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, the pituitary gland (a pea-shaped
structure located below the thalamus), and the adrenal (also called
"suprarenal") glands (small, conical organs on top of the kidneys).
These organs and their interactions constitute 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. 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, HPG axis, HPT axis, and the
hypothalamic–neurohypophyseal system are the four major
neuroendocrine systems through which the hypothalamus and pituitary
direct neuroendocrine function.
3 Immune system
4.1 Stress and disease
4.2 Stress and development
4.2.1 Prenatal stress
4.2.2 Early life stress
5 See also
7 External links
The key elements of the HPA axis are:
The paraventricular nucleus of the hypothalamus, which contains
neuroendocrine neurons that 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
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.
Release of 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
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
There is bi-directional communication and feedback between the HPA
axis and 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
Schematic overview of the hypothalamic-pituary-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 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. 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
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.
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.
Stress and development
Schematic overview of the hypothalamic-pituary-adrenal (HPA) axis.
Stress activates the HPA-axis and thereby enhances the secretion of
glucocorticoids from the adrenals.
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 with behaviour disorders such as attention deficits,
schizophrenia, anxiety and depression; self-reported maternal stress
is associated with a higher irritability, emotional and attentional
There is growing evidence that prenatal stress can affect HPA
regulation in humans. Children who were stressed prenatally may show
altered cortisol rhythms. For example, several studies have found an
association between maternal depression during pregnancy and childhood
Prenatal stress has also been implicated in a
tendency toward depression and short attention span in childhood.
There is no clear indication that HPA dysregulation caused by prenatal
stress can alter adult behavior.
Early life stress
The role of early life stress in programming the HPA Axis has been
well-studied in animal models. Exposure to mild or moderate stressors
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 prolonged stress can induce a hyper-reactive HPA Axis and
may contribute to lifelong vulnerability to stress. In one widely
replicated experiment, rats subjected to the moderate stress of
frequent human handling during the first two weeks of life had reduced
hormonal and behavioral HPA-mediated stress responses as adults,
whereas rats subjected to the extreme stress of prolonged periods of
maternal separation showed heightened physiological and behavioral
stress responses as adults.
Several mechanisms have been proposed to explain these findings in rat
models of early-life stress exposure. There may be a critical period
during development during which the level of stress hormones in the
bloodstream contribute to the permanent calibration of the HPA Axis.
One experiment has shown that, even in the absence of any
environmental stressors, early-life exposure to moderate levels of
corticosterone was associated with stress resilience in adult rats,
whereas exposure to high doses was associated with stress
Another possibility is that the effects of early-life stress on HPA
functioning are mediated by maternal care. Frequent human handling of
the rat pups may cause their mother to exhibit more nurturant
behavior, such as licking and grooming. Nurturant maternal care, in
turn, may enhance HPA functioning in at least two ways. First,
maternal care is crucial in maintaining the normal stress hypo
responsive period (SHRP), which in rodents, is the first two weeks of
life during which the HPA axis is generally non-reactive to stress.
Maintenance of the SHRP period may be critical for HPA development,
and the extreme stress of maternal separation, which disrupts the
SHRP, may lead to permanent HPA dysregulation. Another way that
maternal care might influence HPA regulation is by causing epigenetic
changes in the offspring. For example, increased maternal licking and
grooming has been shown to alter expression of the glutocorticoid
receptor gene implicated in adaptive stress response. At least one
human study has identified maternal neural activity patterns in
response to video stimuli of mother-infant separation as being
associated with decreased glucocorticoid receptor gene methylation in
the context of post-traumatic stress disorder stemming from early life
stress. Yet clearly, more research is needed to determine if the
results seen in cross-generational animal models can be extended to
Though animal models allow for more control of experimental
manipulation, the effects of early life stress on HPA axis function in
humans has also been studied. One population that is often studied in
this type of research is adult victims of childhood abuse. Adult
victims of childhood abuse have exhibited increased ACTH
concentrations in response to a psychosocial stress task compared to
healthy controls and subjects with depression but not childhood
abuse. In one study, adult victims of childhood abuse that are not
depressed show increased ACTH response to both exogenous CRF and
normal cortisol release. Adult victims of childhood abuse that are
depressed show a blunted ACTH response to exoegenous CRH. A
blunted ACTH response is common in depression, so the authors of this
work posit that this pattern is likely to be due to the participant's
depression and not their exposure to early life stress.
