HPA Axis - The Definitive Guide | Biology Dictionary (2022)


The hypothalamic–pituitary–adrenal (HPA) axis describes a complex feedback system of neurohormones that are sent between the hypothalamus, pituitary gland, and adrenal glands. This negative and positive feedback system regulates the physiological mechanisms of stress reactions, immunity, and fertility.

What is the HPA Axis?

If you are asked this question, the simple answer is a neurohormone feedback system between the hypothalamus and pituitary (hypophysis) glands of the central nervous system and the adrenal glands situated above the kidneys.

A longer answer to “what is the HPA axis” would describe the different mechanisms and how they work. This article will provide the details, looking at the three main structures, HPA axis hormones, and the systems they regulate.


The hypothalamus is a small portion of the brain located above the brainstem and under the thalamus. It is part of the diencephalon. It contains huge numbers of interconnected nerve fibers that connect the nervous system with the endocrine system.

The hypothalamus is split into lobes; the lobe that steers the HPA axis is the anterior lobe. This lobe is divided into different nuclei of gray matter that secrete neurohormones. The most important HPA axis nuclei are the paraventricular nucleus which secretes corticotropin-releasing hormone (CRH) and the supra-optic nucleus that secretes arginine vasopressin (AVP).

(Video) 2-Minute Neuroscience: HPA Axis

The trigger that causes the hypothalamus to increase production and release of CRH and AVP is stress. Stress is not only psychological – infection, medication, pregnancy, and our metabolism can produce an HPA axis stress response, as do thousands of other autonomic and somatic stimuli. Our sleep and wake patterns (circadian rhythms) can heighten and dampen stress responses, as do certain levels of hormones in the bloodstream.

Pituitary Gland

HPA axis pituitary tissue has many receptors for corticotropin-releasing hormone and vasopressin. These neurohormones are transported from the hypothalamus via connecting blood vessels – the distance from the hypothalamus to the pituitary gland is very short.

When the CRH and AVP receptors of the pituitary have detected the presence of these two hypothalamic neurohormones, the pituitary gland is stimulated to produce adrenocorticotropic hormone (ACTH). On its own, vasopressin has a much weaker effect; in combination with CRH, ACTH production is greater. As with the hypothalamus, this gland produces many different hormones. Of these, only ACTH is part of the HPA axis definition.

ACTH is secreted into the blood circulation.

Adrenal Glands

The two adrenal glands (suprarenal glands) sit on top of the kidneys, one on the right and one on the left kidney.

(Video) Depression in the Brain Part 1: The Stress/HPA Axis Model

When levels reach a certain point, adrenal gland receptors signal the two adrenal glands to produce the final chemical of the HPA axis – cortisol. Just as with ACTH, when certain levels of corticosteroids are detected in the blood, the brain will signal the hypothalamus to stop producing and secreting as much corticotropin-releasing hormone and arginine vasopressin. It also tells the pituitary gland to produce less ACTH – this is negative feedback via an inhibitory pathway. Limbic HPA axis regulation via the hippocampus, prefrontal cortex, and amygdala seems to occur by way of direct neuron connections and endocrine pathways. The limbic system regulates our emotions and memory and may play a role in HPA axis depression and other axis-related mood disorders.

Cortisol in the HPA Axis

The HPA axis hormone that causes the most physiological effects is cortisol. The presence of higher levels of cortisol in the blood makes us ready to react and stop the body from ‘wasting’ energy on things not so important to our immediate survival. When given the choice of running from a stampede of cattle and protecting us from any harmful bacteria these cattle might bring with them, the body makes the obvious choice and prepares us for flight. Adrenaline (also released from the adrenal glands) is the immediate fight/flight response. To sustain this response if the potential danger does not pass quickly, cortisol is required.

The steroid hormone cortisol has an extremely broad range of functions. Also called stress hormone, levels fluctuate throughout the day – high when we wake up and low when we are asleep. Many psychological disorders are caused by cortisol curve imbalances and, similarly, many pathologies upset cortisol production and the entire HPA axis.

When levels of cortisol are chronically high, glucocorticoid receptors become resistant to it. Cortisol receptors are found all over the body. This is why chronic stress is associated with so many different pathologies that range from cardiovascular disease to depression, infertility to muscle pain, and diabetes to integumentary (skin, hair, and nail) disorders.


