Tag: glucocorticoids

Glucocorticoid receptor polymorphisms and haplotypes associated with chronic fatigue syndrome

Abstract:

Chronic fatigue syndrome (CFS) is a significant public health problem of unknown etiology, the pathophysiology has not been elucidated, and there are no characteristic physical signs or laboratory abnormalities. Some studies have indicated an association of CFS with deregulation of immune functions and hypothalamic-pituitary-adrenal (HPA) axis activity.

In this study, we examined the association of sequence variations in the glucocorticoid receptor gene (NR3C1) with CFS because NR3C1 is a major effector of the HPA axis. There were 137 study participants (40 with CFS, 55 with insufficient symptoms or fatigue, termed as ISF, and 42 non-fatigued controls) who were clinically evaluated and identified from the general population of Wichita, KS. Nine single nucleotide polymorphisms (SNPs) in NR3C1 were tested for association of polymorphisms and haplotypes with CFS.

We observed an association of multiple SNPs with chronic fatigue compared to non-fatigued (NF) subjects (P < 0.05) and found similar associations with quantitative assessments of functional impairment (by the SF-36), with fatigue (by the Multidimensional Fatigue Inventory) and with symptoms (assessed by the Centers for Disease Control Symptom Inventory).

Subjects homozygous for the major allele of all associated SNPs were at increased risk for CFS with odds ratios ranging from 2.61 (CI 1.05-6.45) to 3.00 (CI 1.12-8.05). Five SNPs, covering a region of approximately 80 kb, demonstrated high linkage disequilibrium (LD) in CFS, but LD gradually declined in ISF to NF subjects. Furthermore, haplotype analysis of the region in LD identified two associated haplotypes with opposite alleles: one protective and the other conferring risk of CFS.

These results demonstrate NR3C1 as a potential mediator of chronic fatigue, and implicate variations in the 5′ region of NR3C1 as a possible mechanism through which the alterations in HPA axis regulation and behavioural characteristics of CFS may manifest.

 

Source: Rajeevan MS, Smith AK, Dimulescu I, Unger ER, Vernon SD, Heim C, Reeves WC. Glucocorticoid receptor polymorphisms and haplotypes associated with chronic fatigue syndrome. Genes Brain Behav. 2007 Mar;6(2):167-76. http://onlinelibrary.wiley.com/doi/10.1111/j.1601-183X.2006.00244.x/full (Full article)

 

Glucocorticoids and glucocorticoid receptors: mediators of fatigue?

Abstract:

Fatigue is a common problem; when chronic and disabling, subjects can be categorized as having chronic fatigue syndrome (CFS). Whilst it is most likely a multifactorial condition of biopsychosocial origin, the nature of the pathophysiological component remains unclear. There has been a wealth of interest in the possible hypothalamo-pituitary-adrenal (HPA) axis dysfunction in CFS, and whether such changes may mediate fatigue.

On balance, there appears to be reduced cortisol output in a proportion of patients, together with heightened negative feedback and glucocorticoid receptor function. There is evidence for impaired adrenocorticotropic hormone (ACTH) and cortisol responses to a variety of challenges. However, there is no evidence for a specific or uniform dysfunction of the HPA axis.

Evidence that these changes may be related to symptom production comes from randomized controlled trials of glucocorticoid replacement therapy, which have shown improvements in fatigue and disability. Given the many factors that may impinge on the HPA axis in CFS, such as inactivity, sleep disturbance, psychiatric comorbidity, medication and ongoing stress, it seems likely that there is not a single or specific change to the HPA axis in CFS and that the observed HPA axis disturbances are of multifactorial etiology. This is further supported by a comparison of neuroendocrine findings in other conditions in which fatigue is prominent, showing both similarities and differences with the pattern in CFS.

 

Source: Cleare AJ. Glucocorticoids and glucocorticoid receptors: mediators of fatigue? Acta Neuropsychiatr. 2003 Dec;15(6):341-53. doi: 10.1046/j.1601-5215.2003.00050.x. http://www.ncbi.nlm.nih.gov/pubmed/26983770

 

Enhanced glucocorticoid sensitivity in patients with chronic fatigue syndrome

Abstract:

OBJECTIVE: Alterations of the immune-neuroendocrine interplay have been described in chronic fatigue syndrome (CFS). Employing a recently developed method, the study set out to investigate whether patients with CFS have an altered sensitivity to glucocorticoids (GCs) when under stress.

