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The HPA axis / stress regulation axis

The HPA axis / stress regulation axis

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

Activation and inhibition of the HPA axis occur via different mechanisms:

  • Activation
    • Psychological stress: Emotional or cognitive stress such as fear, anger or worry can activate the HPA axis. The amygdala in particular acts as a stress sensor and sends signals to the hypothalamus.
    • Physical stress: Physical stress such as injuries, inflammation or infections can stimulate the HPA axis. Cytokines that are released during inflammatory processes can increase the activity of the HPA axis. The solitary nucleus in the brain stem plays an important role here.
  • Escapement
    • Negative feedback: The activity of the HPA axis is inhibited by the most recently released stress hormone cortisol. If the release of cortisol is high enough, the HPA axis is deactivated via glucocorticoid receptors.
  • Regulation
    • Neurotransmitters: Various neurotransmitters can influence the HPA axis. Dopamine, serotonin, noradrenaline and acetylcholine stimulate the activity of the HPA axis, while GABA, glycine, somatostatin and endocannabinoids have an inhibitory effect. These neurotransmitters interact primarily in the hypothalamus and pituitary gland.
    • Hormones: Hormones such as CRH, ACTH and cortisol play a central role in the activation and regulation of the HPA axis. CRH is produced in the hypothalamus and stimulates the release of ACTH in the pituitary gland. ACTH in turn stimulates the production of cortisol in the adrenal cortex.
    • Changes with age and gender: The activity of the HPA axis can change with age and gender. The activity of the HPA axis is often increased in older people and in women. There are also gender-specific differences in hormone production and the reaction of the HPA axis.

Chronic stress can lead to changes in the HPA axis, such as increased production of CRH and vasopressin or reduced sensitivity of target receptors for cortisol.

In mental illnesses such as depression, anxiety disorders and anorexia, the HPA axis is usually permanently activated.
Hypercortisolism, an excessively high level of stress hormones, is associated with various mental and physical illnesses, such as depression, anxiety disorders and metabolic syndrome.

Underactivity of the HPA axis, in particular a lack of CRH, correlates with diseases such as adrenal insufficiency and chronic fatigue syndrome.
Hypocortisolism, an excessively low level of stress hormones, can be caused by genetic factors, chronic stress or physical trauma and is associated with the aforementioned disorders of HPA axis underactivation.

The function of the HPA axis can be measured with endocrine stimulation and suppression tests.

SHR, the most commonly used animal model for ADHD, suffers from a permanently overactivated HPA axis. Dexamethasone, a glucocorticoid receptor agonist, shuts down the HPA axis and eliminates the high blood pressure and ADHD symptoms of SHR.

1. Basics of the HPA axis - the stress response

1.1. Hypothalamus / pituitary / adrenal cortex network

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

The HPA axis is 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 gland
    • Pea-shaped structure under the hypothalamus
  • Adrenal cortex
    • Small, conical organs that sit on the kidneys

The HPA axis is the main part of the hormonal system that controls reactions to stress. It also regulates many other processes (e.g. digestion, immune system, mood and emotions, sexuality, energy storage and utilization). 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

Stress hormone production is triggered by 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 reduced by selective D1 and D2 antagonists. In particular, ACTH (pituitary gland) and corticosterone (adrenal cortex) were reduced.
  • Serotonin67
    • Lesions of the raphe nuclei reduce the responses of the HPA axis to stressors such as immobilization, light stimulation, glutamate administration to the PVN or stimulation of the dorsal hippocampus or central amygdala.8
  • Acetylcholine7
  • Noradrenaline7
    • There are reciprocal (mutual) neuronal connections between CRH and noradrenergic locus coeruleus cells. CRH and noradrenaline thus stimulate each other, primarily via noradrenergic α1 receptors.910
      This enables the interaction of the HPA axis, the autonomic nervous system and the cardiovascular system to generate short-term and more sustainable stress reactions.
  • Histamine11

