Neuroendocrine
Abnormalities
Bakheit AM, Behan PO, Dinan TG, Gray CE, O'Keane V. Possible upregulation of hypothalamic 5-hydroxytryptamine receptors in patients with postviral fatigue syndrome. British Medical Journal 1992; 304(6833): 1010-2.
Abstract: OBJECTIVE-To study the dynamic function of hypothalamic 5-hydroxytryptamine receptors in patients with postviral fatigue syndrome. DESIGN-Prospective comparison of patients with postviral fatigue syndrome with two control groups. SETTING-Department of neurology, University of Glasgow, Southern General Hospital; department of psychiatry, St James's Hospital, Dublin. SUBJECTS-15 patients with postviral fatigue syndrome, 13 age and sex matched healthy subjects, and 13 patients with primary depression. MAIN OUTCOME MEASURES-Serum prolactin concentrations before and one, two, and three hours after administration of buspirone. RESULTS-Because of the effects of sex hormones on prolactin secretion data for men and women were analysed separately. There was no significant difference in baseline prolactin concentrations between patients with postviral fatigue syndrome and healthy subjects or those with primary depression. However, the percentage difference between peak and baseline values was significantly higher in patients with postviral fatigue syndrome than the control groups (one way analysis of variance: women, p = 0.003; men, p = 0.004). CONCLUSIONS-The results suggest upregulation of hypothalamic 5-hydroxytryptamine receptors in patients with postviral fatigue syndrome but not in those with primary depression. The buspirone challenge test may therefore be useful in distinguishing these two conditions. Larger studies are required to explore the potential value of drugs acting on central 5-hydroxytryptamine receptors in the treatment of patients with the postviral fatigue syndrome.
Bakheit AM, Behan PO, Watson WS, Morton JJ. Abnormal arginine-vasopressin secretion and water metabolism in patients with postviral fatigue syndrome. Acta Neurologica Scandinavica 1993; 87(3): 234-8.
Abstract: Water metabolism and the responses of the neurohypophysis to changes in plasma osmolality during the water loading and water deprivation tests were studied in nine patients with postviral fatigue syndrome (PVFS) and eight age and six-matched healthy control subjects. Secretion of arginine-vasopressin (AVP) was erratic in these patients as shown by lack of correlation between serum and urine osmolality and the corresponding plasma AVP levels. Patients with PVFS had significantly low baseline arginine-vasopressin levels when compared with healthy subjects. Patients with PVFS as a group also showed evidence of increased total body water content. These results may be indicative of hypothalamic dysfunction in patients with PVFS.
Bearn J, Allain T, Coskeran P, Munro N, Butler J, McGregor A, Wessely S. Neuroendocrine responses to d-fenfluramine and insulin-induced hypoglycemia in chronic fatigue syndrome. Biological Psychiatry 1995; 37(4): 245-52.
Abstract: Chronic fatigue syndrome (CFS) is a disorder characterized by severe physical and mental fatigue and fatiguability of central rather than peripheral origin. We hypothesized that CFS is mediated by changes in hypothalamopituitary function and so measured the adrenocorticotrophic hormone (ACTH), cortisol, growth hormone, and prolactin responses to insulin-induced hypoglycemia, and the ACTH, cortisol, and prolactin responses to serotoninergic stimulation with dexfenfluramine in nondepressed CFS patients and normal controls. We have shown attenuated prolactin responses to hypoglycemia in CFS. There was also a greater ACTH response and higher peak ACTH concentrations (36.44 ± 4.45 versus 25.60 ± 2.78 pg ml), whereas cortisol responses did not differ, findings that are compatible with impaired adrenal cortical function. This study provided evidence for both pituitary and adrenal cortical impairment in CFS and further studies are merited to both confirm and determine more precisely their neurobiological basis so that rational treatments can be evolved.
Bennett AL, Mayes DM, Fagioli LR, Guerriero R, Komaroff AL. Somatomedin C (insulin-like growth factor I) levels in patients with chronic fatigue syndrome. Journal of Psychiatric Research 1997; 31(1): 91-96.
