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Cortisol is not a neurotransmitter, but a (stress) hormone. It is the most important hormone of the HPA axis.

1. Functioning of the cortisol system

Cortisol is the most important stress hormone of the HPA axis. Its effect goes far beyond stress symptoms.
The importance of cortisol primarily relates to the regulation of the HPA axis (especially its re-silencing), the control of the immune system (cessation of inflammatory response and increase of foreign body fight, TH1/TH2 shift), and also the mediation of stress responses.
See more at The HPA axis / stress regulation axis.

1.1. Reaction

The catecholamine system (catecholamines: dopamine, norepinephrine, epinephrine), which is also highly relevant to stress, responds rapidly via G-protein-coupled receptors.

In contrast, the cortisol system reacts

  • On the one hand slowly via regulation of gene expression and

  • Furthermore rapidly by non-gene expression modifying mechanisms (receptor binding)

  • The cortisol released into the blood by the adrenal gland is bound to proteins to 90 %. Only when the binding capacity of these proteins is exceeded does cortisol bind non-specifically to albumin and is released into the blood.1

  • Elevations in cortisol correlate with concomitant stress-induced release of norepinephrine and α1-adrenergic receptor activation.23

  • Higher aggression correlates with lower arousal following personal rejection as a stressor.4
    Aggressiveness thus correlates with a flattened cortisol stress response.

  • High restraint and social desirability correlate with an increased cortisol stress response to the stressor of social rejection in most studies.5

  • Men show higher cortisol stress response than women67

  • Cortisol influences learning during anxiety, fear, and other stress.8

1.2. Receptors

Cortisol binds to two types of receptors, the mineralocorticoid receptor (MR) and the glucocorticoid receptor (GR). These have different cortisol affinities and therefore together form a receptor system that has different tasks.9
According to the balance hypothesis, the MR type, which increases in excitability through stimulation, and the GR type, which decreases in excitability through stimulation, form a balance. This balance can be disturbed by prolonged cortisol release (in chronic stress).10
The two receptors also have different effects on memory.

The MR and GR receptors become active in different ways upon cortisol binding:

  • Immediate (hormonal effect, fast)
  • Gene-expressing effect (slow) as a transcription factor:
    • Addressing the MR or GR
    • Causes receptor translocation to the nucleus.
      In this process, the receptors retreat into the cell nucleus and can then no longer be addressed. This causes a reduction in receptor activity.
    • There direct or indirect interaction with specific glucocorticoid response elements (GRE) in nuclear DNA
    • Alters expression of numerous genes.11
      e.g. from
      • Enzymes of gluconeogenesis
      • Β2-adrenoceptors

The MR and GR are associated with heat shock proteins.

1.2.1. Mineralocorticoid receptor (MR)

The mineralocorticoid receptor (MR, aldosterone receptor, NR3C2) primarily regulates:

  • The effects of the basal cortisol level
  • The evaluation of new situations
  • The initiation and organization of the stress response

When MR are isolated under laboratory conditions, they bind the mineralocorticoid aldosterol as strongly as cortisol, but the latter 10 times more strongly than GR.

  • Kd approx. 0.5-2 nm for cortisol, corticosterone and aldosterone12

In the body (predominantly) as well as in the brain (partially), however, the enzyme HSD-11β occurs in the immediate vicinity of MR. HSD-11β type 2 transforms cortisol pre-receptorially into the inactive cortisone, so that the MR hardly binds to cortisol and quite predominantly to adlosterone,13 while HSD-11β type 1 promotes cortisol regeneration. MR and 11β-HSD in the brain and body

In the brain, MRs appear to bind predominantly glucocorticoids (except in relation to blood pressure and salt appetite)14, because in the brain the pre-receptor metabolism of cortisol to inactive cortisone by 11β-HSD type 2 is less pronounced.13 Thus, in the brain, MRs are often 10 times more cortisol-affinity than GRs, resulting in GRs being addressed in the brain only when cortisol is very strongly suppressed. 11β-HSD type 2 - cortisol inhibitory

11β-HSD type 2 is a high-affinity dehydrogenase that deactivates glucocorticoids, thereby attenuating the effects of cortisol and cortiscosterone so that MR bind more strongly or only to aldosterone

