HRT use by younger women linked to dementia, study says. Experts disagree

By Sandee LaMotte, CNN

(CNN) — Women in their 50s who took estrogen and progestin hormone replacement therapy for menopausal symptoms had an increased risk of dementia within 20 years, a new observational study found. Symptoms of menopause can include hot flashes, chills, night sweats, sleep problems, mood changes and vaginal dryness and pain during sex.

“The major novel finding of this study is that we observed a persistent, increased rate of dementia for women treated for the short term around the average age of natural menopause, which is about 51 years,” said lead study author Dr. Nelsan Pourhadi, a researcher at the Danish Dementia Research Centre at Copenhagen University Hospital Rigshospitalet in Denmark.

However, experts who treat and study menopause say the study is unable to draw a direct connection to later-life dementia and that the overall benefits of hormone replacement therapy, or HRT, far outweigh the risks for many patients.

“One finding in the study was a link between dementia and the use of HRT for a very short time span, under a year. That’s biologically implausible,” said Pauline Maki, a professor of psychiatry, psychology, and obstetrics and gynecology and director of women’s mental health research at the University of Illinois at Chicago. She was not involved in the study.

David Curtis, an honorary professor at UCL Genetics Institute at University College London, agrees that the link is “biologically implausible.” He was also not involved in the research.

“An even more convincing (explanation) is that some women were actually prescribed HRT because they had memory problems,” he said in a statement.

Women who have hot flashes, mood or sleep issues — all of which affect cognition — are definitely more likely to seek out and use HRT, said Dr. Kejal Kantarci, a professor of radiology in the division of neuroradiology at the Mayo Clinic in Rochester, Minnesota, who was not involved in the study.

“That means women who choose to use hormone therapies may actually be the ones who are already at risk for dementia,” said Kantarci, who cowrote an editorial that was published along with the new study.

“My coauthor and I are very concerned that the message from this study will be that hormone therapies cause dementia, and that’s not what’s happening here.”

Just an association

The new study, published Wednesday in The BMJ journal, examined medical records for nearly 56,000 Danish women between 2000 and 2018. Over 5,500 of those women were later diagnosed with dementia or Alzheimer’s disease. Researchers compared people with dementia who had used hormone therapy, even briefly, with those from the larger group who had not.

However, the study only looked at people who used a certain type of HRT — a combination of estrogen and progestin that was widely prescribed at that time, said Andrea Lenzi, a professor of endocrinology at the University of Rome La Sapienza, who was not involved in the study.

“Over the years, however, the therapies have changed a lot, both in terms of type of drugs and dosages, and therefore the side effects of today’s therapy may be quite different from those of HRT from back then,” she said in a statement.

People with a uterus must use both estrogen and progesterone to avoid thickening of the lining of the womb that can lead to endometriosis. Once the uterus has been removed, only estrogen treatment can be used. Today, there are a number of options besides oral HRT, including patches and creams.

After controlling for a number of other factors that might affect the development of dementia, such as age, sex, diabetes, thyroid disease, hypertension, and socioeconomic factors, the study found women who used the dual hormone replacement had a 24% increased rate of dementia compared with women who had never been on HRT.

“The median (average) age between the first hormonal treatment and the actual dementia diagnosis was around 18 years (after starting to take HRT),” Pourhadi told CNN.

The chance of being diagnosed with dementia went up with years spent on HRT, the study found. When women used 12 or more years of hormone therapy, the association with a diagnosis of dementia rose to 74%, Pourhadi said.

“But it should be noted that these percentages have some uncertainties and are not meant to translate directly to a risk,” he told CNN. “This is an observational study and cannot determine causality, so further studies are needed to investigate whether the association we found is explained by a causal link between menopausal hormone therapy and dementia.”

Could it be hot flashes instead?

There is a possibility the connection is real, said Maki, who is also senior director of research for the University of Illinois’s Center for Research on Women and Gender.

A 2019 observational study of Finnish women, as well as two other studies done in the UK and Taiwan, have also shown a very small increased risk for Alzheimer’s disease, especially when using combination hormones long-term, she said.

However, recent research points to another plausible explanation for the findings — it’s the hot flashes themselves that may be driving the higher risk for dementia, said Maki, who coauthored a number of the papers.

“Our studies found that hot flashes are linked to heart disease, white matter hyperintensities (lesions) in the brain, alterations in brain structure and alterations in brain function,” Maki said.

Hot flashes are associated with “reduced blood vessel function and brain-specific blood flow,” said Susan Davis, a professor of chronic disease and aging and director of the Women’s Health Research Program at Monash University in Melbourne, Australia, who was not involved with the new study.

“The real elephant in the room for this analysis is: is the observed risk of dementia in MHT users due to the use of oral synthetic MHT or due to the reasons why women ever took MHT? This has been overlooked,” she said in a statement.

Randomized clinical trials done in recent years on women in their 50s taking HRT up to age 55 — the recommended cutoff according to the North American Menopause Society — have shown a “zero, zilch” connection between cognitive decline and hormone therapy, Maki said.

“We now have three clinical trials — which is the gold standard of research — that all say if you’re taking hormone therapies at a younger age during the menopausal transition, the cognitive decline doesn’t occur,” she said. “And in fact, in the one trial that did the neuro imaging, they actually found a reduction in Alzheimer’s disease biomarkers in the brain.”

While the new findings may “cause alarm” for younger women taking HRT, the study “highlights just how much we still don’t know about the effects of hormones on women’s brain health,”  said Amanda Heslegrave, a senior research fellow at the UK Dementia Research Institute in London, who was not involved with the study.

“It should be a call to action to make this a priority area of research,” Heslegrave said in a statement.

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