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Hypothalamic-pituitary-adrenal axis
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[[File:HPA axis.png|alt=Top circle: hypothalamus, middle circle: anterior pituitary, bottom circle: adrenal cortex|thumb|Hypothalamic-pituitary-adrenal axis summary]] The '''hypothalamic–pituitary–adrenal axis''' ('''HPA axis''' or '''HTPA axis''') is a complex set of direct influences and feedback interactions among three components of the [[neuroendocrine system]]: the [[hypothalamus]], the [[pituitary gland]], and the [[adrenal glands]]. The primary function of the HPA axis is to maintain daily metabolic homeostasis, it helps regulate many body processes, including [[digestion]], the [[immune system]], [[mental health|mood and emotions]], sexuality, and [[energy]] storage and expenditure. The HPA axis is notably responsive to psychological stress and anticipated activity levels in a feed-forward manner. == Feedback loop == The negative feedback loop of the HPA axis can be described by these three components: # The [[paraventricular nucleus]] of the [[hypothalamus]] contains [[neuroendocrine system|neuroendocrine]] neurons that synthesize and secrete [[vasopressin]] and [[corticotropin-releasing hormone]] (CRH). # These two peptides regulate the secretion of [[adrenocorticotropic hormone]] (ACTH) by the [[pituitary gland]]. ACTH in turn acts on the adrenal cortex, which produces [[glucocorticoid]] hormones (mainly [[cortisol]] in humans as well as mineralocorticoids like [[aldosterone]]) in response to stimulation by ACTH. # [[Glucocorticoid]]s in turn act back on the hypothalamus and pituitary to suppress CRH and ACTH production in a negative feedback cycle.{{citation needed}} In the [[brain]], cortisol acts on two types of receptor – mineralocorticoid receptors and glucocorticoid receptors, and these are expressed by many different types of neurons. 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. == Role in the body == The HPA axis has a central role in regulating many [[Homeostasis|homeostatic]] systems in the body, including the [[energy metabolism|metabolic system]], [[cardiovascular system]], [[immune system]], reproductive system and [[central nervous system]]. The HPA axis integrates physical and psychosocial influences to anticipate metabolic demands, in order to allow an organism to adapt effectively to its environment, use resources, and optimize survival.<ref name="isbn_9780444530400" /> The release of CRH from the hypothalamus is concerned with maintaining metabolic homeostasis and is primarily determined by the [[sleep]]/wake cycle (circadian rhythm), but is also moderated by psychological [[stress]], physical activity, illness and through inhibitory feedback from elevated cortisol levels in the blood. In healthy individuals, cortisol rises rapidly after wakening, reaching a peak within 30–45 minutes. It then gradually falls over the day, rising again in late afternoon. Cortisol levels then fall in late evening, reaching a trough during the middle of the night. This corresponds to the rest-activity cycle of the organism.<ref name="isbn_9780444530400">{{cite book | title = The hypothalamus-pituitary-adrenal axis | last1 = Besedovsky | first1 = Hugo | last2 = Chrousos | first2 = George | last3 = Rey | first3 = Adriana Del | date = 2008|publisher=Academic|isbn=9780444530400|edition=1st|location=Amsterdam}}</ref> An abnormally flattened circadian cortisol cycle has been linked with [[chronic fatigue syndrome]].<ref>{{cite journal|vauthors=MacHale SM, Cavanagh JT, Bennie J, Carroll S, Goodwin GM, Lawrie SM | date = Nov 1998 | title = Diurnal variation of adrenocortical activity in chronic fatigue syndrome|journal=Neuropsychobiology|volume=38|issue=4 | pages = 213–7|doi=10.1159/000026543|pmid=9813459}}</ref> However, this flattening can be explained by altered circadian rhythm and lower physical activity levels.<ref>{{Cite journal | last = Chung | first = Sooyoung | last2 = Son | first2 = Gi Hoon | last3 = Kim | first3 = Kyungjin | date = 2011-05-01 | title = Circadian rhythm of adrenal glucocorticoid: Its regulation and clinical implications | url = http://www.sciencedirect.com/science/article/pii/S0925443911000329|journal=Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease|volume=1812|issue=5 | pages = 581–591|doi=10.1016/j.bbadis.2011.02.003|issn=0925-4439}}</ref> Anatomical connections between brain areas such as the [[amygdala]], [[hippocampus]], prefrontal cortex and [[hypothalamus]] facilitate increased activation of the HPA axis.