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The cortisol responses to acute stress show a rough pattern in different disorders: mental disorders with internalizing symptoms predominantly show an excessive cortisol response to acute stress, while disorders with externalizing symptoms tend to have a flattened cortisol stress response.
In those affected by early childhood stress, the dexamethasone test showed an excessive cortisol response.1
People affected by early childhood stress generally showed increased levels of inflammatory biomarkers (inflammation values) due to the lack of cortisol response.23
Preterm infants - and here even more so girls - had a higher cortisol level on waking, a flatter CAR and an excessive cortisol response to the TSST-C as a stressor compared to full-term infants. Preterm infants also had more emotional problems and poorer memory performance. The authors conclude that early childhood stress alters the response values of the HPA axis and thus causes susceptibility to stress.4
1.2. Anxiety / stress of the mother during pregnancy¶
The mother’s level of anxiety during pregnancy correlated with the intensity of the infant’s stress response: the babies’ cortisol response was elevated 5 weeks after birth, but had leveled off by 8 weeks and 12 months. The correlation with the mothers’ cortisol levels was comparatively lower.5
The functions of the PFC are divided hemispherically. The right side of the PFC is responsible for controlling stress and negative emotions, while the left side is responsible for controlling positive emotions. If the EEG activity of the right hemisphere is particularly strong, this causes increased anxiety and leads to particularly defensive behavior. In these individuals, basal blood cortisol levels and cerebral CRH levels are significantly elevated. Cortisol responses to acute stressors are also significantly elevated.6
In 78 young adult women, attachment problems correlated with a higher cortisol response to the TSST-G as a stressor, regardless of age, smoking status, menstrual phase and body mass index. An insecure attachment style (high insecurity and high attachment seeking) caused a higher cortisol reactivity than an avoidant (high insecurity and low attachment seeking) or secure attachment style. The time of the cortisol peak or the cortisol decrease after the stress did not correlate with an attachment style.7
Like ADHD-HI and ADHD-I, depression has two different manifestations, which also differ in terms of the cortisol stress response.
Melancholic (endogenous) and psychotic depression are characterized by an excessive cortisol stress response (like ADHD-I). Atypical depression and bipolar depression (bipolar disorder) are characterized by a flattened cortisol stress response (like ADHD-HI).
More on this at ⇒ Melancholic and atypical depression
In depression, the glucocorticoid receptor appears to be endowed with reduced sensitivity, whereas in PTSD the glucocorticoid receptor shows increased sensitivity. In mice, an HDAC6 inhibitor normalized glucocorticoid receptor sensitivity and social behavior without altering the glucocorticoid response to the DEX/CRH test.9
In mild depression in the period before menstruation, a flattened cortisol response to stress was observed.11 Only during the luteal phase of menstruation (from menstruation to ovulation) is the sensitivity to benzodiazepines, ethanol (alcohol) and GABA steroids reduced in PMD, but not in the follicular phase between ovulation and menstruation, which indicates a temporary receptor downregulation.12
For bipolar depression, the studies predominantly show a flattened cortisol stress response, otherwise a normal cortisol stress response. This is consistent with the distribution in ADHD-HI, where a flattened cortisol stress response also predominates, but normal cortisol stress responses were also found. In addition, there appears to be an excessive amylase stress response, which suggests involvement of the autonomic nervous system in bipolar disorder.
Studies on the cortisol stress response in bipolar depression
In type 1 bipolar depression, a flattened cortisol and elevated amylase stress response was found, which correlated with antipsychotic medication.14
From this, the authors conclude that the changes in stress responses are a consequence of the medication rather than a characteristic of the disease itself.
An excessive amylase response was also found in another study in bipolar women and men.15
In our opinion, the fact that the unaffected twins of the test subjects showed normal stress responses suggests that this is a consequence of the illness and not a genetic disposition. This is further supported by the fact that the children of parents affected by bipolar do not show a different cortisol stress response than children of healthy parents.16
In our opinion, the fact that an excessive cortisol stress response is usually observed in unipolar psychotic depression could indicate that this is a consequence of the illness and not a consequence of the medication. If antipsychotic medication caused a flattened cortisol response, this would also be found to be typical in psychotic unipolar depression.
