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Hypothalamic-Pituitary-Adrenal Axis in Chronic Fatigue Syndrome
Several neuroendocrine studies have suggested hypoactivation of the hypothalamic-pituitary-adrenal axis in chronic fatigue syndrome. One possible determinant of this neuroendocrine abnormality, as well as the primary symptom of fatigue, is reduced hypothalamic secretion of corticotropin-releasing hormone (CRH).
Date: 3/2/2005 4:13:36 PM ( 19 y ) ... viewed 6344 times Abnormalities in response to vasopressin infusion in chronic fatigue syndrome -----------------------------------------------------------------------------
Margaret Altemus (a,*), Janet K. Dale (b), David Michelson(d), Mark A. Demitrack(d), Philip W. Gold(c) and Stephen E. Straus(b)
a Weill Medical College, Cornell University, Box 244, 1300 York Avenue, New York, NY 10021, USA b Laboratory of Clinical Investigation, National Institute of Allergy and Infectious Diseases, 10 Center Drive, Room 11N228, Bethesda, MD 20892-1888, USA c Clinical Neuroendocrinology Branch, National Institute of Mental Health, 10 Center Drive, Room 2D46, Bethesda, MD 20892-1284, USA d Lilly Research Laboratories, Indianapolis, IN, USA * Corresponding author. Tel.: +1-212-746-3751; fax: +1-212-746-3870; email: maltemus@mail.med.cornell.edu
Received 23 March 2000; revised 30 June 2000; accepted 25 July 2000. Available online 17 November 2000.
Abstract
Several neuroendocrine studies have suggested hypoactivation of the hypothalamic-pituitary-adrenal axis in chronic fatigue syndrome. One possible determinant of this neuroendocrine abnormality, as well as the primary symptom of fatigue, is reduced hypothalamic secretion of corticotropin-releasing hormone (CRH). Because CRH and vasopressin secreted from the hypothalamus act synergistically at the pituitary to activate ACTH secretion, the ACTH response to peripheral infusion of vasopressin can provide an indirect measure of hypothalamic CRH secretion. We measured the ACTH and cortisol response to a one hour infusion of arginine vasopressin in 19 patients with chronic fatigue syndrome and 19 age and sex matched healthy volunteers. Patients with chronic fatigue syndrome had a reduced ACTH response to the vasopressin infusion and a more rapid cortisol response to the infusion. These results provide further evidence of reduced hypothalamic CRH secretion in patients with chronic fatigue syndrome.
Author Keywords: Vasopressin; ACTH; CRH; Chronic fatigue syndrome; Cortisol; HPA axis
1. Introduction
Chronic fatigue syndrome is a clinical disorder of unknown and probably heterogeneous etiology. The syndrome is currently defined as continuous or relapsing, debilitating fatigue, which, together with at least 4 of 8 other signs and symptoms, has persisted for at least six months in the absence of any other fatigue associated medical condition (Fukuda and Holmes). Although many cases of chronic fatigue syndrome develop following an acute infectious illness, some cases seem to occur independent of infection and onset may be associated with other types of physical or emotional stress (Demitrack, 1994). It is postulated that the chronic fatigue syndrome is perpetuated by a persisting, pathological response to the onset stress which includes symptoms of fatigue and low-grade inflammation (Demitrack and Strober). It is unclear whether the syndrome arises from a central nervous system dysfunction or a more peripheral abnormality at the neuromuscular junction, in muscle, or in immunologic activity. Although several investigators have failed to detect abnormalities in peripheral neuromuscular function in patients with chronic fatigue syndrome (Edwards; Gibson; Kent; Lloyd; Riley and Rutherford), a recent study found an increase in central motor fatigue (Samii et al., 1996). The pervasive symptoms of impaired concentration and memory in patients with chronic fatigue syndrome also point to central nervous system involvement in the etiology of the fatigue symptoms.
