Brain Longevity: Hormones and Brain Health
This month’s blog post addresses an important topic that is of high interest to all of us, and what Dr Dominique Fradin-Read likes to call “brain longevity.”
How can we keep a sharp brain and avoid memory lapses and cognitive difficulties that can be a threat as we age?
A review of the role of various hormones on brain function is presented here. Our next blog will address ways to protect our brain against aging, focusing on the importance of hormone replacement.
Both female and male hormones influence the brain in various ways. Therefore, both sexes are at risk of cognitive decline over time. However, statistics show that women are at a higher risk of Alzheimer's and present with brain fog after menopause earlier than men, which suggests the importance of the protective role of estrogen and progesterone on the neurons.
Estrogen and brain function
Four different hypotheses have been studied and confirmed the impact of estrogens, especially Estradiol (E2), on the brain
The cholinergic hypothesis: acetylcholine is the neurotransmitter produced in certain neurons and is responsible for our cognitive performance. It enhances memory and comprehensibility. These neurons have receptors to estradiol on their surface and it is now clear that the level of this hormone influences their function. These are the neurons implicated in the development of Alzheimer which supports the higher ratio of cases of women after menopause versus men.
The dopamine hypothesis: the second neurotransmitter dopamine is also involved in cognitive function. Its decrease is associated with brain fog, lack of interest and motivation and even brain apathy. Parkinson’s disease impacts the production of dopamine in the brain and patients often present with early signs of attention deficit and later on the sign of dementia. Here again, the role of estrogens is important, and this explains why men and women after menopause are more at risk of developing Parkinson’s disease than younger females.
The mitochondrial aging hypothesis: this is a relatively recent discovery and a crucial mechanism of action of estrogens on the brain cells. Mitochondria are small organelles found in every cell of the body and are responsible for the energy at the cellular level through the production of ATP. We can compare them to the powerhouse of the cells. A dysfunction of the mitochondria at any organ level can cause propound disturbances of the metabolism of this organ; this is particularly true with the brain. Another essential role of mitochondria is to support synaptic brain plasticity, the ability to adapt and refine the connections between neurons, constantly improving brain circuits as we age.
The mechanism of action of estrogen at this level is complex. The role of estrogen is to assist the transport of glucose into the neurons (sugar being the main nutrient for the brain cells). Glucose is a vital metabolic fuel for the brain, providing energy for physiological functions such as thinking, learning, and memory. When glucose levels are low, the brain cannot produce neurotransmitters in an optimal way which disrupts communication between neurons. When estrogens decline after menopause, the neurons are deprived of good levels of glucose, and change their metabolism into a ketone’s metabolic mode for survival. Some might argue that ketones can be a “good” nutrient for neurons. It is true for short periods or in conditions where the source of sugar decreases or the demand is high, ketones can rescue the brain providing fuel to the brain when glucose gets low. What is showing in recent studies is that long-term exposure to ketones can also lead to dysregulation of the energy homeostasis of the brain and trigger other abnormalities, such as a reduction of the antioxidant defense, accumulation of misfolded proteins, and initiation of damaging inflammatory processes. In summary, we need to be mindful that the best fuel for the brain is glucose and that estrogen levels impact the ability of the brain's mitochondria to use it and produce energy.
The inflammatory hypothesis: chronic low-grade inflammation has been identified as a cause of aging and in particular brain aging, Increased levels of inflammatory markers and cytokines such as CRP, IL-6… are linked to reduced cognitive performance. Women after menopause, for various reasons, tend to display higher levels of inflammatory markers. Estrogens have been shown to protect the central nervous system from chronic inflammation and neurodegeneration. Estradiol in particular acts at the level of certain receptors to inhibit the action of immune system cells called macrophage (microglia) that increase the inflammatory process in the brain and the destruction of neurons. To illustrate this finding, we know that patients suffering from Multiple Sclerosis (MS) tend to see their condition improve during pregnancy when estrogen levels are high and worsen after menopause.
