The HPA axis, or hypothalamic-pituitary-adrenal axis, is a complex set of interactions between the hypothalamus, pituitary gland, and adrenal glands. It plays a critical role in regulating stress responses, mood, digestion, immune function, and energy storage and expenditure in the body. The pathway of the axis results in the production of cortisol.

The stress response aims to provide energy for an extended period of time. It does not need to be fast, so it uses hormones to transmit signals.

When a chronic stressor is perceived, the hypothalamus releases Corticotrophin Releasing Factor (CRF), and the bloodstream transports this to the pituitary gland which then produces Adrenocorticotrophic hormone (ACTH).

The bloodstream also transports this to the adrenal glands. The cortex of the adrenal glands produces corticosteroids, the most important being cortisol.

Cortisol mobilizes glucose stored in the liver; this provides a constant supply of energy for the body to deal with the stressor.

The hypothalamus is located just above the brain stem and is key in controlling many of the body’s functions, including releasing hormones and maintaining the body’s internal balance.

The pituitary gland is also situated just above the brain stem and is a small pea-sized organ that tells other glands to release hormones.

The adrenal glands are located on top of the kidneys, which produce hormones that help regulate metabolism, the immune system, and blood pressure, as well as the response to stress and other functions.

Activation of the HPA axis initiates several behavioral and physiological changes that can improve an individual’s chance of survival when faced with homeostasis challenges.

Our initial stress response occurs almost immediately and results in the secretion of hormones called epinephrine and norepinephrine.

These hormones enact changes to the body to maintain homeostasis during times of stress, such as increasing the heart rate and perspiration.

Sometime later, the HPA axis is stimulated in response to signals such as elevated norepinephrine levels.

How Does the HPA Axis Work?

When something stressful happens, the sympathetic nervous system mediates the initial response. This causes the release of the hormones epinephrine and norepinephrine, which triggers physical responses to stress, such as increased heart rate.

About 10 seconds after this initial response, the HPA axis will be stimulated. Firstly, the hypothalamus will release corticotropin-releasing hormone (CRH). CRH is the central regulator of the HPA axis.

As well as CRH increasing the activity of the sympathetic nervous system, it also works by signaling the pituitary gland, which is located just below the hypothalamus.

There are two parts to the pituitary gland, the posterior and anterior pituitary gland. Both release different types of hormones to their target organs which have varying effects.

For the HPA axis, the anterior pituitary gland releases a hormone into the bloodstream, with the adrenal glands as the target organ. This hormone is called the adrenocorticotropic hormone (ACTH).

The pituitary gland releases ACTH and travels down to the adrenal glands above the kidneys. The adrenal glands are composed of the adrenal medulla, located in the center of the glands, and the adrenal cortex, the outermost layer of the glands.

The adrenal medulla is usually activated during the initial stages of stress and releases epinephrine to stimulate the fight or flight response. The adrenal cortex, which is the target destination of ACTH, produces steroid hormones.

There are 3 layers to the adrenal cortex, but the second layer, the zona fasciculata is of particular interest in the HPA axis. ACTH binds to the receptors of the adrenal cortex, where the zona fasciculata produces a hormone called cortisol, a type of glucocorticoid.

Glucocorticoids are hormones that can affect metabolism and have anti-inflammatory and immunosuppressive effects. Cortisol is then released from the adrenal cortex where it has various effects on the body. Cortisol is the primary stress hormone that increases sugars (glucose) in the bloodstream.

Cortisol (Stress Hormone)

Cortisol helps to mobilize the body’s energy through the use of glucose so that the body has enough energy to cope with a prolonged stressor.

This release of cortisol causes several effects on the body to help it deal with stressors that last longer than a few minutes. An important function is that cortisol increases blood pressure.

This then results in more blood supplying the skeletal muscles in a stressful situation requiring physical exertion, such as running away or fighting.

The anti-inflammatory effects of cortisol are brought about by reducing the proinflammatory secretion of cytokine and histamine and stabilizing the membranes of cell components, lysosomes.

