Tag: HPA axis

Cellular and molecular mechanisms of interaction between the neuroendocrine and immune systems under chronic fatigue syndrome in experiment

Abstract:

One of the main mechanisms of chronic fatigue syndrome development involves disturbances of interaction between the immune and neuroendocrine systems. The adequate experimental model for the search of these mechanisms is induction of fatigue in animals via the single intraperitoneal administration of synthetic double-stranded RNA – Poly I : C.

Investigation of alterations in cytotoxic and proliferation activities of splenocytcs, the intensity of immunomodulatory cytokines signaling via the sphingomyelin pathways in membrane P2 fraction of the brain cortex, as well as the activity of hypothalamic-pituitary adrenal (HP A) axis in the dynamics of chronic fatigue syndrome in rats has performed. Inhibition of both cytotoxic and proliferative activities of splenocytes during the period of fatigue development has been shown. Priority data concerning the suppression of the activity of neutral sphingomyelinase (nSMase) – the key enzyme of the sphingomyelin cascade – in membranes ofthe cells from the brain cortex on the 3d day after Poly I : C administration to rats have been obtained.

It was found that Poly I : C injection to rats led to disturbed HPA axis functions which was manifested by decreased corticosterone concentration in standard functional assays with ACTH and hydrocortisone administration.

It is suggested that disturbances in interaction between the immune and neuroendocrine systems during development of chronic fatigue syndrome, including alterations in HPA axis activity, are realized both on the level of changes in the activity of immune-competent cells and immediately on membranes of the brain cells.

 

Source: Rybakina EG, Shanin SN, Fomicheva EE, Korneva EA. Cellular and molecular mechanisms of interaction between the neuroendocrine and immune systems under chronic fatigue syndrome in experiment. Ross Fiziol Zh Im I M Sechenova. 2009 Dec;95(12):1324-35. [Article in Russian] https://www.ncbi.nlm.nih.gov/pubmed/20141043

 

Activity of hypothalamic-pituitary-adrenal axis by induction of experimental chronic fatigue syndrome

Abstract:

Changes in the activity of hypothalamic-pituitary adrenal (HPA) axis were investigated in experimental model of chronic fatigue syndrome(CFS) induced by intraperitoneal administration of synthetic double-stranded RNA (polyriboinosinic: polyribocytidylic acid, Poly I : C) to rats in the dose of 3 mg/kg body weight. In order to reveal functional changes in different links of the HPA axis, standard probes with intraperitoneal administration of ACTH and hydrocortisone against the background of cold stress application and Poly I : C injections were performed. A single injection of Poly I : C led to disordered HPA axis functions which was manifested by decreased sensitivity of the cells in the adrenal gland in response to ACTH, and suppression of the mechanism of negative feedback resulting in significant fall of corticosterone concentration in standard assays with ACTH and hydrocortisone administration.

 

Source: Fomicheva EE, Filatenkova TA, Rybakina EG. Activity of hypothalamic-pituitary-adrenal axis by induction of experimental chronic fatigue syndrome. Ross Fiziol Zh Im I M Sechenova. 2009 Jan;95(1):11-8. [Article in Russian] https://www.ncbi.nlm.nih.gov/pubmed/19323439

 

Does hypothalamic-pituitary-adrenal axis hypofunction in chronic fatigue syndrome reflect a ‘crash’ in the stress system?

Abstract:

The etiopathogenesis of chronic fatigue syndrome (CFS) remains poorly understood. Although neuroendocrine disturbances – and hypothalamic-pituitary-adrenal (HPA) axis hypofunction in particular – have been found in a large proportion of CFS patients, it is not clear whether these disturbances are cause or consequence of the illness.

After a review of the available evidence we hypothesize that that HPA axis hypofunction in CFS, conceptualized within a system-biological perspective, primarily reflects a fundamental and persistent dysregulation of the neurobiological stress system. As a result, a disturbed balance between glucocorticoid and inflammatory signaling pathways may give rise to a pathological cytokine-induced sickness response that may be the final common pathway underlying central CFS symptoms, i.e. effort/stress intolerance and pain hypersensitivity.

This comprehensive hypothesis on HPA axis hypofunction in CFS may stimulate diagnostic refinement of the illness, inform treatment approaches and suggest directions for future research, particularly focusing on the neuroendocrine-immune interface and possible links between CFS, early and recent life stress, and depression.

