Neuro-Endocrine Abnormalities in
Chronic Fatigue Syndrome & Fibromyalgia
In 1991, NIH researchers showed conclusive evidence that CFS was a biophysiological disorder and not psychologically based, as some had suggested. Studies showed activation of the HPA Axis and elevated levels of cortisol in depressed patients. Persons with CFS and FM (PWCs), however, had suppression of the HPA axis with low CRH and low 24 hour cortisol production. Subsequently, HPA axis suppression in CFS and FM has been associated with modest abnormalities in the thyroid, adrenal glands, and gonads. Thus DHEA (or DHEA-S) is low, growth hormone (or IGF1) is suppressed, LH and FSH tend to be low, PRL tends to be elevated, TSH is variable, and sex hormones are generally depressed. ACTH or Cortrosyn Stimulation Tests generally show a “flat” or minimal response. Salivary studies have shown a variable response in the morning cortisol, with low values and lack of diurnal variation thereafter. These endocrine abnormalities may be responsible for many of the symptoms experienced by PWCs.
From a management standpoint, it is important to assure that thyroid hormones, estrogen, and testosterone are physiologic. The literature also supports that supplementation with hGH and DHEA may provide modest benefits in some patients, although the expense of the former may outweigh its benefit. Prolactinemia is minimal and seldom symptomatic. Supplementation with low dose cortisol (up to 12.5mg of oral hydrocortisone) was shown to be modestly beneficial in one study, but higher doses actually led to significant adrenal suppression.
Neuropsychobiology. 2007;55(2):112-20. Epub 2007 Jun 27
Hypothalamic-pituitary-adrenal axis function in chronic fatigue syndrome.
Van Den Eede F, Moorkens G, et alia.
Department of Psychiatry, University Hospital Antwerp, Edegem, Belgium. email@example.com
There is evidence for a hypofunction of the hypothalamic-pituitary-adrenal (HPA) axis in a proportion of the patients with chronic fatigue syndrome (CFS), despite the negative studies and methodological difficulties. In this review, we focus on challenge studies and on the role of the HPA axis in the pathogenesis of CFS. Mild hypocortisolism, blunted adrenocorticotropin response to stressors and enhanced negative feedback sensitivity to glucocorticoids are the main findings. Several underlying mechanisms have been proposed. Currently, it is a matter of debate whether these disturbances have a primary role in the pathogenesis of CFS. However, even if the HPA axis dysfunctions are secondary to other factors, they are probably a relevant factor in symptom propagation in CFS.
J Clin Endocrinol Metab. 1991 Dec;73(6):1224-34
Evidence for impaired activation of the hypothalamic-pituitary-adrenal axis in patients with chronic fatigue syndrome.
Demitrack MA, Dale JK, Straus SE, et alia.
Clinical Neuroendocrinology Branch, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland.
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.
Ann N Y Acad Sci. 1998 May 1;840:684-97
Evidence for and pathophysiologic implications of hypothalamic-pituitary-adrenal axis dysregulation in fibromyalgia and chronic fatigue syndrome.
Demitrack MA, Crofford LJ.
Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, Indiana 46285, USA.
Chronic fatigue syndrome (CFS) is characterized by profound fatigue and an array of diffuse somatic symptoms. Our group has established that impaired activation of the hypothalamic-pituitary-adrenal (HPA) axis is an essential neuroendocrine feature of this condition. The relevance of this finding to the pathophysiology of CFS is supported by the observation that the onset and course of this illness is excerbated by physical and emotional stressors. It is also notable that this HPA dysregulation differs from that seen in melancholic depression, but shares features with other clinical syndromes (e.g., fibromyalgia). How the HPA axis dysfunction develops is unclear, though recent work suggests disturbances in serotonergic neurotransmission and alterations in the activity of AVP, an important co-secretagogue that, along with CRH, influences HPA axis function. In order to provide a more refined view of the nature of the HPA dusturbance in patients with CFS, we have studied the detailed, pulsatile characteristics of the HPA axis in a group of patients meeting the 1994 CDC case criteria for CFS. Results of that work are consistent with the view that patients with CFS have a reduction of HPA axis activity due, in part, to impaired central nervous system drive. These observations provide an important clue to the development of more effective treatment to this disabling condition.
