National Alzheimer’s Awareness Month
How Women’s Reproductive Health Can Drive Brain Aging and Inform Alzheimer’s Prevention
By: T. Morgan Moody, MS4
Editor’s Note: November is National Alzheimer’s Awareness Month, so we are featuring research on how endogenous and exogenous estrogen exposures might impact cognitive aging and Alzheimer’s dementia among women. T. Morgan Moody, a former FACTS elective participant, summarized a 2022 article published in the Frontiers of Aging Neuroscience by researchers Jett S, Malviya N, Schelbaum E, et al.
From menarche to menopause, 17β-estradiol is the primary circulating hormone in fertile women. This sex hormone is primarily produced in the ovaries, although other tissues, including the brain, liver, and adipose tissue, are also involved in hormone production. Estrogen produced in the brain is utilized locally for the regulation of neuronal function, metabolism, morphology, and number. Many research studies have established the neuroprotective, anti-inflammatory, and vasodilatory effect of estradiol in the brain. The level of sex hormones that a female is exposed to throughout her lifetime decreases significantly after menopause, playing a major role in the decrease in cognitive function and an increased risk of Alzheimer’s dementia. Alzheimer’s dementia is the most common cause of dementia; after female sex, age is the most significant risk factor.  Given the established correlation between lifetime circulating estrogen levels and the risk of dementia, further research on lifetime endogenous and exogenous estrogen exposure lends insight into preventative and therapeutic strategies to combat this debilitating disease process.
“Many research studies have established the neuroprotective, anti-inflammatory, and vasodilatory effect of estradiol in the brain.”
A woman’s reproductive lifespan can differ based on the onset of menarche and the timing of menopause. An early menarche combined with a late menopause contributes to greater endogenous estrogen exposure throughout her life. Recent studies have investigated the hormonal changes and lifetime exposure associated with the risk of Alzheimer’s dementia. Several found an association between longer reproductive periods and positive cognitive outcomes and a decreased risk of cardiovascular disease and Alzheimer’s dementia. Additionally, if a woman becomes pregnant during her reproductive years, estrogen levels can increase up to 300 times the normal level followed by a decreased circulating level of estrogen postpartum. Data overwhelmingly suggests the benefit of endogenous estrogen exposure on cognitive function, but the data regarding parity and cognitive decline has been inconsistent. Overall, studies examining cognitive performance at the time of birth have reported long- and short-term benefits of pregnancy on cognitive function and aging. Moreover, studies have found that spontaneous menopause is superior to surgical menopause when it comes to minimizing a risk of Alzheimer’s dementia and neuropathology.
“Data overwhelmingly suggests the benefit of endogenous estrogen exposure on cognitive function.”
While endogenous estrogen is the most common estrogen exposure, exogenous estrogen use has increased in the last few decades. A woman may encounter exogenous estrogen exposure via hormonal contraceptives, hormonal replacement, and endocrine therapy, often used to treat breast cancer. Despite the widespread use of hormonal birth control, there is limited and conflicting data on its impact on the brain. Some studies suggest a reduced risk of cognitive impairment, while others show no impact on the incidence rate of dementia.  Data supporting the use of hormone replacement therapy to reduce the risk for Alzheimer’s dementia is similarly mixed, with the greatest potential benefit observed among women under the age of 60 who start hormone replacement therapy shortly after the onset of menopausal symptoms. For women over 60 or those 10 to 20 years past the onset of menopause, hormone therapy appears less favorable due to the greater absolute risks of dementia, coronary heart disease, stroke, and venous thromboembolism.  Lastly, endocrine therapy for hormone receptor-positive breast cancer can include estrogen blockers and aromatase inhibitors to suppress estrogenic function throughout the body. However, the influence of endocrine therapy remains unclear; endocrine therapy is often combined with chemotherapy, which has well-documented detrimental effects on bodily functions and cognitive and brain function. Further research is needed on all exogenous estrogen therapies to produce more generalizable results.
“Data supporting the use of hormone replacement therapy to reduce the risk for Alzheimer’s dementia is similarly mixed, with the greatest potential benefit observed among women under the age of 60 who start hormone replacement therapy shortly after the onset of menopausal symptoms.”
Individuals could benefit from the use of fertility awareness-based methods (FABMs) by learning to recognize hormonal abnormalities, including low estradiol states. These methods can be utilized early in a women’s reproductive years through menopause at little to no cost to the patient and without pharmaceutical intervention. A woman with low circulating levels of estrogen may experience limited cervical fluid and anovulatory cycles resulting in oligomenorrhea, amenorrhea or infertility, which are more easily identifiable when women chart their cycle. Earlier recognition of hormonal abnormalities and treatment using a restorative reproductive approach can lead to a longer, more consistent lifetime estrogen exposure and the reduced risk of Alzheimer’s dementia.
Given the observed connection between the female sex and risk of Alzheimer’s dementia and cognitive aging, there is need for further research on the important role of endogenous estradiol. Inconsistent findings between studies regarding endogenous and exogenous estrogen exposure may be due to length of exposure, age of initiation, formulation, and dosage throughout their lifetime. More in-depth clinical studies are needed to investigate the unique relationship between sex, age, sex steroid hormones, and the risk for Alzheimer’s dementia in the development of preventative care.
 Jett S, Malviya N, Schelbaum E, et al. Endogenous and Exogenous Estrogen Exposures: How Women’s Reproductive Health Can Drive Brain Aging and Inform Alzheimer’s Prevention. Front Aging Neurosci. 2022;14:831807. Published 2022 Mar 9. doi:10.3389/fnagi.2022.831807
 The NAMS 2017 Hormone Therapy Position Statement Advisory Panel. The 2017 hormone therapy position statement of The North American Menopause Society. Menopause. 2017;24(7):728-753. doi:10.1097/GME.0000000000000921
ABOUT THE AUTHOR
T. Morgan Moody, MS4
T. Morgan Moody is a 4th year medical student at Oklahoma State College of Osteopathic Medicine in Tulsa, Oklahoma. She completed her undergraduate degree in psychology at the University of Oklahoma in Norman, Oklahoma. She is interested in pursuing a career in women’s health in rural and underserved communities. Morgan became interested in fertility-awareness based methods so she would be able to provide contraception to all her patients regardless of their background.