 

Source: Van Houdenhove B, Van Den Eede F, Luyten P. Does hypothalamic-pituitary-adrenal axis hypofunction in chronic fatigue syndrome reflect a ‘crash’ in the stress system? Med Hypotheses. 2009 Jun;72(6):701-5. doi: 10.1016/j.mehy.2008.11.044. Epub 2009 Feb 23. https://www.ncbi.nlm.nih.gov/pubmed/19237251

 

Neuroendocrine and immune network re-modeling in chronic fatigue syndrome: an exploratory analysis

Abstract:

This work investigates the significance of changes in association patterns linking indicators of neuroendocrine and immune activity in patients with chronic fatigue syndrome (CFS). Gene sets preferentially expressed in specific immune cell isolates were integrated with neuroendocrine data from a large population-based study.

Co-expression patterns linking immune cell activity with hypothalamic-pituitary-adrenal (HPA), thyroidal (HPT) and gonadal (HPG) axis status were computed using mutual information criteria. Networks in control and CFS subjects were compared globally in terms of a weighted graph edit distance. Local re-modeling of node connectivity was quantified by node degree and eigenvector centrality measures. Results indicate statistically significant differences between CFS and control networks determined mainly by re-modeling around pituitary and thyroid nodes as well as an emergent immune sub-network.

Findings align with known mechanisms of chronic inflammation and support possible immune-mediated loss of thyroid function in CFS exacerbated by blunted HPA axis responsiveness.

 

Source: Fuite J, Vernon SD, Broderick G. Neuroendocrine and immune network re-modeling in chronic fatigue syndrome: an exploratory analysis. Genomics. 2008 Dec;92(6):393-9. doi: 10.1016/j.ygeno.2008.08.008. Epub 2008 Oct 1. http://www.sciencedirect.com/science/article/pii/S0888754308001948 (Full article)

 

Alterations in diurnal salivary cortisol rhythm in a population-based sample of cases with chronic fatigue syndrome

Abstract:

OBJECTIVE: To examine diurnal salivary cortisol rhythms and plasma IL-6 concentrations in persons with chronic fatigue syndrome (CFS), persons not fulfilling a diagnosis of CFS (we term them cases with insufficient symptoms or fatigue, ISF) and nonfatigued controls (NF). Previous studies of CFS patients have implicated the hypothalamic-pituitary-adrenal axis and the immune system in the pathophysiology of CFS, although results have been equivocal.

METHODS: Twenty-eight people with CFS, 35 persons with ISF, and 39 NF identified from the general population of Wichita, Kansas, were admitted to a research ward for 2 days. Saliva was collected immediately on awakening (6:30 AM), at 08:00 AM, 12 noon, 4:00 PM, 8:00 PM and at bedtime (10:00 PM) and plasma was obtained at 7:30 AM. Salivary cortisol concentrations were assessed using radioimmunoassay, and plasma IL-6 was measured using sandwich enzyme-linked immunosorbent assay.

RESULTS: People with CFS demonstrated lower salivary cortisol concentrations in the morning and higher salivary cortisol concentrations in the evening compared with both ISF and NF groups indicating a flattening of the diurnal cortisol profile. Mean plasma IL-6 concentrations were highest in CFS compared with the other groups, although these differences were no longer significant after controlling for BMI. Attenuated decline of salivary cortisol concentrations across the day and IL-6 concentration were associated with fatigue symptoms in CFS.

CONCLUSIONS: These results suggest an altered diurnal cortisol rhythm and IL-6 concentrations in CFS cases identified from a population-based sample.

 

Source: Nater UM, Youngblood LS, Jones JF, Unger ER, Miller AH, Reeves WC, Heim C. Alterations in diurnal salivary cortisol rhythm in a population-based sample of cases with chronic fatigue syndrome. Psychosom Med. 2008 Apr;70(3):298-305. doi: 10.1097/PSY.0b013e3181651025. Epub 2008 Mar 31. https://www.ncbi.nlm.nih.gov/pubmed/18378875

 

Attenuated morning salivary cortisol concentrations in a population-based study of persons with chronic fatigue syndrome and well controls

Abstract:

CONTEXT: A substantial body of research on the pathophysiology of chronic fatigue syndrome (CFS) has focused on hypothalamic-pituitary-adrenal axis dysregulation. The cortisol awakening response has received particular attention as a marker of hypothalamic-pituitary-adrenal axis dysregulation.

OBJECTIVE: The objective of the current study was to evaluate morning salivary cortisol profiles in persons with CFS and well controls identified from the general population.

