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Frank B. Hu, MD; Francine Grodstein, ScD; Charles H. Hennekens, MD; Graham A. Colditz, MD; Michelle Johnson, MD; JoAnn E. Manson, MD; Bernard Rosner, PhD; Meir J. Stampfer, MD

Arch Intern Med. 1999;159:1061-1066.

Background  Early natural menopause has been postulated to increase the risk of cardiovascular disease.

Objective  To examine the relation of age at natural menopause with risk of coronary heart disease (CHD) and stroke in the Nurses' Health Study.

Methods  Analysis was restricted to 35,616 naturally postmenopausal women who never used estrogen replacement therapy and with no diagnosed cardiovascular disease at baseline, followed up from 1976 to 1994. Information on menopausal status, age at menopause, and other risk factors was obtained in 1976 and updated every 2 years by mailed questionnaires.

Results  During 354,326 person-years of follow-up, we documented 757 incident cases of CHD and 350 incident cases of stroke. After adjusting for age, smoking status, and other cardiovascular risk factors, the relative risks (RRs) across categories of age at natural menopause (<40, 40-44, 45-49, 50-54, and 55 years) were 1.53, 1.42, 1.10, 1.00 (reference), and 0.95, respectively; the RR for each 1-year decrease in age at natural menopause was 1.03 (95% confidence interval, 1.01-1.05). Elevated risk with younger age at menopause was observed among current smokers (RR, 1.04 [95% CI, 1.01-1.07] for each 1-year decrease in age at natural menopause) but not among never smokers (RR, 1.00; 95% CI, 0.96-1.04). Age at natural menopause was not significantly associated with ischemic stroke (RR, 1.01; 95% CI, 0.97-1.04) or hemorrhagic stroke (RR, 1.03; 95% CI, 0.97-1.10).

Conclusions  We observed an overall significant association between younger age at menopause and higher risk of CHD among women who experienced natural menopause and never used hormone therapy. This increased risk was observed among current smokers but not among never smokers. The apparent elevated risk of CHD with decreased age at natural menopause among smokers might reflect residual confounding by smoking.

From the Departments of Nutrition (Drs Hu and Stampfer), Epidemiology (Drs Hennekens, Colditz, Manson, and Stampfer), and Health Policy and Management (Dr Johnson), Harvard School of Public Health; and Channing Laboratory (Drs Grodstein, Colditz, Manson, Rosner, and Stampfer) and the Division of Preventive Medicine (Drs Hennekens and Manson), Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Mass.

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