hypothalamic–pituitary–adrenal axis hypothalamic–pituitary–adrenal axis 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") glands (small, conical organs on top of the kidneys). these organs and their interactions constitute the hpa axis. schematic of the hpa axis (crh, corticotropin-releasing hormone; acth, adrenocorticotropic hormone) hypothalamus, pituitary gland and adrenal cortex the hpa axis is 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. it is the common mechanism for interactions among glands, hormones, and parts of the midbrain that mediate the general adaptation syndrome (gas). while steroid hormones are produced mainly in vertebrates, the physiological role of the hpa axis and corticosteroids in stress response is so fundamental that analogous systems can be found in invertebrates and monocellular organisms as well. the hpa axis, hypothalamic–pituitary–gonadal axis (hpg), hypothalamic–pituitary–thyroid axis (hpt), and the hypothalamic–neurohypophyseal system are the four major neuroendocrine systems through which the hypothalamus and pituitary direct neuroendocrine function. anatomy the key elements of the hpa axis are: the paraventricular nucleus of the hypothalamus, which contains neuroendocrine neurons which synthesize and secrete vasopressin and corticotropin-releasing hormone (crh). these two peptides regulate: 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 cortex, which 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. crh and vasopressin are released from neurosecretory nerve terminals at the median eminence. crh is transported to the anterior pituitary through the portal blood vessel system of the hypophyseal stalk and vasopressin is transported by axonal transport to the 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 biosynthesis of corticosteroids 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 receptor – mineralocorticoid receptors 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. 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 proopiomelanocortin (pomc) into acth and β-endorphins. epinephrine and norepinephrine (e/ne) are 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. function release of corticotropin-releasing hormone (crh) from the hypothalamus is influenced by 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. an abnormally flattened circadian cortisol cycle has been linked with chronic fatigue syndrome, insomnia and burnout. the hpa axis has a central role in regulating many 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. anatomical connections between brain areas such as the amygdala, hippocampus, prefrontal cortex and hypothalamus facilitate activation of the hpa axis. 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 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. 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 the immune system. a number of cytokines, such as il-1, il-6, 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, 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. the cns is in many ways "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 through neuroendocrine pathways, such as the hpa axis. the hpa axis is responsible for modulating inflammatory responses that occur throughout the body. 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. interactions 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 (e.g. il-1, tnf alpha, and ifn gamma) and increasing the levels of anti-inflammatory cytokines (e.g. il-4, il-10, and il-13) in immune cells, such as monocytes and neutrophils 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. stress schematic overview of the hypothalamic-pituitary-adrenal (hpa) axis. stress activates the hpa-axis and thereby enhances the secretion of glucocorticoids from the adrenals. stress and disease the hpa axis is involved in the neurobiology and pathophysiology of 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, which are routinely prescribed for many of these 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. particularly in rodents, it has been shown that females may lack the ability to tolerate as well as process stress (particularly for chronic stress) due to possible down regulation of glucocorticoid receptor expression as well as a deficiency of fkbp51 binding protein in the cytosol. by constantly activating the hpa axis, this could lead to higher instances of stress and disorders that would only get worse with chronic stress. specifically in rodents, females show greater activation of the hpa axis following stress than males. these differences also likely arise due to the opposing actions that certain sex steroids have, such as testosterone and oestrogen. oestrogen functions 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. however, more studies are required to better understand the underlying basis of these sex differences. experimental studies have investigated many different types of stress, and their effects on the hpa axis in many different circumstances. 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. several monoamine neurotransmitters are important in regulating the hpa axis, especially dopamine, serotonin and norepinephrine (noradrenaline). there is evidence that an increase in oxytocin, resulting for instance 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 a feature of mammals and other vertebrates. 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 dominant fish. serotonin (5ht) appeared to be the active neurotransmitter involved in mediating stress responses, and increases in serotonin are related to increased plasma α-msh levels, 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. however, the study mentions that plasma cortisol was not affected by dietary l-tryptophan. the drug ly354740 (also known as eglumegad, an agonist of the metabotropic glutamate receptors 2 and 3) has been shown to interfere in the hpa axis, with chronic oral administration of this drug leading to markedly reduced baseline cortisol levels in bonnet macaques (macaca radiata); acute infusion of ly354740 resulted in a marked diminution of yohimbine-induced stress response in those animals. studies on people show that the hpa axis is activated in different ways during chronic stress depending on the type of stressor, the person's response to the stressor and other factors. stressors that are uncontrollable, threaten physical integrity, or involve trauma tend to have a high, flat diurnal profile of cortisol release (with lower-than-normal levels of cortisol in the morning and higher-than-normal levels in the evening) resulting in a high overall level of daily cortisol release. on the other hand, controllable stressors tend to produce higher-than-normal morning cortisol. stress hormone release tends to decline gradually after a stressor occurs. in post-traumatic stress disorder there appears to be lower-than-normal cortisol release, and it is thought that a blunted hormonal response to stress may predispose a person to develop ptsd. it is also known that hpa axis hormones are related to certain skin diseases and skin homeostasis. there is evidence shown that the hpa axis hormones can be linked to certain stress related skin diseases and skin tumors. this happens when hpa axis hormones become hyperactive in the brain. prenatal stress there is evidence that prenatal stress can influence hpa regulation. in animal experiments, exposure to prenatal stress has been shown to cause a hyper-reactive hpa stress response. rats that have been prenatally stressed have elevated basal levels and abnormal circadian rhythm of corticosterone as adults. additionally, they require a longer time for their stress hormone levels to return to baseline following exposure to both acute and prolonged stressors. prenatally stressed animals also show abnormally high blood glucose levels and have fewer glucocorticoid receptors in the hippocampus. in humans, prolonged maternal stress during gestation is associated with mild impairment of intellectual activity and language development in their children, and