HRT, even short-term, linked to risk of dementia in women

Short-term and cyclical use of estrogen and progestogen therapy for menopausal symptoms is linked to an increased risk of dementia, according to results of a large observational study.

Investigators found that women in their 50s who took hormone replacement therapy (HRT) for menopausal symptoms had a 24% increased risk of developing dementia and Alzheimer’s disease (AD) 20 years later compared to those who did not use HRT. The risk was present even in women who used HRT for short periods at menopause beginning.

However, researchers and experts not involved in the research warn that further studies are needed to determine whether the increased risk of dementia comes from HRT use or whether women requiring HRT have other risk factors. underlying risk of dementia.

“We cannot guarantee that our results illustrate a causal relationship, or whether they represent an underlying disposition to dementia in women requiring HRT,” said lead investigator Nelsan Pourhadi, MD, of the Danish Center for Dementia Research at Copenhagen University Hospital Rigshospitalet. Medscape Medical News.

Dr Nelson Pourhadi

Yet, he added, the findings supported the evidence of the Women’s Health Initiative Memory Study (WHIMS), the largest randomized trial of menopausal hormone therapy and dementia.

THE results were published online on June 28 in BMJ.

Conflicting findings

Before WHMIS was published in 2003, HRT was widely prescribed to relieve symptoms of menopause. However, WHIMS, which included more than 4,000 women aged 65 or over, found HRT was associated with a two-fold increased risk of dementia.

Studies published since then have yielded mixed results, adding to the controversy surrounding the safety of HRT.

To find out whether age of initiation or duration of HRT affects health outcomes, Pourhadi and his team undertook the observational study.

Between 2000 and 2018, researchers followed more than 60,000 Danish women between the ages of 50 and 60 using diagnostic and prescribing information from Denmark’s National Patient Registry.

Registry records showed that nearly 5,600 women developed dementia and 56,000 did not develop dementia. Of the 5600 women with dementia, 1460 had a diagnosis of AD.

Almost 18,000 participants in the study sample received HRT – 1,790 (29%) in the dementia group and 16,150 (32%) in the control group. Half started treatment before the age of 53 and the other half stopped it within 4 years. About 90% used oral medications, which included a combination of estrogen and progestin.

The median age at which participants started HRT was 53 years for cases and controls, and the median duration of use was 4 years.

Longer use equals higher risk

Compared with those not using HRT, those using estrogen-progestin therapy had a 24% increased risk of developing dementia from any cause (relative risk [HR], 1.24; 95% CI, 1.17 – 1.44).

The increased risk of dementia was similar between continuous (estrogen and progestin taken daily) and cyclic (estrogen and progestin taken daily 10 to 14 days per month) regimens.

Longer durations of HRT use were associated with increased risk, ranging from a 21% increased risk (RR, 1.21; 95% CI, 1.09, 1.35) for those who used for 1 year or less at a 74% increased risk (RR, 1.74; 95% CI, 1.45, 2.10) for use for 12 years or more.

Women who started HRT between the ages of 45 and 50 had a 26% increased risk of developing dementia from any cause (RR, 1.26; 95% CI, 1.13, 1.41) while women who started HRT between 51 and 60 had a 21% higher risk (RR, 1.21; 95% CI, 1.12, 1.29).

Progestogen-only or vaginal-estrogen-only therapy has not been associated with the development of dementia.

The investigators noted that since this is an observational study, “further studies are warranted to determine whether the association observed in this study between use of menopausal hormone therapy and increased risk dementia illustrates a causal effect”.

No causal relationship

In an accompaniment editorialKejal Kantarci, MD, professor of radiology at the Mayo Clinic in Rochester, Minnesota, noted that three clinical trials, including the The whims of young women (WHIMS-Y) in 2013, did not show a link between cognitive function and HRT.

Dr Kejal Kantarci

“Although Pourhadi and colleagues’ study was carefully performed using national registries, the observed associations may be artificial and should not be used to infer a causal relationship between hormone therapy and dementia risk. These results cannot inform shared decision-making about the use of hormone therapy for menopausal symptoms,” she states in the editorial.

Also commenting on the results, Amanda Heslegrave, PhD, senior researcher at the UK Dementia Research Institute in London, England, said in a statement from the UK’s Science Media Center that while the study “may cause concern for women taking HRT, she highlights how little we still know about the effects of hormones on women’s brain health, and with promising treatments on the horizon, this should be a call to action to make this a priority research area.

There was no specific funding for the study. Kantarci said he worked on an unpaid educational activity on Alzheimer’s disease for Biogen Inc. and is the principal investigator of a study of a PET imaging ligand for Alzheimer’s disease, to which Eli Lilly and Avid Radiopharmaceuticals donated supplies.

BMJ. 2023;381:e072770, p1404. Full Text, Editorial

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