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Thehypothalamic–pituitary–adrenal axis (HPA axis orHTPA axis) is a complex set of direct influences andfeedback interactions among three components: thehypothalamus (a part of thebrain located below thethalamus), thepituitary gland (a pea-shaped structure located below the hypothalamus), and theadrenal (also called "suprarenal")glands (small,conical organs on top of thekidneys). Theseorgans and their interactions constitute theHPA axis.
The HPA axis is a majorneuroendocrine system[1] that controls reactions tostress and regulates many body processes, includingdigestion,immune responses,mood andemotions,sexual activity, and energy storage and expenditure. It is the common mechanism for interactions amongglands,hormones, and parts of themidbrain that mediate thegeneral adaptation syndrome (GAS).[2]
Whilesteroidhormones are produced mainly invertebrates, thephysiological role of the HPA axis andcorticosteroids in stress response is so fundamental thatanalogous systems can be found ininvertebrates andmonocellular organisms as well.
The HPA axis,hypothalamic–pituitary–gonadal (HPG) axis,hypothalamic–pituitary–thyroid (HPT) axis, and thehypothalamic–neurohypophyseal system are the four majorneuroendocrine systems through which thehypothalamus andpituitary directneuroendocrine function.[1]
The key elements of the HPA axis are:[3]
CRH andvasopressin are released fromneurosecretory nerve terminals at themedian eminence. CRH is transported to the anterior pituitary through theportal blood vessel system of thehypophyseal stalk and vasopressin is transported byaxonal transport to theposterior pituitary gland. There, CRH and vasopressin act synergistically to stimulate the secretion of stored ACTH from corticotrope cells. ACTH is transported by theblood to theadrenal cortex of theadrenal gland, where it rapidly stimulates the biosynthesis ofcorticosteroids such ascortisol fromcholesterol. 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 receptors andglucocorticoid receptors, and these are expressed by many different types of neurons. One important target of glucocorticoids is thehypothalamus, which is a major controlling centre of the HPA axis.[4]
Vasopressin can be thought of as "water conservation hormone" and is also known as "antidiuretic hormone(ADH)". It is released when the body isdehydrated and has potent water-conserving effects on the kidney. It is also a potentvasoconstrictor.[5]
Important to the function of the HPA axis are some of the following feedback loops:
Release ofcorticotropin-releasing hormone (CRH) from the hypothalamus is influenced bystress, 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.[6] An abnormally flattened circadian cortisol cycle has been linked withchronic fatigue syndrome,[7]insomnia[8] andburnout.[9]
The HPA axis has a central role in regulating manyhomeostatic systems in the body, including themetabolic system,cardiovascular system,immune system,reproductive system andcentral nervous system. The HPA axis integrates physical andpsychosocial influences in order to allow an organism to adapt effectively to its environment, use resources, and optimize survival.[6]
Anatomical connections between brain areas such as theamygdala,hippocampus,prefrontal cortex and hypothalamus facilitate activation of the HPA axis.[10] Sensory information arriving at the lateral aspect of theamygdala is processed and conveyed to the amygdala'scentral nucleus, which then projects out to several parts of the brain involved in responses to fear. At the hypothalamus, fear-signaling impulses activate both thesympathetic nervous system and the modulating systems of the HPA axis.
Increased production of cortisol during stress results in an increased availability ofglucose in order to facilitatefighting or fleeing. As well as directly increasing glucose availability, cortisol also suppresses the highly demanding metabolic processes of theimmune system, resulting in further availability of glucose.[6]
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 ofglucocorticoids. Deficiencies of thehippocampus may reduce the memory resources available to help a body formulate appropriate reactions to stress.[11]
There is bi-directional communication and feedback between the HPA axis and theimmune system. A number ofcytokines, such asIL-1,IL-6,IL-10 andTNF-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.[6]
In many ways, theCNS is "immune privileged", but it plays an important role in the immune system and is affected by it in turn. The CNS regulates the immune system throughneuroendocrine pathways, such as the HPA axis. The HPA axis is responsible for modulatinginflammatory responses that occur throughout the body.[12][13]
During an immune response,proinflammatory cytokines (e.g. IL-1) are released into the peripheral circulation system and can pass through theblood–brain barrier where they can interact with the brain and activate the HPA axis.[13][14][15] Interactions between theproinflammatory cytokines and the brain can alter themetabolic activity ofneurotransmitters and cause symptoms such as fatigue,depression, and mood changes.[13][14] Deficiencies in the HPA axis may play a role in allergies and inflammatory/ autoimmune diseases, such asrheumatoid arthritis andmultiple sclerosis.[12][13][16]
When the HPA axis is activated bystressors, such as animmune response, high levels ofglucocorticoids are released into the body and suppress immune response by inhibiting the expression of proinflammatory cytokines (e.g.IL-1,TNF alpha, andIFN gamma) and increasing the levels of anti-inflammatory cytokines (e.g.IL-4,IL-10, andIL-13) in immune cells, such asmonocytes andneutrophils.[13][14][16][17]
The relationship between chronic stress and its concomitant activation of the HPA axis, and dysfunction of the immune system is unclear; studies have found bothimmunosuppression and hyperactivation of the immune response.[17]
Activation of the HPA axis causes release of glucocorticoids, which target numerous organ systems to activate energy reserves in response to stress demands.[18] 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.[18]
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There is evidence thatprenatal stress can influence HPA regulation. In humans, prolongedmaternal stress duringgestation is associated with mildimpairment of intellectual activity andlanguage development in their children, and with behavior disorders such asattention deficits,schizophrenia,anxiety anddepression; self-reported maternal stress is associated with a higher irritability, emotional and attentional problems.[19]
There is evidence that prenatal stress can affect HPA regulation in humans. Children who were stressed prenatally may show alteredcortisol rhythms. Prenatal stress has also been implicated in a tendency toward depression and short attention span in childhood.[20][better source needed]
Exposure to mild or moderatestressors 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 prolongedstress can induce a hyper-reactive HPA axis and may contribute to lifelong vulnerability to stress.[21]
Adult survivors of childhood abuse have exhibited increasedACTH concentrations in response to apsychosocial stress task compared to unaffected controls and subjects withdepression, but not childhood abuse.[22]
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.[23] The programming of the HPA axis is strongly influenced by the perinatal and early juvenile environment, or "early-life environment".[24] 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.[24]
•The hypothalamic–neurohypophyseal system secretes two peptide hormones directly into the blood, vasopressin and oxytocin. ...
•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.
•The hypothalamic–pituitary–thyroid axis consists of hypothalamic thyrotropin-releasing hormone (TRH); the anterior pituitary hormone thyroid–stimulating hormone (TSH); and the thyroid hormones T3 and T4.
•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.
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