Women taking menopause hormone therapy in pill form had higher rates of blood clots in the legs and lungs than women not using hormones, according to a large Danish study published this week in The BMJ. The link held at every dose and treatment length the researchers examined. Women using patches, gels, or sprays showed no general increase in clot risk.
The findings matter for the many U.S. women in their 50s and 60s weighing treatment for hot flashes, night sweats, and poor sleep. The extra risk was small in absolute terms, and the study was observational, so it shows an association rather than proof that the pills caused the clots. Still, it gives women and clinicians sharper detail on a practical question: whether the way estrogen enters the body changes the risk.
The timing is notable. The FDA announced it would remove broad boxed warnings from menopause hormone products in November 2025. In February, it approved label changes for six hormone therapy products that removed statements about cardiovascular disease, breast cancer, and probable dementia from the boxed warning, the agency's most prominent safety warning. The Danish data add a route-by-route view of clot risk to those treatment conversations.
Inside the Danish Registry Numbers
Researchers searched national health registries for women aged 50 to 69 living in Denmark between 2003 and 2021, according to the BMJ Group summary of the research. They identified 9,807 women with a first venous thromboembolism (a clot in a vein, usually in the leg or lung), 18,460 with an ischemic stroke, and 11,974 with a heart attack. Each case was matched by birth year with women who had no clotting disease, about 200,000 in all, and prescription records showed who was using hormones and in what form.
Among women not using hormones, baseline rates were 15.8 vein clots, 20.3 strokes, and 13.0 heart attacks per 10,000 person-years. Oral estrogen, alone or with a progestin, was tied to about one extra vein clot for every 1,055 women treated for a year. The comparable figures were one extra stroke per 1,642 women and one extra heart attack per 3,846 women.
The stroke and heart attack signals were confined to women taking high-dose oral estradiol, above 1 mg a day, for more than a year, and they rose with longer use. Transdermal therapy, which delivers hormones through the skin, showed no general rise in clotting events regardless of regimen, dose, or duration. One exception was a higher heart attack rate with a cyclic regimen that combined an estrogen patch or gel with a progestogen for part of each month, which the authors said rested on sparse data.
Put another way, most women taking oral therapy in the study never developed a clot. The results point to a modest shift in risk that becomes more meaningful for women who already have other clot risk factors or who take higher doses for years. The authors said the pattern highlights the importance of the delivery route in keeping risk low.
What the Study Can and Cannot Show
This was a nationwide nested case-control study, a form of observational research that can reveal patterns across large populations but cannot prove cause and effect. The researchers lacked data on body mass index, smoking, and age at menopause, all of which can affect clot risk. The authors also noted that the results may not apply to more ethnically diverse populations, such as the United States.
The research was externally peer-reviewed. The authors said the study's large size, detailed prescription data, extensive health information, and long follow-up suggest the results are robust. The British Menopause Society said the work adds real-world evidence to support individualized prescribing and noted that hormone therapy remains an effective, well-established treatment for menopause symptoms. The society added that the absolute increases in risk remain small.
Dr. Amani Meaidi, a physician and research group leader in gynecology and obstetrics at Copenhagen University Hospital of North Zealand in Denmark, wrote a linked opinion piece in The BMJ. She told Healio that menopausal hormone therapy "should not be viewed as one uniform treatment." She said transdermal therapy is preferred based on the findings. When pills are appropriate, she said, clinicians should consider the lowest effective dose, ideally no more than 1 mg of estradiol a day, and regularly reassess the need for treatment.
Women Who Should Pay Closest Attention
The findings are most relevant to women already taking oral estrogen and to those deciding between pills and skin-based products. Clinicians generally weigh clot risk more heavily for women with obesity, limited mobility, recent surgery, a history of smoking, or a family history of clots. Women who had a prior clot were excluded from this study, and their treatment decisions typically need specialist input.
A deep vein clot can cause swelling, pain, warmth, or redness, usually in one leg. A clot that travels to the lungs can cause sudden shortness of breath, chest pain that worsens with breathing, a rapid heartbeat, or coughing up blood. Those symptoms, along with signs of stroke such as facial drooping, arm weakness, or slurred speech, require emergency care.
Women should not stop or switch prescribed hormones on their own. A reasonable next step is to ask a clinician which route and dose they are using, whether a patch or gel would suit their health history, and how often the need for treatment should be reviewed. Coverage can differ between pills, patches, and gels, so a pharmacist can check a plan's formulary before a switch.
More label updates are likely, since the FDA said in February that 29 drug companies had submitted proposed labeling changes at its request. Meaidi also called for research that better identifies which women benefit most from hormone therapy and who faces higher risk. For now, the study offers reassurance about skin-based therapy and a clear reason to review oral dosing, while the absolute risk remains low for most healthy women in their 50s.
Key Questions Answered
What did the Danish study find? Women using oral menopause hormone therapy had a higher rate of blood clots in the legs or lungs than nonusers. Women using patches, gels, or sprays showed no general increase.
Does this prove hormone pills cause blood clots? No. The study was observational and shows an association, not cause and effect. Researchers also lacked data on body weight and smoking.
How large is the added risk? Researchers estimated about one extra vein clot for every 1,055 women taking oral therapy for a year. The absolute risk is small for most women.
Were strokes and heart attacks affected? Higher stroke and heart attack rates appeared only with high-dose oral estradiol, above 1 mg a day, used for more than a year.
Should I stop taking my hormone pills? Do not stop or change prescribed medication without speaking with a clinician. Ask whether your dose and route still fit your health history.
What symptoms need urgent care? Sudden shortness of breath, chest pain, one-sided leg swelling, facial drooping, or slurred speech require emergency evaluation.
Published by Medicaldaily.com
