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The HPA axis / stress regulation axis

The HPA axis / stress regulation axis

HPA axis is the short form for Hypothalamic-pituitary-adrenal axis (German abbreviation: HHNA axis). English: hypothalamic-pituitary-adrenal axis (English and common abbreviation: HPA axis).
It is also called stress axis or stress response axis.

1. Basics of the HPA axis - the stress response

1.1. Hypothalamus / pituitary / adrenal cortex network

In addition to the autonomic nervous system and the noradrenergic network (originating from the locus coeruleus), the hypothalamic-pituitary-adrenal (HPA) axis is the body’s major physiological stress response system.1

The HPA axis represents a complex sequence of direct influences, interactions, and feedback loops between three endocrine glands that communicate with each other through various hormones:

  • Hypothalamus
    • Control center of the internal milieu / homeostasis. It regulates2
      • Thyroid function
      • Body temperature
      • Growth
      • Sleep-wake rhythm
      • The internal clock
      • Appetite
      • Saturation
      • Energy balance
      • Body weight
      • Salt and water balance
      • Sex drive
  • Pituitary
    • Pea-shaped structure under the hypothalamus
  • Adrenal cortex
    • Small, conical organs sitting on the kidneys

The HPA axis is the main part of the hormonal system that controls responses to stress. In addition, it regulates many other processes (e.g. digestion, immune system, mood and emotions, sexuality, energy storage and use). It is a mechanism of interactions between glands, hormones, and parts of the midbrain that mediates the General Adaptation Syndrome.3

1.1.1. Hypothalamus (1st stage)

The hypothalamus is involved in the regulation of4

  • Body temperature
  • Appetite and weight
  • Birth
  • Growth
  • Breast milk production
  • Sleep-wake cycle (circadian rhythm)
  • Sex drive
  • Emotions
  • Behavior

Triggers of stress hormone production include limbic, cortical, and other input signals.
The production of various stress hormones by the hypothalamus is activated / enhanced by

  • Dopamine5
    • Activation of the HPA axis by 6 hours of prolonged immobilization stress in rats was decreased by selective D1 and D2 antagonists. In particular, ACTH (pituitary) and corticosterone (adrenal cortex) were decreased.
  • Serotonin67
    • Lesions of the raphe nuclei diminish HPA axis responses to stressors such as immobilization, light stimulation, glutamate administration to the PVN, or stimulation of the dorsal hippocampus or central amygdala.8
  • Acetylcholine7
  • Norepinephrine7
    • Reciprocal (mutual) neuronal connections exist between CRH and noradrenergic locus coeruleus cells. CRH and noradrenaline thereby stimulate each other, primarily by means of noradrenergic α1-receptors.910
      This allows the HPA axis, autonomic nervous system, and cardiovascular system to interact to produce short-term and more sustained stress responses.
  • Histamine11

and inhibited by

  • CRH itself, by means of presynaptic CRH receptors9
    • Norepinephrine, by the way, inhibits itself comparatively by means of noradrenergic α2-receptors910
  • GABA6 and its agonists, such as benzodiazepines or barbiturates11

The paraventricular nucleus of the hypothalamus (Nucleus paraventricularis, PVN)

  • Controls the learning of fear as well as the expression of fear in the lateral central amygdala.12 This is mediated by BDNF (which is decreased in ADHD). Decreased BDNF in the PVN suppressed fear response and fear learning, whereas increased BDNF in the PVN increased fear response learning and caused unconditioned fear responses.
  • The nucleus coeruleus inhibits the dorsal paraventricular hypothalamus by a dopamine increase mediated by it. Stress reduces this inhibition, so that stress disinhibits the PVN. Thus, the nucleus coeruleus regulates the stress sensitivity of the paraventricular hypothalamus.13
  • The PVN receives direct signals from several pathways outside the hypothalamus that regulate homeostatic functions:8
    • Regulation of fluid and electrolyte balance
      • Organum subfornicale (SFO, subfornical organ)
      • Medial preoptic nucleus (mnPOA)
      • Organum vasculosum laminae terminalis (OVLT)
    • Transmission of afferents of the autonomic nervous system and the immune system
      • Norepinephrine
      • Adrenalin
      • Glucagon-like peptide 1 (GLP-1)
      • Somatostatin
      • Substance P
      • Enkephalin
      • Neuropeptidergic neurons in the nucleus tractus solitarii (NTS)
      • Neuropeptidergic neurons in the parabrachial nuclei (PBN)
    • Hypothalamic nuclei (GABAerg, directly to CRH neurons of the PVN; administration of the GABA-A antagonist muscimol into the PVN suppresses the stress response of the HPA axis), which suppress autonomic, metabolic immunological, and arousal signaling, et al
      • Dorsomedial hypothalamus (DMH)

      • Medial preoptic area (mPOA)

        • Medial: GABAerg = stress inhibiting on PVN and thus on HPA axis8
        • Lateral preoptic area = glutamatergic = stimulating on PVN and thus on HPA axis8
        • Medial: possibly mediates the stress-increasing effect of estrogens, whereas testosterone applied to the mesial preoptic area decreases the HPA axis response8
      • Lateral hypothalamus (LHA)

      • Nucleus arcuatus (ARC)

        • This is sensitive to glucose, leptin and insulin and could activate the HPA axis by means of the PVN in case of too low as well as too high energy balance
        • Medial ARC: GABAerg
      • Periventricular nucleus

      • Anterior hypothalamic nucleus (AHN)

      • Ventral corpus mamillare (PMV, ventral mammilar body)