Abstract: Chronic fatigue syndrome is a disorder clinically quite similar to fibromyalgia syndrome, and it is of interest to examine if these two syndromes have pathogenetic as well as clinical features in common. Somatomedin C levels have been found to be lower in patients with fibromyalgia syndrome than in healthy controls. An attractive hypothesis relating sleep disturbance, altered somatotropic neuroendocrine function and fibromyalgia symptoms has been put forward as a plausible pathogenic mechanism for fibromyalgia syndrome. We therefore sought to investigate the level of somatomedin C in patients with chronic fatigue syndrome. Somatomedin C levels were determined by radioimmunoassay in frozen serum specimens from 49 patients with CFS and 30 healthy blood donor control subjects of similar age and gender. Somatomedin C levels were higher in patients with CFS than in healthy control subjects (255.3 ± 68.5 vs 211.9 ± 76.2, P = 0.01). There was no effect of gender, use of nonsteroidal anti-inflammatory drugs or tricyclic drugs on levels of somatomedin C. There was a tendency for somatomedin C levels to fall with age. In contrast to patients with fibromyalgia, in whom levels of somatomedin C have been found to be reduced, levels in patients with CFS were found to be elevated. Thus, despite the clinical similarities between these two conditions, they may be associated with different abnormalities of sleep and/or of the somatotropic neuroendocrine axis.
Chaudhuri A, Majeed T, Dinan T, Behan PO. Chronic fatigue syndrome: a disorder of central cholinergic transmission. Journal of Chronic Fatigue Syndrome 1997; 3(1): 3-16.
Cleare AJ, Bearn J, Allain T, McGregor A, Wessely S, Murray RM, O'Keane V. Contrasting neuroendocrine responses in depression and chronic fatigue syndrome. Journal of Affective Disorders 1995; 34(4): 283-9.
Abstract: Hypothalamic-pituitary-adrenal (HPA) axis and central 5-HT function were compared in chronic fatigue syndrome (CFS), depression and healthy states. 10 patients with CFS and 15 patients with major depression were matched for age, weight, sex and menstrual cycle with 25 healthy controls. Baseline-circulating cortisol levels were highest in the depressed, lowest in the CFS and intermediate between the two in the control group (P = 0.01). Prolactin responses to the selective 5-HT-releasing agent d-fenfluramine were lowest in the depressed, highest in the CFS and intermediate between both in the healthy group (P = 0.01). Matched pair analysis confirmed higher prolactin responses in CFS patients than controls (P = 0.05) and lower responses in depressed patients than controls (P = 0.003). There were strong inverse correlations between prolactin and cortisol responses and baseline cortisol values. These data confirm that depression is associated with hypercotisolaemia and reduced central 5-HT neurotransmission and suggest that CFS may be associated with hypocortisolaemia and increased 5-HT function. The opposing responses in CFS and depression may be related to reversed patterns of behavioural dysfunction seen in these conditions. These findings attest to biological distinctions between these disorders.
Cooke WT. Neurological manifestations of malabsorption. Postgraduate Medical Journal 1978; 54: 760-62.
Summary: The clinical and pathological findings in patients with neurological disorders in association with disordered function of the small intestine, in particular coeliac disease, are outlined. The possible significance of the abnormalities of pyridoxine, tyrosine and tryptophan metabolism are considered in relation to biopterin derivatives and their relevance to neurological dysfunction.
Crofford LJ, Demitrack MA. Evidence that abnormalities of central neurohormonal systems are key to understanding fibromyalgia and chronic fatigue syndrome. Rheumatic Diseases Clinics of North America 1996; 22(2): 267-84.
