HRT, Even Short-Term Use, Linked to Dementia Risk in Women

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

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 with those who didn't use HRT. The risk was present even in women who used HRT for brief periods at menopause onset.

However, both the investigators and experts not involved in the research caution that further studies are needed to explore whether the increased risk of dementia stems from HRT use or whether women in need of HRT have other underlying dementia risk factors.

"We cannot guarantee that our findings illustrate a causal relationship, or if they represent underlying disposition to dementia in women in need of HRT," lead investigator Nelsan Pourhadi, MD, from the Danish Dementia Research Centre at Copenhagen University Hospital Rigshospitalet, told Medscape Medical News.

Dr Nelsan Pourhadi

Still, he added, the findings supported evidence from the Women's Health Initiative Memory Study (WHIMS), the largest randomized trial on menopausal hormone therapy and dementia.

The findings were published online June 28 in BMJ.

Conflicting Findings

Before WHIMS was published in 2003, HRT was widely prescribed to relieve menopausal symptoms. However, WHIMS, which included more than 4000 women aged 65 years or older, revealed that HRT was associated with a twofold increased risk of dementia.

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

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

Between 2000 and 2018, the researchers tracked more than 60,000 Danish women aged 50 to 60 years using diagnosis and prescription information from Denmark's National Registry of Patients.

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

Nearly 18,000 participants in the study sample received HRT — 1790 (29%) in the dementia group and 16,150 (32%) in the control group. Half started treatment before age 53 years and half stopped within 4 years. Roughly 90% used oral medications, which included a combination of estrogen and progestin.

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

Longer Use Equals Greater Risk

Compared with those who did not use HRT, those who used estrogen-progestin therapy had a 24% increased risk of developing all-cause dementia (hazard ratio [HR], 1.24; 95% CI, 1.17 - 1.44).

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

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

Women who started HRT between the age of 45 and 50 had a 26% increased risk of developing all-cause dementia (HR, 1.26; 95% CI, 1.13 - 1.41) while women who initiated HRT between age 51 and 60 had a 21% greater risk (HR, 1.21; 95% CI, 1.12 - 1.29).

Progestin-only or vaginal-estrogen-only therapy was not associated with the development of dementia.

The investigators noted that because this is an observational study, "further studies are warranted to explore if the observed association in this study between menopausal hormone therapy use and increased risk of dementia illustrates a causal effect."

No Causal Relationship

In an accompanying editorial, Kejal Kantarci, MD, a professor of radiology at the Mayo Clinic in Rochester, Minnesota, noted that three clinical trials, including the WHIMS of Younger Women (WHIMS-Y) in 2013, did not show a link between cognitive function and HRT.

Dr Kejal Kantarci

"Although Pourhadi and colleagues' study was done carefully using national registries, the observed associations could be artefactual and 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," she states in the editorial.

Also commenting on the findings, Amanda Heslegrave, PhD, a senior research fellow at the UK Dementia Research Institute in London, England, said in a release from the UK's Science Media Centre that while the study "may cause alarm for women taking HRT, it highlights just how much we still don't know about the effects of hormones on women's brain health, and with promising treatments on the horizon it should be a call to action to make this a priority area of research."

There was no specific funding for the study. Kantarci reported working on an unpaid educational activity on Alzheimer's disease for Biogen Inc. and is the PI on 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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