Both the clinical symptomatology of chronic fatigue syndrome and previous neuroendocrine studies have suggested impaired activation of the hypothalamic-pituitary-adrenal axis in patients with the syndrome (Demitrack, 1994). Adrenal steroid deficiency and adrenal steroid withdrawal is associated with several symptoms characteristic of chronic fatigue syndrome including fatigue, arthralgias, myalgias, adenopathy, exacerbation of allergic responses, feverishness, and changes in mood, cognition, and sleep (Henneman et al., 1955). Because glucocorticoids play a major role in restraint of inflammatory processes (Munck et al., 1984), reduced activation of HPA axis could contribute to symptoms and signs of chronic mild inflammation in patients with chronic fatigue syndrome and reported subtle abnormalities in laboratory measures of cell mediated and humoral immunity (Kent; Mawle and Strober). In addition, there have been reports of varying degrees of symptom improvement during treatment with hydrocortisone (Cleare and McKenzie) and fludrocortisone, a mineralocorticoid (Bou-Holaigah et al., 1995).
Many neuroendocrine studies of chronic fatigue syndrome, but not all (Bearn; Wood and Young), have noted reduced HPA axis activity in chronic fatigue syndrome. Positive findings include reductions in urinary free cortisol ( Demitrack and Scott), reduced plasma (Demitrack and Poteliakhoff) and salivary (Strickland et al., 1998) cortisol levels, reduced adrenal cortisol and dehydroepiandrosterone (DHEA) responses to moderate and high dose adrenocorticotropin (ACTH) stimulation (DeBecker; Demitrack and Scott), and reduced cortisol and ACTH responses to administration of corticotropin- releasing hormone (CRH) (Demitrack; Scott and Scott), ipsapirone (Dinan et al., 1997), and naloxone (Scott et al., 1998c). These endocrine findings are most compatible with a mild central adrenal insufficiency, due to either a deficiency of corticotropin releasing hormone or some other central stimulus to the pituitary adrenal axis.
In order to further define the determinants of impaired activation of the hypothalamic-pituitary-adrenal axis in patients with chronic fatigue syndrome, we compared ACTH and cortisol responses to an intravenous infusion of vasopressin between patients with chronic fatigue syndrome and controls. Pituitary ACTH secretion in response to vasopressin is markedly potentiated by concomitant corticotropin-releasing hormone stimulation of the pituitary (DeBold et al., 1984). Prior dose-response and circadian studies of vasopressin infusion in healthy controls have shown significantly reduced ACTH and cortisol responses to vasopressin infusion in the evening when the nadir of hypothalamic CRH secretion occurs (Salata et al., 1988), suggesting that this test is sensitive to fluctuations of CRH secretion within the physiological range. Thus the degree of ACTH response to vasopressin infusion can provide an indirect measure of ambient hypothalamic corticotropin-releasing hormone secretion, particularly if performed in the morning, when hypothalamic CRH secretion is relatively high.
2. Methods
2.1. SUBJECTS
Six men and 19 women who met 1988 and 1994 CDC criteria (Fukuda and Holmes) for chronic fatigue syndrome and who were evaluated extensively under NIAID Chronic Fatigue Syndrome research protocols participated in the study. Six of these women were unable to tolerate the vasopressin infusion due to development of abdominal pain during the infusion, and are not included in the analyses, resulting in a total sample of 6 men and 13 women with chronic fatigue syndrome.
All chronic fatigue syndrome patients were interviewed using the Diagnostic Interview Schedule, version IIIR (Robins and Helzer, 1986), a structured psychiatric diagnostic interview. Although the modifications in 1994 of the original CDC diagnostic criteria permitted inclusion of patients with comorbid major depression (Fukuda et al., 1994), patients with current major depression or major depression at the time of onset of the chronic fatigue syndrome were not included in this study. No subjects with disabling pain or pain symptoms of more than mild intensity were included. Patients with concurrent substance abuse were also excluded, except for one patient who was using tobacco regularly at the time of testing. Of the 19 patients who tolerated the infusion, three had no lifetime history of a psychiatric disorder. At the time of the study, one patient met criteria for generalized anxiety disorder, two subjects had social phobia, and 11 met criteria for somatoform pain disorder, due to symptoms of chronic sore throat, myalgias, and headache, which are also diagnostic criteria for chronic fatigue syndrome. Patients with additional past psychiatric diagnoses included one with generalized anxiety disorder, one with social phobia, one with post-traumatic stress disorder, two additional patients with somatoform pain disorder, two with major depression, one with a history of dysthymia, and two with past diagnoses of other depressive syndromes. In addition, several patients had drug dependencies in the past, which ended more than two years prior to entry into this study. Six patients had a past history of nicotine dependence, four had a history of alcohol abuse, and one had a history of cocaine use.