        • Moderates PVN for diseases
        • Reactive as well as anticipatory
        • Is innervated by limbic forebrain structures
    • Nucleus striae terminalis (bed nucleus of the stria terminalis, external amygdala)
      • Mainly GABAerg, thus inhibiting PVN
  • The PVN is addressed by ascending signals from the pons and midbrain, which are relevant to the integration of reflexive stress and are closely associated with the autonomic nervous system8
    • Parabrachial nuclei (part of the pons, in the hindbrain)
      • These mediate
        • Excitation
        • Waking state (glutamaterg)
        • Blood glucose control
        • Thermoregulation
        • Taste
        • Pleasure
    • Periaqueductal gray (part of the tegmentum)
      • Coordinates fear and flight reflexes
      • The ventrolateral periaqeductal gray addresses the medial PVN, which receives c-fos signals at quite a few stressors

GABA and the dorsomedial hypothalamus

  • Has GABAergic and glutamatergic neurons, by means of which it can inhibit or stimulate stress responses in the PVN, depending on which neurons are being targeted.8
  • Shows increased c-fos levels on swimming stress (especially ventrolateral GABAergic neurons).14
  • Sends GABAerg to the medial PVN15
  • Lesions of the ventrolateral dorsomedial hypothalamus increase the stress responses of the HPA axis because of the absence of the inhibitory GABAergic influence on the PVN.1617
  • In contrast, stimulation of GABAergic neurons in the ventrolateral dorsomedial hypothalamus has a stress-inhibitory effect on the PVN.18
  • In contrast, administration of kynurenic acid (a glutamate NMDA receptor antagonist) to the ventrolateral dorsomedial hypothalamus prolongs the cortisol stress response; therefore, glutamate from the ventrolateral dorsomedial hypothalamus is thought to inhibit the HPA axis.8
  • In contrast, glutamate from the dorsal end of the dorsomedial hypothalamus appears to increase ACTH release.19

The hypothalamus then produces the following stress hormones:

1.1.1.1 CRH (corticotropin-releasing hormone)

CRH is also called corticotropin-releasing factor (CRF).

Detailed at CRH.

1.1.1.2. POMC (proopiomelanocortin)
  • POMC activates the generation of further hormones in the pituitary gland, e.g
    • ACTH
    • Lipotropin
  • POMC is a precursor of beta-endorphin
1.1.1.3. Beta-endorphin
  • Is synthesized from POMC
  • Biological equivalent of morphine
  • High binding affinity to M-opioid receptors
  • Significantly lower binding to K-opioid receptors
  • Is inhibited by glucocorticoids (cortisol)10
1.1.1.4. TRH

Also called thyroliberin, thyrotropin releasing hormone or protirelin.

Insufficient production of TRH can cause (tertiary) hypothyroidism (as can disruption of the portal vasculature between the hypothalamus and pituitary gland, so-called Pickardt syndrome.20

Serotonin and adrenaline activate TRH production.

1.1.2. Pituitary (2nd stage): ACTH

If the pituitary gland is stimulated by messenger substances from the hypothalamus, it also produces various hormones.

1.1.2.1. Secretions of the pituitary gland
1.1.2.1.1. ACTH (adrenocorticotropic hormone)

The most important hormone of the pituitary gland is ACTH.
For a comprehensive account of the stress hormone ACTH, which is important in humans in the context of the HPA axis, see ACTH.

ACTH stimulates the release of

  • Cortisol in the adrenal cortex
  • DHEA in the adrenal cortex
1.1.2.1.2. Beta-endorphin
  • Reduces pain sensation
  • Increases body temperature
  • Is inhibited by glucocorticoids (cortisol)10
1.1.2.1.3. TSH, thyroxine stimulating hormone

Hypopituitarism can cause (secondary) hypothyroidism due to deficient TSH production.20

1.1.2.2. Influences on the pituitary gland
1.1.2.2.1. Activating influences on the pituitary gland
  • Glutamate
  • Acetylcholine
  • Dopamine
  • Norepinephrine
    • Especially oxytocin release during birth
  • Adenosine triphosphate (ATP)
  • Cholecystokinin (CCK)
1.1.2.2.2. Inhibitory influences on the pituitary gland
  • GABA
  • Glycine
  • Dopamine
  • Somatostatin
  • Endocannabinoids
    • Especially oxytocin release during birth

1.1.3. Adrenal cortex (3rd stage): Corticoids (including cortisol)

Among other things, the adrenal cortex produces

  • The glucocorticoids
    • Cortisol
    • Corticosterone
  • The mineralocorticoid aldosterol
  • The steroid hormone DHEA
1.1.3.1. Corticosterone

Corticosterone is much less relevant than cortisol in humans.

  • Has an inhibitory effect on the pyramidal cells of the hippocampus
  • Forms an excitation equilibrium with CRH as a counterpole to the latter.21
  • Has only a weak mineralocorticoid and glucocorticoid effect in humans
1.1.3.2. Cortisol

For a comprehensive account of the stress hormone cortisol, which is extremely important in humans in the context of the HPA axis, see Cortisol.

1.2. Changes in the HPA axis by sex and age

1.2.1. Functional differences of the HPA axis by sex

The physiological functioning of the HPA axis is sex-specific.

One study examined cholinergic stimulation of the HPA axis.22
If the nicotinic acetylcholine receptors are inhibited, acetylcholine has a vasopressin-decreasing effect in males and a vasopressin-increasing effect in females. In addition, acetylcholine increases the release of vasopressin and ACTH more in males than in females.

Exam details

Male and female rats were treated 1. with the acetylcholinesterase inhibitor physostigmine.
2. treated first with scopolamine, an antagonist of muscarinic choline receptors, and subsequently with the acetylcholinesterase inhibitor physostigmine.
3. treated first with mecamylamine, an antagonist of nicotinic choline receptors, and subsequently with the acetylcholinesterase inhibitor physostigmine.

An acetylcholinesterase inhibitor inhibits the conversion of acetylcholine to other substances so that more acetylcholine is present. Receptor antagonists inhibit the respective receptors.

