Association of Age at Onset of Menopause and Time Since Onset of Menopause With Cardiovascular Outcomes, Intermediate Vascular Traits, and All-Cause Mortality: A Systematic Review and Meta-analysis
Open accessAbstract
Importance: As many as 10% of women experience natural menopause by the age of 45 years. If confirmed, an increased risk of cardiovascular disease (CVD) and all-cause mortality associated with premature and early-onset menopause could be an important factor affecting risk of disease and mortality among middle-aged and older women. Objective: To systematically review and meta-analyze studies evaluating the effect of age at onset of menopause and duration since onset of menopause on intermediate CVD end points, CVD outcomes, and all-cause mortality. Data Sources: Medical databases (ie, Medline, EMBASE, and Web of Science) until March 2015. Study Selection: Studies (ie, observational cohort, case-control, or cross-sectional) that assessed age at onset of menopause and/or time since onset of menopause as exposures as well as risk of cardiovascular outcomes and intermediate CVD end points in perimenopausal, menopausal, or postmenopausal women. Data Extraction and Synthesis: Studies were sought if they were observational cohort, case-control, or cross-sectional studies; reported on age at onset of menopause and/or time since onset of menopause as exposures; and assessed associations with risk of CVD-related outcomes, all-cause mortality, or intermediate CVD end points. Data were extracted by 2 independent reviewers using a predesigned data collection form. The inverse-variance weighted method was used to combine relative risks to produce a pooled relative risk using random-effects models to allow for between-study heterogeneity. Main Outcomes and Measures: Cardiovascular disease outcomes (ie, composite CVD, fatal and nonfatal coronary heart disease [CHD], and overall stroke and stroke mortality), CVD mortality, all-cause mortality, and intermediate CVD end points. Results: Of the initially identified references, 32 studies were selected that included 310 329 nonoverlapping women. Outcomes were compared between women who experienced menopause younger than 45 years and women 45 years or older at onset; the relative risks (95% CIs) were 1.50 (1.28-1.76) for overall CHD, 1.11 (1.03-1.20) for fatal CHD, 1.23 (0.98-1.53) for overall stroke, 0.99 (0.92-1.07) for stroke mortality, 1.19 (1.08-1.31) for CVD mortality, and 1.12 (1.03-1.21) for all-cause mortality. Outcomes were also compared between women between 50 and 54 years at onset of menopause and women younger than 50 years at onset; there was a decreased risk of fatal CHD (relative risk, 0.87; 95% CI, 0.80-0.96) and no effect on stroke. Time since onset of menopause in relation to risk of developing intermediate cardiovascular traits or CVD outcomes was reported in 4 observational studies with inconsistent results. Conclusions and Relevance: The findings of this review indicate a higher risk of CHD, CVD mortality, and overall mortality in women who experience premature or early-onset menopause.
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Women who had experienced early (aged <45) menopause (natural and unnatural) have a 20% higher risk of mortality after cardiovascular disease than women who had experienced menopause at age 45 or older.
“Women who had experienced early (aged <45) menopause (natural and unnatural) had a 20% higher risk of mortality after cardiovascular disease than women who had experienced menopause at age 45 or older.57”
From Association between the reproductive health of young women and cardiovascular disease in later life: umbrella review (2020) · cites this paper as [57]
Early menopause is associated with an increased risk of developing ischaemic heart disease (fatal and non-fatal outcomes).
“Specifically, an increased risk of developing ischaemic heart disease (fatal and non-fatal outcomes) but not stroke was seen.57”
From Association between the reproductive health of young women and cardiovascular disease in later life: umbrella review (2020) · cites this paper as [57]
Early menopause is not associated with an increased risk of stroke.
“Specifically, an increased risk of developing ischaemic heart disease (fatal and non-fatal outcomes) but not stroke was seen.57”
From Association between the reproductive health of young women and cardiovascular disease in later life: umbrella review (2020) · cites this paper as [57]
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- Authors
- Muka, T., Oliver-Williams, C., Kunutsor, S., Laven, J. S. E., Fauser, B. C. J. M., Chowdhury, R., Kavousi, M., & Franco, O. H.
- Affiliations
- Erasmus MC (NL)
- Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, England
- University of Cambridge (GB)
- University Medical Center Utrecht (NL)
- Corresponding author
- Muka, Taulant
- ORCID
- Venue
- JAMA Cardiology
- Publisher
- American Medical Association (AMA)
- Published
- 2016-10-01
- Volume
- 1
- Issue
- 7
- Pages
- 767
- ISSN
- 2380-6583 (ISSN-L)
- OpenAlex
- W2520538161
- Cited by
- 826
- References
- 53
- Citations by year
- 2026: 114 · 2025: 103 · 2024: 101 · 2023: 84 · 2022: 99 · 2021: 90 · 2020: 73 · 2019: 63 · 2018: 57 · 2017: 36 · 2016: 5
- FWCI
- 7.88
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- JAMA Cardiology (publishedVersion)
- PubMed (publishedVersion)
- EUR Research Repository (Erasmus University Rotterdam) (publishedVersion)
- Explore Bristol Research (publishedVersion, other-oa)
- EUR Research Repository (Erasmus University Rotterdam) (submittedVersion)
- Utrecht University Repository (Utrecht University) (submittedVersion, other-oa)
- Bristol Research (University of Bristol) (submittedVersion, other-oa)
- Funders
- National Institute for Health and Care Research (NF-SI-0512-10165)
- British Heart Foundation (RG/13/13/30194, RG/08/014/24067)
- AXA Research Fund
- Medical Research Council (MR/L003120/1)
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Menopause: Health Impacts and Treatments
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Hormonal and reproductive studies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Estrogen and related hormone effects
- Keywords
- early menopause, time since menopause, cardiovascular disease, coronary artery disease, stroke, stroke mortality, all-cause mortality, postmenopausal women, cardiovascular risk factors, middle-aged women, premature menopause, blood pressure, insulin resistance, dyslipidemia
- MeSH terms
- Cardiovascular Diseases, Coronary Disease, Cross-Sectional Studies, Female, Humans, Menopause, Menopause, Premature, Middle Aged, Age of Onset, Stroke
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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