11β-HSD Type 2 can be found in

  • Kidney (distal nephron)15
    • 11β-HSD2 deficiency or inhibition causes mineralocorticoid excess and causes hypertension by overactivation of renal MR with cortisol/corticosterol.
  • Placenta15
  • Fetus (also brain)15
    • Protection against premature maturation of fetal tissue and consequent developmental activation (also in placenta)
  • Ventromedial and paraventricular (PVN) nuclei of the hypothalamus (moderate)13
  • Amygdala (moderate)13
  • Locus coeruleus (moderate)13
  • Subcommissural organ (moderate)13
  • Nucleus tractus solitarus (NTS) (moderate)13
    The latter brain regions are associated with the regulation of blood pressure and salt starvation, which are primarily activated by the mineralocorticoid aldosterone and not by glucocorticoids, suggesting 11β-HSD type 2 -associated MR. Most other regions of the brain where MR is found are subject to control by glucocorticoids, such as cognition in the hippocampus. Therefore, it is likely that the majority of MR-positive cells brain (e.g., in the hippocampus) are 11β-HSD2-negative because they predominantly bind glucocorticoids in vivo.

As we understand it, cortisol-tolerant resilencing of the HPA axis occurs primarily through GR in the hypothalamus, so MR here is unlikely to be associated with 11β-HSD type 2 - or only slightly so, to allow selective addressing of hypothalamic GR only at high cortisol levels. In the hypothalamus, colocations of GR and MR are found in parvocellular but not in magnocellular regions of the PVN16 11β-HSD type 1 - cortisol enhancing

11β-HSD type 1, which is present in most intact cells, catalyzes the regeneration of active glucocorticoids, enhancing the cellular effects of cortisol and corticosterone.
11β-HSD1 is found in:15

  • Liver
  • Fat tissue
  • Muscles
  • Pancreatic islets
  • Inflammatory cells
  • Gonads
  • In obesity also in adipose tissue
    • 11β-HSD1 deficiency or inhibition improve metabolic syndrome
  • Brain of adults, not in fetuses
    • Exacerbates glucocorticoid-induced cognitive decline in old age
    • 11β-HSD1 deficiency or inhibition improve cognitive function in aging
    • Effect in human therapy still unclear Occurrence of the MR

MR occur with the greatest density:

  • In limbic neurons17
  • Hippocampus17
    • Stimulation of MR receptor in hippocampus increases neuronal excitability (GR decreases it)9
  • Dentate gyrus17
  • Amygdala17
  • Lateral septal nuclei17
  • In some cortical regions17
  • Entorhinal cortex18
  • Motor output neurons18
  • Very low in the hypothalamus18 MR Agonists

Agonists of MR are

  • Aldosterone18
  • Cortisol18
  • Corticosterone18
  • Fludrocortisone
    • Activation of the MR by the MR agonist fludrocortisone was able to increase emotional empathy in borderline patients. Cognitive empathy remained unchanged.19

1.2.2. Glucocorticoid receptor (GR)

The glucocorticoid receptor (GR, NR3C1) plays a central role in the stress response. When stress activates the HPA axis, cortisol and other glucocorticoids are released from the adrenal gland and bind to the GR.20 In addition, the GR is also involved in brain development and neuroplasticity.12 Rats exposed to a new environment for 3 minutes each in the first 21 days showed increased sensitivity of the GR, which enhanced the inhibitory effect of glucocorticoids on neuronal excitability and plasticity of the CA1 field.21
This goes hand in hand with the fact that early childhood stress affects the expression of GR and MR.

The GR is associated with 2 heat shock proteins9 Appearance of the GR

The GR occurs with the greatest density17

  • In the parvocellular paraventricular nucleus (PVN) of the hypothalamus
  • In neurons of ascending aminergic pathways
  • In limbic neurons, trans-synaptically modulating PVN function via pathways acting on an inhibitory hypothalamic GABA network surrounding the PVN
  • Hippocampus
    • Not in CA3 of adults
    • Stimulation of GR receptor in hippocampus decreases neuronal excitability (MR increases it)9
  • Dentate gyrus
  • Amygdala
  • Lateral septal nuclei
  • In some cortical regions Agonists of the GR

Binding affinity: dexamethasone > cortisol, corticosterone > aldosterone18

  • Cortisol
    • The GR, due to its 10-fold weaker cortisol binding than MR, is only addressed at very high cortisol levels when all MRs are occupied, i.e
      • For ultradian pulses22
      • The daily maximum or
      • For stress response.
      • Kd approx. 10-20 nm for cortisol and corticosterone12
  • Dexamethasone
    • Selective GR agonist
    • Feedback loop between GR and SERT20
      • Dexamethasone binding to GR increases SERT expression in a SERT gene variant-dependent manner23
      • SERT gene variants affect GR, MR, and FKBP5 expression after early stress24 Antagonists of the GR

