Endocrine System – Page 6 – American ME and CFS Society

Chronic ACTH autoantibodies are a significant pathological factor in the disruption of the hypothalamic-pituitary-adrenal axis in chronic fatigue syndrome, anorexia nervosa and major depression

Abstract:

Dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis is a commonly recognized feature of many pathological conditions. Abnormal adrenal responses to experimental manipulation have been well documented in patients suffering from chronic fatigue syndrome, anorexia nervosa and major depression. Yet no defect of any single organ, gland or brain region has been identified as a cause of these abnormalities. The disruption of the HPA axis that occurs in these conditions can be understood if an interfering factor is present in these patients.

Evidence indicates that this interfering factor is adrenocorticotropin hormone (ACTH) autoantibodies. Chronic high levels of ACTH autoantibodies will significantly disrupt the HPA axis and force the body to compensate for an impaired cortisol response. The resulting effect of chronic ACTH autoantibody interference is the manifestation of adrenocortical insufficient symptoms and psychological disturbances. Some symptoms ofchronic fatigue syndrome, anorexia nervosa and major depression, such as anxiety, are the adverse effects of mechanisms compensating for less effective ACTH due to autoantibodies. Furthermore, these patients engage in extraordinary behaviors, such as self-injury, to increase their cortisol levels. When this compensation is inadequate, symptoms of adrenocortical insufficiency appear.

Corticosteroid supplements have been demonstrated to be an effective treatment for chronic fatigue syndrome, anorexia nervosa and major depression. It allows the patients to have the corticosteroids they require for daily functioning and daily stressors. This therapy will relieve the patients of their symptoms of adrenocortical insufficiency and permit their cortisol-stimulating mechanisms to operate at levels that will not cause pathological problems.

Source: Wheatland R. Chronic ACTH autoantibodies are a significant pathological factor in the disruption of the hypothalamic-pituitary-adrenal axis in chronic fatigue syndrome, anorexia nervosa and major depression. Med Hypotheses. 2005;65(2):287-95. http://www.ncbi.nlm.nih.gov/pubmed/15885924

Disturbed adrenal function in adolescents with chronic fatigue syndrome

Abstract:

OBJECTIVE: To investigate adrenal function in children and adolescents with chronic fatigue syndrome (CFS) compared with age-matched controls.

METHODS: Case-control study of low dose (500 ng/m2) synacthen tests (LDST) in 23 adolescents with CFS and 17 age-matched controls. Serum cortisol concentrations were measured at 5-min intervals from 10 to 45 minutes. Peak serum cortisol concentration, time to peak, rise in cortisol and area under the curve (AUC) were derived.

RESULTS: Patients with CFS had significantly lower mean cortisol levels during the LDST (p <0.001), lower peak cortisol (p <0.025), reduced cortisol AUC (p <0.005) and longer time to peak cortisol (p <0.05). Abnormalities were seen in both sexes but were more pronounced in females. Unstimulated adrenal androgen and 17-hydroxyprogesterone concentrations were normal.

CONCLUSIONS: Adolescents with CFS have subtle alterations in adrenal function suggesting a reduction in central stimulation of the adrenal glands. The more pronounced effects in females may reflect differential central effects of stress on hypothalamic-pituitary-adrenal axis regulation between the sexes.

Source: Segal TY, Hindmarsh PC, Viner RM. Disturbed adrenal function in adolescents with chronic fatigue syndrome. J Pediatr Endocrinol Metab. 2005 Mar;18(3):295-301. http://www.ncbi.nlm.nih.gov/pubmed/15813608

Normal opioid tone and hypothalamic-pituitary-adrenal axis function in chronic fatigue syndrome despite marked functional impairment

Abstract:

OBJECTIVE: To determine whether the functional impairment seen in chronic fatigue syndrome (CFS) is associated with reduced levels of central opioids and/or deficiency of the hypothalamic-pituitary-adrenal (HPA) axis.

DESIGN: Single-blinded case-control study measuring functional and psychological status, basal hormonal parameters and ACTH/cortisol response to naloxone and ovine corticotrophin-releasing hormone (oCRH) vs. placebo in people with CFS and healthy controls.

