Editing Hypothalamic–pituitary–adrenal axis

{{short description|Set of physiological feedback interactions}}
[[File:HPA Axis Diagram (Brian M Sweis 2012).svg|right|thumb|350px|Schematic of the HPA axis (CRH, [[corticotropin-releasing hormone]]; ACTH, [[adrenocorticotropic hormone]])]]
[[File:HPA-axis - anterior view (with text).svg|right|thumb|Hypothalamus, pituitary gland, and adrenal cortex]]
The '''hypothalamic–pituitary–adrenal axis''' ('''HPA axis''' or '''HTPA axis''') is a complex set of direct influences and [[feedback]] interactions among three components: the [[hypothalamus]] (a part of the [[brain]] located below the [[thalamus]]), the [[pituitary gland]] (a pea-shaped structure located below the hypothalamus), and the [[adrenal]] (also called "suprarenal") [[Adrenal gland|glands]] (small, [[conical]] organs on top of the [[kidneys]]). These [[organs]] and their interactions constitute the [[HPS axis]].

The HPA axis is a major [[neuroendocrine system]]<ref name="NHM-Neuroendocrine systems">{{cite book | vauthors = Malenka RC, Nestler EJ, Hyman SE | editor = Sydor A, Brown RY | title = Molecular Neuropharmacology: A Foundation for Clinical Neuroscience | year = 2009 | publisher = McGraw-Hill Medical | location = New York | isbn = 9780071481274 | pages = 246, 248–259 | edition = 2nd | chapter = Chapter 10: Neural and Neuroendocrine Control of the Internal Milieu | quote = <br />•The hypothalamic–neurohypophyseal system secretes two peptide hormones directly into the blood, vasopressin and oxytocin.&nbsp;...<br />•The hypothalamic–pituitary–adrenal (HPA) axis. It comprises corticotropin-releasing factor (CRF), released by the hypothalamus; adrenocorticotropic hormone (ACTH), released by the anterior pituitary; and glucocorticoids, released by the adrenal cortex.<br />•The hypothalamic–pituitary–thyroid axis consists of hypothalamic thyrotropin-releasing hormone (TRH); the anterior pituitary hormone thyroid–stimulating hormone (TSH); and the thyroid hormones T<sub>3</sub> and T<sub>4</sub>.<br />•The hypothalamic–pituitary–gonadal axis comprises hypothalamic gonadotropin–releasing hormone (GnRH), the anterior pituitary luteinizing hormone (LH) and follicle-stimulating hormone (FSH), and the gonadal steroids.}}</ref> that controls reactions to [[stress (medicine)|stress]] and regulates many body processes, including [[digestion]], [[immune response]]s, [[Mood (psychology)|mood]] and [[emotion]]s, [[Human sexual activity|sexual activity]], and energy storage and expenditure. It is the common mechanism for interactions among [[gland]]s, [[hormone]]s, and parts of the [[midbrain]] that mediate the [[general adaptation syndrome]] (GAS).<ref>{{cite book |last=Selye |first=Hans |title=Stress without distress |year=1974 |publisher=Lippincott |location=Philadelphia |isbn=978-0-397-01026-4 |url-access=registration |url=https://archive.org/details/stresswithoutdis00sely}}{{page needed|date=April 2014}}</ref>

While [[steroid]] [[hormone]]s are produced mainly in [[vertebrate]]s, the [[physiological]] role of the HPA axis and [[corticosteroid]]s in stress response is so fundamental that [[analogous]] systems can be found in [[invertebrate]]s and [[Unicellular organism|monocellular]] organisms as well.

The HPA axis, [[hypothalamic–pituitary–gonadal axis|hypothalamic–pituitary–gonadal (HPG) axis]], [[hypothalamic–pituitary–thyroid axis|hypothalamic–pituitary–thyroid (HPT) axis]], and the [[hypothalamic–neurohypophyseal system]] are the four major [[Neuroendocrine cell|neuroendocrine]] systems through which the [[hypothalamus]] and [[Pituitary gland|pituitary]] direct [[Neuroendocrine cell|neuroendocrine]] function.<ref name="NHM-Neuroendocrine systems" />

