HPA axis dysfunction, or adrenal fatigue, leads to higher risk for many cognitive, mood, and mental disorders. Learn how to test for and treat it naturally.
If your lifestyle is overwhelming you with stress and it never lets up, you might find yourself alternately wired … and tired.
After more time goes by, you might feel anxious, burned out, depressed, and exhausted.
What’s behind all this?
It may be a condition known as HPA axis dysfunction, commonly known as adrenal fatigue.
What Is the HPA Axis?
Our bodies strive for physiological balance, or homeostasis, from the smallest organelles to our biggest organs.
It is our neurotransmitters and hormones — our chemical communication system — that are responsible for a balance that allows us to thrive.
On a daily basis, however, that balance is challenged by various stressors.
Stressors can be emotional upset, what we eat or drink, social pressure, work deadlines, almost anything.
These stressful events are countered by our fight-or-flight response, initiating a cascade of hormones and neurotransmitters that shout DANGER!
This stress response, known as the HPA axis, is a complex set of feedback mechanisms mediated by the brain’s hypothalamus, the pituitary gland (at the base of the brain), and the adrenal glands (above the kidneys).
The HPA axis has a lot to do with our mental and physical health, how alert or tired we feel, and how well we can handle our stressors.
When HPA axis function is stimulated, we experience a temporary loss of homeostasis as we try to counteract the stressor.
The release of cortisol, norepinephrine, and adrenaline shift into high gear.
As these hormones and neurotransmitters respond to our stress, they cause immediate behavioral and physical changes. (1)
Behavioral effects can include increased arousal and alertness, nervousness and anxiety, loss of appetite, and disinterest in sexual activity.
Physical changes include increased heart rate and blood pressure and a shift of blood supply away from our internal organs to our nervous system, arms, and legs.
Stress has activated our sympathetic nervous system, the excitatory part of our nervous system that produces fight-or-flight readiness.
How Does the HPA Axis Work?
When we perceive a threat, the amygdala, our “fear center” deep inside the brain, sends messages to the hypothalamus. (2)
The hypothalamus is “command central,” signalling the adrenal medulla (the inside of the gland) to secrete the stress hormones adrenaline and norepinephrine. (3)
This is what happens if, for example, you’re startled by an unexpected door slamming shut.
When you see that there is no threat, stress hormones dissipate and the body starts to calm.
However, if the stressor lasts more than a few seconds, the amygdala signals the HPA axis to move into high gear.
The hypothalamus initiates the HPA chemical cascade by releasing a hormone, corticotropin-releasing factor (CRF), that tells the pituitary gland to escalate the stress response.
The pituitary consequently releases adrenocorticotropic hormone (ACTH) to stimulate the adrenal cortex (the outside of the gland) to produce cortisol.
Cortisol is a major stress hormone that, during threat, raises blood glucose so that we have the energy to fight or flee.
It also controls inflammation to help in the event of injury.
HPA Axis Symptoms
What happens biochemically when the HPA axis responds to a perceived threat?
When You’re on High Alert
A high level of cortisol is stimulatory — in the wee hours of the morning, an overactive mind is a common cause of waking. (4)
High adrenaline raises the heart rate, respiratory rate, and blood glucose, while norepinephrine raises blood pressure and promotes wakefulness, alertness, arousal, vigilance, and memory. (5, 6, 7, 8, 9)
Learn more —
How to Balance Norepinephrine Levels Naturally
When the Stress Is Past
So that you don’t burn out your stress response system, you have a built-in mechanism to return it to normal once the stressor is gone.
The hippocampus, the brain center for short-term memory, plays a key role in rolling back the stress response. (15)
When you perceive that the threat is gone, the hippocampus serves as a brake on the HPA axis, telling it to return to normal. (16)
Cortisol, norepinephrine, and adrenaline levels return to normal, and we begin to relax — homeostasis has happily returned.
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HPA Axis Dysfunction (Adrenal Fatigue) and Its Effects
If you cannot escape from a perceived threat, you may find yourself experiencing chronic stress.
When you first register a stressor, your HPA axis goes on high alert.
You experience possible anxiety, disrupted sleep, and disturbed digestion.
Depending upon how resilient your HPA axis is, you may spend a shorter or longer time in this high-alert phase — maybe weeks or even months.
Sooner or later, however, your adrenals get tired of pumping out adrenaline and cortisol at such elevated levels.
Cortisol levels begin to fall, and you may begin to feel a deep fatigue. (17)
Since you still have your life to live, you must “run” on something.
That something is usually norepinephrine produced by the sympathetic nervous system.
Were you able to look through a window into your neuroendocrine system, you might see both an elevated level of norepinephrine and a falling level of cortisol.
You have joined the ranks of the “wired and tired.”
You may now have HPA axis dysfunction!
HPA axis dysfunction is the technically correct term for what’s commonly known as adrenal fatigue.
Testing may be important at this point.
It may provide your health care professional with the information to help you avoid total exhaustion and begin rebuilding the health of your stress response system.
Commonly, cortisol testing is done via saliva samples, usually four samples spread throughout the day to map cortisol’s daily rhythm.
Testing neurotransmitters, such as norepinephrine and adrenaline, is done most easily via urine.
Neurotransmitter testing is accurate, pain-free, and available through specialty functional laboratories that measure key neurotransmitters such as serotonin, dopamine, norepinephrine, epinephrine, GABA, and glutamate.