Heim and colleagues have proposed that early life stress, such as
childhood abuse, can induce a sensitization of the HPA axis, resulting
in particular heightened neuronal activity in response to
stress-induced CRF release. With repeated exposure to stress, the
sensitized HPA axis may continue to hypersecrete CRF from the
hypothalamus. Over time, CRF receptors in the anterior pituitary will
become down-regulated, producing depression and anxiety symptoms.
This research in human subjects is consistent with the animal
literature discussed above.
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. The programming of the HPA axis is
strongly influenced by the perinatal and early juvenile environment,
or “early-life environment.”  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. Widely studied in animal models (e.g. licking and
grooming/LG in rat pups), the consistency of maternal care has
been shown to have a powerful influence on the offspring's
neurobiology, physiology, and behavior. Whereas maternal care improves
cardiac response, sleep/wake rhythm, and growth hormone secretion in
the neonate, it also suppresses HPA axis activity. In this manner,
maternal care negatively regulates stress response in the neonate,
thereby shaping his/her susceptibility to stress in later life. These
programming effects are not deterministic, as the environment in which
the individual develops can either match or mismatch with the former's
“programmed” and genetically predisposed HPA axis reactivity.
Although the primary mediators of the HPA axis are known, the exact
mechanism by which its programming can be modulated during early life
remains to be elucidated. Furthermore, evolutionary biologists contest
the exact adaptive value of such programming, i.e. whether heightened
HPA axis reactivity may confer greater evolutionary fitness.
Various hypotheses have been proposed, in attempts to explain why
early life adversity can produce outcomes ranging from extreme
vulnerability to resilience, in the face of later stress.
Glucocorticoids produced by the HPA axis have been proposed to confer
either a protective or harmful role, depending on an individual's
genetic predispositions, programming effects of early-life
environment, and match or mismatch with one's postnatal environment.
The predictive adaptation hypothesis (1), the three-hit concept of
vulnerability and resilience (2) and the maternal mediation hypothesis
(3) attempt to elucidate how early life adversity can differentially
predict vulnerability or resilience in the face of significant stress
in later life. These hypotheses are not mutually exclusive but
rather are highly interrelated and unique to the individual.
(1) The predictive adaptation hypothesis: this hypothesis is in
direct contrast with the diathesis stress model, which posits that the
accumulation of stressors across a lifespan can enhance the
development of psychopathology once a threshold is crossed. Predictive
adaptation asserts that early life experience induces epigenetic
change; these changes predict or “set the stage” for adaptive
responses that will be required in his/her environment. Thus, if a
developing child (i.e., fetus to neonate) is exposed to ongoing
maternal stress and low levels of maternal care (i.e., early life
adversity), this will program his/her HPA axis to be more reactive to
stress. This programming will have predicted, and potentially be
adaptive in a highly stressful, precarious environment during
childhood and later life. The predictability of these epigenetic
changes is not definitive, however – depending primarily on the
degree to which the individual's genetic and epigenetically modulated
phenotype “matches” or “mismatches” with his/her environment
(See: Hypothesis (2)).
(2) Three-Hit Concept of vulnerability and resilience: this
hypothesis states that within a specific life context, vulnerability
may be enhanced with chronic failure to cope with ongoing adversity.
It fundamentally seeks to explicate why, under seemingly
indistinguishable circumstances, one individual may cope resiliently
with stress, whereas another may not only cope poorly, but
consequently develop a stress-related mental illness. The three
“hits” – chronological and synergistic – are as follows:
genetic predisposition (which predispose higher/lower HPA axis
reactivity), early-life environment (perinatal – i.e. maternal
stress, and postnatal – i.e. maternal care), and later-life
environment (which determines match/mismatch, as well as a window for
neuroplastic changes in early programming). (Figure 1)6 The
concept of match/mismatch is central to this evolutionary hypothesis.
In this context, it elucidates why early life programming in the
perinatal and postnatal period may have been evolutionarily selected
for. Specifically, by instating specific patterns of HPA axis
activation, the individual may be more well equipped to cope with
adversity in a high-stress environment. Conversely, if an individual
is exposed to significant early life adversity, heightened HPA axis
reactivity may “mismatch” him/her in an environment characterized
by low stress. The latter scenario may represent maladaptation due to
early programming, genetic predisposition, and mismatch. This mismatch
may then predict negative developmental outcomes such as
psychopathologies in later life.
