The lively debate over the benefits and liabilities of hormone replacement therapy (HRT) for menopausal women has quieted a bit in recent years as research has gradually eroded the findings of the 2002 Women’s Health Initiative study linking the treatment to a higher risk of breast cancer. The Food and Drug Administration last year moved to remove its black-box warning on HRT, a move echoed this year by the American College of Obstetricians and Gynecologists in its own guidelines for doctors and patients. The American College of Physicians followed suit last month.
Still, you can hardly call it a popular option: One recent study found that, despite an uptick in recent years, fewer than 4 percent of U.S. women seen in outpatient care were using HRT to manage their hormones. But the results of research released last week may fuel a new debate: What if HRT can lower the risk of dementia?
As Ariana Eunjung Cha reports in The Washington Post, researchers at Sweden’s Karolinska Institutet have found that lifetime estrogen exposure — whether through oral contraceptives or HRT — may be linked to healthier brain aging. Indeed, those study participants who employed both methods exhibited the healthiest brain profiles.
This is not an insignificant insight when you consider that women are far more likely than men to suffer from Alzheimer’s. For senior study author Anna Marseglia, PhD, the results suggest a novel diagnostic and treatment approach. “Given the lack of sex-specific prevention strategies for cognitive disorders, clarifying estrogen’s long-term impact on brain and cognition remains an important clinical priority in the era of personalized medicine,” she writes in the journal Neurology.
Marseglia and her team analyzed data from 352 women with an average age of 70 who were cognitively healthy when they participated in the Gothenburg Birth Cohort study. Participants completed questionnaires to identify sociodemographic and lifestyle factors as well as medical conditions and reproductive health concerns. They also gave blood and cerebrospinal fluid (CSF) samples at the beginning of the study period.
Five years later, researchers examined members of the original group who had available brain-imaging data and found that those who had a longer reproductive span — later menopause — or used oral contraceptives and HRT exhibited greater white-matter integrity and better neurovascular status. In other words, the tendency of estrogen to ease inflammation and promote blood flow throughout the brain may have helped protect these women’s brain health.
“In our study, the observed lower [cerebral small vessel disease] burden among estrogen-exposed women may reflect estrogen’s role in maintaining vascular integrity and supporting glymphatic function — a hypothesis that warrants further investigation,” Marseglia writes.
Following on the heels of research suggesting that menopause reflects a neurological as well as a reproductive transition, including a recent JAMA Network Open study that links earlier menopause with faster cognitive decline, the Karolinska findings may lead us to assume that HRT will soon be seeing a renaissance among menopausal women, but Marseglia offers some caveats.
The results don’t prove that estrogen necessarily prevents dementia, only that there seems to be an association between its use and a lower risk of the disease, she notes. The reliance upon self-reported estrogen and oral contraceptive use may be unreliable due to “recall bias,” and the composition of the study cohort — well-educated, generally healthy women — may make it difficult to translate the results to the general public.
“Our results,” she writes, “should be interpreted as contributing to mechanistic understanding rather than immediate clinical translation.”
And as Riley Bove, MD, a University of California, San Francisco neurology professor, tells The Washington Post, estrogen’s effect on cognitive function may vary based on when you begin taking 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,” she explains.
More research — and debate — will be forthcoming.
“We cannot really deny that we see an association, a possible beneficial impact,” Marseglia says. “We just need to understand if it is there for every woman, under which conditions and in which time window.”
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