HPA Axis

1. Introduction – the HPA System

Every day, we face multiple challenges, which lead to a wide range of reactions involving various systems in our body. These challenges are commonly known as stressors, and they cause alterations to the body’s normal functioning. Some examples of stressors include toxins and allergens, which are widely known as environmental stressors. Stressors can also be psychological, including a wide range of personal events, such as financial strain, relationship problems, family issues, social challenges, and many others.

All these stressors directly affect the body, altering the normal function of hormones, affecting the function of different body systems, and potentially leading to adverse physiological consequences. To counter the effects of stress, our body has evolved a complex response system involving multiple organs, cells and biochemical pathways. A key mechanism our body uses to deal with stress is the hypothalamus-pituitary-adrenal (HPA) axis or HPA system, which links stressors or perceived stress and our body’s physiological response to stress.

The HPA system or HPA axis is a neuroendocrine system activated in response to actual or perceived threats. In practice, the HPA axis involves the coordinated action of the hypothalamus, anterior pituitary, and adrenal glands. These organs orchestrate the body’s response to stress by regulating various physiological processes, including metabolism, immune responses, and the autonomic nervous system (ANS) through hormones.

Understanding the function of the HPA axis is essential for understanding and treating a wide range of health problems, including immune system dysfunction, mood disorders, metabolic disease, and cardiovascular disease.

2. HPA axis: the basics

HPA axis and Stress Hormones

The Hypothalamus – The first component of the HPA axis is the hypothalamus, a part of the brain located just below the thalamus (Figure 1).

Figure 1. Location of the Hypothalamus in humans. Source: Wikimedia Commons.

The hypothalamus is involved in a wide range of functions, including maintaining homeostasis, reproduction, fight-or-flight reactions, feeding, and sleep. Within the context of the HPA axis and the body’s response to stress, the hypothalamus is one of the first responders to stressors, releasing corticotropin-releasing hormones into the bloodstream.

The Pituitary gland – this small gland, about the size of a pea- is located just below the hypothalamus and divided into two parts, the anterior pituitary and posterior pituitary. The hypothalamus controls this gland, and it is responsible for the release of multiple hormones, including:

• Adrenocorticotropic hormone – accountable for the release of other hormones, such as cortisol;
• Beta-endorphin – involved in pain relief;
• Thyroid-stimulating hormone – induces the secretion of metabolic hormones from the thyroid;
• Follicle-stimulating hormone and luteinising hormone – regulate the function of the reproductive system;
• Growth hormone- promotes growth and
• Prolactin is involved in milk production in women.

The Adrenal Glands—also known as suprarenal glands—are triangle-shaped glands located on top of each kidney (Figure 2). These glands produce hormones that regulate various bodily functions, including metabolism, immune system, blood pressure, and response to stress.

Figure 2. Location of the Adrenal Glands in humans. Source: Wikimedia Commons.

The essential hormones released by the adrenal glands include:

• Cortisol – multiple functions, including processing of fats, proteins and carbohydrates, suppresses inflammation, regulates blood pressure and increases blood sugar;
• Aldosterone – regulates blood pressure and critical electrolytes (sodium and potassium).
• DHEA and Androgenic Steroids are precursor hormones converted into male or female hormones.
• Epinephrine (Adrenaline) and Norepinephrine (Noradrenaline) are involved in the body’s flight or fight stress response. More specifically, these hormones can increase heart rate and force of heart contractions, increase blood flow to the muscles and brain, relax smooth muscles in the airway, and help glucose metabolism.

The HPA Axis in action: a coordinated set of functions

Our body’s response to stress follows a coordinated set of steps involving multiple organs and biochemical pathways:

• When a stressor enters the body, the initial response occurs through the sympathetic nervous system, producing epinephrine and norepinephrine, which increase heart rate and perspiration.
• Almost immediately, the HPA axis is activated due to the elevated levels of norepinephrine and releases corticotropin-releasing hormone (also known as CRH) into the bloodstream.
• The increased levels of CRH signal the pituitary gland to release adrenocorticotropic hormone (ACTH) into the bloodstream.
• When ACTH reaches the adrenal glands, they are prompted to release the hormone cortisol, which increases blood pressure and cardiac output. Cortisol also increases circulating glucose levels, the body’s key source of cellular energy. These physiological changes are meant to provide more blood for skeletal muscles and more energy to cells. All these actions seek to give the body the tools needed to respond to a perceived source of stress, which may require swift action (e.g. running from danger).
• Once the stressor is no longer present, the HPA axis must shut down. This occurs through a self-regulatory system, where the presence of high levels of cortisol causes the hypothalamus and pituitary glands to stop producing their hormones. This eventually shuts down cortisol production, and the HPA axis goes to OFF mode. This is possible because the hypothalamus and pituitary glands contain cortisol-activated cellular receptors.

Figure 3. The HPA axis and Stress Hormone. The self-regulatory role of cortisol. It is modified from Wikimedia Commons.

HPA Axis and body function

The HPA axis influences multiple bodily functions well beyond our stress response. These include:

• HPA axis and stress—Through its coordinated effect on hormone release, the HPA axis plays a crucial role in helping our body respond to stressors.
• HPA axis and Glycaemic function—Alterations to optimal glycaemic function (hyperglycemia or hypoglycemia) are stressors that activate the HPA axis, leading to chronic high levels of cortisol, which leads to an unhealthy metabolism.
• HPA axis and inflammation – glucocorticoids, like cortisol, are potent anti-inflammatory agents. Cortisol down-regulates inflammatory pathways in different tissues and immune cells.
• HPA axis and Circadian Rhythms – these two systems are tightly linked in the regulation of metabolic functions of the body in response to the environment. Circadian rhythms, also known as the sleep/wake cycle, regulate the body’s physiology during sleep or wake states in response to light environmental changes (day vs night). Together with the HPA axis, these systems help our body function optimally throughout the day and night. To learn more about Circadian Rhythms and health, please see our article on this topic.

HPA Axis Dysfunction

Due to its broad physiological effect, HPA axis dysfunction can lead to multiple different pathologies, including metabolic, immune, and psychological disorders, among many others.  Some examples of conditions associated with HPA axis dysfunction include:

Conditions associated with increased activity of the HPA axis:

• Cushing’s syndrome
• Chronic stress
• Melancholic depression
• Anorexia nervosa
• Obsessive-compulsive disorder
• Panic disorder
• Chronic, active alcoholism
• Alcohol and narcotic withdrawal
• Diabetes mellitus
• Central obesity (metabolic syndrome)
• Post-traumatic stress disorder in children
• Hyperthyroidism

Conditions associated with decreased activity of the HPA axis:

• Adrenal insufficiency
• Atypical/seasonal depression
• Chronic fatigue syndrome
• Fibromyalgia
• Premenstrual tension syndrome
• Climacteric depression
• Nicotine withdrawal
• Adult post-traumatic stress disorder
• Hypothyroidism
• Rheumatoid arthritis
• Asthma
• Eczema

3. Measuring the HPA axis function

To assess the status of the HPA axis and determine if there is a malfunction, it is essential to perform different clinical tests, including tests for:

• Cortisol levels – This hormone is a crucial marker for HPA axis status and is widely used by clinicians and researchers. Some of the cortisol tests available may include:
  • Serum Total Cortisol
  • Serum Free Cortisol
  • Urinary Cortisol
  • Hair Cortisol
  • Salivary Cortisol

Among these tests, salivary cortisol is one of the preferred approaches due to its ease of sampling and reliability.

• Salivary DHEA and DHEA(S )– The adrenal glands produce these hormones, and their use as clinical markers may serve to assess the function of the adrenal glands.
• Cortisol: DHEA(S) ratio measures the relative activity of both hormones, and a low ratio is often associated with a dysfunctional HPA axis.
• Salivary secretory immunoglobulin–A is a biomarker used to assess the status of the immune system, particularly the mucosal immune system.
• Salivary Alpha-Amylase—This marker may be used to assess stress-induced changes in the sympathetic nervous system. However, more research and wider implementation may be needed.
• Heart Rate Variability (HRV)—Current studies suggest that HRV is linked to changes in the autonomic nervous system due to stress. However, further research is needed to confirm the reliability of this marker as a measure of stress.

