Hypothalamic-pituitary-adrenal axis





The hypothalamic-pituitary-adrenal axis refers to a complex set of influences and feedback interactions among three components: the hypothalamus, the pituitary gland and the adrenal glands.



The  HPA axis, a major 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. 



The HPA axis  helps regulate many systems in the body, including: the metabolic system, cardiovascular system, immune system, reproductive system and central nervous system. 



The HPA axis functions by the 


interactions among glands, hormones, and parts of the midbrain that mediate the general adaptation syndrome (GAS).



It integrates physical and psychosocial influences allowing adaptation  to the environment.



There are four major neuroendocrine systems through which the hypothalamus and pituitary direct neuroendocrine functions: 



The HPA axis



hypothalamic-pituitary-gonadal axis (HPG)



hypothalamic-pituitary-thyroid axis (HPT)



hypothalamic-neurohypophyseal system 



HPA axis elements are:



The paraventricular nucleus of the hypothalamus.



the adrenal cortex,



The paraventricular  nucleus 


contains neuroendocrine neurons which synthesize and secrete vasopressin and corticotropin-releasing hormone (CRH). 



CRH and vasopressin are released from neurosecretory nerve terminals at the median eminence. 



Vasopressin and corticotropin-releasing hormone (CRH) peptides regulate the  anterior lobe of the pituitary gland. 



CRH and vasopressin stimulate the secretion of adrenocorticotropic hormone (ACTH).



ACTH acts on the adrenal cortex, to produces glucocorticoid hormones in response to stimulation.



Glucocorticoids act on the hypothalamus and pituitary to suppress CRH and ACTH production in a negative feedback cycle.



Corticotropin-releasing hormone is transported to the anterior pituitary through the portal blood vessel system of the hypophyseal stalk.



Vasopressin is transported by axonal transport to the posterior pituitary gland. 



At the pituitary 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.



ACTH rapidly stimulates biosynthesis of corticosteroids such as cortisol from cholesterol. 



In the brain, cortisol acts on two types of receptors, mineralocorticoid receptors and glucocorticoid receptors.



Mineralocorticoid receptors and glucocorticoid receptors are expressed by many different types of neurons. 



The hypothalamus is an important 


target of glucocorticoids, and is a major controlling center of the HPA axis.



Vasopressin is also known as antidiuretic hormone, and is a water conserving hormone.



Vasopressin is also a potent vasoconstrictor.



Feedback loops in the HPA axis: 



Cortisol produced in the adrenal cortex will negatively feedback to inhibit both the hypothalamus and the pituitary gland. 



Cortisol production reduces the secretion of CRH and vasopressin, and also directly reduces  ACTH and endorphins.



Epinephrine and norepinephrine (E/NE) are produced by the adrenal medulla through sympathetic stimulation and effects of cortisol.



Epinephrine and norepinephrine positively feedback to the pituitary and increases ACTH and ?-endorphins.



Hypothalamic release of CRH 


is influenced by stress, physical activity, illness, by blood levels of cortisol and by circadian rhythm.



Cortisol levels rise rapidly after wakening, a peaking within 30�45 minutes. 



Cortisol levels then gradually fall over the day, rising again in late afternoon. 



Cortisol levels fall in late evening, reaching a trough during the middle of the night, corresponding to the rest-activity cycle.



A flat circadian cortisol cycle has been linked with chronic fatigue syndrome, insomnia and burnout.



Brain connections between areas such as the amygdala, hippocampus, prefrontal cortex and hypothalamus facilitate activation of the HPA axis.



Sensory information arriving at the amygdala is processed and conveyed 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 occurs during stress which increases glucose levels and availability.



Cortisol suppresses the highly demanding metabolic processes of the immune system, resulting in further availability of glucose.



Atrophy of the hippocampus occurs when exposed to severe stress caused by prolonged exposure to high concentrations of glucocorticoids.



Hippocampus inadequacies may reduce the memory resources that help  


 formulate appropriate reactions to stress.



There is positive and negative communication and feedback between the HPA axis and immune system.