The mean (p/m SEM) age of subjects with chronic fatigue syndrome was 39.7 p/m 1.6 years and the mean duration of illness was 3.7 p/m 0.6 years. All patients were fully ambulatory. At the time of testing, 9 were employed full or part-time and 10 were fully disabled. In 16 of the 19 patients, onset of chronic fatigue syndrome was precipitated by an acute febrile illness. All patients had a complete medical and psychiatric history, physical exam, EKG, chest x-ray and screening laboratory exams to rule out the presence of concurrent medical or psychiatric illness or concurrent substance abuse. Screening laboratory tests included complete blood count with differential, complete chemistry panel, thyroid function tests, ANA, RF, HIV Ab, urinalysis and urine toxicology screen. At the time of vasopressin stimulation testing, subjects had been off all medications, for at least 2 weeks. No subjects were using oral contraceptives or estrogen replacement therapy. Five patients discontinued antidepressant medication in order to participate in the study: three were taking low doses of antidepressants, either amitryptiline (10-30 mg) or synequan (10 mg).
Nineteen normal volunteers recruited through the NIH normal volunteer program participated in the study. They were matched for age within three years and sex to chronic fatigue syndrome patients who completed the one-hour infusion of vasopressin. All subjects with chronic fatigue syndrome and all control subjects were caucasian. Menstrual cycle phase was not controlled in either subject group. Mean age of the normal volunteers was 38.9 p/m 1.7 years. Each normal volunteer underwent a thorough psychiatric diagnostic interview, medical history, physical exam, screening blood tests, and electrocardiogram. None had evidence of a current or past history of chronic fatigue, or any neurological, endocrine, cardiovascular, hepatic, renal, hematologic or psychiatric illness. No volunteers were taking any medications, including oral contraceptives or oestrogen replacement therapy, or using alcohol, tobacco, or other drugs on a regular basis.
The study was approved by the NIMH Institutional Review Board and all subjects gave informed consent before participation.
2.2. VASOPRESSIN STIMULATION
All subjects reported to a day hospital unit in the NIH Clinical Center for testing at 0700 h after an overnight fast. Subjects were instructed not to use caffeine, alcohol or tobacco during the 24 hours preceding the test. Intravenous catheters were placed in both forearm veins at 0730 h. All blood samples were collected in prechilled glass tubes containing potassium EDTA as an anticoagulant. Blood was drawn at 15-minute intervals from 0830 h to 0930 h for determination of baseline ACTH and cortisol. From 0930 h to 1030 h, an infusion of arginine vasopressin (arginine vasopressin (aqueous pitressin), Parke-Davis, Morris Plains, NJ) was given at a dose of 1 mIU/kg/min. Blood was sampled at 15 minute intervals during the infusion and for one hour afterwards, stored on ice and spun down within three hours of collection, after which the plasma was frozen on dry ice and stored at -70 C until assayed. Heart rate and blood pressure were recorded at 15-minute intervals throughout the procedure.
2.3. CLINICAL RATINGS
Subjects completed self-administered rating scales to assess mood and arousal level, including the Profile of Mood States (POMS) (McNair et al., 1981), the Beck Depression Inventory (Beck et al., 1961) and a modified version of the Karnofsky scale (Karnofsky and Burchenal, 1949). In addition, observer-rated assessment of mood was performed using the 21-item Hamilton Depression Rating Scale (Hamilton, 1967).
2.4. HORMONE ASSAYS
Commercial radioimmunoassay kits were used to measure cortisol (Diagnostic Products, Los Angeles, CA) and ACTH (IRMA) (Nichols Institute, San Juan Capistrano, CA). The sensitivity for cortisol was 1 ug/dl and 1.5 pg/ml for ACTH. Chronic fatigue syndrome patients and paired controls were run together in the same assays. Intraassay and interassay coefficients of variation were 3.2 and 4.5% for ACTH and 5.7% and 7.1% for cortisol. Vasopressin was measured by radioimmunoassay as previously described (Altemus et al., 1992) at the start and end of the vasopressin infusion. The detection limit for vasopressin was 0.4 pg/ml. All vasopressin samples were run in a single assay. Values below the detection limit of the assay were assigned the value of the detection limit for statistical analyses. One patient and six controls did not have plasma vasopressin measurements due to insufficient sample volume.