Abstract: Fibromyalgia (FM) and chronic fatigue syndrome (CFS) fall into the spectrum of what might be termed stress-associated syndromes by virtue of frequent onset after acute or chronic stressors and apparent exacerbation of symptoms during periods of physical or emotional stress. These illnesses also share perturbation of the hypothalamic-pituitary-adrenal axis and sympathetic stress response systems. In this article, the authors discuss the specific neurohormonal abnormalities found in FM and CFS and potential mechanisms by which dysfunction of neurohormonal stress-response systems could contribute to vulnerability to stress-associated syndromes and to the symptoms of FM and CFS.
Crowford LJ, Demitrack MA. Evidence that abnormalities of central neurohormonal systems are key to understanding fibromyalgia and chronic fatigue syndrome. Rheumatic Disease Clinics of North America 1996; 22: 267-284.
Demitrack MA, Dale JK, Straus SE, Laue L, Listwak SJ, Kruesi MJ, Chrousos GP, Gold PW. Evidence for impaired activation of the hypothalamic-pituitary-adrenal axis in patients with chronic fatigue syndrome. Journal of Clinical Endocrinology and Metabolism 1991; 73(6): 1224-34.
Abstract: Chronic fatigue syndrome is characterized by persistent or relapsing debilitating fatigue for at least 6 months in the absence of a medical diagnosis that would explain the clinical presentation. Because primary glucocorticoid deficiency states and affective disorders putatively associated with a deficiency of the arousal-producing neuropeptide CRH can be associated with similar symptoms, we report here a study of the functional integrity of the various components of the hypothalamic-pituitary-adrenal axis in patients meeting research case criteria for chronic fatigue syndrome. Thirty patients and 72 normal volunteers were studied. Basal activity of the hypothalamic-pituitary-adrenal axis was estimated by determinations of 24-h urinary free cortisol-excretion, evening basal plasma total and free cortisol concentrations, and the cortisol binding globulin-binding capacity. The adrenal cortex was evaluated indirectly by cortisol responses during ovine CRH (oCRH) stimulation testing and directly by cortisol responses to graded submaximal doses of ACTH. Plasma ACTH and cortisol responses to oCRH were employed as a direct measure of the functional integrity of the pituitary corticotroph cell. Central CRH secretion was assessed by measuring its level in cerebrospinal fluid. Compared to normal subjects, patients demonstrated significantly reduced basal evening glucocorticoid levels (89.0 ± 8.7 vs. 148.4 ± 20.3 nmol/L; P less than 0.01) and low 24-h urinary free cortisol excretion (122.7 ± 8.9 vs. 203.1 ± 10.7 nmol/24 h; P less than 0.0002), but elevated basal evening ACTH concentrations. There was increased adrenocortical sensitivity to ACTH, but a reduced maximal response [F(3.26, 65.16) = 5.50; P = 0.0015). Patients showed attenuated net integrated ACTH responses to oCRH (128.0 ± 26.4 vs. 225.4 ± 34.5 pmol/L.min, P less than 0.04). Cerebrospinal fluid CRH levels in patients were no different from control values (8.4 ± 0.6 vs. 7.7 ± 0.5 pmol/L; P = NS). Although we cannot definitively account for the etiology of the mild glucocorticoid deficiency seen in chronic fatigue syndrome patients, the enhanced adrenocortical sensitivity to exogenous ACTH and blunted ACTH responses to oCRH are incompatible with a primary adrenal insufficiency. A pituitary source is also unlikely, since basal evening plasma ACTH concentrations were elevated. Hence, the data are most compatible with a mild central adrenal insufficiency secondary to either a deficiency of CRH or some other central stimulus to the pituitary-adrenal axis. Whether a mild glucocorticoid deficiency or a putative deficiency of an arousal-producing neuropeptide such as CRH is related to the clinical symptomatology of the chronic fatigue syndrome remains to be determined.
Demitrack MA, Gold PW, Dale JK, Krahn DD, Kling MA, Straus SE. Plasma and cerebrospinal fluid monoamine metabolism in patients with chronic fatigue syndrome - preliminary findings. Biological Psychiatry 1992; 32(12): 1065-77.