Physostigmine causes:

  • Vasopressin increased (significantly more in males than in females)
  • ACTH elevated (significantly more in males than in females)
  • Cortisol elevated (in males as in females; increase in males higher compared to basal level, in females higher absolute level)

Physostigmine with prior scolopamine administration causes:

  • Vasopressin increased (significantly more in males than in females)
  • ACTH elevated (significantly more in males than in females)
  • Cortisol elevated (in both males and females)

Physostigmine with prior mecamylamine administration causes:

  • Vasopressin decreased in males, increased in females
  • ACTH decreased (in males as well as in females)
  • Cortisol decreased (in both males and females)

1.2.2. Cortisol level differences by gender

Cortisol levels differ by gender.

For example, basal cortisol levels appear to be lower in healthy girls than in healthy boys, whereas in disruptive behavior disorder sufferers, basal cortisol levels appear to be lower in boys than in girls.23

1.2.3. HPA axis and age

With age, the activity of the HPA axis increases, showing a higher nocturnal cortisol rise in healthy elderly and a higher cortisol rise in depressed elderly.24252627 This could be caused by a decrease in cortisol feedback controlled by the mineral corticoid receptor (MR).28

1.3. Modes of the HPA axis: day-to-day business and emergency response (stress)

The HPA axis and its secretion of stress hormones, especially cortisol, knows two different modes. One is the diurnal rhythm, also called circadian rhythm, which moderates everyday life, the other is the reaction to expected or occurred stressors, the stress response.

1.3.1. Circadian daily rhythm of the HPA axis

ACTH and cortisol are highest about 20 minutes after waking (CAR, cortisol awakening response). The daytime level then decreases continuously, with a small intermediate peak at midday, until shortly after midnight. Then it slowly rises again to briefly jump after waking.

The high CAR upon awakening causes glucocorticoid receptors to become partially occupied,829 which is important for the function of quite a few systems.30 For example, partial occupancy of hippocampal glucocorticoid receptors is required for efficient performance of learning and memory tasks,3031 which is why it is thought that glucocorticoids may set the tone of information processing in the brain.8 Control of this rhythmic activity is coordinated by contributions from the suprachiasmatic nucleus3031 , the critical pacemaker of numerous body rhythms.
The negative feedback system for resetting the HPA axis interacts with the circadian system.32 Possibly, this could be related to the shift of the circadian rhythm in 75% of ADHD sufferers

1.3.2. Stress responses of the HPA axis

The second mode of the HPA axis is a very intense response with high releases of stress hormones in emergency situations: the stress response to potentially existentially threatening dangers. This section deals primarily with this stress response. It can occur in two variants: as a reaction to actually existing stressors or as an anticipated reaction to feared stressors.8

1.3.2.1. Response to actual stressors

The response to actual stressors is used to cope with potentially life-threatening circumstances that actually exist / have occurred - the stressors.

1.3.2.2. Anticipated response to feared stressors

This response serves as a precautionary measure to adequately counter anticipated stressors.

Triggers for such anticipatory responses of the HPA axis include:8

  • Innate programs
    • Predators
    • Unknown environments/situations
    • Social challenges
    • Species-specific threats (e.g., lighted rooms for rodents, dark rooms for humans)
  • Learned programs
    • Classically conditioned stimuli
    • Contextually conditioned stimuli
    • Negative reinforcement/frustration

According to our hypothesis, ADHD mediates its symptoms via the same neurophysiological mechanisms as chronic stress (dopamine (wirk) deficiency and noradrenaline (wirk) deficiency in dlPFC, striatum, and cerebellum). In this respect, neurophysiologically, ADHD and chronic stress are identical symptoms. ADHD does not require adequate stressors to trigger symptoms.
With this in mind, one might think of an out-of-control (anticipated) stress response of the HPA axis as a possible explanation for ADHD. This thought certainly still involves an HPA axis response to stressors, because even if the HPA axis response is exaggerated, it needs stressors to trigger the response. We suspect a change in the thresholds for the HPA axis response/shutdown as the reason for mediating the ADHD symptoms, so stressors may well still be required to trigger the HPA axis responses (= symptoms). This is consistent with the observation that ADHD sufferers lose their symptoms after a few weeks in an extremely low-stimulus environment (remote mountain hut without internet).

The HPA axis response places a significant burden on the body, consuming significant energy resources.33 This explains why untreated ADHD serves as a precursor to subsequent more severe mental disorders, tripling the risk of anxiety disorders and quadrupling the risk of depression.

The brain generates memory-controlled inhibitory and excitatory pathways to control glucocorticoid responses. For example, memory circuits may reduce responsiveness to contextual stimuli with repeated exposure (habituation) or activate responses to innocuous cues that are actually associated with an emerging threat. The broad spectrum of these responses is controlled by limbic brain regions such as the hippocampus, amygdala, and PFC.8

1.4. Activation, deactivation, and regulation of the HPA axis stress response

1.4.1. Influence of dopamine on the HPA axis

This section is based on “Involvement of dopamine in the regulation of the HPA axis” by Ben-Jonathan.34

Dopamine influences the HPA axis via

  • Hypothalamus
    • In rats, spatial proximity was found between catecholaminergic fibers and CRH neurons within the nucleus paraventricularis of the hypothalamus. The paraventricular nucleus appears to receive selective dopaminergic innervation that likely influences pituitary and adrenal functions via hypothalamic CRH
  • Pituitary
    • More than 75 % of the cells of the human pituitary gland have D2 receptors. This means that not only the approximately 30 % lactotropic and melanotropic pituitary cell cells carry D2 receptors
    • Corticotroph cell clusters of the anterior pituitary lobe show varying numbers of D2 receptors. Corticotropic adenomas are associated with Cushing’s syndrome.In keeping with this
      long-term treatment with dopamine agonists such as cabergoline can effectively control cortisol secretion in 30-40% of patients
    • There have also been reports of joint expression of somatostatin receptors and D2R in corticotropic adenomas
    • In murine pituitary corticotropic cells, 9-cis-retinoic acid induced the number of functional D2 receptors and increased their sensitivity to the dopamine agonist bromocriptine. Combined administration of 9-cis-retinoic acid and bromocriptine decreased POMC levels, ACTH release, and cell viability more efficiently than either alone. This may represent a potential treatment for patients with ACTH-dependent Cushing’s syndrome
      Dopastatin, which can bind to SSTR as well as D2 receptors, showed antisecretory activity in human corticotropic tumors in vitro. Repeated administration of dopastatin in humans increased the amount of highly active dopaminergic metabolites, which eventually blocked the effect of dopastatin. Therefore, further development of dopastatin was stopped.