==Anatomy==
The key elements of the HPA axis are:<ref>{{Cite web |date=2015-05-18 |title=Getting to know the HPA axis |url=https://www.nrdc.org/bio/kristi-pullen-fedinick/getting-know-hpa-axis |access-date=2023-08-08 |website=www.nrdc.org |language=en |archive-date=2023-08-10 |archive-url=https://web.archive.org/web/20230810072553/https://www.nrdc.org/bio/kristi-pullen-fedinick/getting-know-hpa-axis |url-status=live }}</ref>
* The [[paraventricular nucleus]] of the [[hypothalamus]]: It contains [[neuroendocrine]] [[neuron]]s which synthesize and secrete [[vasopressin]] and [[corticotropin-releasing hormone]] (CRH).
* The [[Anterior pituitary|anterior lobe]] of the [[pituitary gland]]: CRH and vasopressin stimulate the anterior lobe of pituitary gland to secrete [[adrenocorticotropic hormone]] (ACTH), once known as [[Corticotropin-releasing hormone|corticotropin]].
* The [[adrenal cortex]]: It produces [[glucocorticoid]] hormones (mainly [[cortisol]] in 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.

[[Corticotropin-releasing hormone|CRH]] and [[vasopressin]] are released from [[Neurosecretion|neurosecretory]] nerve terminals at the [[median eminence]]. CRH is transported to the anterior pituitary through the [[Portal venous system|portal blood vessel system]] of the [[Hypophysial stalk|hypophyseal stalk]] and vasopressin is transported by [[axon]]al transport to the [[posterior pituitary|posterior pituitary gland]]. 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 the biosynthesis of [[corticosteroid]]s such as [[cortisol]] from [[cholesterol]]. Cortisol is a major stress hormone and has effects on many tissues in the body, including the brain. In the brain, cortisol acts on two types of receptors: [[mineralocorticoid receptor]]s and [[glucocorticoid]] receptors, and these are expressed by many different types of neurons. One important target of glucocorticoids is the [[hypothalamus]], which is a major controlling centre of the HPA axis.<ref>{{Cite journal |last1=Tasker |first1=Jeffrey G. |last2=Herman |first2=James P. |date=14 July 2011 |title=Mechanisms of rapid glucocorticoid feedback inhibition of the hypothalamic–pituitary–adrenal axis |journal=Stress |volume=14 |issue=4 |pages=398–406 |doi=10.3109/10253890.2011.586446 |pmid=21663538 |pmc=4675656 }}</ref>

Vasopressin can be thought of as "water conservation hormone" and is also known as "[[antidiuretic]] hormone(ADH)". It is released when the body is [[Dehydration|dehydrated]] and has potent water-conserving effects on the kidney. It is also a potent [[vasoconstrictor]].<ref>{{Citation|last1=Cuzzo|first1=Brian|title=Vasopressin (Antidiuretic Hormone, ADH)|date=2019|url=http://www.ncbi.nlm.nih.gov/books/NBK526069/|work=StatPearls|publisher=StatPearls Publishing|pmid=30252325|access-date=2019-10-19|last2=Lappin|first2=Sarah L.|archive-date=2021-03-25|archive-url=https://web.archive.org/web/20210325180413/https://www.ncbi.nlm.nih.gov/books/NBK526069/|url-status=live}}</ref>

Important to the function of the HPA axis are some of the following 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 [[proopiomelanocortin]] (POMC) into ACTH and β-endorphins.
* [[Epinephrine]] and [[norepinephrine]] (E/NE) are produced by the [[adrenal medulla]] through [[Sympathetic nervous system|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.

==Function==
Release of [[corticotropin-releasing hormone]] (CRH) from the hypothalamus is influenced by [[stress (medicine)|stress]], physical activity, illness, by blood levels of cortisol and by the sleep/wake cycle ([[circadian rhythm]]). 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"/> 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 |title=Diurnal variation of adrenocortical activity in chronic fatigue syndrome |journal=Neuropsychobiology |volume=38 |issue=4 |pages=213–7 |date=November 1998 |pmid=9813459 |doi=10.1159/000026543|s2cid=46856991 }}</ref> [[insomnia]]<ref>{{cite journal |vauthors=Backhaus J, Junghanns K, Hohagen F |title=Sleep disturbances are correlated with decreased morning awakening salivary cortisol |journal=Psychoneuroendocrinology |volume=29 |issue=9 |pages=1184–91 |date=October 2004 |pmid=15219642 |doi=10.1016/j.psyneuen.2004.01.010|s2cid=14756991 }}</ref> and [[Occupational burnout|burnout]].<ref>{{cite journal |vauthors=Pruessner JC, Hellhammer DH, Kirschbaum C |title=Burnout, perceived stress, and cortisol responses to awakening |journal=Psychosom Med |volume=61 |issue=2 |pages=197–204 |year=1999 |pmid=10204973 |url=http://www.psychosomaticmedicine.org/cgi/pmidlookup?view=long&pmid=10204973 |doi=10.1097/00006842-199903000-00012|url-access=subscription }}</ref>