PATIENTS: Twelve people with CFS and 11 age-matched controls.

MEASUREMENTS: Hormonal parameters: basal levels of 09:00 h plasma cortisol, dehydroepiandrosterone sulfate (DHEAS) and IGF-1. 24-h urinary free cortisol. Plasma ACTH and cortisol response to naloxone 125 microg/kg, oCRH 1 microg/kg and placebo (normal saline). Psychological parameters: SF-36, Hamilton Depression Score, Hospital Anxiety and Depression Scale and Fatigue Scale.

RESULTS: There were highly significant differences between the CFS subjects and the controls with respect to the measures of fatigue and physical functioning. However, there were no differences in basal levels of 09:00 h cortisol (367 +/- 37 vs. 331 +/- 39 nmol/l, P = 0.51), DHEAS (4.2 +/- 0.6 vs. 4.0 +/- 0.5 micromol/l, P = 0.81), 24-h urinary free cortisol (182 +/- 27 vs. 178 +/- 21 nmol/24 h, P = 0.91) or IGF-1 (145 +/- 19 vs. 130 +/- 11 microg/l, P = 0.52) between the CFS group and controls, respectively. There was also no difference between the groups with respect to the ACTH and cortisol response to either oCRH or naloxone.

CONCLUSIONS: Our data do not support an aetiological role for deficiency in central opioids or the HPA axis in the symptoms of CFS.

Source: Inder WJ1, Prickett TC, Mulder RT. Normal opioid tone and hypothalamic-pituitary-adrenal axis function in chronic fatigue syndrome despite marked functional impairment. Clin Endocrinol (Oxf). 2005 Mar;62(3):343-8. http://www.ncbi.nlm.nih.gov/pubmed/15730417

Hypothalamic-pituitary-gonadal axis hormones and cortisol in both menstrual phases of women with chronic fatigue syndrome and effect of depressive mood on these hormones

Abstract:

BACKGROUND: Chronic fatigue syndrome (CFS) is a disease which defined as medically unexplained, disabling fatigue of 6 months or more duration and often accompanied by several of a long list of physical complaints. We aimed to investigate abnormalities of hypothalamic-pituitary-gonadal (HPG) axis hormones and cortisol concentrations in premenopausal women with CFS and find out effects of depression rate on these hormones.

METHODS: We examined follicle stimulating hormone (FSH), luteinizing hormone (LH), estradiol, progesterone and cortisol concentrations in 43 premenopausal women (mean age: 32.86 +/- 7.11) with CFS and compared matched 35 healthy controls (mean age: 31.14 +/- 6.19). Patients were divided according to menstrual cycle phases (follicular and luteal) and compared with matched phase controls. Depression rate was assessed by Beck Depression Inventory (BDI), and patients with high BDI scores were compared to patients with low BDI scores.

RESULTS: There were no significant differences in FSH, LH, estradiol and progesterone levels in both of menstrual phases of patients versus controls. Cortisol levels were significantly lower in patients compared to controls. There were no significant differences in all hormone levels in patients with high depression scores versus patients with low depression scores.

CONCLUSION: In spite of high depression rate, low cortisol concentration and normal HPG axis hormones of both menstrual phases are detected in premenopausal women with CFS. There is no differentiation between patients with high and low depression rate in all hormone levels. Depression condition of CFS may be different from classical depression and evaluation of HPG and HPA axis should be performed for understanding of pathophysiology of CFS and planning of treatment.

Source: Cevik R, Gur A, Acar S, Nas K, Sarac AJ. Hypothalamic-pituitary-gonadal axis hormones and cortisol in both menstrual phases of women with chronic fatigue syndrome and effect of depressive mood on these hormones. BMC Musculoskelet Disord. 2004 Dec 8;5:47. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC539265/ (Full article)

Association between chronic fatigue syndrome and the corticosteroid-binding globulin gene ALA SER224 polymorphism

Abstract:

Chronic fatigue syndrome (CFS) is characterized by idiopathic fatigue of greater than 6 months’ duration with postexertional exacerbation and many other symptoms. A trend toward relative hypocortisolism is described in CFS. Twin and family studies indicate a substantial genetic etiologic component to CFS. Recently, severe corticosteroid-binding globulin (CBG) gene mutations have been associated with CFS in isolated kindreds. Human leukocyte elastase, an enzyme important in CBG catabolism at inflammatory sites, is reported to be elevated in CFS. We hypothesized that CBG gene polymorphisms may act as a genetic risk factor for CFS.

