Route alone may not define thrombotic risk with menopausal hormone therapy

Agreement: I Agree Body: Dear Editor, Berggreen and colleagues provide important contemporary evidence on thrombotic outcomes associated with menopausal hormone therapy (MHT) [1]. Their nationwide Danish nested case-control study found that current oral MHT was associated with higher rates of venous thromboembolism (VTE), ischaemic stroke, and myocardial infarction, while transdermal MHT overall was not associated with increased rates of these outcomes. The detailed analyses by route, dose, regimen, treatment duration, and age at initiation are major strengths. We suggest that the conclusion regarding transdermal therapy should be interpreted as reassuring but not definitive for every regimen. The overall estimate for transdermal MHT was compatible with no material increase in VTE (hazard ratio (HR) 0.9, 95% confidence Interval (CI) 0.7 to 1.2), ischaemic stroke ( HR=1.0, 95% CI 0.8 to 1.2), or myocardial infarction ( HR=1.0, 95% CI 0.7 to 1.3). However, the number of transdermal users was substantially lower than that of oral users, and several transdermal subgroup estimates were imprecise. In particular, transdermal combined cyclic therapy was associated with myocardial infarction (HR 2.1, 95% CI 1.1 to 4.1), an estimate based on few exposed cases and therefore requiring cautious interpretation [1]. Recent evidence also suggests that thrombotic risk may depend on the full MHT regimen rather than route alone. In a Swedish nationwide register-based emulated target trial of women aged 50-58 years initiating MHT, transdermal combined MHT was associated with VTE compared with non-initiation in both intention-to-treat analysis (HR 1.46, 95% CI 1.09 to 1.95) and per-protocol analysis (HR 1.67, 95% CI 1.16 to 2.41) [2]. In that study, "transdermal combined" included transdermal oestrogen with oral, transdermal, or local progestogen. Conversely, neither transdermal combined nor transdermal unopposed oestrogen was associated with the composite cardiovascular outcome [2]. These findings should not be interpreted as establishing causality, but they indicate that conclusions about "transdermal therapy" may mask meaningful heterogeneity related to progestogen exposure, regimen, dose, and patient selection. A 2025 systematic review of MHT in women with VTE risk factors found that transdermal oestrogen was not associated with increased VTE risk across the included studies, whereas oral oestrogen, especially when combined with a synthetic progestogen, had a less favourable VTE profile. The authors nevertheless emphasised heterogeneity in MHT formulations, routes, doses, and underlying VTE risk factors, and called for more contemporary data [3]. Thus, the available evidence broadly supports transdermal oestrogen as a potentially preferable option when VTE risk is a concern, but does not establish uniform safety for all transdermal oestrogen-progestogen regimens. The randomised Women's Health Initiative trial remains important causal evidence that a specific oral regimen conjugated equine oestrogen plus medroxyprogesterone acetate can increase cardiovascular and thromboembolic harms [4]. However, it did not compare oral with transdermal oestradiol and cannot determine the comparative safety of current transdermal regimens. Future studies should make direct, adjusted comparisons between oral and transdermal MHT, stratified by oestrogen dose, progestogen type and route, and cyclic versus continuous regimen. Meanwhile, clinical counselling should integrate route of administration with dose, progestogen, baseline VTE and cardiovascular risk, and the patient's indication and treatment priorities. 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. Johansson T, Karlsson T, Bliuc D, et al. Contemporary menopausal hormone therapy and risk of cardiovascular disease: Swedish nationwide register based emulated target trial. BMJ. 2024;387:e078784. Published 2024 Nov 27. doi:10.1136/bmj-2023-078784 3. Hicks A, Robson D, Tellis B, Smith S, Dunkley S, Baber R. Safety of menopause hormone therapy in postmenopausal women at higher risk of venous thromboembolism: a systematic review. Climacteric. 2025;28(5):497-509. doi:10.1080/13697137.2025.2503874 4. Rossouw JE, Anderson GL, Prentice RL, et al. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results From the Women's Health Initiative randomized controlled trial. JAMA. 2002;288(3):321-333. doi:10.1001/jama.288.3.321 No competing Interests: Yes The following competing Interests: Electronic Publication Date: Saturday, October 3, 2026 - 08:03 AI use: No, I have not used AI Highwire Comment Subject: Contemporary menopausal hormone therapy and thrombotic disease: nationwide nested case-control study Workflow State: Released Full Title: Route alone may not define thrombotic risk with menopausal hormone therapy Highwire Comment Response to: Contemporary menopausal hormone therapy and thrombotic disease: nationwide nested case-control study Check this box if you would like your letter to appear anonymously:: Last Name: Ahmad First name and middle initial: Umair Email: umairahmad0711@gmail.com Address: Hyderabad, India Occupation: MBBS Affiliation: Ayaan Institute of Medical Sciences, Hyderabad, India BMJ: Additional Article Info: Rapid response