Alzheimer’s disease (AD) is twice as common in women than in men. This issue of menopause and menopausal hormone therapy has garnered quite a lot of attention over the last 10-20 years in particular. Does menopausal hormone therapy(MHT) increase risk of AD or decrease risk or in some and not others based on other factors? A recent observational study published in June 2023 triggered the conversation anew.
Using Danish health registries, the researchers investigated the associations of hormone therapy (HT) with dementia later in life and found an increased risk of dementia with either short term or long term use of HT.
Two well respected colleagues and experts in menopause and MHT, JoAnn E Manson, MD, DrPH, MACP and Kenjal M Kantarci, MD, MS provided an analysis at the invitation of the North American Menopause Society.
Here is some selected history to be aware of. The Women’s Health Initiative Memory Study (WHIMS) was a randomized trial published in 2003. This study reported that menopausal estrogen plus the synthetic progestin was associated with a two fold increase in the risk of dementia in women older than 65 years. But this increased risk did not occur in women who started HT when they were in the 50-55 year range as reported in 2013 in the updated WHIMS-Y trial— basically, WHIMS of younger women. Two other randomized trials tested the effects of estrogen and a progestogen on cognitive function in women who started shortly after menopause. In both of those trials, cognitive function was no worse or better compared with placebo.
This new study by Pourhadi and colleagues reports an association with increased risk of dementia in women using HT before age 55 and for 5 years or less. This is the age that the Menopause Society recommends initiating hormones. This new study contradicts those of the WHIMS-Y trial and other trials that report no negative effect on cognitive function in women who start HT early in menopause.
The question is, why is there a difference in their study vs. others? Our two menopause experts and I think there are confounding factors that are related to this study’s observation of higher dementia risk even in younger women starting HT early in menopause (within 5 years of last menstrual period or even within 10 years or before age 60.) The fact that they report increased dementia risk with less than one year of use of HT emphasizes the point that there are confounding factors because this is not considered biologically plausible.
This observational study was conducted by having available to them the records of the population of Denmark and HT prescriptions. The researchers investigated different regimens including cyclic or continuous estrogen plus progestogen regimens, the age of initiation of HT and duration of use of HT.
Previous observational studies have been conflicting on the risks and benefits of HT in regard to cognitive function and dementia. The concern with the current study is that observational associations are prone to artifactual errors and thus a cause and effect between HT and dementia risk cannot be inferred. Some of the confounding variables that can influence a study like this is that vasomotor symptoms, especially at night, are associated with a higher volume of white matter hyperintensity on brain imaging, which is a marker of poor brain vascular health. Approximately two-thirds of women report cognitive difficulties during the menopause transition and may experience a temporary reduction in their cognitive processing speed. Women who report cognitive changes, vasomotor symptoms and sleep disturbances are likely to seek HT more often than women who do not have these symptoms.
These issues are some of the primary reasons why we cannot use this study to conclude if the use of menopausal HT increases the risk of dementia in younger women. I am still highly influenced by the biological mechanisms, animal studies and human studies that point to HT actually reducing the risk of dementia and Alzheimer’s disease when started before the age of 60 or within the first 10 years of menopause, and even better yet, within the first five years. I use this body of evidence to inform my recommendations to women who in particular have a mother, father, or sibling with a history of Alzheimer’s Disease. I also encourage the reader to seek out the book: Estrogen Matters by Avrum Bluming MD and Carol Tavris PhD and as it relates to the subject of HT and the brain, read chapter 5.
References:
Pourhadi N, Morch L, Holm E, et al. Menopausal hormone therapy and dementia: nationwide, nested case-control study. BMJ 2023;381, June 28.
Estrogen Matters; Avrum Bluming MD and Carol Tavris; 2018. Little, Brown Spark publishers
The 2022 Hormone Therapy Position Statement of The North American Menopause Society. Menopause: The Journal of The North American Menopause Society Vol. 29, No. 7, pp. 767-794