and inhibited by

  • CRH itself, via presynaptic CRH receptors9
    • Noradrenaline also inhibits itself comparatively via 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 and the expression of fear in the lateral central amygdala.12 This is mediated by BDNF (which is reduced in ADHD). Decreased BDNF in the PVN suppressed fear response and fear learning, while increased BDNF in the PVN increased fear response learning and caused unconditioned fear responses.
  • The nucleus coeruleus inhibits the dorsal paraventricular hypothalamus through a dopamine increase mediated by it. Stress reduces this inhibition, so that stress disinhibits the PVN. The nucleus coeruleus thus regulates the stress sensitivity of the paraventricular hypothalamus.13
  • The PVN receives direct signals from several pathways outside the hypothalamus that regulate homeostatic functions8
    • 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
      • Noradrenaline
      • 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 (GABAergic, directly on 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 signals, among others.
      • 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, while testosterone applied to the mesial preoptic area reduces the HPA axis response8
      • Lateral hypothalamus (LHA)

      • Arcuate nucleus (ARC)

        • This is sensitive to glucose, leptin and insulin and could activate the HPA axis via the PVN if the energy balance is too low or too high
        • Medial ARC: GABAerg
      • Periventricular nucleus

      • Anterior hypothalamic nucleus (AHN)

      • Ventral corpus mamillare (PMV, ventral mammary body)

        • Moderates PVN in case of illness
        • Reactive and anticipatory
        • Is innervated by limbic forebrain structures
    • Nucleus striae terminalis (bed nucleus of the stria terminalis, external amygdala)
      • Primarily GABAergic, therefore inhibitory to PVN
  • The PVN is addressed by ascending signals from the pons and midbrain, which are relevant for the integration of reflexive stress and are closely connected to the autonomic nervous system8
    • Parabrachial nuclei (part of the pons, in the hindbrain)
      • Convey these
        • Arousal
        • Waking state (glutamatergic)
        • Blood sugar control
        • Thermoregulation
        • Flavor
        • Pleasure
    • Periaqueductal gray (part of the tegmentum)
      • Coordinates fear and flight reflexes
      • The ventrolateral periaqueductal gray addresses the medial PVN, which receives c-FOS signals from a number of stressors

GABA and the dorsomedial hypothalamus

  • Has GABAergic and glutamatergic neurons, by means of which it can inhibit or stimulate the stress reactions in the PVN, depending on which neurons are addressed.8
  • Shows increased c-fos values in response to swimming stress (especially ventrolateral GABAergic neurons).14
  • Sends GABAerg to the medial PVN15
  • Lesions of the ventrolateral dorsomedial hypothalamus increase the stress reactions of the HPA axis, as the inhibitory GABAergic influence on the PVN is no longer present.1617
  • Stimulation of GABAergic neurons in the ventrolateral dorsomedial hypothalamus, on the other hand, has a stress-inhibiting effect on the PVN.18
  • In contrast, the administration of kynurenic acid (a glutamate NMDA receptor antagonist) into the ventrolateral dorsomedial hypothalamus prolongs the cortisol stress response, which is why it is assumed that glutamate from the ventrolateral dorsomedial hypothalamus inhibits the HPA axis.8
  • Glutamate from the dorsal end of the dorsomedial hypothalamus, on the other hand, 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 known as corticotropin-releasing factor (CRF).

Detailed presentation at CRH.

1.1.1.2. POMC (proopiomelanocortin)
  • POMC activates the generation of other 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 thyreoliberin, thyrotropin releasing hormone or protirelin.

Insufficient production of TRH can trigger (tertiary) hypothyroidism (as well as an interruption of the portal vascular system between the hypothalamus and pituitary gland, so-called Pickardt’s syndrome).20

Serotonin and adrenaline activate TRH production.

1.1.2. Pituitary gland (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.
A comprehensive description of the stress hormone ACTH, which is important in humans as part of the HPA axis, can be found at ACTH ACTH.