Endocr Rev. 2003 Apr;24(2):236-52
The neuroendocrinology of chronic fatigue syndrome.
Section of Neurobiology of Mood Disorders, Division of Psychological Medicine, The Institute of Psychiatry, London SE5 8AZ, United Kingdom. firstname.lastname@example.org
Chronic fatigue syndrome (CFS) is a common and disabling problem; although most likely of biopsychosocial origin, the nature of the pathophysiological components remains unclear. There has been a wealth of interest in the endocrinology of this condition, which will be reviewed in this article. Most studied has been the hypothalamic-pituitary-adrenal (HPA) axis; although the quality of many studies is poor, the overall balance of evidence points to reduced cortisol output in at least some patients, with some evidence that this is linked to symptom production or persistence. There is evidence for heightened negative feedback and glucocorticoid receptor function and for impaired ACTH and cortisol responses to a variety of challenges. However, there is no evidence for a specific or uniform dysfunction of the HPA axis. 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 HPA axis disturbance is heterogeneous and of multifactorial etiology in CFS. Studies assessing GH, dehydroepiandrostenedione and its sulfate, melatonin, leptin, and neuroendocrine-monoamine interactions are also reviewed. There is some evidence from these studies to suggest alterations of dehydroepiandrostenedione sulfate function and abnormal serotonin function in CFS, but whether these changes are of functional importance remains unclear. To obtain a clearer assessment of the etiological and pathophysiological relevance of endocrine changes in CFS, it is suggested that more prospective cohort studies be undertaken in groups at high risk for CFS, that patients with CFS are followed up into recovery, and that multidimensional assessments are undertaken to unravel the influence of the various confounding factors on the observed endocrine changes in CFS.
Int J Immunopathol Pharmacol. 2001 Jan-Apr;14(1):11-15
Chronic fatigue syndrome: circadian rhythm and hypothalamic-pituitary-adrenal (HPA) axis impairment.
Racciatti D, Guagnano MT, Vecchiet J, et alia.
Clinic of Infectious Diseases, University of Chieti, Chieti, Italy
Chronic Fatigue Syndrome (CFS) is a clinical condition characterized by a persistent or relapsing debilitating fatigue at rest, lasting more than 6 months, and made worse by exercise. At the present moment, there are three potential etiopathogenic factors: immunologic, viral and neuroendocrine. The purpose of our study was to evaluate possible alterations of the hypothalamic-pituitary-adrenal (HPA) axis in our CFS patients by studying the circadian rhythms of prolactin (PRL), thyrotropic hormone (TSH), adrenocorticotropic hormone (ACTH), and cortisol (CS). A total of 36 patients were enrolled according to the Centers for Disease Control and Prevention case-definition criteria. Twenty healthy subjects were included as controls. Blood samples were taken every 4 hours during a single 24-hour period. We performed a fluorometric enzyme immunoassay with serum PRL, cortisol and TSH, and an immunoradiometric assay with plasma ACTH. The circadian rhythms of PRL, TSH, ACTH and CS were statistically significant in both CFS and control groups. At 24:00 and 04:00 hrs the CFS patients showed lower ACTH levels than healthy subjects (p < 0.001); the PRL levels were higher at 04.00 h in CFS patients than in healthy subjects.
Rheum Dis Clin North Am. 2000 Nov;26(4):989-1002
Neuroendocrine perturbations in fibromyalgia and chronic fatigue syndrome.
Neeck G, Crofford LJ.