  • Suppresses antibody production
  • Stimulates proinflammatory T-cell death
  • Modulates glucose homeostasis
    • Increases gluconeogenesis in the liver
    • Stimulates muscles to break down protein for an energy supply
    • Increases lipolysis in adipose tissuefatty acids are used as an energy source
    • Lowers insulin production in the pancreas
    • Increases glucagon production in the pancreas
  • Enhances the activity of epinephrine (adrenalin) and norepinephrine
  • Aids in bone formation

HPG Axis

The HPA axis is also modulated by another axis that initiates in the hypothalamus – the hypothalamic-pituitary-gonadal axis (HPG axis). This axis is only included as it has become clear in the last decade that gonadal hormones strongly influence how the body responds to cortisol and how much and when cortisol is produced. The fact that significantly more women than men suffer from depression and anxiety is probably due to this interaction. It is thought that estradiol elevates cortisol levels for longer periods, turning healthy acute stress responses into pathogenic chronic responses.

Postpartum depression, where the endocrine organ of the placenta causes huge alterations in maternal stress hormone levels, may also be the specific result of HPA axis dysfunction. Furthermore, women with chronic stress seem to find it harder to start a family. As nearly all psychiatric disorders involve HPA axis dysregulation of the stress response, both axes are being studied in depth. Perhaps the specific diagnosis of HPA axis depression is not so far away.

(Video) Role of the HPA Axis and the Neuroendocrine System in Psychiatric Disorders

HPA Axis Dysfunction

HPA axis dysfunction symptoms can occur as a result of damage or disease in the hypothalamus, pituitary gland, and adrenal glands. Other causes are low HPA axis hormone quality and a lack of or resistant receptors for these hormones. As the link between the HPA axis and limbic system, HPG axis, and other physiological pathways is not yet fully understood, treatment is not always successful.


Primary adrenal insufficiency means the adrenal glands produce too little cortisol – one cause is autoimmune reactions that see adrenal cells as foreign material. This pathology is called Addison’s disease. Secondary adrenal insufficiency occurs when the various tissues of the HPA axis are not functioning correctly because of tumor development, infection, or trauma.

However, the most common cause of hypocortisolism is long-term cortisone medication. This is not a form of adrenal insufficiency. Unlike primary and other secondary causes that are unable to produce cortisone in the necessary quantities, continuously high levels of synthetic cortisol cause HPA axis suppression via a negative feedback pathway. Remember that when cortisol reaches certain levels in the blood, the hypothalamus is told to stop producing CRH and AVP, and the pituitary to reduce ACTH production. In turn, the adrenal glands stop producing cortisol.

A person suffering from hypocortisolism will feel extremely fatigued and lose weight. Nausea and vomiting are also associated with Addison disease, as is skin discoloration (hyperpigmentation) due to disturbances in another closely-linked hormone – melanocyte-stimulating hormone.


Cushing’s syndrome is the result of too much ACTH produced in the pituitary gland (usually by a benign tumor) over longer periods – this increases cortisol levels. Cushing’s syndrome can also be due to adrenal gland pathology that leads to cortisol overproduction.

Ectopic secretion of cortisol describes cortisol production in foreign tissue, like the tissue of a tumor. This means that the usual HPA axis feedback mechanisms do not affect cortisol production. Hypercortisolism can also be caused by corticosteroid use – usually in the shorter term and with too high doses.

Symptoms are very broad. This shows how the HPA axis is linked to so many other endocrine pathways. Symptoms include insulin resistance and the development of diabetes mellitus, acne, and hirsutism (females) due to increased androgen (male) hormone production. A very telling group of female symptoms is the combination of moon face, facial hair, acne, buffalo hump, and apple shape. Immunity is low and wounds do not heal quickly.

(Video) HPA Axis and Adrenal Stress Assessment for Health Coaches - Feb. 2020

Treatment for psychological-induced hypercortisolism (constant anxiety and obsessive-compulsive disorders, for example) may include lifestyle changes that integrate relaxation techniques and certain supplements. HPA axis dysregulation might not immediately benefit from supplements but these can reduce HPA axis stress signals – for example, some herbs are calming to the mind, and vitamins and minerals aid physiological function, meaning less stress is produced by autonomic and somatic pathways in the body.

HPA Axis and Adrenal Fatigue

According to many scientific papers, adrenal fatigue is not an accepted pathology. As with thyroid disorders, some people believe that slightly imbalanced levels of cortisol are not detectable in a blood test. When an HPA axis test (blood test) does not show anything specific, some patients refuse to believe that ‘nothing is wrong’. For many, the diagnosis of adrenal fatigue allows them to give a cause to many different symptoms.

