Cortisol and stress axis changes in other disorders.

Cortisol responses to acute stress show a rough pattern in different disorders: mental disorders with internalizing symptoms predominantly show an exaggerated cortisol response to acute stress, whereas disorders with externalizing symptoms tend to show a flattened cortisol stress response.

• 1. Early childhood stress
  • 1.1. Premature births
  • 1.2. Anxiety / stress of the mother in pregnancy
  • 1.3. Binding problems
• 2. Depression
• 3. Dysthymia
• 4. Premenstrual dysphoric disorder (PMD)
• 5. Burnout
• 6. Bipolar Disorder / Bipolar Depression
• 7. Mania
• 8. Traumas
• 9. PTSD - Post Traumatic Stress Disorder
• 10. Borderline
• 11. Anxiety disorders
• 12. Panic disorders
• 13. Repressors
• 14. Psychopathy
• 15. Schizophrenia
• 16. Neurodermatitis and other inflammatory diseases
• 17. Chronic fatigue syndrome (CFS)
• 18. Chronic lower abdominal pain
• 19. Neurological diseases (e.g. multiple sclerosis)
• 20. Dementia, Alzheimer
• 21. Obesity
• 22. Hypertension
• 23. Allergies
• 24. Overtraining
• 25. Learning Disabilities

1. Early childhood stress¶

In those affected by early childhood stress, the dexamethasone test showed an exaggerated cortisol response.¹

Affected individuals from early childhood stress basically showed elevated levels of inflammatory biomarkers (inflammatory levels) due to the lack of cortisol response.²³

1.1. Premature births¶

Preterm infants-and more so girls-had higher cortisol on awakening, flatter CAR, and an exaggerated cortisol response to the TSST-C as a stressor compared with full-term infants. Preterm infants had more emotional problems and poorer memory performance at the same time. The authors conclude that early childhood stress alters HPA axis response levels, causing stress vulnerability.⁴

1.2. Anxiety / stress of the mother in pregnancy¶

The mother’s level of anxiety during pregnancy correlated with the intensity of the infant’s stress response: the babies’ cortisol response was excessive 5 weeks after birth, but had leveled off by 8 weeks and 12 months. The correlation with the mothers’ cortisol level 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, the left side 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. Likewise, cortisol responses to acute stressors are significantly elevated.⁶

1.3. Binding problems¶

In 78 young adult women, attachment problems correlated with a higher cortisol response to TSST-G as a stressor, independent of age, smoking status, menstrual phase, and body mass index. In this regard, an insecure attachment style (high insecurity and high attachment seeking) produced a higher cortisol reactivity than an avoidant (high insecurity and low attachment seeking) or secure attachment style. The timing of the cortisol peak or the cortisol decline after stress did not correlate with attachment style.⁷

2. Depression¶

Depression, like ADHD-HI and ADHD-I, knows two distinct manifestations that are also distinguished on the basis of the cortisol stress response.

Melancholic (endogenous) and psychotic depression are characterized by an exaggerated cortisol stress response (like ADHD-I). Atypical depression and bipolar depression (bipolar disorder) are characterized by a flattened cortisol stress response (like ADHD-HI).
See more at ⇒ Melancholic and atypical depression

In depression, the proinflammatory cytokines are

• Tumor necrosis factor
• Interleukin 1β (IL-1β)
• Interleukin IL-6
  increased, as well as the likewise in inflammatory reactions relevant
• C-reactive protein (CRP)⁸

In depression, the glucocorticoid receptor appears to be endowed with decreased sensitivity, whereas in PTSD, the glucocorticoid receptor shows increased sensitivity. In mice, an HDAC6 inhibitor normalized glucocorticoid receptor sensitivity and social behavior without concomitantly altering the glucocorticoid response to the DEX/CRH test.⁹

3. Dysthymia¶

Children with dysthymia, unlike those with depression, have been found to have decreased basal cortisol levels.¹⁰

