Health

Oral vs. Transdermal HRT: Study Links Oral Therapy to Higher Blood Clot Risk

By Dr Natalie Singh - Health Editor Updated September 24, 2026

Current use of oral menopausal hormone therapy is associated with an increased risk of blood clots in the legs and lungs regardless of dose or treatment duration, according to a nationwide nested case-control study published in The BMJ in September 2026. Researchers examining Danish health registry data found that while oral hormone replacement therapy formulations elevate the risk of venous thromboembolism across all regimens, risks for ischemic stroke and heart attacks were restricted to prolonged use of high-dose oral treatments.

Danish Registry Study Design and Findings

Led by researchers investigating contemporary menopausal hormone therapy and thrombotic disease, the study utilized health registry data for women aged 50 to 69 living in Denmark between 2003 and 2021. The team identified 9,807 women diagnosed with a first venous thromboembolism, 18,460 women diagnosed with an ischemic stroke, and 11,974 women diagnosed with a myocardial infarction, or heart attack. These individuals were matched by birth year to control groups consisting of 49,035, 92,300, and 59,870 women without thrombotic disease, respectively. Prescription records assessed the links between hormone therapy use and thrombotic disease based on administration route, dose, duration, and the age treatment started. Women using oral menopausal hormone therapy showed a 60% higher risk for venous thromboembolism compared to nonusers, with a hazard ratio of 1.6, as reported by Healio. Unexposed women experienced baseline rates of 15.8 cases of venous thromboembolism, 20.3 cases of ischemic stroke, and 13.0 cases of heart attack per 10,000 person-years. Taking oral estrogen therapy—whether on its own or combined with progestin—was linked to a rise in annual absolute rates by 0.09% for venous thromboembolism, 0.06% for ischemic stroke, and 0.03% for heart attack. This means that roughly one additional case of venous thromboembolism occurs for every 1,055 women on oral hormone therapy for a year, along with one extra stroke for every 1,642 women and one additional heart attack for every 3,846 women.

Dose and Duration Impact on Stroke and Heart Attack Risk

The study established that increased risks for arterial events like ischemic stroke and myocardial infarction are not uniform across all oral regimens. These risks were confined to women taking high-dose oral estradiol of more than 1 mg per day for longer than one year, with risks rising alongside extended duration of use. Specifically, women receiving high-dose oral estradiol exceeding 1 mg daily experienced elevated risks for ischemic stroke and myocardial infarction compared to nonusers. Conversely, low-dose oral estradiol of 1 mg or less daily was not linked to an increased risk for ischemic stroke or myocardial infarction when compared against women not using hormone therapy. Amani Meaidi, a physician and research group leader in the department of gynecology and obstetrics at Copenhagen University Hospital of North Zealand, noted to Healio that this distinction is clinically important, suggesting that dose and duration are particularly relevant for arterial events.

Transdermal Hormone Therapy Safety Profiles

Transdermal hormone therapy delivered via the skin through patches, gels, or sprays demonstrated no general increased risk for thrombotic events, regardless of regimen, active ingredients, dose, or treatment duration. The authors noted that this finding highlights the critical role that the route of administration plays in minimizing thrombotic risk for menopausal patients. The sole exception observed among transdermal delivery methods was an increased heart attack rate among women utilizing combined transdermal cyclic therapy, which involves continuous transdermal estrogen paired with a progestogen added for part of the cycle to induce a monthly bleed. However, the study authors emphasized that this specific estimate relied on sparse data.

Clinical Implications and Study Limitations

Meaidi emphasized to Healio that menopausal hormone therapy should not be viewed as one uniform treatment, noting that its thrombotic risk depends heavily on the route of administration, the estrogen dose, and the duration of treatment. Estradiol was used among more than 96% of women receiving hormone therapy in the cohort, with 88% of participants utilizing an oral product. Because the investigation was an observational study, it cannot definitively establish cause and effect. The study authors also acknowledged limitations, including a lack of data on menopause age, body mass index, and smoking status, adding that results may not directly apply to other, more ethnically diverse populations. Nevertheless, the large population design, detailed prescription records, comprehensive sociodemographic information, and extended follow-up period support the robustness of the findings.