2.5. STATISTICAL ANALYSIS
Repeated measures analysis of variance was used to examine differences between patients and controls in basal ACTH and cortisol (Time -60 to time 0) and the ACTH and cortisol responses to the vasopressin infusion (time 0 to time 120). In the case of a significant group difference or a significant interaction between group and time, post-hoc comparisons between patients and normal controls were made at each time point using two-tailed t tests with the Bonferroni correction for multiple comparisons. Pearson's product-moment correlations were used to test for relationships among clinical variables and the maximal rise in ACTH and cortisol (peak-baseline) for each subject. All data are expressed as mean p/m SEM.
3. Results
3.1. BASAL ACTH AND CORTISOL
There was no group difference between patients and controls during the one hour blood sampling period prior to the vasopressin infusion in either ACTH (F(1,36)=0.24, P=0.63) or cortisol (F(1,36)=0.71, P=0.40). Mean ACTH level calculated from the five basal samples was 15.4 p/m 0.9 pg/ml in the patients and 14.1 p/m 0.8 pg/ml in the control group. Mean basal cortisol level was 9.2 p/m ug/dl in the patients and 8.0 p/m 0.5 ug/dl in the control group. There was a significant decline in cortisol (F(4,144)=10.7, P<0.0001) and ACTH (F(4,144)=4.6, P<0.01) during the one hour baseline period. (Fig. 1).
----------------------------------------------------------------------------- Fig. 1. ACTH (top) and cortisol (bottom) response to 1 IU/kg/min infusion of arginine vasopressin for 60 minutes in patients with chronic fatigue syndrome (#) and controls (O). All data are expressed as mean p/m SEM. Significant group by time interaction effects in ANOVA for ACTH (F(8,288)=3.6, P<0.001) and cortisol (F(8,288)=6.5, P<0.0001). The maximal change (peak-basal) in ACTH and cortisol are shown in the insets, *P<0.05, post hoc Bonferroni corrected t test. -----------------------------------------------------------------------------
3.2. VASOPRESSIN STIMULATION
There was no difference between chronic fatigue syndrome patients and controls in basal or peak plasma vasopressin levels. Basal values were at or close to the detection limit of the assay in both patients and controls (0.6 p/m .08 vs. 0.6 p/m 0.12 pg/ml, t=0.37, P=NS). Vasopressin values at the end of the vasopressin infusion were also similar in patients and controls (91.7 p/m 9.5 vs. 92.8 p/m 16.0 pg/ml, t=0.1, P=NS).
There was a significant change in plasma ACTH in response to the vasopressin infusion (F(8,288)=60.8, P<0.0001) and a significant interaction between diagnosis and the change in ACTH over time (F(8,288)=3.63, P<0.0005). Compared to control subjects, patients with chronic fatigue syndrome seemed to have a blunted ACTH response to vasopressin infusion. Post-hoc tests did not reveal a significant difference between subject groups in mean ACTH concentrations at any single time point. Comparison of maximal change in ACTH (peak-basal) showed a trend towards a reduced change in the patient group (22.0 p/m 3.2 vs. 29.9-3.2 pg/ml, t=1.7, P<0.1). (Fig. 1).
There also was a significant change in cortisol in response to the vasopressin infusion (F(8,288)=76.1, P<0.0001) and a significant interaction between diagnosis and the change in cortisol over time (F(8,288)=6.5, P<0.0001). Patients with chronic fatigue syndrome had a faster onset of the cortisol response than controls. There was no evidence of a difference between groups in the maximal change in cortisol (peak-basal) (13.1 p/m 1.5 vs. 12.1 p/m 1.3 ug/dl, t=0.5, P=NS). (Fig. 1).
There was no difference between patients and controls in the ratio of change in ACTH to change in cortisol (0.014 p/m 0.005 vs 0.016 p/m 0.006, t=0.36, P=NS).
There was a significant negative correlation between the basal ACTH level and the magnitude of the cortisol response to the vasopressin infusion in the patients (N=19, r=-0.65) but not in the controls (N=19, r=0.38). This correlation was not significant, however, after correction for multiple comparisons.
There was a significant correlation between the plasma vasopressin level at the termination of the one hour vasopressin infusion and the area under the curve of ACTH (N=31, P=0.46, P<0.01) and cortisol (N=31, P=0.49, P<0.01).
There was not significant change in heart rate or systolic or diastolic blood pressure in the patient or control group over the course of the infusion.
