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The hypothalamic-pituitary-adrenal axis (HPA axis) is a major part of the neuroendocrine system that controls reactions to stress and has important functions in regulating various body processes such as digestion, the immune system and energy usage. Species from humans to the most ancient organisms share components of the HPA axis. It is the mechanism for a set of interactions among glands, hormones and parts of the mid-brain that mediate a general adaptation syndrome.


The key elements of the HPA axis are:

  • The paraventricular nucleus of the hypothalamus, which contains neuroendocrine neurons that synthesise and secrete vasopressin and corticotropin-releasing hormone (CRH). These two peptides regulate
  • The anterior lobe of the pituitary gland. In particular, CRH and vasopressin stimulate the secretion of adrenocorticotropic hormone (ACTH). ACTH in turn acts on
  • The adrenal cortices, which produces glucocorticoid hormones (mainly cortisol in humans)response to stimulation by ACTH. Glucocorticoids in turn act back at the hypothalamus and pituitary (negative feedback).

CRH and vasopressin are released from neurosecretory nerve terminals at the median eminence. They are transported to the anterior pituitary through the portal blood vessel system of the hypophyseal stalk. There, CRH and vasopressin act synergistically to stimulate the secretion of stored ACTH from corticotrope cells. ACTH is transported by the blood to the adrenal cortex of the adrenal gland, where it rapidly stimulates biosynthesis of corticosteroids from cholesterol. Cortisol has effects on many tissues in the body, including on the brain. In the brain, cortisol acts at two types of receptor - mineralocorticoid receptors and glucocorticoid receptors, and these are expressed by many different types of neuron. One important target of glucocorticoids is the hippocampus, which is a major controlling centre of the HPA axis.


Release of CRH from the hypothalamus is influenced by stress, by blood levels of cortisol and by the sleep/wake cycle. In healthy individuals, cortisol rises rapidly after wakening, reaching a peak within 30-45 minutes. It then gradually reduces over the day, rising again in late afternoon. Cortisol levels then fall in late evening, reaching a trough during the middle of the night. An abnormally flattened circadian cortisol cycle has been linked with chronic fatigue syndrome (1), insomnia (2) and burnout (3).

Anatomical connections between amygdala, hippocampus, and hypothalamus facilitate activation of the HPA axis. Sensory information arriving at the lateral aspect of the amygdala is processed and conveyed to the central nucleus, which projects to several parts of the brain involved in responses to fear. At the hypothalamus, fear-signaling impulses activate both the sympathetic nervous system and the modulating systems of the HPA axis.

Increased production of cortisol mediates alarm reactions to stress, facilitating an adaptive phase of a general adaptation syndrome in which alarm reactions are suppressed, allowing the body to attempt countermeasures.

Glucocorticoids have many important functions, including modulation of stress reactions but in excess they can be damaging. Atrophy of the hippocampus in humans and animals exposed to severe stress is believed to be caused by prolonged exposure to high concentrations of glucocorticoids. Deficiencies of the hippocampus may reduce the memory resources available to help a body formulate appropriate reactions to stress.

The HPA axis is involved in the neurobiology of mood disorders and functional illnesses, including anxiety disorder, bipolar disorder, post-traumatic stress disorder, clinical depression, burnout, chronic fatigue syndrome and irritable bowel syndrome.


Experimental studies have investigated many different types of stress, and their effects on the HPA axis in many different circumstances (4). Stressors can be of many different types - in experimental studies in rats, a distinction is often made between "social stress" and "physical stress", but both types activate the HPA axis, though via different pathways (5). Several monoamine neurotransmitters are important in regulating the HPA axis, especially dopamine, serotonin and norepinephrine (noradrenaline).

The HPA axis is a feature of other vertebrates as well as of mammals. For example, biologists studying stress in fish showed that social subordination leads to chronic stress, related to reduced aggressive interactions, to lack of control and to the constant threat imposed by dominant fish. Serotonin (5HT) appeared to be the active neurotransmitter involved in mediating stress responses, and increases in serotonin are related to increased plasma α-MSH levels, which causes skin darkening (a social signal in salmonoid fish), activation of the HPA axis, and inhibition of aggression. Inclusion of the amino acid L-tryptophan, a precursor of 5HT, in the feed of rainbow trout made the trout less aggressive and less responsive to stress (6). However, the study mentions that plasma cortisol was not affected by dietary L-tryptophan.

Pituitary-adrenal axis

In medicine and physiology, the Pituitary-adrenal axis, also termed the Hypothalamus-pituitary-adrenal axis, is the hormonal system of which the effector organ is the adrenal cortex.

Adrenal and pituitary

The adrenal cortex produces cortisol in response to stimulation by corticotropin (or: ACTH, adrenocorticotropic hormone). The pituitary gland, specifically the corticotroph cells, sense the blood levels of cortisol. If the levels are too low, more ACTH is secreted and the cortical activity is increased.

The hypothalamus

The hypothalamus controls the rate at which the corticotroph cells respond. In acute illness, higher cortisol levels are needed (see adrenal insufficiency). This is achieved by the hypothalamus secreting higher levels of CRH (corticotropin releasing hormone) into the portal system. This stimulates the corticotroph cells to a higher set point, leading to increased ACTH and cortisol levels.

Regulation at hypothalamus level

The hypothalamus can be affected by stress of an emotional or physical nature; the CRH pulse rate (it is secreted in pulses; the rate determines its function) is increased in response to systemic inflammation, namely IL-1, IL-6 and TNF alpha.





1. MacHale SM et al.(1998) Diurnal variation of adrenocortical activity in chronic fatigue syndrome Neuropsychobiology 38:213-7

2. Backhaus J et al. (2004) Sleep disturbances are correlated with decreased morning awakening salivary cortisol Psychoneuroendocrinology 29:1184-91

3. Pruessner JC et al. (1999) Burnout, perceived stress, and cortisol responses to awakening Psychosom Med 61:197-204

4. Douglas AJ. Stress. 2005 Mar;8(1):1-3

5. Engelmann M, Landgraf R, Wotjak CT. Front Neuroendocrinol. 2004 Sep-Dec;25(3-4):132-49

6. Winberg S, Overli O, Lepage O. J Exp Biol. 2001 Nov;204(Pt 22):3867-76.