The ages at which a person starts and stops menstruating could affect their risk of developing dementia later in life, according to the largest study of its kind.
The analysis included health information from 273,260 women participating in the UK Biobank, and the findings suggest that those who start their period younger and go through menopause at an older age have healthier aging brains, relatively speaking.
Specifically, researchers at University College London found that people who menstruated for 34 to 37 years had a 28 percent lower risk of dementia compared to those with a shorter “reproductive period.”
This correlation seemed to depend on both when menstruation began and when it stopped, either naturally or through reproductive surgery.
In humans, estradiol is the most potent of the estrogen family of hormones. Its level rises and falls throughout life, peaks during the reproductive years and declines with menopause.
The current study uses menstruation as an indicator of these hormone levels. Participants who began menstruating at age 15 or older showed a 12 percent increased risk of dementia. Meanwhile, those who experienced menopause after age 50 had a 24 percent diminished risk of dementia.
Hormone replacement therapy, which supplements estrogen after menopause, did not appear to affect the results. The associations were also consistent between people who carried genetic risk factors for dementia and those who did not.
“Based on the results of this study, estrogen could play a protective role in women in the development of dementia,” concludes the UCL team.
If that turns out to be true, it could help explain why more than 60 percent of people who develop this neurocognitive disorder are women. In fact, apart from age, sex is the biggest predictor of dementia development known to scientists.
However, the effect of sex hormones on the aging female brain is not well understood. To date, the vast majority of brain research has been conducted on male brains.
Only 2 percent of published neuroimaging studies even bother to mention hormonal factors, and only 0.5 percent have delved deeper. More than half of these studies found statistically significant associations between female sex steroids and changes in the brain.
For example, in postmortem brains from women who died with Alzheimer’s disease (the most common form of dementia), scientists have measured relatively low estrogen levels.
Follow-up studies in animals have revealed that the mammalian brain is very sensitive to estrogen, especially in regions associated with learning and memory. Some results in rodents even suggest that estradiol may improve neuronal connections in the hippocampus and possibly reduce the buildup of protein plaques associated with Alzheimer’s.
However, similar research with human brains has yielded conflicting results.
In 2021, a study of 99 middle-aged women revealed that longer reproductive duration, indicating that more years of exposure to estradiol, was associated with greater volumes of gray matter in the brain, a tissue that is reduced in volume in those with Alzheimer’s.
However, in 2020, an analysis of 16,854 women found that greater lifetime exposure to sex hormones was associated with further apparent signs of brain aging, no less.
To separate these conflicting results, the UCL researchers conducted what they say is, to their knowledge, the largest analysis to date. Their findings suggest that cumulative lifetime exposure to estrogen is closely related to healthy brain aging.
One of their most concerning findings is that people who underwent reproductive surgery faced an 8 percent increased risk of dementia.
Fortunately, it appears that this risk can be significantly reduced if surgery is performed later in life (between the patient’s 40s and 50s, rather than their 20s and 30s).
The UCL authors, however, point out that many of these surgeries are unnecessary and are performed too young. By some estimates, about 90 percent of hysterectomy surgeries are performed for benign conditions, and 54 percent of women in the United States undergoing hysterectomies have both ovaries removed. More than a third of this group was under 44 years old.
“When women undergo surgery for such benign conditions, they experience an abrupt decrease in estrogen exposure and accelerated changes in the nervous system in the perimenopausal period,” the UCL researchers explain.
“(R)reproductive surgery should be considered as an increased risk of dementia in clinical practice.”
The current analysis has produced some of the strongest observational results to date, but can only reveal associations at the population level.
Much more research is needed to determine how estrogen might directly affect brain aging and what we can do about it. There is even a possibility that other sex hormones, such as progesterone, also play an overlooked protective role.
While the current study did not show better cognitive health outcomes among those who received hormone replacement therapy, some researchers have theorized in the past that it is the timing of these treatments that matters for brain health, not just whether they occur or not.
Much more research is needed to determine why women tend to develop dementia at such high rates than men, and how that risk can be reduced.
If we want to truly understand cognitive decline, experts say it is imperative to prioritize studies of the female brain in the future.
The study was published in The American Journal of Geriatric Psychiatry.