Tag: HPA axis

The role of hypocortisolism in chronic fatigue syndrome

Abstract:

BACKGROUND: There is accumulating evidence of hypothalamic-pituitary-adrenal (HPA) axis hypofunction in chronic fatigue syndrome (CFS). However, knowledge of this hypofunction has so far come exclusively from research in adulthood, and its clinical significance remains unclear. The objective of the current study was to assess the role of the HPA-axis in adolescent CFS and recovery from adolescent CFS.

METHOD: Before treatment, we compared the salivary cortisol awakening response of 108 diagnosed adolescent CFS patients with that of a reference group of 38 healthy peers. Salivary cortisol awakening response was measured again after 6 months of treatment in CFS patients.

RESULTS: Pre-treatment salivary cortisol levels were significantly lower in CFS-patients than in healthy controls. After treatment recovered patients had a significant rise in salivary cortisol output attaining normalization, whereas non-recovered patients improved slightly, but not significantly. The hypocortisolism found in CFS-patients was significantly correlated to the amount of sleep. Logistic regression analysis showed that an increase of one standard deviation in the difference between pre- and post-treatment salivary cortisol awakening response was associated with a 93% higher odds of recovery (adjusted OR 1.93 (1.18 to 3.17), p=0.009). Pre-treatment salivary cortisol did not predict recovery.

CONCLUSIONS: Hypocortisolism is associated with adolescent CFS. It is not pre-treatment cortisol but its change to normalization that is associated with treatment success. We suggest that this finding may have clinical implications regarding the adaptation of future treatment strategies.

Copyright © 2014 Elsevier Ltd. All rights reserved.

 

Source: Nijhof SL, Rutten JM, Uiterwaal CS, Bleijenberg G, Kimpen JL, Putte EM. The role of hypocortisolism in chronic fatigue syndrome. Psychoneuroendocrinology. 2014 Apr;42:199-206. doi: 10.1016/j.psyneuen.2014.01.017. Epub 2014 Jan 30. https://www.ncbi.nlm.nih.gov/pubmed/24636516

 

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)

 

Unstimulated cortisol secretory activity in everyday life and its relationship with fatigue and chronic fatigue syndrome: a systematic review and subset meta-analysis

Abstract:

The hypothalamic-pituitary-adrenal (HPA) axis is a psychoneuroendocrine regulator of the stress response and immune system, and dysfunctions have been associated with outcomes in several physical health conditions. Its end product, cortisol, is relevant to fatigue due to its role in energy metabolism.

The systematic review examined the relationship between different markers of unstimulated salivary cortisol activity in everyday life in chronic fatigue syndrome (CFS) and fatigue assessed in other clinical and general populations. Search terms for the review related to salivary cortisol assessments, everyday life contexts, and fatigue. All eligible studies (n=19) were reviewed narratively in terms of associations between fatigue and assessed cortisol markers, including the cortisol awakening response (CAR), circadian profile (CP) output, and diurnal cortisol slope (DCS).

Subset meta-analyses were conducted of case-control CFS studies examining group differences in three cortisol outcomes: CAR output; CAR increase; and CP output. Meta-analyses revealed an attenuation of the CAR increase within CFS compared to controls (d=-.34) but no statistically significant differences between groups for other markers. In the narrative review, total cortisol output (CAR or CP) was rarely associated with fatigue in any population; CAR increase and DCS were most relevant.

Outcomes reflecting within-day change in cortisol levels (CAR increase; DCS) may be the most relevant to fatigue experience, and future research in this area should report at least one such marker. Results should be considered with caution due to heterogeneity in one meta-analysis and the small number of studies.

Copyright © 2013 The Authors. Published by Elsevier Ltd.. All rights reserved.

 

Source: Powell DJ, Liossi C, Moss-Morris R, Schlotz W. Unstimulated cortisol secretory activity in everyday life and its relationship with fatigue and chronic fatigue syndrome: a systematic review and subset meta-analysis. Psychoneuroendocrinology. 2013 Nov;38(11):2405-22. doi: 10.1016/j.psyneuen.2013.07.004. Epub 2013 Aug 2. http://www.psyneuen-journal.com/article/S0306-4530(13)00254-0/fulltext (Full article)

 

A review of hypothalamic-pituitary-adrenal axis function in chronic fatigue syndrome

Abstract:

Hypothalamic-pituitary-adrenal (HPA) axis dysfunction has been found in a high proportion of chronic fatigue syndrome (CFS) patients and includes enhanced corticosteroid-induced negative feedback, basal hypocortisolism, attenuated diurnal variation, and a reduced responsivity to challenge. A putative causal role for genetic profile, childhood trauma, and oxidative stress has been considered.

In addition, the impact of gender is demonstrated by the increased frequency of HPA axis dysregulation in females. Despite the temporal relationship, it is not yet established whether the endocrine dysregulation is causal, consequent, or an epiphenomenon of the disorder. Nonetheless, given the interindividual variation in the effectiveness of existing biological and psychological treatments, the need for novel treatment strategies such as those which target the HPA axis is clear.

 

Source: Tomas C, Newton J, Watson S. A review of hypothalamic-pituitary-adrenal axis function in chronic fatigue syndrome. ISRN Neurosci. 2013 Sep 30;2013:784520. doi: 10.1155/2013/784520. eCollection 2013. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4045534/ (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.

Copyright © 2012 Elsevier Inc. All rights reserved.

