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Neurobiologist Anna Marseglia had long studied the forces that shape the aging brain. But as she entered her 40s, amid a fierce cultural debate over hormone therapy, she found herself increasingly curious about estrogen.
Recent studies had linked a longer reproductive span — the years between a woman’s first period and menopause — with a lower risk of Alzheimer’s and dementia. But what about estrogen from outside the body, she wondered. Did years spent taking birth control pills or hormone therapy count, too?
Her latest study, published Wednesday in the journal Neurology, offers a tentative answer.
Among 352 cognitively healthy 70-year-old women, those with longer reproductive spans showed physiological signs of healthier brain aging: less damage to its tiny blood vessels and better-preserved white matter, the tissue that allows different parts of the brain to communicate. Then came the more provocative finding. Women who had used both oral contraceptives and hormone therapy had the healthiest brain profiles of all.
“I was personally very excited,” said Marseglia, the study’s senior author and an assistant professor of aging epidemiology and brain health at the Karolinska Institute in Stockholm. More than a dozen researchers from Yale University, Harvard Medical School and other international universities collaborated on the study.
The paper does not prove that estrogen — or hormone therapy — caused those differences. But it raises the possibility that it could extend the period of beneficial exposure beyond natural menopause. And it adds a new piece of evidence to a much broader reassessment of hormone therapy, a treatment whose risks and benefits have been fiercely debated for more than two decades.
Hormone therapy prescriptions in the United States plummeted nearly 40 percent within a year of a landmark 2002 Women’s Health Initiative study linking the treatment to higher risks of breast cancer, heart disease and stroke. But in the years since, researchers have reexamined those findings and concluded that the age at which women begin hormone therapy appears to change the balance of its risks and benefits.
Late last year, the Food and Drug Administration moved to lift its black-box warning about hormone therapy based on the old study. And last month, the American College of Obstetricians and Gynecologists made that shift explicit for doctors and patients, issuing new guidelines that embraced hormone therapy as a first-line treatment more strongly than it had in the past. The American College of Physicians issued similar recommendations Oct. 5.
Neither group recommends hormone therapy for brain protection, but the science around its neurological effects is rapidly evolving.
‘Estrogen years’ and gaps
Estrogen sits at the intersection of two big mysteries in women’s brain health: why women are disproportionately affected by Alzheimer’s — they account for nearly two-thirds of Americans with the disease — and what happens to the brain when estrogen drops sharply at menopause.
The hormone is best known for the role it plays in reproduction, but its reach extends far beyond the ovaries. Estrogen receptors pervade the brain, including in regions involved in memory and cognition. The hormone also affects inflammation, blood flow to the brain, and the ability of blood vessels to expand and contract. At menopause, that changes abruptly. Production of estradiol, the body’s most potent estrogen, plummets.
Caroline Just, a neurologist at the Cleveland Clinic, said in an interview the shift triggers changes throughout the body. Blood pressure and cholesterol can rise in women who previously had healthy numbers. Researchers now are asking whether an equally consequential transition is taking place in the brain.
The search for what drives Alzheimer’s has focused heavily on two proteins, amyloid and tau. But scientists increasingly see the aging brain as a more complicated system, with vascular health another potential axis that can interact with the disease. Autopsy studies have identified damage to the brain’s blood vessels in roughly half of people with Alzheimer’s or more, bolstering this theory.
The National Institutes of Health is now funding work to add vascular health to the traditional Alzheimer’s biomarker framework, part of a broader recognition that dementia often arises from several forms of damage to the aging brain.
Just co-authored a recent review examining what scientists know about menopause and brain health. The research, she said, increasingly points to menopause as a neurological transition as well as a reproductive one.
One clue comes from the timing of menopause. In a study of more than 2,600 older women published in August in JAMA Network Open, younger age at menopause was associated overall with faster cognitive decline and an earlier Alzheimer’s diagnosis. Among women who went through menopause naturally, the median age was 50, but the ages varied widely.
Researchers found a physical difference, as well: For every five years younger a woman was at menopause, she accumulated about 15 percent more white-matter damage over a decade later in life.
