HPA Axis (Hypothalamic Pituitary Adrenal Axis)

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The body is constantly working to maintain chemical and hormonal equilibrium or homeostasis, but it can be somewhat challenging with chronic stress and constant activation from several bodily responses. So, what helps to regulate and control these responses?

The hypothalamic-pituitary-adrenal axis (or the HPA Axis) is vital to managing bodily stressors. It directly affects the functioning of the thyroid gland, the adrenal gland, and the gonads. It also influences growth, milk production during pregnancy and controls water balance through cortisol.

The HPA axis is super important in controlling stress and stress responses. So, let’s see how it regulates all the various body processes such as digestion, the immune system, mood and sexuality, and energy usage.

How The Hypothalamic-Pituitary-Adrenal Axis Works

A stress response is triggered when you’re experiencing extreme stress, either from the environment, physiologically, or psychologically.

Let’s look at how the HPA axis works, starting with the initial stress response.

Initial Stress Response

Let’s use the example of being attacked by a moth when you have Lepidopterophobia (the fear of moths or butterflies).

The moth enters your room and starts flying around – getting a bit too close to you, triggering your fight or flight response.

The moment the moth enters the room, your sympathetic nervous system starts by releasing hormones like epinephrine and norepinephrine, which triggers resulting physical responses like an increased heart rate and alertness.

Approximately 10 seconds after the initial sympathetic nervous system response, the HPA axis becomes stimulated.

When the HPA axis is triggered, it stimulates the hypothalamus, releasing a hormone called Corticotrophin Releasing Factor (CRF). CRF is a central regulator of the HPA axis.

The CRF is then transported into the bloodstream and finds itself in the pituitary gland while still increasing sympathetic nervous responses.

The Pituitary Gland

The CRF reaches the pituitary gland, which stimulates two responses.

The first response is triggered by the release of adrenocorticotropic hormone or ACTH in the anterior pituitary gland.

The ACTH is then transported through the bloodstream into the adrenal glands – small pyramid-like structures located on top of the kidneys.

Adrenal glands comprise an adrenal medulla, located in the center of the gland, and an adrenal cortex, the outermost layer of the glands.

The adrenal medulla is usually triggered by initial stress responses to release epinephrine and norepinephrine and does not have as vital a role in this stage of the stress response.

The adrenal cortex, on the other hand, becomes the target destination for ACTH and produces corticosteroids.

In the adrenal cortex, specifically the zona fasciculata, the ACTH binds to receptors to produce a hormone called cortisol.

Cortisol falls under the group of glucocorticoids, which are hormones that affect metabolism. They also have immunosuppressive and anti-inflammatory effects.

From the zona fasciculata, cortisol is released into the body – with the main effect of the hormone being an increase in glucose entering the bloodstream, resulting in a sustainable source of energy during stress responses.

The Role Of Cortisol In The Stress Response

You want to think of cortisol as your natural built-in alarm system – i.e., a natural response to stress.

Cortisol aids the body by mobilizing energy through glucose stored in the liver, acting as a source of energy to deal with the attacking moth. 

Cortisol supplies the body with more blood and energy to sustain the increased blood pressure, heart rate, and awareness associated with the fight-or-flight response.

It also reduces the proinflammatory secretion of cytokine and histamine.

These are all vital chemical reactions, and nearly all bodily cells have cortisol receptors.

Through activating the HPA axis, several behavioral and physiological changes occur that can increase one’s chance of survival in a dangerous situation.

Stress responses are amazing in that they occur almost immediately and help you to overcome challenges you wouldn’t be able to without these stress hormones.

And when working in conjunction with epinephrine and norepinephrine, the body can still maintain homeostasis, even during stress.