Department of Rheumatology, University of Giessen, Bad Nauheim, Germany. email@example.com
A large body of data from a number of different laboratories worldwide has demonstrated a general tendency for reduced adrenocortical responsiveness in CFS. It is still not clear if this is secondary to CNS abnormalities leading to decreased activity of CRH- or AVP-producing hypothalamic neurons. Primary hypofunction of the CRH neurons has been described on the basis of genetic and environmental influences. Other pathways could secondarily influence HPA axis activity, however. For example, serotonergic and noradrenergic input acts to stimulate HPA axis activity. Deficient serotonergic activity in CFS has been suggested by some of the studies as reviewed here. In addition, hypofunction of sympathetic nervous system function has been described and could contribute to abnormalities of central components of the HPA axis. One could interpret the clinical trial of glucocorticoid replacement in patients with CFS as confirmation of adrenal insufficiency if one were convinced of a positive therapeutic effect. If patient symptoms were related to impaired activation of central components of the axis, replacing glucocorticoids would merely exacerbate symptoms caused by enhanced negative feedback. Further study of specific components of the HPA axis should ultimately clarify the reproducible abnormalities associated with a clinical picture of CFS. In contrast to CFS, the results of the different hormonal axes in FMS support the assumption that the distortion of the hormonal pattern observed can be attributed to hyperactivity of CRH neurons. This hyperactivity may be driven and sustained by stress exerted by chronic pain originating in the musculoskeletal system or by an alteration of the CNS mechanism of nociception. The elevated activity of CRH neurons also seems to cause alteration of the set point of other hormonal axes. In addition to its control of the adrenal hormones, CRH stimulates somatostatin secretion at the hypothalamic level, which, in turn, causes inhibition of growth hormone and thyroid-stimulating hormone at the pituitary level. The suppression of gonadal function may also be attributed to elevated CRH because of its ability to inhibit hypothalamic luteinizing hormone-releasing hormone release; however, a remote effect on the ovary by the inhibition of follicle-stimulating hormone-stimulated estrogen production must also be considered.
Serotonin (5-HT) precursors such as tryptophan (5-HTP), drugs that release 5-HT, or drugs that act directly on 5-HT receptors stimulate the HPA axis, indicating a stimulatory effect of serotonergic input on HPA axis function. Hyperfunction of the HPA axis could also reflect an elevated serotonergic tonus in the CNS of FMS patients. The authors conclude that the observed pattern of hormonal deviations in patients with FMS is a CNS adjustment to chronic pain and stress, constitutes a specific entity of FMS, and is primarily evoked by activated CRH neurons.
Growth Horm IGF Res. 1998 Apr;8 Suppl B:131-3
Effect of growth hormone treatment in patients with chronic fatigue syndrome: a preliminary study.
Moorkens G, Wynants H, Abs R.
Department of Internal Medicine, University Hospital Antwerp, Belgium.
The efficacy of growth hormone (GH) therapy was evaluated in patients with chronic fatigue syndrome (CFS) who had peak serum GH levels below 10 microg/l during stage-controlled sleep. Twenty patients (7 men, 13 women; age range, 30-60 years) with CFS were randomized to receive placebo or GH therapy, 6.7 microg/kg/day (0.02 IU/kg/day), for 12 weeks. Following this double-blind treatment period, the 17 patients remaining in the study were given GH therapy at the above dose for an open period of 9 months. Mean (+/- SD) serum levels of insulin-like growth factor I (IGF-I) increased during GH treatment, from 173 +/- 46 microg/I to 296 +/- 89 microg/l (P < 0.001); IGF-I SDS values increased from -0.45 +/- 1.14 to +1.43 +/- 1.09 (P < 0.001). Fat-free mass and total body water were significantly increased after 12 months of treatment. Although quality of life, as assessed using two different questionnaires, did not improve significantly during GH treatment, four patients were able to resume work after a long period of sick leave.
Int J Mol Med. 1998 Jan;1(1):143-6
Dehydroepiandrosterone sulfate deficiency in chronic fatigue syndrome.
Kuratsune H, Yamaguti K, Sawada M, et alia
Department of Hematology and Oncology, Osaka University Medical School, Suita city, Osaka 565, Japan.
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.
J Affect Disord. 2005 Aug;87(2-3):299-304
Diurnal patterns of salivary cortisol and cortisone output in chronic fatigue syndrome.
Jerjes WK, Cleare AJ, Wessely S, Wood PJ, Taylor NF.