1.4.2. Activation of the HPA axis

1.4.2.1. Activation of the HPA axis according to brain regions
1.4.2.1.1. Amygdala

The amygdala is the conductor of stress regulation, focusing on the activation of stress systems, as well as the central agency for mediating emotions.

The amygdala receives information from many other areas and is the main region for evaluating this information for its potential danger. The amygdala thus defines whether a situation is harmless (no stress response), a minor challenge (activation of the autonomic nervous system), or potentially dangerous (activation of the HPA axis). Since the amygdala regulates the activity of the HPA axis, an overactivated amygdala, which is especially common in anxiety disorders, leads to an overactivation of the HPA axis.

1.4.2.1.2. Sympathetic nervous system

The sympathetic nervous system (part of the autonomic nervous system consisting of the sympathetic and parasympathetic nervous systems) influences HPA axis activity by modulating the responsiveness of the adrenal cortex to ACTH.353637

1.4.2.1.3. Brainstem

Dopaminergic and noradrenergic pathways from the brainstem stimulate CRH production in the hypothalamus (starting point of the HPA axis).388

1.4.2.1.4. Nucleus solitarius (NTS, nucleus of the tractus solitarius in the medulla oblongata)

The nucleus solitarius regulates the HPA axis via39404142

  • Neuropeptide Y
  • Glucagon-like peptide 1 (GLP-1)
    • For psychological and homeostatic stress
    • GLP-1 is only formed in the NTS
    • GLP-1 receptor antagonists prevent ACTH and corticosterone release in response to stress in open-field rodents.43
      This suggests that GLP-1 is required for an anticipated stress response of the HPA axis.8
  • Inhibin-β
  • Somatostatin
  • Enkephalin and its analogs44
  • Norepinephrine (directly at the paraventricular nucleus of the hypothalamus)8
  • Adrenaline (directly at the paraventricular nucleus of the hypothalamus)8

The nucleus solitarius is also probably involved in the regulation of the parasympathetic nervous system by the nucleus ambiguus and the dorsal motor nucleus of the vagus nerve.39

In addition, the NTS is strongly stimulated by the area postrema, which is thought to have a weakened blood-brain barrier to cytokines (in this case, IL-1-β) and is thought to be at least partially responsible for the activation of the HPA axis by cytokines.845

1.4.2.1.5. Stria terminalis

The anterior part of the bed nucleus of the stria terminalis activates the dorsal part of the parvocellular paraventricular nucleus of the hypothalamus39

The anteroventral nucleus of the stria terminalis activates the dorsal part of the parvocellular paraventricular nucleus of the hypothalamus as well as the paraventricular nucleus of the hypothalamus.39

1.4.2.1.6. Dorsomedial component of the dorsomedial hypothalamus

A dorsomedial component of the dorsomedial hypothalamus activates the dorsal part of the parvocellular paraventricular nucleus of the hypothalamus.39

1.4.2.1.7. Nucleus arquates

The nucleus arquates activates the dorsal part of the parvocellular paraventricular nucleus of the hypothalamus39

1.4.2.1.8. Nucleus tractus solitarii

The nucleus tractus solitarii activates the dorsal part of the parvocellular paraventricular nucleus of the hypothalamus39

1.4.2.1.9. Dorsal raphe nuclei

The dorsal raphe nuclei activate the nucleus paraventricularis of the hypothalamus.39

1.4.2.1.10. Tuberomammillary nucleus of the hypothalamus

The tuberomammillary nucleus of the hypothalamus activates the paraventricular nucleus of the hypothalamus.39

1.4.2.1.11. Supramammillary nucleus

The supramammillary nucleus activates the nucleus paraventricularis of the hypothalamus.39

1.4.2.1.12. Spinal cord

The spinal cord activates the nucleus paraventricularis of the hypothalamus.39

1.4.2.2. Activation of the HPA axis by mechanisms
1.4.2.2.1. Inflammations

In (presumably melancholic and psychotic, but not atypical and bipolar) depression and anorexia, the HPA axis is apparently permanently activated by proinflammatory cytokines from inflammatory processes. In the aforementioned depressions, elevated cortisol blood levels are detectable during the depressive phases.46

1.4.2.2.2. Decreasing glucose level (hypoglycemia)

A falling glucose level (hypoglycemia) also activates the HPA axis.46

1.4.2.3. Activation of the HPA axis according to stress hormones / neurotransmitters
1.4.2.3.1. CRH (hypothalamus)

The formation of CRH is enhanced by

  • Norepinephrine (primarily)47
    • Norepinephrine activates the paraventricular nucleus of the hypothalamus via α1 adrenoceptors, not via beta-adrenergic receptors84849
    • But modulated by other messenger substances8
      • High levels of norepinephrine may have inhibitory effects on ACTH, which is mediated by beta-adrenergic receptors48
      • The effects of norepinephrine on the activity of parvocellular neurosecretory neurons can be blocked with tetrodotoxin or glutamate receptor antagonists, suggesting that norepinephrine effects are mediated by glutamate rather than directly by CRH50
      • One study suggests that stimuli that sensitize HPA stress responses decrease norepinephrine and epinephrine innervation of small cell groups (= parvocellular neurons) in the paraventricular nucleus of the hypothalamus (PVN), suggesting that increased excitability is associated with a decrease in catecholamines in the PVN.51
  • Adrenalin52
  • Neuropeptide Y47
  • Serotonin,5347 by activation of serotonin 2A receptors in the paraventricular nucleus of the hypothalamus5439
  • Acetylcholine47
  • By stress-induced POMC peptides (propiomelanocorticotropins: ß-endorphin, MSH) from the nucleus arcuatus of the hypothalamus47
1.4.2.3.2. ACTH (pituitary gland)

