Cortisol

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

• 1. How the cortisol system works
  • 1.1. Reaction
  • 1.2. Receptors
    • 1.2.1. Mineralocorticoid receptor (MR)
      • 1.2.1.1. MR and 11β-HSD in the brain and body
        • 1.2.1.1.1. 11β-HSD type 2 - cortisol inhibiting
        • 1.2.1.1.2. 11β-HSD type 1 - cortisol boosting
      • 1.2.1.2. Appearance of the MR
      • 1.2.1.3. MR agonists
    • 1.2.2. Glucocorticoid receptor (GR)
      • 1.2.2.1. Appearance of the GR
      • 1.2.2.2. Agonists of the GR
      • 1.2.2.2. Antagonists of the GR
      • 1.2.2.3. Control ranges of the GR
      • 1.2.2.4. Gene variants of the GR
    • 1.2.3. Pregnane X receptor (PXR / SXR)
    • 1.2.4. Receptor heterodimers: MRMR, GRGR, MRGR
    • 1.2.5. Stress changes the GR/MR balance
  • 1.3. Tonic (basal) and phasic (stress-related) cortisol
  • 1.4. Circadian basal cortisol rhythm
• 2. Effect on cortisol
  • 2.1. Boosts cortisol
  • 2.2. Inhibits cortisol
• 3. Control ranges of cortisol
  • 3.1. Behavioral effect of cortisol
  • 3.2. Endocrine effect of cortisol
    • 3.2.1. Cortisol has an activating effect
      • 3.2.1.1. Cortisol activates dopamine
      • 3.2.1.2. Cortisol activates noradrenaline
      • 3.2.1.3. Cortisol activates serotonin
      • 3.2.1.4. Cortisol activates the amygdala
      • 3.2.1.5. Cortisol activates energy mobilization
      • 3.2.1.6. Cortisol increases vasoconstriction
    • 3.2.2. Cortisol has an inhibitory effect
    • 3.2.3. Cortisol inhibits the stress systems
      • 3.2.3.1. Cortisol inhibits the HPA axis
      • 3.2.3.2. Cortisol inhibits the sympathetic nervous system
  • 3.3. Cortisol and the immune system
    • 3.3.1. Cortisol inhibits inflammation (promoted by CRH)
    • 3.3.2. Immunological consequences of too little cortisol (hypocortisolism)
    • 3.3.3. Immunological consequences of too much cortisol (hypercortisolism)
  • 3.4. Neurotoxic effects of glucocorticoids (cortisol) during prolonged stress
    • 3.4.1. General effects of cortisol during stress
    • 3.4.2. Neurotoxic effects of cortisol
  • 3.5. Cortisol influences brain development
  • 3.6. Cortisol influences energy balance
  • 3.7. Cortisol influences catecholamines
  • 3.8. Cortisol influences gene expression, transcription factors and brain regions
• 4. Measurement of cortisol

1. How the cortisol system works¶

Cortisol is a corticosteroid.
Corticosteroids include

• Mineral corticosteroids:
  • Aldosterone
• Glucocorticosteroids
  influence the protein, carbohydrate and fat metabolism
  • Cortisol
  • Corticosterone
  • Dexamethasone
    • slow-acting artificial glucocorticoid
• Androgens
  stimulate protein metabolism, increase muscle mass

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 (in particular its resetting), the control of the immune system (ending the inflammatory reaction and increasing the fight against foreign bodies, TH1/TH2 shift) as well as the mediation of stress reactions.
Find out more at ⇒ The HPA axis / stress regulation axis.

1.1. Reaction¶

The catecholamine system (catecholamines: dopamine, noradrenaline, adrenaline), which is also highly relevant for stress, reacts quickly via G-protein-coupled receptors.

The cortisol system, on the other hand, reacts

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

• Also rapidly through non-gene expression modifying mechanisms (receptor binding)

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

• Increases in cortisol correlate with a simultaneous stress-induced release of noradrenaline and α1-adrenergic receptor activation.²³

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

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

• Men show a 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 receptor, the mineralocorticoid receptor (MR) and the glucocorticoid receptor (GR). These have different cortisol affinities and therefore together form a receptor system that has different functions.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 the case of chronic stress).¹⁰
The two receptors also have different effects on memory.