In addition to reducing inflammation, estrogens play an important protective role in supporting the survival of the brain cells. A population of specific cells exists in the brain called astrocytes and oligodendrocytes. These cells have a mission to support the good function of the neurons with the production of neurotrophin compounds needed for the nourishment of neurons. One of these compounds is the Brain Derived Neurotrophic Factor (BDNF). The interaction between BDNF and estrogen is extremely complex and not yet fully elucidated. It seems that it occurs at the gene expression level, and it is bidirectional, with estrogens enhancing the production of BDNF and BDNF sensitizing the effects of estrogens at the neuron receptors. The result of both actions is to maintain healthy neurons that can function optimally.
Besides these effects of estrogen influencing neurons involved directly in intellectual brain function, we should also mention the impact of emotions on memory and cognitive performance. Estrogens can affect the function of the hippocampus and the amygdala, two brain regions in the limbic system highly involved in the regulation of emotions, stress response but also memory and learning. It is easy to understand that, when estrogens start to decline during the luteal phase of the female cycle just before periods, and even more when peri-menopause hits, the chaotic situation of neurotransmitters in these two brain regions can cause both mood imbalances and brain fog.
Progesterone and brain function
Progesterone is the second female hormone that has been considered for years for its protective effect on the brain cells both on its own and through its various metabolites.
What is fascinating to note is that progesterone is not only produced in the ovary after ovulation but is also synthesized locally in the brain by specific neurons and glial cells (the nourishing cells of the brain). It is called a neuro-steroid, and it is involved in many processes of brain metabolism including neuroprotection and myelin production, neuromodulation and mood regulation with support of specific neurotransmitters (GABA in particular), as well as learning and memory.
Unfortunately, few studies have been performed to study the influence of natural micronized progesterone on cognitive function. Most trials were done with the introduction of synthetic progestogens that do not present the same protective benefits as natural progesterone. Some limited clinical trials have shown that progesterone can limit the inflammatory response and reduce brain edema after traumatic brain injury, and it has been suggested that intravenous infusion of progesterone in such cases could reduce the damaging effects of the toxic environment caused in the brain by the traumatic event.
What is well documented are the effects of progesterone and its metabolites, one of them called allopregnanolone, to reduce anxiety, improve sleep, and consequently support cognitive brain function and memory. Micronized natural progesterone administered to women after menopause improved various sleep outcomes in randomized clinical trials. It seems obvious that a good night's sleep will help the next day with concentration and intellectual performance.
More studies might be necessary to show the direct effect of natural progesterone on cognitive function. However, the benefits offered by this hormone on mood balance, anxiety and stress reduction, and sleep support suffice to recommend it when its levels start to decline around perimenopause.
Testosterone and brain function
Testosterone is synthesized at the level of the testicles in men and the adrenal gland in both sexes. In addition, the active biosynthesis of testosterone can occur locally de novo in the brain as a metabolite of cholesterol; it is therefore also a neuro-steroid that binds to androgen receptors located in the limbic system. The limbic system includes the amygdala and the hippocampus and is the part of the brain that regulates behaviors and emotions. Male hormones, essentially testosterone, seem to have a role as modulators of this limbic system.
Decreased levels of testosterone linked to aging have been associated with increased risk of anxiety and depression. This phenomenon appears to be partly linked to the genotype of the androgen receptors, and in appropriate patients with low testosterone levels, testosterone substitution can increase positive mood and decrease anxiety.
If it is clear that female hormones, estrogens essentially, have an essential impact on brain function and support cognitive function or memory, the research is still inconclusive for testosterone. Neuroimaging studies show that, besides its fixation on the limbic system, testosterone can also be found in subcortical areas of the brain involved in cognitive function and spatial memory. What makes it even more complicated is that testosterone can be metabolized into estrogens; it becomes more difficult to know the part each hormone plays in brain function.
What is known is that general mental and intellectual functions usually decline with declined testosterone levels and aging. Genetic factors are involved in the process and the effect of testosterone varies between males and females. Current data suggest that testosterone supplementation in men of all ages with low level of testosterone enhances vigor and energy and consequently can impacts cognitive functions as well as mood.
More research is needed to establish the physiopathology of testosterone on the brain cells and its real impact on brain function.
In our next blog, Dr. Read will address the clinical evaluation of declined hormones levels and the potential interventions to help preserve “brain longevity.”
Dr. Read and the VitaLifeMD team specialize in hormone replacement therapy. Our treatments achieve a healthy hormone balance for any age by customizing each treatment based on your symptoms and laboratory results. Learn more about our programs here, and contact us to become a patient.