The formation of ACTH is enhanced by

  • CRH (primarily)
    • Norepinephrine (via CRH)52
    • Adrenaline (via CRH)52
  • Vasopressin55
  • Interleukin-2 (IL-2)
  • Tumor Necrosis Factor (TNF)
  • Delta(9)-tetrahydrocannabinol
  • Chronic inhibition of nitric oxide synthase
  • Glucagon-like peptide 1 (GLP-1) injected into the paraventricular nucleus of the hypothalamus (PVN) increases ACTH, but not when injected into amygdala.43

See more at ACTH.

1.4.2.3.3. Cortisol (adrenal cortex)

The effect of cortisol is reduced by cortisol antagonists:

  • FKBP51
    • FKBP51 is a functional antagonist of the glucocorticoid receptor (GR)56
    • The FKBP5 gene polymorphisms rs1360780, rs4713916, and rs3800737 cause increased FKBP51 concentrations in blood and thus an enhanced cortisol response to psychosocial stress. Downregulation of the HPA axis is slowed and remains incomplete for prolonged periods, even with repeated stress exposure. In contrast, the FKBP5 gene polymorphism Bcl1 shows an anticipatory cortisol response to psychosocial stress.57

1.4.3. Deactivation of the HPA axis

This presentation is incomplete and only mentions individual possible approaches.

1.4.3.1. Deactivation of the HPA axis according to brain regions
1.4.3.1.1. PFC

The HPA axis is controlled and regulated by several other parts of the brain. The PFC has inhibitory effects on the HPA axis.38 The PFC is activated by slightly elevated levels of norepinephrine and dopamine and deactivated by very high levels of norepinephrine,5859 60 61 thus eliminating the inhibitory influence on the HPA axis. Similarly, CRH inhibits PFC performance (especially working memory) in a dose-dependent manner. CRH antagonists abolish this effect.6263

The PFC (along with the hippocampus) is capable of controlling cortisol release64. Consequently, blockade of the PFC leads to an uncontrolled cortisol stress response.

1.4.3.1.2. Hippocampus

The hippocampus is also involved in inhibition of the HPA axis.3864

The hippocampus is damaged by prolonged high cortisol levels. Prolonged high cortisol levels thus simultaneously damage the inhibition of the HPA axis exerted by the hippocampus (vicious circle).

Further, there are interactions between the hippocampus and amygdala, which overall affects stress systems.10

When the amygdala is activated by the PFC, it inhibits the PFC and hippocampus, whose inhibitory effects on the HPA axis are thereby attenuated.

1.4.3.1.3. Stria terminalis (pBST)

Posterior subregions of the bed nucleus of the stria terminalis (pBST) inhibit the dorsal part of the parvocellular paraventricular nucleus of the hypothalamus by means of mostly GABAergic influences. This leads to a pronounced inhibition of HPA axis responses in the forebrain,39

1.4.3.1.4. Medial preoptic area (mPOA)

The medial preoptic area (mPOA) inhibits the dorsal part of the parvocellular paraventricular nucleus of the hypothalamus by means of mostly GABAergic influences.39

1.4.3.1.5. Ventrolateral part of the dorsomedial hypothalamus

The ventrolateral part of the dorsomedial hypothalamus inhibits the dorsal part of the parvocellular paraventricular nucleus of the hypothalamus by means of mostly GABAergic influences.39

1.4.3.1.6. Peri-PVN region

Local neurons in the peri-PVN region inhibit the dorsal part of the parvocellular paraventricular nucleus of the hypothalamus by means of mostly GABAergic influences.39

1.4.3.2. Deactivation of the HPA axis according to hormones / neurotransmitters
1.4.3.2.1. Deactivation of the HPA axis by cortisol

Cortisol effect on acute stress: inhibition of the HPA axis.

On prolonged stress, cortisol further enhances HPA axis activity (see above for HPA axis activation).

  • Cortisol inhibits the hypothalamus and pituitary gland after short-term stress, which inhibits the release of CRH and ACTH and thus reduces further cortisol production again (negative feedback of the HPA axis).1656667 This causes a healthy stress system to downregulate again after brief activation.
  • Cortisol
    • Inhibits POMC gene transcription68
    • Lowers the expression of vasopressin68
    • Blocks the stimulatory effects of CRH68
    • Inhibits the expression of CRH receptors in the pituitary gland68
    • Hydrocortisol does not inhibit (within 3 hours) the release of ACTH69
  • Cortisol inhibits the locus coeruleus and thus norepinephrine release in the CNS.
    Norepinephrine is the stress hormone of the CNS. Cortisol inhibits the release of norepinephrine in the PVN (which is primarily fed from the medulla, less so from the locus coeruleus).70 If this inhibition is impaired (by hypocortisolism), the affected individual lacks an important “stress brake.”7167 In contrast, a study in rats found that cortisol increases norepinephrine levels in the locus coeruleus (as well as in the PFC and striatum).72 Thus, a difference lies in the site of origin of norepinephrine. We hypothesize that this contradiction might be further resolved if differentiation is made between different levels of cortisol and different durations of cortisol exposure.
  • In ADHD-I, the cortisol response to acute stress is very often excessive; in ADHD-HI, it is often reduced, which is why the (already damaged) stress system is overloaded (tendency in ADHD-I) or not downregulated again (tendency in ADHD-HI).

