Tag: HPA axis

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

 

The sympathetic nerve–an integrative interface between two supersystems: the brain and the immune system

Abstract:

The brain and the immune system are the two major adaptive systems of the body. During an immune response the brain and the immune system “talk to each other” and this process is essential for maintaining homeostasis. Two major pathway systems are involved in this cross-talk: the hypothalamic-pituitary-adrenal (HPA) axis and the sympathetic nervous system (SNS). This overview focuses on the role of SNS in neuroimmune interactions, an area that has received much less attention than the role of HPA axis.

Evidence accumulated over the last 20 years suggests that norepinephrine (NE) fulfills the criteria for neurotransmitter/neuromodulator in lymphoid organs. Thus, primary and secondary lymphoid organs receive extensive sympathetic/noradrenergic innervation. Under stimulation, NE is released from the sympathetic nerve terminals in these organs, and the target immune cells express adrenoreceptors.

Through stimulation of these receptors, locally released NE, or circulating catecholamines such as epinephrine, affect lymphocyte traffic, circulation, and proliferation, and modulate cytokine production and the functional activity of different lymphoid cells. Although there exists substantial sympathetic innervation in the bone marrow, and particularly in the thymus and mucosal tissues, our knowledge about the effect of the sympathetic neural input on hematopoiesis, thymocyte development, and mucosal immunity is extremely modest.

In addition, recent evidence is discussed that NE and epinephrine, through stimulation of the beta(2)-adrenoreceptor-cAMP-protein kinase A pathway, inhibit the production of type 1/proinflammatory cytokines, such as interleukin (IL-12), tumor necrosis factor-alpha, and interferon-gamma by antigen-presenting cells and T helper (Th) 1 cells, whereas they stimulate the production of type 2/anti-inflammatory cytokines such as IL-10 and transforming growth factor-beta.

Through this mechanism, systemically, endogenous catecholamines may cause a selective suppression of Th1 responses and cellular immunity, and a Th2 shift toward dominance of humoral immunity. On the other hand, in certain local responses, and under certain conditions, catecholamines may actually boost regional immune responses, through induction of IL-1, tumor necrosis factor-alpha, and primarily IL-8 production.

Thus, the activation of SNS during an immune response might be aimed to localize the inflammatory response, through induction of neutrophil accumulation and stimulation of more specific humoral immune responses, although systemically it may suppress Th1 responses, and, thus protect the organism from the detrimental effects of proinflammatory cytokines and other products of activated macrophages.

The above-mentioned immunomodulatory effects of catecholamines and the role of SNS are also discussed in the context of their clinical implication in certain infections, major injury and sepsis, autoimmunity, chronic pain and fatigue syndromes, and tumor growth.

Finally, the pharmacological manipulation of the sympathetic-immune interface is reviewed with focus on new therapeutic strategies using selective alpha(2)- and beta(2)-adrenoreceptor agonists and antagonists and inhibitors of phosphodiesterase type IV in the treatment of experimental models of autoimmune diseases, fibromyalgia, and chronic fatigue syndrome.

 

Source: Elenkov IJ, Wilder RL, Chrousos GP, Vizi ES. The sympathetic nerve–an integrative interface between two supersystems: the brain and the immune system. Pharmacol Rev. 2000 Dec;52(4):595-638. http://pharmrev.aspetjournals.org/content/52/4/595.long (Full article)

 

Self-reported sensitivity to chemical exposures in five clinical populations and healthy controls

Abstract:

Two hundred and twenty-five subjects, including normal volunteers and patients with previously documented seasonal affective disorder (SAD),chronic fatigue syndrome (CFS), Cushing’s syndrome, Addison’s disease and obsessive-compulsive disorder (OCD), completed a self-rated inventory of reported sensitivity to various chemical exposures.

Patients with CFS, Addison’s disease and SAD self-reported more sensitivity to chemical exposures than normal controls. In addition, women reported more sensitivity than men.

This report suggests that chemical sensitivity may be a relevant area to explore in certain medical and psychiatric populations. A possible relationship between reported chemical sensitivity and hypothalamic-pituitary-adrenal (HPA)-axis functioning is discussed.