A total of 248 patients with CFS defined by Centers for Disease Control criteria, and 248 controls were recruited. Sequencing and restriction enzyme testing of the CBG gene coding region allowed detection of severe CBG gene mutations and a common exon 3 polymorphism (c.825G–>T, Ala-Ser224).

Plasma CBG levels were measured in 125 CFS patients and 198 controls by radioimmunoassay. Total and free (calculated and measured) cortisol levels were ascertained in single samples between 8-10 a.m. The age of onset (mid 30s) and gender ratio (2.2:1, female:male) of the patients were similar to those reported in U.S. epidemiologic studies.

A trend toward a preponderance of serine224 homozygosity among the CFS patients was noted, compared with controls (chi2 = 5.31, P = 0.07). Immunoreactive-CBG (IR-CBG) levels were higher in Serine/Alanine (Ser/Ala) than Ala/Ala subjects and higher again in Ser/Ser subjects, this effect was strongest in controls; Ser/Ser: 46.1+/-1.8 (n = 31, P = 0.03) vs. Ser/Ala: 42.4+/-1.0 (n = 56, P = 0.05) vs. Ala/Ala: 40.8+/-1.7 microg/mL (n = 21). Despite higher CBG levels, there was a nonsignificant trend toward lower total and free plasma cortisol in serine allele positive patients, total cortisol: Ser/Ser: 13.3+/-1.4 (n = 34) vs. Ser/Ala: 14.0+/-0.7 (n = 66) vs. Ala/Ala: 15.4+/-1.0 (n = 23).

Homozygosity for the serine allele of the CBG gene may predispose to CFS, perhaps due to an effect on hypothalamic-pituitary-adrenal axis function related to altered CBG-cortisol transport function or immune-cortisol interactions.

Source: Torpy DJ, Bachmann AW, Gartside M, Grice JE, Harris JM, Clifton P, Easteal S, Jackson RV, Whitworth JA. Association between chronic fatigue syndrome and the corticosteroid-binding globulin gene ALA SER224 polymorphism. Endocr Res. 2004 Aug;30(3):417-29. http://www.ncbi.nlm.nih.gov/pubmed/15554358

Basal circadian and pulsatile ACTH and cortisol secretion in patients with fibromyalgia and/or chronic fatigue syndrome

Abstract:

The objective of this study was to evaluate and compare the basal circadian and pulsatile architecture of the HPA axis in groups of patients with FMS, CFS, or both syndromes with individually matched control groups.

Forty patients with either FMS (n = 13), FMS and CFS (n = 12), or CFS (n = 15) were matched by age (18-65), sex, and menstrual status to healthy controls. Subjects were excluded if they met criteria for major Axis I psychiatric disorders by structured clinical interview (SCID). Subjects were admitted to the General Clinical Research Center where meals and activities were standardized. Blood was collected from an intravenous line every 10 min over 24 h for analysis of ACTH and cortisol. Samples were evaluable for ACTH in 36 subject pairs and for cortisol in 37 subject pairs.

There was a significant delay in the rate of decline from acrophase to nadir for cortisol levels in patients with FMS (P <.01). Elevation of cortisol in the late evening quiescent period was evident in half of the FMS patients compared with their control group, while cortisol levels were numerically, but not significantly, lower in the overnight period in patients with CFS compared with their control group. Pulsatility analyses did not reveal statistically significant differences between patient and control groups.

We conclude that the pattern of differences for basal circadian architecture of HPA axis hormones differs between patients with FMS and CFS compared to their matched control groups. The abnormalities in FMS patients are consistent with loss of HPA axis resiliency.

