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Although reproductive hormones are implicated in cerebral small vessel disease in women, few studies consider measured hormones in relation to white matter hyperintensity volume, a key indicator of cerebral small vessel disease linked to future risk for stroke, dementia, and mortality. Studies of hormones and the brain in women typically focus on estradiol, the main ovarian estrogen. However, hallmark changes of menopause include decreases in estradiol as well as increases in follicle-stimulating hormone (FSH), a pituitary hormone and hallmark indicator of ovarian age. Another key estrogen in the body is estrone, which is produced primarily by body fat and may be particularly important when estradiol stabilizes at low levels post-menopause. Although these hormonal changes have implications for the brain, few studies consider endogenous levels of estradiol, estrone, and FSH in relation to brain white matter hyperintensities.

Investigators including Rebecca Thurston, PhD (Pittsburgh Foundation Chair in Women's Health and Dementia and Professor of Psychiatry, Clinical and Translational Science, Epidemiology and Psychology); Minjie Wu, PhD (Assistant Professor of Psychiatry); and Howard Aizenstein, MD, PhD (Charles F. Reynolds III and Ellen G. Detlefsen Endowed Chair in Geriatric Psychiatry and Professor of Bioengineering and Clinical and Translational Science), from Pitt Psychiatry, examined associations of endogenous estrone, estradiol, and follicle-stimulating hormone in relation to white matter hyperintensity volume in late-midlife women. 

They found that higher estradiol and estrone were associated with lower whole-brain white matter hyperintensity volume, and higher follicle-stimulating hormone with higher whole-brain white matter hyperintensity volume. In addition, associations of estrone and FSH, but not estradiol, to white matter hyperintensity volume persisted with adjustment for body size and other cardiovascular disease risk factors.

“Collectively, these findings underscore the importance of endogenous reproductive hormones, particularly estrone and FSH, to women's cerebrovascular health in late midlife. They indicate the importance of moving beyond a sole focus on estradiol when we are investigating women’s brain health. They also point to the importance of reproductive hormones not only for the vasculature in the body, but also for the brain,” said Dr. Thurston, corresponding author of the study, which was recently published in Alzheimer's & Dementia.

Reproductive Hormones in Relation to White Matter Hyperintensity Volumes in Midlife Women
Thurston RC, Chang Y, Wu M, Harrison EM, Aizenstein HJ, Derby CA, Barinas-Mitchell E, Maki PM
Alzheimer's Dement. 2024; 1-9. https://doi.org/10.1002/alz.14093