Contemporary menopausal hormone therapy and thrombotic disease: nationwide nested case-control study

Objectives To investigate associations between current use of menopausal hormone therapy and development of venous thromboembolism, ischaemic stroke, and myocardial infarction.

Design Nationwide nested case-control study.

Setting National Danish health registries.

Participants 9807 women with venous thromboembolism, 18 460 women with ischaemic stroke, and 11 974 women with myocardial infarction were identified in a cohort of women of 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 (PMOS, previously known as polycystic ovary syndrome). Cases were matched by birth year to a total of 49 035, 92 300, and 59 870 women without thrombotic disease, respectively.

Main outcome measures Receiving a first time diagnosis of venous thromboembolism, ischaemic stroke, or myocardial infarction.

Results Among women who had not used menopausal hormone therapy, incidence rates of venous thromboembolism, ischaemic stroke, and myocardial infarction per 10 000 person years were 15.8, 20.3, and 13.0, respectively. Compared with no current use, current use of oral oestrogen therapy (alone or combined with progestin) was associated with increased rates of venous thromboembolism (hazard ratio 1.6, 95% CI 1.5 to 1.8), ischaemic stroke (1.3, 1.2 to 1.4), and myocardial infarction (1.2, 1.1 to 1.3). The absolute risk increase per year was 0.09% (95% confidence interval (CI) 0.08 to 0.13%) for venous thromboembolism, 0.06% (0.04 to 0.08%) for ischaemic stroke, and 0.03% (0.01 to 0.04%) for myocardial infarction, corresponding to numbers needed to harm for one year of use of 1055 (95% CI 791 to 1266), 1642 (1232 to 2463), and 3846 (2564 to 7692), respectively.

Use of oral forms of oestradiol was consistently associated with increased venous thromboembolic risk compared with no current use. Oral oestradiol doses >1 mg/day used for more than one year was associated with increased risks of ischaemic stroke and myocardial infarction, with risks increasing with treatment duration (stroke hazard ratio 1.8, 95% CI 1.4 to 2.2 and myocardial infarction hazard ratio 1.8, 1.4 to 2.4 for >5 years of use compared with no current use).

Transdermal therapy was not associated with increased thrombotic rates compared with no current use, with the exception of increased risk of myocardial infarction with transdermal combined cyclic therapy (hazard ratio 2.1, 95% CI 1.1 to 4.1).

Conclusions Compared with no current use of any hormone therapy, oral menopausal hormone therapy was associated with increased venous thromboembolic risk regardless of dosage and treatment duration, while prolonged use of high dose oral oestradiol (>1 mg/day) showed elevated risks of ischaemic stroke and myocardial infarction. No increased thrombotic risks were observed with transdermal therapy.

https://www.bmj.com/content/394/bmj-2026-100688