Current use of oral menopausal hormone therapy may increase the risk of venous thromboembolism (VTE) regardless of dosage and treatment duration compared with no use, according to a study.
Furthermore, prolonged use of high-dose oral oestradiol (>1 mg/day) elevates the risks of ischaemic stroke and myocardial infarction (MI), while transdermal therapy does not increase thrombotic risks.
This nationwide nested case-control study used the national Danish health registries to identify women aged 50‒69 years living in Denmark between 2003 and 2021 without a medical history of venous thrombosis, arterial thrombosis, cancer, liver disease, thrombophilia, oophorectomy, infertility treatment, endometriosis, or polyendocrine metabolic ovarian syndrome.
Of the women, 9,807 had VTE, 18,460 had ischaemic stroke, and 11,974 had MI. Participants were matched by birth year to 49,035, 92,300, and 59,870 women without thrombotic disease, respectively.
The incidence rates of VTE, ischaemic stroke, and MI among women who had not used menopausal hormone therapy were 15.8, 20.3, and 13.0 per 10,000 person-years, respectively. [BMJ 2026;394:e100688]
Current use of oral oestrogen therapy (alone or combined with progestin), compared with no current use, correlated with increased rates of VTE (hazard ratio [HR], 1.6, 95 percent confidence interval [CI], 1.5‒1.8), ischaemic stroke (HR, 1.3, 95 percent CI, 1.2‒1.4), and MI (HR, 1.2, 95 percent CI, 1.1‒1.3).
The absolute risk increase per year was 0.09 percent (95 percent CI, 0.08‒0.13) for VTE, 0.06 percent (95 percent CI, 0.04‒0.08) for ischaemic stroke, and 0.03 percent (95 percent CI, 0.01‒0.04) for MI. The corresponding numbers needed to harm for 1 year of oral therapy use were 1,055 (95 percent CI, 791‒1,255), 1,642 (95 percent CI, 1,232‒2,463), and 3,846 (95 percent CI, 2,564‒7,692).
Moreover, use of oral oestradiol showed a consistent association with a higher VTE risk compared with no current use. Oral oestradiol doses >1 mg/day used for >1 year also correlated with elevated risks of ischaemic stroke and MI. Such risks increased with duration (stroke: HR, 1.8, 95 percent CI, 1.4‒2.2; MI: HR, 1.8, 95 percent CI, 1.4‒2.4 for >5 years of use vs no current use).
On the other hand, transdermal therapy did not correlate with higher thrombotic rates compared with no current use, except for an increased risk of MI with transdermal plus cyclic therapy (HR, 2.1, 95 percent CI, 1.1‒4.1).
Coagulation factors
“Exogeneous oestrogen is known to cause hypercoagulability by increasing multiple coagulation factors involved in the development of venous thromboembolism,” the investigators said. [Menopause 2011;18:873-879]
“The effects on the arterial system are less well understood, although post-trial analyses have indicated that oral combined oestrogen-progestin therapy may promote atherogenesis, which could potentially explain the increased arterial thrombotic risk observed with oral high-dose and long-term treatment observed in this study,” they added. [J Clin Endocrinol Metab 2018;104:293-300]
In contrast, transdermal therapy bypasses the hepatic first pass metabolism, which is known to increase hepatic synthesis of prothrombotic factors. This potentially explains the different risk profiles between oral and transdermal formulations, according to the investigators. [J Women Health 2012;21:161-169]
“The findings from this study, together with earlier evidence, indicate that the thrombotic risk associated with contemporary systemic menopausal hormone therapy is influenced by the method of use, the daily oestrogen dose, and treatment duration,” the investigators said.
“These insights may inform clinical practice, guiding clinicians and patients in making evidence-based decisions to minimize thrombotic risk of hormone therapy,” they added.
“Future research should further explore the long-term cardiovascular risks associated with different treatment regimens and the influence of individual cardiovascular risk profiles including age at menopause onset,” the investigators said.