Menopause hormone tablets were linked to more blood clots in a Danish study; patches and gels were not

How a woman takes menopausal hormone therapy may matter for her risk of blood clots. A study drawing on the records of women aged 50 to 69 across Denmark over 18 years found that hormone tablets were linked to more blood clots in the legs and lungs. Hormones delivered through the skin, as patches, gels or sprays, were not.

The study was published on September 23 in the BMJ. The extra risk it found is small in absolute terms, about one additional clot a year for every thousand women on tablets. It is an observational study, so it cannot prove the tablets were responsible, and it had no information on smoking or body weight. Its value is in the detail: modern preparations, sorted by dose, duration and route.

What the Danish hormone therapy study did

Hormone therapy replaces the estrogen that falls away at menopause, usually together with a progestin, a second hormone that protects the lining of the womb. It is prescribed to relieve hot flashes and night sweats. Its link to clots has been known since a large American trial was halted in 2002, but that trial tested a single tablet.

The Danish team asked the same question about today’s products. They used national health registers covering women living in Denmark between 2003 and 2021, and built what is called a nested case-control study. That means they found every woman with a first diagnosis of one of three conditions and compared her hormone prescriptions with those of women the same age who had not been diagnosed.

The three conditions were venous thromboembolism, meaning a clot in a deep vein that can travel to the lungs; ischemic stroke, the kind caused by a blocked artery; and heart attack. The registers yielded 9,807 women with a clot, 18,460 with a stroke and 11,974 with a heart attack, 40,241 in all. They were matched by birth year with 201,205 women who had none of these.

Women with a history that would cloud the comparison were left out, including those with earlier clots, cancer or liver disease. Other potentially influential factors such as income, education, medication use and pre-existing conditions were also taken into account.

Hormone tablets and blood clots, strokes and heart attacks

The clearest result concerned tablets and clots. Compared with women not currently using hormones, those taking estrogen by mouth, with or without a progestin, had a 60% higher rate of venous thromboembolism. The authors conclude that oral menopausal hormone therapy was associated with increased venous thromboembolic risk regardless of dosage and treatment duration. Oral means taken by mouth.

Tablets were also associated with a 30% higher rate of stroke and a 20% higher rate of heart attack. Those two increases turned out to be concentrated. They were confined to women taking more than 1 mg a day of estradiol, the main form of estrogen, for more than a year, with risks increasing with treatment duration. After more than five years at that dose, the rate of each was about 80% higher than in non-users.

Outcome	Rate in women not using hormones, per 10,000 a year	Extra cases with tablets, per 10,000 women a year	Women taking tablets for a year for one extra case
Clot in leg or lung	15.8	About 9	1,055
Stroke	20.3	About 6	1,642
Heart attack	13.0	About 3	3,846

Patches, gels and sprays showed no increase in blood clots

Hormones absorbed through the skin told a different story. The authors’ summary is that no increased thrombotic risks were observed with transdermal therapy, transdermal meaning through the skin and thrombotic meaning related to clots.

That held across nearly all the comparisons the authors made. “Transdermal therapy was not associated with increased thrombotic rates regardless of regimen, active ingredients, dose, and duration of use,” the authors said.

They flagged one exception. Women using a regimen that pairs continuous estrogen through the skin with a progestin for part of each month had a higher rate of heart attack. The authors themselves treat it with doubt, and they note this estimate is based on sparse data.

A biological reason for the difference has been proposed for years. Andrew Shelling, a professor of obstetrics and gynecology at the University of Auckland who was not involved in the study, pointed to oral formulations that involve metabolism in the liver. Swallowed hormones are processed there, which alters the proteins that make blood clot. Hormones taken through the skin largely avoid that step.

How small the added blood clot risk is

A 60% increase sounds large. It is an increase on a small number.

Among Danish women in their fifties and sixties who did not use hormones, about 16 in every 10,000 had a first clot each year. With tablets, the study’s estimate is about nine more. Put another way, 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.

Experts not connected with the study read the figures the same way. “This study confirms the findings of other studies around the world. The overall risk is fairly small,” said Cindy Farquhar, a professor of obstetrics and gynecology at the University of Auckland. Farquhar added that the risk was higher in older women and at higher doses.

Shelling set the risk against what the treatment is for. In Shelling’s view the absolute risk is low in most women and is outweighed by the benefits of menopause symptom relief. Shelling also noted that other things affect a woman’s chance of a clot, among them obesity, smoking, earlier illness and age.

How the result fits with earlier hormone therapy studies

It repeats a pattern seen in other countries’ records.

In 2019 a team at the University of Nottingham ran a similar analysis in two large databases of British family doctors’ records. Tablets were associated with 58% higher odds of a clot. Transdermal preparations were not associated with risk of venous thromboembolism. The authors remarked that prescribing had not caught up: transdermal treatment appears to be underused, with the overwhelming preference still for oral preparations.

In 2024 a Swedish group used national registers to follow 919,614 women, comparing those who started hormone therapy with those who did not. A higher risk of venous thromboembolism was observed for oral continuous combined therapy, meaning estrogen and a progestin taken together every day, with a rate about 61% higher, and for other tablet regimens. That study did not clear skin delivery entirely. It found a clot rate about 46% higher with one combination given through the skin, a result the Danish data did not repeat.

Behind all three stands the trial that changed practice. The Women’s Health Initiative randomly assigned 16,608 American women to a combined hormone tablet or placebo. After a mean of 5.2 years of follow-up, the data and safety monitoring board recommended stopping the trial, because harms were outrunning benefits. That board is the independent committee that watches a trial’s results as they come in. Clots in the lungs alone were among the harms, at about eight extra cases per 10,000 women a year. The Danish figure of nine also counts clots in the legs, so the two are not measured alike, but they are of the same order, from a different design and a different product.

What the registry studies add is the contrast with skin delivery, which the American trial did not test.

What the Danish study cannot show

Cause. Women were not assigned to tablets or patches. Doctors and patients chose, and the choice may track things that also affect clotting.

Missing measures. The authors acknowledge a lack of data on menopause age, body mass index, and smoking. Body mass index is a measure of weight for height. Smoking and obesity both raise the risk of clots, strokes and heart attacks. If women given tablets differed on those from women given patches, some of the gap could come from that.

Other populations. The results come from Denmark and its mix of products. They may not carry over to other preparations or to more ethnically varied populations.

Rare regimens. Some combinations were used by few women, which is why the one adverse signal for a skin regimen is hard to interpret.

Benefits. The study counted clots, strokes and heart attacks. It did not weigh them against relief from symptoms, or against effects on bones or other conditions.

Whether hormone therapy, and which form, suits a particular woman depends on her symptoms, age and medical history, which is assessed by her doctor. Do not stop or change a prescribed medicine without talking to your doctor.

In Danish national records, menopausal hormone tablets were associated with about nine extra blood clots a year per 10,000 users and skin-delivered hormones with no detectable increase, in an observational study that lacked data on smoking and weight.