cortisol – Page 3 – American ME and CFS Society

Stress management skills, cortisol awakening response, and post-exertional malaise in Chronic Fatigue Syndrome

Abstract:

Chronic Fatigue Syndrome (CFS) is characterized in part by debilitating fatigue typically exacerbated by cognitive and/or physical exertion, referred to as post-exertional malaise (PEM). In a variety of populations, the cortisol awakening response (CAR) has stood out as a marker of endocrine dysregulation relevant to the experience of fatigue, and may therefore be particularly relevant in CFS.

This is the first study to examine PEM and the CAR in a sample of individuals with CFS. The CAR has also been established as a stress-sensitive measure of HPA axis functioning. It follows that better management of stress could modulate the CAR, and in turn PEM. In this cross-sectional study, we hypothesized that greater Perceived Stress Management Skills (PSMS) would relate to lower reports of PEM, via the impact of PSMS on the CAR.

A total of 117 adults (72% female) with a CFS diagnosis completed self-report measures of PSMS and PEM symptomatology and a two-day protocol of saliva collection. Cortisol values from awakening and 30 min post-awakening were used to compute the CAR. Regression analyses revealed that greater PSMS related to greater CAR and greater CAR related to less PEM severity. Bootstrapped analyses revealed an indirect effect of PSMS on PEM via the CAR, such that greater PSMS related to less PEM, via a greater CAR. Future research should examine these trends longitudinally and whether interventions directed at improving stress management skills are accompanied by improved cortisol regulation and less PEM in individuals with CFS.

Source: Hall DL, Lattie EG, Antoni MH, Fletcher MA, Czaja S, Perdomo D, Klimas NG. Stress management skills, cortisol awakening response, and post-exertional malaise in Chronic Fatigue Syndrome. Psychoneuroendocrinology. 2014 Nov;49:26-31. doi: 10.1016/j.psyneuen.2014.06.021. Epub 2014 Jul 6. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4165790/ (Full article)

A role for homeostatic drive in the perpetuation of complex chronic illness: Gulf War Illness and chronic fatigue syndrome

Erratum in

PLoS One. 2014;9(4):e94161.
PLoS One. 2014;9(6):e100355.

Abstract:

A key component in the body’s stress response, the hypothalamic-pituitary-adrenal (HPA) axis orchestrates changes across a broad range of major biological systems. Its dysfunction has been associated with numerous chronic diseases including Gulf War Illness (GWI) and chronic fatigue syndrome (CFS). Though tightly coupled with other components of endocrine and immune function, few models of HPA function account for these interactions.

Here we extend conventional models of HPA function by including feed-forward and feedback interaction with sex hormone regulation and immune response. We use this multi-axis model to explore the role of homeostatic regulation in perpetuating chronic conditions, specifically GWI and CFS. An important obstacle in building these models across regulatory systems remains the scarcity of detailed human in vivo kinetic data as its collection can present significant health risks to subjects. We circumvented this using a discrete logic representation based solely on literature of physiological and biochemical connectivity to provide a qualitative description of system behavior. This connectivity model linked molecular variables across the HPA axis, hypothalamic-pituitary-gonadal (HPG) axis in men and women, as well as a simple immune network. Inclusion of these interactions produced multiple alternate homeostatic states and sexually dimorphic responses.

Experimental data for endocrine-immune markers measured in male GWI subjects showed the greatest alignment with predictions of a naturally occurring alternate steady state presenting with hypercortisolism, low testosterone and a shift towards a Th1 immune response. In female CFS subjects, expression of these markers aligned with an alternate homeostatic state displaying hypocortisolism, high estradiol, and a shift towards an anti-inflammatory Th2 activation. These results support a role for homeostatic drive in perpetuating dysfunctional cortisol levels through persistent interaction with the immune system and HPG axis. Though coarse, these models may nonetheless support the design of robust treatments that might exploit these regulatory regimes.

