A study of 1 million women found that HRT pills were linked to more blood clots at every dose, while patches and gels were not. Yet 88% of the women on HRT in the study were taking pills.
Since a major trial raised alarms about hormone therapy in 2002, women starting it for hot flashes and night sweats have heard the same advice: take the lowest dose for the shortest time. Most take it as a daily pill. Danish researchers have now gone through the prescription and hospital records of more than one million women aged 50 to 69, followed for a median of nine years, to see which kinds of HRT were linked to blood clots, strokes and heart attacks. The dose turned out to matter less for clots than many women would expect.
How the Danish records were used
Denmark records every hospital diagnosis and every filled prescription under a single personal number, which lets researchers follow an entire population. The team, led by Julie Berggreen and Amani Meaidi, studied women living in Denmark between 2003 and 2021 who had no history of blood clots, cancer, liver disease, or several hormone-related conditions.
Within that group, they found 9,807 women who developed a first blood clot in the legs or lungs, 18,460 who had a first ischemic stroke, and 11,974 who had a first heart attack. Each was compared with five women of the same birth year who had none of these events. The researchers then checked who was using hormone therapy at the time, in what form, at what dose, and for how long. They adjusted for income, education, living situation, high blood pressure, diabetes, heart conditions, migraine, hysterectomy, and medications such as statins, aspirin and antidepressants.
Among women using hormone therapy, 88% took it as a pill. Oestradiol, the main form of estrogen prescribed in Denmark, made up more than 96% of use.
Where the extra HRT blood clots came from
Among women who were not using hormones, about 16 in 10,000 developed a blood clot in the legs or lungs each year. Women taking HRT as a pill had a 1.6 times higher rate. In absolute terms, that comes to about one extra clot for every 1,055 women taking the pill for a year, or roughly 9 extra clots per 10,000 women. Pills were also linked to more strokes (one extra per 1,642 women per year) and heart attacks (one extra per 3,846).
The clot link held across every oral dose, regimen and treatment length the team examined. Lower doses helped somewhat: high doses above 1 mg of oestradiol a day carried a 1.3 times higher clot rate than low doses, and the risk peaked in the first year of high-dose use, at 3.2 times the rate in non-users. But even low-dose pills were linked to more clots than no hormones at all.
Strokes and heart attacks followed a different pattern. Low-dose pills showed no increase in either. The extra risk appeared only with high-dose pills, and it grew the longer women stayed on them. After more than five years of high-dose oral therapy, stroke and heart attack rates were both about 1.8 times those of non-users. In this study, 60% of women on pills were taking the high dose.
Patches, gels and sprays told a different story. Women using hormones through the skin had no overall increase in blood clots, strokes or heart attacks, whatever the dose or duration. The one exception was a higher heart attack rate in women using a skin product combined with a progestogen taken for part of each month to trigger a monthly bleed, an estimate the authors say rests on sparse data.
The authors point to the liver as a likely explanation. Swallowed estrogen passes through the liver first, where it is thought to boost the production of clotting proteins. Estrogen absorbed through the skin skips that step.
What earlier studies found
The pattern for HRT and blood clots is not new. The Women’s Health Initiative trial in 2002, which used a different, older estrogen pill, reported higher rates of blood clots and strokes in women taking combined hormone therapy, and its results reshaped prescribing worldwide. In 2019, a study of UK primary care records found that oral HRT was linked to a higher risk of venous blood clots while skin-based therapy was not, closely matching the new Danish numbers.
Not every study agrees on strokes. The authors note that some randomized trials found no stroke link, though most tested older estrogen types and did not compare doses, and a recent analysis designed to mimic a trial found no stroke link for either pills or patches. What the Danish study adds is detail: how risk changes with dose, regimen and years of use for the estradiol products women are prescribed today.
Hormone therapy has been getting a second look on other fronts too. In August, a study of 21,000 women linked estrogen-only therapy to fewer Alzheimer’s changes in the brain.
What the study cannot show
This is an observational study, so it shows links between HRT and blood clots, not proof that pills cause them. The registries had no data on body weight, smoking, or age at menopause, all of which affect clot risk. The authors argue this is unlikely to explain the results. Doctors often steer women with more heart risk factors toward patches, which should make patches look worse, not better. And women who had stopped hormones showed no increased risk, which points to the drug rather than a lasting trait of the women who take it.
The results apply to oestradiol, the estrogen used in Denmark. They may not carry over to conjugated equine estrogens, long common in the United States, or to micronized progesterone, which is increasingly prescribed. The study population was also largely of one ethnic background.
For an individual woman, the absolute risks are small, and hormone therapy can bring real relief from menopause symptoms. The findings suggest the form of treatment deserves as much attention as the dose. Women taking HRT pills should not stop suddenly, and can raise the question of patches or gels with their doctor.
The study received no funding. Some authors reported presentation fees, travel support or grants from Astellas, Bayer, the Novo Nordisk Foundation, Gedeon Richter, Pfizer, Merck and Radiometer.
Source
Berggreen J, Pourhadi N, Wood-Kurland H, et al. “Contemporary menopausal hormone therapy and thrombotic disease: nationwide nested case-control study.” The BMJ, 2026.
DOI: 10.1136/bmj-2026-100688
Also cited
Writing Group for the Women’s Health Initiative Investigators. “Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women’s Health Initiative randomized controlled trial.” JAMA, 2002.
DOI: 10.1001/jama.288.3.321
Vinogradova Y, Coupland C, Hippisley-Cox J. “Use of hormone replacement therapy and risk of venous thromboembolism: nested case-control studies using the QResearch and CPRD databases.” The BMJ, 2019.
DOI: 10.1136/bmj.k4810
