Hypothalamic pituitary adrenal axis
Editor-In-Chief: C. Michael Gibson, M.S., M.D. 
The hypothalamic-pituitary-adrenal axis (HPA axis) is 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.
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. 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 vasopression, and also directly reduces the cleavage of proopiomelanocortin into ACTH and ß-endorphins.
- Epinephrine and norepinephrine is produced from 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 ß-endorphins.
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.
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). In herbal medicine, adaptogens work by reregulating the HPA axis.
The HPA axis is a feature of other vertebrates as well as of mammals. 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 salmon oid 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.
- Hypothalamic-pituitary-gonadal axis
- Cushing's syndrome
- Adrenal insufficiency
- Addison's disease
- ↑ 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. PMID 16019594.
- ↑ Engelmann M, Landgraf R, Wotjak C. "The hypothalamic-neurohypophysial system regulates the hypothalamic-pituitary-adrenal axis under stress: an old concept revisited". Front Neuroendocrinol. 25 (3–4): 132–49. PMID 15589266.
- ↑ (Winberg S, Ã˜verli Ã˜, Lepage O (2001). "Suppression of aggression in rainbow trout (Oncorhynchus mykiss) by dietary L-tryptophan". J Exp Biol. 204 (Pt 22): 3867–76. PMID 11807104.
- 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 18:4758-99
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
- Winston, David & Maimes, Steven. “Adaptogens: Herbs for Strength, Stamina, and Stress Relief,” Healing Arts Press, (2007)