Both Natural and Surgical Premature Menopause Increase the Risk of Cardiovascular Disease
Key findings
- In a very large cohort of postmenopausal women, natural and surgical menopause before age 40 were associated with a modest but significantly increased risk of a composite of cardiovascular diseases
- Premature menopause was also associated with a significantly greater incidence of certain individual cardiovascular diseases, as well as incident hypertension, hyperlipidemia and type 2 diabetes
- The risk of coronary artery disease, aortic stenosis and atrial fibrillation increased progressively as age at menopause decreased, but all women who experienced menopause before age 50 were at greater risk
- ?These results suggest the need for early lifestyle modification to mitigate the long-term risk for cardiovascular disease associated with premature menopause
Premature menopause, before age 40, has been associated with increased risk of coronary artery disease (CAD), stroke and heart failure, according to systematic reviews and meta-analyses. The American College of Cardiology/American Heart Association (ACC/AHA) guidelines recommend using a history of premature menopause to guide the management of asymptomatic women who are at intermediate risk of atherosclerotic cardiovascular disease (ASCVD) at midlife. However, few studies have investigated the longer-term risk of ASCVD after premature menopause, the risk of nonatherosclerotic CVD or whether risk differs between women with natural versus surgical menopause. In JAMA, Michael C. Honigberg, MD, MPP, cardiology fellow, Pradeep Natarajan, MD, MMSc, director of the Cardiovascular Disease Prevention Center at Massachusetts General Hospital, and colleagues reported prospective data addressing these issues.
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Study Design
The researchers analyzed data on 144,260 women from the U.K. Biobank, a prospective, observational, population-based cohort study that recruited >500,000 adults between 2006 and 2010. At the initial study visit, these women were age 40 to 69 (average, 60), did not have congenital heart disease and did not have any of the cardiovascular (CV) diseases that would be investigated in the current study. 4,904 (3.4%) of those women experienced natural menopause before age 40 and 644 (0.4%) experienced surgical menopause before age 40. All women were followed for a median of seven years. The primary outcome was incident CAD (newly diagnosed during follow-up), heart failure, aortic stenosis, mitral regurgitation, atrial fibrillation or flutter, ischemic stroke, peripheral artery disease and/or venous thromboembolism.
Primary Outcome
The incidence of one or more CV diseases was 3.9% among women with menopause at age ≥40, 6% among women with natural premature menopause and 7.6% among women with surgical premature menopause. The incidence rates were:
- 5.70 per 1000 woman-years for women without premature menopause
- 8.78 per 1000 woman-years for women with natural premature menopause (P < .001 vs. women without premature menopause)
- 11.27 per 1000 woman-years for women with surgical premature menopause (P < .001 vs. women without premature menopause)
After adjustment for conventional CV risk factors, both types of premature menopause remained independently associated with incident CVD:
- Natural premature menopause — HR, 1.36; 95% CI, 1.19–1.56; P < .001
- Surgical premature menopause — HR, 1.87; 95% CI, 1.36–2.58; P < .001
Individual Diseases and Risk Factors
When the researchers considered CV diseases individually rather than as a composite:
- Natural premature menopause was associated with a significantly greater risk of aortic stenosis (HR, 2.37), venous thromboembolism (HR, 1.70), ischemic stroke (HR, 1.50), CAD (HR, 1.39) and atrial fibrillation (HR, 1.25).
- Surgical premature menopause was associated with a significantly increased risk of mitral regurgitation (HR, 4.13), venous thromboembolism (HR, 2.73), heart failure (HR, 2.57) and CAD (HR, 2.52).
Premature menopause was also associated with increased risk of incident hypertension, hyperlipidemia and type 2 diabetes.
Effect of Age at Menopause
The researchers looked at the risk associated with a range of menopausal age thresholds: before age 50, before age 45, before age 35 and before age 30, all compared to a reference group with menopause at age 50 or later. Compared with the older group, greater risk of CAD, aortic stenosis and atrial fibrillation were observed at progressively younger ages at menopause. The largest hazards were observed among women who had the onset of menopause before age 30, but all women who experienced menopause before age 50 were at increased risk.
The Need for "Primordial Prevention"
Premature menopause does not seem to be merely comorbid with conventional CV risk factors. Since a greater risk of acquiring CV risk factors (hypertension, hyperlipidemia and type 2 diabetes) was observed, it may be that premature menopause actually increases chances of developing those conditions.
A history of premature menopause thus suggests a need for "primordial prevention"—the use of targeted nonpharmacologic strategies to reduce the onset of modifiable risk factors.
The study results also have implications for prescribing statins. ACC/AHA guidelines recommend considering premature menopause when making decisions about statin prescription, but only when menopause occurred before age 40. In contrast, this study suggests that premature menopause should be regarded as a risk continuum: women are at greatest CVD risk if they experienced menopause before age 30, and they are also at increased risk if menopause occurred between ages 40 and 49.
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