Current use of oral menopausal hormone therapy (commonly known as hormone replacement therapy or HRT) is associated with an increased risk of blood clots in legs / lungs regardless of dose or treatment duration, finds a large Danish study published by The BMJ today.
Conversely, stroke and heart attack risks were limited to prolonged use of high-dose oral hormone therapy, while transdermal hormone therapy (delivered via the skin as patches, gels, or sprays) showed no general increased blood clot risk.
Hormone therapy relieves menopausal symptoms such as hot flushes and night sweats. Some studies have linked oral hormone therapy to rare but serious blood clots known as venous thromboembolism and stroke, but evidence for heart attack remains inconsistent.
To explore this further, researchers searched Danish health registry data for women aged 50-69 living in Denmark between 2003 and 2021 and diagnosed with a first venous thromboembolism, ischaemic stroke, or heart attack (myocardial infarction).
They identified 9,807 women with venous thromboembolism, 18,460 women with ischaemic stroke, and 11,974 women with heart attack. These women were matched by birth year to a total of 49,035, 92,300, and 59,870 women without thrombotic disease, respectively.
Prescription records were then used to assess any links between hormone therapy use and thrombotic disease according to several variables including route of administration, dose, duration of use, and age treatment was started.
None of the women had a history of blood clots, cancer, liver disease, endometriosis, polycystic ovary syndrome, fertility treatment or surgery to remove ovaries (oophorectomy). Other potentially influential factors such as income, education, medication use and pre-existing conditions were also taken into account.
Among women unexposed to hormone therapy, rates of venous thromboembolism, ischaemic stroke, and heart attack were 15.8, 20.3, and 13.0 per 10,000 person-years, respectively.
Oral oestrogen therapy (alone or with progestin) was associated with absolute increased rates of 0.09% for venous thromboembolism, 0.06% for ischaemic stroke, and 0.03% for heart attack per year. This corresponds to one extra venous thromboembolism case per 1,055 women taking oral hormone therapy for one year, one extra stroke per 1,642, and one extra heart attack per 3,846.
Oral therapy was consistently associated with increased venous thromboembolism risk, whereas increased stroke and heart attack risks were confined to those taking high-dose oral oestradiol (above 1 mg/day) for more than a year, rising with longer use.
Conversely, transdermal therapy showed no general increased thrombotic risk regardless of regimen, dose, or duration, which the authors say highlights the importance of delivery route in minimising risk.
One exception was an increased heart attack rate among women using combined transdermal cyclic therapy (continuous oestrogen through the skin with progestogen added for part of the cycle to induce a monthly bleed), although the authors note this estimate is based on sparse data.
This is an observational study so can’t establish cause and effect, and the authors acknowledge a lack of data on menopause age, body mass index, and smoking, and that results may not apply to other more ethnically diverse populations. However, they say the large population design, use of detailed prescription data, the extensive health and sociodemographic information on the study population, and long follow-up suggest the results are robust.
They conclude: “Current use of any oral menopausal hormone therapy was associated with an increased venous thromboembolism risk, whereas ischaemic stroke and myocardial infarction risk was only increased with oral high-dose therapy used for more than one year.”
They add: “Transdermal therapy was not associated with increased thrombotic rates regardless of regimen, active ingredients, dose, and duration of use.”
The BMJ
Observational study
People
Contemporary menopausal hormone therapy and thrombotic disease: nationwide nested case-control study
23-Sep-2026
: All authors have completed the ICMJE uniform disclosure form at http://www.icmje.org/disclosure-of-interest/ and declare: no support from any organisation for the submitted work; AM has received presentation fees from Astellas. CTP has received grants from Bayer and the Novo Nordisk Foundation. EL has received presentation fees from Gedeon Richter and Pfizer, travel support for meetings from Merck, Astellas, and Gedeon Richter, and a fee from Radiometer. All other authors declare no financial support for the submitted work, no financial relationships with any organisations that might have an interest in the submitted work in the previous three years, and no other relationships or activities that could appear to have influenced the submitted work.