Menopausal Hormone Therapy Thrombotic Risk Varies by Dose, Route of Administration

While taking oral menopausal hormone therapy, women faced increased thrombotic risks that varied by the method of use, dosage, and duration of treatment, a nationwide study from Denmark showed.

Venous thromboembolic risk remained elevated across treatment characteristics, with a hazard ratio of 1.6 with current use of oral estrogen with or without progestin versus no current use, corresponding to an absolute 0.09% risk per year and a number needed to harm of 1,055 with 1 year of use, reported researchers led by Julie Berggreen, MD, of Nordsjællands Hospital in Hillerød, Denmark.

Only high estradiol doses of more than 1 mg per day for more than 1 year came with elevated risk of stroke (HR 1.5 vs no current use, 95% CI 1.4-1.6) and myocardial infarction (HR 1.4, 95% CI 1.2-1.6), whereas oral low-dose estradiol use carried no increased risk of these outcomes (HR 1.0, 95% CI 0.9-1.1, and HR 0.9, 95% CI 0.8-1.1, respectively).

Notably, transdermal therapy appeared to be safer, showing increased risk only for myocardial infarction with combined cyclic therapy (HR 2.1, 95% CI 1.1-4.1), “supporting the importance of method of use in minimizing risk of thrombosis,” the researchers reported in The BMJ.

In an accompanying opinion piece, co-author Amani Meaidi, MD, PhD, of Copenhagen University Hospital of North Zealand in Denmark, argued for a nuanced message from the data.

“These findings do not support describing menopausal hormone therapy as simply safe or unsafe; the results instead suggest that there is no single risk profile for hormone therapy. Risk may depend on the therapy prescribed, the method of use, the dosage, and duration of treatment,” she wrote.

While the FDA removed boxed warnings of cardiovascular disease, breast cancer, and probable dementia risk from menopausal hormone therapy earlier this year, clinicians still need to be honest about uncertainty and communicate both what we do know and what we do not know regarding safety, Meaidi said.

“The goal should not be to return to an era in which women were unnecessarily frightened away from effective treatment, but neither should we enter an era in which enthusiasm for menopause care makes uncertainty disappear from the conversation,” she wrote.

“It is well recognized that oral estrogen replacement increases the risk of leg vein clots, which can cause life-threatening lung blood clots,” observed Robert Storey, BM, DM, of the University of Sheffield in England, who wasn’t involved with the study.

“Taking oral estrogen replacement leads to a spike in the level that stimulates the liver to increase production of factors that stimulate blood clot formation. Similarly, it is well described that estrogen replacement patches don’t carry the same risk since they don’t stimulate the liver in the same way, so the study results confirm this in a convincing way,” he wrote in comments posted on the U.K. Science Media Centre website.

“The increased risk of stroke and heart attack associated with high dose oral estrogen replacement reported in this study raises concerns about this treatment, even though it remains uncertain whether this treatment is directly responsible since these observational studies cannot exclude other explanations that are not apparent from the data,” Storey said.

The study encompassed Danish health registry and prescription record data for women ages 50-69 living in Denmark between 2003 and 2021 who were diagnosed with a first venous thromboembolism (9,807), ischemic stroke (18,460), or myocardial infarction (11,974). They were matched by birth year to a total of 49,035, 92,300, and 59,870 women without thrombotic disease, respectively.

Exclusion criteria included history of blood clots, cancer, liver disease, endometriosis, polyendocrine metabolic ovarian syndrome (previously known as polycystic ovary syndrome), fertility treatment, and oophorectomy. Analyses were adjusted for income, education, health conditions (hypertension, atrial fibrillation, cardiomyopathy, heart failure, valvulopathy, diabetes, thyroid disease, kidney disease, chronic obstructive pulmonary disease, and migraine), hysterectomy, and use of statins, bisphosphonates, anticoagulants, aspirin, antidepressants, and antipsychotics.

While the observational study could not establish cause and effect, other limitations included lack of data on age at menopause, body mass index, and smoking, as well as the lack of population diversity that might limit generalizability to other more ethnically diverse populations.