Another study found an increased high-frequency heart rate variability (HF-HRV) as a stress response in bipolar patients in addition to a flattened cortisol stress response, while the HF-HRV as well as the cortisol level were reduced in the resting state.17
Unlike non-affected people, bipolar sufferers showed a flattened cortisol response to tryptophan administration.18
In other studies, a normal cortisol stress response was found in bipolar.1915
The cortisol level on awakening and the cortisol awakening response were also normal.19
5 studies on a total of 120 bipolar patients found around 80 % nonsuppression. With regard to pure mania, in 15 studies with a total of around 330 test subjects, around half of those affected by mania showed suppression, while the other half showed nonsuppression on the dexamethasone test. 20
An excessive cortisol response (nonsupression) to the dexamethasone/CRH test was found in both remitted and non-remitted bipolar patients.21
It is possible that the cortisol response changes depending on the phase of the illness. In an older long-term study, a cortisol nonsupression to the dexamethasone test was found in half of the bipolar patients during the depressive phases, but in none of the bipolar patients in a euthymic (balanced) or manic phase.22
Bipolar depressives (depression with manic phases) have a higher risk of depression than unipolar depressives (depression without manic phases):23
No deviations in the basal cortisol values
Cortisol stress responses were unfortunately not investigated
CAR cortisol increase / cortisol decrease over the day increased in men, not in women
Deviations in the C-reactive protein
8 % (men: 48 % instead of 40 %) to 10 % (women: 46 % instead of 36 %) more active smokers
Slightly lower alcohol consumption
Slightly increased physical activity
Slightly increased BMI
Reduced sleep
Inflammation values
For men
Inflammation values increased (not significant)
Increased use of anti-inflammatory medication (not significant)
For women
Inflammation values unchanged
Reduced use of anti-inflammatory medication (not significant)
Treatment of bipolar and schizophrenia patients with the glucocorticoid antagonist mifepristone initially led to a considerable increase in cortisol levels in the first 7 days and to a considerable drop in cortisol levels from the 21st day onwards.24
In bipolar 1, an excessive ACTH response to CRH (in lithium-treated, mood-balanced patients without acute symptoms) could predict the likelihood of a (hypo)manic phase in the following 6 months.25
Acute tryptophan depletion (resulting in serotonin deficiency) in lifelong symptom-free direct relatives of bipolar 1 and bipolar 2 sufferers and in controls without bipolar relatives showed26
A decrease in cortisol and an improvement in mood in bipolar 2 relatives
In bipolar 1 relatives and controls a decrease in cortisol and a deterioration in mood
Increased manic symptoms in lithium-treated manic patients
No changes were observed in bipolar sufferers who had been symptom-free for 1 to 15 years
In mania, the cortisol response of the HPA axis to dexamethasone generally appears to be increased, as is the ACTH response to CRH. in one study, cortisol levels had normalized 6 months after the mania symptoms had subsided, but ACTH levels had not.27
Traumatic childhood experiences correlate with a flattened cortisol response to stress.28
In adults with post-traumatic stress disorder, the corticoid receptors are hypersensitive. This is accompanied by reduced cortisol levels in the blood.29
In trauma, exaggerated suppression of cortisol on the low-dose dexamethasone test (0.5 mg rather than 1 mg DEX) has been observed, e.g. in adolescents exposed to earthquake-related trauma,30 women with childhood sexual abuse31 and in women with childhood sexual abuse and chronic pelvic pain,32 although this could also be the result of reported decreased adrenocortical responsiveness.
