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Early Age at Natural Menopause Linked to Increased Stroke Risk

SAN DIEGO—Women who go through natural menopause before age 42 are at twice the risk of ischemic stroke as other women, a prospective study suggests.

The study of 1,430 women who participated in the Framingham Heart Study or the Framingham Offspring Study also showed that those who enter natural menopause after age 54 are 69 percent less likely to have any type of stroke compared with women who undergo menopause before age 42.

The data suggest that four percent to five percent of all strokes in women can be attributed to early age at menopause, said Lynda D. Lisabeth, PhD, assistant professor of epidemiology and neurology at the University of Michigan in Ann Arbor. The findings were reported at the American Stroke Association International Stroke Conference in February, and simultaneously published online in the journal Stroke.

Participants included women who survived stroke-free until age 60, experienced natural menopause, and did not use estrogen before menopause. The women were followed for an average of 22 years, during which time 234 of them suffered an ischemic stroke at an average age of 80 years.


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At baseline, seven percent of participants had a history of cardiovascular disease, 32 percent were current smokers, 19 percent had taken hormone-replacement therapy, and one percent had a history of atrial fibrillation.

“The results still held when the analysis was limited to those who had never smoked nor used estrogen,” Dr. Lisabeth said.

While reasons for an increased risk of ischemic stroke among women with early menopause are not clear, early loss of ovarian function coupled with a prolonged low estrogen state is a plausible hypothesis, she said.

That said, “the biology is all mixed up,” Dr. Lisabeth told Neurology Today. “On the one hand, there is evidence that estrogen deficiency promotes cardiovascular disease, perhaps through functional or structural changes in the arteries.

“On the other hand, hormone-replacement therapy increased stroke risk in the Women's Health Initiative,” she noted. [The findings were reported in a 2002 study in the Journal of the American Medical Association.]

What is needed, Dr. Lisabeth said, is more research into the impact of endogenous estrogen on stroke risk.

“Future studies, with measures of endogenous hormones, are needed to unravel the relationship between hormonal changes that occur with menopause, either premature or at the usual onset, and ischemic stroke,” she and colleagues write. “Given the increased stroke burden in women, it is critical to understand risk factors unique to women so that new strategies for prevention can be considered.”

In the meantime, “it would be a good health tactic to make sure women who experience early menopause know the warning signs of stroke,” commented Ralph L. Sacco, MD, chairman of neurology at the University of Miami Miller School of Medicine and neurologist-in-chief at Jackson Memorial Hospital.

While such advice is of course prudent for all patients, these women should know of their possibly heightened stroke risk, he said. “They may need to be more diligent about risk factors such as high blood pressure, diabetes, and elevated cholesterol levels,” Dr. Sacco said.

Menopause at age 40 or younger — termed premature ovarian failure — affects one percent to two percent of women, with an additional three percent to 10 percent of women experiencing early, natural menopause before age 45, Dr. Lisabeth said. •


Lisabeth LD, Beiser AS, Wolf PA, et al. Age at natural menopause and risk of ischemic stroke: The Framingham Heart Study. Stroke 2009; E-pub 2009 Feb. 20.
    Rossouw JE, Anderson GL, Ockene J, et al., for the Writing Group for the Women's Health Initiative Investigators. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: Principal results from the Women's Health Initiative randomized controlled trial. JAMA 2002;288:321–333.