Study Links Oral Menopausal Hormone Therapy to Thrombotic Risk

Current use of oral menopausal hormone therapy was associated with an increased rate of venous thromboembolism (VTE) in a nationwide Danish study published in The BMJ, while transdermal therapy was not. Risks of ischemic stroke and myocardial infarction (MI) were elevated only with high-dose oral therapy, according to the authors.¹

The investigators used national health registries to identify 9807 women with VTE, 18,460 with ischemic stroke, and 11,974 with MI among 1,060,082 eligible women aged 50 to 69 years followed between 2003 and 2021. Each case was matched by birth year to controls without thrombotic disease: 49,035, 92,300, and 59,870 women, respectively.¹

Oral Therapy Tied to Higher Rates of All Three Events

The reference group was women with no current use of any hormone therapy. Among them, incidence rates per 10,000 person-years were 15.8 for VTE, 20.3 for ischemic stroke, and 13.0 for MI.¹

Compared with no current use, current use of oral therapy, alone or combined with a progestin, was associated with a hazard ratio (HR) of 1.6 (95% CI, 1.5-1.8) for VTE, 1.3 (95% CI, 1.2-1.4) for ischemic stroke, and 1.2 (95% CI, 1.1-1.3) for MI. The absolute risk increase per year was 0.09% (95% CI, 0.08%-0.13%) for VTE, 0.06% (95% CI, 0.04%-0.08%) for ischemic stroke, and 0.03% (95% CI, 0.01%-0.04%) for MI. The corresponding numbers needed to harm for 1 year of use were 1055 (95% CI, 791-1266), 1642 (95% CI, 1232-2463), and 3846 (95% CI, 2564-7692).¹

Most current users took oral therapy (88%), and 73% used a combined estrogen-progestin regimen. Estradiol accounted for more than 96% of use, and norethisterone was the most common progestin, used in 80% of combined therapy.¹

Investigators noted that dose also mattered. High-dose oral estradiol (more than 1 mg daily) carried an HR of 1.8 (95% CI, 1.6-2.0) for VTE, compared with 1.3 (95% CI, 1.1-1.6) for low-dose oral use (1 mg or less daily). For ischemic stroke, the HR was 1.5 (95% CI, 1.4-1.6) with high-dose therapy and 1.0 (95% CI, 0.9-1.1) with low-dose therapy. For MI, the HRs were 1.4 (95% CI, 1.2-1.6) and 0.9 (95% CI, 0.8-1.1), respectively.¹

In a subcohort of new users, VTE risk was highest during the first year of high-dose oral therapy (HR, 3.2; 95% CI, 2.3-4.3). Arterial risk also followed a different pattern. For high-dose oral use for more than 5 years, the HR was 1.8 for both ischemic stroke (95% CI, 1.4-2.2) and MI (95% CI, 1.4-2.4). Oral low-dose therapy was not associated with increased stroke or MI risk regardless of duration.¹

Transdermal therapy was not associated with higher rates of VTE (HR, 0.9; 95% CI, 0.7-1.2), ischemic stroke (HR, 1.0; 95% CI, 0.8-1.2), or MI (HR, 1.0; 95% CI, 0.7-1.3) compared with no current use. The exception was MI with transdermal combined cyclic therapy (HR, 2.1; 95% CI, 1.1-4.1), an estimate the authors described as based on sparse data.¹

Limitations and Comparison With Trial Data

The study was observational, so residual and unmeasured confounding may remain. Body mass index and smoking status were not available in the Danish registries, and the authors also lacked data on age at menopause onset. That gap is particularly relevant to the higher risk seen among women who started therapy before age 50 years and those with long-term, high-dose use, which may partly reflect confounding by indication.¹

The population was predominantly ethnically homogeneous, and conjugated equine estrogens were used only negligibly, so the findings apply specifically to estradiol formulations. Bioidentical progesterone was not captured.¹

The VTE estimate for oral therapy is in line with a National Institute for Health and Care Excellence synthesis of 7 randomized trials (n = 34,379), which reported a risk ratio of 1.8 (95% CI, 1.5-2.1). The authors cautioned that most of those trials used conjugated equine estrogens rather than estradiol.¹

Opinion on Reassurance and Evidence

In a companion opinion piece, Amani Meaidi, MD, PhD, research group leader in the Department of Gynaecology and Obstetrics at Copenhagen University Hospital of North Zealand in Denmark and a co-author of the study, said the results illustrate why the safety question remains open.²

Meaidi pointed to the FDA's 2025 decision, after convening an expert panel, to remove the boxed warning from hormone therapy products. Whether earlier risk communication was too broad is an important question, she wrote, but removing a warning does not resolve the uncertainties underlying the risk.²

The findings do not support describing hormone therapy as simply safe or unsafe, according to Meaidi. She wrote that risk may depend on the therapy prescribed, the method of use, the dosage, and the duration of treatment.²

"We have spent decades learning that fear can outrun evidence," Meaidi wrote, adding that reassurance should not do the same.²

She called for research designed to capture differences between individual women rather than average treatment effects alone. Key unanswered questions include who is most likely to benefit, for whom the balance of benefits and harms is less favorable, and how age, comorbidities, and baseline risk modify those effects.²

REFERENCES

1. Berggreen J, Pourhadi N, Wood-Kurland H, Løkkegaard E, Torp-Pedersen C, Meaidi A. Contemporary menopausal hormone therapy and thrombotic disease: nationwide nested case-control study. BMJ. 2026;394:e100688. Published 2026 Sep 23. doi:10.1136/bmj-2026-100688

2. Meaidi A. We still do not know the answers to fundamental questions about menopause. BMJ. 2026;394:e100911. Published 2026 Sep 23. doi:10.1136/bmj-2026-100911