Hypothalamic Pituitary Adrenal Axis (HPA)

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The Endocrine system controls a plethora of physiological aspects in humans and other higher organisms, including metabolism, reproduction, and reactions to stress. The various organs and glands within this system cooperate to ensure the effective functioning of the organism through various pathways. One such pathway is the Hypothalamic Pituitary Adrenal Axis.

The Hypothalamic Pituitary Adrenal Axis is a neuroendocrine pathway linking the hypothalamus and pituitary gland to the adrenal glands. This Axis supports the organism's body during stress-inducing situations, promoting survival and homeostasis by regulating specific bodily functions.

The Hypothalamic Pituitary Adrenal Axis is a mechanism that prepares our bodies to take on a stressful situation. This system monitors various chemical levels inside our bodies and adjusts hormones accordingly while operating across multiple organs and glands. Below we investigate how this system works, the major organs, hormones, and glands involved, and issues relating to the dysfunction of this Axis.

Understanding The Hypothalamic Pituitary Adrenal Axis

The Hypothalamic Pituitary Adrenal Axis (HPA) is an intricate part of humans' and other mammals' coping mechanisms during high stress. When presented with a stressful situation, the Axis acts together to release cortisol into the body, preparing it for high-intensity activities over a long time.

These stresses are from physical and emotional sources. The HPA is a fundamental part of the endocrine system. This process is not time-dependent, so the Axis involves hormones, which take a longer time to work than nerves but persist for longer.

The endocrine system is a fascinating part of human anatomy, with the pituitary gland and the hypothalamus taking front and center stage.

Plenty of our daily lives are controlled by hormones secreted by the hypothalamus, pituitary gland, and other organs, including:

  • Energy levels
  • Fight or flight responses
  • Growth
  • Metabolism
  • Mood
  • Reproduction
  • Recovery
  • Stress

There are several major “role players” in the endocrine system, including:

  • Adrenal gland
  • Hypothalamus
  • Ovary
  • Pancreas
  • Parathyroid
  • Pineal body
  • Pituitary gland
  • Testis
  • Thymus
  • Thyroid

Due to the sheer size of the endocrine system, various subdivisions and pathways control various reactions and processes. One of these pathways is the Hypothalamic Pituitary Adrenal Axis.

What Is The Hypothalamic Pituitary Adrenal Axis’s Function?

The primary function of the HPA is to stimulate the adrenal glands to produce cortisol. Aside from this function, the HPA regulates other aspects of the organism's physiology to promote homeostasis during stress-inducing situations.

Maintaining homeostasis is critical to ensuring the optimal functioning of an organism.

To this extent, the Hypothalamic Pituitary Adrenal Axis plays a role. The HPA is fundamentally the interactions between the hypothalamus, pituitary gland, and adrenal glands, particularly during stress-inducing events.

The end goal of this pathway (and these interactions) of producing cortisol is to prepare the body for a “fight or flight” situation. This preparation includes providing the body with sufficient energy for an extended duration.

The HPA alters behavioral and physiological components of the organism (e.g., human) to ensure that the organism has all the tools required to survive the stressful situation it is currently facing.

The Hypothalamic Pituitary Adrenal Axis: Location, Composition, And Operation

The Axis is formed by various organs and glands, communicating and operating in conjunction with one another.

The essential components of this Axis include:

The Hypothalamus

The hypothalamus is a diminutive but critical region of the brain, located towards the base, where the optic nerves crossover at the optic chiasm.

The hypothalamus fulfills an "oversight" role in the endocrine system, and its primary function is to release/secrete, stimulant, or suppression hormones by monitoring changes in the body.

The hypothalamus releases Corticotropin-releasing hormone (CRH), an essential hormone for dealing with emotional and physical stress.

These (and other) hormones cause the pituitary gland (nearby) to release or suppress its hormone secretions, including adrenocorticotropic hormone (ACTH), which stimulates the body's cortisol synthesis. 

Furthermore, the hypothalamus directly controls/influences appetite, blood pressure, sleep, temperature, and water balance in the body.

The Anterior Pituitary Gland

The Pituitary gland is adjacent to the hypothalamus and is responsible for much of the endocrine system, although only the size of a pea on the brain's underside. This gland is split into two parts, the anterior (adenohypophysis) and the posterior (neurohypophysis)

The anterior pituitary gland accounts for roughly 80% of the total size. Some of the hormones produced here include:

  • Adrenocorticotropic hormone (ACTH)
  • Follicle-stimulating hormone (FSH)
  • Growth hormone (GH)
  • Luteinizing hormone (LH)
  • Prolactin
  • Thyroid-stimulating hormone (TSH)

These hormones target specific organs and elicit the desired responses in the body.

Once the hypothalamus secretes Corticotropin-releasing hormone, the pituitary gland begins secreting adrenocorticotropic hormone (ACTH), which moves towards the adrenal gland on top of the kidneys.

