Could a woman's exposure to estrogen over her lifetime affect the health of her brain's blood vessels as she ages? A recent study suggests that it does, although it did not establish that hormone therapy protects the brain.

The new research reports that women with longer reproductive lifespans and those who used hormone replacement therapy (HRT) during menopause had fewer signs of damage to their brains' small blood vessels in their 70s. But the findings do not establish that hormone therapy prevents brain disease, and they should not be interpreted as a reason to begin treatment.

Because women have a higher lifetime risk of Alzheimer's disease than men, understanding how hormones influence brain aging is an important area of investigation.

The study, led by researchers at Sweden's Karolinska Institute and published in the journal Neurology, examined 352 women from Gothenburg, Sweden. All were 70 years old at the beginning of the study and showed no signs of impaired cognitive functioning. Researchers used magnetic resonance imaging (MRI) to examine the participants' brains at age 70 and again five years later. They then compared the scans with information about each woman's age at her first menstrual period, when she entered menopause and also recorded whether she had used oral contraceptives or HRT during menopause.

Several indicators of brain health, including small-vessel disease, the structure of the brain's white matter and the thickness of the cerebral cortex in regions vulnerable to Alzheimer's disease, were measured. Small-vessel disease involves damage to the tiny blood vessels that supply the brain. Such damage can interfere with the delivery of oxygen and nutrients and is associated with an increased risk of cognitive decline, stroke and dementia.

The findings revealed an association between a longer reproductive lifespan (the interval between a woman's first period and menopause) and a lower burden of small-vessel disease later in the life. HRT use was also associated with less small-vessel disease and a more favorable microstructure in the brain's white matter. Women who reported using both oral contraceptives during their reproductive years and HRT during menopause had the most favorable overall profile for vascular brain health.

Women in their 70s with longer reproductive lifespans and those who used hormone replacement therapy during menopause had fewer signs of damage to the small blood vessels in their brains.

“These findings suggest that the brain's blood vessels may play an important role in the link between estrogen and brain aging", senior author Anna Marsi Glia, an assistant professor in the Department of Neurobiology, Care Sciences and Society at Karolinska Institute, said in a press release. She suggested that hormonal exposure at different stages of life may have cumulative effects on the brain's blood vessels. Because women have a higher lifetime risk of Alzheimer's disease than men, understanding how hormones influence brain aging is an important area of investigation.

There are, however, substantial reasons to interpret these results cautiously. The study was observational, meaning researchers examined associations rather than assigning women to receive hormones or a placebo. It therefore cannot demonstrate that estrogen or HRT caused the differences in brain scans. Hormone-use information was self-reported, and investigators lacked detailed data about treatment doses, formulations and when therapy began.

The findings also do not address the full range of potential harms associated with hormone therapy. Other research, including the large women's health initiative trials, has linked combined estrogen-progestin therapy to increased breast cancer risk, as well as other potential harms.

Decisions about HRT should take into account an individual's symptoms, medical history, breast cancer risk, age, timing of menopause and the type and duration of treatment.

The National Cancer Institute notes that breast cancer risk varies according to the hormone formulation, duration of use and individual circumstances. Estrogen-only therapy has a different risk profile and is generally prescribed systematically only to women who have had a hysterectomy.

Crucially, the new study did not establish that any potential vascular benefits outweigh these risks. Nor did it demonstrate that HRT prevents Alzheimer's disease, dementia or cognitive decline. First author Julia Lorenzan, a researcher at Yale University and former postdoctoral researcher at Karolinska Institute, emphasized that distinction: "The results cannot therefore be used as a basis for recommending hormone therapy for preventive purposes."

The findings provide another question for researchers to investigate, not a new prescription for women considering hormone treatment for menopausal symptoms. Decisions about HRT should be individualized, taking into account symptoms, medical history, breast cancer risk, age, timing of menopause and the type and duration of treatment. Women should discuss the potential benefits and harms with their healthcare providers rather than using this study alone to guide treatment.

The study is published in Neurology.