4. HPA-guided treatments

Once diagnostic testing has been completed and a malfunction has been identified in the HPA axis, different treatment approaches can be used, which include:

• Vitamins and Minerals -these micronutrients are essential co-factors in a wide range of biochemical reactions in the body. Some examples of essential vitamins and minerals include:
  • Vitamin C
  • B Vitamins
  • Sodium
  • Potassium
  • Calcium
  • Magnesium, and
  • Zinc

For more information on micronutrients and the HPA axis, please see our article on this topic.

• Omega-3 Fatty Acids and Phospholipids – these biomolecules have been shown to reduce elevated cortisol levels and
• Probiotics and Supplements – including certain probiotics (life bacterial strains) in your diet can help improve the composition of the gut microbiome. Recent studies show that certain probiotic supplements, such as Bifidobacterium or Lactobacillus, can positively affect our body’s response to stress. For more information on probiotics, please see our article on this topic.
• Adaptogens and other botanicals include herbal-based compounds that can help our body respond to stress. Some examples include:
  • Eleuthero root – Eleutherococcus senticosus
  • Rhodiola root – Rhodiola rosea
  • Schisandra seed/fruit – Schisandra chenensis
  • Ashwagandha root – Withania somnifera
  • American Ginseng root – Panax quinquefolius
  • Korean/Red Ginseng – Panax ginseng

For more information on using adaptogens and botanicals for the HPA axis, please see our article on this topic.

• Physical activity – daily exercise can help our body deal with stress. Studies show that regular exercise can stimulate the HPA axis and improve multiple metabolic signals involved with the HPA axis by improving the management of blood glucose levels and reducing inflammatory signalling. For more information on the role exercise in the HPA axis, please see our article on this topic.
• Sleep—this essential body function can directly affect the function of the HPA axis. Both the length and quality of sleep can affect the HPA axis and the production of cortisol. For more information on the role of sleep on the HPA axis, please see our article on this topic.
• Mind/Body Interventions: These include practices that help reduce stress and pain while improving overall health. Some common interventions include yoga, Tai Chi, meditation, prayer, Qigong, and “forest bathing.”

5. Functional Medicine and the HPA axis

At AUSCFM, we employ a holistic approach to treating disorders related to the HPA axis. This is the crucial difference between the “conventional approach” and the approach used by a Functional Medicine doctor (Table 1).

Table 1. Differences between conventional and functional medicine approaches.

Based on our comprehensive diagnostic approach, our functional medicine doctor creates a patient-centred treatment plan to tackle the source of your HPA axis dysfunction from the inside out.

At AUSCFM, our ultimate goal is to resolve the underlying pathologies driving your symptoms to restore you to optimal health.

Our treatment plan depends on the specific drivers of your HPA axis dysfunction and may involve the use of the following:

• Medical-grade anti-inflammatories to reduce inflammation.
• Supplements that are specific for HPA axis dysfunction.
• Mineral or vitamin supplements to correct any micronutrient deficiencies.
• Botanicals or probiotics to normalise the balance of the gut microbiota.
• A personalised nutrition, sleep and exercise plan aims to restore the optimal function of your body.

At AUSCFM, you will be treated by functional medicine doctors with ample experience using a holistic and multi-disciplinary approach to health care. Our doctors will prescribe personalised therapies that are right for your condition.

References

1. Guilliams, T. G. (2015). The role of stress and the HPA axis in chronic disease management. Stevens Point: Point Institute.
2. Leistner, C., & Menke, A. (2020). Hypothalamic–pituitary–adrenal axis and stress. Handbook of Clinical Neurology, 175, 55-64.
3. DeMorrow S. Role of the Hypothalamic-Pituitary-Adrenal Axis in Health and Disease. Int J Mol Sci. 2018 Mar 26;19(4):986.
4. Russell, G., Lightman, S. The human stress response. Nat Rev Endocrinol 15, 525–534 (2019).
5. Reddy S, Reddy V, Sharma S. Physiology, Circadian Rhythm. [Updated 2023 May 1]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK519507/
6. National Library of Medicine. DHEA Sulfate Test. https://medlineplus.gov/lab-tests/dhea-sulfate-test/