DESIGN AND SETTING: We conducted a case-control study at an outpatient research clinic.

CASES AND OTHER PARTICIPANTS: We screened a sample of 19,381 residents of Georgia and identified those with CFS and a matched sample of well controls. Seventy-five medication-free CFS cases and 110 medication-free well controls provided complete sets of saliva samples.

MAIN OUTCOME MEASURES: We assessed free cortisol concentrations in saliva collected on a regular workday immediately upon awakening and 30 and 60 min after awakening.

RESULTS: There was a significant interaction effect, indicating different profiles of cortisol concentrations over time between groups, with the CFS group showing an attenuated morning cortisol profile. Notably, we observed a sex difference in this effect. Women with CFS exhibited significantly attenuated morning cortisol profiles compared with well women. In contrast, cortisol profiles were similar in men with CFS and male controls.

CONCLUSIONS: CFS was associated with an attenuated morning cortisol response, but the effect was limited to women. Our results suggest that a sex difference in hypocortisolism may contribute to increased risk of CFS in women.

 

Source: Nater UM, Maloney E, Boneva RS, Gurbaxani BM, Lin JM, Jones JF, Reeves WC, Heim C. Attenuated morning salivary cortisol concentrations in a population-based study of persons with chronic fatigue syndrome and well controls. J Clin Endocrinol Metab. 2008 Mar;93(3):703-9. Epub 2007 Dec 26. https://www.ncbi.nlm.nih.gov/pubmed/18160468

 

Possible use of repeated cold stress for reducing fatigue in chronic fatigue syndrome: a hypothesis

Abstract:

BACKGROUND: Physiological fatigue can be defined as a reduction in the force output and/or energy-generating capacity of skeletal muscle after exertion, which may manifest itself as an inability to continue exercise or usual activities at the same intensity. A typical example of a fatigue-related disorder is chronic fatigue syndrome (CFS), a disabling condition of unknown etiology and with uncertain therapeutic options. Recent advances in elucidating pathophysiology of this disorder revealed hypofunction of the hypothalamic-pituitary-adrenal axis and that fatigue in CFS patients appears to be associated with reduced motor neurotransmission in the central nervous system (CNS) and to a smaller extent with increased fatigability of skeletal muscle. There is also some limited evidence that CFS patients may have excessive serotonergic activity in the brain and low opioid tone.

PRESENTATION OF THE HYPOTHESIS: This work hypothesizes that repeated cold stress may reduce fatigue in CFS because brief exposure to cold may transiently reverse some physiological changes associated with this illness. For example, exposure to cold can activate components of the reticular activating system such as raphe nuclei and locus ceruleus, which can result in activation of behavior and increased capacity of the CNS to recruit motoneurons. Cold stress has also been shown to reduce the level of serotonin in most regions of the brain (except brainstem), which would be consistent with reduced fatigue according to animal models of exercise-related fatigue. Finally, exposure to cold increases metabolic rate and transiently activates the hypothalamic-pituitary-adrenal axis as evidenced by a temporary increase in the plasma levels of adrenocorticotropic hormone, beta-endorphin and a modest increase in cortisol. The increased opioid tone and high metabolic rate could diminish fatigue by reducing muscle pain and accelerating recovery of fatigued muscle, respectively.

TESTING THE HYPOTHESIS: To test the hypothesis, a treatment is proposed that consists of adapted cold showers (20 degrees Celsius, 3 minutes, preceded by a 5-minute gradual adaptation to make the procedure more comfortable) used twice daily.

IMPLICATIONS OF THE HYPOTHESIS: If testing supports the proposed hypothesis, this could advance our understanding of the mechanisms of fatigue in CFS.

 

Source: Shevchuk NA. Possible use of repeated cold stress for reducing fatigue in chronic fatigue syndrome: a hypothesis. Behav Brain Funct. 2007 Oct 24;3:55. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2164952/ (Full article)

 

Combined dexamethasone/corticotropin-releasing factor test in chronic fatigue syndrome

Abstract:

BACKGROUND: Studies of hypothalamic-pituitary-adrenal (HPA) axis function in chronic fatigue syndrome (CFS) point to hypofunction, although there are negative reports. Suggested mechanisms include a reduced hypothalamic or supra-hypothalamic stimulus to the HPA axis and enhanced sensitivity to the negative feedback of glucocorticoids. The aim of the current study was to investigate HPA axis function in CFS with the dexamethasone/corticotropin-releasing factor (Dex/CRF) test, in analogy with research in affective disorders.