The HPA axis has a central role in regulating many [[Homeostasis|homeostatic systems]] in the body, including the [[metabolic system]], [[cardiovascular system]], [[immune system]], [[reproductive system]] and [[central nervous system]]. The HPA axis integrates physical and [[psychosocial]] influences in order to allow an organism to adapt effectively to its environment, use resources, and optimize survival.<ref name="isbn_9780444530400">{{cite book | editor-last=del Rey | editor-first=A. | editor-last2=Chrousos | editor-first2=G. P. | editor-last3=Besedovsky | editor-first3=H. O. | others=Berczi, I.; Szentivanyi A., series [[Editor-in-chief|EICs]] | title=The Hypothalamus-Pituitary-Adrenal Axis | publisher=Elsevier Science | publication-place=Amsterdam London | series=NeuroImmune Biology | volume=7 | year=2008 | isbn=978-0-08-055936-0 | oclc=272388790 | url=https://books.google.com/books?id=nJSYf879en4C | access-date=27 February 2022 | page= | archive-date=10 August 2023 | archive-url=https://web.archive.org/web/20230810072626/https://books.google.com/books?id=nJSYf879en4C | url-status=live }}</ref>

Anatomical connections between brain areas such as the [[amygdala]], [[hippocampus]], [[prefrontal cortex]] and hypothalamus facilitate activation of the HPA axis.<ref>{{Cite book|title=Discovering behavioral neuroscience : an introduction to biological psychology|last=Laura|first=Freberg|others=Freberg, Laura,, Container of (work): Freberg, Laura.|isbn=9781305088702|edition= Third|location=Boston, MA|pages=504|oclc=905734838|date = 2015-01-01}}</ref> Sensory information arriving at the lateral aspect of the [[amygdala]] is processed and conveyed to the amygdala's [[central nucleus]], which then projects out 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 during stress results in an increased availability of [[glucose]] in order to facilitate [[Fight-or-flight response|fighting or fleeing]]. As well as directly increasing glucose availability, cortisol also suppresses the highly demanding metabolic processes of the [[immune system]], resulting in further availability of glucose.<ref name="isbn_9780444530400"/>

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 [[glucocorticoid]]s. Deficiencies of the [[hippocampus]] may reduce the memory resources available to help a body formulate appropriate reactions to stress.<ref>{{cite journal |last1=Frankiensztajn |first1=Linoy Mia |last2=Elliott |first2=Evan |last3=Koren |first3=Omry |title=The microbiota and the hypothalamus-pituitary-adrenocortical (HPA) axis, implications for anxiety and stress disorders |journal=Current Opinion in Neurobiology |date=June 2020 |volume=62 |pages=76–82 |doi=10.1016/j.conb.2019.12.003|pmid=31972462 |s2cid=210836469 }}</ref>

==Immune system==

There is bi-directional communication and feedback between the HPA axis and the [[immune system]]. A number of [[cytokines]], such as [[Interleukin 1-alpha|IL-1]], [[Interleukin-6 receptor|IL-6]], [[IL-10 family|IL-10]] and [[Tumor necrosis factor|TNF-alpha]] can activate the HPA axis, although IL-1 is the most potent. The HPA axis in turn modulates the immune response, with high levels of cortisol resulting in a suppression of immune and inflammatory reactions. This helps to protect the organism from a lethal overactivation of the immune system, and minimizes tissue damage from inflammation.<ref name="isbn_9780444530400"/>