Other Roles Of Cortisol In The Body

While cortisol is important in the fight-or-flight response, it also plays other roles in the body that include:

  • Acting as an anti-inflammatory agent
  • Regulating salt and water balance
  • Supporting a developing fetus
  • Regulating metabolism and blood sugar levels
  • Regulates blood pressure
  • Aids in the sleep and wake cycle
  • Boosts energy
  • Controls how the body uses carbs, fats, and proteins

Interestingly, cortisol can also influence your memory and how you learn.

It’s been indicated that cortisol and stress can inhibit effective memory retrieval. Frequently, this phenomenon will affect emotional memories more strongly than neutral memories.

Cortisol is also believed to enhance memory consolidation by facilitating habit-based learning, which could result in addictions such as drinking too much or risks of relapsing.

Additionally, cortisol acts during immense stress to inhibit unimportant activities within the body to focus on the danger.  

One example of this is the reduced desire to consume food, as it would not be essential for survival during the time you are experiencing immediate danger.

Negative Feedback Loop

Cortisol is continually released for several hours after the fight-or-flight response is triggered.

At some point, the cortisol levels reach a certain concentration in the blood.

The hypothalamus and hippocampus detect this high concentration and initiate the negative feedback loop to inhibit the release of cortisol by activating the glucocorticoid receptor in the brain.

The state of alertness dwindles as cortisol does, and homeostasis is maintained. (National Library of Medicine)

The goal of the negative feedback loop is to protect the body against too long HPA activity which can result in other problems.

Quick Summary

The HPA axis is a system that is regulated by the sympathetic nervous system, which is triggered by a source of stress.

The nerves signal to the glands involved in the HPA axis and release hormones, specifically cortisol, which increases energy production to sustain the body after the fight-or-flight response.

After a few hours, cortisol reaches a threshold that triggers a negative feedback loop, ultimately restoring homeostasis in the body.

While the moth was an uncommon example, the HPA axis is vital to ensuring we react in dangerous situations.

It can also be triggered when you experience stress at work or school or when you have anxiety.

With anxiety, prolonged periods of stress, and continual cortisol exposure, some problems can arise in the body.

HPA Axis Dysfunction

So, you now know that the HPA axis is important in stress regulation and responses.

But what about overstimulation of the HPA axis when you have continual anxiety or are facing periods of immense stress – financial stress or having to work through trauma or grief?

Well, this is when the system becomes a bit dysfunctional.

Overstimulation of the HPA axis can result in a variety of physical or psychiatric issues.

HPA axis dysfunction could be a result of:

  • Current life stressors
  • Genetics
  • Biological or pharmaceutical causes
  • Environment (especially trauma)

Putting the body under stress, intentionally or not, can result in a variety of stress-related problems.

Below are listed the most common symptoms people with HPA axis dysfunction could feel:

  • Difficulties coping with stress
  • Feeling overwhelmed
  • Experiencing burnout
  • Unexplainable tiredness
  • Irritability
  • Frequent illness
  • Feeling exaggerated responses to normal stress (like shaking, panic attacks, etc.)

There are also conditions related to over-exposure to cortisol, including:

Cushing’s Syndrome

Cushing’s syndrome occurs from the overproduction of cortisol by the body or as a result of oral corticosteroid medications.

Some signs of Cushing syndrome include:

  • A fatty hump between your neck and shoulders
  • A rounder face
  • Purple or pink stretch marks
  • High blood pressure
  • Bone loss

Sometimes, people with Cushing’s syndrome can also develop type 2 diabetes.

Treatments include restoring normal cortisol levels and improving symptoms.

Often, the earlier you start to treat the symptoms, the easier it will be to recover fully. (Mayoclinic)

Cushing’s Disease

Cushing’s disease differs from Cushing’s syndrome and occurs when a pituitary adenoma, or non-cancerous tumor, forms on the pituitary gland.

The benign tumor causes the pituitary to produce too much ACTH, producing too much cortisol and disrupting normal hormone levels.

About 10% of the time, pituitary adenomas will produce too much ACTH. (OSHU Brain Institute).