ACTH stimulates the release of

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

Hypofunction of the pituitary gland can cause (secondary) hypothyroidism due to a lack of 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
  • Noradrenaline
    • In particular oxytocin release during birth
  • Adenosine triphosphate (ATP)
  • Cholecystokinin (CCK)
1.1.2.2.2. Inhibiting influences on the pituitary gland
  • GABA
  • Glycine
  • Dopamine
  • Somatostatin
  • Endocannabinoids
    • In particular oxytocin release during birth

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

Among other things, the adrenal cortex forms

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

Corticosterone is much less relevant in humans than cortisol.

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

A comprehensive description of the stress hormone cortisol, which is extremely important in humans as part of the HPA axis, can be found at Cortisol.

1.2. Changes in the HPA axis by gender and age

1.2.1. Functional differences of the HPA axis by gender

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

One study investigated the 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 strongly in males than in females.

Examination details

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

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

Physostigmine has the same effect:

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

Physostigmine with prior administration of scolopamine:

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

Physostigmine with prior administration of mecamylamine:

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

1.2.2. Cortisol value differences according to gender

Cortisol levels differ according to gender.

For example, basal cortisol levels appear to be lower in healthy girls than in healthy boys, while 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 increasing age, the activity of the HPA axis increases, showing a higher nocturnal cortisol increase in healthy older people and a higher cortisol increase in depressed older people.24252627 This could be caused by a decrease in cortisol feedback controlled by the mineralocorticoid 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, in particular cortisol, has two different modes. One is the daily rhythm, also known as the circadian rhythm, which moderates everyday life, the other is the reaction to expected or actual stressors, the stress response.

1.3.1. Circadian rhythm of the HPA axis

ACTH and cortisol are at their highest around 20 minutes after waking up (CAR, cortisol awakening response). The daytime level then decreases continuously, with a small peak at midday, until shortly after midnight. It then slowly rises again, only to increase sharply after waking up.

The high CAR after waking up causes the glucocorticoid receptors to be partially occupied,829 which is important for the function of several systems.30 For example, partial occupancy of the hippocampal glucocorticoid receptors is required for efficient performance of learning and memory tasks,3031 which is why it is assumed that glucocorticoids can determine the tone of information processing in the brain.8 The 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 It is possible that this could be linked to the shift in the circadian rhythm in 75% of ADHD sufferers.

1.3.2. Stress reactions of the HPA axis

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

1.3.2.1. Reaction to actual stressors

The reaction to actual stressors serves the purpose of coping with potentially life-threatening circumstances that actually exist or have occurred - the stressors.

1.3.2.2. Anticipated reaction to feared stressors

This reaction serves as a precautionary measure to adequately counter expected stressors.

Triggers for such anticipatory reactions of the HPA axis are mentioned:8

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

According to our hypothesis, ADHD mediates its symptoms via the same neurophysiological mechanisms as chronic stress (dopamine (active) deficiency and noradrenaline (active) deficiency in the dlPFC, striatum and cerebellum). In this respect, ADHD and chronic stress are neurophysiologically identical symptoms. ADHD does not require adequate stressors to trigger the symptoms.
Against this background, one could think of an out-of-control (anticipated) stress response of the HPA axis as a possible explanation for ADHD. This idea still includes a reaction of the HPA axis to stressors, because even if the reaction of the HPA axis is excessive, it needs stressors to trigger the reaction. We suspect a change in the threshold values for the response / deactivation of the HPA axis as the reason for the mediation of ADHD symptoms, so that stressors are still required to trigger the reactions of the HPA axis (= 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 with no internet).

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

The brain can generate memory-driven inhibitory and excitatory pathways to control glucocorticoid responses. For example, memory circuitry can 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. Influencing the HPA axis through dopamine

This section is based on the section “Involvement of dopamine in the regulation of the HPA axis” by Ben-Jonathan34

Dopamine influences the HPA axis via

  • Hypothalamus
    • In rats, a spatial proximity was found between catecholaminergic fibers and CRH neurons within the paraventricular nucleus of the hypothalamus. The paraventricular nucleus appears to receive selective dopaminergic innervation, which probably influences pituitary and adrenal functions via hypothalamic CRH.
  • Pituitary gland
    • More than 75 % of the cells of the human pituitary gland have D2 receptors. This means that it is not only the approximately 30 % of lactotropic and melanotropic pituitary cells that carry D2 receptors.
    • Corticotropic cell clusters of the anterior pituitary lobe show different numbers of D2 receptors. Corticotropic adenomas are associated with Cushing’s syndrome
      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 co-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 both SSTR and 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. The further development of dopastatin was therefore stopped.

