Tag: cortisol

Hypothalamic-pituitary-adrenal axis reactivity in chronic fatigue syndrome and health under psychological, physiological, and pharmacological stimulation

Abstract:

OBJECTIVES: Subtle alterations of the hypothalamic-pituitary-adrenal (HPA) axis in chronic fatigue syndrome (CFS) have been proposed as a shared pathway linking numerous etiological and perpetuating processes with symptoms and observed physiological abnormalities. Because the HPA axis is involved in the adaptive responses to stress and CFS patients experience a worsening of symptoms after physical and psychological stress, we tested HPA axis functioning with three centrally acting stress tests.

METHODS: We used two procedures mimicking real-life stressors and compared them with a standardized pharmacological neuroendocrine challenge test. CFS patients were compared with healthy control subjects regarding their cardiovascular and endocrine reactivity in a psychosocial stress test and a standardized exercise test, and their endocrine response in the insulin tolerance test (ITT).

RESULTS: Controlling for possible confounding variables, we found significantly lower ACTH response levels in the psychosocial stress test and the exercise test, and significantly lower ACTH responses in the ITT, with no differences in plasma total cortisol responses. Also, salivary-free cortisol responses did not differ between the groups in the psychosocial stress test and the exercise test but were significantly higher for the CFS patients in the ITT. In all tests CFS patients had significantly reduced baseline ACTH levels.

CONCLUSIONS: These results suggest that CFS patients are capable of mounting a sufficient cortisol response under different types of stress but that on a central level subtle dysregulations of the HPA axis exist.

 

Source: Gaab J, Hüster D, Peisen R, Engert V, Heitz V, Schad T, Schürmeyer TH, Ehlert U. Hypothalamic-pituitary-adrenal axis reactivity in chronic fatigue syndrome and health under psychological, physiological, and pharmacological stimulation. Psychosom Med. 2002 Nov-Dec;64(6):951-62. http://www.ncbi.nlm.nih.gov/pubmed/12461200

 

Neuropsychological performance and noradrenaline function in chronic fatigue syndrome under conditions of high arousal

Abstract:

RATIONALE: Subjective and objective impairments in neuropsychological function have been reported in chronic fatigue syndrome (CFS) patients under conditions of high arousal. These impairments may reflect impaired central noradrenaline function such as impaired post-synaptic alpha-2 adrenoceptor function.

OBJECTIVES: To determine whether high-dose clonidine has greater agonist effects at central post-synaptic alpha-2 receptors in CFS patients than controls under conditions of high arousal. As a result clonidine may reverse neuropsychological deficits underlying symptoms of poor concentration and memory.

METHODS: High-dose clonidine (2.5 mg/kg) and placebo challenge tests were given in random order to ten medication-free CFS patients without anxiety disorders, depressive disorders or migraine and ten matched healthy controls under the same stressors (timed neuropsychological testing, venous sampling, intravenous drug administration). Growth hormone, cortisol, blood pressure, pulse rate, visual analogue scales of subjective neuropsychological performance and the performance on several tests from a computerised neuropsychological battery were measured.

RESULTS: In CFS patients versus controls, clonidine enhanced both growth hormone ( P = 0.028) and cortisol release ( P = 0.021) and increased speed in the initial stage of a planning task ( P = 0.023). There were no other differences between CFS patients and controls on hormonal, physiological, symptomatic or neuropsychological measures.

CONCLUSIONS: Under conditions of high arousal, CFS patients may display supersensitive central post-synaptic alpha-2 adrenoceptor function associated with the release of cortisol and growth hormone and initial thinking time in planning tasks.

 

Source: Morriss RK, Robson MJ, Deakin JF. Neuropsychological performance and noradrenaline function in chronic fatigue syndrome under conditions of high arousal. Psychopharmacology (Berl). 2002 Sep;163(2):166-73. Epub 2002 Jul 30. http://www.ncbi.nlm.nih.gov/pubmed/12202963

 

Low-dose dexamethasone suppression test in chronic fatigue syndrome and health

Abstract:

OBJECTIVE: Subtle dysregulations of the hypothalamus-pituitary-adrenal axis in chronic fatigue syndrome have been described. The aim of this study was to examine the negative feedback regulations of the hypothalamus-pituitary-adrenal axis in chronic fatigue syndrome.

METHODS: In 21 patients with chronic fatigue syndrome and 21 healthy control subjects, awakening

and circadian salivary free cortisol profiles were assessed over 2 consecutive days and compared with awakening and circadian salivary free cortisol profiles after administration of 0.5 mg of dexamethasone at 11:00 PM the previous day.