The cytokines, such as IL-1, IL-6, IL-10 and TNF-alpha can activate the HPA axis.



IL-1 is the most potent cytokine activator  of the HPA.



The HPA axis modulates the immune response, with high levels of cortisol resulting in a suppression of immune and inflammatory reactions. 



The CNS regulates the immune system through neuroendocrine pathways, such as the HPA axis, which is responsible for modulating inflammatory responses that occur throughout the body.



Proinflammatory cytokines are released into the circulation during an immune response by and can pass through the blood brain barrier where they can interact with the brain and activate the HPA axis.



The interaction between the proinflammatory cytokines and the brain can alter the metabolic activity of neurotransmitters and cause symptoms such as fatigue, depression, and mood changes.



Deficiencies in the HPA axis may play a role in allergies and inflammatory/ autoimmune diseases, such as rheumatoid arthritis and multiple sclerosis.



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:  IL-1, TNF alpha, and IFN gamma and increasing the levels of anti-inflammatory cytokines IL-4, IL-10, and IL-13 in immune cells, such as monocytes and neutrophils.



The HPA axis is involved in mood disorders and functional illnesses, including anxiety disorder, bipolar disorder, insomnia, posttraumatic stress disorder, borderline personality disorder, ADHD, major depressive disorder, burnout, chronic fatigue syndrome, fibromyalgia, irritable bowel syndrome, and alcoholism.



Antidepressants are routinely prescribed for many of these above illnesses, serve to regulate HPA axis function.



Sex differences are prevalent in humans with respect to psychiatric stress-related disorders such as anxiety and depression, where women experience these disorders more often than men.



Estrogens function to enhance stress-activated ACTH and CORT secretion while testosterone functions to decrease HPA axis activation and works to inhibit both ACTH and CORT responses to stress.



Social stress and physical stress 


both activate the HPA axis, though via different pathways.



Monoamine neurotransmitters regulate the HPA axis.



The neurotransmitters include dopamine, serotonin and norepinephrine.



An increase in the hormone oxytocin, resulting from positive social interactions, acts to suppress the HPA axis and thereby counteracts stress, promoting positive health effects such as wound healing.



The HPA axis is activated during chronic stress.



Stressors that threaten physical well being, integrity, or involve trauma appear  to have a high, flat diurnal pattern of cortisol release: lower-than-normal levels of cortisol in the morning and higher-than-normal levels in the evening.



Such stress results  in a high overall level of daily cortisol release. 



Stress that is controllable produces higher-than-normal morning cortisol. 



Stress hormone release declines gradually after a stressor occurs. 



In post-traumatic stress disorder a lower-than-normal cortisol release, and blunted hormonal response to stress may predispose a person to develop PTSD.



HPA axis hormones can be linked to certain stress related skin diseases and skin tumors: HPA axis hormones become hyperactive in the brain.



Prolonged maternal stress during pregnancy is associated with mild impairment of intellectual activity, language development, behavior disorders such as attention deficits, schizophrenia, anxiety and depression.



Self-reported maternal stress is associated with a higher irritability, emotional and attentional problems.



Children stressed in utero may show altered cortisol rhythms. 



There is an association between maternal depression during pregnancy and childhood cortisol levels.



Prenatal stress HPA dysregulation does not alter adult behavior.



Adult victims of childhood abuse have exhibited increased ACTH concentrations in response to a psychosocial stress task.



The HPA axis is strongly influenced by the perinatal and early juvenile environment.



Maternal stress and caregiving may constitute early life adversity, which profoundly influenced, if not permanently alters, the offspring’s stress and emotional regulating systems.



Maternal care improves cardiac response, sleep/wake rhythm, and growth hormone secretion in the neonate, it also suppresses HPA axis activity. 



Maternal care negatively regulates stress response in the neonate: shaping his/her susceptibility to stress in later life. 



Early life adversity can produce outcomes ranging from extreme vulnerability to resilience, in the face of later stress. 



The HPA axis  plays a clear role in the production of corticosteroids, which govern many facets of brain development and responses to ongoing environmental stress. 


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