Elevated cardiovascular risk associated with hormone replacement therapy: A comprehensive analysis of reproductive factors and atherosclerotic cardiovascular disease outcomes in the UK Biobank cohort
- 1School of Public Health, Department of Medicine Xi'an Jiaotong University Xi'an Shaanxi China
- 2Key Laboratory of Disease Prevention, Control and Health Promotion Xi'an Shaanxi China
Abstract
Introduction: The cardiovascular effects of hormone replacement therapy (HRT) remain controversial. This study investigated HRT‐associated atherosclerotic cardiovascular disease (ASCVD) risk, focusing on reproductive characteristics.
Material and Methods: This prospective cohort study analyzed 170 250 women aged 40–69 years from UK Biobank (2006–2024). Cox proportional hazards regression models were employed to estimate ASCVD risk, with stratification by reproductive characteristics (age at menarche, age at menopause, and menopausal status) and age groups (≤45, 46–55, >55 years). Mediation analysis was conducted to examine potential biological pathways through sex hormones, inflammatory markers, and lipid profiles. All analyses were adjusted for demographic factors, socioeconomic status, lifestyle factors, and reproductive history.
Results: During follow‐up, 11 357 women (6.67%) developed ASCVD. HRT users demonstrated elevated ASCVD risk (adjusted HR 1.13, 95% CI 1.08–1.18, p < 0.001), primarily from increased ischemic stroke. Risk varied by reproductive characteristics: late menarche showed highest risk (HR 1.15, 95% CI 1.08–1.24), followed by late menopause (HR 1.25, 95% CI 1.01–1.54). Perimenopause demonstrated the most pronounced elevation (HR 1.28, 95% CI 1.12–1.46). Women ≤45 years had 77% higher ASCVD risk with HRT use. Dose–response relationships between HRT duration (≥5 years) and ASCVD risk were observed (p overall = 0.009, p nonlinear = 0.004). Mediation analysis revealed minimal indirect effects through traditional biomarkers (<2%), suggesting direct vascular mechanisms.
Conclusions: HRT increases ASCVD risk with substantial variation by reproductive characteristics. Findings support reproductive profile‐based cardiovascular risk assessment for personalized HRT prescribing.
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BibTeX
@article{wang2026elevated,
title = {{Elevated cardiovascular risk associated with hormone replacement therapy: A comprehensive analysis of reproductive factors and atherosclerotic cardiovascular disease outcomes in the UK Biobank cohort}},
author = {Mengchun Wang and Can Zhang and Chunlai Yang and Baosen Meng and Xiaohui Li and Qian Huang and Baibing Mi},
journal = {Acta Obstetricia et Gynecologica Scandinavica},
year = {2026},
month = aug,
doi = {10.1111/aogs.70316},
url = {https://doi.org/10.1111/aogs.70316},
note = {CC BY-NC 4.0},
}
RIS
TY - JOUR
TI - Elevated cardiovascular risk associated with hormone replacement therapy: A comprehensive analysis of reproductive factors and atherosclerotic cardiovascular disease outcomes in the UK Biobank cohort
AU - Mengchun Wang
AU - Can Zhang
AU - Chunlai Yang
AU - Baosen Meng
AU - Xiaohui Li
AU - Qian Huang
AU - Baibing Mi
PY - 2026
DA - 2026/08/20
JO - Acta Obstetricia et Gynecologica Scandinavica
DO - 10.1111/aogs.70316
UR - https://doi.org/10.1111/aogs.70316
AB - Introduction: The cardiovascular effects of hormone replacement therapy (HRT) remain controversial. This study investigated HRT‐associated atherosclerotic cardiovascular disease (ASCVD) risk, focusing on reproductive characteristics. Material and Methods: This prospective cohort study analyzed 170 250 women aged 40–69 years from UK Biobank (2006–2024). Cox proportional hazards regression models were employed to estimate ASCVD risk, with stratification by reproductive characteristics (age at menarche, age at menopause, and menopausal status) and age groups (≤45, 46–55, >55 years). Mediation analysis was conducted to examine potential biological pathways through sex hormones, inflammatory markers, and lipid profiles. All analyses were adjusted for demographic factors, socioeconomic status, lifestyle factors, and reproductive history. Results: During follow‐up, 11 357 women (6.67%) developed ASCVD. HRT users demonstrated elevated ASCVD risk (adjusted HR 1.13, 95% CI 1.08–1.18, p < 0.001), primarily from increased ischemic stroke. Risk varied by reproductive characteristics: late menarche showed highest risk (HR 1.15, 95% CI 1.08–1.24), followed by late menopause (HR 1.25, 95% CI 1.01–1.54). Perimenopause demonstrated the most pronounced elevation (HR 1.28, 95% CI 1.12–1.46). Women ≤45 years had 77% higher ASCVD risk with HRT use. Dose–response relationships between HRT duration (≥5 years) and ASCVD risk were observed (p overall = 0.009, p nonlinear = 0.004). Mediation analysis revealed minimal indirect effects through traditional biomarkers (<2%), suggesting direct vascular mechanisms. Conclusions: HRT increases ASCVD risk with substantial variation by reproductive characteristics. Findings support reproductive profile‐based cardiovascular risk assessment for personalized HRT prescribing.
SN - 0001-6349
SN - 1600-0412
ER -