Source: Craddock TJ, Fritsch P, Rice MA Jr, del Rosario RM, Miller DB, Fletcher MA, Klimas NG, Broderick G. A role for homeostatic drive in the perpetuation of complex chronic illness: Gulf War Illness and chronic fatigue syndrome. PLoS One. 2014 Jan 8;9(1):e84839. doi: 10.1371/journal.pone.0084839. ECollection 2014. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3885655/ (Full article)

Linking disease symptoms and subtypes with personalized systems-based phenotypes: a proof of concept study

Abstract:

A dynamic systems model was used to generate parameters describing a phenotype of Hypothalamic-Pituitary-Adrenal (HPA) behavior in a sample of 36 patients with chronic fatigue syndrome (CFS) and/or fibromyalgia (FM) and 36 case-matched healthy controls. Altered neuroendocrine function, particularly in relation to somatic symptoms and poor sleep quality, may contribute to the pathophysiology of these disorders.

Blood plasma was assayed for cortisol and ACTH every 10 min for 24h. The dynamic model was specified with an ordinary differential equation using three parameters: (1) ACTH-adrenal signaling, (2) inhibitory feedback, and (3) non-ACTH influences. The model was “personalized” by estimating an individualized set of parameters from each participant’s data. Day and nighttime parameters were assessed separately.

Two nocturnal parameters (ACTH-adrenal signaling and inhibitory feedback) significantly differentiated the two patient subgroups (“fatigue-predominant” patients with CFS only versus “pain-predominant” patients with FM and comorbid chronic fatigue) from controls (all p’s<.05), whereas daytime parameters and diurnal/nocturnal slopes did not. The same nocturnal parameters were significantly associated with somatic symptoms among patients (p’s<.05). There was a significantly different pattern of association between nocturnal non-ACTH influences and sleep quality among patients versus controls (p<.05).

Although speculative, the finding that patient somatic symptoms decreased when more cortisol was produced per unit ACTH, is consistent with cortisol’s anti-inflammatory and sleep-modulatory effects. Patients’ HPA systems may compensate by promoting more rapid or sustained cortisol production. Mapping “behavioral phenotypes” of stress-arousal systems onto symptom clusters may help disentangle the pathophysiology of complex disorders with frequent comorbidity.

Comment in: A moving target: taking aim at the regulatory dynamics of illness. [Brain Behav Immun. 2012]

Source: Aschbacher K, Adam EK, Crofford LJ, Kemeny ME, Demitrack MA, Ben-Zvi A. Linking disease symptoms and subtypes with personalized systems-based phenotypes: a proof of concept study. Brain Behav Immun. 2012 Oct;26(7):1047-56. doi: 10.1016/j.bbi.2012.06.002. Epub 2012 Jun 9. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3725324/ (Full article)

Increased HDAC in association with decreased plasma cortisol in older adults with chronic fatigue syndrome

Abstract:

Hypocortisolism is a frequent finding in individuals with chronic fatigue syndrome (CFS) with other research findings implying potential dysregulation of glucocorticoid signaling. Glucocorticoid signaling is under the influence of several pathways, several of which are of interest in the study of CFS. Oxidative stress and decreased antioxidant capacity are known to disrupt the hypothalamic-pituitary-adrenal (HPA) axis (Epel et al., 2004) and the presence of histone deacetylases (HDAC) could also impact glucocorticoid signaling.

The intent of this pilot study was to investigate the relationship among oxidative stress elements, select HDAC’s (2/3) and glucocorticoid receptor signaling in an elderly sample with CFS. Findings suggest increased histone deacetylase activity, lower total antioxidant power, in the context of decreased plasma cortisol and increased plasma dehydroepiandrosterone concomitant with decreased expression of the encoding gene for the glucocorticoid receptor. These findings support the presence of HPA axis dysregulation in elderly individuals with CFS.

