Dementia is a global health concern, and recent research suggests that it affects women more than men. Even after accounting for differences in survival rates, women have a higher incidence of dementia compared to men. This indicates the existence of sex-related risk factors contributing to the development of dementia. One such factor is the hormone estrogen, which has both neuroprotective and neuroimaging properties. The use of exogenous systemic estrogen in managing menopausal symptoms has been a subject of interest, particularly regarding its impact on dementia risk.
According to BMJ, the Women’s Health Initiative Memory Study, conducted in 2003, reported an increased risk of dementia in women aged 65 years and older who underwent menopausal hormone therapy. However, the study’s findings may not be entirely relevant in a contemporary setting, as the recommended timing and duration of hormone therapy have since changed. Current recommendations suggest hormone therapy be used around the time of menopause, ideally for a maximum of five years.
Moreover, the study did not differentiate between subtypes of dementia and only examined conjugated estrogens, not the leading estrogen, estradiol, found in modern menopausal hormone therapy products. Large-scale observational studies have provided further insights into the association between menopausal hormone therapy and dementia risk. Some of these studies have found a positive correlation between the long-term use of hormone therapy and the development of Alzheimer’s disease. However, these studies were limited in their ability to capture complete exposure history, especially regarding short-term use around the onset of menopause.
The impact of the progestogen component in menopausal hormone therapy on dementia risk remains uncertain. Observational studies have suggested that combining progestogen with estrogen may intensify the potential neuroimaging effect, potentially favoring cyclic progestogen treatment over continuous therapy. However, distinguishing between these treatment types has proven challenging in previous studies.
A recent nationwide, nested case-control study aimed to investigate the association between menopausal hormone therapy and the development of dementia. The study categorized treatment regimens as cyclic or continuous estrogen-progestogen therapy and also analyzed short-term users aged 55 years or younger, as per current recommendations. The study revealed that exposure to menopausal hormone therapy with estrogen and progestogen was associated with an increased risk of all-cause dementia, late-onset dementia, and Alzheimer’s disease.
Furthermore, the longer the duration of treatment, the higher the hazard rates for developing dementia. Both continuous and cyclic estrogen-progestogen regimens exhibited similar associations with dementia development. Interestingly, short-term users who exclusively received treatment at 55 years or younger also showed an increased rate of dementia. Notably, progestogen-only treatment and vaginal estrogen were not associated with dementia development.
The Women’s Health Initiative Memory Study, the largest randomized, double-blind, placebo-controlled trial on this topic, reported an increased risk of dementia in postmenopausal women treated with estrogen and progestogen after one year of use. Brain MRI scans of the trial participants supported these findings by showing a correlation between menopausal hormone therapy and brain atrophy, a radiological finding strongly associated with cognitive decline and dementia.
Recent large-scale observational studies have also suggested a positive association between long-term menopausal hormone therapy use and Alzheimer’s disease. However, due to the age restrictions of these studies, information on short-term hormone therapy use, especially around menopause, was limited, leading to potential misclassification of treatment exposure and dilution of the observed association.
The nationwide study boasts a large, unselected study population, a robust method of identifying dementia cases, and an almost complete treatment history. By restricting the analysis to women aged 50-60 years in 2000, the study aimed to diminish potential biases observed in previous observational studies. However, the age restriction led to a lower median age of dementia onset compared to the general population. Despite this limitation, the findings remained consistent for late-onset dementia.
The recent nationwide study provides valuable insights into the association between menopausal hormone therapy and dementia risk. The research highlights the increased rate of dementia associated with estrogen-progestogen treatment, regardless of treatment duration or regimen type. However, further studies are required to differentiate between treatment modes and specific types of progestogen. Understanding the potential risks and benefits of hormone therapy is essential for healthcare professionals and women considering menopausal symptom management.