In many ways, the [[Central nervous system|CNS]] is "[[immune privilege]]d", but it plays an important role in the immune system and is affected by it in turn. The CNS regulates the immune system through [[neuroendocrine]] pathways, such as the HPA axis. The HPA axis is responsible for modulating [[Inflammation|inflammatory responses]] that occur throughout the body.<ref name="MD">{{cite journal|last1=Marques-Deak|first1=A|last2=Cizza|first2=G|last3=Sternberg|first3=E|title=Brain-immune interactions and disease susceptibility|journal=Molecular Psychiatry|date=February 2005|volume=10|issue=3|pages=239–250|doi=10.1038/sj.mp.4001643|pmid=15685252|s2cid=17978810|doi-access=}}</ref><ref name="Otmishi">{{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|title=Neuroimmune Interaction in Inflammatory Diseases|journal=Clinical Medicine: Circulatory, Respiratory, and Pulmonary Medicine|date=2008|volume=2|pages=35–44|pmc=2990232|pmid=21157520|doi=10.4137/ccrpm.s547}}</ref>

During an immune response, [[proinflammatory cytokines]] (e.g. IL-1) are released into the peripheral circulation system and can pass through the [[blood–brain barrier]] where they can interact with the brain and activate the HPA axis.<ref name="Otmishi"/><ref name="Tian">{{cite journal|last1=Tian|first1=Rui|last2=Hou|first2=Gonglin|last3=Li|first3=Dan|last4=Yuan|first4=Ti-Fei|title=A Possible Change Process of Inflammatory Cytokines in the prolonged Chronic Stress and its Ultimate Implications for Health|journal=The Scientific World Journal|date=June 2014|volume=2014|pages=780616|pmc=4065693|doi=10.1155/2014/780616|pmid=24995360|doi-access=free}}</ref><ref name="Hall">{{cite journal|last1=Hall|first1=Jessica|last2=Cruser|first2=desAgnes|last3=Podawiltz|first3=Alan|last4=Mummert|first4=Diana|last5=Jones|first5=Harlan|last6=Mummert|first6=Mark|title=Psychological Stress and the Cutaneous Immune Response: Roles of the HPA Axis and the Sympathetic Nervous System in Atopic Dermatitis and Psoriasis|journal=Dermatology Research and Practice|date=August 2012|volume=2012|pages=403908|doi=10.1155/2012/403908|pmid=22969795|pmc=3437281|doi-access=free}}</ref> Interactions between the [[proinflammatory cytokines]] and the brain can alter the [[metabolic activity]] of [[neurotransmitters]] and cause symptoms such as fatigue, [[Depression (mood)|depression]], and mood changes.<ref name="Otmishi"/><ref name="Tian"/> Deficiencies in the HPA axis may play a role in allergies and inflammatory/ autoimmune diseases, such as [[rheumatoid arthritis]] and [[multiple sclerosis]].<ref name="MD"/><ref name="Otmishi"/><ref name="Bellavance">{{cite journal|last1=Bellavance|first1=Marc-Andre|last2=Rivest|first2=Serge|title=The HPA-immune axis and the immunomodulatory actions of glucocorticoids in the brain|journal=Frontiers in Immunology|date=March 2014|volume=5|pages=136|doi=10.3389/fimmu.2014.00136|pmid=24744759|pmc=3978367|doi-access=free}}</ref>

When the HPA axis is activated by [[stressors]], such as an [[immune response]], high levels of [[glucocorticoids]] are released into the body and suppress immune response by inhibiting the expression of proinflammatory cytokines (e.g. [[Interleukin 1|IL-1]], [[TNF alpha]], and [[IFN gamma]]) and increasing the levels of anti-inflammatory cytokines (e.g. [[Interleukin 4|IL-4]], [[Interleukin 10|IL-10]], and [[Interleukin 13|IL-13]]) in immune cells, such as [[monocytes]] and [[neutrophils]].<ref name="Otmishi"/><ref name="Tian"/><ref name="Bellavance"/><ref name="Padgett">{{cite journal|last1=Padgett|first1=David|last2=Glaser|first2=Ronald|title=How stress influences the immune response|journal=Trends in Immunology|date=August 2003|volume=24|issue=8|pages=444–448|doi=10.1016/S1471-4906(03)00173-X|url=http://www.direct-ms.org/pdf/ImmunologyGeneral/Stress%20and%20immunity.pdf|access-date=12 February 2016|pmid=12909458|archive-url=https://web.archive.org/web/20160327154337/http://www.direct-ms.org/pdf/ImmunologyGeneral/Stress%20and%20immunity.pdf|archive-date=2016-03-27|url-status=dead}}</ref>

