Hypothalamic pituitary adrenal axis

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.

Anatomy
The HPA axis includes parts of the hypothalamus, the anterior lobe of the pituitary gland, the adrenal cortices, hormones, systems that transport hormones and feedback mechanisms that transport cortisol from adrenal glands back to the hypothalamus and to other parts of the brain.

The hypothalamus releases corticotropin-releasing factor (CRF) from an area along the median eminence. The hormone is transported to the anterior lobe of the pituitary through the portal blood vessel system of the hypophyseal stalk, which descends from the hypothalamus. In the anterior pituitary gland, CRF stimulates release of stored adrenocorticotropic hormone (ACTH), which is transported by the blood to the adrenal cortex of the adrenal gland, where it rapidly stimulates biosynthesis of corticosteroids from cholesterol.

Function
Release of CRF 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 (MacHale, 1998), insomnia (Backhaus, 2004) and burnout (Pruessner, 1999).

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 hosts projections to several parts of the brain in involved 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 the glucocorticoid 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 serve important functions including modulation of stress reactions but they can be damaging. Atrophy of the hippocampus in humans and animals exposed to severe stress is believed to be caused by the presence of excessive stress-induced glucocorticoids. Deficiencies of the hippocampus are believed to reduce the memory resources available to help a body formulate appropriate reactions to stress.

The HPA axis is believed to be 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.

Research
Researchers have focused on the effects of monoamine neurotransmitters in regulating the activity of the HPA axis, especially dopamine, serotonin and norepinephrine (noradrenaline). In work sponsored by the Swedish Research Council for Environment, Agricultural Sciences and Spatial Planning, biologists studying the effects of stress in fish populations have identified correlations between social stress and reactions along the HPA axis.

The studies 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.

The research found stress-induced increases in serotonin appear to relate to increased plasma & levels, which causes skin darkening (a potential social signal in salmonoid fish), activation of the HPA axis, inhibition of aggressive behavior and a suppression of behavioral responsiveness to environmental stimuli.

Further research indicated treatment with L-dopa, a close chemical cousin of dopamine, reverses both stress-related increases of plasma cortisol and stress-related inhibition of aggressive behavior. Conversely, inclusion of the amino acid L-tryptophan, a precursor of serotonin, in the feed of rainbow trout populations made the populations overall less aggressive and less responsive to stress. Researchers suggested that providing fish food rich in L-tryptophan would tend to most reduce aggressiveness in dominant fish, who tend to eat more than less socially dominant fish because they more aggressively compete for food.

General

 * "Aversive and appetitive events evoke the release of corticotropin-releasing hormone and bombesin-like peptides at the central nucleus of the amygdala" by Z. Merali et al. in J Neurosci volume 18(12), pages 4758-66 (1998).

Relation to illnesses

 * "Sleep disturbances are correlated with decreased morning awakening salivary cortisol" by J. Backhaus et al. in Psychoneuroendocrinology volume 29(9), pages 1184-91 (2004).
 * "Burnout, perceived stress, and cortisol responses to awakening" by J. C. Pruessner et al. in Psychosom Med volume 61(2), pages 197-204 (1999).
 * "Diurnal variation of adrenocortical activity in chronic fatigue syndrome" by S. M. MacHale et al. in Neuropsychobiology volume 38(4), pages 213-7 (1998).
 * "Actual stress, psychopathology and salivary cortisol levels in the irritable bowel syndrome (IBS)" by F. R. Patacchioli et al. in J Endocrinol Invest. volume 24(3), pages 173-7 (2001).