In PTSD, an increase in noradrenaline in the spinal fluid correlates with the severity of the symptoms.33
In PTSD, a reduced basal cortisol level, an increased number of lymphatic glucocorticoid receptors, an increased cortisol suppression to dexamethasone and an increased release of ACTH to metapyrone were found.343536
In PTSD, basal CRH levels continued to be elevated without CRH correlating directly with PTSD symptoms. In contrast, basal cortisol levels were reduced and the reduction correlated significantly with PTSD symptoms. 37
Most studies have found an increased cortisol response to acute stress in PTSD, with dexamethasone leading to increased cortisol suppression, suggesting that the cortisol response to ACTH is enhanced.3839
In another small study of (only 18) women, a flattened cortisol response was found in PTSD and no change in the ACTH response. Furthermore, the ACTH and cortisol response to dexamethasone was flattened.40
The majority of the studies are consistent with other findings that PTSD is primarily associated with internalizing symptoms and hardly with externalizing symptoms.41 The small second study contradicts this.
In contrast, the results on basal cortisol levels in PTSD are contradictory (not increased or decreased).42
The contradictory results could be interpreted to mean that different stress phenotypes also occur in PTSD.
In a stress test on rats, changes in the glucocorticoid/mineralocorticoid ratio were found that could explain the changes in PTSD.43
In depression, the glucocorticoid receptor appears to be endowed with reduced sensitivity, whereas in PTSD the glucocorticoid receptor shows increased sensitivity. In mice, an HDAC6 inhibitor normalized glucocorticoid receptor sensitivity and social behavior without altering the glucocorticoid response to the DEX/CRH test.9
In borderline sufferers without comorbid PTSD, the DST showed an increased ACTH response, in borderline sufferers with comorbid PTSD a significantly weakened ACTH response.44
Anxiety disorders correlate with increased morning (CAR) or serum cortisol levels.4546
A meta-analysis of 732 adults with acute (partly social) anxiety disorder showed a reduced cortisol response to acute stress in women and an increased cortisol response in men.47
People with social anxiety disorder who had suffered early maltreatment showed significantly higher cortisol responses to the TSST as a psychosocial stressor than people with social anxiety disorder without early maltreatment, than PTSD sufferers without early maltreatment and than non-affected people.48
Repression is a coping style characterized by low anxiety and a high need to defend oneself. This could be associated with externalizing behaviour. Women with a high repressor score were significantly more likely to show a flattened cortisol stress response and lower subjective stress perception on the TSST.50
ADHD-affected children showed a flattened cortisol stress response to the TSST the more they showed psychopathic traits (callous unemotional traits/CU traits) such as lack of empathy, coldness of feeling, etc.51
In a group of subjects with high CU trait values, resting cortisol levels were found to be greatly reduced.52
A flattened cortisol stress response was found in schizophrenia. The higher the anxiety in people with schizophrenia, the lower the cortisol stress response.19
The cortisol level on awakening and the cortisol awakening response were normal.19
16. Neurodermatitis and other inflammatory diseases¶
Atopic immune disorders (such as atopic dermatitis) could be due to an excessive immune response caused by low cortisol levels. Cortisol inhibits the inflammation promoted by CRH (first stage of the HPA axis) by means of inflammatory cytokines. If the release of cortisol (third stage of the HPA axis) is too low, inflammation is not sufficiently inhibited.53
Too little cortisol (hypocortisolism) causes inflammatory problems:54
A study on cortisol response to the TSST-C in children with atopic neurodermatitis showed significantly attenuated cortisol responses compared to a non-atopic control group. The reduced cortisol responses to the stressor could not be explained by corticosteroid medication or differences in personality variables. This confirms that atopic dermatitis is an inflammatory response.57
A study on cortisol response to the TSST-C in children with allergic asthma also showed significantly attenuated cortisol responses compared to a non-atopic control group. The reduced cortisol responses to the stressor could not be explained by corticosteroid medication or differences in personality variables.57
States of exhaustion that cannot be explained medically in any other way,
which are not the result of special stress
Is not reduced by rest
Causes substantial restriction of professional and social activities
In addition, at least 4 of the following symptoms are fulfilled:
Non-restorative sleep
Memory / concentration problems
Muscle pain (myalgia)
Joint pain (arthralgia)
Sore throat
Pressure-sensitive lymph nodes on the neck / under the armpits
Headache
Particularly intense and persistent fatigue after exertion
CFS, like other inflammatory disorders, often occurs as a result of severe viral infections, e.g. after Epstein-Barr or XMRV. It is suspected that these infections unbalance the immune system in conjunction with the stress response system that models it. Elevated levels of pro-inflammatory cytokines, e.g. IL-6 or TNF-alpha, have been found, indicating subtle chronic inflammatory processes. IL-6 triggers symptoms of fatigue.56
In CFS, the cortisol awakening response (CAR) (only in women) and the basal cortisol level are reduced.56 The CAR is particularly pronounced in early sexual abuse.56
One study found normal basal cortisol levels and cortisol awakening responses in CFS, but increased and prolonged cortisol suppression in response to a reduced dexamethasone dose of 0.5 mg.58 In the dexamethasone test, an administration of 1 mg DEX is usual.