This leads to the consideration (thesis) on this side, whether in ADHD-HI sufferers (not: ADHD-I sufferers) a phasic (not: permanent) administration of cortisol (e.g. dexamethasone) could cause a short-term calming and in the medium term a regeneration of the HPA axis.

1.4.3.2.2. Deactivation of the HPA axis by oxytocin

Oxytocin (OXT) is a neuropeptide and acts as a hormone in the body and a neurotransmitter in the brain.

Oxytocinergic pathways lead from the hypothalamus to the forebrain. From there, oxytocin has an inhibitory effect on the amygdala and HPA axis, reducing anxiety and stress.73 Oxytocin and vasopressin promote social affiliation and attachment formation.747576 77. The increase in stress resistance from close social interactions is mediated by increased levels of oxytocin in the paraventricular nucleus of the hypothalamus. An increase in oxytocin there decreases cortisol release in response to acute stress. This potentially opens up the use of oxytocin in stress-induced disorders. . Oxytocin mediates the anxiety-reducing effects of sexual interactions. .7879

In socioemotional dysfunctions such as autism spectrum disorder, borderline personality disorder, anxiety disorders, PTSD, and schizophrenia, social anxiety disorder in particular is caused by disturbances in oxytocin / vasopressin balance in the brain.808182
Oxytocin has an anxiety-inhibiting and antidepressant effect, whereas vasopressin promotes anxiety and depressive behavior.83 Oxytocin inhibits social anxiety in particular.82 Social phobias may be the result of downregulation of oxytocin receptors due to prolonged treatment with oxytocin.82

Oxytocin reduces ACTH formation.8485

Singing in a choir also increased oxytocin levels in contrast to singing alone, while both types of singing increased well-being and decreased cortisol levels. It seems that it is not so much the activity of singing that increases oxytocin levels as the stress- and arousal-reducing experience of singing together.86

As a result, social contact and trusting tenderness are stress inhibitors by increasing oxytocin levels.

1.4.3.2.3. Deactivation of the HPA axis by melatonin

Melatonin is a hormone.
A study in rats that had mental stress induced by atopic dermatitis (neurodermatitis) found evidence that high-dose melatonin (20 mg / kg) could equalize the stress effect on the HPA axis, the autonomic nervous system, and the stress-induced changes in dopamine and norepinephrine levels, and as a result eliminated ADHD symptomatology.72 In humans, melatonin is given in dosages of 1 to 5 mg total (rather than per kg), so the amount used in the study was several hundred times the dosage commonly used in humans. Therefore, for the time being, a use of melatonin as a stress-buster is not foreseeable.
Nevertheless, it would be worthwhile to investigate the question of stress reduction by melatonin in more detail.

Melatonin reduces the effects of cortisol in relation to dopamine and norepinephrine:

Melatonin effect on dopamine:
Cortisol decreased dopamine levels in the locus coeruleus, PFC, and striatum.
20 mg/kg melatonin counteracted dopamine reduction by cortisol in all three brain areas.72

Melatonin effect on norepinephrine:
Cortisol increased norepinephrine levels in the locus coeruleus, PFC, and striatum.
20 mg/kg melatonin counteracted noradrenaline elevation by cortisol in all three brain areas.72

In ADHD sufferers as in people with sleep problems, the evening rise of melatonin is delayed.87 In children between 6 and 12 years of age with ADHD and sleep problems, sleep onset was delayed by 50 minutes, which corresponded to the delay in melatonin rise. Otherwise, sleep did not differ significantly.
Since in everyday life the start of school is the same for all children, this explains that ADHD sufferers with sleep problems have considerably greater difficulties in everyday life.

The nocturnal melatonin rise correlates with the nocturnal depletion of cortisol88 and occurs later in children than in the elderly. In addition, the timing of sleep shifts forward in the elderly relative to the timing of the evening melatonin rise.89

Elevated serum melatonin levels have been found in ADHD.90

1.4.3.2.4. Deactivation of the HPA axis by endocannabinoids

Endocannabinoids significantly inhibit the HPA axis.91 In addition, they slightly inhibit the release of

  • Norepinephrine
  • Glutamate
  • GABA
  • Acetylcholine
  • Serotonin
1.4.3.2.5. Deactivation of the HPA axis by endogenous opiates

Endogenous opiates cause:92

  • Reduction in tonic excitatory activity (triggered by norepinephrine and CRH)
  • high phasic activity
  • Initation of recreation
  • reduced sensation of pain

Repeated social stress releases high levels of endogenous opiates. These bind to the opiate receptor. With simultaneous administration of the opiate receptor antagonist naxolone, psychosocial stress can therefore trigger withdrawal symptoms.92

1.4.3.2.6. Deactivation of the HPA axis by endogenous morphines

Endogenous morphines are largely controlled by dopamine. Their effect depends strongly on the current situation:93
When excitation is present, there is a conversion of dopamine to norepinephrine to epinephrine resulting in increased alertness, wakefulness, and energy
When relaxation is induced, inhibition of the locus coeruleus and sympatho-medullary stress axis occurs, as well as inhibition of norepinephrine and increase of dopamine by inhibition of dopamine beta-hydroxylase, which inhibits the conversion of dopamine to norepinephrine, leaving more dopamine.