The MR and GR receptors become active in different ways when cortisol is bound:

• Immediate (hormonal effect, fast)
• Gene-expressing effect (slow) as a transcription factor:
  • Addressing the MR or GR
  • Causes receptor translocation into the cell nucleus.
    The receptors retract 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 the nuclear DNA
  • Alters the 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) is the main regulator:

• 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 just as strongly as cortisol, but the latter is 10 times stronger than the GR.

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

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

1.2.1.1. MR and 11β-HSD in the brain and body¶

In the brain, MR (except in relation to blood pressure and salt appetite) appear to bind predominantly glucocorticoids¹⁴, because the pre-receptor metabolism of cortisol to inactive cortisone by 11β-HSD type 2 (11β-HSD2) is less pronounced in the brain.¹³ In the brain, the MR are therefore often 10 times more cortisol-affine than the GR, which means that GR are only addressed in the brain when there is very strong cortisol suppression.

1.2.1.1.1. 11β-HSD type 2 - cortisol inhibiting¶

11β-HSD type 2 (11β-HSD2) is a high-affinity dehydrogenase that deactivates glucocorticoids and thus attenuates the effect of cortisol and cortiscosterone so that MR binds 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 the fetal tissue and the resulting developmental activation (also in the 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 appetite, 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 can be assumed that the majority of MR-positive cells in the brain (e.g. in the hippocampus) are 11β-HSD2-negative, as they predominantly bind glucocorticoids in vivo.

According to our understanding, the cortisolergic resilencing of the HPA axis is primarily effected by GR in the hypothalamus, so that the MR here are not or only slightly associated with 11β-HSD type 2 - to enable selective addressing of the 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

1.2.1.1.2. 11β-HSD type 1 - cortisol boosting¶

11β-HSD type 1 (11β-HSD1), which is present in most intact cells, catalyzes the regeneration of active glucocorticoids and thus enhances the cellular effect of cortisol and corticosterone.
11β-HSD1 can be found in:¹⁵

• Liver
• Adipose tissue
• Muscles
• Pancreatic islets
• Inflammatory cells
• Gonads
• In obesity, also in fatty tissue
  • 11β-HSD1 deficiency or inhibition improve metabolic syndrome
• Adult brain, not in fetuses
  • Exacerbates glucocorticoid-induced cognitive decline in old age
  • 11β-HSD1 deficiency or inhibition improves cognitive function in old age
  • Effect in human therapy still unclear

1.2.1.2. Appearance of the MR¶

MR occur with the highest density:

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

1.2.1.3. 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, which bind to the GR.²⁰ The GR is also involved in brain development and neuroplasticity.¹² Rats exposed to a novel environment for 3 minutes in the first 21 days showed an 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 influences the expression of GR and MR.

The GR is associated with 2 heat shock proteins.⁹

1.2.2.1. Appearance of the GR¶

The GR occurs with the highest density¹⁷

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

1.2.2.2. Agonists of the GR¶

Binding affinity: dexamethasone > cortisol, corticosterone > aldosterone¹⁸

• Cortisol
  • Due to its 10-fold weaker cortisol binding than MR, the GR is only addressed at very high cortisol levels when all MR are occupied, i.e
    • For ultradian pulses²²
    • The daily maximum or
    • For stress reactions.
    • 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 depending on the SERT gene variant²³
    • SERT gene variants influence GR, MR and FKBP5 expression after early stress²⁴

1.2.2.2. Antagonists of the GR¶

Mifepristone (RU 486) is a GR antagonist.²⁵

1.2.2.3. Control ranges of the GR¶

The GR regulates / influences ¹⁷²⁶

• The expression of around 10 % of all genes¹²
• The reactivation of the HPA axis to end the stress response²⁷
• Quickly the neuronal excitability²⁸
• The mobilization of energy for the recovery and restoration phase
• The promotion of memory formation to remember the current stress process for future stress reactions
• Activation of CRH and ascending aminergic pathways in the amygdala
• The metabolization of enzymes
• Has an 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