<ref>{{Cite journal | last = Veer | first = Ilya M. | last2 = Oei | first2 = Nicole Y.L. | last3 = Spinhoven | first3 = Philip | last4 = van Buchem | first4 = Mark A. | last5 = Elzinga | first5 = Bernet M. | last6 = Rombouts | first6 = Serge A. R.B. | date = 2012-07-01 | title = Endogenous cortisol is associated with functional connectivity between the amygdala and medial prefrontal cortex | url = http://www.sciencedirect.com/science/article/pii/S0306453011003532|journal=Psychoneuroendocrinology|volume=37|issue=7|pages=1039–1047|doi=10.1016/j.psyneuen.2011.12.001|issn=0306-4530}}</ref><ref name=":0">{{Cite journal | last = Jankord | first = Ryan | last2 = Herman | first2 = James P. | date = Dec 2008 | title = LIMBIC REGULATION OF HYPOTHALAMO-PITUITARY-ADRENOCORTICAL FUNCTION DURING ACUTE AND CHRONIC STRESS | url = https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2637449/|journal=Annals of the New York Academy of Sciences|volume=1148 | pages = 64–73|doi=10.1196/annals.1410.012|issn=0077-8923|pmc=2637449|pmid=19120092|issue=|quote=|access-date=|via=}}</ref> Increased activation of the HPA axis can occur both reflexively in response to physical challenge and may also occur in the absence of physical challenges in an anticipatory manner.<ref name=":0" /> Responses to physical challenges are initiated by stimuli that threaten metabolic homeostasis and can result from stimulation of ascending brain systems or circumventricular organs, which in turn project to the hypothalamic paraventricular nucleus.<ref name=":0" /> Anticipatory responses on the other hand, are initiated either by innate responses, for example, instinctual fear, or emotional responses to the recall of prior experiences, in both cases preparing the organism to homeostatic challenges. These anticipatory responses require activation the limbic system or other systems that can anticipate potential homeostatic threat and signal to the paraventricular nucleus through indirect connections.<ref name=":0" /> 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. == Immune system == There is bi-directional communication and feedback between the HPA axis and immune system<ref name="MD2">{{cite journal | last1 = Marques-Deak | first1 = A | last2 = Cizza | first2 = G | last3 = Sternberg | first3 = E | date = February 2005 | title = Brain-immune interactions and disease susceptibility | url = http://www.nature.com/mp/journal/v10/n3/pdf/4001643a.pdf | journal=Molecular Psychiatry|volume=10 | pages = 239–250|doi=10.1038/sj.mp.4001643|access-date = 13 February 2016}}</ref><ref name="Otmishi2">{{cite journal | last1 = Otmishi | first1 = Peyman | last2 = Gordon | first2 = Josiah | last3 = El-Oshar | first3 = Seraj | last4 = Li | first4 = Huafeng | last5 = Guardiola | first5 = Juan | last6 = Saad | first6 = Mohamed | last7 = Proctor | first7 = Mary | last8 = Yu | first8 = Jerry | date = 2008 | title = Neuroimmune Interaction in Inflammatory Diseases | url = https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2990232/pdf/ccrpm-2008-035.pdf | journal=Clinical Medicine: Circulatory, Respiratory, and Pulmonary Medicine|volume=2 | pages = 35–44|pmid=21157520|access-date = 14 February 2016}}</ref>. A number of [[cytokines]], such as [[interleukin 1|IL-1]], [[interleukin 6|IL-6]], [[interleukin 10|IL-10]] and [[TNF-alpha]] can activate the HPA axis, although IL-1 is the most potent. The HPA axis in turn modulates the immune response: high levels of cortisol suppress immune and inflammatory reactions and trigger immune cells such as [[Monocyte|monocytes]] and [[Neutrophil|neutrophils]] to release anti-inflammatory cytokines (e.g. [[interleukin 4|IL-4]], [[interleukin 10|IL-10]], and [[Interleukin 13|IL-13]]). <ref name="Otmishi2" /><ref name="Tian2">{{cite journal | last1 = Tian | first1 = Rui | last2 = Hou | first2 = Gonglin | last3 = Li | first3 = Dan | last4 = Yuan | first4 = Ti-Fei | date = June 2014 | title = A Possible Change Process of Inflammatory Cytokines in the prolonged Chronic Stress and its Ultimate Implications for Health | url = https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4065693/pdf/TSWJ2014-780616.pdf | journal=The Scientific World Journal|volume=|pages=1–8|doi=10.1155/2014/780616|pmid=24995360|access-date = 13 February 2016}}</ref><ref name="Bellavance2">{{cite journal | last1 = Bellavance | first1 = Marc-Andre | last2 = Rivest | first2 = Serge | date = March 2014 | title = The HPA-immune axis and the immunomodulatory actions of glucocorticoids in the brain | url =https://www.researchgate.net/profile/Marc_Andre_Bellavance/publication/261764460_Bellavance_MA_Rivest_S._The_HPA_-_Immune_Axis_and_the_Immunomodulatory_Actions_of_Glucocorticoids_in_the_Brain._Front_Immunol_5_136/links/55c2286108aeb975673e3b9f.pdf | journal=Frontiers in Immunology|volume=5|pages=1–13|doi=10.3389/fimmu.2014.00136|access-date = 11 February 2016}}</ref><ref name="Padgett2">{{cite journal | last1 = Padgett | first1 = David | last2 = Glaser | first2 = Ronald | date = August 2003 | title = How stress influences the immune response | url = http://www.direct-ms.org/pdf/ImmunologyGeneral/Stress%20and%20immunity.pdf | journal=Trends in Immunology|volume=24|issue=8 | pages = 444–448|doi=10.1016/S1471-4906(03)00173-X|pmid=12909458|access-date = Feb 12, 2016}}</ref> This helps to protect the organism from a potentially lethal overactivation of the immune system, and minimizes tissue damage from inflammation.<ref name="isbn_97804445304003">{{cite book | title = The hypothalamus-pituitary-adrenal axis | last1 = Besedovsky | first1 = Hugo | last2 = Chrousos | first2 = George | last3 = Rey | first3 = Adriana Del | date = 2008|publisher=Academic|isbn=9780444530400|edition=1st|location=Amsterdam}}</ref> == Role in human disease == The HPA axis controls our body's responses to physical or emotional stress, and is being investigated as a possible cause for [[Myalgic encephalomyelitis]].<ref>{{Cite web | url = https://www.cdc.gov/me-cfs/about/possible-causes.html | title = Possible Causes {{!}} Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) {{!}} CDC | last = CDC | first = | date = 2017-07-14 | website = [[Centers for Disease Control and Prevention]]|language=en-us|archive-url=|archive-date=|url-status=|access-date=2018-10-05}}</ref> Deficiencies in the HPA axis may play a role in allergies and inflammatory/ autoimmune diseases, such as [[rheumatoid arthritis]] and [[multiple sclerosis]].<ref name="MD2" /><ref name="Otmishi2" /><ref name="Bellavance2" /> The relationship between chronic stress and its concomitant activation of the HPA axis, and dysfunction of the immune system is unclear; studies have found both immunosuppression and hyperactivation of the immune response.<ref name="Padgett2" /> == In ME/CFS == ==Notable studies== *1996, [https://www.ncbi.nlm.nih.gov/pubmed/8842569 Dissociation of body-temperature and melatonin secretion circadian rhythms in patients with chronic fatigue syndrome] *2000, Chronic Fatigue Syndrome: A Dysfunction of the Hypothalamic-Pituitary-Adrenal Axis<ref>{{Cite journal | last = Addington | first = John W. | date = 2000-01-01 | title = Chronic Fatigue Syndrome | url = https://doi.org/10.1300/J092v07n02_06|journal=Journal of Chronic Fatigue Syndrome|volume=7|issue=2 | pages = 63–74|doi=10.1300/J092v07n02_06|issn=1057-3321}}</ref> [http://dx.doi.org/10.1300/J092v07n02_06 (Abstract)] *2018, High-fidelity discrete modeling of the HPA axis: a study of regulatory plasticity in biology<ref>{{Cite journal | last = Sedghamiz | first = Hooman | last2 = Morris | first2 = Matthew | authorlink2 = Matthew Morris | last3 = Craddock | first3 = Travis J.A. | authorlink3 = Travis Craddock | last4 = Whitley | first4 = Darrell | last5 = Broderick | first5 = Gordon | authorlink5 = Gordon Broderick | date = Jul 17, 2018 | title = High-fidelity discrete modeling of the HPA axis: a study of regulatory plasticity in biology | url = https://bmcsystbiol.biomedcentral.com/articles/10.1186/s12918-018-0599-1|journal=BMC Systems Biology|volume=12|issue=76|pages=|doi=10.1186/s12918-018-0599-1|via=}}</ref> [https://bmcsystbiol.biomedcentral.com/articles/10.1186/s12918-018-0599-1 (Abstract)] ==See also == *[[Hypothalamic-pituitary-gonadal axis]] (HPG axis) *[[Hypothalamus]] *[[Pituitary gland]] *[[Adrenal gland]] *[[Hormone]] ==Learn more == ==References== {{Reflist}} [[Category:Body systems]] [[Category:Endocrine system]]
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