Cortisol can also influence learning and memory. It has been found that cortisol and stress can both transiently block memory retrieval, with retrieval of emotional memories being more strongly affected than neutral memories.

Likewise, cortisol is believed to enhance memory consolidation, mostly information, which is emotionally arousing, thus, cortisol can be implicated in facilitating habit-based learning. Cortisol acts during the experience of serious stressors to also inhibit the activity of processes that are deemed unimportant at the time of stress.

For instance, the desire for reproductive activity is inhibited as this would not be essential for survival at the time of serious stress.

Cortisol is often released for several hours after encountering a stressor. At a certain blood concentration of cortisol in the bloodstream, this is sensed by receptors in the areas of the brain such as the hypothalamus and hippocampus.

The cortisol exerts what is known as negative feedback to the hypothalamus, which releases CRH, therefore inhibiting this hormonal release. Cortisol also inhibits the anterior pituitary gland, which releases ACTH, thus inhibiting this hormonal release.

This then leads to a shutting off of the stress response because at this point, homeostasis has returned. These negative feedback loops are designed to protect the body against prolonged HPA activity.

The nerves regulate the HPA axis, which act as a sensor for all the stress in the environment and then relays these signals to all of the glands involved in the HPA axis.

An example of when the HPA may be activated is when someone is experiencing extended periods of stress at work or when someone is facing a lot of anxiety.

The HPA axis is, therefore, integral in our healthy response to stress. Overall, a healthy stress response is characterised by a quick rise in cortisol levels, followed by a rapid decline when the stressful situation ends.

HPA Axis Dysfunction

As discussed, the HPA axis is important for regulating the body’s response to stress. However, there can be instances where this response is experiencing issues, such as being overstimulated, which can result in physical and/or psychiatric problems.

Causes of HPA axis dysfunction could result from genetics, biological causes (e.g., from medications), early-life environment (e.g., childhood trauma), and current life stressors.

Some of the general symptoms of HPA dysfunction include:

Feeling irritable
Frequent illnesses
Difficulty coping with stress
Feeling unexplainable tiredness
Feeling overwhelmed
Experiencing an exaggerated response to stress

A condition called hypercortisolism, also known as Cushing syndrome, is a condition that can occur when the body has too much of the hormone cortisol over a long period.

This condition could be caused by taking high doses of corticosteroid medication over time or the body producing too much cortisol or ACTH. People with Cushing syndrome often experience symptoms such as weight gain, fatty tissue deposits, fragile skin, slow healing of cuts and infections, and acne.

Individuals with elevated cortisol levels, in general, may experience a suppressed immune system response making them more susceptible to infections. High levels of cortisol could also lead to other physical conditions, such as:

Diabetes
Hypertension
Obesity
Menstrual irregularities
Muscle weakness
Insomnia
Cardiovascular disease

Chronic stress from life events can repeatedly cause the HPA to be over-activated and for longer periods of time. Chronic stress, such as from work, illness, or bereavement, can shift the normal circadian rhythm of the release of cortisol as well as during stress-induced occurrences.

After chronic stress, cortisol baseline levels are elevated. This can result in the body’s cortisol response to acute stress being lessened. It may also take longer for stress-induced cortisol levels to return to pre-stress levels.

Chronic stress can make the HPA axis more sensitive, resulting in higher cortisol exposure or higher cortisol burden following each stressful episode. When there is excessive exposure, this is when it can influence the development of neuropsychiatric and metabolic disorders.

Long-term stress resulting in the over-activation of the HPA axis can result in the development of mental health conditions.

Overstimulation of the HPA axis and high cortisol levels have been found to be implicated in mood disorders such as depression (Moylan et al., 2013) and linked with anxiety, mood swings, and irritability.

Posttraumatic stress disorder (PTSD), a condition that can be developed after experiencing traumatic events, has also been shown to be a possible factor of HPA axis dysfunction due to increased levels of chronic stress being experienced.