Mifepristone (RU 486) is a GR antagonist.25 Control ranges of the GR

The GR regulates / influences 1726

  • The expression of around 10% of all genes12
  • The re-activation of the HPA axis to stop the stress response27
  • Quickly increases neuronal excitability28
  • The mobilization of energy for the recovery and restoration phase
  • Promoting memory formation to recall the current stress process for future stress responses
  • The activation of CRH and ascending aminergic pathways in the amygdala
  • The metabolization of enzymes
  • Has anti-inflammatory effect by binding cortisol to GR in the cytosol of leukocytes11
    • Induces synthesis of anti-inflammatory cytokines
    • Inhibits NF-κB (one of the most important pro-inflammatory transcription factors)
  • Attention29
  • Perception29
  • Memory29
  • Emotional processing29
  • Learning GR gene variants

The GR-9β haplotype of the glucocorticoid receptor gene NR3C1 causes increased GRβ expression30 and has been associated with ADHD.31 However, the GRβ variant does not bind cortisol, is transcriptionally inactive, and is considered a dominant-negative inhibitor of the functional GRα variant.32 The GR-9β-stabilizing polymorphism has been associated with increased ACTH and cortisol stress responses33
In contrast, the Bcll GG haplotype of GR showed a flattened cortisol stress response in males and a greatly increased cortisol stress response in females (although the subjects were all using hormonal contraception)33

Prolonged stress exposure decreases GR expression. This could cause a decreased negative feedback of the HPA axis. A slower decline in cortisol levels to baseline after an acute stressor was observed, i.e., a prolonged time to recovery34
The combined inhibitory effect of the GR-9β haplotype and stress load may reduce GR activity to pathologically low levels, contributing to ADHD-related behavior. The GR-9β haplotype of the glucocorticoid receptor gene NR3C1 is associated with increased ADHD risk. In carriers of this haplotype, stress exposure and ADHD severity correlate more strongly than in noncarriers. This gene-environment interaction is further enhanced when affected individuals were also carriers of the homozygous 5-HTTLPR L allele rather than the S allele. These bilateral and trilateral interactions were reflected in the gray matter volume of the cerebellum, parahippocampal gyrus, intracalcarine cortex, and angular gyrus. This provides evidence that gene variants in the HPA axis stress response pathway influence how stress exposure affects ADHD severity and brain structure.20

1.2.3. Pregnan-X receptor (PXR / SXR)

The nuclear receptor called SXR in humans occurs in several subtypes. PRX.1 binds

  • Pregnenolone and its metabolites

    • 17α-Hydroxypregnenolone
    • Progesterone
    • 17α-hydroxyprogesterone
    • 5β-Pregnan-3,20-dione
  • Cholesterol (weak)

  • Synthetic glucocorticoid agonists

    • Dexamethasone t-butyl acetate (strong)
    • 6,16α-dimethyl pregnenolone (a pregnenolone derivative) (strong)
    • Dexamethasone-21-acetate (moderate)
    • Dexamethasone (weak)
  • Glucocorticoid antagonists

    • Pregnenolone 16α-carbonitrile (moderate)
    • Mifepristone (RU486) (moderate)

but not

  • Cortisone
  • Corticosterol

Overall, PXR binds with much lower affinity than GR and MR.35 Of the PXR-1 agonists, only dexamethasone t-butyl acetate binds to PXR2.

The PXR receptor is abundant in the liver and rare in the brain. The receptor is found CNS capillaries where it directly upregulates p-glycoprotein, which may represent a protective mechanism in chronically high plasma cortisol levels.13

1.2.4. Receptor heterodimers: MRMR, GRGR, MRGR

When MR and GR receptors are in a cell at the same time, they can heterodimerize, i.e. form MRGR, GRGR or MRGR.
It is possible that the three different dimers serve to increase cellular sensitivity to different corticoid concentrations due to different affinities for corticosteroids. Cortisol levels differ greatly across circadian rhythms and after stress exposure.36

