Risk of Postmenopause Stroke Goes Back to Woman's Reproductive Years

A woman's cumulative exposure to estrogen remained protective against certain types of strokes after menopause, no matter how researchers estimated such exposure in a large Chinese cohort study.

Stroke risk was significantly lower with greater lifetime estrogen exposure due to reproductive factors according to three composite indicators:

• Reproductive lifespan: adjusted HR 0.95 for highest vs lowest quartile (95% CI 0.92-0.98)

• Endogenous estrogen exposure: adjusted HR 0.85 (95% CI 0.82-0.89)

• Total estrogen exposure: adjusted HR 0.87 (95% CI 0.84-0.90)

These results for total stroke applied for ischemic stroke and intracerebral hemorrhage (ICH) specifically. The findings by stroke subtype support the literature that has shown that female study participants with a longer reproductive lifespan have a lower risk of stroke, according to maternal health researcher Peige Song, PhD, of School of Public Health and Women's Hospital, Zhejiang University School of Medicine, in China, and colleagues.

"Lifetime cumulative estrogen exposure due to reproductive factors adopted in our study might act as early warning indicators for stroke and its subtypes," the study authors reported in Neurology.

"They may also allow for individual reproductive factors to be comprehensively and visibly comparable, and this would be of major clinical and public health importance. Moreover, the findings from this study might help to increase awareness on sex-specific risk factors for stroke and provide innovation for effective stroke prevention, such as targeting female patients who have a short duration of estrogen exposure with timely screening," the researchers added.

Estrogen production ceases during the postmenopausal phase, which is thought to be accompanied by a loss of cardiovascular protection for women.

Yet estrogen and progestin therapy are not endorsed for the primary prevention of chronic conditions. The U.S. Preventive Services Task Force gives this hormone combination a "D" rating (not recommended) in postmenopausal women, and estrogen alone has a "D" as well for patients who have had a hysterectomy.

In the U.S., stroke is the fifth leading cause of death in women. Sex-specific risk factors for stroke include high blood pressure during pregnancy and certain types of birth control.

The present study counted 122,939 postmenopausal women in the China Kadoorie Biobank. All reported no prior stroke at enrollment in 2004-2008.

Median age at menarche, menopause, and baseline was 16 years, 49 years, and 58 years, respectively.

Reproductive lifespan was defined as the years between menarche and menopause. Endogenous estrogen exposure is a measure that subtracts years of pregnancy and contraceptive use, whereas total estrogen exposure adds these periods of relatively high blood estrogen levels.

Study participants were found to have a median reproductive lifespan of 33 years, 27.3 years for endogenous estrogen exposure, and 32.5 years for total estrogen exposure.

The incidence of stroke and its subtypes was gathered from a national registry over a median follow-up period of 8.9 years. Investigators identified 15,139 new-onset stroke cases, including 12,853 ischemic strokes, 2,580 ICH cases, and 269 subarachnoid hemorrhage cases.

Notably, Song's group found that the associations between lifetime cumulative estrogen exposure due to reproductive factors and SAH strokes were relatively weak. The highest quartile of reproductive lifespan appeared at increased risk of SAH, but this finding may be attributed to limited statistical power, the authors suggested.

They also acknowledged that the study left room for recall bias due to the reliance on participants' self-reported reproductive history. Additionally, it was not possible to adjust for genetic factors, early life factors, or diet, among other unreported variables in the China Kadoorie Biobank.

"Estrogen exposure throughout life could potentially be a useful indicator of a person's risk of different types of stroke following menopause," Song said in a press release. "However, more research is needed on the biological, behavioral, and social factors that may contribute to the link between estrogen exposure and stroke risk across a woman's lifespan."

Comment