1.4.2. Activation of the HPA axis

1.4.2.1. Activation of the HPA axis by brain region
1.4.2.1.1. Amygdala

The amygdala is the conductor of stress regulation, whereby the activation of the stress systems is in the foreground, as well as the central instance for the mediation of 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 reaction), a minor challenge (activation of the autonomic nervous system) or a potential danger (activation of the HPA axis). As the amygdala regulates the activity of the HPA axis, an overactivated amygdala, which is particularly 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. Brain stem

Dopaminergic and noradrenergic pathways from the brain stem 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 by means of39404142

  • 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 rodents in the open field.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
  • Noradrenaline (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 said to have a weakened blood-brain barrier for cytokines (here: IL-1-β) and is 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 paraventricular nucleus 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 paraventricular nucleus of the hypothalamus.39

1.4.2.1.12. Spinal cord

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

1.4.2.2. Activation of the HPA axis by mechanism
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, increased cortisol blood levels can be detected during the depressive phases.46

Conversely, corticosteroids inhibit the production of cytokines.47 In this way, the immune system regulates inflammation (via cytokines) and the HPA axis (via glucocorticoids) mutually and form a cycle to maintain homeostasis.

1.4.2.2.2. Falling glucose levels (hypoglycemia)

A drop in glucose levels (hypoglycemia) also activates the HPA axis.46

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

The formation of CRH is enhanced by

  • Noradrenaline (primarily)48
    • Noradrenaline activates the paraventricular nucleus of the hypothalamus via α1 adrenoceptors, not via beta-adrenergic receptors84950
    • But modulated by other messenger substances8
      • High noradrenaline levels can have inhibitory effects on ACTH, which is mediated by beta-adrenergic receptors49
      • The effects of noradrenaline on the activity of parvocellular neurosecretory neurons can be blocked with tetrodotoxin or glutamate receptor antagonists, suggesting that noradrenaline effects are mediated by glutamate rather than directly by CRH51
      • One study suggests that stimuli that sensitize HPA stress responses reduce noradrenaline and adrenaline innervation of the 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.52
  • Adrenalin53
  • Neuropeptide Y48
  • Serotonin,5448 through activation of serotonin 2A receptors in the paraventricular nucleus of the hypothalamus5539
  • Acetylcholine48
  • By stress-induced POMC peptides (propiomelanocorticotropins: ß-endorphin, MSH) from the arcuate nucleus of the hypothalamus48
1.4.2.3.2. ACTH (pituitary gland)

The formation of ACTH is increased by

  • CRH (primarily)
    • Noradrenaline (via CRH)53
    • Adrenaline (via CRH)53
  • Vasopressin56
  • 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 the amygdala.43

Find out 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)57
    • The FKBP5 gene polymorphisms rs1360780, rs4713916 and rs3800737 cause increased FKBP51 concentrations in the blood and thus an increased cortisol response to psychosocial stress. The downregulation of the HPA axis is slowed and remains incomplete for a long time, even with repeated exposure to stress. In contrast, the FKBP5 gene polymorphism Bcl1 shows an anticipatory cortisol response to psychosocial stress.58

1.4.3. Deactivation of the HPA axis

This description is incomplete and only mentions individual possible approaches.

1.4.3.1. Deactivation of the HPA axis by brain region
1.4.3.1.1. PFC

The HPA axis is controlled and regulated by various other parts of the brain. The PFC has an inhibitory effect on the HPA axis.38 The PFC is activated by slightly elevated noradrenaline and dopamine levels and deactivated by very high noradrenaline levels,5960 61 62 which eliminates the inhibitory influence on the HPA axis. CRH also inhibits the performance of the PFC (especially working memory) in a dose-dependent manner. CRH antagonists neutralize this effect.6364

The PFC (along with the hippocampus) is able to control the release of cortisol65. Consequently, a blockade of the PFC leads to an uncontrolled cortisol stress response.