1.2.5. Stress alters the GR/MR balance

  • Early childhood stress results in decreased expression of GR, whereas MR is not decreased or even increased.
    Corticosteroid receptor hypothesis of depression This implies that the deactivation of the HPA axis is impaired.
  • Long-term hypersecretion of glucocorticoids under stress causes downregulation of glucocorticoid receptors (GR) in the hippocampus.
    In short-term stress situations, no downregulation occurs; the negative feedback mechanism remains intact. Prolonged stress causes downregulation of the GR, so that the shutdown of the HPA axis by cortisol (mediated by the GR) no longer functions.37
  • Together with the flattened cortisol stress response in ADHD-HI (with hyperactivity), decreased GR levels lead to a decreased shutdown response of the GR. As a result, the HPA axis does not shut down again, but remains permanently activated.
  • In ADHD-I, on the other hand, cortisol responses to acute stress are excessive, so that GRs are frequently addressed, which is why ADHD-I, unlike ADHD-HI, is likely to have an excessively frequent or too early shutdown of the HPA axis.
  • A gene responsible for MR is a candidate gene for the development of ADHD.38

1.3. Tonic (basal) and phasic (stress-related) cortisol

Cortisol has regulatory functions outside of stress regulation via basal (tonic) cortisol levels, which are subject to a circadian diurnal rhythm.
In contrast, the phasic (acute) cortisol stress response has specific roles with respect to stress regulation.

The diurnal tasks of cortisol are handled by the mineralocorticoid receptor (MR), which is 10 times more cortisol affine than the glucocorticoid receptor (GR). Because lower cortisol levels initially bind to the MR, the GR is activated only at very high cortisol levels, such as those that occur in response to an acute severe stressor (cortisol stress response).

1.4. Circadian basal cortisol rhythm

  • The hormone relay of the HPA axis is released in 7 to 10 spurts throughout the day.
  • Blood cortisol levels:
    • Highest value 30 to 60 minutes after awakening (cortisol awakening response, CAR)
      • Usual: 165-690 nmol/l (total cortisol) or 5-23 nmol/l (free cortisol).
    • Very strong drop until 9 o’clock in the morning
    • Further significant drop until noon
    • Weak further drop until the evening
    • Lowest value before sleep and in first sleep phase
    • Approx. 2 hours after midnight slight increase until getting up
    • Measurements must be made over daily profile or at identical time of day
    • Cortisol (as well as other stress hormones) can already increase by pricking when blood is drawn. See below under measurement of cortisol.
    • Salivary cortisol levels correspond to blood cortisol levels

2. Effect on cortisol

2.1. Boosting cortisol

Cortisol enhancing:

  • 11β-hydroxysteroid dehydrogenase (11β-HSD, HSD-11β)12
    • Enzyme family13
      • HSD-11β type 1 activates glucocorticoids
      • HSD-11β type 2 deactivates glucocorticoids
        • See below under “Inhibits cortisol
    • Arguably the most important regulator of access of endogenous glucocorticoids to their receptors (GR or MR)
    • Essential function within the HPA axis
  • ACTH
  • Norepinephrine39
  • IGF140
    • IGF1 has its own IGF1 receptors that are found throughout the adrenal gland. Decreased IGF1 levels and a calorie deficit can thus cause lowered cortisol levels.
  • Serotonin
    • Serotonin precursors increase cortisol levels
      • D,L-5-hydroxytryptophan (oxitriptan, intermediate in serotonin synthesis from L-tryptophan)41
      • Tryptophan42
    • Serotonin reuptake inhibitors increase the cortisol stress response
      • Escitalopram at higher dosage (20 mg) increases cortisol response to acute stress4344
      • Fluvoxamine45
        • Fluvoxamine is an SSRI, so the cortisol increase follows the pattern of serotonin described above
      • Desipramine45
        • Desipramine, in addition to its primary norepinephrine reuptake inhibition, is also secondarily a serotonin reuptake inhibitor, so that the cortisol increase follows the pattern of serotonin described above
        • Consequently also imipramine, as this is converted to desipramine
      • The same has been reported for other SSRIs46
    • Serotonin agonists increase cortisol levels
      • D-Fenfluramine (a drug no longer available due to heart valve damage) increases cortisol levels47
  • Caffeine
    • Increases resting norepinephrine levels and the norepinephrine stress response48
    • Potentiates (doubles) the adrenal stress response48
    • Potentiates (doubles) the cortisol stress response48
    • The effects were independent of the amount and habit of coffee consumption. No habituation effects seem to occur.48
    • The caffeine-induced increase in cortisol occurs in both women and men, but differs somewhat in effect.6
  • Food intake
    • High-protein meals increased cortisol levels, in contrast to low-protein meals49
    • Food intake increased cortisol levels in 37 of 40 subjects50
    • In women, the cortisol response might be more determined by metabolic effects than in men6