Department of Clinical Biochemistry, King's College Hospital, Denmark Hill, London SE5 9RX, United Kingdom. firstname.lastname@example.org
BACKGROUND: The aim of the present study was to obtain a naturalistic measure of diurnal hypothalamic-pituitary-adrenal (HPA) axis output in CFS patients unaffected by medication or comorbid psychiatric disorder likely to influence the axis. METHOD: Cortisol and cortisone levels were measured in saliva samples collected from 0600 h to 2100 h at 3-h intervals in CFS patients and healthy controls. RESULTS: Mean cortisol and cortisone concentrations were significantly lower in patients than controls across the whole day, as were levels at each individual time point except 2100 h. Cosinor analysis showed a significant diurnal rhythm of cortisol and cortisone that was not phase-shifted in CFS compared to controls. However, there was a lower rhythm-adjusted mean and a lower amplitude in CFS patients. The cortisol/cortisone ratio showed no diurnal rhythm and did not differ between CFS subjects and controls. LIMITATIONS: The sample size was relatively small, and drawn from specialist referral patients who had been ill for some time; generalisation of these results to other populations is therefore unwarranted. CONCLUSION: The main findings of this study are to provide further evidence for reduced basal HPA axis function in at least some patients with CFS and to show for the first time that salivary cortisone is also reduced in CFS and has a diurnal rhythm similar to that of cortisol. We have also demonstrated that the cortisol/cortisone ratio remains unchanged in CFS, suggesting that increased conversion of cortisol to cortisone cannot account for the observed lowering of salivary cortisol.
JAMA. 1998 Sep 23-30;280(12):1061-6
Low-dose hydrocortisone for treatment of chronic fatigue syndrome: a randomized controlled trial.
McKenzie R, O'Fallon A, Dale J, Demitrack M, Sharma G, et alia
Laboratory of Clinical Investigation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892-1888, USA.
CONTEXT: Chronic fatigue syndrome (CFS) is associated with a dysregulated hypothalamic-pituitary adrenal axis and hypocortisolemia. OBJECTIVE: To evaluate the efficacy and safety of low-dose oral hydrocortisone as a treatment for CFS. DESIGN: A randomized, placebo-controlled, double-blind therapeutic trial, conducted between 1992 and 1996. SETTING: A single-center study in a tertiary care research institution. PATIENTS: A total of 56 women and 14 men aged 18 to 55 years who met the 1988 Centers for Disease Control and Prevention case criteria for CFS and who withheld concomitant treatment with other medications. INTERVENTION: Oral hydrocortisone, 13 mg/m2 of body surface area every morning and 3 mg/m2 every afternoon, or placebo, for approximately 12 weeks. MAIN OUTCOME MEASURES: A global Wellness scale and other self-rating instruments were completed repeatedly before and during treatment. Resting and cosyntropin-stimulated cortisol levels were obtained before and at the end of treatment. Patients recorded adverse effects on a checklist. RESULTS: The number of patients showing improvement on the Wellness scale was 19 (54.3%) of 35 placebo recipients vs 20 (66.7%) of 30 hydrocortisone recipients (P =.31). Hydrocortisone recipients had a greater improvement in mean Wellness score (6.3 vs 1.7 points; P=.06), a greater percentage (53% vs 29%; P=.04) recording an improvement of 5 or more points in Wellness score, and a higher average improvement in Wellness score on more days than did placebo recipients (P<.001). Statistical evidence of improvement was not seen with other self-rating scales. Although adverse symptoms reported by patients taking hydrocortisone were mild, suppression of adrenal glucocorticoid responsiveness was documented in 12 patients who received it vs none in the placebo group (P<.001). CONCLUSIONS: Although hydrocortisone treatment was associated with some improvement in symptoms of CFS, the degree of adrenal suppression precludes its practical use for CFS.
Lancet. 1999 Feb 6;353(9151):455-8
Low-dose hydrocortisone in chronic fatigue syndrome: a randomised crossover trial.
Cleare AJ, Heap E, Malhi GS, Wessely S, O'Keane V, Miell J.