1.4.3.1.2. Hippocampus

The hippocampus is also involved in the inhibition of the HPA axis.3865

The hippocampus is damaged by persistently high cortisol levels. Prolonged high cortisol levels therefore also damage the inhibition of the HPA axis, which the hippocampus exerts (vicious circle).

There are also interactions between the hippocampus and the amygdala, which influences the stress systems as a whole.10

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

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 the HPA axis reactions 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 after hormones / neurotransmitters
1.4.3.2.1. Deactivation of the HPA axis by cortisol

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

In response to prolonged stress, cortisol further increases the activity of the HPA axis (see above on activation of the HPA axis).

  • 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 (negative feedback of the HPA axis).1666768 As a result, a healthy stress system is regulated down again after brief activation.
  • Cortisol
    • Inhibits POMC gene transcription69
    • Lowers the expression of vasopressin69
    • Blocks the stimulatory effects of CRH69
    • Inhibits the expression of CRH receptors in the pituitary gland69
    • Hydrocortisol does not inhibit the release of ACTH (within 3 hours)70
  • Cortisol inhibits the locus coeruleus and thus the release of noradrenaline in the CNS.
    Noradrenaline is the stress hormone of the CNS. Cortisol inhibits the release of noradrenaline in the PVN (which is primarily secreted from the medulla, less so from the locus coeruleus).71 If this inhibition is restricted (due to hypocortisolism), the affected person lacks an important “stress brake”.7268 In contrast, a study on rats found that cortisol increases the noradrenaline level in the locus coeruleus (as well as in the PFC and in the striatum).73 A difference therefore lies in the site of origin of noradrenaline. We hypothesize that this contradiction could possibly be further resolved by differentiating 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 is not regulated down again (tendency in ADHD-HI).

This leads us to consider (thesis) whether a phasic (not: permanent) administration of cortisol (e.g. dexamethasone) could bring about a short-term calming and medium-term regeneration of the HPA axis in ADHD-HI and ADHD-C sufferers (not: ADHD-I sufferers).

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 as 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, thereby reducing anxiety and stress.74 Oxytocin and vasopressin promote social affiliation and bonding.757677 78. The increase in stress resistance through close social interactions is mediated by an increased oxytocin level in the paraventricular nucleus of the hypothalamus. An increase in oxytocin there reduces the release of cortisol in response to acute stress. This may open up the use of oxytocin in stress-induced disorders. . Oxytocin mediates the anxiety-reducing effect of sexual interactions. .7980

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 the oxytocin / vasopressin balance in the brain.818283
Oxytocin has an anxiety-inhibiting and antidepressant effect, while vasopressin promotes anxiety and depressive behavior.84 Oxytocin inhibits social anxiety in particular.83 Social phobias can be the result of downregulation of oxytocin receptors due to prolonged treatment with oxytocin.83

Oxytocin reduces the production of ACTH.8586

Singing in a choir also increased oxytocin levels in contrast to singing alone, while both types of singing increased well-being and lowered cortisol levels. The activity of singing appears to increase oxytocin levels less than the stress- and arousal-reducing experience of singing together.87

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 with atopic dermatitis-induced psychological stress 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 noradrenaline levels, resulting in the elimination of ADHD symptoms.73 In humans, melatonin is given in doses of 1 to 5 mg in total (and not per kg), so the amount used in the study was several hundred times the dose usually used in humans. The use of melatonin as a stress inhibitor is therefore not foreseeable for the time being.
Nevertheless, it would be worthwhile investigating the question of stress reduction through melatonin in more detail.

