A Danish study has linked HRT to dementia, but experts say the research is far from clearcut

Menopause is having a moment, but its time in the limelight hasn’t always been easy.

Just as we were starting to overturn the long-held belief that hormone replacement therapy (HRT) causes breast cancer, a new Danish study has linked it to dementia. Globally it’s sparked a flurry of disturbing headlines in the media claiming “HRT may increase the risk of dementia”, which in turn has led to anger in the pro-HRT ranks who believe that HRT is the missing link in dementia prevention.

It’s also met with a backlash from some in the medical community who say the study has limitations, and as one BMJ editorial put it, it “should not be used to infer a causal relationship between hormone therapy and dementia risk. These findings cannot inform shared decision making about use of hormone therapy for menopausal symptoms.”

The observational study of data from Danish national registries starting in 2000 reported that hormone treatment was associated with an increased risk of dementia with either short term or long-term use (hazard rate ratio of 1.24, 95% confidence interval of 1.17 to 1.35). The majority of those followed for 18 years were taking oral equine oestrogen plus synthetic progestin norethisterone and were compared to those who had never taken HRT.

It now joins a relatively small collection of other observational studies, many of which have inferred an increased risk, but they sit at odds with the even smaller handful of randomised controlled trials, including the WHIMS study that show a neutral effect if HRT is started in your mid 40’s to mid 50’s, or a slightly elevated increase if initiated in your mid 60’s. One recent Finnish study found that oestrogen therapy was protective for carriers of the APOE4 gene.

So, why so many conflicting results?

For a start, there are questions about how the studies on dementia and HRT are structured, the ages of the women, when they started their HRT, the types used and how to compare them. And then, there simply aren’t that many of them. As one review of dementia risk factors noted: “although larger RCT data for older women with late-life hormone therapy (HT) exist, there is a dearth of larger RCTs that examine HT in younger women. One review of 22 double-blinded RCTs found that only 30% of women were 50 to 59 years old during baseline, the age at which women are mostly likely considered for HT to alleviate symptoms.”

A dearth of data is one thing, but what is the data we do have telling us?

According to Professor Susan Davis, Director of the Women’s Health Research Program in the School of Public Health and Preventive Medicine at Monash University “the real elephant in the room for this analysis is: is the observed risk of dementia in menopausal hormone therapy (MHT) users is due to the use of oral synthetic MHT or due to the reasons why women ever took MHT?”

Professor Davis says most women who take MHT are seeking relief for hot flushes and sweats, sleep disturbance and/or mood symptoms—and hot flushes are associated with reduced blood vessel function and brain-specific blood flow, and poor sleep and low mood are both established risk factors for dementia.

Gynaecologist Vikram Talaulikar, associate specialist at the reproductive medicine unit in University College London Hospitals NHS Foundation Trust and Hon. Associate Professor at University College London, agrees.

He says the fact that these observational studies are consistently showing a small link means we should be look for what the possible linking factors are. “These women have hot flushes and insomnia for example. They may be the link, not the HRT. The symptoms could be the issue, not the HRT.”

He points out that the Danish paper does say this, but adds that many risk factors mentioned in the study were not evaluated, such as lower socioeconomic status and fewer years of education, as well as comorbidities including high blood pressure, diabetes and thyroid disease.

Another issue with many of these studies, according to Professor Kaarin Anstey, Director of the Ageing Futures Institute at the University of New South Wales and a Senior Principal Research Scientist at Neuroscience Research Australia, is that “dementia occurs late in life so the studies that have followed women long enough to see if they develop dementia, are evaluating the types of HRT that were prescribed 20 or 30 years ago.”

Professor Anstey says the methodological and research limitations and the length of follow-up time needed mean we can’t currently say whether one type of HRT is better than another, or whether modern formulations have a different risk profile. “If we commence HRT at age 50, we may need 25 – 35 years of follow up to see incident dementia,” she explains.

Where does that leave prescribers and patients?

For Dr Marita Long, a GP with a special interest in dementia and board member of the Australasian Menopause Society, the key takeaway is to focus on the known risk factors for dementia.

“I think the message is we have clear known risk factors that may contribute to 40% of dementia cases worldwide and we would get more bang for our buck focussing on these, rather than influencing doctors to not treat menopause symptoms,” Dr Long says.

According to Dr Vikram Talaulikar, nothing really changes. He says if doctors have patients who are still on these older forms of HRT it’s worth having a chat with them about swapping to the newer body identical versions which have a better safety profile overall, so they can make an informed choice.

Dr Long concurs. “I think it’s about the woman sitting in front of you, the symptoms, the formulation that will work best for them – cost, availability, preference for oral/transdermal, their comorbidities etc. Most women use transdermal options now but some will prefer a pill.
At this stage, there’s not enough evidence to not prescribe for bothersome symptoms of menopause.”

Existing guidelines say we should not be prescribing HRT for preventative measures when it comes to brain health—and experts agree that there’s no change to that.

Both Professor Anstey and Dr Long say the study raises an opportunity to talk about dementia risk factors with patients, and they repeat the often-heard refrain, “more research is needed”.