 

Source: Nawab SS, Miller CS, Dale JK, Greenberg BD, Friedman TC, Chrousos GP, Straus SE, Rosenthal NE. Self-reported sensitivity to chemical exposures in five clinical populations and healthy controls. Psychiatry Res. 2000 Jul 24;95(1):67-74. http://www.ncbi.nlm.nih.gov/pubmed/10904124

 

The 1microg short Synacthen test in chronic fatigue syndrome

Abstract:

OBJECTIVE: Many studies suggest mild hypocortisolism in chronic fatigue syndrome (CFS), usually assumed to be due to reduced suprahypothalamic drive to the hypothalamo-pituitary-adrenal (HPA) axis. We wished to explore further the state of the HPA axis in CFS using the 1 microg low dose short Synacthen test.

DESIGN: Subjects received an intravenous bolus of 1 microg Synacthen; samples for cortisol estimation were taken at baseline and 2, 10, 20, 30, 40 and 60 minutes after injection.

PATIENTS: We tested 20 subjects suffering from CFS according to the criteria of the Center for Diseases Control without psychiatric comorbidity and 20 matched healthy controls. All subjects were drug free for at least 1 month.

MEASUREMENTS: We calculated the cortisol responses to the test as the maximum cortisol attained, the incremental rise in cortisol over baseline (Deltavalue) and as the integrated area under the curve.

RESULTS: There were no significant differences in baseline cortisol or cortisol responses between patients and controls. However, responses generally were low, and many subjects’ peak responses were prior to the standard 30 minute sampling time.

CONCLUSIONS: These results do not lend support to the theory that patients with chronic fatigue syndrome have a low adrenal reserve. However, results from studies assessing the HPA axis are proving to be inconsistent. We suggest that many other factors may be contributing to HPA axis alterations in chronic fatigue syndrome, including sleep disturbance, inactivity, altered circadian rhythmicity, illness chronicity, concomitant medication and comorbid psychiatric disturbance. These sources of heterogeneity need to be considered in future studies, and may explain the inconsistent findings to date.

Comment in: The 1microg Synacthen test in chronic fatigue syndrome. [Clin Endocrinol (Oxf). 2000]

 

Source: Hudson M, Cleare AJ. The 1microg short Synacthen test in chronic fatigue syndrome. Clin Endocrinol (Oxf). 1999 Nov;51(5):625-30. http://www.ncbi.nlm.nih.gov/pubmed/10594524

 

Small adrenal glands in chronic fatigue syndrome: a preliminary computer tomography study

Abstract:

No inclusive or satisfactory biomedical explanation for chronic fatigue syndrome (CFS) has as yet been forwarded. Recent research suggests that a dysregulated hypothalamic-pituitary-adrenal axis (HPA) may be contributory, and in particular that there may be diminished forward drive and adrenal under-stimulation.

In this preliminary study we wished to examine a cohort of CFS patients in whom evidence for such hypofunctioning was found. Our aim was to establish whether these patients had altered adrenal gland size.

Patients were recruited from a fatigue clinic. Those who fulfilled the Centre for Disease Control and Prevention (CDC) criteria underwent a 1 microgram adrenocorticotropin (ACTH) stimulation test, a test of adrenal gland functioning.

Eight subjects (five females, three males) with a subnormal response to this test underwent a computer tomography (CT) adrenal gland assessment. Measurements were compared with those from a group of 55 healthy subjects.

The right and left adrenal gland bodies were reduced by over 50% in the CFS subjects indicative of significant adrenal atrophy in a group of CFS patients with abnormal endocrine parameters.

This is the first study to use imaging methods to measure adrenal gland size in CFS. It is a limitation of this study that a selected CFS sample was employed. A future larger study would optimally employ an unselected cohort of CFS patients. This study has implications not only for the elucidation of CFS pathophysiology, but also for possible therapeutic strategies.

 

Source: Scott LV, Teh J, Reznek R, Martin A, Sohaib A, Dinan TG. Small adrenal glands in chronic fatigue syndrome: a preliminary computer tomography study. Psychoneuroendocrinology. 1999 Oct;24(7):759-68. http://www.ncbi.nlm.nih.gov/pubmed/10451910

 

Differences in adrenal steroid profile in chronic fatigue syndrome, in depression and in health

Abstract:

BACKGROUND: Hyperactivity and hypoactivity of the HPA have been forwarded as of pathophysiological relevance in major depressive disorder and chronic fatigue syndrome (CFS), respectively.