1.4.3.2.7. Deactivation of the HPA axis by neuropeptides

Neuropeptide-Y inhibits the stress response in part by inhibiting CRH action.92

1.4.3.3. Deactivating effect on stress hormones
1.4.3.3.1. CRH

Education is mitigated by

  • Autoregulatory noradrenergic and autoregulatory CRH neurons via presynaptic CRH1 and α2 receptors, respectively47
  • GABA (gamma-aminobutyric acid)47
  • Substance P activated primarily via peripheral afferents47
    • Inhibits stress-induced activation of the HPA axis9495 via neurokinin-1 receptors96
  • Cortisol
1.4.3.3.2. ACTH

Education is mitigated by

  • Cortisol
  • Oxytocin
1.4.3.3.3. Cortisol

Education is mitigated by

  • Oxytocin

1.5. Prevention of HPA axis activation

This presentation is incomplete and only mentions individual possible approaches.

1.5.1. Sport is stress preventive

Trained men showed on psychological stressors (TSST) compared to untrained men97

  • Significantly lower cortisol response (with somewhat lower basal cortisol levels)
  • Significantly lower heart rate increase
  • Significantly higher calmness, better mood, and tended to have lower anxiety responses to mental stress exposure

1.5.2. Massages are stress preventive

Massage therapy causes a 31% decrease in cortisol response to stress and an increase in dopamine and serotonin of about 30%.98

It is likely that this is mediated primarily by the release of oxytocin.

1.5.3. Singing (especially in choir) could be stress preventive

The stress-reducing effect of singing in a choir, which (unlike singing alone) causes an increase in oxytocin and thus a reduction in cortisol, could also have a stress-preventive character. Solo singing does not reduce oxytocin levels, but it does reduce cortisol levels.86

1.5.4. Social support is stress preventive

Subjects who were accompanied by a friend before and during TSST had decreased cortisol levels as a stress response.99

1.5.5. Oxytocin is stress preventive

Subjects who received oxytocin as a nasal spray prior to TSST had lower stress and anxiety levels. The highest reduction in anxiety and cortisol response occurred with a combination of companionship by a friend and oxytocin administration.99

Further approaches, such as mindfulness training, which is particularly recommended, can be found at ADHD - Treatment and Therapy.

2. Changes of the HPA axis due to chronic stress

Chronic stress causes typical changes in the HPA axis.
In the following representations, it must be remembered that they are only representations of momentary states. Chronic stress, however, is characterized by a temporal change component - like any state caused by a long-lasting increased or decreased level of certain neurotransmitters, hormones, peptides or other substances binding to receptors. Long-lasting changes in levels of such substances can trigger receptor and transporter downregulation or upregulation. Prolonged administration of substances can deactivate brain areas previously responsible for the production of these substances.
Depending on the duration of the stress, the consequences presented can therefore be amplified or reversed.

2.1. Changes in CRH due to chronic stress

  • Is elevated in the paraventricular nucleus (PVN) of the hypothalamus100101102
  • Increased number of CRH-immunoreactive cells expressing arginine vasopressin in the PVN103104105
  • CRH receptors in the pituitary gland reduced106

2.2. Changes in vasopressin due to chronic stress

Vasopressin is increased by chronic stress.100

2.3. Changes in proopiomelanocortin due to chronic stress

Proopiomelanocortin is increased in the pituitary gland by chronic stress.107

2.4. Changes in ACTH due to chronic stress

  • ACTH elevated in the pituitary gland107108109
  • ACTH response to CRH increased110111
  • Basal blood ACTH levels unchanged112113114

2.5. Changes in cortisol due to chronic stress

  • Cortisol response to ACTH increased112115
  • Basal blood cortisol levels elevated (see under hypercortisolism)
  • Glucocorticoid receptors (GRs) in hippocampus reduced by downregulation116117
    • Thereby reduced shutdown of the HPA axis by cortisol (feedback loop disturbed)118119
  • GR mRNA reduced100120
  • Mineralocorticoid receptor (MR) mRNA levels decreased120
  • Activation of central neurotransmitter systems67121122
  • Enhancement of HPA axis activity.67121122
  • Cortisol increases mRNA expression of CRH in the central amygdala.123
  • Cortisol increases the success of pleasurable or compulsive activities (ingestion of sucrose, fat and drugs, or cycling races). This motivates the intake of “comfort food”.123
  • Cortisol systemically increases fat deposits in the abdomen. This causes123
    • An inhibition of catecholamines in the brainstem
    • An inhibition of CRH expression in the hypothalamus
  • While chronic stress and high glucocorticoids increase body weight gain in rats, in humans it causes either increased food intake and weight gain or decreased food intake and weight loss.123124
  • A significant increase in cortisol in response to acute stress is associated with deactivation of the limbic system.125

3. Overactivated and underactivated HPA axis

Overactivity of the HPA axis, especially CRH excess, correlates with:126

  • Chronic stress
  • Cushing’s syndrome
  • Melancholic depression
  • Anxiety
  • Panic disorder
  • Posttraumatic stress in children
  • Obsessive-compulsive
  • Excessive sports (sports addiction)
  • Chronic, active alcoholism
  • Alcohol and narcotic withdrawal
  • Diabetes mellitus
  • Post-traumatic stress disorder in children
  • Hyperthyroidism
  • Pregnancy
  • Hypothalamic oligomenorrhea and amenorrhea
  • Reduced fertility
  • Eating disorders
    • Anorexia nervosa (Anorexia)
    • Obesity
    • Metabolic syndrome
      • Abdominal obesity
      • Hypertension
      • Lipid metabolism disorder with hypertriglyceridemia and lowered HDL cholesterol
      • Insulin resistance
  • Essential hypertension

Underactivity of the HPA axis, especially CRH deficiency, correlates with:126

  • Adrenal insufficiency
  • Atypical/seasonal depression
  • Chronic fatigue syndrome / fatigue
  • Fibromyalgia
  • Premenstrual tension syndrome
  • Climacteric depression
  • Nicotine withdrawal
  • Glucocorticoid discontinuation/withdrawal sequelae
  • After healing of the Cushing’s syndrome
  • After chronic stress
  • Postpartum period
  • Post-traumatic stress disorder in adults
  • Hypothyroidism
  • Rheumatoid arthritis
  • Allergies
    • Asthma
    • Eczema