Slightly low levels of adrenal hormones (not only cortisol) are said to produce fatigue, aches and pains, low blood pressure, dizziness, loss of body hair, and hyperpigmentation. There is – as yet – no evidence that these symptoms are caused by the adrenal glands; however, it is obvious that some of them are associated with the HPA axis. Gaia herbs were developed to treat adrenal fatigue; however, as this disorder does not exist according to the majority of medical professionals, the decision to buy must be up to the individual.

HPA axis supplements could harm the feedback function over the long-term. Some over-the-counter remedies and recreational drugs are known to cause HPA axis dysfunction as, like all neurohormone pathways, balance is easily upset. Use of cannabis, for example, can blunt the cortisol response. While this may cause short-term relaxation, active cannabis users seem to show high levels of cortisol but reduced responsiveness to them. This is almost definitely the result of HPA axis dysregulation. With the introduction of CBD oil, many studies are looking at the effect of marijuana chemicals on stress response feedback mechanisms.




(Video) Hypothalamic pituitary adrenal axis (HPA axis)

  • Harkness K L, Hayden E P (Ed). (2019). The Oxford Handbook of Stress and Mental Health. New York, Oxford University Press.
  • Wilkinson M, Ali Imran S. (2019). Clinical Neuroendocrinology: An Introduction. Cambridge, Cambridge University Press.
  • Spencer, R L., Deak, T. (2017). A Users Guide to HPA Axis Research. Physiology & Behavior, 178, 43–65. https://doi.org/10.1016/j.physbeh.2016.11.014
  • DeMorrow S. (2018). Role of the Hypothalamic-Pituitary-Adrenal Axis in Health and Disease. International journal of molecular sciences, 19(4), 986. https://doi.org/10.3390/ijms19040986
  • Thau L, Gandhi J, Sharma S. (Updated 2020). Physiology, Cortisol. Treasure Island (FL): StatPearls Publishing. Retrieved from: https://www.ncbi.nlm.nih.gov/books/NBK538239/


HPA Axis - The Definitive Guide | Biology Dictionary? ›

Definition. The hypothalamic–pituitary–adrenal (HPA) axis describes a complex feedback system of neurohormones that are sent between the hypothalamus, pituitary gland, and adrenal glands. This negative and positive feedback system regulates the physiological mechanisms of stress reactions, immunity, and fertility.

What is HPA axis? ›

A major component of the homeostatic response is the hypothalamic-pituitary-adrenal (HPA) axis, an intricate, yet robust, neuroendocrine mechanism that mediates the effects of stressors by regulating numerous physiological processes, such as metabolism, immune responses, and the autonomic nervous system (ANS).

What is the correct order of the HPA axis? ›

The HPA axis has three primary components - the hypothalamus, the anterior and posterior pituitary glands, and the adrenal cortex.

What happens when HPA axis is activated? ›

Activation of the HPA axis causes secretion of glucocorticoids, which act on multiple organ systems to redirect energy resources to meet real or anticipated demand.

What are the three components of the HPA axis? ›

The hypothalamic–pituitary–adrenal axis (HPA axis or HTPA axis) is a complex set of direct influences and feedback interactions among three components: the hypothalamus, the pituitary gland (a pea-shaped structure located below the thalamus), and the adrenal (also called "suprarenal") glands (small, conical organs on ...

What stimulates the HPA axis? ›

Limbic system: amygdala

In contrast to the hippocampus and the prefrontal cortex, the amygdala is thought to activate the HPA axis. Stimulation of amygdalar neurons promotes glucocorticoid synthesis and release into the systemic circulation.

What are the symptoms of HPA axis suppression? ›

For men, when the HPA axis becomes suppressed, the symptoms that tend to arise include difficulty sleeping, midday fatigue, anxiety, weakened immunity, depression, aching joints, diminished sex drive, the tendency to feel cold, and loss of muscle mass and strength.

What causes HPA axis dysregulation? ›

The HPA axis dysregulation is widely observed in patients with severe mental illness and it is likely that it occurs as a consequence of exposure to various stressors. However, there is convincing evidence that the gut microbial alterations and increased intestinal permeability contribute to this observation.

How do you test for HPA axis dysfunction? ›

High-dose ACTH stimulation test: This test is used to evaluate the integrity of the HPA axis. It consists of the administration of 250 μg of intravenous corticotropin and measurement of serum cortisol concentrations after 30–60 min.

How long does it take to recover from HPA axis dysfunction? ›

Most patients showed recovery of the HPA axis by 4–12 weeks. However, 13% of patients had persistent adrenal insufficiency at 20 weeks after receiving glucocorticoid therapy.

