Scientific Overview
Stress and Stress Tolerance
HPA Axis
Circadian Rhythms
Immune System
Placebo Effect
Chronic Fatigue Syndrome
Chronic Pain
Psychiatric vs Organic Debate
Irritable Bowel Syndrome
Chronic Lyme Disease
Recovery from ME/CFS

Hypothalamic-Pituitary-Adrenal (HPA) Axis

The HPA axis, which has traditionally been seen as the body's "stress system", and which ultimately controls levels of cortisol and other important stress related hormones, is generally underactive in people suffering from CFS and burnout. New research is beginning to show that the HPA axis should instead be thought of as the body's energy regulator, as it is ultimately responsible for regulating many of the hormones, nervous system activity and energy expenditure in the human body, as well as modulating the immune system and the digestive system. In CFS and burnout the HPA axis tends to be underactive, which likely in many of the various physical and mental symptoms associated with these conditions.

Endocrine Response to Stress

Any stress lasting longer than a few minutes results in increased levels of cortisol being released from the adrenal cortex. The release of cortisol is controlled by the paraventricular nucleus (PVN) of the hypothalamus, where corticotropin-releasing hormone (CRH) is released in response to the stress. CRH then acts on the pituitary gland, causing it to release adrenocorticotrophic hormone (ACTH), which in turn causes the adrenal cortex to release cortisol.

CRH and ACTH are released in short pulses, each of which causes a (roughly) 15 minute sustained release of cortisol from the adrenal cortex, which then has a half-life of 100 minutes in the blood. Prolonged release of ACTH causes the adrenal cortex to increase in size (presumably to cope with a greater need for cortisol production), whereas long-term ACTH deficiency causes it to shrink.

The combined system of CRH-ACTH-cortisol release is referred to as the hypothalamic-pituitary-adrenal axis (or HPA axis). Positive and negative feedback occurs at various sites in the brain to ensure that cortisol production stays within certain bounds, depending on current requirements and stress levels.

The ultimate result of the HPA axis activation is to increase levels of cortisol in the blood during times of stress. Cortisol's main role is in releasing glucose into the bloodstream in order to facilitate the "flight or fight" response. It also suppresses and modulates the immune system, digestive system and reproductive system.

Another important hormone released by the pituitary along with ACTH is beta-endorphin, a morphine-like hormone. Both ACTH and beta-endorphin are similar in structure, and are released together in response to CRH stimulation by the hypothalamus. Endorphins are thought to be important in reducing pain during times of stress.

During normal, non-stress situations, a certain level of cortisol is maintained in the bloodstream. There is a circadian rhythm of ACTH and cortisol release, with the highest levels occurring around 8-10am in the morning and the lowest levels around midnight. Other hormones released by the hypothalamus also follow a circadian rhythm, although not necessarily peaking at the same time. For example, growth hormone release peaks during sleep, and melatonin is released at night.

Stress causes an increased overall cortisol output. During chronic stress, changes occur to the neurons in the PVN and other areas in the brain resulting in increased sustained activation of the HPA axis. Long-term stress, however, can result in negative feedback to the HPA axis, resulting in burnout. Whether or not chronic stress results in high or low cortisol output depends on the nature of the threat, the time since onset, and the person's response to the situation.

The circadian pattern of cortisol release is controlled by the suprachiasmatic nucleus (SCN) of the hypothalamus, also known as the body clock. Nerve signals from the SCN cause the paraventricular nucleus (PVN) of the hypothalamus to release pulses of CRH roughly once per hour, resulting in HPA axis activation and cortisol release. There are also direct links between the SCN and the adrenal gland itself (bypassing the HPA axis) through sympathetic nerve fibres, causing the adrenal gland to become more sensitive to ACTH stimulation during the morning, further adding to the circadian pattern of cortisol release throughout the day.


For more information, see the stress and burnout sections.

Long-term stress can lead to burnout, or exhaustion, due to the suppression of the HPA axis in the brain. Stresses which are thought to be negative and unrewarding are more likely to result in burnout. Cessation of long-term stress can also lead to burnout.

External Links and references

Wikipedia entry on the HPA axis

Herman, J. P., & Cullinan, W. E. (1997). "Neurocircuitry of stress: central control of the hypothalamo-pituitary-adrenocortical axis." Trends in neurosciences, 20(2), 78-84.

Stratakis, Constantine A., and George P. Chrousos. "Neuroendocrinology and pathophysiology of the stress system." Annals of the New York Academy of Sciences 771.1 (1995): 1-18.

Charmandari, Evangelia, Constantine Tsigos, and George Chrousos. "Endocrinology of the stress response 1." Annu. Rev. Physiol. 67 (2005): 259-284.

Miller, Gregory E., Edith Chen, and Eric S. Zhou. "If it goes up, must it come down? Chronic stress and the hypothalamic-pituitary-adrenocortical axis in humans." Psychological bulletin 133.1 (2007): 25.

Papadopoulos, Andrew S., and Anthony J. Cleare. "Hypothalamic.pituitary.adrenal axis dysfunction in chronic fatigue syndrome." Nature Reviews Endocrinology 8.1 (2012): 22-32.

Majzoub, J. A. (2006). Corticotropin-releasing hormone physiology. European Journal of Endocrinology, 155(suppl 1), S71-S76.

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DISCLAIMER: is an educational resource for chronic fatigue syndrome (CFS), myalgic encephalomyelitis (ME), burnout and related disorders, and is not giving medical advice. Seek advice from a medical practitioner before making any changes to your life, or if you experience worsening symptoms. CFS is a diagnosis of exclusion, so it is important to rule out other causes for illness.