METHODS: A total of 21 CFS patients and 20 healthy age- and gender-matched controls underwent a standardized psychosocial stress test (Trier Social Stress Test, TSST). Salivary and plasma cortisol levels were measured repeatedly following exposure to the stressor. GC sensitivity was assessed in vitro by dexamethasone inhibition of lipopolysaccharide-stimulated production of interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNC-α).

RESULTS: Cortisol responses following the TSST did not differ significantly between CFS patients and healthy controls. GC sensitivity differed significantly between CFS patients and healthy controls, with CFS patients showing a greater sensitivity towards GCs (TNF-α: F 1/39 = 7.32, P = 0.01; IL-6: F 1/39 = 9.73, P = 0.004).

CONCLUSION: Consistent with recent evidence, CFS patients are characterized by an enhanced sensitivity to glucocorticoids. The implications for secondary processes, such as the regulatory influence of glucocorticoids on immune processes, are discussed.

 

Source: Gaab J, Rohleder N, Heitz V, Schad T, Engert V, Schürmeyer TH, Ehlert U. Enhanced glucocorticoid sensitivity in patients with chronic fatigue syndrome. Acta Neuropsychiatr. 2003 Aug;15(4):184-91. doi: 10.1034/j.1601-5215.2003.00033.x. http://www.ncbi.nlm.nih.gov/pubmed/26983566

 

LPS-induced IL-10 production in whole blood cultures from chronic fatigue syndrome patients is increased but supersensitive to inhibition by dexamethasone

Abstract:

Several causes have been held responsible for the chronic fatigue syndrome (CFS), including an altered hypothalamus-pituitary-adrenal gland (HPA)-axis activity, viral infections and a reduced Th1 activity. Therefore, it was investigated whether the regulation of IL-10 is different in CFS.

LPS-induced cytokine secretion in whole blood cultures showed a significant increase in IL-10 and a trend towards a decrease in IL-12 as compared with healthy controls. In patients and controls, IL-12 secretion was equally sensitive to suppression by dexamethasone, whereas IL-10 secretion appeared more sensitive in CFS-patients. In controls, IL-10 and IL-12 secretion were inversely correlated with free serum cortisol (r=-0.492, p<0.02 and r=-0.434, p<0.05, respectively). In CFS, such an inverse correlation was found for IL-12 (r=-0.611, p<0.02) but not for IL-10 (r=-0.341, ns).

These data are suggestive for a disturbed glucocorticoid regulation of IL-10 in CFS.

 

Source: Visser J, Graffelman W, Blauw B, Haspels I, Lentjes E, de Kloet ER, Nagelkerken L. LPS-induced IL-10 production in whole blood cultures from chronic fatigue syndrome patients is increased but supersensitive to inhibition by dexamethasone. J Neuroimmunol. 2001 Oct 1;119(2):343-9. http://www.ncbi.nlm.nih.gov/pubmed/11585638

 

Increased sensitivity to glucocorticoids in peripheral blood mononuclear cells of chronic fatigue syndrome patients, without evidence for altered density or affinity of glucocorticoid receptors

Abstract:

BACKGROUND: In this study we tested the hypothesis that the increased sensitivity to glucocorticoids in chronic fatigue syndrome (CFS)-patients can be attributed to an altered functioning of their glucocorticoid receptors (GR).

METHODS: For this purpose, affinity and distribution of the GR were studied in purified, peripheral blood mononuclear cells (PBMC) of 10 CFS patients and 14 controls along with the responsiveness of these cells to glucocorticoids in vitro.

