Patching things up: Make hormone replacement therapy a little safer

EBM Focus - Volume 14, Issue 2

Read the full EBM Focus and earn CME credit.

Reference: BMJ 2019 Jan 9;364:k4810 (level 2 [mid-level] evidence)

Over half of women who enter into menopause will experience significant vasomotor symptoms, significantly impacting quality of life and function. In the late 1990s, as many as 1 in 3 postmenopausal women were prescribed hormone replacement therapy (HRT). As data emerged demonstrating harms of therapy, prescribing dropped dramatically. Current recommendations suggest using the lowest dose of hormone replacement therapy for the shortest duration possible after a discussion of risks and benefits. Observational and meta-analysis level data suggest transdermal HRT may be associated with a lower risk of venous thromboembolism (VTE) compared to oral formulations. In addition, the International Menopause Society recommends transdermal estrogen therapy as first choice for management of menopausal symptoms in obese women. Although no randomized trials have directly compared different formulations of HRT, most prescribing in high-income countries is still for oral formulations alone. In part due to this disconnect between prescribing and recommendations, researchers in the United Kingdom conducted a large case-control study using data from two datasets to evaluate the risk of venous thromboembolism with various formulations of hormone replacement therapy.

Retrospective data from 1998 through 2017 collected in the United Kingdom was used to identify over 78,000 women with VTE, capturing at least 15 years after the general shift away from HRT prescribing due to demonstrated harms. Cases were matched with up to 5 controls by age and practice. Women with a history of anticoagulant prescription and those controls with significant risk factors for VTE such as active cancer or prior VTE were excluded. Women prescribed HRT in the last 90 days leading up to the VTE diagnosis were identified through the same dataset. Women prescribed HRT were more likely to be younger (age 40-49) with normal body weight and fewer comorbid medical conditions. After adjusting for confounders, a logistic regression analysis was conducted and found that 7.2% VTE cases were exposed to HRT, compared to 5.5% of controls (OR 1.38 to 1.48). HRT was estimated to result in nine more cases of VTE per 10,000 women years. Over 85% of prescriptions for HRT in each group were for oral preparations, with only 14% of prescriptions in VTE case group and 19% of controls with prescription for transdermal formulation. When comparing the different formulations of HRT and subsequent risk of VTE, transdermal HRT was not associated with an increased risk of VTE (OR 0.87 to 1.01). When examining specific oral HRT formulations, those containing conjugated equine estrogen had a higher risk of VTE (OR 1.92 to 2.31), even when compared to oral estradiol.

Analysis of this large dataset from a single country further supports previous observational level data that use of transdermal hormone replacement therapy appears to have a lower risk of VTE compared to oral HRT, and transdermal HRT may not increase risk of VTE at all. Importantly, this study did not examine health benefits such as improvement in quality of life as well as other risks such rates of colon cancer or cardiovascular events. Despite earlier studies with similar results, one of the notable findings of this study is how many women continue to be prescribed oral estrogen.

Focus Point: When considering hormone replacement for menopausal women with vasomotor symptoms, observational data continue to support a lower rate of VTE risk with transdermal therapy.

For more information, see the topic Hormonal replacement therapy (HRT) and venous thromboembolism in DynaMed Plus. DynaMed users click here.

DynaMed Plus EBM Focus Editorial Team
This EBM Focus was written by Carina Brown, MD, Faculty Development and Information Mastery Fellow and Clinical Instructor at the University of Virginia. Edited by Alan Ehrlich, MD, Executive Editor at DynaMed Plus and Associate Professor in Family Medicine at the University of Massachusetts Medical School and Katharine DeGeorge, MD, MS, Assistant Professor in Family Medicine at the University of Virginia and Clinical Editor at DynaMed Plus.