ORAL menopausal hormone therapy (MHT) may increase the risk of venous thromboembolism regardless of dose or treatment duration, according to a nationwide Danish study.
The analysis also found that prolonged use of high-dose oral oestradiol was associated with increased risks of ischaemic stroke and myocardial infarction, while transdermal therapy was not associated with an overall increase in thrombotic events.
Researchers conducted a nationwide nested case-control study using Danish health registries, examining women aged between 50 and 69 years between 2003 and 2021.
The analysis identified 9,807 women with venous thromboembolism, 18,460 with ischaemic stroke, and 11,974 with myocardial infarction. Each group was matched by birth year with women who had not experienced the respective thrombotic event.
Prescription data allowed researchers to examine MHT according to route of administration, dose, duration, regimen, and active ingredients.
Among women who had not used MHT, incidence rates per 10,000 person-years were 15.8 for venous thromboembolism, 20.3 for ischaemic stroke, and 13.0 for myocardial infarction.
Compared with no current MHT use, oral oestrogen, either alone or combined with progestin, was associated with a 60% increased rate of venous thromboembolism.
Oral therapy was also associated with 30% and 20% increased rates of ischaemic stroke and myocardial infarction, respectively.
However, the arterial risks varied by dose and duration. Oral oestradiol at doses above 1 mg/day used for more than one year was associated with increased risks of stroke and myocardial infarction.
For use exceeding five years, the hazard ratio was 1.8 for both ischaemic stroke and myocardial infarction compared with no current use.
In contrast, oral MHT was associated with increased venous thromboembolism risk regardless of dose or duration.
Transdermal MHT was not associated with increased overall thrombotic rates, irrespective of regimen, dose, active ingredients, or treatment duration.
An exception was combined cyclic transdermal therapy, which was associated with increased myocardial infarction risk, although the researchers cautioned that this estimate was based on sparse data.
The findings could help inform conversations about MHT selection, particularly among women with existing risk factors for thrombotic disease.
However, the observational design means causality cannot be established. Researchers also lacked information on factors including BMI, smoking, and age at menopause.
The authors conclude that thrombotic risk differs according to the route, dose, and duration of MHT, highlighting the importance of individualised treatment decisions and encourage more research to investigate these links further.
Reference
Berggreen J et al. Contemporary menopausal hormone therapy and thrombotic disease: nationwide nested case-control study. BMJ. 2026;394:e100688. doi:10.1136/bmj-2026-100688.
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