An enzyme that converts testosterone to estrogen appears to have a significant impact on a healthy and injured brain, scientists report.
There's a growing body of evidence that in the healthy brain, aromatase, and the estrogen it enables neurons to produce, help keep our minds sharp and flexible. Now scientists are learning that with injury, aromatase and estrogen expression seem to shift to cells in the brain called astrocytes.
These cells support and nurture stressed brain neurons, said Dr. Darrell Brann, Regents' Professor and Vice Chairman of the Department of Neuroscience and Regenerative Medicine at the Medical College of Georgia at Georgia Regents University.
Numerous studies, including those in Brann's lab, have shown this shift in aromatase/estrogen expression from neurons to astrocytes following injury.
In Brann's case, the studies have been in the hippocampus, a center of learning, memory, and emotions. When he used a drug to reduce astrocyte's aromatase expression in that region, increased inflammation and brain damage resulted.
A new $1.8 million grant from the National Institute of Health will allow him to further clarify the role of aromatase and estrogen in injury and health and (hopefully) discover therapies that can increase the brain's apparent effort to heal.
The studies are conducted with several laboratory mice, one with aromatase removed from neurons, another with it missing in astrocytes, and a third with aromatase lacking in both brain cell types.
The mice were developed by Brann's lab in collaboration with Dr. Ratna K. Vadlamudi, Professor of Obstetrics and Gynecology at the University of Texas Health Sciences Center.
"We will be able to tell the cell-specific function of estrogen," Brann said. "We want to know what happens when they don't have it. We'll study the plasticity, the connectivity of neurons in these knockouts, and we'll consider their cognitive function using behavioral tests."
They'll also see what happens to inflammation and recovery when aromatase expression can't increase as it probably should following injury.
Brann is not surprised that usually supportive astrocytes levels would increase the following injury and thinks estrogen is critical to the expanded role.
"In a non-injury situation, we see it mostly in the neurons, so it much [sic] has some functions such as plasticity and connectivity normally," he said.
Following injury, when astrocytes start making aromatase then estrogen, the emphasis appears to shift to protection and recovery.
He added that as with every built-in protective mechanism, astrocyte support is not 100% foolproof; sometimes natural recovery mechanisms get overwhelmed by the extent of the injury.
However, Brann hopes that, in addition to better understanding what estrogen does in the brain typically and following injury, the new studies will point toward new therapies that augment the apparent natural recovery effort.
Neurons highly express aromatase in a healthy hippocampus.
Following a traumatic injury or stroke, the high expression appears to shift to astrocytes, a type of glial cell, found in abundance in the central nervous system that generally provides support and cushion for neurons.
Astrocytes are known to become more active after brain injury, unleashing more supportive, healing factors that many scientists are convinced also help lower inflammation and boost their protection of neurons.
However, if astrocytes remain activated for too much time, they can also cause problems, including gliosis, which is mostly a scar-like wad of glial cells in the area living neurons previously occupied.
"You have to regulate all these factors being released tightly," Brann said.
Even in culture, neurons will connect and communicate, but scientists add an aromatase inhibitor to the mix, which blocks connectivity.
Some of the initial in vivo studies in zebra finches demonstrated that aromatase levels increased following a brain injury, which also supports a protective role for the protein. More brain damage results when aromatase inhibitors are given.
"There seemed to be more inflammation," Brann said.
Part of what he wants to learn about how estrogen aids brain connectivity and plasticity, is exploring whether it regulates brain-derived neurotrophic factor, which is known to have a role in both.
Brann also plans to pursue the role of aromatase and estrogen in neurodegenerative diseases, such as Alzheimer's, where there is some early evidence that missing aromatase increases plaque development.
Naturally high estrogen levels in premenopausal women have long been considered protective of stroke as well as heart attacks and other maladies.
The link between hormones and traumatic brain injury
Numerous studies have demonstrated that hormonal imbalances are linked to traumatic brain injury (TBI). Hypopituitarism (a disease where the pituitary gland manufactures healthy growth hormone levels) is quite common following brain injuries – as high as two-thirds to one-half of those patients.
The worst part of this heartbreaking development is that the hormone deficiency may lie undetected for decades following the trauma. Tragically, this makes a bad situation far worse, as the brain deterioration and memory loss continue to increase unchecked.
But why? Why does this happen? Why would damage to the brain result in hormone levels going into a free-fall?
To answer those questions, we need to start with the pituitary gland. Often referred to as “the master gland” the pituitary is the command center of other endocrine glands.
However, the pituitary is controlled by the hypothalamus gland. The hypothalamus monitors the pituitary by telling the gland how much of its hormones to release.
The hypothalamus then receives feedbacks by neurological input from virtually all of the body. This process is crucial to maintaining hormonal balance.
Knowing this connection, it is now apparent that damage to the brain, even in small amounts, can wreak havoc on the hypothalamic-pituitary system and have devastating consequences on our hormonal equilibrium.
In fact, it is the unsettling of the hormonal system that plays a huge role in the broad range of neurological problems of TBI, not the brain injury itself.
The hormone estradiol plays a critical role in the growth of neurons by both decreasing inflammation and promoting the growth of dendrites.
Dendrites resemble tree branches sprouting from the ends of neurons that receive signals from other neurons and send electrical stimulation to the heart of the attached neuron.
Testosterone is converted to estradiol in men’s brains when aromatase is present, and this helps to lessen the impact of the brain injury.
Studies have concluded that low levels of estradiol are lower cognition scores in both men and women.
Conversely, healthy testosterone levels boosted scores on the Mini-Mental Status Examination. Other studies have arrived at similar conclusions. Also, recovery from TBI occurs more often in patients with high testosterone levels.
Hormone Replacement Therapy (HRT) and prevention of dementia
This is, of course, no guarantee that dementia, mild cognitive impairment (MCI) and Alzheimer’s Disease (AD) can be prevented.
However, every one of the above-mentioned brain disorders has one thing in common: diminished hormone levels. Healthy hormone levels can provide a degree of protection from these dreaded mind afflictions.
But this could become a case of “too much of a good thing.” Studies have concluded that there may be a “golden mean” level of hormones where more may negate the benefits that HRT can deliver.
The key is to measure and monitor to determine that hormonal “sweet-spot.”
And that’s why you need to contact us
A grim, sad fact: most hormonal deficiencies are not even identified, let alone treated. Despite the growing mountain of evidence that has established a direct link between low hormone levels and TBI, very few doctors are considering HRT for treatment of the injured brain.
But we do! At our clinic, our main priority is to ensure that your hormones are at optimal levels...not too high and not too low. We have the experienced to determine precisely the dosage that will give the maximum benefit to your entire body – and that includes your mind as well.
Considering the association of low hormones with brain impairment, it is recommended that everyone, not just people dealing with TBI, to undergo hormone testing.
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