Age at Iatrogenic Menopause and Cardiovascular Morbidity and Mortality
4 affiliations
- 1Department of Applied Health Sciences, School of Health Sciences, College of Medicine and Health, University of Birmingham, Birmingham, United Kingdom
- 2Royal Free Hospital NHS Foundation Trust, London, United Kingdom
- 3Cerrahpasa Faculty of Medicine, Institute of Graduate Studies, Istanbul University–Cerrahpasa, Istanbul, Turkey
- 4Department of Endocrinology, Queen Elizabeth Hospital, University Hospitals Birmingham, Birmingham, United Kingdom
Abstract
Importance: Iatrogenic menopause is common, but its long-term cardiovascular consequences remain uncertain, particularly by age at menopause.
Objective: To quantify associations between iatrogenic menopause and cardiovascular morbidity and mortality and evaluate whether age at iatrogenic menopause is a modifier.
Data Sources: In this systematic review and meta-analysis, Scopus, MEDLINE, PubMed, Embase, Cochrane Central Register of Controlled Trials (CENTRAL), CINAHL, and PsycINFO were searched from January 2004 to March 2026.
Study Selection: Observational studies and randomized clinical trials reporting cardiovascular morbidity or mortality among women with iatrogenic menopause before natural menopause age compared with naturally menopausal or age-matched controls were included.
Data Extraction and Synthesis: Data were extracted in duplicate by 2 independent reviewers, with consensus resolution. The study followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses reporting guideline.
Main Outcomes and Measures: Primary outcomes were cardiovascular morbidity, cardiovascular and all-cause mortality, and a composite of cardiovascular morbidity and cardiovascular mortality, quantified as random-effects pooled hazard ratios (PHRs) with 95% CIs, irrespective of heterogeneity and with age at menopause as a moderator. Meta-regression estimates were clustered by source cohort.
Results: Of 14 409 records, 36 studies were included with 2 617 942 women (mean [SD] age, 55.52 [12.41] years for the iatrogenic menopause cohort and 45.58 [16.02] years for comparators); median follow-up was 16.0 years (range, 4.8-36.0 years). Iatrogenic menopause vs comparators was associated with higher risk of all-cause mortality (PHR, 1.08; 95% CI, 1.01-1.16), cardiovascular events (PHR, 1.25; 95% CI, 1.12-1.39), coronary heart disease (PHR, 1.48; 95% CI, 1.07-2.03), and stroke (PHR, 1.22; 95% CI, 1.15-1.28). Mortality excesses were confined to iatrogenic menopause before age 45 years (cardiovascular mortality: PHR, 1.20 [95% CI, 1.04-1.37]; all-cause mortality: PHR, 1.15 [95% CI, 1.06-1.25]), with null estimates at or after age 45 years (cardiovascular mortality: PHR, 0.95 [95% CI, 0.81-1.11]; all-cause mortality: PHR, 0.99 [95% CI, 0.89-1.09]). In a post hoc meta-regression on the composite outcome, each increasing 5-year increment in age at iatrogenic menopause was associated with lower risk (HR, 0.89; 95% CI, 0.83-0.97) based on 37 estimates from 11 independent populations.
Conclusions and Relevance: In this study, iatrogenic menopause was associated with higher cardiovascular morbidity, most consistently stroke, and with cardiovascular and all-cause mortality excesses before age 45 years at menopause. Older age at iatrogenic menopause was associated with progressively lower risk of cardiovascular morbidity and mortality, supporting a period of elevated risk before age 45 years rather than a single threshold age.
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BibTeX
@article{armeni2026iatrogenic,
title = {{Age at Iatrogenic Menopause and Cardiovascular Morbidity and Mortality}},
author = {Eleni Armeni and Ipek Betul Ozcivit Erkan and Punith Kempegowda},
journal = {JAMA Network Open},
year = {2026},
month = oct,
doi = {10.1001/jamanetworkopen.2026.37545},
url = {https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2854757},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Age at Iatrogenic Menopause and Cardiovascular Morbidity and Mortality
AU - Eleni Armeni
AU - Ipek Betul Ozcivit Erkan
AU - Punith Kempegowda
PY - 2026
DA - 2026/10/02
JO - JAMA Network Open
DO - 10.1001/jamanetworkopen.2026.37545
UR - https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2854757
AB - Importance: Iatrogenic menopause is common, but its long-term cardiovascular consequences remain uncertain, particularly by age at menopause. Objective: To quantify associations between iatrogenic menopause and cardiovascular morbidity and mortality and evaluate whether age at iatrogenic menopause is a modifier. Data Sources: In this systematic review and meta-analysis, Scopus, MEDLINE, PubMed, Embase, Cochrane Central Register of Controlled Trials (CENTRAL), CINAHL, and PsycINFO were searched from January 2004 to March 2026. Study Selection: Observational studies and randomized clinical trials reporting cardiovascular morbidity or mortality among women with iatrogenic menopause before natural menopause age compared with naturally menopausal or age-matched controls were included. Data Extraction and Synthesis: Data were extracted in duplicate by 2 independent reviewers, with consensus resolution. The study followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses reporting guideline. Main Outcomes and Measures: Primary outcomes were cardiovascular morbidity, cardiovascular and all-cause mortality, and a composite of cardiovascular morbidity and cardiovascular mortality, quantified as random-effects pooled hazard ratios (PHRs) with 95% CIs, irrespective of heterogeneity and with age at menopause as a moderator. Meta-regression estimates were clustered by source cohort. Results: Of 14 409 records, 36 studies were included with 2 617 942 women (mean [SD] age, 55.52 [12.41] years for the iatrogenic menopause cohort and 45.58 [16.02] years for comparators); median follow-up was 16.0 years (range, 4.8-36.0 years). Iatrogenic menopause vs comparators was associated with higher risk of all-cause mortality (PHR, 1.08; 95% CI, 1.01-1.16), cardiovascular events (PHR, 1.25; 95% CI, 1.12-1.39), coronary heart disease (PHR, 1.48; 95% CI, 1.07-2.03), and stroke (PHR, 1.22; 95% CI, 1.15-1.28). Mortality excesses were confined to iatrogenic menopause before age 45 years (cardiovascular mortality: PHR, 1.20 [95% CI, 1.04-1.37]; all-cause mortality: PHR, 1.15 [95% CI, 1.06-1.25]), with null estimates at or after age 45 years (cardiovascular mortality: PHR, 0.95 [95% CI, 0.81-1.11]; all-cause mortality: PHR, 0.99 [95% CI, 0.89-1.09]). In a post hoc meta-regression on the composite outcome, each increasing 5-year increment in age at iatrogenic menopause was associated with lower risk (HR, 0.89; 95% CI, 0.83-0.97) based on 37 estimates from 11 independent populations. Conclusions and Relevance: In this study, iatrogenic menopause was associated with higher cardiovascular morbidity, most consistently stroke, and with cardiovascular and all-cause mortality excesses before age 45 years at menopause. Older age at iatrogenic menopause was associated with progressively lower risk of cardiovascular morbidity and mortality, supporting a period of elevated risk before age 45 years rather than a single threshold age.
SN - 2574-3805
ER -