Alzheimer’s and Brain Awareness Month
Estrogen, Mitochondria, and their Impact on Brain Aging: A Review
By: Gabrielle Riley
Director’s Note: During Alzheimer’s and Brain Awareness Month, we highlight an article published in Frontiers in Aging Neuroscience by Lejri et al titled, “Mitochondria, Estrogen and Female Brain Aging.” [1] The 2018 article was summarized by Gabrielle Riley, who participated in the FACTS elective as a medical student. The authors explored the role of mitochondria in estrogen synthesis and its implications for brain health. Given estrogen’s important role in cognitive health, the article also addresses potential interventions, including hormone replacement therapy (HRT). If you are interested in learning more about the peri-menopausal period and HRT, check our parts C and J of our online CME course and remember FACTS members receive a 20% discount on CME and conference registrations, so join FACTS today!
Introduction
Mitochondria are vital organelles involved in cellular calcium regulation, metabolism, cell turnover, and production of ATP. They generate energy and reactive oxygen species (ROS) and contribute to cellular health. Mitochondria are essential for steroid hormone synthesis, including estrogen, which plays diverse roles in brain modulation and neuronal health. As estrogen levels decline during menopause, the risk of osteoporosis, heart disease, and dementia increase. Estradiol, the predominant estrogen, has neuroprotective effects, influencing mitochondrial metabolism and potentially contributing to the longevity advantage in females. A hallmark of aging, mitochondrial dysfunction affects the energy-demanding brain and may contribute to neurodegenerative diseases.
“Mitochondria are essential for steroid hormone synthesis, including …estradiol, the predominant estrogen, (which) has neuroprotective effects, influencing mitochondrial metabolism and potentially contributing to the longevity advantage in females.”
Estrogen’s Protective effects
Mitochondrial dysfunction helps fuel the gradual decline in physiological functions in aging. As energy production diminishes in the brain and ROS output rises, a pro-oxidant state develops. Mitochondrial functions decline with age, including electron transport chain (ETC) activity and antioxidant defense enzyme levels. The loss of estrogen at menopause correlates with decreased antioxidant defenses. Animal studies support these findings, showing changes in brain metabolism and oxidative stress during reproductive aging. Yet, estrogen may mitigate the mitochondrial dysfunction that leads to increased oxidation. Although mitochondrial DNA is vulnerable to oxidative damage in aging, estrogen may play a role in DNA repair.
Mitochondria and Estrogen Synthesis
Mitochondria are central to the initial step in steroid hormone synthesis yielding pregnenolone, the precursor for steroids and neurosteroids. Cholesterol must first enter the mitochondria to be changed into pregnenolone, which is converted into various steroid hormones, including estrogen, once outside the mitochondria. Since steroid hormone synthesis relies on the health of the mitochondria, it follows that impaired mitochondria could result in hormonal imbalance.
Estrogen Impacts Brain Development and Aging
Estrogen’s influence extends beyond endocrine regulation to pivotal roles in central nervous system (CNS) development and function. From fetal stages to adulthood, male and female sex hormones impact neural circuit expansion and sex-specific behaviors and differentiation in the mammalian brain. During puberty, estrogen and testosterone levels influence structural and functional differences between male and female brains, which is evident in specific brain regions.
“During puberty, estrogen and testosterone levels influence structural and functional differences between male and female brains, which is evident in specific brain regions.”
Estrogen exerts its effects through diverse pathways, with estrogen receptors present outside traditional CNS regions, indicating their involvement in various brain functions. Estrogen’s effects begin in utero through its influence on the development of neuronal connections. Brain plasticity continues through puberty and adulthood, and estrogen plays an essential role in maintaining and regulating network integrity. During peri- and post-menopause, disruptions in neurosteroids like estrogen can have an adverse effect on CNS-hippocampal activities such as memory, cognition, and attention.
“During peri- and post-menopause, disruptions in neurosteroids like estrogen can have an adverse effect on CNS-hippocampal activities such as memory, cognition, and attention.”
Estrogen Pathways in the CNS
Estrogen uses various pathways in the CNS, three of which are found in mitochondria: estrogen receptors (ER), brain-derived neurotrophic factor (BDNF), and sirtuin 3 (SIRT3) pathways.
CNS Pathway via estrogen receptors
Several types of estrogen receptors are present within mitochondria. ERα receptors in human cerebral endothelium mediate estrogen’s protective effects on mitochondrial function and ROS reduction. Estrogen response elements in mitochondrial DNA enhance mitochondrial-encoded gene expression. ERs may also interact with mitochondrial respiratory complex proteins, impacting brain function and the aging process.
CNS Pathway via brain-derived neurotrophic factor
Research suggests the brain-derived neurotrophic factor (BDNF) pathway is linked to age-related cognitive decline. Decreased BDNF signaling in the CNS during aging may contribute to cognitive deficits and conditions such as Alzheimer’s disease. In the hippocampus, males generally exhibit lower BDNF levels than females. The coordinated action of BDNF and estrogen is crucial to maintain synaptic function and plasticity with advancing age.
CNS pathway via mitochondrial enzyme SIRT3
The mitochondrial enzyme SIRT3 plays a central role in regulating cellular metabolism, oxidative stress response, and aging. Its overexpression prevents neuronal dysfunction and supports synaptic plasticity, whereas its scarcity induces mitochondrial defects and increased ROS. Estrogen-related receptor binding elements in the mitochondrial SIRT3 promoter region suggest estrogen’s involvement in regulation of this enzyme.
Implications for Estrogen Replacement Therapy
Studies show a decline in brain metabolic function following the loss of estrogen from surgical removal of the ovaries or reproductive endocrine aging. In the female brain, estrogen regulates glucose metabolism, ATP production, and mitochondrial respiration. These favorable actions of estrogen on a woman’s brain and cellular health suggest estrogen could be a promising therapeutic approach to counteract mitochondrial impairments associated with aging.
Female sex is a significant risk factor for Alzheimer’s disease, particularly during the perimenopause-to-menopause transition. Research indicates the optimal window of opportunity for estrogen replacement therapy (ERT) in women is early in the endocrine aging process, during perimenopause and early post-menopause. Initiating ERT at that time may help prevent age-related cognitive decline and decrease the risk of dementia. However, the effectiveness of ERT depends on factors such as treatment formulation, delivery mode, and regimen.
Research indicates the optimal window of opportunity for estrogen replacement therapy (ERT) in women is early in the endocrine aging process, during perimenopause and early post-menopause… (and) at that time may help prevent age-related cognitive decline and decrease the risk of dementia.
Conclusion
Studies over the last two decades have shown a connection between mitochondrial dysfunction, estrogen levels or production, and cognitive abilities. Although more research is needed on humans to understand these relationships better, the existing literature presents a compelling case for individualized ERT in perimenopausal or early postmenopausal women.
References
[1] Lejri, I., Grimm, A., & Eckert, A. (2018). Mitochondria, Estrogen and Female Brain Aging. Frontiers in Aging Neuroscience, 10. https://doi.org/10.3389/fnagi.2018.00124.
ABOUT THE AUTHOR
Gabrielle Riley
Gabrielle Riley is a fourth-year medical student at Kansas City University in Kansas City, MO. She completed her undergraduate degree at Missouri State University in Springfield, MO and a master’s degree at KCU before medical school. She plans to pursue residency in pediatric neurology and is passionate about neuroimmunology, global health, and child healthcare advocacy. She enrolled in the FACTS elective because she had never heard of natural family planning methods and wanted to gain more insight on all options to offer her future patients.