1.2.2.4. Gene variants of the GR¶

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 an increased ACTH and cortisol stress response³³
In contrast, the Bcll GG haplotype of the GR showed a flattened cortisol stress response in men and a greatly increased cortisol stress response in women (although the test subjects were all using hormonal contraception)³³

Prolonged stress reduces GR expression. This could result in reduced negative feedback from the HPA axis. A slower decline in cortisol levels to baseline after an acute stressor was observed, i.e. a longer time to recovery³⁴
The combined inhibitory effect of the GR-9β haplotype and stress exposure can reduce GR activity to a pathologically low level and thus contribute to ADHD-related behavior. The GR-9β haplotype of the glucocorticoid receptor gene NR3C1 is associated with an increased risk of ADHD. In carriers of this haplotype, stress exposure and ADHD severity correlate more strongly than in non-carriers. This gene-environment interaction is even stronger if the affected individuals were also carriers of the homozygous 5-HTTLPR L allele instead of the S allele. These two- and three-way interactions were reflected in the gray matter volume of the cerebellum, the parahippocampal gyrus, the intracalcarine cortex and the angular gyrus. This proves that gene variants in the stress response pathway of the HPA axis influence how stress exposure affects the severity of ADHD and brain structure.²⁰

1.2.3. Pregnane 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-pregnane-3,20-dione

• Cholesterol (low)

• 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 significantly 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 in CNS capillaries, where it directly upregulates p-glycoprotein, which could represent a protective mechanism for chronically high plasma cortisol levels.¹³

1.2.4. Receptor heterodimers: MRMR, GRGR, MRGR¶

If MR and GR receptors are present 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 corticosteroid concentrations due to their different affinity for corticosteroids. Cortisol levels vary greatly according to the circadian rhythm and stress levels.³⁶

1.2.5. Stress changes the GR/MR balance¶

• Early childhood stress leads to a reduced expression of GR, while the number of MR is not reduced or even increased.
  ⇒ Corticosteroid receptor hypothesis of depression This means that the shutdown of the HPA axis is impaired.
• Long-term hypersecretion of glucocorticoids under stress causes downregulation of glucocorticoid receptors (GR) in the hippocampus.
  No downregulation occurs in short-term stress situations; 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), reduced GR levels lead to a reduced GR shutdown response. As a result, the HPA axis does not shut down again, but remains permanently activated.
• In ADHD-I, on the other hand, the cortisol responses to acute stress are excessive, so that the GR are frequently addressed, which is why in ADHD-I, in contrast to ADHD-HI, there is likely to be an excessively frequent or premature 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 the basal (tonic) cortisol level, which is subject to a circadian daily rhythm.
The phasic (acute) cortisol stress response, on the other hand, has specific tasks with regard to stress regulation.

The daily tasks of cortisol are carried out via the mineralocorticoid receptor (MR), which has 10 times more cortisol affinity than the glucocorticoid receptor (GR). As lower cortisol levels initially bind to the MR, the GR is only activated at very high cortisol levels, as 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 waking up (Cortisol Awakening Response, CAR)
    • Usual: 165-690 nmol/l (total cortisol) or 5-23 nmol/l (free cortisol).
  • Very strong drop until 9 a.m
  • Further significant drop until midday
  • Weak further decline until the evening
  • Lowest value before sleep and in the first sleep phase
  • Approx. 2 hours after midnight slight increase until getting up
  • Measurements must be taken using a daily profile or at the same time of day
  • Cortisol (as well as other stress hormones) can already increase when a blood sample is taken. See below under measurement of cortisol.
  • Salivary cortisol levels correspond to blood cortisol levels

2. Effect on cortisol¶

2.1. Boosts cortisol¶

Are cortisol-boosting:

• 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 “Inhibiting cortisol”
  • Probably the most important regulator of the access of endogenous glucocorticoids to their receptors (GR or MR)
  • Essential function within the HPA axis
• ACTH
• Noradrenaline³⁹
• IGF1⁴⁰
  • IGF1 has its own IGF1 receptors, which are found throughout the adrenal gland. Reduced IGF1 levels and a calorie deficit can thus cause a lowered cortisol level.
• Serotonin
  • Serotonin precursors increase the cortisol level
    • D,L-5-hydroxytryptophan (oxitriptan, intermediate product in the synthesis of serotonin from L-tryptophan)⁴¹
    • Tryptophan⁴²
  • Serotonin reuptake inhibitors increase the cortisol stress response
    • Escitalopram in higher doses (20 mg) increases the cortisol response to acute stress⁴³⁴⁴
    • Fluvoxamine⁴⁵
      • Fluvoxamine is an SSRI, so the increase in cortisol follows the pattern of serotonin described above
    • Desipramine⁴⁵
      • In addition to primarily inhibiting noradrenaline reuptake, desipramine is also a secondary serotonin reuptake inhibitor, so that the increase in cortisol 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 the cortisol level
    • D-Fenfluramine (a drug no longer available due to heart valve damage) increases cortisol levels⁴⁷
• Caffeine
  • Increases the noradrenaline level at rest and the noradrenaline stress response⁴⁸
  • Potentiates (doubles) the adrenaline stress response⁴⁸
  • Potentiates (doubles) the cortisol stress response⁴⁸
  • The effects were independent of the amount and habit of coffee consumption. There do not appear to be any habituation effects.⁴⁸
  • The caffeine-induced increase in cortisol occurs in both women and men, but differs slightly in its effect.⁶
• Food intake
  • High-protein meals increased cortisol levels, in contrast to low-protein meals⁴⁹
  • Food intake increased cortisol levels in 37 out of 40 test subjects⁵⁰
  • In women, the cortisol response may be more strongly determined by metabolic effects than in men⁶

2.2. Inhibits cortisol¶

Inhibit cortisol:

• 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
  • Probably the most important regulator of the 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 deficiency and other IGF1 deficiencies can inhibit cortisol production

3. Control ranges of cortisol¶

Cortisol crosses the blood-brain barrier (unlike adrenaline and noradrenaline) and can therefore act as a hormone in the body and as a neurotransmitter in the brain.

3.1. Behavioral effect of cortisol¶

Cortisol changes:

• Behavior⁵⁵
  • Submissive behavior⁵⁶
• Feelings⁵⁷
  • E.g. fear⁵⁵
  • Mood⁵⁵⁵⁷
    • Cortisol has a depression-promoting effect⁵⁸
• Memory performance⁵⁷
  • At a moderate level: improvement⁵⁵
  • At high level: deterioration⁵⁵
    • Stress-induced cortisol release leads to overstimulation of noradrenaline α1 receptors in the PFC. Noradrenaline impairs the function of the PFC and working memory via noradrenaline α1 receptors. The simultaneous addressing of these receptors intensifies 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¶

3.2.1.1. Cortisol activates dopamine¶

Dopamine^{6061 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 noradrenaline levels in the cells and thus their effect.⁵⁹
* Glucocorticoids regulate dopamine release in the PFC and the ventral tegmentum (VTA, one of the most important brain regions for dopamine production) via glucocorticoid receptors (GR) in the PFC (and not in the VTA) and alter the firing of dopaminergic projections.⁵⁹
* Cortisol activates the mesocorticolimbic dopaminergic system⁶³

3.2.1.2. Cortisol activates noradrenaline¶

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 noradrenaline levels in the cells and thus their effect. Increased noradrenaline levels in the PFC impair the function of the PFC.⁵⁹

3.2.1.3. 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 DRN and in the brain regions addressed by them with serotonin.
• Only hopeless, but not remediable stress leads to an increase in serotonin in the DRN, hippocampus and amygdala.
  On the other hand, stress that is not unavoidable increases the release of serotonin in the periaqueductal gray.
  Corticosterone plays a decisive role in these effects by stimulating tryptophan hydroxylase activity and serotonin metabolism in the brain.
  Unlike noradrenergic cells in the nucleus coeruleus, the firing rate of DRN serotonin cells does not increase with stress, although stress increases cFos expression.