RESULTS: Patients with chronic fatigue syndrome had normal salivary free cortisol profiles but showed enhanced and prolonged suppression of salivary free cortisol after the administration of 0.5 mg of dexamethasone in comparison to the control subjects.

CONCLUSIONS: Enhanced negative feedback of the hypothalamus-pituitary-adrenal axis could be a plausible explanation for the previously described alterations in hypothalamus-pituitary-adrenal axis functioning in chronic fatigue syndrome. Because similar changes have been described in stress-related disorders, a putative role of stress in the pathogenesis of the enhanced feedback is possible.

 

Source: Gaab J, Hüster D, Peisen R, Engert V, Schad T, Schürmeyer TH, Ehlert U. Low-dose dexamethasone suppression test in chronic fatigue syndrome and health. Psychosom Med. 2002 Mar-Apr;64(2):311-8. http://www.ncbi.nlm.nih.gov/pubmed/11914448

 

The neuroendocrinology of chronic fatigue syndrome and fibromyalgia

Abstract:

BACKGROUND: Disturbance of the HPA axis may be important in the pathophysiology of chronic fatigue syndrome (CFS) and fibromyalgia. Symptoms may be due to: (1) low circulating cortisol; (2) disturbance of central neurotransmitters; or (3) disturbance of the relationship between cortisol and central neurotransmitter function. Accumulating evidence of the complex relationship between cortisol and 5-HT function, make some form of hypothesis (3) most likely. We review the methodology and results of studies of the HPA and other neuroendocrine axes in CFS.

METHOD: Medline, Embase and Psychlit were searched using the Cochrane Collaboration strategy. A search was also performed on the King’s College CFS database, which includes over 3000 relevant references, and a citation analysis was run on the key paper (Demitrack et al. 1991).

RESULTS: One-third of the studies reporting baseline cortisol found it to be significantly low, usually in one-third of patients. Methodological differences may account for some of the varying results. More consistent is the finding of reduced HPA function, and enhanced 5-HT function on neuroendocrine challenge tests. The opioid system, and arginine vasopressin (AVP) may also be abnormal, though the growth hormone (GH) axis appears to be intact, in CFS.

CONCLUSIONS: The significance of these changes, remains unclear. We have little understanding of how neuroendocrine changes relate to the experience of symptoms, and it is unclear whether these changes are primary, or secondary to behavioural changes in sleep or exercise. Longitudinal studies of populations at risk for CFS will help to resolve these issues.

 

Source: Parker AJ, Wessely S, Cleare AJ. The neuroendocrinology of chronic fatigue syndrome and fibromyalgia. Psychol Med. 2001 Nov;31(8):1331-45. http://www.ncbi.nlm.nih.gov/pubmed/11722149

 

Familial corticosteroid-binding globulin deficiency due to a novel null mutation: association with fatigue and relative hypotension

Abstract:

Corticosteroid-binding globulin is a 383-amino acid glycoprotein that serves a hormone transport role and may have functions related to the stress response and inflammation. We describe a 39-member Italian-Australian family with a novel complete loss of function (null) mutation of the corticosteroid-binding globulin gene. A second, previously described, mutation (Lyon) segregated independently in the same kindred. The novel exon 2 mutation led to a premature termination codon corresponding to residue -12 of the procorticosteroid-binding globulin molecule (c.121G–>A).

Among 32 family members there were 3 null homozygotes, 19 null heterozygotes, 2 compound heterozygotes, 3 Lyon heterozygotes, and 5 individuals without corticosteroid-binding globulin mutations. Plasma immunoreactive corticosteroid-binding globulin was undetectable in null homozygotes, and mean corticosteroid-binding globulin levels were reduced by approximately 50% at 18.7 +/- 1.3 microg/ml (reference range, 30-52 microg/ml) in null heterozygotes. Morning total plasma cortisol levels were less than 1.8 microg/dl in homozygotes and were positively correlated to the plasma corticosteroid-binding globulin level in heterozygotes. Homozygotes and heterozygote null mutation subjects had a high prevalence of hypotension and fatigue.

Among 19 adults with the null mutation, the systolic blood pressure z-score was 12.1 +/- 3.5; 11 of 19 subjects (54%) had a systolic blood pressure below the third percentile. The mean diastolic blood pressure z-score was 18.1 +/- 3.4; 8 of 19 subjects (42%) had a diastolic blood pressure z-score below 10.

