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The hypothalamic-pituitary-adrenal axis (HPA axis) also known as the limbic-hypothalamic-pituitary-adrenal axis (LHPA axis) and, occasionally, as the hypothalamic-pituitary-adrenal-gonadotropic axis, refers to a complex set of direct influences and feedback interactions between: the hypothalamus, a hollow, funnel-shaped part of the brain; the pituitary gland, a pea-shaped structure located below the hypothalamus; and the adrenal or suprarenal gland, a small, paired, pyramidal organ located at the top of each kidney.
The fine, homeostatic interactions between these three organs constitute the HPA axis, a major part of the neuroendocrine system that controls reactions to stress and regulates various body processes including digestion, the immune system, mood and sexuality, and energy usage. Species from humans to the most ancient organisms share components of the HPA axis. It is the mechanism for a set of interactions among glands, hormones and parts of the mid-brain that mediate a general adaptation syndrome (GAS)..
The key elements of the HPA axis are:
- The paraventricular nucleus of the hypothalamus, which contains neuroendocrine neurons that synthesise 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 cortices, which produce 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. They are transported to the anterior pituitary through the portal blood vessel system of the hypophyseal stalk. 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 on the brain. In the brain, cortisol acts at two types of receptor - mineralocorticoid receptors and glucocorticoid receptors, and these are expressed by many different types of neuron. One important target of glucocorticoids is the hippocampus, 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.
Release of CRH from the hypothalamus is influenced by stress, by blood levels of cortisol and by the sleep/wake cycle. 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. An abnormally flattened circadian cortisol cycle has been linked with chronic fatigue syndrome (MacHale, 1998), insomnia (Backhaus, 2004) and burnout (Pruessner, 1999).
Anatomical connections between brain areas such as the amygdala, hippocampus, and hypothalamus facilitate activation of the HPA axis. Sensory information arriving at the lateral aspect of the amygdala is processed and conveyed to the central nucleus, which projects 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 mediates alarm reactions to stress, facilitating an adaptive phase of a general adaptation syndrome in which alarm reactions including the immune response are suppressed, allowing the body to attempt countermeasures.
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.
The HPA axis is involved in the neurobiology of mood disorders and functional illnesses, including anxiety disorder, bipolar disorder, post-traumatic stress disorder, clinical depression, burnout, chronic fatigue syndrome and irritable bowel syndrome.
Stress and disease
The HPA axis is involved in the neurobiology 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.
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.
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.
Adrenal and pituitary
The adrenal cortex produces cortisol in response to stimulation by corticotropin (or: ACTH, adrenocorticotropic hormone). The pituitary gland, specifically the corticotroph cells, sense the blood levels of cortisol. If the levels are too low, more ACTH is secreted and the cortical activity is increased.
The hypothalamus controls the rate at which the corticotroph cells respond. In acute illness, higher cortisol levels are needed (see adrenal insufficiency). This is achieved by the hypothalamus secreting higher levels of CRH (corticotropin releasing hormone) into the portal system. This stimulates the corticotroph cells to a higher set point, leading to increased ACTH and cortisol levels.
Regulation at hypothalamus level
Now what controls the hypothalamus? This can be stress of emotional or physical nature; the CRH pulse rate (it is secreted in pulses; the rate determines its function) is increased in response to systemic inflammation, namely IL-1, IL-6 and TNF alpha.
- ACTH stimulation test
- Addison's disease
- Adrenal insufficiency
- Allostatic load
- Cortisol awakening response
- Cushing's syndrome
- Dexamethasone suppression test
- Hypothalamo hypophyseal system
- Hypothalamic-pituitary-gonadal axis
- Hypothalamic-pituitary-thyroid axis
- Selye, Hans (1974). Stress without distress, Philadelphia: Lippincott.
- Robert L. Spencer, Kent E. Hutchinson, Alcohol, Aging, and the Stress Response, Alcohol Research and Health, Winter 1999.
- Carmine M. Pariante, Institute of Psychiatry, King’s College London Depression, stress and the adrenal axis. The British Society for Neuroendocrinology, 2003.
- Douglas A (2005). Central noradrenergic mechanisms underlying acute stress responses of the Hypothalamo-pituitary-adrenal axis: adaptations through pregnancy and lactation.. Stress 8 (1): 5–18.
- Engelmann M, Landgraf R, Wotjak C (2004). The hypothalamic-neurohypophysial system regulates the hypothalamic-pituitary-adrenal axis under stress: an old concept revisited.. Front Neuroendocrinol 25 (3-4): 132–49.
- Courtney E. Detillion et al: Social facilitation of wound healing, Psychoneuroendocrinology, Volume 29, Issue 8, September 2004, Pages 1004-1011, DOI 10.1016/j.psyneuen.2003.10.003
- (Winberg S, Øverli Ø, Lepage O (2001). Suppression of aggression in rainbow trout (Oncorhynchus mykiss) by dietary L-tryptophan.. J Exp Biol 204 (Pt 22): 3867–76.
- PMID 17201569 (PMID 17201569)
- Merali Z. et al. (1998) Aversive and appetitive events evoke the release of corticotropin-releasing hormone and bombesin-like peptides at the central nucleus of the amygdala J Neurosci 18:4758-66
Relation to illnesses
- Backhaus J et al. (2004) Sleep disturbances are correlated with decreased morning awakening salivary cortisol Psychoneuroendocrinology 29:1184-91
- Pruessner JC et al. (1999) Burnout, perceived stress, and cortisol responses to awakening Psychosom Med 61:197-204
- MacHale SM et al.(1998) Diurnal variation of adrenocortical activity in chronic fatigue syndrome Neuropsychobiology 38:213-7
- Patacchioli FR et al. (2001) Actual stress, psychopathology and salivary cortisol levels in the irritable bowel syndrome (IBS) J Endocrinol Invest 24:173-7
- NeuroWiki page on HPA axis
- Mind-Body-Health.net page on HPA axis
- Dorlands/Elsevier a_76/12172218
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