Department of Psychological Medicine, Guy's King's and St Thomas' School of Medicine and the Institute of Psychiatry, London, UK. email@example.com
BACKGROUND: Reports of mild hypocortisolism in chronic fatigue syndrome led us to postulate that low-dose hydrocortisone therapy may be an effective treatment. METHODS: In a randomised crossover trial, we screened 218 patients with chronic fatigue. 32 patients met our strict criteria for chronic fatigue syndrome without co-morbid psychiatric disorder. The eligible patients received consecutive treatment with low-dose hydrocortisone (5 mg or 10 mg daily) for 1 month and placebo for 1 month; the order of treatment was randomly assigned. Analysis was by intention to treat. FINDINGS: None of the patients dropped out. Compared with the baseline self-reported fatigue scores (mean 25.1 points), the score fell by 7.2 points for patients on hydrocortisone and by 3.3 points for those on placebo (paired difference in mean scores 4.5 points [95% CI 1.2-7.7], p=0.009). In nine (28%) of the 32 patients on hydrocortisone, fatigue scores reached a predefined cut-off value similar to the normal population score, compared with three (9%) of the 32 on placebo (Fisher's exact test p=0.05). The degree of disability was reduced with hydrocortisone treatment, but not with placebo. Insulin stress tests showed that endogenous adrenal function was not suppressed by hydrocortisone. Minor side-effects were reported by three patients after hydrocortisone treatment and by one patient after placebo. INTERPRETATION: In some patients with chronic fatigue syndrome, low-dose hydrocortisone reduces fatigue levels in the short term. Treatment for a longer time and follow-up studies are needed to find out whether this effect could be clinically useful.
Am J Med. 1998 Mar;104(3):227-31
A randomized, double-blind, placebo-controlled study of growth hormone in the treatment of fibromyalgia.
Bennett RM, Clark SC, Walczyk J.
Department of Medicine, Oregon Health Sciences University, Portland 97201, USA.
PURPOSE: The cause of fibromyalgia (FM) is not known. Low levels of insulin-like growth factor 1 (IGF-1), a surrogate marker for low growth hormone (GH) secretion, occur in about one third of patients who have many clinical features of growth hormone deficiency, such as diminished energy, dysphoria, impaired cognition, poor general health, reduced exercise capacity, muscle weakness, and cold intolerance. To determine whether suboptimal growth hormone production could be relevant to the symptomatology of fibromyalgia, we assessed the clinical effects of treatment with growth hormone. METHODS: Fifty women with fibromyalgia and low IGF-1 levels were enrolled in a randomized, placebo-controlled, double-blind study of 9 months' duration. They gave themselves daily subcutaneous injections of growth hormone or placebo. Two outcome measures--the Fibromyalgia Impact Questionnaire and the number of fibromyalgia tender points-were evaluated at 3-monthly intervals by a blinded investigator. An unblinded investigator reviewed the IGF-1 results monthly and adjusted the growth hormone dose to achieve an IGF-1 level of about 250 ng/mL. RESULTS: Daily growth hormone injections resulted in a prompt and sustained increase in IGF-1 levels. The treatment (n=22) group showed a significant improvement over the placebo group (n=23) at 9 months in both the Fibromyalgia Impact Questionnaire score (P <0.04) and the tender point score (P <0.03). Fifteen subjects in the growth hormone group and 6 subjects in the control group experienced a global improvement (P <0.02). There was a delayed response to therapy, with most patients experiencing improvement at the 6-month mark. After discontinuing growth hormone, patients experienced a worsening of symptoms. Carpal tunnel symptoms were more prevalent in the growth hormone group (7 versus 1); no other adverse events were more common in this group. CONCLUSIONS: Women with fibromyalgia and low IGF-1 levels experienced an improvement in their overall symptomatology and number of tender points after 9 months of daily growth hormone therapy. This suggests that a secondary growth hormone deficiency may be responsible for some of the symptoms of fibromyalgia.
Psychoneuroendocrinology. 1999 Oct;24(7):759-68
Small adrenal glands in chronic fatigue syndrome: a preliminary computer tomography study.
Scott LV, Dinan TG.
Department of Psychiatry, Trinity College Dublin Medical School, St. James's, Hospital, Ireland.
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.