4. Premenstrual dysphoric disorder (PMD)¶

A flattened cortisol response to stress has been observed in mild depression during the pre-menstrual period.¹¹ Only during the luteal phase of menstruation (from menstruation to ovulation) is sensitivity to benzodiazepines, ethanol (alcohol), and GABA steroids reduced in PMD, but not in the follicular phase between ovulation and menstruation, suggesting temporary receptor downregulation.¹²

5. Burnout¶

In burnout, exaggerated suppression of cortisol was observed on the low-dose dexamethasone test (0.5 mg instead of 1 mg DEX).¹³

6. Bipolar Disorder / Bipolar Depression¶

For Bipolar Depression, the studies show predominantly a flattened cortisol stress response, and 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 exaggerated amylase stress response, suggesting autonomic nervous system involvement in bipolar disorder.

It is possible that the cortisol response changes depending on the phase of illness. In an older long-term study, cortisol nonsupression to the dexamethasone test was found in half of bipolar sufferers during depressive phases, but in no bipolar sufferers in a euthymic (balanced) or manic phase.²²

Bipolar depressives (depression with manic phases) have compared to unipolar depressives (depression without manic phases):²³

• No deviations of basal cortisol levels
  • Cortisol stress responses were unfortunately not studied
• CAR cortisol rise/cortisol fall over the day increased in men, not in women
• Deviations in C-reactive protein
• 8% (men: 48% instead of 40%) to 10% (women: 46% instead of 36%) more active smokers
• Somewhat lower alcohol consumption
• Slightly increased physical activity
• Slightly increased BMI
• Reduced sleep
• Inflammation levels
  • For men
    • Inflammation levels increased (not significant)
    • Increased use of anti-inflammatory medications (not significant)
  • For women
    • Inflammation values unchanged
    • Lower use of anti-inflammatory medications (not significant)

Treatment of bipolar and schizophrenia subjects with the glucocorticoid antagonist mifepristone initially resulted in a substantial increase in cortisol levels during the first 7 days and a substantial decrease in cortisol levels beginning on day 21.²⁴

In bipolar 1, an exaggerated ACTH response to CRH (in lithium-treated, mood-balanced sufferers without acute symptoms) could predict the likelihood of a (hypo)manic phase in the following 6 months.²⁵

Acute tryptophan minimization (resulting in serotonin deficiency) in lifelong symptom-free direct relatives of bipolar 1 and bipolar 2 sufferers and in controls without bipolar relatives showed²⁶

• In bipolar 2 relatives, a cortisol decrease and mood improvement
• In bipolar 1 relatives and controls, a cortisol decline and mood deterioration
• Increased manic symptoms in lithium-treated manic patients
• No changes were noted in bipolar sufferers who had been symptom-free for 1 to 15 years

7. Mania¶

In mania, the HPA axis cortisol response to dexamethasone usually appears elevated, as does the ACTH response to CRH. 6 months after mania symptoms had subsided, cortisol levels had normalized in one study, but ACTH levels had not.²⁷

8. Traumas¶

Traumatic childhood experiences correlate with a flattened cortisol response to stress.²⁸

In adults with post-traumatic stress disorder, corticoid receptors are hypersensitive. This is associated with decreased cortisol levels in the blood.²⁹

Exaggerated suppression of cortisol to low-dose dexamethasone (0.5 mg rather than 1 mg DEX) has been observed in trauma , e.g., Adolescents Exposed to Earthquake-Related Trauma,³⁰ Women with Childhood Sexual Abuse³¹ and Women with Childhood Sexual Abuse and Chronic Pelvic Pain,³² although this may also be the result of reported decreased adrenocortical responsiveness.

9. PTSD - Post Traumatic Stress Disorder¶

In PTSD, an increase in norepinephrine in the spinal fluid correlates with symptom severity.³³

In PTSD, decreased basal cortisol levels, increased lymphoid glucocorticoid receptors, increased cortisol suppression to dexamethasone, and increased secretion of ACTH to metapyrone have been noted.³⁴³⁵³⁶
Elevated basal CRH levels continued to be seen in PTSD, with no direct correlation of CRH with PTSD symptoms. In contrast, basal cortisol levels were decreased and the decrease correlated significantly with PTSD symptoms. ³⁷

Most studies 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 a small other study of (only 18) women, a flattened cortisol response was found in PTSD and no change in ACTH response. Furthermore, both the ACTH and cortisol response to dexamethasone was flattened.⁴⁰

The majority of the research is consistent with further findings that PTSD is associated primarily with internalizing symptoms and rarely 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 conflicting results could be interpreted to mean that different stress phenotypes also occur in PTSD.