Ultimately, the conservation of the HPA axis has underscored its
critical adaptive roles in vertebrates, so, too, various invertebrate
species over time. 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. With these findings, animal
model research has served to identify what these roles are – with
regards to animal development and evolutionary adaptation. In more
precarious, primitive times, a heightened HPA axis may have served to
protect organisms from predators and extreme environmental conditions,
such as weather and natural disasters, by encouraging migration (i.e.
fleeing), the mobilization of energy, learning (in the face of novel,
dangerous stimuli) as well as increased appetite for biochemical
energy storage. In contemporary society, the endurance of the HPA axis
and early life programming will have important implications for
counseling expecting and new mothers, as well as individuals who may
have experienced significant early life adversity.
Other major neuroendocrine systems
ACTH stimulation test
Cortisol awakening response
Dexamethasone suppression test
Major depressive disorder
^ a b Malenka RC, Nestler EJ, Hyman SE (2009). "Chapter 10: Neural and
Neuroendocrine Control of the Internal Milieu". In Sydor A, Brown RY.
Molecular Neuropharmacology: A Foundation for Clinical Neuroscience
(2nd ed.). New York: McGraw-Hill Medical. pp. 246, 248–259.
•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.
^ Selye, Hans (1974). Stress without distress. Philadelphia:
Lippincott. ISBN 978-0-397-01026-4. [page needed]
^ a b c d editors, volume; Besedovsky, Hugo; Chrousos, George; Rey,
Adriana Del (2008). The hypothalamus-pituitary-adrenal axis (1st ed.).
Amsterdam: Academic. ISBN 9780444530400.
^ MacHale SM, Cavanagh JT, Bennie J, Carroll S, Goodwin GM, Lawrie SM
(November 1998). "Diurnal variation of adrenocortical activity in
chronic fatigue syndrome". Neuropsychobiology. 38 (4): 213–7.
doi:10.1159/000026543. PMID 9813459.
^ Backhaus J, Junghanns K, Hohagen F (October 2004). "Sleep
disturbances are correlated with decreased morning awakening salivary
cortisol". Psychoneuroendocrinology. 29 (9): 1184–91.
doi:10.1016/j.psyneuen.2004.01.010. PMID 15219642.
^ Pruessner JC, Hellhammer DH, Kirschbaum C (1999). "Burnout,
perceived stress, and cortisol responses to awakening". Psychosom Med.
61 (2): 197–204. doi:10.1097/00006842-199903000-00012.
^ a b Marques-Deak, A; Cizza, G; Sternberg, E (February 2005).
"Brain-immune interactions and disease susceptibility" (PDF).
Molecular Psychiatry. 10: 239–250. doi:10.1038/sj.mp.4001643.
Retrieved 13 February 2016.
^ a b c d e f Otmishi, Peyman; Gordon, Josiah; El-Oshar, Seraj; Li,
Huafeng; Guardiola, Juan; Saad, Mohamed; Proctor, Mary; Yu, Jerry
(2008). "Neuroimmune Interaction in Inflammatory Diseases" (PDF).
Clinical Medicine: Circulatory, Respiratory, and Pulmonary Medicine.
2: 35–44. PMC 2990232 . PMID 21157520. Retrieved 14
^ a b c Tian, Rui; Hou, Gonglin; Li, Dan; Yuan, Ti-Fei (June 2014). "A
Possible Change Process of Inflammatory
Cytokines in the prolonged
Chronic Stress and its Ultimate Implications for Health" (PDF). The
Scientific World Journal. 2014: 1–8. doi:10.1155/2014/780616.
PMC 4065693 . PMID 24995360. Retrieved 13 February
^ Hall, Jessica; Cruser, desAgnes; Podawiltz, Alan; Mummert, Diana;
Jones, Harlan; Mummert, Mark (August 2012). "Psychological Stress and
the Cutaneous Immune Response: Roles of the HPA Axis and the
Sympathetic Nervous System in Atopic Dermatitis and Psoriasis".
Dermatology Research and Practice. 2012: 1–11.
doi:10.1155/2012/403908. Retrieved 14 February 2016.
^ a b Bellavance, Marc-Andre; Rivest, Serge (March 2014). "The
HPA-immune axis and the immunomodulatory actions of glucocorticoids in
the brain" (PDF). Frontiers in Immunology. 5: 1–13.
doi:10.3389/fimmu.2014.00136. Retrieved 11 February 2016.