Abstract: The syndrome of chronic fatigue, feverishness, diffuse pains, and other constitutional complaints, often precipitated by an acute infectious illness and aggravated by physical and emotional stressors, has a lengthy history in the medical literature. The Centers for Disease Control (CDC) recently formulated a case definition, renaming the illness "chronic fatigue syndrome." Nevertheless, there remain few biological data that can validate the existence of this syndrome as distinct from a wide variety of other, largely psychiatric disorders, and little understanding of its pathogenesis. In the present study, basal plasma and cerebrospinal fluid levels of the monoamine metabolites, 3-methoxy-4-hydroxyphenylglycol (MHPG), 5-hydroxyindoleacetic acid (5-HIAA), and homovanillic acid (HVA) were determined in 19 patients meeting CDC research case criteria for chronic fatigue syndrome and in 17 normal individuals. Patients with chronic fatigue syndrome showed a significant reduction in basal plasma levels of MHPG and a significant increase in basal plasma levels of 5-HIAA. Although the functional significance of these findings has not been definitively elucidated, they are compatible with the clinical presentation of a syndrome associated with chronic lethargy and fatigue, and with evidence of persistent immune stimulation, and lend support to the idea that chronic fatigue syndrome represents a clinical entity with potential biological specificity.
Demitrack MA. Neuroendocrine correlates of chronic fatigue syndrome: a brief review. Journal of Psychiatric Research 1997; 31(1): 69-82.
Abstract: Chronic fatigue syndrome remains one of the more perplexing syndromes in contemporary clinical medicine. One approach to understanding this condition has been to acknowledge its similarities to other disorders of clearer pathophysiology. In this review, a rationale for the study of neuroendocrine correlates of chronic fatigue syndrome is presented, based in part on the clinical observation that asthenic or fatigue states share many of the somatic symptom characteristics seen in recognized endocrine disorders. Of additional interest is the observation that psychological symptoms, particularly disturbances in mood and anxiety, are equally prominent in this condition. At this time, several reports have provided replicated evidence of disruptions in the integrity of the hypothalamic-pituitary-adrenal axis in patients with chronic fatigue syndrome. It is notable that the pattern of the alteration in the stress response apparatus is not reminiscent of the well-understood hypercortisolism of melancholic depression but, rather, suggests a sustained inactivation od central nervous system components of this system. Recent work also implicates alterations in central serotonergic tone in the overall pathophysiology of this finding. The implications of these observations are far from clear, but they highlight the fact that, though chronic fatigue syndrome overlaps with the well-described illness category of major depression, these are not identical clinical conditions.
Hyams KC. Identification of Gulf War syndrome: methodological issues and medical illnesses. Journal of the American Medical Association 1997; 278(5): 384.
Jefferies WM. Mild adrenocortical deficiency, chronic allergies, autoimmune disorders and the chronic fatigue syndrome: a continuation of the cortisone story. Medical Hypotheses 1994; 42(3): 183-189.
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.
Majeed T, Dinan TG, Behan PO. Pyridostigmine-induced growth hormone responses: evidence for cholinergic supersensitivity in CFS. Journal of Chronic Fatigue Syndrome 1996; 2(2/3): 118-119.
Abstract: OBJECTIVES. Acetylcholine (ACH) supersensitivity is associated with depression. This study is undertaken to assess the ACH function in patients with chronic fatigue syndrome. METHODS. Sixteen healthy subjects (8 males and 8 females) and twelve patients (six male and six females) with CFS were tested. Subjects presented at 9 a.m. following an overnight fast. Pyridostigmine (120 mg orally) was administered at 0 min. Blood samples were taken at 0, +60, +120, +180 and +240 min for measurement of growth hormone. Delta growth hormone (DGH difference: between baseline values and the maximum increase postpyridostigmine administration) measures were used to compare the resonses. Student's t-test was used where appropriate. Results were expressed as mean ± SEM. RESULTS. All subjects responded to pyridostigmine with an increase in plasma growth hormone. A mean DGH in CFS of 17.07 ± 2.57 Mu/l was significantly elevated compared to a man DGH of 6.84 ± 1.26 Mu/l in healthy controls (P=0.0024). CONCLUSION. This study also demonstrated acetylcholine receptor supersensitivity in patients with CFS as reported previously in depressives.