The findings reinforce the question at the heart of Marseglia’s study.
“People who had minimally interrupted estrogen tended to do better, and that makes a lot of sense. A lot of the problems we run into with cognitive health are when estrogen drops,” Just said.
Increasingly, researchers are asking whether the brain may be shaped not just by the presence or absence of estrogen at any one moment, but by something like a lifetime tally of a woman’s “estrogen years.”
The critical window hypothesis
Natural production, however, is only part of many women’s exposure to estrogen. Millions also get estrogen in the form of birth control and, later, hormone therapy.
If the brain keeps some record of its years of estrogen exposure, does it matter where that estrogen comes from?
For decades, the question has produced conflicting, and often confusing, answers.
In 2003, a major study found that women taking estrogen plus progestin had roughly twice the risk of probable dementia as those taking a placebo. The finding has not been overturned outright. But the women in that study were 65 or older when they enrolled — much older than women who typically begin hormone therapy today.
That distinction has become increasingly important. Riley Bove, a professor of neurology at the UCSF Weill Institute for Neurosciences, said evidence accumulated over the last two decades suggests that the brain may respond differently to estrogen depending on when it is given. Scientists increasingly suspect there may be a critical window for hormone therapy: Starting it around menopause may be very different from introducing estrogen after the brain has gone years without it.
“For women who haven’t been producing estrogen for 10 years or more, the idea is that their receptors or tissues may respond differently than they would in women who have had continuous exposure,” Bove said. “That was the tragedy of the analyses.”
This year, two large observational studies provided new evidence that menopausal hormone therapy might be associated with a lower risk of dementia. One, published in August in Alzheimer’s & Dementia, followed roughly 183,000 postmenopausal women in the UK Biobank and found a lower risk among women who began menopausal hormone therapy between ages 46 and 56.
Another study, published in the September issue of Neurology, found that women who had used estrogen-only hormone therapy had lower odds of developing dementia later in life. The researchers also examined autopsied brains and found fewer signs of Alzheimer’s pathology among estrogen users.
Together, the findings add to evidence that timing matters. Now researchers are probing another possible source of estrogen’s uneven effects: the health of the woman receiving it.
The health factor
Jill Daniel, a professor of brain science at Tulane University, has spent years studying estrogen’s effects on the brain. In healthy mice, hormone therapy consistently improves memory. But when the animals are fed a high-fat diet or develop high blood pressure, the effect can reverse, and their memory gets worse.
Daniel sees hints of the same pattern in women. Analyses of medical records suggest that women with Type 2 diabetes or poor cardiovascular health may be less likely to see potential brain benefits from hormone therapy.
Daniel suspects there may be a tipping point in the hippocampus, a brain region critical to learning and memory. As cells become unhealthy, she said, the machinery that allows them to respond to estrogen may begin to break down.
The research is still early. The evidence, Daniel said, is “very tantalizing,” but much remains unknown.
How all these factors interact — timing, underlying health and the type of hormone therapy — remains an open question.
“We cannot really deny that we see an association, a possible beneficial impact,” Marseglia said. “We just need to understand if it is there for every woman, under which conditions and in which time window.”
For now, researchers urge caution. There is not enough evidence to prescribe menopausal hormone therapy to prevent Alzheimer’s or dementia.
That distinction is important as the medical guidance around hormone therapy changes. Both the American College of Obstetricians and Gynecologists and the American College of Physicians recommend it as a first-line treatment for hot flashes, night sweats and related menopausal symptoms in women without certain cancers or other contraindications. The ACOG says treatment generally should begin before age 60 or within 10 years of menopause. The new recommendations put more emphasis on tailoring the type, dose and timing of treatment to an individual woman’s symptoms, health and preferences.
In 10 or 15 years, Just suspects, doctors may have a much better idea of who stands to benefit most from this approach.
For now, Just said, “the reasons to get hormone therapy are all non-neurological. For people who want to be on it to reduce the risk of dementia, we just don’t have that yet.”