Source: Crofford LJ, Young EA, Engleberg NC, Korszun A, Brucksch CB, McClure LA, Brown MB, Demitrack MA. Basal circadian and pulsatile ACTH and cortisol secretion in patients with fibromyalgia and/or chronic fatigue syndrome. Brain Behav Immun. 2004 Jul;18(4):314-25. http://www.ncbi.nlm.nih.gov/pubmed/15157948

Cortisol and hypothalamic-pituitary-gonadal axis hormones in follicular-phase women with fibromyalgia and chronic fatigue syndrome and effect of depressive symptoms on these hormones

Abstract:

We investigated abnormalities of the hypothalamic-pituitary-gonadal axis and cortisol concentrations in women with fibromyalgia and chronic fatigue syndrome (CFS) who were in the follicular phase of their menstrual cycle, and whether their scores for depressive symptoms were related to levels of these hormones.

A total of 176 subjects participated – 46 healthy volunteers, 68 patients with fibromyalgia, and 62 patients with CFS. We examined concentrations of follicle-stimulating hormone, luteinizing hormone (LH), estradiol, progesterone, prolactin, and cortisol. Depressive symptoms were assessed using the Beck Depression Inventory (BDI).

Cortisol levels were significantly lower in patients with fibromyalgia or CFS than in healthy controls (P < 0.05); there were no significant differences in other hormone levels between the three groups. Fibromyalgia patients with high BDI scores had significantly lower cortisol levels than controls (P < 0.05), and so did CFS patients, regardless of their BDI scores (P < 0.05). Among patients without depressive symptoms, cortisol levels were lower in CFS than in fibromyalgia (P < 0.05).

Our study suggests that in spite of low morning cortisol concentrations, the only abnormalities in hypothalamic-pituitary-gonadal axis hormones among follicular-phase women with fibromyalgia or CFS are those of LH levels in fibromyalgia patients with a low BDI score. Depression may lower cortisol and LH levels, or, alternatively, low morning cortisol may be a biological factor that contributes to depressive symptoms in fibromyalgia. These parameters therefore must be taken into account in future investigations.

Source: Gur A, Cevik R, Nas K, Colpan L, Sarac S. Cortisol and hypothalamic-pituitary-gonadal axis hormones in follicular-phase women with fibromyalgia and chronic fatigue syndrome and effect of depressive symptoms on these hormones. Arthritis Res Ther. 2004;6(3):R232-8. Epub 2004 Mar 15. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC416440/ (Full article)

Levels of DHEA and DHEAS and responses to CRH stimulation and hydrocortisone treatment in chronic fatigue syndrome

Abstract:

BACKGROUND: An association between chronic fatigue syndrome (CFS) and abnormalities of the hypothalamo-pituitary-adrenal axis has been described, and other adrenal steroid abnormalities have been suggested. Dehydroepiandrostenedione (DHEA) and its sulphate (DHEA-S), apart from being a precursor of sex steroids, have other functions associated with memory, depression and sleep. It has been suggested that CFS may be associated with a state of relative DHEA(-S) deficiency. Therefore we investigated basal levels of DHEA(-S), the cortisol/DHEA molar ratio and the responsiveness of DHEA to stimulation by corticotrophin-releasing hormone (CRH). Recent studies have also suggested that low dose hydrocortisone may be effective at reducing fatigue in CFS. We therefore also assessed these parameters prior to and following treatment with low dose oral hydrocortisone.

METHODS: Basal levels of serum DHEA, DHEAS and cortisol were measured in 16 patients with CFS without depression and in 16 controls matched for age, gender, weight, body mass index and menstrual history. CRH tests (1 g/kg i.v.) were carried out on all subjects and DHEA measured at 0, +30 and +90 min. In the patient group, CRH tests were repeated on two further occasions following treatment with hydrocortisone (5 or 10 mg, p.o.) or placebo for 1 month each in a double-blind cross over study protocol.