RESULTS: Affinity (Kd) and number of GR was not different in PBMC of CFS patients when compared with the controls (Kd, 12.9 +/- 8.9 nmol vs 18.8 +/- 16.2 nmol and GR number, 4,839 +/- 2,824/ cell vs 4,906 +/- 1,646/cell). Moreover, RT-PCR revealed no differences in GR messenger RNA expression. Nevertheless, PBMC from CFS patients showed an increased sensitivity to glucocorticoids in vitro. In CFS patients 0.01 micromol dexamethasone suppressed PBMC proliferation by 37%, whereas the controls were only suppressed by 17% (P < 0.01). Addition of phorbol 12-myristate 13-acetate to the cultures rendered the cells resistant to dexamethasone with regard to proliferation and IL-10 and IFN-gamma production, but not to IL-2 and TNF-alpha production in both patients and controls. No difference between patients and controls was observed in this respect

CONCLUSIONS: In conclusion, PBMC of CFS patients display an increased sensitivity to glucocorticoids, which cannot be explained by number or affinity of the GR but should rather be attributed to molecular processes beyond the actual binding of the ligand to the GR.

 

Source: Visser J, Lentjes E, Haspels I, Graffelman W, Blauw B, de Kloet R, Nagelkerken L. Increased sensitivity to glucocorticoids in peripheral blood mononuclear cells of chronic fatigue syndrome patients, without evidence for altered density or affinity of glucocorticoid receptors. J Investig Med. 2001 Mar;49(2):195-204. http://www.ncbi.nlm.nih.gov/pubmed/11288761

 

Altered glucocorticoid regulation of the immune response in the chronic fatigue syndrome

Abstract:

It is increasingly recognized that glucocortiocoids (GCs) can have subtle modulatory effects in immunoregulation rather than having generalized immunosuppressive effects. GCs suppress Th1 cells and cellular immunity, but may favor Th2 responses and humoral immunity. The chronic fatigue syndrome (CFS) appears to be associated with a disturbed HPA-axis. Moreover, CFS patients show several immunological changes suggestive of decreased cellular immunity. It is postulated herein that in CFS patients a decreased Th1/Th2 balance may be the result of selective effects of GC on the IL-10/IL-12 regulatory circuit.

 

Source: Visser JT, De Kloet ER, Nagelkerken L. Altered glucocorticoid regulation of the immune response in the chronic fatigue syndrome. Ann N Y Acad Sci. 2000;917:868-75. http://www.ncbi.nlm.nih.gov/pubmed/11268418

 

Decreased bone mineral density during low dose glucocorticoid administration in a randomized, placebo controlled trial

Abstract:

OBJECTIVE: While osteoporosis and bone fractures are clearly recognized side effects of high dose glucocorticoids, the effect of low dose glucocorticoids remains controversial. We investigated the effect of 3 months of low dose hydrocortisone on bone mineral density (BMD).

METHODS: Subjects, 18 to 55 years old with chronic fatigue syndrome and no medical or psychiatric illness requiring medication, were randomized in a double blind, placebo controlled trial to receive oral hydrocortisone, 13 mg/m2 body surface area every morning and 3 mg/m2 every afternoon (25 to 35 mg/day, equivalent to about 7.5 mg prednisone/day) or placebo for 12 weeks. Before and after treatment BMD of the lumbar spine was measured by dual energy x-ray absorptiometry.

RESULTS: We studied 23 subjects (19 women, 4 men). For the 11 hydrocortisone recipients there was a mean decrease in BMD: mean change from baseline of the lateral spine was -2.0% (95% CI -3.5 to -0.6. p = 0.03) and mean change of the anteroposterior spine was -0.8% (95% CI -1.5 to -0.1, p = 0.06). Corresponding changes for the 12 placebo recipients were +1.0% (95% CI -1.0 to 3.0, p = 0.34) and +0.2% (95% CI -1.4 to 1.5, p = 0.76).

CONCLUSION: A 12 week course of low dose glucocorticoids given to ambulatory subjects with chronic fatigue syndrome was associated with a decrease in BMD of the lumbar spine. This decrease was statistically significant in lateral spine measurements and nearly so in anteroposterior spine measurements.