3.3. EFFECTS OF ILLNESS SEVERITY AND DEPRESSION
The mean score on the Hamilton Depression Rating interview of the patients was 13.8 p/m 0.7 and the mean score on the Beck Depression Inventory questionnaire was 11.9 p/m 1.1. Only two of the 19 patients with chronic fatigue syndrome had scores greater than 16 on the Hamilton Depression Rating or greater than 19 on the Beck Depression Inventory, indicating moderate to severe depression. The mean activity score of the patients was 5.2 p/m 0.5, corresponding to ability to do many light and no heavy activities on most days. There were no significant correlations between any of the hormonal measures and any of the ratings of activity, depression or fatigue or duration of illness.
4. Discussion
The reduced ACTH response to vasopressin infusion in patients with chronic fatigue syndrome in this study provides further support for the hypothesis that impairment of hypothalamic CRH secretion is associated with the syndrome of chronic fatigue. The blunted ACTH response to the vasopressin infusion in the subjects with chronic fatigue syndrome and the similar ACTH to cortisol ratios in chronic fatigue syndrome subjects and controls argue against a primary adrenal insufficiency in the illness. The more rapid cortisol response to the infusion in patients with chronic fatigue syndrome is consistent with our earlier report of enhanced adrenocortical sensitivity to low doses of ACTH (Demitrack et al., 1991) and is compatible with a secondary adrenal insufficiency. Although these findings are relatively subtle, the effect size of the ANOVAs is moderate: delta=0.66 for ACTH and delta=0.5 for cortisol (Diggle et al., 1996). One other study of vasopressin challenge in chronic fatigue syndrome used a less potent 10 ug bolus dose of desmopressin in the early afternoon, which did not produce a clear ACTH or cortisol response in either the subjects with chronic fatigue syndrome or control subjects (Scott et al., 1999).
Multiple other abnormalities of HPA axis regulation which could produce the observed reduction in ACTH response to vasopressin infusion in subjects with chronic fatigue syndrome should be considered. A smaller pituitary reserve of ACTH, or accelerated metabolism of ACTH could produce this finding. A reduced ACTH response also could be caused by relative insensitivity of pituitary vasopressin or CRH receptors. Preclinical studies suggest that in chronic inflammatory states there is a relative shift from dominance of CRH to AVP in control of HPA axis activity (Harbuz et al., 1992). The blunted ACTH response to vasopressin in chronic fatigue syndrome could reflect an impact of relatively increased vasopressin in hypophyseal portal blood to down-regulate pituitary vasopressin receptors, as has been suggested in multiple sclerosis ( Michelson et al., 1994). It is also possible that the accelerated cortisol response to the vasopressin infusion at 30 minutes in patients with chronic fatigue syndrome caused the blunting of the ACTH response seen at the 60-90 minute time points. However, the available data suggest that glucocorticoids are less effective in suppresing vasopressin induced ACTH release than CRH-induced ACTH release (Antoni, 1993). Glucocorticoid feedback sensitivity appears to be enhanced in individuals with post-traumatic stress disorder and atopic dermatitis (Rupprecht and Yehuda), two other disorders associated with subtle reductions in HPA axis activity (Buske and Yehuda). This aspect of HPA axis regulation has not been studied in chronic fatigue syndrome, but increased glucocorticoid feedback sensitivity also could contribute to our finding of a blunted ACTH response to vasopressin in these subjects.
In contrast to prior reports of reduced basal cortisol levels in patients with chronic fatigue syndrome (Demitrack; Poteliakhoff; Scott and Strickland), we found similar levels of ACTH and cortisol in patients and controls. Similar basal cortisol levels in patients and controls in this may be due to heterogeneity of chronic fatigue syndrome. It is possible that a relatively larger proportion of the subjects in the current study did not have prominent hypothalamic-pituitary-adrenal axis hypoactivation. In addition, longer duration of illness may be more strongly associated with reductions in basal cortisol levels. The average duration of illness in this study was 3.7 years, and in our earlier study in which chronic fatigue syndrome was associated with reduced basal cortisol levels, the average duration of illness 7.2 years (Demitrack et al., 1991). In the few other studies of hypothalamic-pituitary- adrenal axis function which reported duration of illness, there was no difference in basal cortisol levels and the mean duration of illness was 2.5 years (Young et al., 1998) and 4.8 years (Scott and Scott).