What kind of stress activates HPA axis? ›

As with stress, acute alcohol consumption also directly and indirectly activates the HPA axis by resulting in elevated levels of glucocorticoids (Richardson et al. 2008). In fact, alcohol and other drugs of abuse have been described as a physiological stressor because they can activate the HPA axis.

What are the 3 stress hormones? ›

Stress hormones include, but are not limited to:
  • Cortisol, the main human stress hormone.
  • Catecholamines such as adrenaline and norepinephrine.
  • Vasopressin.
  • Growth hormone.

How do you fix HPA axis dysfunction? ›

Use the following tips to rebalance your HPA axis and support healing.
  1. Clean Up Your Diet. Focus on balancing your blood sugar. ...
  2. Avoid Caffeine. Caffeine mimics the stress response. ...
  3. Engage in Stress Reduction. ...
  4. Incorporate Movement and Regular Exercise. ...
  5. Get Regular Sun Exposure. ...
  6. Support Your Sleep! ...
  7. Can Supplements Help?
Jul 20, 2017

How does PTSD affect the HPA axis? ›

The blunted HPA axis response in PTSD is thought to be due to increased negative feedback sensitivity via enhanced GR responsiveness (Yehuda et al., 2009; Hartmann et al., 2012; Schöner et al., 2017). FK506 binding protein 5 (FKBP5) is thought to be a regulator of GR sensitivity.

What controls the release of cortisol? ›

The release of cortisol is under control of the hypothalamus-pituitary-adrenal (HPA) axis. Corticotropin-releasing hormone (CRH) is released by the paraventricular nucleus (PVN) of the hypothalamus.

How do you heal HPA axis naturally? ›

Seven Steps to Help You Follow an HPA Axis Dysfunction Diet
  1. Avoid Eating Processed, Refined Foods that Stress the HPA Axis. ...
  2. Avoid Dieting. ...
  3. Don't Skimp on Carbohydrates, but Be Sure to Choose Nutrient-Dense Carbs. ...
  4. Regulate Your Blood Sugar. ...
  5. Support Your Gut Microbiome.
Jul 3, 2020

Can HPA axis be corrected? ›

Cortisol output of the HPA axis can in reality be manipulated either directly or indirectly through several interventions. The most direct approaches involve (1) inhibition of cortisol synthesis at the level of the adrenal gland or (2) inhibition of CRH induced ACTH synthesis by the pituitary.

What are the symptoms of low cortisol? ›

Too Little Cortisol
  • Changes in your skin, like darkening on scars and in skin folds.
  • Being tired all the time.
  • Muscle weakness that grows worse.
  • Diarrhea, nausea, and vomiting.
  • Loss of appetite and weight.
  • Low blood pressure.

What happens when HPA axis is suppressed? ›

When the HPA axis becomes suppressed, the body is not able to properly regulate stress and energy levels, which can manifest in symptoms such as fatigue, suppressed immune system, depression, and anxiety.

What causes HPA axis dysfunction? ›

There are several ways that a woman may develop HPA axis dysfunction: Exposure to prenatal stress. Presence of maternal depression, lack of mothering skills that result in neglect or separation from mom. Early-life exposure to extreme or prolonged stress caused by trauma, abuse and neglect.

What are the signs of adrenal gland problems? ›

  • Extreme fatigue.
  • Weight loss and decreased appetite.
  • Darkening of your skin (hyperpigmentation)
  • Low blood pressure, even fainting.
  • Salt craving.
  • Low blood sugar (hypoglycemia)
  • Nausea, diarrhea or vomiting (gastrointestinal symptoms)
  • Abdominal pain.
Nov 24, 2020

How does PTSD affect the HPA axis? ›

The blunted HPA axis response in PTSD is thought to be due to increased negative feedback sensitivity via enhanced GR responsiveness (Yehuda et al., 2009; Hartmann et al., 2012; Schöner et al., 2017). FK506 binding protein 5 (FKBP5) is thought to be a regulator of GR sensitivity.


1. Assessing Stress Response and Resiliency with Genova's Adrenal Stress Profile
(BioBalance Wellness Institute)
2. Dave Asprey and Hacking Your HPA Axis: Law #4
(Dr. Joel Rosen)
3. Adrenal Cortex: Hypothalamic Pituitary Adrenal Axis
4. Case Studies, Patterns, and Clinical Pearls: The HPA Axis
(Precision Analytical)
5. HPA Axis Healing & Coping Strategies
(Miles Naturopathics)
6. What Is Adrenal Fatigue? (and all about your HPA Axis)

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