 

Source: McKenzie R, Reynolds JC, O’Fallon A, Dale J, Deloria M, Blackwelder W, Straus SE. Decreased bone mineral density during low dose glucocorticoid administration in a randomized, placebo controlled trial. J Rheumatol. 2000 Sep;27(9):2222-6. http://www.ncbi.nlm.nih.gov/pubmed/10990237

 

Elevated, sustained peroxynitrite levels as the cause of chronic fatigue syndrome

Abstract:

The etiology of chronic fatigue syndrome (CFS) has been both obscure and highly contentious, leading to substantial barriers to both clear diagnosis and effective treatment.

I propose here a novel hypothesis of CFS in which either viral or bacterial infection induces one or more cytokines, IL-1beta IL-6, TNF-alpha and IFN-gamma. These induce nitric oxide synthase (iNOS), leading to increased nitric oxide levels. Nitric oxide, in turn, reacts with superoxide radical to generate the potent oxidant peroxynitrite. Multiple amplification and positive feedback mechanisms are proposed by which once peroxynitrite levels are elevated, they tend to be sustained at a high level.

This proposed mechanism may lower the HPA axis activity and be maintained by consequent lowered glucocorticoid levels. Similarities are discussed among CFS and autoimmune and other diseases previously shown to be associated with elevated peroxynitrite. Multiple pharmacological approaches to the treatment of CFS are suggested by this hypothesis.

Comment in: Nitric oxide and the etiology of chronic fatigue syndrome: giving credit where credit is due. [Med Hypotheses. 2005]

 

Source: Pall ML. Elevated, sustained peroxynitrite levels as the cause of chronic fatigue syndrome. Med Hypotheses. 2000 Jan;54(1):115-25. http://www.ncbi.nlm.nih.gov/pubmed/10790736

 

Chronic fatigue disorders: an inappropriate response to arginine vasopressin?

Abstract:

Chronic fatigue disorders are characterized by a subjectively defined group of symptoms such as chronic fatigue, mental confusion, exertional malaise, weight changes, and/or diffuse multi-joint pains.

Significant clinical overlap exists between chronic fatigue disorders and the syndrome of serum inappropriate anti-diuretic hormone (SIADH). Both chronic fatigue disorders and SIADH are characterized by lethargy and mental confusion. Both disorders can be induced or exacerbated by viral illnesses, physical exertion, emotional stress and/or hypotension. Both can be treated with salt loading and glucocorticoids.

Therefore, altered water metabolism resulting from inappropriate release and/or response to arginine vasopressin (AVP) is proposed as a pathophysiological basis of certain chronic fatigue disorders. Moreover, these data suggest that salt loading and/or direct inhibition of AVP may be an effective therapeutic approach in individuals with chronic fatigue disorders.

 

Source: Peroutka SJ. Chronic fatigue disorders: an inappropriate response to arginine vasopressin? Med Hypotheses. 1998 Jun;50(6):521-3. http://www.ncbi.nlm.nih.gov/pubmed/9710328

 

Mild adrenocortical deficiency, chronic allergies, autoimmune disorders and the chronic fatigue syndrome: a continuation of the cortisone story

Abstract:

The possibility that patients with disorders that improve with administration of large, pharmacologic dosages of glucocorticoids, such as chronic allergies and autoimmune disorders, might have mild deficiency of cortisol production or utilization has received little attention.

Yet evidence that patients with rheumatoid arthritis improved with small, physiologic dosages of cortisol or cortisone acetate was reported over 25 years ago, and that patients with chronic allergic disorders or unexplained chronic fatigue also improved with administration of such small dosages was reported over 15 years ago, suggesting that these disorders might be associated with mild adrenocortical deficiency.

The apparent reasons for the failure of these reports to be confirmed or mentioned in medical textbooks and the facts needed to restore perspective are reviewed, and the need for further studies of the possible relationship of a mild deficiency of the production or utilization of cortisol and possibly other normal adrenocortical hormones to the development of these disorders is discussed.

 

Source: Jefferies WM. Mild adrenocortical deficiency, chronic allergies, autoimmune disorders and the chronic fatigue syndrome: a continuation of the cortisone story. Med Hypotheses. 1994 Mar;42(3):183-9. http://www.ncbi.nlm.nih.gov/pubmed/8057974