METHODS: This study examines cortisol levels in the two disorders, and also assesses levels of the adrenal androgens, dehydroepiandrosterone (DHEA) and its sulphate derivative (DHEA-S), and 17-alpha-hydroxyprogesterone; 15 subjects with CFS diagnosed according to CDC criteria, 15 subjects with DSM III-R major depression and 11 healthy subjects were compared.

RESULTS: DHEA and DHEA-S levels were significantly lower in the CFS compared to the healthy group; DHEA-S levels, but not DHEA, were lower in the depressives; cortisol and 17-alpha-hydroxyprogesterone did not differ between the three groups.

CONCLUSIONS: A potential role for DHEA, both therapeutically and as a diagnostic tool, in CFS, is suggested.

 

Source: Scott LV, Salahuddin F, Cooney J, Svec F, Dinan TG. Differences in adrenal steroid profile in chronic fatigue syndrome, in depression and in health. J Affect Disord. 1999 Jul;54(1-2):129-37. http://www.ncbi.nlm.nih.gov/pubmed/10403156

 

Desmopressin augments pituitary-adrenal responsivity to corticotropin-releasing hormone in subjects with chronic fatigue syndrome and in healthy volunteers

Abstract:

BACKGROUND: Corticotropin-releasing hormone (CRH) and vasopressin (VP) are the two principal neuropeptide regulators of the hypothalamic-pituitary-adrenal axis in man, with VP serving to augment CRH-induced adrenocorticotropic hormone (ACTH) release. Unlike VP, desmopressin (DDAVP), which is a synthetic analogue of VP, when administered alone, has not been shown in healthy subjects to have consistent ACTH-releasing properties. It has been suggested that chronic fatigue syndrome (CFS), characterized by profound fatigue and a constellation of other symptoms, may be caused by a central deficiency of CRH.

METHODS: We administered 100 micrograms ovine CRH (oCRH) and 10 micrograms DDAVP, both alone and in combination, to a group of subjects with CFS, and to a group of healthy volunteers. Our aim was to establish the effect of DDAVP on CRH-induced ACTH release in these two groups.

RESULTS: The delta-ACTH responses to oCRH were attenuated in the CFS (21.0 +/- 4.5 ng/L) compared to the control subjects (57.8 +/- 11.0 ng/L; t = 3.2, df = 21, p < .005). The delta-cortisol responses were also reduced in the CFS (157.6 +/- 40.7 nmol/L) compared to the healthy subjects (303.5 +/- 20.9 nmol/L; t = 3.1, df = 21, p < .01). The delta-ACTH and delta-cortisol responses to DDAVP alone did not differ between the two groups. On administration of both CRH and DDAVP no response differences between the two groups for either ACTH (p = .3) or cortisol output (p = .87) were established. Comparing the ACTH and cortisol responses to CRH and CRH/DDAVP in only those individuals from each group who had both tests, the cortisol output to the combination was significantly greater in the CFS compared to the healthy group. The ACTH output was also increased in the former group, though this was not significant.

CONCLUSIONS: DDAVP augments CRH-mediated pituitary-adrenal responsivity in healthy subjects and in patients with CFS. That DDAVP was capable of normalizing the pituitary-adrenal response to oCRH in the CFS group suggests there may be increased vasopressinergic responsivity of the anterior pituitary in CFS and/or that DDAVP may be exerting an effect at an adrenal level.

 

Source: Scott LV, Medbak S, Dinan TG. Desmopressin augments pituitary-adrenal responsivity to corticotropin-releasing hormone in subjects with chronic fatigue syndrome and in healthy volunteers. Biol Psychiatry. 1999 Jun 1;45(11):1447-54. http://www.ncbi.nlm.nih.gov/pubmed/10356627

 

A pilot study employing Dehydroepiandrosterone (DHEA) in the treatment of chronic fatigue syndrome

Abstract:

Patients with chronic fatigue syndrome (CFS) frequently associate the disease onset with a period of high physical and/or emotional stress. Alterations in hypothalamic-pituitary adrenal axis (HPA) function have been demonstrated. Although Cortisol production in patients with CFS has proven to be low, Dehydroepiandrosterone (DHEA) production has not been measured. DHEA output may be altered in this population.