^ a b Padgett, David; Glaser, Ronald (August 2003). "How stress
influences the immune response" (PDF). Trends in Immunology. 24 (8):
444–448. doi:10.1016/S1471-4906(03)00173-X. PMID 12909458.
Retrieved 12 February 2016.
^ Spencer RL, Hutchison KE (1999). "Alcohol, aging, and the stress
response". Alcohol Research & Health. 23 (4): 272–83.
^ Pariante CM (August 2003). "Depression, stress and the adrenal
axis". Journal of Neuroendocrinology. 15 (8): 811–2.
doi:10.1046/j.1365-2826.2003.01058.x. PMID 12834443.
^ Douglas AJ (March 2005). "Central noradrenergic mechanisms
underlying acute stress responses of the
Hypothalamo–pituitary–adrenal axis: adaptations through pregnancy
and lactation". Stress. 8 (1): 5–18. doi:10.1080/10253890500044380.
^ Engelmann M, Landgraf R, Wotjak CT (2004). "The
hypothalamic-neurohypophysial system regulates the
hypothalamic–pituitary–adrenal axis under stress: an old concept
revisited". Frontiers in Neuroendocrinology. 25 (3–4): 132–49.
doi:10.1016/j.yfrne.2004.09.001. PMID 15589266.
^ Detillion CE, Craft TK, Glasper ER, Prendergast BJ, DeVries AC
(September 2004). "Social facilitation of wound healing".
Psychoneuroendocrinology. 29 (8): 1004–11.
doi:10.1016/j.psyneuen.2003.10.003. PMID 15219651.
^ Winberg S, Øverli Ø, Lepage O (November 2001). "Suppression of
aggression in rainbow trout (Oncorhynchus mykiss) by dietary
L-tryptophan". The Journal of Experimental Biology. 204 (Pt 22):
3867–76. PMID 11807104.
^ Coplan JD, Mathew SJ, Smith EL, et al. (July 2001). "Effects of
LY354740, a novel glutamatergic metabotropic agonist, on nonhuman
primate hypothalamic–pituitary–adrenal axis and noradrenergic
function". CNS Spectrums. 6 (7): 607–12, 617.
^ Miller GE, Chen E, Zhou ES (January 2007). "If it goes up, must it
come down? Chronic stress and the
hypothalamic–pituitary–adrenocortical axis in humans".
Psychological Bulletin. 133 (1): 25–45.
doi:10.1037/0033-2909.133.1.25. PMID 17201569.
^ Kim JE, Cho BK, Cho DH, Park HJ (July 2013). "Expression of
hypothalamic–pituitary–adrenal axis in common skin diseases:
evidence of its association with stress-related disease activity".
Acta Dermato-venereologica. 93 (4): 387–93.
doi:10.2340/00015555-1557. PMID 23462974.
^ Koehl M, Darnaudéry M, Dulluc J, Van Reeth O, Le Moal M, Maccari S
(September 1999). "
Prenatal stress alters circadian activity of
hypothalamo–pituitary–adrenal axis and hippocampal corticosteroid
receptors in adult rats of both gender". Journal of Neurobiology. 40
^ Weinstock M, Matlina E, Maor GI, Rosen H, McEwen BS (November 1992).
Prenatal stress selectively alters the reactivity of the
hypothalamic-pituitary adrenal system in the female rat". Brain
Research. 595 (2): 195–200. doi:10.1016/0006-8993(92)91049-K.
^ Weinstock M (August 2008). "The long-term behavioural consequences
of prenatal stress" (PDF). Neuroscience and Biobehavioral Reviews. 32
(6): 1073–86. doi:10.1016/j.neubiorev.2008.03.002.
^ Gutteling BM, de Weerth C, Buitelaar JK (December 2004). "Maternal
prenatal stress and 4-6 year old children's salivary cortisol
concentrations pre- and post-vaccination". Stress. 7 (4): 257–60.
doi:10.1080/10253890500044521. PMID 16019591.
^ Buitelaar JK, Huizink AC, Mulder EJ, de Medina PG, Visser GH (2003).
Prenatal stress and cognitive development and temperament in
infants". Neurobiology of Aging. 24 Suppl 1: S53–60; discussion
S67–8. doi:10.1016/S0197-4580(03)00050-2. PMID 12829109.
^ a b Flinn MV, Nepomnaschy PA, Muehlenbein MP, Ponzi D (June 2011).