Excessive cortisol has been shown to have detrimental effects on memory and cognition. This was demonstrated in a study of those who took cortisol treatment at a high dose.

It was found that these individuals had decreased verbal declarative memory and lower immediate and delayed recall performance (Newcomer et al., 1999).

Differences in HPA axis regulation are also associated with problematic alcohol use and dependence. Studies have found that cortisol can interact with the brain’s reward system, which may contribute to alcohol’s reinforcing effects.

Cortisol is thought to influence an individual’s cognitive processes and promote habit-based learning, which may contribute to the formation of drinking habits and the risk of relapse (Stephens & Wand, 2012).

Keeping the HPA Axis Regulating Normally

There are many ways in which to keep the HPA axis regulated normally, although these depend on the situation. If elevated cortisol levels have resulted in Cushing syndrome, there are medications that can be taken to control the excessive production of cortisol.

These can include ketoconazole, mitotane (Lysodren), and metyrapone (Metopirone). Likewise, if taking medications that affect cortisol, it may be beneficial to review this with a health professional if it appears to be contributing to excessive cortisol in the body.

If mental health conditions such as depression and anxiety are the cause of an overactive HPA axis, it may be useful to take medications that tackle these.

This can include antidepressants which work to encourage the circulation of essential neurotransmitters around the brain to reduce symptoms that could be causing depressive feelings and excessive stress.

Psychotherapy could be a useful method to keep the HPA axis regulated normally.

This can be especially useful if also experiencing mental health conditions which may be affecting the HPA axis, such as mood disorders and PTSD. A type of psychotherapy, cognitive behavioral therapy (CBT), has shown effectiveness in treating conditions such as PTSD.

Likewise, counseling sessions can help individuals experiencing excessive stress to recognize what may be triggering their stress and how to control it better.

Biofeedback is another method that can be used to reduce stress. This involves being able to see or hear physiological information about the body, such as being connected to a machine that measures heart rate.

Through being able to see a high heart rate, for instance, this biofeedback can encourage individuals to attempt to lower their heart rate to a normal level and understand which techniques work to enable this to happen.

Finally, there are also some lifestyle changes that can help lower stress levels which should ultimately keep the HPA axis working regularly. These can include:

A healthy diet, with a focus on balancing blood sugar levels
Avoiding caffeine and alcohol
Ensuring a regular sleeping pattern and enough sleep
Taking part in regular exercise, such as aerobic activities
Relaxation techniques such as deep breathing exercises
Meditation, yoga and mindfulness

References

Guilliams, T. G., & Edwards, L. (2010). Chronic stress and the HPA axis. The standard, 9(2), 1-12.

Mayo Clinic. (2021, April 30). Cushing syndrome. https://www.mayoclinic.org/diseases-conditions/cushing-syndrome/symptoms-causes/syc-20351310

Moylan, S., Maes, M., Wray, N. R., & Berk, M. (2013). The neuroprogressive nature of major depressive disorder: pathways to disease evolution and resistance, and therapeutic implications. Molecular psychiatry, 18(5), 595-606.

Neuroscientifically Challenged. (2014, June 4). Know Your Brain: HPA Axis. https://www.neuroscientificallychallenged.com/blog/2014/5/31/what-is-the-hpa-axis

Newcomer, J. W., Selke, G., Melson, A. K., Hershey, T., Craft, S., Richards, K., & Alderson, A. L. (1999). Decreased memory performance in healthy humans induced by stress-level cortisol treatment. Archives of general psychiatry, 56(6), 527-533.

Smith, S. M., & Vale, W. W. (2006). The role of the hypothalamic-pituitary-adrenal axis in neuroendocrine responses to stress. Dialogues in clinical neuroscience, 8(4), 383.

Stephens, M. A. C., & Wand, G. (2012). Stress and the HPA axis: Role of glucocorticoids in alcohol dependence. Alcohol research: current reviews.