The purpose of this uncontrolled, prospective, 6 month study of 23 white women, ages 35-55 was to identify CFS patients with suboptimal serum levels of DHEA-sulphate (DHEA-S), defined as DHEA-S <2.0 microg/mL, and to treat those patients with oral DHEA.

DHEA-S levels were re-measured after 4-6 weeks of oral DHEA therapy (25 mg). If DHEA-S remained <2.0 microg/ mL, or if no clinical response was achieved after 4-6 weeks of therapy, then an increased dose of DHEA was given. Physical and psychological impairment and disability status were measured by the MHAQII before DHEA intervention and at 3-month intervals. Of initially screened patients with CFS, 76% (116 of 153) were ages 35-55, and 89% (103 of 116) had suboptimal (<2.0 microg/mL) production of DHEA-S.

Supplementation with DHEA to CFS patients lead to a significant reduction in the symptoms of CFS: pain (improved by 18%, p = 0.035), fatigue (decreased by 21%, p = 0.009)), activities of daily living (improved by 8.5%, p = 0.058), helplessness (decreased by 11%, p = 0.015), anxiety (decreased by 35%, p < 0.01), thinking (improved by 26%, p < 0.01), memory (improved by 17%, p < 0.05), and sexual problems (improved by 22%, p = 0.06) over the period of the trial.

Further study is necessary to determine the safety and efficacy of supplementation of DHEA to this population in a controlled setting.

 

Source: Himmel PB, Seligman TM. A pilot study employing Dehydroepiandrosterone (DHEA) in the treatment of chronic fatigue syndrome. J Clin Rheumatol. 1999 Apr;5(2):56-9. http://www.ncbi.nlm.nih.gov/pubmed/19078357

 

The hypothalamic-pituitary-adrenal stress axis in fibromyalgia and chronic fatigue syndrome

Abstract:

HPA axis abnormalities in FM, CFS, and other stress-related disorders must be placed in a broad clinical context. We know that interventions providing symptomatic improvement in patients with FM and CFS can directly or indirectly affect the HPA axis. These interventions include exercise, tricyclic anti-depressants, and serotonin reuptake inhibitors. There is little direct information as to how the specific HPA axis perturbations seen in FM can be related to the major symptomatic manifestations of pain, fatigue, sleep disturbance, and psychological distress. Since many of these somatic and psychological symptoms are present in other syndromes that exhibit HPA axis disturbances, it seems reasonable to suggest that there may be some relationship between basal and dynamic function of the HPA axis and clinical manifestations of FM and CFS.

 

Source: Crofford LJ. The hypothalamic-pituitary-adrenal stress axis in fibromyalgia and chronic fatigue syndrome. Z Rheumatol. 1998;57 Suppl 2:67-71. http://www.ncbi.nlm.nih.gov/pubmed/10025087

 

Dehydroepiandrosterone sulfate deficiency in chronic fatigue syndrome

Abstract:

The chronic fatigue syndrome (CFS) is a condition of unknown etiology, characterized by a persistent debilitating fatigue, the muscle-related symptoms and the neuropsychiatric symptoms.

Recently, it has been reported that the patients with CFS might have impaired activation of the hypothalamic-pituitary-adrenal axis, and suggested that a part of the patho-genesis of CFS might be associated with abnormalities of the endocrine system.

Herein, we show that the majority of Japanese patients with CFS had a serum dehydroepiandrosterone sulfate (DHEA-S) deficiency. Serum DHEA-S is one of the most abundantly produced hormones which is secreted from the adrenal glands, and its physiological function is thought to be a precursor of sex steroids. DHEA-S has recently been shown to have physiological properties, such as neurosteroids, which are associated with such psychophysiological phenomena as memory, stress, anxiety, sleep and depression.

Therefore, the deficiency of DHEA-S might be related to the neuropsychiatric symptoms in patients with CFS.

 

Source: Kuratsune H, Yamaguti K, Sawada M, Kodate S, Machii T, Kanakura Y, Kitani T. Dehydroepiandrosterone sulfate deficiency in chronic fatigue syndrome. Int J Mol Med. 1998 Jan;1(1):143-6. http://www.ncbi.nlm.nih.gov/pubmed/9852212