Source: Jason L, Sorenson M, Sebally K, Alkazemi D, Lerch A, Porter N, Kubow S. Increased HDAC in association with decreased plasma cortisol in older adults with chronic fatigue syndrome. Brain Behav Immun. 2011 Nov;25(8):1544-7. doi: 10.1016/j.bbi.2011.04.007. Epub 2011 Apr 28. https://www.ncbi.nlm.nih.gov/pubmed/21549189

The effects of galantamine hydrobromide treatment on dehydroepiandrosterone sulfate and cortisol levels in patients with chronic fatigue syndrome

Abstract:

OBJECTIVE: Mental fatigue, cognitive disorders, and sleep disturbances seen in chronic fatigue syndrome (CFS) may be attributed to cholinergic deficit. A functional deficiency of cholinergic neurotransmission may cause the hypothalamic-pituitary-adrenal axis hypoactivity seen in CFS. Therefore, we investigated the alterations in stress hormones such as cortisol and dehydroepiandrosterone sulfate (DHEAS) in CFS patients before and after 4-week administration of galantamine hydrobromide, a selective acetylcholinesterase inhibitor, and aimed to investigate whether there are any relationships between the probable hormonal changes and cholinergic treatment.

METHODS: Basal levels of cortisol and DHEAS were measured in 29 untreated CFS patients who were diagnosed according to Centers for Disease Control (CDC) criteria and in 20 healthy controls. In the patient group, four weeks after 8 mg/d galantamine hydrobromide treatment, cortisol and DHEAS levels were measured again. After the treatment 22 patients who stayed in study were divided into two subgroups as responders and nonresponders according to the reduction in their Newcastle Research Group ME/CFS Score Card (NRG) scores.

RESULTS: Important findings of this study are lower pre-and post-treatment cortisol levels and in all CFS patients compared to controls (F=4.129, p=0.049; F=4.803, p=0.035, respectively); higher basal DHEAS values and higher DHEAS/cortisol molar ratios which were normalized following four weeks’ treatment with 8 mg/d galantamine hydrobromide in the treatment-respondent group (F=5.382, p=0.029; F=5.722, p=0.025, respectively).

CONCLUSION: The findings of the decrease in basal DHEAS levels and DHEAS/cortisol molar ratios normalizing with galantamine treatment may give some support to the cholinergic deficit hypothesis in CFS.

Source: Turan T, Izgi HB, Ozsoy S, Tanrıverdi F, Basturk M, Asdemir A, Beşirli A, Esel E, Sofuoglu S. The effects of galantamine hydrobromide treatment on dehydroepiandrosterone sulfate and cortisol levels in patients with chronic fatigue syndrome. Psychiatry Investig. 2009 Sep;6(3):204-10. doi: 10.4306/pi.2009.6.3.204. Epub 2009 Jun 23. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2796068/ (Full article)

Enhanced feedback sensitivity to prednisolone in chronic fatigue syndrome

Abstract:

OBJECTIVE: Enhancement of negative feedback control of the HPA axis in patients with chronic fatigue syndrome (CFS) has been reported using the low dose dexamethasone suppression test. We have developed the use of prednisolone (5mg) as a more physiologically appropriate alternative to dexamethasone in the investigation of mild degrees of glucocorticoid resistance or supersensitivity. The objective of the study was to use this test to look for alterations in negative feedback control of the HPA axis in CFS patients.

METHODS: Fifteen patients with CFS were recruited after fulfilling strict criteria including the absence of comorbid psychiatric diagnosis. They collected urine between 0900 and 1800h and saliva at 0900h pre-prednisolone. At midnight, they took prednisolone (5mg) orally and then collected urine and saliva at the same intervals the following day.

RESULTS: Salivary cortisol was lower in CFS subjects pre-prednisolone than controls. Urinary cortisol metabolites were lower in CFS subjects pre-prednisolone, but did not reach significance. Both measures were significantly lower in CFS subjects post-dose. Mean percentage suppression of both salivary cortisol and urinary cortisol metabolites was significantly higher in CFS compared to controls.

CONCLUSION: There is enhanced sensitivity of the HPA axis to negative feedback in CFS as demonstrated using the prednisolone suppression test. This provides further evidence of alterations in the control of the HPA axis in patients with established CFS.