In CFS, an increased sensitivity of the adrenal cortex to ACTH with a simultaneously limited cortisol response has been described.59
Fatigue could be explained by a central activation of pro-inflammatory cytokines. The following are mentioned:60
Interleukin 1ß (IL-1ß)
IL-6
IL-8
CD40L
IFN-alpha.
In addition
C-reactive protein (CRP)
be increased.
A reduction is reported by
IL-16
IL-17
VEGF.
As CFS is a neuroinflammatory disorder, the measurement of cytokines in the blood is not useful.
Women with chronic lower abdominal pain exhibit changes in the HPA axis. They show a significantly reduced cortisol response to CRH test stimulation.61
In multiple sclerosis, the cortisol response of the HPA axis to dexamethasone is generally excessive, while the ACTH response to CRH is unchanged. In MS patients, too, some have a greatly increased cortisol response and others a flattened one.62
Men with a high waist-to-hip ratio (WHR) tend to have an increased cortisol response to stress. Exposure to stress and increases in WHR are specifically associated with poorer performance on declarative memory tasks (spatial recognition memory and pair-associated learning).64
Hypertension is associated with ADHD-HI, not ADHD-I. On this side, it is therefore assumed that high blood pressure is associated with a flattened cortisol response to acute stressors.
In ADHD-HI, it is assumed on this side that there is a lack of or an underfunction of the glucocorticoid receptors, which is why the HPA axis is not properly switched off.
Hypertension can be treated by mineralocorticoid antagonists,65 which indicates an imbalance of too many / too active mineralocorticoid receptors (MR) versus too few / too inactive GR.
Cortisol activates the immune defense against foreign bodies (bacteria, parasites):54
Cortisol inhibits the promotion of inflammation triggered by CRH again (inhibition of pro-inflammatory cytokines)
Instead, cortisol promotes contra-inflammatory (anti-inflammatory) cytokines (T-helper type 2 cytokines, e.g. interleukin IL-4, IL-5, IL-6 and IL-10).
The TH-2 cytokines promoted by cortisol ward off extracellular pathogens (bacteria, parasites) and promote basophils, mast cells and eosinophils, which can promote allergies if excessive.
The change from TH1 inhibition to TH2 promotion triggered by cortisol is also known as the TH1/TH2 shift
Too much cortisol (hypercortisolism), as is typical in ADHD-I, is therefore conducive to allergies.54
“Allergic” asthma, on the other hand, seems to be more of an inflammatory reaction, which is a typical consequence of hypocortisolism, such as occurs in ADHD-HI.
When athletes are in a state of overtraining, the studies show in some cases
Increased basal cortisol levels and a reduced cortisol stress response to further physical stress
and partly
Reduced basal cortisol levels and an increased cortisol stress response to further physical stress.66
These two response profiles could support this hypothesis of different stress phenotypes in humans. It would be compatible with this hypothesis that a flattened cortisol response in the overtraining state could be attributed to a
The explanation with different stress phenotypes, as they are also known in healthy people and in some mental disorders (ADHD-I/ADHD-HI; melancholic/atypical depression), seems in any case more conclusive than the explanations of the flattened cortisol response to physical overload by means of69