RESULTS: Basal levels of DHEA were higher in the patient, compared to the control, group (14.1+/-2.2 vs. 9.0+/-0.90 ng/ml, P=0.04), while levels of DHEAS in patients (288.7+/-35.4 microg/dl) were not different from controls (293.7+/-53.8, P=NS). Higher DHEA levels were correlated with higher disability scores. Basal cortisol levels were higher in patients, and consequently the cortisol/DHEA molar ratio did not differ between patients and controls. Levels of DHEA (8.9+/-0.97 ng/ml, P=0.015) and DHEAS (233.4+/-41.6 microg/dl, P=0.03) were lower in patients following treatment with hydrocortisone. There was a rise in DHEA responsiveness to CRH in the patients after treatment but this did not attain significance (AUCc: 2.5+/-1.7 ng/ml h pre-treatment vs. 6.4+/-1.2 ng/ml h post-hydrocortisone, P=0.053). However, those patients who responded fully to hydrocortisone in terms of reduced fatigue scores did show a significantly increased DHEA responsiveness to CRH (AUCc: -1.4+/-2.5 ng/ml h at baseline, 5.0+/-1.2 ng/ml h after active treatment, P=0.029).

CONCLUSIONS: DHEA levels are raised in CFS and correlate with the degree of self-reported disability. Hydrocortisone therapy leads to a reduction in these levels towards normal, and an increased DHEA response to CRH, most marked in those who show a clinical response to this therapy.

Source: Cleare AJ, O’Keane V, Miell JP. Levels of DHEA and DHEAS and responses to CRH stimulation and hydrocortisone treatment in chronic fatigue syndrome. Psychoneuroendocrinology. 2004 Jul;29(6):724-32. http://www.ncbi.nlm.nih.gov/pubmed/15110921

Associations between neuroendocrine responses to the Insulin Tolerance Test and patient characteristics in chronic fatigue syndrome

Abstract:

OBJECTIVE: Subtle dysregulations of the hypothalamic-pituitary-adrenal (HPA) axis have been proposed as an underlying pathophysiological mechanism in chronic fatigue syndrome (CFS). This study attempted to assess the relationship between patient characteristics and HPA axis functioning using a neuroendocrine challenge test.

METHOD: A test battery designed to assess different dimensions of CFS was given to 18 CFS patients and 17 controls. To evaluate the integrity of the HPA axis, the Insulin Tolerance Test (ITT), a centrally acting neuroendocrine challenge test, was performed on patients and controls. ACTH, salivary free cortisol and total plasma cortisol levels were assessed as a measure of the HPA axis stress response. Correlations of patient characteristics were calculated with integrated responses for all endocrine parameters.

RESULTS: CFS patients had a significantly reduced area under the ACTH response curve (AUC) in the ITT. The AUC was significantly associated with the duration of CFS symptoms (r = -.592, P = .005) and the severity of fatigue symptomatology (r = -.41, P = .045). In addition, duration of CFS was correlated with the severity of fatigue symptoms (r = .38, P = .045). Similar associations were not observed for cortisol parameters.

CONCLUSION: It has been postulated that neuroendocrine dysregulations observed in CFS are of an acquired nature. The results of a strong association between the integrated ACTH response and the duration of CFS emphasizes the need to consider factors known to be risk factors for the chronicity of CFS symptoms, such as profound inactivity, deconditioning and sleep abnormalities, as possible candidates for secondary causes of neuroendocrine dysregulations in CFS.

Source: Gaab J, Engert V, Heitz V, Schad T, Schürmeyer TH, Ehlert U. Associations between neuroendocrine responses to the Insulin Tolerance Test and patient characteristics in chronic fatigue syndrome. J Psychosom Res. 2004 Apr;56(4):419-24. http://www.ncbi.nlm.nih.gov/pubmed/15094026

Disorder of adrenal gland function in chronic fatigue syndrome

Abstract:

Chronic fatigue syndrome (CFS) is defined as constellation of the prolonged fatigue and several somatic symptoms, in the absence of organic or severe psychiatric disease. However, this is an operational definition and conclusive biomedical explanation remains elusive. Similarities between the signs and symptoms of CFS and adrenal insufficiency prompted the research of the hypothalamo-pituitary-adrenal axis (HPA) derangement in the pathogenesis of the CFS.

Early studies showed mild glucocorticoid deficiency, probably of central origin that was compensated by enhanced adrenal sensitivity to ACTH. Further studies showed reduced ACTH response to vasopressin infusion. The response to CRH was either blunted or unchanged. Cortisol response to insulin induced hypoglycaemia was same as in the control subjects while ACTH response was reported to be same or enhanced. However, results of direct stimulation of the adrenal cortex using ACTH were conflicting.