3.2.1.4. Cortisol activates the amygdala¶

Cortisol activates the peptidergic CRH nucleus of the amygdala⁶³

3.2.1.5. Cortisol activates energy mobilization¶

Cortisol stimulates energy mobilization by activating:⁵⁸

• Glycolysis in the liver
• Proteolysis

3.2.1.6. Cortisol increases vasoconstriction¶

Cortisol potentiates the vasoconstriction.⁵⁸

3.2.2. Cortisol has an inhibitory effect¶

Cortisol has an inhibitory effect:

• CRH
  Glucocorticoids (cortisol) inhibit CRH production and thus the first stage of the HPA axis.⁶³
• Noradrenaline
  Glucocorticoids (cortisol) inhibit noradrenaline production in the nucleus coeruleus, and thus indirectly the effects of noradrenaline.⁶³
  Noradrenaline stimulates CRH production and inhibits the function of the PFC (in larger quantities).
• Serotonin
  In the case of reduced availability of the serotonin precursor tryptophan, cortisol causes reduced synthesis, release and metabolism of serotonin and thus an increased risk of depression.⁶⁵
• Beta-endorphin
• Cortisol reduces melatonin in fish⁶⁶
• Gonadotropin secretion in the pituitary gland⁶³
• Growth hormone production⁶³
• Thyrotropin (thyrotropin) secretion⁶³
• Suppresses 5′-deiodinase, which converts the relatively inactive tetraiodothyronine (T4) into 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 a direct effect on the bone⁶³
    • And can thus cause osteoporosis⁶³
  • Hypoththalamic-pituitary-gonadal axis⁵⁸
    • Cortisol significantly reduces testosterone production in Leydig cells
    • Thereby disrupting reproduction in men
  • Bone and muscle growth⁵⁸

3.2.3. Cortisol inhibits the stress systems¶

3.2.3.1. Cortisol inhibits the 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 downregulating the HPA axis, which is designed for a limited period of activity. This works by only the glucocorticoid receptors (GR) - which are only about 1/10 as sensitive to cortisol as the mineralocorticoid receptors (MR) - bringing about the downregulation of the HPA axis. Low cortisol levels, which only utilize the MR, do not cause HPA axis inhibition, but only particularly high cortisol levels (at which the insensitive GR receptors are also addressed after the more sensitive MR receptors are saturated).⁶⁷
When the GR are activated, they downregulate the HPA axis by reducing the release of

• CRH
• Vasopressin
• Cytokines and
• Reduce POMC

and (at least in rats) facilitate the storage of information.⁶⁸ This makes it easier to anchor successful stress management strategies in memory.

3.2.3.2. Cortisol inhibits the 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 of the body’s major homeostatic systems, including innate and acquired immunity⁶⁹
In particular, cortisol inhibits the innate immune system:⁵⁸

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

3.3.1. Cortisol inhibits inflammation (promoted by CRH)¶

Cortisol is the body’s most powerful immune system suppressor, primarily 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 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 only beneficial in the short term. If they are active for too long (due to prolonged stress), they attack cells and tissue, which can lead to chronic inflammatory bowel diseases in addition to the degeneration of cells (cancer) and damage to the immune system.
In order to limit the effect of the pro-inflammatory cytokines promoted by CRH over time, the cortisol released by the HPA axis (which intervenes late during stress) has an inhibitory effect on the 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 antibodies
      • 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 the promotion of 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. With habituation to the stressor, the cortisol stress response decreases, but apparently not (or more slowly?) the IL-6 stress response.⁷²
* Interleukin IL-10
* Interleukin IL-13.
* These TH-2 cytokines defend against extracellular pathogens (bacteria, parasites) and promote basophils, mast cells and eosinophils, which can promote allergies if excessive.
* TH1 inhibition and TH2 promotion is also called TH1/TH2 shift
* In addition to cortisol, noradrenaline also appears to cause a shift from TH1 to TH2, while serotonin and melatonin could mediate a shift from TH2 to TH1.⁷³
* The modulation of neurotransmitters on the TH1/TH2 balance could be relative, with the aim of restoring physiological levels to a previous imbalance in receptor sensitivity and cytokine production.⁷³ This could be relevant 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 partly due to the inhibition of histamine.⁷⁴

3.3.2. Immunological consequences of too little cortisol (hypocortisolism)¶

Inflammatory problems,⁷¹ e.g:

• Neurodermatitis (atopic eczema, neurodermatitis)
• Fibromyalgia
• Intestinal inflammatory disorders

3.3.3. Immunological consequences of too much cortisol (hypercortisolism)¶

Allergies⁷¹

3.4. Neurotoxic effects of glucocorticoids (cortisol) during prolonged stress¶

3.4.1. General effects of cortisol during stress¶

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

Glucocorticoids (cortisol) inhibit the hypothalamus and pituitary gland in two phases. In the fast phase, the release 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 is excreted esterified in the urine. Only about 1 % of cortisol is freely detectable in the urine.⁷⁹

However, cortisol becomes harmful if 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 the activity of the HPA axis^{8283 84} (instead of inhibition with short-term effect)
• Cortisol increases the mRNA expression of CRH in the central amygdala.⁸⁵
• Activation of the autonomic 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)
• Grease buildup in
  • Face
  • Neck
  • Trunk
  • Abdomen (belly)
• Thinner and more fragile skin
• Wound healing worsens
• Osteoporosis
• Kidney stones
• Increased susceptibility to infection
• 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

Gene expression is influenced by the binding of hormones to the corticosteroid receptors.⁹¹

3.5. Cortisol influences brain development¶

Glucocorticoids influence the development of the brain 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
• reduced or excessive glucocorticoid levels cause structural and functional abnormalities in neurons and glial cells
  • Effect often over the entire lifespan
• Glucocorticoids cause the precursor cells of the adrenal medulla to differentiate into chromaffin cells that produce catecholamines.⁹³

Glucocorticoids are regulated by

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

As ADHD is also described as a brain development disorder, the possible influence of glucocorticoids as endogenous stress hormones in the child before or after birth, from transmission via the placenta by the mother or through the introduction of medication, should be kept in mind.

3.6. Cortisol influences energy balance¶

Cortisol influences

• Glycolysis⁸⁹
  The glycolysis of catecholamines is regulated 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 splitting, fat digestion)⁹⁴⁹⁵
  Impairment can be exacerbated by reduced ACTH levels⁸⁹
• Impairment of metabolic adaptation during regeneration phases⁸⁹
• Cortisol increases the success of pleasurable or compulsive activities (intake of sucrose, fat and drugs). This motivates the intake of “comfort food”.⁸⁵
• Cortisol systemically increases the fat deposits in the abdomen. This causes⁸⁵
  • Inhibition of catecholamines in the brain stem and
  • 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 this causes either increased food intake and weight gain or decreased food intake and weight loss.⁸⁵⁹⁶
• Several studies show a correlation between the cortisol stress response and the waist-to-hip ratio, so that a low cortisol stress response is associated with a low waist-to-hip ratio (less pronounced waist), while a high cortisol stress response is associated with a high waist-to-hip ratio (pronounced 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 influences gene expression, transcription factors and brain regions¶

• Cortisol influences up to 20 % of the expressed human genes⁶⁹
• Glucocorticoid receptor interacts reciprocally with transcription factors for the coordinated (highly stochastic) regulation of brain functions, 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 a deactivation of brain regions. Deactivated are¹⁰¹
  • Limbic system
    • Hippocampus
  • Hypothalamus
  • Medio-orbitofrontal cortex (mOFC)
  • Anterior cingulate cortex (ACC)

4. Measurement of cortisol¶

• Salivary cortisol levels correspond to blood cortisol levels, albeit with a time delay of a few minutes
• Cortisol (like other stress hormones) can already increase as a result of a puncture when blood is drawn.¹⁰² Around a third of all adults show an increase in cortisol following a venipuncture for blood sampling,^{103104 105 106} as do 50 to 80 % of children, especially those with ADHD (cortisol increase and alpha-amylase increase).¹⁰⁷
  We therefore strongly recommend a waiting time of 30 to 40 minutes between puncture and blood sampling.¹⁰⁸
  These results can also be seen 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 However, it is questionable 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 (who do not know what is to come after the injection and who may have had to be captured for the blood sample to be taken) than in humans, who are aware that it is only a small prick and that nothing else bad will happen.