The Adrenal Gland

Once the pituitary gland releases ACTH, the adrenal glands begin producing corticosteroid hormones and epinephrine. Once released into the bloodstream, these hormones maintain blood pressure, affect the heart rate, and regulate metabolism.

The adrenal glands are positioned one per kidney and divided into two sections. The inner adrenal medulla and the outer adrenal cortex. They operate under the influence and control of the pituitary gland and hypothalamus, among others.

The adrenal cortex is further divided into three regions: the zona glomerulosa, zona fasciculata, and zona reticularis.

Each of these zones secretes specific hormones, but our focus is on one in particular:

  • Cortisol- is one of the essential stress-related hormones. Cortisol is critical for controlling how the body uses stored energy (fats), proteins, and carbohydrates and regulating blood pressure. Cortisol controls the body’s sleep/wake cycle.

It is also responsible for suppressing inflammation, increasing blood sugar, and decreasing bone formation. This glucocorticoid is critical during stressful situations as it assists your body in "managing" its resources.

Nevers, Receptor Cells, And Other Pathways

Although the Hypothalamus, Pituitary gland, and adrenal glands are the major role players in the Axis, they would be ineffective without the connecting tissues and systems. The nervous, lymphatic, and circulatory systems are critical to the proper functioning of the HPA.

How Does The Hypothalamic Pituitary Adrenal Axis Work?

The HPA comes into effect during stress-inducing incidents.

When you first experience stress, your body releases epinephrine (adrenaline) and norepinephrine (noradrenaline). These stress hormones increase the heart rate and metabolism. They also cause you to perspire more, among other physiological changes.

The sympathetic nervous system controls the secretion of these hormones and works in conjunction with the adrenal glands. These stress hormones are related to the adrenal medulla.

After roughly 10 seconds of these increased norepinephrine hormones, the Hypothalamic Pituitary Adrenal Axis “activates.”

The hypothalamus registers the increased stress hormones and begins secreting Corticotropin-releasing hormone (CRH) (and Arginine Vasopressin (AV)).

Once secreted, the pituitary gland recognizes the CRH and AV via dedicated receptors (CRH-R1 and V1B receptors). The anterior pituitary gland begins producing and releasing Adrenocorticotropic hormone (ACTH) (the increase in CRH also systematically enhances the sympathetic nervous system’s functioning).

After diffusing into the blood, the ACTH moves to the adrenal glands. The ACTH targets the adrenal cortex at the adrenal glands, the area responsible for producing steroid hormones (glucocorticoids).

The adrenal cortex “picks-up” the ACTH through the type 2 melanocortin receptors (MC2-R) and begins synthesizing cortisol

Cortisol is the most significant corticosteroid in the human body, and it works on several organs and systems to prepare the body for stressful situations.

Once released, cortisol stimulates the liver to release its glucose store, regulates blood pressure, and assists the body in using carbohydrates, proteins, lipids, and other dissolved nutrients through various processes, including lipolysis, proteolysis, enhancing vasoconstriction, suppressing reproduction, and alter certain behaviors related to stress.

This suppression and heightening of certain processes promote homeostasis within the body.

This increased blood glucose, and better control of the body's resources, provide the body with sufficient energy to cope with the stressor.

What Is The Benefit Of The Hypothalamic Pituitary Adrenal Axis?

During stress-inducing events, our bodies produce various hormones that prepare us for action. These hormones push our bodies out of a state of homeostasis.

The Hypothalamic Pituitary Adrenal Axis (HPA) helps to regulate and mitigate the effects of these hormones in our bodies, reducing the amount of deviation from the point of equilibrium.

The hypothalamus and pituitary gland “sense” the cortisol (and other hormones) levels in the body and increase the amount of CRH and ACTH in the blood. This regulatory function maintains the organism during a state of stress, ensuring that functions benefiting survival are prioritized.

The hypothalamus and pituitary glands' constant monitoring of hormone levels is called a “negative feedback loop.”

This loop serves a vital dual function. The HPA maintains the cortisol levels during the "crisis." It further tells the body to “switch off” the stress response.

The HPA allows the organism to function at optimal in the “heat of the moment,” with the best chance of survival, while other “less important” bodily functions are reduced.

Normal Functioning Of The Hypothalamic Pituitary Adrenal Axis

Stress is a typical part of any animal’s life, and having a dedicated system to deal with stress means that we are built to handle most types of stress.

When the HPA functions normally, the stress response initiated by cortisol (and other hormones) runs its course and then passes. The elevated cortisol presence in the body inhibits the release of CRH and ACTH, which results in less cortisol production and a return to homeostasis.

The negative-feedback loop associated with the HPA protects the body during extended periods of exposure to cortisol and other stress hormones.

There are certain normal consequences to activation of the HPA, including:

  • Fatigue
  • Hunger
  • Body aches
  • Nausea
  • Depression/anxiety
  • Insomnia
  • Nervousness and irritability

The intensity and duration of the glucocorticoid’s presence in the body impact the normal and effective operation of the HPA.

