The hypothalamic-pituitary-adrenal axis (HPA or HTPA axis), also known as the
limbic-hypothalamic-pituitary-adrenal axis (LHPA axis), is a complex set of direct influences and feedbackinteractions among the hypothalamus(a hollow, funnel-shaped part of the brain), the pituitary gland(a pea-shaped structure located below the hypothalamus), and the adrenal(or suprarenal) glands (small, conical organs on top of the kidneys). The interactions among these organs constitute the HPA axis, a major part of the neuroendocrine system that controls reactions to stress and regulates many body processes, including digestion, the immune system, mood and emotions, sexuality, and energy storage and expenditure. A wide variety of species, from the most ancient organisms to humans, share components of the HPA axis. It is the common mechanism for interactions among glands, hormones, and parts of the midbrain that mediate the general adaptation syndrome(GAS).
The key elements of the HPA axis are:
paraventricular nucleusof the hypothalamus, which contains neuroendocrineneurons that synthesize and secrete vasopressinand corticotropin-releasing hormone(CRH). These two peptidesregulate:
** The anterior lobe of the
pituitary gland. In particular, CRH and vasopressin stimulate the secretion of adrenocorticotropic hormone(ACTH), once known as corticotropin. ACTH in turn acts on:
** the adrenal cortices, which produce
glucocorticoidhormones (mainly cortisolin humans) in response to stimulation by ACTH. Glucocorticoids in turn act back on the hypothalamus and pituitary (to suppress CRH and ACTH production) in a negative feedback cycle.
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 bloodto the adrenal cortexof the adrenal gland, where it rapidly stimulates biosynthesis of corticosteroids such as cortisol from cholesterol. Cortisol is a major stress hormone and 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.
Vasopressin can be thought of as "water conservation hormone" and is also known as "antidiuretic hormone." It is released when the body is dehydrated and has potent water-conserving effects on the kidney. It is also a potent vasoconstrictor.
Important to the function of the HPA axis are some of the feedback loops:
* Cortisol produced in the adrenal cortex will negatively feedback to inhibit both the hypothalamus and the pituitary gland. This reduces the secretion of CRH and vasopressin, and also directly reduces the cleavage of
proopiomelanocortininto ACTH and β-endorphins.
Epinephrineand norepinephrineare produced by the adrenal medulla through sympathetic stimulation and the local effects of cortisol (upregulation enzymes to make E/NE). E/NE will positively feedback to the pituitary and increase the breakdown of POMCs into ACTH and β-endorphins.
Release of CRH from the hypothalamus is influenced by stress, by blood levels of cortisol and by the sleep/wake cycle. In healthy individuals, cortisolrises rapidly after wakening, reaching a peak within 30-45 minutes. It then graduallyfalls over the day, rising again in late afternoon. Cortisol levels then fall in lateevening, reaching a trough during the middle of the night. An abnormally flattenedcircadian cortisol cycle has been linked with
chronic fatigue syndrome(MacHale, 1998), insomnia(Backhaus, 2004) and burnout (Pruessner, 1999).
Anatomical connections between brain areas such as the
amygdala, hippocampus, and hypothalamus facilitate activation of the HPA axis. Sensory information arriving at the lateral aspect of the amygdalais 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 systemand 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 including the immune response 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.
Atrophyof 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 hippocampusmay 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, insomnia, post-traumatic stress disorder, ADHD, major depressive disorder, burnout, chronic fatigue syndrome, fibromyalgia, irritable bowel syndrome, and alcoholism. [Robert L. Spencer, Kent E. Hutchinson, [http://findarticles.com/p/articles/mi_m0CXH/is_4_23/ai_63506636/pg_1 Alcohol, Aging, and the Stress Response] , Alcohol Research and Health, Winter 1999.] Antidepressants, which are routinely prescribed for many of these illnesses, serve to regulate HPA axis function. [Carmine M. Pariante, Institute of Psychiatry, King’s College London [http://www.neuroendo.org.uk/content/view/31/11/ Depression, stress and the adrenal axis.] The British Society for Neuroendocrinology, 2003.]
Experimental studies have investigated many different types of stress, and their effects on the HPA axis in many different circumstances. [cite journal | author=Douglas A | title=Central noradrenergic mechanisms underlying acute stress responses of the Hypothalamo-pituitary-adrenal axis: adaptations through pregnancy and lactation. | journal=Stress | volume=8 | issue=1 | pages=5–18 | year=2005 | pmid=16019594 | doi=10.1080/10253890500044380] 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. [cite journal | author=Engelmann M, Landgraf R, Wotjak C | title=The hypothalamic-neurohypophysial system regulates the hypothalamic-pituitary-adrenal axis under stress: an old concept revisited. | journal=Front Neuroendocrinol | volume=25 | issue=3-4 | pages=132–49 | pmid=15589266 | doi=10.1016/j.yfrne.2004.09.001 | year=2004 ] Several
monoamineneurotransmitters are important in regulating the HPA axis, especially dopamine, serotoninand norepinephrine(noradrenaline). In herbal medicine, adaptogens work by reregulating the HPA axis.
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 dominantfish. Serotonin (5HT) appeared to be the active neurotransmitter involved in mediating stress responses, and increases in serotonin are related to increased plasma -MSHlevels, 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 [(cite journal | author=Winberg S, Ã˜verli Ã˜, Lepage O | title=Suppression of aggression in rainbow trout (Oncorhynchus mykiss) by dietary L-tryptophan. | journal=J Exp Biol | volume=204 | issue=Pt 22 | pages=3867–76 | year=2001 | pmid=11807104] However, the study mentions that plasma cortisol was not affected by dietary L-tryptophan.
ACTH stimulation test
Dexamethasone suppression test
* Merali Z. "et al." (1998) [http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=9614249&query_hl=11 Aversive and appetitive events evoke the release of corticotropin-releasing hormone and bombesin-like peptides at the central nucleus of the amygdala] "J Neurosci" 18:4758-99
Relation to illnesses
* Backhaus J "et al." (2004) [http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15219642&query_hl=3 Sleep disturbances are correlated with decreased morning awakening salivary cortisol] "Psychoneuroendocrinology" 29:1184-91
* Pruessner JC "et al." (1999) [http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=10204973&query_hl=6 Burnout, perceived stress, and cortisol responses to awakening] "Psychosom Med" 61:197-204
* MacHale SM "et al."(1998) [http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=9813459&query_hl=9 Diurnal variation of adrenocortical activity in chronic fatigue syndrome] "Neuropsychobiology" 38:213-7
* Patacchioli FR "et al." (2001) [http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=11314746&query_hl=15 Actual stress, psychopathology and salivary cortisol levels in the irritable bowel syndrome (IBS)] "J Endocrinol Invest" 24:173-7
*Winston, David & Maimes, Steven. “Adaptogens: Herbs for Strength, Stamina, and Stress Relief,” Healing Arts Press, (2007)
* [http://www.ifi.unizh.ch/~andel/neurowiki/nw.cgi?Hypothalamic-Pituitary-Adrenal_Axis NeuroWiki page on HPA axis]
* [http://www.mind-body-health.net/hpa.html Mind-Body-Health.net page on HPA axis]
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