2.2. Inhibits cortisol

Cortisol inhibitors:

  • 11β-hydroxysteroid dehydrogenase (11β-HSD, HSD-11β)12
    • Enzyme family13
      • HSD-11β type 1 activates glucocorticoids
      • HSD-11β type 2 deactivates glucocorticoids
    • Metabolize corticoids within the target cells themselves (pre-receptor metabolism)
    • 11β-HSD catalyze the conversion of cortisol and its inactive metabolite cortisone in humans as well as the conversion of corticosterone and 11-deoxycorticosterone in rodents
    • Arguably the most important regulator of access of endogenous glucocorticoids to their receptors (GR or MR)
    • Essential function within the HPA axis
  • FKB51 (FKBP51, FK506-binding protein 51)
    FKB51 is a functional antagonist of the GR glucocorticoid receptor.51
  • Oxytocin, given nasally, attenuates the cortisol response to acute stress in a dose-dependent manner.52
  • Mifepristone (RU-486)5354
  • Nutritional deficiencies and other IGF1 deficiencies may inhibit cortisol production

3. Cortisol control ranges

Cortisol crosses the blood-brain barrier (unlike epinephrine and norepinephrine), allowing it to act as a hormone in the body and as a neurotransmitter in the brain.

3.1. Behavioral effects of cortisol

Cortisol altered:

  • Behavior55
    • Submissive behavior56
  • Feelings57
    • E.g. fear55
    • Mood5557
      • Cortisol promotes depression58
  • Memory57
    • At moderate level: improvement55
    • At high level: deterioration55
      • Stress-induced cortisol release leads to overstimulation of norepinephrine-α1 receptors in the PFC. Norepinephrine impairs PFC and working memory function via norepinephrine-α1 receptors. Simultaneous addressing of these receptors enhances this effect.59

3.2. Endocrine effect of cortisol

  • Effect on neurotransmitters
    • Formation of catecholamines (dopamine, noradrenaline)55
    • Influences serotonin receptors55

3.2.1. Cortisol has an activating effect Cortisol activates dopamine

Dopamine6061 62
* Stress-induced cortisol release leads to overstimulation of dopamine D1 receptors in the PFC. This has been associated with impaired PFC function and deficits in working memory.59
In the PFC, cortisol blocks catecholamine transporters on glial cells outside the synapses, which cause the removal of excess dopamine and noradrenaline from the cells. If this removal fails, this increases the dopamine and norepinephrine levels in the cells and thus their effect.59
* Glucocorticoids regulate dopamine release in the PFC and ventral tegmentum (VTA, one of the major brain regions of dopamine production) via glucocorticoid receptors (GRs) in the PFC (rather than the VTA) and alter the firing of dopaminergic projections.59
* Cortisol activates the mesocorticolimbic dopaminergic system63 Cortisol activates norepinephrine

Cortisol blocks catecholamine transporters in the PFC on glial cells outside the synapses, which cause the removal of excess dopamine and noradrenaline from the cells. If this removal fails, this increases dopamine and norepinephrine levels in the cells and thus their effect. Increased levels of norepinephrine in the PFC impair its function.59 Cortisol activates serotonin

At least in the short term, cortisol and stress increase serotonin levels64

  • Stress increases neuronal serotonin activity in the dorsal raphe nuclei (DRN). As a result
    • Increased cFos expression in 5-HT neurons
    • 5-HT release in the DRNs and in the brain regions they address with serotonin.
  • Only hopeless, but not remediable, stress leads to serotonin elevation in DRN, hippocampus, and amygdala.
    In contrast, flyable and nonavoidable stress increases serotonin release in the periaqueductal gray.
    Corticosterone plays a crucial role in these effects by stimulating tryptophan hydroxylase activity and serotonin metabolism in the brain.
    Unlike noradrenergic cells in the nucleus coeruleus, stress does not increase the firing rate of serotonin cells in the DRN, although stress does increase cFos expression. Cortisol activates amygdala