4. Hypercortisolism and hypocortisolism

The HPA axis can misrespond in two ways when it is permanently overactivated - it results in

  • Hypercortisolism (75 % - 80 %)
    or
  • Hypocortisolism. (20 % - 25 %)

Hypercortisolism is an excess of the stress hormones cortisol, ACTH, or CRH
Hypocortisolism, on the other hand, is a deficiency in the quantity or effect of the stress hormones cortisol, ACTH, or CRH on the HPA axis.127

4.1. Hypercortisolism

Hypercortisolism is too much cortisol, ACTH, or CRH, or an excess of action of these substances on the receptor side.

4.1.1. Hypercortisolism spectrum disorders

Source128

  • Depression
    • Melancholic depression
    • Psychotic depression
    • Depression pain primarily in the morning, when cortisol levels are relatively highest (corresponding to the excessive cortisol stress response)
    • Not: atypical depression
    • Not: bipolar depression
  • Anxiety disorder
  • Anorexia
  • Obsessive Compulsive Disorder
  • Panic disorder
  • Alcoholism
    Excessive alcohol consumption alters the HPA axis,129 with changes already occurring at the CRH and ACTH levels of the HPA axis in the form of decreased hormone response levels.130
  • Metabolic syndrome
    • Abdominal obesity
    • Hypertension
    • Dyslipidemia
      • Hypertriglyceridemia
        • Dyslipidemia with elevated triacylglyceride blood levels above 2 mmol/l (180 mg/dl)
      • Reduced HDL cholesterol
    • Insulin resistance or impaired glucose tolerance (increased glucose concentration in the blood)
      Main cause of diabetes mellitus type 2 (adult-onset diabetes)
  • Immune system: TH1/TH2 shift
    • Cortisol inhibits CRH-triggered inflammation (less TH1)
      • Thereby reduced susceptibility to inflammation 131
    • Cortisol increases foreign body fighting (more TH2)
      • Thereby increased risk of allergies132

4.2. Hypocortisolism

Hypocortisolism is an insufficient level of cortisol, ACTH, or CRH, or a receptor-side lack of action of these substances.

4.2.1. Triggers of hypocortisolism

4.2.1.1. Genes and environment
  • Genetic causes (e.g., certain FKBP gene polymorphisms)
  • Chronic psychological stress
  • Psychological trauma (e.g. abuse, maltreatment, war victims)
  • Intense physical stress (e.g. infectious diseases)
  • Physical trauma (e.g. traffic accident)
4.2.1.2. Neurophysiological mechanisms
  • Decreased secretion of CRH or ACTH or cortisol133
  • Excessive release of CRH, ACTH, or cortisol with subsequent down-regulation of target receptors
    subsequently reduced sensitivity to negative feedback from hormones
  • Decreased availability of free cortisol
  • Cortisol resistance of target cells133

4.2.2. Possible symptoms of hypocortisolism

Symptoms differ depending on the level at which the hypocortisolism has manifested.133

  • Pain
    • Pain sensitivity133
      • Fibromyalgia134
      • Chronic lower abdominal pain134
    • Feeling sick133
  • Fatigue
    • Chronic Fatigue Syndrome
    • Burnout
    • Hypersomnia (insomnia, daytime sleepiness)
  • Lethargy
  • Hyperphagia
    • Eating disorder
    • Overeating even without feeling hungry
  • Depression
    • Atypical depression133134
      possibly caused by CRF receptor deficiency
      Symptoms occur especially in the 2nd half of the day when cortisol levels are low (corresponding to cortisol stress response weakness)
    • Bipolar Depression
  • Stress intolerance
    • Irritability133
    • High sensitivity133
      • Noise
      • Temperatures
      • Light
      • Movement (also: too many people)
    • Post-traumatic stress disorder
      • Intrusions in PTSD133
        Decreased CRF and norepinephrine activity
    • Anxiety133
  • Increased cardiovascular reactivity133
  • Lack of inhibition of inflammation increased by CRH
    • Result: inflammatory problems132 / chronic inflammatory processes131135
      • Neurodermatitis136
      • Uninhibited activation of NF-kappa B131
      • Autoimmune diseases131135
      • Fibromyalgia (?)
      • Inflammatory bowel disease
      • Asthma
        • Chronic inflammation of the respiratory tract

Cortisol has an inhibitory (depressant) effect on the hypothalamus, among others, and thereby reduces CRH release. Since CRH activates the locus coeruleus and thus increases its norepinephrine release, cortisol indirectly causes a reduction in the norepinephrine level (which is typically highly elevated due to the preceding stress reaction).137138
Further, cortisol has a calming effect on the pituitary gland (which reduces ACTH release).
Cortisol thus overall slows the activation of the HPA axis and the production of further cortisol.
Cortisol is thus a kind of “stress brake” in the central nervous system.
This stress brake is impaired in hypocortisolism due to the cortisol response to stress being too low.133

4.3. Example: Traumas

During traumatic experiences, the brain functions that are required for reactions essential for survival under stress are literally overloaded to such an extent that they collapse. The massive overload of cortisol causes previous processes, which have apparently proved insufficient to ensure survival, to be more easily deleted in order to be replaced by new (more functional) processes.139

5. Measurement of the HPA axis

There are quite a few endocrine stimulation and suppression tests that can be used to measure whether the HPA axis is functioning cleanly.

See more at Pharmacological endocrine function tests.

Related topics:

Cortisol in ADHD Cortisol in other disorders The autonomic nervous system: sympathetic / parasympathetic nervous systemThe amygdala - the stress conductor


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