Addison Disease

Addison’s disease, or adrenal insufficiency, happens when the body does not produce enough cortisol and aldosterone.

Addison’s can occur in individuals of all age groups and sexes and is often life-threatening.

Some of the symptoms and signs include:

  • Extreme fatigue
  • Hyperpigmentation
  • Fainting spells or low blood pressure
  • Salt craving
  • Weight loss due to decreased appetite
  • Gastrointestinal symptoms (nausea, vomiting, etc.)
  • Hypoglycemia

Treatment for Addison’s disease includes taking hormones to replace those that are missing. (Mayo Clinic)


Hypopituitarism occurs when you are deficient in one or more of the pituitary hormones.

Hormone deficiencies can disrupt routine bodily functions, and the symptoms vary based on which hormone/s you’re missing.

Treatment for Hypopituitarism includes taking supplemental hormones to replace those that are missing and controlling symptoms.

Elevated Cortisol Levels

People with elevated cortisol levels are likely to experience many problems. Often, their immune system will be compromised, making it easier to become sick.

Other conditions of elevated cortisol levels include:

  • Diabetes
  • Obesity
  • Muscle weakness
  • Insomnia
  • Cardiovascular disease
  • Hypertension
  • Menstrual irregularities

It is often that individuals experiencing these symptoms or conditions could be facing a time of extreme stress, which causes the HPA axis to be activated for too long.

When this happens, the normal circadian rhythm (rest and wake cycle) can be disrupted, resulting in excessive cortisol release.

It’s also common for the stress-induced cortisol levels to return to the level before the stressor was introduced – making it easy to overexpose to cortisol.

In the long term, over-activation of the HPA axis has the potential to develop into mental health conditions.

A study by Moylan and co found that high cortisol levels and mood disorders like depression had a correlation.

Research has also indicated that post-traumatic stress disorder (PTSD) proved to be a possible factor of HPA axis dysfunction due to continual stress experienced by the individual.

To make the matter worse, for over-exposure to cortisol, a study by Newcomer and co found that excessive cortisol proved to have a negative impact on memory.

They determined that excessive cortisol resulted in decreased verbal declarative memory and delayed recall performance.

HPA axis regulation differences were also seen with addictive behaviors like excessive alcohol use.

Keeping the HPA Axis Regulating Normally

Keeping a healthy body is a goal many have – especially when they are someone who has experienced excessive stress and anxiety.

You can implement various ways to keep your HPA axis response normal, but the treatment approach depends on the situation the person is experiencing.

If you have a diagnosed syndrome like Cushing’s, the treatment approach would be medications that control cortisol production.

With things like mental health problems that are caused by a constantly stimulated HPA axis, it could be useful to consult a medical professional and talk about anti-anxiety medications or therapies like psychotherapy, alternative medicine, biofeedback, counseling sessions, and so on.

Finally, some lifestyle changes can help lower stress levels, which should keep the HPA axis regulated normally. Some of these changes include:

  • Following a healthy diet
  • Avoiding stimulants like alcohol and caffeine
  • Have a regular sleep pattern and have quality sleep
  • Participate in exercise
  • Try mindfulness techniques like yoga and meditation
  • See how you can manage stress in your daily life

Implementing one or more of these changes is sure to decrease stress, resulting in a healthier HPA axis that only responds when required.


The HPA axis is a really important player when it comes to the fight-or-flight response and when working as it should, it maintains alertness after most of the adrenaline passes.

The important hormone in the HPA axis is cortisol, the main hormone responsible for maintaining energy after the stress response.

There is a multitude of syndromes, diseases, and ailments that could arise when the HPA axis is constantly stimulated.

While some should be identified and treated by a medical professional, most people will be able to decrease activation by decreasing stress.




Reference this article:

Practical Psychology. (2022, August). HPA Axis (Hypothalamic Pituitary Adrenal Axis). Retrieved from https://practicalpie.com/hpa-hypothalamic-pituitary-adrenal-axis/.

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