Cortisol and DHEA responses were found to be the same or reduced compared to control subjects. Scott et al found that maximal cortisol increment from baseline is significantly lower in CFS subjects. The same group also found small adrenal glands in some CFS subjects. These varied and inconsistent results could be explained by the heterogeneous study population due to multifactorial causes of the disease and by methodological differences. The aim of our study was to assess cortisol response to low dose (1 microgram) ACTH using previously validated methodology.

We compared cortisol response in the CFS subjects with the response in control and in subjects with suppressed HPA axis due to prolonged corticosteroid use. Cortisol responses were analysed in three subject groups: control (C), secondary adrenal insufficiency (AI), and in CFS. The C group consisted of 39 subjects, AI group of 22, and CFS group of nine subjects. Subject data are presented in table 1.

Low dose ACTH test was started at 0800 h with the i.v. injection of 1 microgram ACTH (Galenika, Belgrade, Serbia). Blood samples for cortisol determination were taken from the i.v. cannula at 0, 15, 30, and 60 min. Data are presented as mean +/- standard error (SE). Statistical analysis was done using ANOVA with the Games-Howell post-hoc test to determine group differences. ACTH dose per kg or per square meter of body surface was not different between the groups.

Baseline cortisol was not different between the groups. However, cortisol concentrations after 15 and 30 minutes were significantly higher in the C group than in the AI group. Cortisol concentration in the CFS group was not significantly different from any other group (Graph 1). Cortisol increment at 15 and 30 minutes from basal value was significantly higher in C group than in other two groups. However, there was no significant difference in cortisol increment between the AI and CFS groups at any time of the test.

On the contrary, maximal cortisol increment was not different between CFS and other two groups, although it was significantly higher in C group than in the AI group. Maximal cortisol response to the ACTH stimulation and area under the cortisol response curve was significantly larger in C group compared to AI group, but there was no difference between CFS and other two groups.

Several previous studies assessed cortisol response to ACTH stimulation. Hudson and Cleare analysed cortisol response to 1 microgram ACTH in CFS and control subjects. They compared maximum cortisol attained during the test, maximum cortisol increment, and area under the cortisol response curve. There was no difference between the groups in any of the analysed parameters. However, authors commented that responses were generally low. On the contrary Scott et al found that cortisol increment at 30 min is significantly lower in the CFS than in the control group. Taking into account our data it seems that the differences found in previous studies papers are caused by the methodological differences.

We have shown that cortisol increment at 15 and 30 min is significantly lower in CFS group than in C group. Nevertheless, maximum cortisol attained during the test, maximum cortisol increment, and area under the cortisol response curve were not different between the C and CFS groups. This is in agreement with our previous findings that cortisol increment at 15 minutes has the best diagnostic value of all parameters obtained during of low dose ACTH test. However, there was no difference between CFS and AI group in any of the parameters, although AI group had significantly lower cortisol concentrations at 15 and 30 minutes, maximal cortisol response, area under the cortisol curve, maximal cortisol increment, and maximal cortisol change velocity than C group. Consequently, reduced adrenal responsiveness to ACTH exists in CFS.

In conclusion, we find that regarding the adrenal response to ACTH stimulation CFS subjects present heterogeneous group. In some subjects cortisol response is preserved, while in the others it is similar to one found in secondary adrenal insufficiency.

Source: Zarković M, Pavlović M, Pokrajac-Simeunović A, Cirić J, Beleslin B, Penezić Z, Ognjanović S, Savić S, Poluga J, Trbojević B, Drezgić M. Disorder of adrenal gland function in chronic fatigue syndrome. Srp Arh Celok Lek. 2003 Sep-Oct;131(9-10):370-4. [Article in Serbian] http://www.ncbi.nlm.nih.gov/pubmed/15058215 (Abstract) http://srpskiarhiv.rs/global/pdf/articles-2003/septembar-oktobar/Adrenalcortexfunctionimpairmentinchronicfatiguesyndrome.pdf (Full article)