Complications Of The Hypothalamic Pituitary Adrenal Axis

Although human bodies are designed to cope with stressful situations through mechanisms like the Hypothalamic Pituitary Adrenal Axis (HPA), it is not always without complications, limitations, and drawbacks.

Some of the complications related to the HPA include:

  • Anxiety, depression, and other mood disorders (potentially even PTSD)
  • Stress associated pathologies

Most of the negative effects are due to chronic exposure to the HPA (and cortisol). A considerable drawback with the HPA is that you don’t have to be in a life or death situation for it to activate.

If you’re in a different type of stressful situation (pressure from work or the family) or if you’re experiencing anxiety, the HPA may be stimulated into action.

Prolonged exposure to elevated cortisol levels results in the body's baseline cortisol level increasing. This increase means that your body is constantly under a state of fatigue, and when a situation arises for "fight or flight," your body is less well adapted and prepared to deal with it.

An example of this is Chronic Fatigue Syndrome.

Aside from reduced effectiveness in using cortisol, the cortisol levels may take longer to come down after a stressful incident.

Substance abuse (like alcohol)  is also linked to affecting effective HPA functioning.

The Effects Of Chronic Exposure To The Hypothalamic Pituitary Adrenal Axis

Chronic exposure to the HPA results in:

  • Reduce immune system functionality
  • Allergies developing
  • Cardiovascular complications
  • Metabolic suppression
  • Neurological function loss (including memory loss)
  • Increased risk of disease (stress and neurological)

Some commonly identified disorders related to prolonged cortisol exposure include:

  • Cardiovascular disease
  • Cushing's syndrome
  • Diabetes
  • Hypertension
  • Insomnia
  • Menstrual irregularities
  • Muscle weakness
  • Obesity

Developmental Issues Of The Hypothalamic Pituitary Adrenal Axis

Aside from chronic exposure to the HPA, abnormalities of the HPA might establish during fetal development, which persists into adulthood, including:

  • Disruptions affect adult autonomic, behavioral, neuroendocrine, and metabolic processes. Central nervous system complications might also develop, like alterations in neuropeptide and neurotransmitter synthesis and synthesis issues in the peripheries of glucocorticoids.
  • Abnormal HPA development might also lead to neurodevelopmental pathologies like significant depressive disorders, anxiety, and schizophrenia in adulthood.

Symptoms Of Dysfunction In The Hypothalamic Pituitary Adrenal Axis

Whether through chronic exposure, intensive exposure, or some other dysfunction, the Hypothalamic Pituitary Adrenal Axis (HPA) may become dysfunctional.

Some of the symptoms of a dysfunctional HPA include:

  • Immuno-suppression.
  • Fatigue (inexplicable).
  • Hair loss.
  • Increased fat deposits in the abdominal region.
  • Irritability.
  • Infertility.
  • Inflammatory skin disorders.
  • Loss of focus and concentration.
  • Your health and well-being are adversely (and severely) affected by stress.
  • Thyroid abnormalities/dysfunction.
  • Unable to manage stress and feelings of being overwhelmed

Treatment Of Hypothalamic Pituitary Adrenal Axis Issues

The best way to ensure optimal functioning of the HPA is through prevention. A healthy lifestyle reduces stress and includes a healthy diet, reducing (or stopping) caffeine and alcohol intake, proper exercising and sleep regime, and relaxation techniques. 

Psychotherapy, counseling,  and biomonitoring tools (like heart rate monitors, blood sugar indicators, etc.) are other methods many people use in controlling HPA dysfunctions.

However, prevention is not always possible, and in situations where there is already the onset of disease, medication is often necessary to control the symptoms/treat the disease.

The table below examines some diseases related to HPA dysfunctions and their treatment methods.

HPA DiseaseTreatmentMedication
Anxiety and depressionMedication (antidepressants) and lifestyle changesProzac, Zoloft, Paxil, Lexapro, and Celexa
Chronic Fatigue SyndromeTherapy (CBT), antidepressants, and lifestyle management. Treatment is tailored and treats symptoms.Amitriptyline, over-the-counter headache tablets.
Cushing's diseaseMedicationketoconazole, mitotane (Lysodren), and metyrapone (Metopirone)
PTSDCognitive-behavioral therapy (CBT) and medication paroxetine and sertraline

Although in some situations, medications are essential for treating HPA-related conditions, a holistic approach is best (i.e., removing or reducing the root cause of the problem, not only treating the symptoms.


The Hypothalamic Pituitary Adrenal Axis (HPA) is an essential part of the endocrine system, tasked with controlling the "fight or flight" response many mammals (humans included) experience. By increasing and decreasing the hormonal cocktail inside the organism, this Axis readies the organism for a high-stress situation. However, chronic exposure to cortisol, the primary glucocorticoid linked to this HPA, has some drawbacks, including mood disorders, anxiety, and stress-related pathogens and diseases.










Reference this article:

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

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