HPA Axis Dysfunction Due to an Elevated Cortisol Level
Ongoing elevated cortisol levels brought about by chronic stress can have many damaging effects.
Since the hippocampus is the seat of short-term memory, short-term memory may begin to fail.
When stress is very intense, it is hard to remember what happened even yesterday!
Learn more —
How to Reduce Cortisol, the Stress Hormone
Blood Glucose Effects
Since elevated cortisol and high levels of norepinephrine raise blood glucose, over time they contribute to insulin resistance and the risk of type 2 diabetes. (21)
For type 2 diabetics, this is dangerous as it can lead to diabetic complications.
For type 1 diabetics, this is risky as it may require the immediate adjustment of their insulin dosage.
Higher blood glucose levels can also encourage overgrowth of the yeast Candida albicans, disrupting gut function with increased gas and bloating and causing more frequent vaginal yeast infections. (22)
Effects on Mood
Immunity Suppression Effects
Cortisol is your body’s main anti-inflammatory substance.
Since inflammation is a major tool of the immune system, higher levels of cortisol are considered to be immunosuppressive.
Suppressed immunity secondary to stress is particularly significant in the elderly, as the detrimental effect of stress on the immune system tends to increase with age. (28)
Here’s a summary of the effects of an elevated cortisol level:
- atrophy of the hippocampus, seat of short-term memory
- elevated blood glucose, contributing to insulin resistance and the risk of type 2 diabetes
- increased risk for major depression
- candida overgrowth
- immune suppression due to inhibition of inflammatory processes
- higher levels of anxiety
HPA Axis Dysfunction Due to a Low Cortisol Level
After prolonged periods of stress, patients often exhibit a lower level of cortisol production in the adrenal glands, indicating reduced HPA axis function.
Reduced HPA axis function is associated with the following conditions:
In addition to pervasive fatigue due to lowered cortisol levels, patients also experience sympathetic nervous system fight-or-flight symptoms. (33)
Chronic Fatigue Syndrome
Post-Traumatic Stress Disorder
Studies consistently show that patients with post-traumatic stress disorder (PTSD) have low cortisol levels. (39)
It is suggested that the low cortisol levels are a result of a prolonged period of HPA hyperactivity following a traumatic event. (40)
This is the type of depression that is accompanied by apathy, fatigue, excess sleeping, and lack of motivation.
Here’s a summary of the effects of a low cortisol level:
- chronic fatigue syndrome
- post-traumatic stress disorder
- atypical depression
Supplements to Treat HPA Axis Dysfunction
If you are in the acute phase of a stress response, controlling your anxiety and high cortisol level is an important first step.
To reduce anxiety, there are several supplements that are useful and readily available on the retail shelf.
GABA is the brain’s primary calming neurotransmitter.
If GABA levels fall, you can feel anxious, nervous, and even suffer panic attacks.
L-theanine is part of the GABA system in the brain, maintaining calm.
Relora®, a blend of two Chinese medicinal herbs (magnolia and philodendron), can also be quite effective in reducing high levels of cortisol. (47)
Phosphatidylserine or phosphorylated serine is a nutraceutical that has been shown to reduce raised cortisol levels post-exercise. (48)
If you have been highly stressed for quite a while, and find yourself fatigued throughout the day, you may have tired adrenals (adrenal insufficiency).
A class of herbs called adaptogens are very useful in regulating homeostasis of the HPA axis and aiding adrenal gland recovery.
Adaptogens are defined as “a pharmacological group of herbal preparations that increase tolerance to mental exhaustion and enhance attention and mental endurance in situations of decreased performance.” (49)
Rather than being used continually, adaptogens are most effective when used only during stressful periods or when recovering from the same. (50)
Many retail adrenal formulas contain some combination of the following adaptogenic herbs:
Arctic Root (Rhodiola rosea)
- Significantly reduces generalized anxiety disorder (GAD) symptoms (51)
- Anti-inflammatory effects (52)
- Effective treatment for chronic fatigue (53)
- Can be used for acute stress, active in 30 minutes (54)
Siberian ginseng (Eleutherococcus senticosus)
- Broad anti-fatigue, anti-stress, and antioxidant properties (55)
- Cardioprotective action during stress (56)
- Can help with behavioral deficits from sleep deprivation (57)
Ginseng (Panax ginseng)
- Calms HPA axis function during stressful events (58)
- Effective anti-inflammatory and antioxidant effects (59, 60)
- Antidepressant effects in animal study (61)
Ashwagandha (Withania somnifera)
- Significant anti-stress action (62)
- Used for nervous exhaustion, insomnia, and weakness due to stress
- Shown to reduce inflammation in neurons (63)
HPA Axis Dysfunction: The Bottom Line
The HPA axis is a complex network of interactions between the hypothalamus and pituitary and adrenal glands that controls the body’s stress response.
Chronic stress can lead to HPA axis dysfunction, affecting your mental and physical health in multiple ways.
Tests are available that may help you learn more about the biochemical imbalances underlying to your HPA axis dysfunction.
Additionally, there are natural supplements that can moderate your stress response and help you return to a more stress-resilient state.
About the author
Ramona Richard, NC, MS is a technical writer and Education Director for Sanesco Health. Her years as an instructor of advanced nutrition, combined with her consulting practice and experience in the industry, have given Ms. Richard a depth of understanding of human nutrition, broad clinical expertise, and polished skills in training others in this field.