METHOD: Thirty-four well-characterized female CFS patients and 25 healthy control subjects participated in the low-dose Dex/CRF test. Current major depressive episode was an exclusion criterion. History of early-life stress (ELS) was assessed with the Structured Trauma Interview.

RESULTS: Salivary cortisol responses after 0.5 mg Dex were lower in CFS patients than in controls (before 100 microg CRF, p=0.038; after 100 microg CRF, p=0.015). A secondary analysis revealed an influence of early-life stress and of oestrogen intake. After removal of the 10 participants who were taking an oral oestrogen, patients without a history of ELS showed lower cortisol responses than patients with ELS and controls (before CRF, p=0.005; after CRF, p=0.008).

CONCLUSIONS: CFS is globally associated with reduced cortisol responses in the combined low-dose Dex/CRF test, but this effect is only clearly present in CFS patients without a history of ELS. This study provides further support for an enhanced glucocorticoid negative feedback and/or a reduced central HPA axis drive in CFS. Furthermore, it demonstrates that ELS is an important variable to consider in CFS research.

 

Source: Van Den Eede F, Moorkens G, Hulstijn W, Van Houdenhove B, Cosyns P, Sabbe BG, Claes SJ. Combined dexamethasone/corticotropin-releasing factor test in chronic fatigue syndrome. Psychol Med. 2008 Jul;38(7):963-73. Epub 2007 Sep 6. https://www.ncbi.nlm.nih.gov/pubmed/17803834

 

Overlap between atypical depression, seasonal affective disorder and chronic fatigue syndrome

Abstract:

OBJECTIVE: We reviewed previous studies that have described an association between abnormal functioning of the hypothalamic-pituitary-adrenal axis and depression. In addition to melancholic depression, a spectrum of conditions may be associated with increased and prolonged activation of the hypothalamic-pituitary-adrenal axis. In contrast another group of states is characterized by hypoactivation of the stress system, rather than sustained activation, in which chronically reduced secretion of corticotropin releasing factor may result in pathological hypoarousal and an enhanced hypothalamic-pituitary-adrenal negative feedback. Patients with atypical depression, seasonal affective disorder and chronic fatigue syndrome fall in this category.

METHOD: The literature data on the overlap between the key-words were reviewed, summarized and discussed.

RESULTS: Many studies suggest that these conditions themselves overlap biologically, showing hypofunction of central corticotropin releasing factor neuronal systems.

CONCLUSIONS: Therefore, in the real world of clinical practice, patients often present in a grey area between classical idiopathic fatigue and early chronic atypical depression and/or seasonal depression. This underscores the potential common biological links underpinning common symptom clusters not only between depression (atypical and seasonal) and chronic fatigue syndrome, but also other conditions characterized by the hypothalamic-pituitary-adrenal axis mainly diminished the corticotropin releasing factor activity.

 

Source: Juruena MF, Cleare AJ. Overlap between atypical depression, seasonal affective disorder and chronic fatigue syndrome. Rev Bras Psiquiatr. 2007 May;29 Suppl 1:S19-26. [Article in Portuguese] http://www.scielo.br/scielo.php?script=sci_arttext&pid=S1516-44462007000500005&lng=en&nrm=iso&tlng=en (Full article)

 

Hypothalamic-pituitary-adrenal axis function in chronic fatigue syndrome

Abstract:

There is evidence for a hypofunction of the hypothalamic-pituitary-adrenal (HPA) axis in a proportion of the patients with chronic fatigue syndrome (CFS), despite the negative studies and methodological difficulties. In this review, we focus on challenge studies and on the role of the HPA axis in the pathogenesis of CFS. Mild hypocortisolism, blunted adrenocorticotropin response to stressors and enhanced negative feedback sensitivity to glucocorticoids are the main findings. Several underlying mechanisms have been proposed. Currently, it is a matter of debate whether these disturbances have a primary role in the pathogenesis of CFS. However, even if the HPA axis dysfunctions are secondary to other factors, they are probably a relevant factor in symptom propagation in CFS.

 

Source: Van Den Eede F, Moorkens G, Van Houdenhove B, Cosyns P, Claes SJ. Hypothalamic-pituitary-adrenal axis function in chronic fatigue syndrome. Neuropsychobiology. 2007;55(2):112-20. Epub 2007 Jun 27. http://www.karger.com/Article/FullText/104468 (Full article)