Source: Jerjes WK, Taylor NF, Wood PJ, Cleare AJ. Enhanced feedback sensitivity to prednisolone in chronic fatigue syndrome. Psychoneuroendocrinology. 2007 Feb;32(2):192-8. Epub 2007 Feb 5. https://www.ncbi.nlm.nih.gov/pubmed/17276605

Urinary cortisol and cortisol metabolite excretion in chronic fatigue syndrome

Abstract:

OBJECTIVES: Reduced basal hypothalamic-pituitary-adrenal (HPA) axis output in chronic fatigue syndrome (CFS) has been inferred from low cortisol levels in blood, saliva, and urine in some studies. Because > 95% of cortisol is metabolized before excretion, we assessed cortisol output by assay of both cortisol metabolites and free cortisol in 24-hour urine collections and also investigated sex differences in these between CFS and control groups.

METHOD: We calculated total urinary cortisol metabolites (TCM) and cortisol metabolite ratios from individual steroid data in 40 patients (20 males and 20 females) with CFS who were free of medication or comorbid psychiatric disorder likely to influence the HPA axis. Results were compared with those of 40 healthy volunteers (20 males and 20 females) well matched for age and body mass index. Data for free cortisol was obtained on 28 of the patients and 27 of the controls.

RESULTS: The mean of TCM and cortisol metabolite ratios was not significantly different between patients and controls for either sex (p > .05 for all parameters). Previously established sex differences were confirmed in our controls and were found to be similar in CFS for TCM and the ratios 11OH/11OXO, 5alpha/5beta THF, and 20OH/20OXO (see text) (p < .005, p < .05, p < .05, and p < .005, respectively). Urinary free cortisol values were numerically (but not statistically) lower in patients with CFS than controls, and correlated inversely with fatigue levels in patients.

CONCLUSION: The finding of normal urinary cortisol metabolite excretion in patients with CFS is at variance with earlier reports that CFS is a hypocortisolemic state. If serum and saliva cortisol levels are lower in CFS, this would suggest that metabolic clearance of cortisol is faster in patients with CFS than controls. This study also demonstrates that sex differences must be taken into account when interpreting results in patients with CFS.

Source: Jerjes WK, Taylor NF, Peters TJ, Wessely S, Cleare AJ. Urinary cortisol and cortisol metabolite excretion in chronic fatigue syndrome. Psychosom Med. 2006 Jul-Aug;68(4):578-82. https://www.ncbi.nlm.nih.gov/pubmed/16868267

Diurnal excretion of urinary cortisol, cortisone, and cortisol metabolites in chronic fatigue syndrome

Abstract:

OBJECTIVE: The aim of this study was to obtain comprehensive information on basal hypothalamic-pituitary-adrenal (HPA) axis activity in chronic fatigue syndrome (CFS) patients who were not affected by medication or comorbid psychiatric disorder likely to influence the HPA axis.

METHOD: Steroid analysis of urine collections from 0600 to 2100 h at 3-h intervals in CFS patients and in controls.

RESULTS: Urinary free cortisol and cortisone concentrations showed a significant normal diurnal rhythm, but levels were lower across the cycle in CFS. In contrast, while urinary cortisol metabolites also showed a normal diurnal rhythm, levels were not significantly different between the CFS and controls at any time. Derived metabolite ratios were similar in both groups.

CONCLUSION: This study provides further evidence for reduced basal HPA axis function in patients with CFS, based on lower free cortisol and cortisone levels, but this is not corroborated by cortisol metabolite data. The difference between these measures cannot be explained by an altered timing of the diurnal rhythm.

Comment in: Comment on “diurnal excretion of urinary cortisol, cortisone, and cortisol metabolites in chronic fatigue syndrome”. [J Psychosom Res. 2006]

Source: Jerjes WK, Peters TJ, Taylor NF, Wood PJ, Wessely S, Cleare AJ. Diurnal excretion of urinary cortisol, cortisone, and cortisol metabolites in chronic fatigue syndrome. J Psychosom Res. 2006 Feb;60(2):145-53. https://www.ncbi.nlm.nih.gov/pubmed/16439267