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

Melatonin effect on dopamine:
Cortisol reduced dopamine levels in the locus coeruleus, the PFC and the striatum.
20 mg/kg melatonin counteracted the dopamine reduction caused by cortisol in all three brain areas.73

Melatonin effect on noradrenaline:
Cortisol increased the noradrenaline level in the locus coeruleus, in the PFC and in the striatum.
20 mg/kg melatonin counteracted the noradrenaline increase caused by cortisol in all three brain areas.73

In both ADHD sufferers and people with sleep problems, the evening rise in melatonin is delayed.88 In children between the ages of 6 and 12 with ADHD and sleep problems, the onset of sleep was delayed by 50 minutes, which corresponded to the delay in the rise in melatonin. Otherwise, sleep did not differ significantly.
Since the start of school is the same for all children in everyday life, this explains why ADHD sufferers with sleep problems have considerably greater difficulties in everyday life.

The nocturnal rise in melatonin correlates with the nocturnal reduction of cortisol89 and occurs later in children than in older people. In addition, the time of sleep is shifted forward in older people in relation to the time of the evening melatonin rise.90

An elevated serum melatonin level was found in ADHD.91

1.4.3.2.4. Deactivation of the HPA axis by endocannabinoids

Endocannabinoids significantly inhibit the HPA axis.92 They also slightly inhibit the release of

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

Endogenous opiates cause:93

  • Reduction in tonic arousal activity (triggered by noradrenaline and CRH)
  • high phasic activity
  • Initiation of recovery
  • reduced sensation of pain

Repeated social stress releases high levels of endogenous opiates. These bind to the opiate receptor. If the opiate receptor antagonist naxolone is administered at the same time, psychosocial stress can therefore trigger withdrawal symptoms.93

1.4.3.2.6. Deactivation of the HPA axis by endogenous morphines

Endogenous morphines are mainly controlled by dopamine. Their effect depends heavily on the current situation:94
If excitation is present, dopamine is converted to noradrenaline to adrenaline, resulting in increased attention, alertness and energy.
When relaxation is induced, the locus coeruleus and the sympatho-medullary stress axis are inhibited, noradrenaline is inhibited and dopamine is increased by inhibiting dopamine beta-hydroxylase, which inhibits the conversion of dopamine to noradrenaline so that more dopamine remains.

1.4.3.2.7. Deactivation of the HPA axis by neuropeptides

Neuropeptide-Y inhibits the stress response by inhibiting CRH activity, among other things.93

1.4.3.3. Deactivating effect on stress hormones
1.4.3.3.1. CRH

Education is attenuated by

  • Autoregulatory noradrenergic and autoregulatory CRH neurons via presynaptic CRH1 and α2 receptors, respectively48
  • GABA (gamma-aminobutyric acid)48
  • Substance P, which is primarily activated via peripheral afferents48
    • Inhibits stress-induced activation of the HPA axis9596 via neurokinin-1 receptors97
  • Cortisol
1.4.3.3.2. ACTH

Education is attenuated by

  • Cortisol
  • Oxytocin
1.4.3.3.3. Cortisol

Education is attenuated by

  • Oxytocin

1.5. Prevention of HPA axis activation

This description is incomplete and only mentions individual possible approaches.

1.5.1. Sport prevents stress

Trained men responded to psychological stressors (TSST) in comparison to untrained men98

  • Significantly lower cortisol response (with slightly lower basal cortisol level)
  • Significantly lower increase in heart rate
  • Significantly greater calmness, better mood and a tendency to react less anxiously to psychological stress

1.5.2. Massages prevent stress

Massage therapy reduces the cortisol response to stress by 31% and increases dopamine and serotonin by around 30%.99

It can be assumed that this is primarily mediated by the release of oxytocin.

1.5.3. Singing (especially in a choir) could prevent stress

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. Singing in a choir does not reduce oxytocin levels, but it does reduce cortisol levels.87

1.5.4. Social support prevents stress

Subjects who were accompanied by a friend before and during the TSST had lower cortisol levels as a stress response.100

1.5.5. Oxytocin is stress-preventive

Test subjects who received oxytocin as a nasal spray before the TSST showed lower stress and anxiety levels. The highest reduction in anxiety and cortisol response was seen with a combination of being accompanied by a friend and receiving oxytocin.100

Further approaches, such as the highly recommended mindfulness training, can be found at ADHD - treatment and therapy.

