not occur with transdermal estrogen. However, this new study really moves the needle, not only because of its large size, but because it looks at the formulation of estrogen—oral conjugated estrogen versus oral estradiol. It also looks at doses of oral and transdermal estrogen, estrogen alone versus combined estrogen plus progestin, and at the modifying effects of age and body mass index (BMI) on these associations.

This large study was conducted using United Kingdom primary care research databases that included 80,000 women with a first VTE and nearly 400,000 women without VTE. About 5%-7% of the women had a prescription for hormone therapy during the 90 days prior to the VTE event.

The researchers found that for oral estrogen alone, there was a 40% increased risk for VTE, and with oral estrogen plus progestin, there was a 73% increased risk. The formulation of estrogen and progestin made a difference, where oral conjugated estrogen was associated with greater risk than oral estradiol—about a 15% difference in risk for VTE.

The greatest risk was seen with oral conjugated equine estrogen (CEE) plus medroxyprogesterone acetate (MPA)—a relative risk of about 2.1, which was almost exactly what the Women's Health Initiative[2] found with CEE plus MPA. In contrast, transdermal estradiol was not associated with increased risk for VTE; the relative risk was 0.93. There really was no clear signal that the dose was making a difference; doses less than or greater than 50 µg had similar results. Younger women (aged 50-54) and even those under age 60 years tended to have lower risk for VTE than older women, and women with a BMI < 25 kg/m2 tended to have lower risk than women in the overweight or obese categories.

Overall, this is quite strong evidence that transdermal estradiol, and even vaginal estrogen, did not increase the risk for VTE, whereas there was a substantial increase in risk with the oral hormone therapy product. These findings suggest that it will be helpful to discuss the VTE risk with our patients in shared decision-making, and to mention that there appear to be advantages of the transdermal route over the oral route for patients who are going to be taking hormone therapy, and perhaps to encourage the transdermal formulation as the first option for them. The findings also suggest that a one-size-fits-all black box warning, the class labeling for hormone therapy that warns of the increased risk for VTE with all formulations and routes of delivery, should be reconsidered based on the growing evidence that transdermal estradiol and vaginal estrogen do not increase the risk for VTE.

Thank you so much for your attention. This is JoAnn Manson.


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