It should be noted that the vasopressin infusion was terminated early due to gastrointestinal distress in six of the twenty-five chronic fatigue syndrome patients who entered the study, but none of the nineteen healthy control subjects reported significant gastrointestinal distress. The six patients who developed these side effects could not be distinguished from the other chronic fatigue syndrome patients by any physical symptoms or psychological characteristics. This finding suggests that despite a reduced pituitary ACTH response to vasopressin infusion in chronic fatigue syndrome patients, vasopressin receptors in the gastrointestinal tract may be hypersensitive in some of these patients. Alternatively, a number of other neurotransmitter or neuropeptide abnormalities may increase gastrointestinal tract irritability in these patients. Compared to control subjects, individuals with chronic fatigue syndrome also reported more nausea in response to single dose administration of the serotonin 1A receptor agonist buspirone (Bakheit and Sharpe).
The high rate of comorbid mood, anxiety and somatoform disorders in our sample agrees with several prior studies of patients with chronic fatigue syndrome syndrome (Demitrack; Gold; Hickie; Katon; Kruesi; Lane and Manu). Dysregulation of the acute hypothalamic-pituitary adrenal response to infection or psychological stress and subsequent failure of adaptive restoration of homeostasis in the hypothalamic-pituitary-adrenal axis may mediate symptom development in chronic fatigue syndrome as well as in patients with chronic mood and anxiety disorders (Demitrack and Heim). Evidence of reduced hypothalamic-pituitary adrenal axis activity has been found in several medical and psychiatric syndromes characterized by predominant symptoms of fatigue or anergic depression including seasonal affective disorder ( Joseph-Vanderpool et al., 1991), hypothyroidism (Bigos and Kamilaris), chronic pain syndromes (Heim et al., 1998) and fibromyalgia (Griep et al., 1993 and McCain). In addition, persistent mild degrees of adrenal failure have been reported in chronic infectious states in humans (Kendrowa; Membreno and Southern).
In summary, our finding of a reduced ACTH response and an accelerated cortisol response to vasopressin infusion in patients with chronic fatigue syndrome is subtle, but significant. There are multiple possible interpretations of these data, but the findings are consistent with prior reports of blunted HPA axis activity in patients with chronic fatigue syndrome using other measures of HPA axis function. The cause of reduced hypothalamic-pituitary-adrenal axis activity in patients with chronic fatigue syndrome remains to be determined. Abnormalities in serotonergic (Bakheit; Bearn; Cleare; Dinan and Sharpe) and opiate (Scott et al., 1998c) systems have been suggested. Impaired activation of the hypothalamic-pituitary-adrenal axis in chronic fatigue syndrome also could be secondary to chronic infection or to reduced physical activity (Luger and Saltin).
Further work is needed to determine whether hypoactivity of the hypothalamic- pituitary-adrenal axis in chronic fatigue syndrome plays a role in producing the symptoms and signs of the illness, or whether it is an epiphenomenon of the syndrome without functional consequences. Recent reports of symptom improvement during mineralocorticoid and glucocorticoid treatment suggests that deficiencies of these hormones do play a role in the symptom profile of chronic fatigue syndrome. In addition to the arousing effects of glucocorti- coids, CRH and vasopressin, the hypothalamic neuropeptides which are the principal stimulants of the hypothalamic pituitary adrenal axis, are also arousal-producing and cause physiological and behavioral activation when administered centrally to animals (Britton; Brown and Sutton). A subpopulation of CRH neurons in the paraventricular nucleus of the hypothalamus projects to autonomic structures in the brainstem and spinal cord (Sawchenko, 1987) and hypothalamic CRH has been shown to increase arousal and activity (Menzaghi and Monnikes). It is unknown whether centrally-directed and pituitary-directed hypothalamic CRH neurons are regulated in parallel. However, reduced activity of both populations of hypothalamic CRH neurons could produce reductions in cognitive and physiological arousal as well as hypoactivation of the hypothalamic-pituitary-adrenal axis. Additional treatment trials of adrenal steroids and pharmacologic agents which stimulate the hypothalamic-pituitary- adrenal axis centrally will help to clarify the importance of hypoactivity of the axis to generation of the chronic fatigue syndrome.
Acknowledgements
We would like to thank the NIAID fellows for clinical care of the chronic fatigue syndrome patients, the nurses of the 3 East and 11 West Clinical Research Units for their assistance with the infusion studies, and Jessica Zonana for her help with manuscript preparation.
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