Cortisol activates the peptidergic CRH nucleus of the amygdala63 Cortisol activates energy mobilization

Cortisol stimulates energy mobilization by activating:58

  • Glycolysis in the liver
  • Proteolysis Cortisol increases vasoconstriction

Cortisol potentiates vasoconstriction.58

3.2.2. Cortisol has an inhibitory effect

Cortisol has an inhibitory effect on:

  • CRH
    Glucocorticoids (cortisol) inhibit CRH production and thus the first stage of the HPA axis.63
  • Norepinephrine
    Glucocorticoids (cortisol) inhibit norepinephrine production in the nucleus coeruleus, and thus indirectly inhibit the effects of norepinephrine.63
    Norepinephrine stimulates CRH production and (in larger amounts) inhibits PFC function.
  • Serotonin
    In the case of decreased availability of the serotonin precursor tryptophan, cortisol causes decreased synthesis, release, and metabolism of serotonin and thus an increased risk for depression.65
  • Beta-endorphin
  • Cortisol reduces melatonin in fish66
  • Gonadotropin release in the pituitary gland63
  • Growth hormone production63
  • Thyrotropin (thyrotropin) secretion63
  • Suppresses 5′-deiodinase, which converts the relatively inactive tetraiodothyronine (T4) to triiodothyronine (T3)63
  • Makes the target tissues of sex steroids and growth factors resistant to these63
  • Acts on the fatty tissue by means of insulin,63 what
    • Visceral obesity63
    • Insulin resistance63
    • Dyslipidemia63
    • Hypertension (metabolic syndrome X) 63
      • Which has direct effects on the bone63
      • And so can cause osteoporosis63
    • Hypoththalamic-pituitary-gonadal axis58
      • Cortisol markedly reduces testosterone production in Leydig cells
      • Thereby disturbance reproduction in the male
    • Bone and muscle growth58

3.2.3. Cortisol inhibits stress systems Cortisol inhibits HPA axis

Cortisol is the (temporally) last stress hormone of the HPA axis and, in addition to some stress activations, also has the task of down-regulating the HPA axis, which is designed for a limited duration of activity. This works by having only the glucocorticoid receptors (GR) - which are about 1/10 as sensitive to cortisol as the mineralocorticoid receptors (MR) - effect the down-regulation of the HPA axis. Low levels of cortisol that exhaust only the MR do not cause HPA axis inhibition, only particularly high levels of cortisol (at which, after saturation of the more sensitive MR receptors, the insensitive GR receptors are also targeted).67
When the GRs are activated, they downregulate the HPA axis by inhibiting the release of

  • CRH
  • Vasopressin
  • Cytokines and
  • Reduce POMC

and (at least in rats) facilitate information storage.68 As a result, successful stress management strategies are more easily anchored in memory. Cortisol inhibits sympathetic nervous system

Cortisol reduces the activity of the sympathetic nervous system:58

  • at rest
  • during stress
  • after stress

3.3. Cortisol and the immune system

Cortisol affects all major homeostatic systems of the body, including innate and acquired immunity69
In particular, cortisol inhibits the innate immune system:58

  • Inhibition of NF-kB
    • inhibits its proinflammatory effect in
      • Macrophages
      • Monocytes
      • T cells
    • suppresses production of
      • inflammatory cytokines, such as:
        • IL-6
        • TNF-alpha
        • IL-1beta
        • IFN-gamma
      • inflammatory acute phase proteins
        • CRPhs
        • Ferritin
        • Ceruloplasmin
      • inflammatory prostaglandins

3.3.1. Cortisol inhibits (the inflammation promoted by CRH)

Cortisol is the most potent endogenous immune system suppressor, predominantly by inhibiting the pro-inflammatory transcription factor NF-kappa B (NF-kB)
During stress, the sympathetic nervous system (activating part of the autonomic nervous system that intervenes early during stress) promotes the production of pro-inflammatory (pro-inflammatory) cytokines (inflammatory proteins or T-helper type 1 cytokines = TH1 cytokines), e.g. tumor necrosis factor alpha, interleukin IL-1, IL-2 and IL-12, interferon gamma), which are, however, only beneficial in the short term. If they are active for too long (due to prolonged stress), they attack cells and tissues, which, in addition to degeneration of cells (cancer) and damage to the immune system, can lead to chronic inflammatory bowel diseases.
To temporally limit the effect of pro-inflammatory cytokines promoted by CRH, cortisol released by the HPA axis (intervening late during stress) has an inhibitory effect on pro-inflammatory cytokines:

  • Cortisol inhibits the production of interleukin IL-12 and IL-1870
    • This inhibits TH1 responses
      • This is characterized by inhibition of
        • Immunoglobulin IG-G3 antibody
        • Tumor necrosis factor TNF-a,
        • Interferon IFN-c
        • Interleukin IL-2

Cortisol activates defense against foreign bodies (bacteria, parasites)7170
* Cortisol promotes TH2 responses
* This is characterized by promotion of anti-inflammatory (anti-inflammatory) cytokines (T-helper type 2 cytokines / TH-2 cytokines), e.g.
* Interleukin IL-4,
* Interleukin IL-5
* Interleukin IL-6
* Stress causes an increased cortisol and TNF-α stress response. Upon habituation to the stressor, the cortisol stress response decreases, but apparently not (or slower?) the IL-6 stress response.72
* Interleukin IL-10
* Interleukin IL-13.
* These TH-2 cytokines repel extracellular pathogens (bacteria, parasites) and promote basophils, mast cells, and eosinophils, which can promote allergies if they overgrow.
* TH1 inhibition and TH2 promotion is also called TH1/TH2 shift
* In addition to cortisol, norepinephrine also appears to shift TH1 to TH2, whereas serotonin and melatonin may mediate a shift from TH2 to TH1.73
* Neurotransmitter modulation on TH1 / TH2 balance could be relative, with the goal of restoring physiological levels to a previous imbalance in receptor sensitivity and cytokine production.73 This could be relevant in relation to the efficacy of antidepressants and other drugs that affect these neurotransmitters.

  • Cortisol also reduces the formation of edema (water retention).
    • The migration of cells and fluid from the intravascular space into the tissue is prevented. This is based, among other things, on the inhibition of histamine.74

3.3.2. Immunological consequences of too little cortisol (hypocortisolism)

Inflammatory problems,71 ex:

  • Neurodermatitis (atopic eczema, neurodermatitis)
  • Fibromyalgia
  • Inflammatory bowel disease

3.3.3. Immunological consequences of too much cortisol (hypercortisolism)


3.4. Neurotoxic effects of glucocorticoids (cortisol) in prolonged stress

3.4.1. General effects of cortisol during stress

Glucocorticoids (in humans this is primarily cortisol) are the most important stress hormones, which basically not only allow, stimulate or suppress stress responses, but also cause a preparation of a physical response to a subsequent (expected) stressor.75 Glucocorticoids have a neuroprotective effect (at low levels and short durations of action), so that they protect against harmful consequences of stress,76 for example, by increasing certain mRNA expressions.767776

Glucocorticoids (cortisol) dampen the hypothalamus and pituitary gland in two phases. In the fast phase the output and in the slow phase the synthesis of CRH and ACTH is inhibited.78

Cortisol has a blood plasma half-life of approx. 1.7 hours, is broken down enzymatically by the liver and excreted in esterified form in the urine. Only about 1 % of cortisol is freely detectable in the urine.79

However, cortisol becomes harmful when it is released for too long, especially in early childhood and adolescence.

Glucocorticoids (e.g., cortisol) influence behavior and cause neurochemical and neurodegenerative changes in the brain.8081

Cortisol influences

  • Activation of central neurotransmitter systems828384
  • Enhancement of HPA axis activity8283 84 (rather than inhibition for short-term effects)
  • Cortisol increases mRNA expression of CRH in the central amygdala.85
  • Activation of the vegetative nervous system. Cortisol thus prepares a stress response of the heart and blood vessels.86

3.4.2. Neurotoxic effects of cortisol

Prolonged high cortisol release causes specific stress symptoms:87

  • Muscle atrophy
  • Hyperglycemia (elevated blood sugar)
  • Fat deposit in
    • Face
    • Neck
    • Tribe
    • Abdomen (abdomen)
  • Skin thinner and more fragile
  • Wound healing worsens
  • Osteoporosis
  • Kidney stones
  • Susceptibility to infection increased
  • Hypertension (high blood pressure)
  • Excitability
  • Depression
    • The administration of artificial glucocorticoids also increases the risk of depression88
    • Cortisol influences mood and affect89 negative mood90
  • Psychoses
  • Appetite disorders
  • Libido disorders
  • Impotence
  • Sleep disorders
  • Amenorrhea (absence of menstruation)
  • Memory problems