In a stress experiment in 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 decreased sensitivity, whereas in PTSD, the glucocorticoid receptor shows increased sensitivity. In mice, an HDAC6 inhibitor normalized glucocorticoid receptor sensitivity and social behavior without concomitantly altering the glucocorticoid response to the DEX/CRH test.⁹

10. Borderline¶

In borderline sufferers without comorbid PTSD, the DST showed an increased ACTH response; in borderline sufferers with comorbid PTSD, the DST showed a significantly attenuated ACTH response.⁴⁴

11. Anxiety disorders¶

Anxiety disorders correlate with elevated morning (CAR) or serum cortisol levels.⁴⁵⁴⁶

A meta-analysis of 732 adults with acute (some social) anxiety disorder showed a decreased cortisol response to acute stress in women and an increased cortisol response in men.⁴⁷

Social anxiety disorder sufferers who had suffered early maltreatment showed significantly higher cortisol responses to the TSST as a psychosocial stressor than social anxiety disorder sufferers without early maltreatment, PTSD sufferers without early maltreatment, and non-sufferers.⁴⁸

12. Panic disorders¶

In panic disorders, the HPA axis cortisol response to dexamethasone is increased, as is the ACTH response to CRH.⁴⁹

13. Repressors¶

Repression is called a coping style characterized by low anxiety and a high need for defense. This could be associated with externalizing behavior. Women with a high Repressor score were significantly more likely to show a flattened cortisol stress response and lower subjective feelings of stress on the TSST.⁵⁰

14. Psychopathy¶

ADHD-affected children showed a more 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 levels, greatly reduced resting cortisol levels were found.⁵²

15. Schizophrenia¶

A flattened cortisol stress response was found in schizophrenia. The higher the anxiety in schizophrenia sufferers, the lower the cortisol stress response.¹⁹

Cortisol level on awakening and cortisol awakening response were normal.¹⁹

16. Neurodermatitis and other inflammatory diseases¶

Atopic immune disorders (such as atopic dermatitis) could be due to an exaggerated immune response due to lowered cortisol levels. Cortisol re-inhibits inflammation promoted by CRH (first stage of the HPA axis) by means of inflammatory cytokines. If cortisol release (third stage of the HPA axis) is too low, inflammation is not sufficiently inhibited.⁵³

Too little cortisol (hypocortisolism) causes inflammatory problems:⁵⁴

• Neurodermatitis
• Fibromyalgia⁵⁵⁵⁶
• Inflammatory bowel disease⁵⁶
• Asthma

A study of cortisol responses to the TSST-C in children with atopic atopic dermatitis showed significantly attenuated cortisol responses compared with a nonatopic 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 of cortisol responses to the TSST-C in children with allergic asthma also showed significantly attenuated cortisol responses compared with a nonatopic control group. The reduced cortisol responses to the stressor could not be explained by corticosteroid medication or differences in personality variables.⁵⁷

17. Chronic fatigue syndrome (CFS)¶

CFS is characterized by

• Does not already exist for life
• Lasting at least 6 months
• States of exhaustion that cannot be medically explained in any other way,
  that 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 exhaustion after exertion

CFS, like other inflammatory disorders, often occurs as a result of severe viral infections, e.g., following Epstein-Barr or XMRV. These are thought to upset the immune system in conjunction with the stress response system that models it. Elevated levels of proinflammatory cytokines have been found, e.g., IL-6 or TNF-alpha, suggesting subtle chronic inflammatory processes. IL-6 triggers symptoms of exhaustion.⁵⁶

In CFS, the cortisol awakening response (CAR) (only in women) and basal cortisol levels are decreased.⁵⁶ 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 to decreased dexamethasone administration of 0.5 mg.⁵⁸ In dexamethasone testing, administration of 1 mg DEX is common.