Chronic fatigue syndrome, exercise, cortisol and lymphadenopathy

Dear Sir,

As in the past [1], the effects of exercise in the treatment of chronic fatigue syndrome (CFS) are conflicting. Indeed, while Powell et al. [2], in 2004, reported that graded exercise was beneficial to CFS patients, Black et al. [3] have lately written that ‘overall mood, muscle pain intensity, and time spent each day with fatigue worsened following increased activity’ [3] in CFS patients, despite the fact that their increase in daily physical activity was rather moderate (28%) [3]. The virtually opposite effects of exercise in different groups of CFS patients [1–3] may reflect their different cortisol levels [1], which, just as occurred some years ago [1], continue to be contradictory. For example, Inder et al. [4], in March 2005, reported that cortisol levels were normal in their patients with CFS, whereas Segal et al. [5], in the same month, reported that their subjects with CFS had hypocortisolism.

Considering that most features of CFS, such as ‘debilitating fatigue, an abrupt onset precipitated by a stressor, feverishness, arthralgias, myalgias, adenopathy, postexertional fatigue, exacerbation of allergic responses, and disturbances in mood and sleep are all characteristic of glucocorticoid insufficiency’ [6], it is not surprising that hypocortisolism has been convincingly shown to be implicated in the pathophysiology of CFS [7]. Therefore, especially the postexertional fatigue caused by glucocorticoid insufficiency [6] strongly suggests that exercise could be of benefit to CFS patients with high [1] or normal cortisol levels [4], whereas it could be harmful to CFS patients with hypocortisolism [1, 5, 6]. Unfortunately, because of the misleading coexistence of quite different diagnostic criteria for CFS [1], it is difficult to predict the patients with CFS who are more likely to have hypocortisolism and which would worsen with exercise. However, it is arguable that the presence or absence of lymphadenopathy [8], which is a sign of hypocortisolism [6, 9] and is one of the 43 clinical features that CFS shares with Addison’s disease [10–12], could reliably discriminate CFS patients who may worsen with exercise from those who may improve with it. Indeed, lymphadenopathy, unlike other symptoms of CFS [11, 12], many of which are non-specific and can also be found in depression and other affective disorders [11, 12], is far from being common in physical diseases and is absent in psychiatric conditions.

You can read the rest of this comment here: http://onlinelibrary.wiley.com/doi/10.1111/j.1365-2796.2005.01526.x/full

Source: Baschetti R. Chronic fatigue syndrome, exercise, cortisol and lymphadenopathy. J Intern Med. 2005 Sep;258(3):291-2. http://onlinelibrary.wiley.com/doi/10.1111/j.1365-2796.2005.01526.x/full (Full article)

Salivary cortisol as a predictor of postoperative fatigue

Abstract:

OBJECTIVE: Some patients with chronic fatigue syndrome (CFS) exhibit low basal cortisol levels, but it is not known whether low cortisol is a cause of CFS, predates the onset of CFS symptoms, or is an epiphenomenon caused by the behavioral changes typical of CFS. Because elective surgery is one of the few predictable risk factors for chronic fatigue, in this study, we followed a cohort of surgery patients from before to 6 months after their operation to test these theories.

METHOD: One hundred sixty-one patients completed fatigue questionnaires and provided salivary cortisol samples before undergoing an elective inpatient surgical procedure, and then 2 days, 3 weeks, and 6 months afterward.

RESULTS: Controlling for relevant demographic and surgical variables and for preoperative fatigue, low preoperative cortisol did not predict postoperative fatigue severity on any occasion (p > .05). Similarly, there was no correlation between low postoperative cortisol and postoperative fatigue severity at 3 weeks or 6 months (p > .05). Although 16 patients met our case definition for “chronic fatigue” at the 6-month follow up, low preoperative and low postoperative cortisol did not significantly predict fatigue caseness (p > .05).

CONCLUSIONS: Any association between chronic fatigue and low cortisol would seem to develop after the onset of fatigue symptoms. Low cortisol is therefore unlikely to be the primary cause of chronic fatigue states.

Source: Rubin GJ, Hotopf M, Papadopoulos A, Cleare A. Salivary cortisol as a predictor of postoperative fatigue. Psychosom Med. 2005 May-Jun;67(3):441-7. http://www.ncbi.nlm.nih.gov/pubmed/15911908