Binding of hormones to corticosteroid receptors affects gene expressions.91

3.5. Cortisol influences brain development

Glucocorticoids influence brain development before and after birth and are essential for healthy brain maturation.13 Glucocorticoids92

  • initiate terminal maturation
  • reshape axons and dendrites
  • influence the survival of neurons and glial cells
  • decreased or excessive glucocorticoid levels cause structural and functional abnormalities in neurons and glial cells
    • Effect often over entire lifespan
  • Glucocorticoids cause adrenal medullary progenitor cells to differentiate into chromaffin cells that produce catecholamines.93

The regulation of glucocorticoids takes place through

  • HPA axis
  • pre-receptor metabolism (HSD-11β type 1 and 2)

Since ADHD is also circumscribed as a brain developmental disorder, the possible influence of glucocorticoids as endogenous stress hormones of the child before or after birth, from transmission via placenta by the mother or by medication entry, should be kept in mind.

3.6. Cortisol influences energy balance

Cortisol influences

  • Glycolysis89
    The regulation of glycolysis of catecholamines is carried out by glucocorticoids
  • Gluconeogenesis89
    together with impaired glycolysis, can lead to reduced energy supply from carbohydrate metabolism during prolonged exercise
  • Cortisol increases adrenaline-induced lipolysis (fat cleavage, fat digestion)9495
    Impairment may be exacerbated by decreased ACTH levels89
  • Impairment of metabolic adaptation in regeneration phases89
  • Cortisol increases the success of pleasurable or compulsive activities (ingestion of sucrose, fat, and drugs). This motivates the intake of “comfort food”.85
  • Cortisol systemically increases fat deposits in the abdomen. This causes85
    • An inhibition of catecholamines in the brainstem and
    • An inhibition of CRH expression in the hypothalamus, which inhibits CRH-induced ACTH stimulation
  • 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.8596
  • Several studies show a correlation between cortisol stress response and waist-to-hip ratio, such that a low cortisol stress response is associated with a low waist-to-hip ratio (low waist) whereas a high cortisol stress response is associated with a high waist-to-hip ratio (high waist).979899

3.7. Cortisol influences catecholamines

Cortisol influences

  • Catecholamine biosynthesis89 by promoting catecholamine-producing enzymes100
  • Catecholamine storage89
  • Inhibition of catecholamine degradation100
  • Synthesis, density, affinity, and response of adrenergic ß2-receptors89
  • The production of second messengers induced by ß- or α1- adrenoreceptors89

3.8. Cortisol affects gene expression, transcription factors, and brain regions

  • Cortisol affects up to 20% of expressed human genes influenced69
  • Glucocorticoid receptor interacts reciprocally with transcription factors for coordinated (highly stochastic) regulation of brain function, growth, immunity, and metabolism:69
    • AP1
    • CoUPTF1
    • NFκB
    • STATs, d
      The effect of cortisol can change if stress lasts for a long time.
  • A significant increase in cortisol in response to acute stress is associated with deactivation of brain regions. Deactivated are101
    • Limbic system
      • Hippocampus
    • Hypothalamus
    • Medio-orbitofrontal cortex (mOFC)
    • Anterior cingulate cortex (ACC)

4. Cortisol measurement

  • Salivary cortisol levels correspond to blood cortisol levels, albeit with a time delay of several minutes
  • Cortisol (as well as other stress hormones) can already increase by puncture during blood sampling.102 About one third of all adults already show a rise in cortisol in response to a venipuncture for blood sampling,103104 105 106 likewise 50 to 80 % of children, especially in ADHD (cortisol rise and alpha-amylase rise).107
    Therefore, a waiting time of 30 to 40 minutes between puncture and blood sampling is strongly recommended.108
    These results are also evident in animals. In cows, blood cortisol levels were 2.07 to 3.81 ng/ml immediately after venipuncture and 1.43 to 2.61 ng/ml 18 minutes later, i.e. significantly lower by 31% on average.109 It is questionable, however, whether these differences in animals really result from the puncture itself or whether it is not rather a stress reaction to the fear of an unknown treatment. It would be understandable that such fear is greater in animals (which do not know what is in store for them after the puncture and which may first have to be captured for the blood sample) than in humans, who are aware that it is only a small prick and that nothing else bad will happen.

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