In CFS, an increased sensitivity of the adrenal cortex to ACTH with a concomitant cortisol response limited in magnitude has been described.⁵⁹

Fatigue could be explained by central activation of proinflammatory cytokines. Named are:⁶⁰

• Interleukin 1ß (IL-1ß)
• IL-6
• IL-8
• CD40L
• IFN-alpha.

Besides this

• C-reactive protein (CRP)

be increased.

A reduction is reported from

• IL-16
• IL-17
• VEGF.

Because CFS is a neuroinflammatory disorder, measurement of cytokines in the blood is not useful.

18. Chronic lower abdominal pain¶

Women with chronic lower abdominal pain exhibit alterations in the HPA axis. They show a markedly decreased cortisol response to CRH test stimulation.⁶¹

19. Neurological diseases (e.g. multiple sclerosis)¶

In multiple sclerosis, the HPA axis cortisol response to dexamethasone is usually excessive, whereas the ACTH response to CRH is unchanged. In this context, even in MS patients, some stand out with a severely exaggerated and others with a flattened cortisol response.⁶²

20. Dementia, Alzheimer¶

In dementia and Alzheimer’s disease, daytime cortisol levels appear to be significantly elevated.⁶³

21. Obesity¶

Men with a high waist-to-hip ratio (WHR) tend to have an increased cortisol response to stress loading. Exposure to stress and increases in WHR are specifically associated with poorer performance on declarative memory tasks (spatial recognition memory and pairwise associated learning).⁶⁴

22. Hypertension¶

Hypertension is associated with ADHD-HI, not ADHD-I. On this side, hypertension is therefore thought to be associated with a flattened cortisol response to acute stressors.
In ADHD-HI, on this side, it is suspected that there is a deficiency or underfunction of glucocorticoid receptors, which is why the HPA axis is not shut down cleanly.

Hypertension can be treated by mineralocorticoid antagonists,⁶⁵ indicating an imbalance of too many/too active mineralocorticoid receptors (MR) versus too few/too inactive GR.

23. Allergies¶

Cortisol activates the immune defense against foreign bodies (bacteria, parasites):⁵⁴

• Cortisol re-inhibits CRH-triggered inflammation promotion (inhibition of proinflammatory cytokines)
• Cortisol instead promotes contrainflammatory (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 repel extracellular pathogens (bacteria, parasites) and promote basophils, mast cells, and eosinophils, which can promote allergies when they are in excess.
• The shift from TH1 inhibition to TH2 promotion triggered by cortisol is also called TH1/TH2 shift

Too much cortisol (hypercortisolism), which is typical in ADHD-I, is therefore allergy-promoting.⁵⁴

“Allergic” asthma, on the other hand, seems to be more of an inflammatory response, which is a typical consequence of hypocortisolism, such as occurs in ADHD-HI.

24. Overtraining¶

In the case of an overtraining condition of athletes, the studies show partly

• Elevated basal cortisol levels and a decreased cortisol stress response to further physical exertion
  and partly
• Decreased basal cortisol levels and increased cortisol stress response to further physical stress.⁶⁶

These two response profiles could support the present hypothesis of different stress phenotypes in humans. Consistent with this would be that a flattened cortisol response in the overtraining state could be attributed to a

• Reduced ACTH stimulation⁶⁷
• Decreased ACTH sensitivity of the adrenal cortex.⁶⁸

The explanation with different stress phenotypes, as they are also known in healthy persons and in some mental disorders (ADHD-I/ADHD-HI; melancholic/atypical depression), seems to be more conclusive than the explanations of the flattened cortisol response to physical overload by means of⁶⁹

• Adrenal cortex depletion
• Reversible adrenocortical insufficiency
• Addisonoid overtraining
• Stage of resistance according to Selye’s model
• Non-specific stressors after physical training
  or
• Increased cortisol elimination rate under stress

25. Learning Disabilities¶

Stress-induced elevated cortisol levels impede the hippocampus’s nighttime processing of learned activities.⁷⁰