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)

 

Genetics and Gene Expression Involving Stress and Distress Pathways in Fibromyalgia with and without Comorbid Chronic Fatigue Syndrome

Abstract:

In complex multisymptom disorders like fibromyalgia syndrome (FMS) and chronic fatigue syndrome (CFS) that are defined primarily by subjective symptoms, genetic and gene expression profiles can provide very useful objective information.

This paper summarizes research on genes that may be linked to increased susceptibility in developing and maintaining these disorders, and research on resting and stressor-evoked changes in leukocyte gene expression, highlighting physiological pathways linked to stress and distress. These include the adrenergic nervous system, the hypothalamic-pituitary-adrenal axis and serotonergic pathways, and exercise responsive metabolite-detecting ion channels.

The findings to date provide some support for both inherited susceptibility and/or physiological dysregulation in all three systems, particularly for catechol-O-methyl transferase (COMT) genes, the glucocorticoid and the related mineralocorticoid receptors (NR3C1, NR3C2), and the purinergic 2X4 (P2X4) ion channel involved as a sensory receptor for muscle pain and fatigue and also in upregulation of spinal microglia in chronic pain models. Methodological concerns for future research, including potential influences of comorbid clinical depression and antidepressants and other medications, on gene expression are also addressed.

 

Source: Light KC, White AT, Tadler S, Iacob E, Light AR. Genetics and Gene Expression Involving Stress and Distress Pathways in Fibromyalgia with and without Comorbid Chronic Fatigue Syndrome. Pain Res Treat. 2012;2012:427869. doi: 10.1155/2012/427869. Epub 2011 Sep 29. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3200121/ (Full article)

 

Hypothalamic-pituitary-adrenal axis dysfunction in chronic fatigue syndrome

Abstract:

The weight of current evidence supports the presence of the following factors related to hypothalamic-pituitary-adrenal (HPA) axis dysfunction in patients with chronic fatigue syndrome (CFS): mild hypocortisolism; attenuated diurnal variation of cortisol; enhanced negative feedback to the HPA axis; and blunted HPA axis responsiveness. Furthermore, HPA axis changes seem clinically relevant, as they are associated with worse symptoms and/or disability and with poorer outcomes to standard treatments for CFS.

Regarding etiology, women with CFS are more likely to have reduced cortisol levels. Studies published in the past 8 years provide further support for a multifactorial model in which several factors interact to moderate HPA axis changes. In particular, low activity levels, depression and early-life stress appear to reduce cortisol levels, whereas the use of psychotropic medication can increase cortisol. Addressing these factors-for example, with cognitive behavioral therapy-can increase cortisol levels and is probably the first-line approach for correcting HPA axis dysfunction at present, as steroid replacement is not recommended.

Given what is now a fairly consistent pattern of findings for the type of HPA axis changes found in CFS, we recommend that future work focuses on improving our understanding of the cause and relevance of these observed changes.

Comment in: Neuroendocrine correlates of childhood trauma in CFS. [Nat Rev Endocrinol. 2012]

 

Source: Papadopoulos AS, Cleare AJ. Hypothalamic-pituitary-adrenal axis dysfunction in chronic fatigue syndrome. Nat Rev Endocrinol. 2011 Sep 27;8(1):22-32. doi: 10.1038/nrendo.2011.153. https://www.ncbi.nlm.nih.gov/pubmed/21946893

 

An Etiological Model for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

Abstract:

Kindling might represent a heuristic model for understanding the etiology of Myalgic Encephalomyelitis/chronic fatigue syndrome (ME/CFS). Kindling occurs when an organism is exposed repeatedly to an initially sub-threshold stimulus resulting in hypersensitivity and spontaneous seizure-like activity. Among patients with ME/CFS, chronically repeated low-intensity stimulation due to an infectious illness might cause kindling of the limbic-hypothalamic-pituitary axis. Kindling might also occur by high-intensity stimulation (e.g., brain trauma) of the limbic-hypothalamic-pituitary axis. Once this system is charged or kindled, it can sustain a high level of arousal with little or no external stimulus and eventually this could lead to hypocortisolism. Seizure activity may spread to adjacent structures of the limbic-hypothalamic-pituitary axis in the brain, which might be responsible for the varied symptoms that occur among patients with ME/CFS. In addition, kindling may also be responsible for high levels of oxidative stress, which has been found in patients with ME/CFS.

 

Source: Jason LA, Sorenson M, Porter N, Belkairous N. An Etiological Model for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. Neurosci Med. 2011 Mar 1;2(1):14-27. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3166239/ (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.

Copyright © 2011 Elsevier Inc. All rights reserved.

 

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 HPA axis in the pathogenesis of chronic fatigue syndrome

Abstract:

Chronic fatigue syndrome (CFS) is a clinical syndrome characterized by profound disabling chronic fatigue associated with a wide array of other physical symptoms. Its etiology is currently unknown. Among the various hypotheses, considerable interest has been placed in the hypothalamus-pituitary-adrenal axis as a possible target of the pathogenesis of CFS. This article reviews the available scientific evidence about a role of hypothalamic-pituitary-adrenal axis in the pathogenesis of chronic fatigue syndrome.

 

Source: Ursini F, Succurro E, Grembiale A, Gagliardi DA, Arturi F. The HPA axis in the pathogenesis of chronic fatigue syndrome. Clin Ter. 2010;161(5):461-4. [Article in Italian] https://www.ncbi.nlm.nih.gov/pubmed/20949245