Patarca R, Bell IR, Fletcher MA. Pteridines and neuroimmune function and pathology. Journal of Chronic Fatigue Syndrome 1997; 3(1): 69-86.
Scott LV, Dinan TG. The neuroendocrinology of chronic fatigue syndrome. Journal of Chronic Fatigue Syndrome 1996; 2(4): 49-59.
Abstract: Since the introduction of operationalized criteria, there has been considerable interest in the pathophysiology of chronic fatigue syndrome (CFS). There is an increasing volume of evidence to support the view that patients with this syndrome have unique neuroendocrinology patterns. Central to this endocrine dysfunction is altered hypothalamic-pituitary-adrenal axis (HPA) activity. The cardinal findings include attenuated adrenocorticotrophic hormone (ACTH) responses to corticotropin-releasing hormone (CRH) and low 24-hour urinary cortisol. These are compatible with a mild central adrenal insufficiency. Adrenal steroids have wide-spread impact in the brain, and of particular importance is their dense concentration on serotonergic and noradrenergic neurotransmitter pathways. Using a variety of different challenge drugs, a supersensitivity of the serotonergic 5 HT 1A receptor has been demonstrated although the results have not been entirely consistent. A blunting of dexamethasone-induced growth hormone release has been described and may reflect a relatively subsensitivity of the steroid receptor. It is proposed that the disruption of the HPA, which may be triggered bya number of stressors including infections, may represent a primary phenomenon, and that the neurotransmitter abnormalities described are in fact secondarily heralded by prolonged HPA dysregulation.
Sharpe M, Hawton K, Clements A, Cowen PJ. Increased brain serotonin function in men with chronic fatigue syndrome. British Medical Journal 1997; 315: 164-5.
Wessely S. The neuropsychiatry of chronic fatigue syndrome. Ciba Foundation Symposium 1993; 173: 212-29.
Abstract: This paper explores the relationship between chronic fatigue syndrome (CFS) and psychiatric disorder, with special reference to neuropsychiatry, Topics reviewed include (1) epidemiological evidence of central disorder in CFS; (2) evidence from longitudinal studies of an interaction between vulnerability to CFS and psychiatric disorder; and (3) evidence from neuroimaging, neuropsychology, neurophysiology and neuroendocrinology of disordered CNS function in CFS. The most impressive evidence of CNS disturbance comes from neuroendocrinological studies, which suggest a role of hypothalamic disorder as a final common pathway for CFS. It is concluded that the equal and opposite tendencies of psychiatry to be 'brainless' and neurology to be 'mindless' have led to needless controversy over the nature of CFS. Now that the contributions of psychiatric disorder to CFS, and of neurobiological dysfunction to psychiatric disorder, are both established, it will be possible to make real advances in understanding the nature of CFS.
Yatham LN, Morehouse RL, Chisholm BT, Haase DA, MacDonald DD, Marrie TJ. Neuroendocrine assessment of serotonin (5-HT) function in chronic fatigue syndrome. Canadian Journal of Psychiatry 1995; 40(2): 93-96.
Abstract: Prolactin and cortisol responses to dl-fenfluramine challenge were examined in 11 patients with chronic fatigue syndrome and in 11 healthy controls who were age and gender matched. After obtaining two baseline samples, each subject was given 60 mg of dl-fenfluramine orally and further blood samples were drawn hourly during the following five hours in order to measure prolactin and cortisol levels. There was no difference in either baseline or fenfluramine-induced hormonal responses between patients with chronic fatigue syndrome and controls. There was also no correlation between depression scores on HAM-D and hormonal responses in patients with chronic fatigue syndrome. The findings of this study do not support a role for 5-HT in chronic fatigue syndrome.