Premenopausal cardiovascular disease and age at natural menopause: a pooled analysis of over 170,000 women
Early menopause is associated with an increased risk of subsequent cardiovascular disease (CVD). Few studies have investigated the converse. We examined whether premenopausal CVD events are associated with early age at menopause. We pooled the individual data of 177,131 women from nine studies. We used multinomial logistic regression models to estimate multivariable relative risk ratios (RRR) and 95% confidence intervals (CI) for the associations between age at onset of premenopausal CVD events—including coronary heart disease (CHD) and stroke—and age at natural menopause. Altogether 1561 (0.9%) premenopausal participants reported CVD events (including 1130 CHD and 469 stroke) at a mean age of 41.3 years. Compared with women without any premenopausal CVD events, women who experienced a first CVD event before age 35 years had a twofold risk of menopause before age 45 years (early menopause); adjusted RRR (95% CI) of 1.92 (1.17, 3.14) for any CVD, 1.86 (1.01, 3.43) for CHD and 2.17 (1.43, 3.30) for stroke. Women who experienced a first premenopausal CVD event after age 40 years underwent a natural menopause at the expected age (around 51 years). These associations were robust to adjustment for smoking status, BMI, educational level, race/ethnicity, age at menarche, parity, hypertension and family history of CVD. For premenopausal women, a first CVD event before age 35 years is associated with a doubling of the risk of an early menopause, while a first CVD event occurred after 35 years indicates a normal menopause at around 51 years. Shared genetic and environmental factors (such as smoking), as well as compromised vasculature following CVD events, may contribute to this outcome.
KeywordsPremenopausal Cardiovascular disease Age at menopause Pooled analysis
The data on which this research is based were drawn from 9 observational studies. The research included data from the ALSWH, the University of Newcastle, Australia, and the University of Queensland, Australia. We are grateful to the Australian Government Department of Health for funding and to the women who provided the survey data. MCCS was supported by VicHealth and the Cancer Council, Victoria, Australia. WLHS was funded by a grant from the Swedish Research Council (Grant No. 521-2011-2955). NSHD has core funding from the UK Medical Research Council (MC UU 12019/1). NCDS is funded by the Economic and Social Research Council. ELSA is funded by the National Institute on Aging (Grants 2RO1AG7644 and 2RO1AG017644-01A1) and a consortium of UK government departments. The Whitehall II study has been supported by grants from the Medical Research Council. Baseline survey of the JNHS was supported in part by a Grant-in-Aid for Scientific Research (B: 14370133, 18390195) from the Japan Society for the Promotion of Science, and by the grants from the Japan Menopause Society. This research has been conducted using the UK Biobank resource under application 26629. All studies would like to thank the participants for volunteering their time to be involved in the respective studies. The findings and views in this paper are not necessarily those of the original studies or their respective funding agencies.
GDM and DZ conceptualized the study. GDM interpreted the results, and revised the manuscript critically. DZ analysed and interpreted data, and drafted the manuscript. HFC and NP harmonised the data and revised the manuscript. AJD, RH, DK, EJB, FB, GGG, PD, JSL, HM, KH, HOA, EW provided study data and revised the manuscript.
InterLACE project is funded by the Australian National Health and Medical Research Council Project Grant (APP1027196). GDM is supported by Australian National Health and Medical Research Council Principal Research Fellowship (APP1121844). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
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Conflict of interest
The authors declare that they have no conflict of interest.
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