Hormone replacement therapy (HRT) is linked with dementia in later life, even if just taken for a short time around the start of menopause, a nationwide Danish study suggests.
Results from the large, observational study contradict randomized trials suggesting no effect on cognitive function for women assigned to HRT during the early menopause.
Trial findings have, however, previously linked HRT with a two-fold increased risk of dementia when used in older women, above 65 years of age.
The current nested, case-control study of all Danish women found that estrogen plus progestin (synthetic progestogen) HRT was associated with a 24% increased risk of all-cause dementia compared with no such use, systemic or vaginal estrogen-only treatment, and perimenopausal progestin-only therapy.
“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,” the researchers report in the BMJ
HRT is widely used to relieve common menopausal symptoms such as hot flushes and night sweats. Treatments may include tablets containing estrogen—either alone or with progestin—and skin patches, gels and creams.
Alzheimer’s is twice as common in women than men, therefore exposure to anything in midlife that may affect the risk in women is of considerable interest.
For the current study, Nelsan Pourhadi, from the Danish Dementia Research Center in Copenhagen, and colleagues examined data on 5589 women of dementia and 55,890 age-matched control individuals without dementia between 2000 and 2018.
Participants were identified from registry data and included all Danish women who were aged 50–60 years in 2000 without a history of dementia and who had no underlying reason stopping them from using HRT.
The average age at dementia diagnosis was 70 years and, prior to this, 1782 (32%) cases and 16154 (29%) control individuals had received estrogen-progestin therapy from an average age of 53 years.
The average duration for which it was taken was 3.8 years for cases and 3.6 years among control individuals.
Longer use of HRT was associated with higher rates of dementia, with a 21% increased rate with use for less than a year to 74% for more than 12 years.
Continuous and cyclic estrogen-progestin regimens were similarly associated with development of all cause dementia.
But progestin-only treatment and vaginal estrogen were not associated with development of dementia.
In an accompanying editorial, Kejal Kantarci, PhD, a Mayo Clinic professor of radiology and JoAnn E Manson, PhD, professor of medicine at Brigham and Women’s Hospital, suggest that a causal link between HRT and dementia risk in the study is unlikely.
“In particular, increased dementia risk with less than one year of hormone treatment is not biologically plausible, further supporting the presence of confounding factors,” they noted.
“These findings cannot inform shared decision making about use of hormone therapy for menopausal symptoms,” the researchers maintained.
“Randomized clinical trials provide the strongest evidence on the effect of hormone therapy on dementia risk. Furthermore, brain imaging biomarkers might help to identify the effects of hormone treatment on dementia pathophysiology at an earlier stage, making assessment of its influence on dementia risk in trials of recently postmenopausal women feasible.”