Idiopathic chronic fatigue was present in 12 of 14 adult null heterozygote subjects (86%) and in 2 of 3 null homozygotes. Five cases met the Centers for Disease Control criteria for chronic fatigue syndrome. Fatigue questionnaires revealed scores of 25.1 +/- 2.5 in 18 adults with the mutation vs. 4.2 +/- 1.5 in 23 healthy controls (P < 0.0001).

Compound heterozygosity for both mutations resulted in plasma cortisol levels comparable to those in null homozygotes. Abnormal corticosteroid-binding globulin concentrations or binding affinity may lead to the misdiagnosis of isolated ACTH deficiency. The mechanism of the association between fatigue and relative hypotension is not established by these studies. As idiopathic fatigue disorders are associated with relatively low plasma cortisol, abnormalities of corticosteroid-binding globulin may be pathogenic.

 

Source: Torpy DJ, Bachmann AW, Grice JE, Fitzgerald SP, Phillips PJ, Whitworth JA, Jackson RV. Familial corticosteroid-binding globulin deficiency due to a novel null mutation: association with fatigue and relative hypotension. J Clin Endocrinol Metab. 2001 Aug;86(8):3692-700. http://www.ncbi.nlm.nih.gov/pubmed/11502797

 

Urinary free cortisol in chronic fatigue syndrome

Abstract:

OBJECTIVE: The authors measured 24-hour urinary free cortisol in a group of well-characterized patients with chronic fatigue syndrome.

METHOD: They obtained 24-hour urine collections from 121 consecutive clinic patients with chronic fatigue syndrome and 64 comparison subjects without the syndrome.

RESULTS: Urinary free cortisol was significantly lower in the subjects with chronic fatigue syndrome regardless of the presence or absence of current or past comorbid psychiatric illness. Lower levels of urinary free cortisol were not related to medication use, sleep disturbance, or disability levels.

CONCLUSIONS: There is mild hypocortisolism in chronic fatigue syndrome. Whether a primary feature or secondary to other factors, hypocortisolism may be one factor contributing to the symptoms of chronic fatigue syndrome.

 

Source: Cleare AJ, Blair D, Chambers S, Wessely S. Urinary free cortisol in chronic fatigue syndrome. Am J Psychiatry. 2001 Apr;158(4):641-3. http://www.ncbi.nlm.nih.gov/pubmed/11282703

 

Melatonin levels in women with fibromyalgia and chronic fatigue syndrome

Abstract:

OBJECTIVE: Fibromyalgia (FM) and chronic fatigue syndrome (CFS) are stress associated disorders mainly affecting women. FM is characterized primarily by widespread musculoskeletal pain, and CFS by profound debilitating fatigue, but there is considerable overlap of clinical symptoms between these 2 syndromes. Neuroendocrine abnormalities have been noted in both FM and CFS and desynchronization of circadian systems has been postulated in their etiology. The pineal hormone melatonin is involved in synchronizing circadian systems and the use of exogenous melatonin has become widespread in patients with FM and CFS.

METHODS: We examined the characteristics and relationship of melatonin and cortisol levels in premenopausal women with FM (n = 9) or CFS (n = 8), compared to age and menstrual cycle phase matched controls. Blood was collected from an indwelling intravenous catheter every 10 min over 24 h, and plasma melatonin and cortisol were determined by radioimmunoassay at 60 and 10 min intervals, respectively.

RESULTS: Night time (23:00-06:50) plasma melatonin levels were significantly higher in FM patients compared to controls (p<0.05), but there was no significant difference in melatonin levels between CFS patients and controls. No differences in the timing of cortisol and melatonin secretory patterns and no internal desynchronization of the 2 rhythms were found in either patient group, compared to controls.

CONCLUSION: Raised plasma melatonin concentrations have been documented in several other conditions that are associated with dysregulation of neuroendocrine axes. Increased melatonin levels may represent a marker of increased susceptibility to stress induced hypothalamic disruptions. These data indicate that there is no rationale for melatonin replacement therapy in patients with FM and CFS.

 

Source: Korszun A, Sackett-Lundeen L, Papadopoulos E, Brucksch C, Masterson L, Engelberg NC, Haus E, Demitrack MA, Crofford L. Melatonin levels in women with fibromyalgia and chronic fatigue syndrome. J Rheumatol. 1999 Dec;26(12):2675-80. http://www.ncbi.nlm.nih.gov/pubmed/10606381

 

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

 

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