2. Changes in the HPA axis due to chronic stress

Chronic stress causes typical changes in the HPA axis.
It should be borne in mind that the following illustrations are only representations of momentary states. Chronic stress, however, is characterized by a temporal change component - like any condition that is caused by a long-lasting increased or decreased level of certain neurotransmitters, hormones, peptides or other substances that bind to receptors. Long-lasting changes in the levels of such substances can trigger receptor and transporter down- or upregulation. The prolonged administration of substances can deactivate areas of the brain that were previously responsible for the production of these substances.
Depending on the duration of the stress, the consequences described can therefore be intensified or reversed.

2.1. Changes in CRH due to chronic stress

  • Is elevated in the paraventricular nucleus (PVN) of the hypothalamus101102103
  • Increased number of CRH-immunoreactive cells expressing arginine vasopressin in the PVN104105106
  • CRH receptors in the pituitary gland reduced107

2.2. Changes in vasopressin due to chronic stress

Vasopressin is increased by chronic stress.101

2.3. Changes in proopiomelanocortin due to chronic stress

Proopiomelanocortin is increased in the pituitary gland by chronic stress.108

2.4. Changes in ACTH due to chronic stress

  • Increased ACTH in the pituitary gland108109110
  • ACTH response to CRH increased111112
  • Basal blood ACTH level unchanged113114115

2.5. Changes in cortisol due to chronic stress

  • Cortisol response to ACTH increased113116
  • Elevated basal blood cortisol levels (see under hypercortisolism)
  • Glucocorticoid receptors (GRs) in the hippocampus reduced by downregulation117118
    • This reduces the shutdown of the HPA axis by cortisol (feedback loop disrupted)119120
  • GR-mRNA reduced101121
  • Mineralocorticoid receptor (MR) mRNA levels reduced121
  • Activation of central neurotransmitter systems68122123
  • Enhancement of the activity of the HPA axis.68122123
  • Cortisol increases the mRNA expression of CRH in the central amygdala.124
  • Cortisol increases the success of pleasurable or compulsive activities (intake of sucrose, fat and drugs or cycling). This motivates the intake of “comfort food”.124
  • Cortisol systemically increases the fat deposits in the abdomen. This causes124
    • Inhibition of catecholamines in the brain stem
    • Inhibition of CRH expression in the hypothalamus
  • While chronic stress and high glucocorticoids increase body weight gain in rats, in humans this causes either increased food intake and weight gain or decreased food intake and weight loss.124125
  • A significant increase in cortisol in response to acute stress is associated with a deactivation of the limbic system.126

3. Overactivated and underactivated HPA axis

Overactivity of the HPA axis, especially CRH excess, correlates with:127

  • Chronic stress
  • Cushing’s syndrome
  • Melancholic depression
  • States of anxiety
  • Panic disorder
  • Post-traumatic stress in children
  • Obsessive-compulsive neuroses
  • Excessive sport (sports addiction)
  • Chronic, active alcoholism
  • Alcohol and narcotics withdrawal
  • Diabetes mellitus
  • Post-traumatic stress disorder in children
  • Hyperthyroidism
  • Pregnancy
  • Hypothalamic oligomenorrhea and amenorrhea
  • Reduced fertility
  • Eating disorders
    • Anorexia nervosa (anorexia nervosa)
    • Obesity
    • Metabolic syndrome
      • Abdominal obesity
      • High blood pressure
      • Lipid metabolism disorder with hypertriglyceridemia and low HDL cholesterol
      • Insulin resistance
  • Essential hypertension

Underactivity of the HPA axis, in particular CRH deficiency, correlates with:127

  • Adrenal insufficiency
  • Atypical/seasonal depression
  • Chronic fatigue syndrome / fatigue
  • Fibromyalgia
  • Premenstrual tension syndrome
  • Climacteric depression
  • Nicotine withdrawal
  • Glucocorticoid discontinuation/withdrawal consequences
  • After recovery from 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 malfunction in two ways if it is permanently overactivated - this 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 amount or effect of the stress hormones cortisol, ACTH or CRH on the HPA axis.128