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="Padgett"/>

==Stress==
[[File:ХПА-оска на стрес во мозокот.jpg|thumb|175px|right| Schematic overview of the hypothalamic-pituitary-adrenal (HPA) axis. Stress activates the HPA-axis and thereby enhances the secretion of glucocorticoids from the adrenals.]]

Activation of the HPA axis causes release of glucocorticoids, which target numerous organ systems to activate energy reserves in response to stress demands.<ref name="herman">{{cite journal |vauthors=Herman JP, McKlveen JM, Ghosal S, Kopp B, Wulsin A, Makinson R, Scheimann J, Myers B |title=Regulation of the Hypothalamic-Pituitary-Adrenocortical Stress Response |journal=Comprehensive Physiology |volume=6 |issue=2 |pages=603–21 |date=March 2016 |pmid=27065163 |doi=10.1002/cphy.c150015|pmc=4867107 |isbn=978-0-470-65071-4 }}</ref> The HPA stress response is controlled mostly by neural mechanisms, which cause release of corticotrophin releasing hormone (CRH). Neural mechanisms determining responses to chronic stress are different from those that control acute reactions. Individual responses to acute or chronic stress are determined by multiple factors, including age, gender, genetics, environmental factors, and early life experiences.<ref name=herman/>

===Stress and development===
{{medical references|section|date=March 2025}}
====Prenatal stress====

There is evidence that [[prenatal stress]] can influence HPA regulation. In humans, prolonged [[Prenatal stress|maternal stress]] during [[gestation]] is associated with mild [[Cognitive impairment|impairment of intellectual activity]] and [[language development]] in their children, and with behavior disorders such as [[ADHD|attention deficits]], [[schizophrenia]], [[anxiety]] and [[mood disorders|depression]]; self-reported maternal stress is associated with a higher irritability, emotional and attentional problems.<ref>{{cite journal |author=Weinstock M |title=The long-term behavioural consequences of prenatal stress |journal=Neuroscience and Biobehavioral Reviews |volume=32 |issue=6 |pages=1073–86 |date=August 2008 |pmid=18423592 |doi=10.1016/j.neubiorev.2008.03.002 |s2cid=3717977 |url=http://www.hkmacme.org/course/2008BW07-01-00/SP0708.pdf |access-date=2014-05-04 |archive-date=2023-08-10 |archive-url=https://web.archive.org/web/20230810072550/http://www.hkmacme.org/course/2008BW07-01-00/SP0708.pdf |url-status=live }}</ref>

There is evidence that prenatal stress can affect HPA regulation in humans. Children who were stressed prenatally may show altered [[cortisol]] rhythms. Prenatal stress has also been implicated in a tendency toward depression and short attention span in childhood.<ref>{{cite journal |vauthors=Buitelaar JK, Huizink AC, Mulder EJ, de Medina PG, Visser GH |title=Prenatal stress and cognitive development and temperament in infants |journal=Neurobiology of Aging |volume=24 |pages=S53–60; discussion S67–8 |year=2003 |issue=Suppl 1 |pmid=12829109 |doi=10.1016/S0197-4580(03)00050-2|s2cid=3008063 }}</ref>{{better source|date=March 2025}}

====Early life stress====
Exposure to mild or moderate [[stressor]]s early in life has been shown to enhance HPA regulation and promote a lifelong resilience to stress. In contrast, early-life exposure to extreme or prolonged [[Stress (biology)|stress]] can induce a hyper-reactive HPA axis and may contribute to lifelong vulnerability to stress.<ref name="Flinn MV, Nepomnaschy PA, Muehlenbein MP, Ponzi D 1611–29">{{cite journal |vauthors=Flinn MV, Nepomnaschy PA, Muehlenbein MP, Ponzi D |title=Evolutionary functions of early social modulation of hypothalamic–pituitary–adrenal axis development in humans |journal=Neurosci Biobehav Rev|volume=35|issue=7 |pages=1611–29 |date=June 2011|pmid=21251923 |doi=10.1016/j.neubiorev.2011.01.005|s2cid=16950714 }}</ref> 

