Premature menopause, defined as either surgical or natural menopause before 40 years of age, is associated with an increased risk for cardiovascular disease, according to study results published in JAMA.

Cardiovascular disease is the leading cause of death among women worldwide. In 2018/2019 guidelines from the American College of Cardiology/American Heart Association on cholesterol and primary prevention, a history of premature menopause was used to refine atherosclerotic cardiovascular disease risk. However, limited data are available on long-term cardiovascular risk associated with premature menopause.

The goal of the current study was to explore whether premature menopause is associated with an increased risk for a range of cardiovascular diseases, as well as to assess whether risk differs between natural and surgical premature menopause.

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The researchers used data from UK Biobank, a large-scale, population-based observational cohort of adult residents of the United Kingdom recruited between 2006 and 2010. For the study’s primary outcome, they compared the composite of incident coronary artery disease, heart failure, aortic stenosis, mitral regurgitation, atrial fibrillation, ischemic stroke, peripheral artery disease, and venous thromboembolism among women with natural vs surgical premature menopause and a reference group of postmenopausal women without premature menopause.

The study cohort included 144,260 postmenopausal women (mean age at enrollment, 59.9 years). Of these, 4904 women (3.4%) had nature premature menopause and 644 (0.4%) had surgical premature menopause. The women were followed up for a median of 7 years.

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Of 138,712 women with menopause at age ≥40 years, any incident cardiovascular disease diagnosis was evident in 5415 women (3.9%) compared with 292 of 4904 (6.0%) women with natural menopause and 49 of 644 (7.6%) women with surgical menopause.

The incidence rate of the primary outcome was 5.70/1000 woman-years for those without premature menopause and 8.78/1000 woman-years for those with natural premature menopause (rate difference, +3.08/1000 woman-years [95% CI, 2.06-4.10]; P <.001) compared with women without premature menopause. The rate was 11.27/1000 woman-years for women with surgical premature menopause (rate difference, +5.57/1000 woman-years [95% CI, 2.41-8.73]; P <.001) compared with women without premature menopause.

For natural premature menopause, the hazard ratio for the primary outcome after adjustment for conventional cardiovascular risk factors and use of menopausal hormone therapy was 1.36 (95% CI, 1.19-1.56; P <.001). For surgical premature menopause, the hazard ratio was 1.87 (95% CI, 1.36-2.58; P <.001).

The researchers detailed several study limitations, including determination of age at menopause based on self-report, missing data on indications for prior bilateral oophorectomy and specific hormonal therapy preparations and doses, and the possibility of “a healthy participant selection bias,” which has been noted for the UK Biobank population.

“Natural and surgical premature menopause (before age 40 years) were associated with a small but statistically significant increased risk for a composite of cardiovascular diseases among postmenopausal women. Further research is needed to understand the mechanisms underlying these associations,” concluded the researchers.

Disclosure: Several study authors declared affiliations with the pharmaceutical industry. Please see the original reference for a full list of authors’ disclosures.

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Honigberg MC, Zekavat SM, Aragam K, et al. Association of premature natural and surgical menopause with incident cardiovascular disease [published online November 18, 2019]. JAMA. doi:10.1001/jama.2019.19191