A large Danish registry study published in The BMJ reveals that oral menopausal hormone therapy is linked to an increased risk of venous thromboembolism across all doses and durations. However, elevated risks of stroke and heart attack are restricted to high-dose oral estradiol taken for over a year. Conversely, transdermal therapies show no overall increased risk. Experts like Dr. Amani Meaidi emphasize that these findings demand nuanced clinical conversations rather than labeling hormone therapy as simply safe or unsafe.
Oral hormone therapy and blood clot risks
- ▪A Danish study published in The BMJ found that current use of oral menopausal hormone therapy is associated with an increased risk of venous thromboembolism regardless of dose or treatment duration.
- ▪Current use of oral estrogen therapy was associated with absolute annual risk increases of 0.09% for venous thromboembolism, 0.06% for ischemic stroke, and 0.03% for heart attack.
Impact of oral estradiol dosage and duration
- ▪Oral estradiol doses of more than 1 mg per day used for over five years were associated with a hazard ratio of 1.8 for both stroke and myocardial infarction.
- ▪Ischemic stroke and heart attack risks were confined to oral estradiol of over 1 mg per day for more than one year; doses of 1 mg or less carried no increased risk.
Study methodology and population
- ▪The study matched 9,807 women with venous thromboembolism, 18,460 with ischemic stroke, and 11,974 with heart attack to 49,035, 92,300, and 59,870 controls without thrombotic disease, respectively.
- ▪The nationwide nested case-control study analyzed Danish health registry data from 2003 to 2021 for women aged 50 to 69 with no history of blood clots, cancer, liver disease, or oophorectomy.
- ▪The study's observational design prevents establishing direct cause and effect, and it lacked data on age at menopause, body mass index, smoking, and ethnically diverse populations.
Safety profile of transdermal therapy
- ▪Robert Storey of the University of Sheffield noted that transdermal patches avoid stimulating the liver to produce blood clotting factors, unlike oral estrogen which causes a stimulatory spike.
- ▪Transdermal menopausal hormone therapy delivered via patches, gels, or sprays showed no general increased risk of blood clots, stroke, or heart attack regardless of dose or duration.
- ▪An exception to transdermal safety was an increased heart attack risk associated with combined transdermal cyclic therapy, though researchers noted this estimate was based on sparse data.
Clinical communication and risk profiles
- ▪Amani Meaidi stated that clinicians must communicate both knowns and unknowns regarding safety, especially after the FDA removed boxed warnings of cardiovascular and cancer risks earlier in 2026.
- ▪Study co-author Amani Meaidi argued that the findings do not support describing menopausal hormone therapy as simply safe or unsafe, as risk profiles depend on method, dose, and duration.
Debatable claims
- ▪Clinicians should prescribe transdermal hormone therapy over oral therapy for menopausal symptoms
- ▪The FDA's removal of boxed warnings on menopausal hormone therapy is justified
- ▪The cardiovascular risks of oral menopausal hormone therapy outweigh its benefits
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