Adult survivors of childhood abuse have exhibited increased [[ACTH]] concentrations in response to a [[psychosocial]] stress task compared to unaffected controls and subjects with [[Depression (mood)|depression]], but not childhood abuse.<ref name = "Heim et al. 2000">{{cite journal |author1=Heim C. |author2=Newport D. J. |author3=Heit S. |author4=Graham Y. P. |author5=Wilcox M. |author6=Bonsall R. |author7=Nemeroff C. B. | year = 2000 | title = Pituitary-adrenal and autonomic responses to stress in women after sexual and physical abuse in childhood | journal = JAMA | volume = 284 | issue = 5| pages = 592–597 | doi=10.1001/jama.284.5.592 | pmid=10918705| doi-access=free }}</ref>

The HPA axis was present in the earliest vertebrate species, and has remained highly conserved by strong positive selection due to its critical adaptive roles.<ref>{{cite journal | author = Denver RJ | date = Apr 2009 | title = Structural and functional evolution of vertebrate neuroendocrine stress systems | url = https://deepblue.lib.umich.edu/bitstream/2027.42/74370/1/j.1749-6632.2009.04433.x.pdf | journal = Ann N Y Acad Sci | volume = 1163 | issue = 1 | pages = 1–16 | doi = 10.1111/j.1749-6632.2009.04433.x | pmid = 19456324 | hdl = 2027.42/74370 | bibcode = 2009NYASA1163....1D | s2cid = 18786346 | hdl-access = free | access-date = 2019-09-01 | archive-date = 2023-08-10 | archive-url = https://web.archive.org/web/20230810073053/https://deepblue.lib.umich.edu/bitstream/handle/2027.42/74370/j.1749-6632.2009.04433.x.pdf;jsessionid=63DD8A308C8F78D25A2FD5213858CF25?sequence=1 | url-status = live }}</ref> The programming of the HPA axis is strongly influenced by the perinatal and early juvenile environment, or "early-life environment".<ref name="Neurosci Biobehav Rev 2009">{{cite journal |vauthors=Oitzl MS, Champagne DL, van der Veen R, de Kloet ER | date = May 2010 | title = Brain development under stress: hypotheses of glucocorticoid actions revisited | journal = Neurosci Biobehav Rev | volume = 34 | issue = 6| pages = 853–66 | doi = 10.1016/j.neubiorev.2009.07.006 | pmid = 19631685 | s2cid = 25898149 }}</ref> Maternal stress and differential degrees of caregiving may constitute early life adversity, which has been shown to profoundly influence, if not permanently alter, the offspring's stress and emotional regulating systems.<ref name="Neurosci Biobehav Rev 2009"/>

==See also==
;Other major neuroendocrine systems
* [[Hypothalamic–neurohypophyseal system]]
* [[Hypothalamic–pituitary–gonadal axis]]
* [[Hypothalamic–pituitary–thyroid axis]]

;Related topics<!-- new links in alphabetical order please -->
{{columns-list|colwidth=30em|
* [[ACTH stimulation test]]
* [[Allostatic load]]
* [[Antidepressants]]
* [[Cortisol awakening response]]
* [[Dexamethasone]]
* [[Dexamethasone suppression test]]
* [[Fight-or-flight response]]
* [[Hydrocortisone]]
* [[Major depressive disorder]]
* [[Psychoneuroendocrinology]]
* [[Sickness behavior]]
}}
;Conditions
* [[Addison's disease]]
* [[Adrenal insufficiency]]
* [[Cushing's syndrome]]

==References==
{{reflist|30em}}

==External links==
{{Commons}}
* [http://www.mind-body-health.net/hpa.html Mind-Body-Health.net page on HPA axis]
* [https://www.integrativepro.com/articles/the-hpa-axis HPA Axis: Explanation of the Body's Central Stress Response System w/Diagram]

{{Endocrinology physiology}}

{{DEFAULTSORT:Hypothalamic-pituitary-adrenal axis}}
[[Category:Anxiety]]
[[Category:Attention]]
[[Category:Neuroendocrinology]]
[[Category:Stress (biology)]]