Women Hitting Menopause Before 40 May Face a Long Window of Cardiac Risk

Premature onset of menopause was associated with a higher lifetime risk of coronary heart disease (CHD), according to an observational study.

Across six U.S. cohorts, Black and white women who reached menopause before age 40 had a roughly 40% greater lifetime risk of CHD after age 55, reported Priya Freaney, MD, of Northwestern University Feinberg School of Medicine in Chicago, and colleagues.

“This suggests that premature onset of menopause is an important risk-enhancing factor for lifetime risk and should be routinely assessed in clinical practice to consider intensification of preventive efforts,” they noted in JAMA Cardiology.

“It remains unclear if the menopausal transition truly represents a more disease-permissible vascular environment or whether those who experience premature menopause are the same individuals who already have a disease-permissible vascular environment where risk is unmasked and premature menopause is a marker,” Freaney and team wrote. “However, these data support the perimenopausal period as a unique window of opportunity to measure, monitor, and modify [cardiovascular disease] risk in women.”

This study extends prior work establishing premature menopause as a risk-enhancing factor for atherosclerotic cardiovascular disease. Previously, a U.K. Biobank study had shown that there is a short-term risk of CHD (over a median 7-year follow-up) associated with premature menopause, whether by natural or surgical means.

Menopause is the point at which menstruation and fertility end, marked by declining estrogen levels. It typically starts around the age of 50, though up to 12% of women experience onset between the ages of 40 to 44. Another 2% to 4% of women start menopause even earlier, prior to the age of 40, in what is known as premature ovarian insufficiency.

“While the etiology of premature menopause is not known, it is likely variable between racial groups and is associated with a variety of genetic, biological, and environmental factors, including early menarche, health behaviors, obesity, and weathering,” the study authors explained.

“As the natural estrogen declines, no matter what age it happens in, cholesterol and blood pressure go up, body fat distribution shifts to the abdomen, muscle mass gets lower, blood sugars can become dysregulated, and arteries stiffen,” said Freaney in a press release. “Together, these changes over a short period increase the risk of heart disease.”

This prospective cohort study was based on the Cardiovascular Disease Lifetime Risk Pooling Project, with individual-level data coming from six U.S. cohorts. The researchers included postmenopausal women (ages 55-69) free of CHD at baseline; 3,522 were Black (mean age 61.2) and 6,514 were white (mean age 60).

Premature menopause was more frequent in Black women (15.5%) versus white women (4.8%).

Altogether, the study had 163,600 person-years of follow-up spanning 1964 to 2018.

Premature menopause was associated with an increased risk of CHD, defined as a fatal or nonfatal myocardial infarction or death due to CHD, in both Black women (HR 1.41, 95% CI 1.04-1.90) and white women (HR 1.39, 95% CI 1.03-1.87) compared with peers who had their onset of menopause at age 40 or later.

Meanwhile, no significant relationship was found between premature menopause and years lived free of CHD.

Freaney and colleagues cautioned that the study relied on self-reports of menopause, which may have introduced a degree of misclassification. Another limitation was the inability to adjust for some sex-specific cardiovascular risk factors (e.g., polycystic ovarian syndrome or hypertensive disorders of pregnancy) or use of hormone therapy due to inconsistent information available.

Notably, the study had also excluded individuals with surgically induced menopause and those of other races.