"Evolutionary functions of early social modulation of
hypothalamic–pituitary–adrenal axis development in humans".
Neuroscience and Biobehavioral Reviews. 35 (7): 1611–29.
doi:10.1016/j.neubiorev.2011.01.005. PMID 21251923.
^ Liu D, Diorio J, Tannenbaum B, et al. (September 1997). "Maternal
care, hippocampal glucocorticoid receptors, and
hypothalamic–pituitary–adrenal responses to stress". Science. 277
(5332): 1659–62. doi:10.1126/science.277.5332.1659.
^ Macrì S, Würbel H (December 2006). "Developmental plasticity of
HPA and fear responses in rats: a critical review of the maternal
mediation hypothesis". Hormones and Behavior. 50 (5): 667–80.
doi:10.1016/j.yhbeh.2006.06.015. PMID 16890940.
^ de Kloet ER, Sibug RM, Helmerhorst FM, Schmidt MV, Schmidt M (April
2005). "Stress, genes and the mechanism of programming the brain for
later life". Neuroscience and Biobehavioral Reviews. 29 (2): 271–81.
doi:10.1016/j.neubiorev.2004.10.008. PMID 15811498.
^ Schechter DS, Moser DA, Paoloni-Giacobino A, Stenz A, Gex-Fabry M,
Aue T, Adouan W, Cordero MI, Suardi F, Manini A, Sancho Rossignol A,
Merminod G, Ansermet F, Dayer AG, Rusconi Serpa S (epub May 29, 2015).
Methylation of NR3C1 is related to maternal PTSD, parenting stress and
maternal medial prefrontal cortical activity in response to child
separation among mothers with histories of violence exposure.
Frontiers in Psychology. [permanent dead link]
^ Heim C.; Newport D. J.; Heit S.; Graham Y. P.; Wilcox M.; Bonsall
R.; Nemeroff C. B. (2000). "Pituitary-adrenal and autonomic responses
to stress in women after sexual and physical abuse in childhood".
JAMA. 284 (5): 592–597. doi:10.1001/jama.284.5.592.
^ a b c Heim C.; Newport D.J.; Bonsall R.; Miller A.H.; Nemeroff C.B.
(2001). "Altered Pituitary-
Adrenal Axis Responses to Provocative
Challenge Tests in Adult Survivors of Childhood Abuse". Am J
Psychiatry. 158 (4): 575–581. doi:10.1176/appi.ajp.158.4.575.
^ Denver RJ (Apr 2009). "Structural and functional evolution of
vertebrate neuroendocrine stress systems". Ann N Y Acad Sci. 1163:
^ a b Oitzl MS, Champagne DL, van der Veen R, de Kloet ER (May 2010).
"Brain development under stress: hypotheses of glucocorticoid actions
revisited". Neurosci Biobehav Rev. 34 (6): 853–66.
doi:10.1016/j.neubiorev.2009.07.006. PMID 19631685.
^ a b Horton TH (Jan 2005). "Fetal origins of developmental
plasticity: animal models of induced life history variation". Am J Hum
Biol. 17 (1): 34–43. doi:10.1002/ajhb.20092.
^ Matthews SG (Mar 2000). "Antenatal glucocorticoids and programming
of the developing CNS". Pediatr Res. 47: 291–300.
doi:10.1203/00006450-200003000-00003. PMID 10709726.
^ a b Champagne FA, Francis DD, Mar A, Meaney MJ (Aug 2003).
"Variations in maternal care in the rat as a mediating influence for
the effects of environment on development". Physiol Behav. 79:
PMID 12954431. CS1 maint: Multiple names: authors list
^ a b c Daskalakis NP, Bagot RC, Parker KJ, Vinkers CH, de Kloet ER
(Sep 2013). "The three-hit concept of vulnerability and resilience:
toward understanding adaptation to early-life adversity outcome".
Psychoneuroendocrinology. 38 (9): 1858–73.
doi:10.1016/j.psyneuen.2013.06.008. PMC 3773020 .
^ a b Roth TL, Matt S, Chen K, Blaze J (Dec 2014). "Bdnf DNA
methylation modifications in the hippocampus and amygdala of male and
female rats exposed to different caregiving environments outside the
homecage". Dev Psychobiol. 56 (8): 1755–63. doi:10.1002/dev.21218.
PMC 4205217 . PMID 24752649.
Media related to HPA axis at Wikimedia Commons
Mind-Body-Health.net page on HPA axis
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