4.1. Hypercortisolism

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

4.1.1. Disorders of the hypercortisolism spectrum

Source129

  • 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,130 whereby the changes already occur at the CRH and ACTH level of the HPA axis in the form of reduced hormone response levels.131
  • Metabolic syndrome
    • Abdominal obesity
    • High blood pressure
    • Fat metabolism disorder
      • Hypertriglyceridemia
        • Lipid metabolism disorder 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 type 2 diabetes mellitus (adult-onset diabetes)
  • Immune system: TH1/TH2 shift
    • Cortisol inhibits the inflammatory response triggered by CRH (less TH1)
      • This reduces susceptibility to inflammation 132
    • Cortisol increases the fight against foreign bodies (more TH2)
      • This increases the risk of allergies133

4.2. Hypocortisolism

Hypocortisolism is a low level of cortisol, ACTH or CRH or a lack of action of these substances on the receptor side.

4.2.1. Triggers of hypocortisolism

4.2.1.1. Genes and the environment
  • Genetic causes (e.g. certain FKBP gene polymorphisms)
  • Chronic psychological stress
  • Psychological trauma (e.g. abuse, maltreatment, victims of war)
  • Intense physical stress (e.g. infectious diseases)
  • Physical trauma (e.g. traffic accident)
4.2.1.2. Neurophysiological mechanisms
  • Reduced release of CRH or ACTH or cortisol134
  • Excessive release of CRH, ACTH or cortisol with subsequent down-regulation of the target receptors
    as a result, reduced sensitivity to negative feedback from the hormones
  • Reduced availability of free cortisol
  • Cortisol resistance of the target cells134

4.2.2. Possible symptoms of hypocortisolism

The symptoms differ depending on the level at which the hypocortisolism has manifested itself.134

  • Pain
    • Sensitivity to pain134
      • Fibromyalgia135
      • Chronic lower abdominal pain135
    • Feeling ill134
  • Tiredness
    • Chronic Fatigue Syndrome
    • Burnout
    • Hypersomnia (sleep addiction, daytime sleepiness)
  • Lethargy
  • Hyperphagia
    • Eating disorder
    • Excessive eating even without feeling hungry
  • Depression
    • Atypical depression134135
      possibly caused by CRF receptor deficiency
      Symptoms occur particularly in the second half of the day when cortisol levels are low (corresponding to the cortisol stress response weakness)
    • Bipolar depression
  • Stress intolerance
    • Irritability134
    • High sensitivity134
      • Noise
      • Temperatures
      • Light
      • Movement (also: too many people)
    • Post-traumatic stress disorder
      • Intrusions in PTSD134
        Reduced CRF and noradrenaline activity
    • States of anxiety134
  • Increased cardiovascular reactivity134
  • Lack of inhibition of the increased inflammation caused by CRH
    • Consequence: inflammatory problems133 / chronic inflammatory processes132136
      • Neurodermatitis137
      • Uninhibited activation of NF-kappa B132
      • Autoimmune diseases132136
      • Fibromyalgia (?)
      • Intestinal inflammatory disorders
      • Asthma
        • Chronic inflammation of the airways

Cortisol has an inhibitory (dampening) effect on the hypothalamus, among other things, and thus reduces the release of CRH. As CRH activates the locus coeruleus and thus increases its release of noradrenaline, cortisol indirectly causes a reduction in the noradrenaline level (which is typically very high due to the preceding stress reaction).138139
Cortisol also has a calming effect on the pituitary gland (which reduces the release of ACTH).
Cortisol thus slows down the activation of the HPA axis and the production of further cortisol.
Cortisol is therefore a kind of “stress brake” in the central nervous system.
This stress brake is impaired in hypocortisolism due to the low cortisol response to stress.134

4.3. Example: Traumas

During traumatic experiences, the brain functions that are necessary for survival reactions under stress are so overloaded that they break down. The massive overload of cortisol has the effect that previous processes, which have apparently proved insufficient to ensure survival, can be deleted more easily and replaced by new (more functional) processes.140

5. Measurement of the HPA axis

There are a number of endocrine stimulation and suppression tests that can be used to measure whether the HPA axis is functioning properly.

More on this 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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