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Psychosomatic Medicine 64:951-962 (2002)
© 2002 American Psychosomatic Society

ORIGINAL ARTICLES

Hypothalamic-Pituitary-Adrenal Axis Reactivity in Chronic Fatigue Syndrome and Health Under Psychological, Physiological, and Pharmacological Stimulation

Jens Gaab, PhD, Dominik Hüster, MSc, Renate Peisen, MSc, Veronika Engert, BSc, Vera Heitz, BSc, Tanja Schad, BSc, Thomas H. Schürmeyer, PhD, MD and Ulrike Ehlert, PhD

From the Center for Psychobiological and Psychosomatic Research (J. G., D.H., R.P., V.E., V.H., T.S., T.H.S., U.E.), University of Trier, Trier, Germany; and the Institute of Psychology (J.G., U.E.), Clinical Psychology II, University of Zürich, Zürich, Switzerland.

Address reprint requests to: Dr. phil. Jens Gaab, Institute of Psychology, Clinical Psychology II, University of Zürich, Zürichbergstr. 43, CH-8044 Zürich, Switzerland. Email: jgaab{at}klipsy.unizh.ch


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

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

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

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

Key Words: chronic fatigue syndrome, • hypothalamic-pituitary-adrenal axis, • psychosocial stress test, • exercise test, • insulin tolerance test, • corticotropin-releasing hormone.

Abbreviations: ACTH = adrenocorticotropin hormone;; ANCOVA = analysis of covariance;; ANOVA = analysis of variance;; AUC = area under curve;; BDI = Beck Depression Inventory;; CFS = chronic fatigue syndrome;; CRH = corticotropin-releasing hormone;; ERGO = incremental ergometry test;; HADS = Hospital Anxiety and Depression Scale;; HPA = hypothalamic-pituitary-adrenal axis;; ITT = insulin tolerance test;; MANOVA = multivariate analysis of variance;; MFI = Multidimensional Fatigue Inventory;; PC = plasma cortisol;; PTSD = posttraumatic stress disorder;; SC = saliva cortisol;; SCL-90-R = Symptom Checklist;; SIP = Sickness Impact Profile;; TSST = Trier Social Stress Test.


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
SUBJECTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Chronic fatigue syndrome (CFS) is characterized by persistent or relapsing debilitating mental and physical fatigue that is exacerbated by minor exertion. Patients typically experience an array of other symptoms, including myalgia, arthralgia, cognitive disturbances, low-grade fever, and sleep disturbances (1). CFS has aroused much interest in the past, but because the syndrome defies an objective biomedical cause and a diagnosis is established through exclusion of explanatory disorders and illnesses (2), there is still controversy about its nosology, etiology, and pathophysiology (3, 4).

The lack of any specific pathological agent or process (5, 6) and the multitude of etiological assumptions from various disciplines (7–10) have prompted the need for an integrative approach. Because the hypothalamic-pituitary-adrenal (HPA) axis plays an important role in the psychoneuroendocrine-immune interaction, it has been proposed as a common pathway (11) possibly linking antecedent factors like stress and personality (12, 13), immunological disturbances (14), and symptomatology (15).

Because of the clinical similarities between CFS and states of glucocorticoid deficiencies as well as early observations of reduced adrenocortical activity in chronically fatigued patients (16), several studies have addressed possible HPA axis dysfunction in CFS patients. In a comprehensive series of tests, Demitrack et al. (17) found evidence of a mild hypocortisolism, possibly of tertiary origin, characterized by low evening cortisol levels, attenuated net integrated ACTH response to ovine CRH, and a hyperresponsive adrenal gland with reduced secretory capacity to increasing doses of exogenous ACTH. Two studies using exogenous CRH confirmed alterations on a pituitary level, most likely due to a reduced sensitivity of pituitary corticotrophs or dysregulations of the arginine vasopressin/CRH interplay (18, 19). Reduced adrenocortical responsiveness was seen using the low-dose ACTH test (20), although this finding could not be replicated in a subsequent study (21). Evaluating the integrity of the HPA axis with the insulin tolerance test (ITT), no significant response differences in both ACTH and cortisol were observable (22). Basal HPA axis activity was found to be normal in salivary-free cortisol (23, 24) and reduced in 24-hour urinary free cortisol (17, 25), whereas one study showed changes in the diurnal pattern of ACTH and cortisol secretion in CFS patients (26).

Although there is ample evidence for disturbances of HPA axis functioning, there is some uncertainty about its level of origin (ie, primary, secondary, or tertiary) as well as the clinical relevance of these findings (27).

Because the main function of the HPA axis is to maintain homeostasis under physiological and psychological stress (28) and because fatigue symptoms are exacerbated by stress and exercise (29, 30), we decided to investigate HPA axis functioning in CFS patients using two tests approximating real-life stressors (a potent psychosocial laboratory stress protocol and a standardized exercise test) and to compare these tests with a standardized pharmacological challenge test (the ITT). With these tests we were able to assess HPA axis integrity on different levels of the HPA axis and the impact of possible HPA axis dysfunctions under physiological circumstances using these diverse stressors (31).


   SUBJECTS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 SUBJECTS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Subjects
A total of 45 subjects participated in this study. Patients were contacted through a German self-help organization. Interested patients received a postal screening questionnaire containing all symptoms required by the US and UK definitions (2, 32). Patients fulfilling the symptom requirement in this screening questionnaire were interviewed over the phone and asked for diagnosed medical illnesses and psychiatric disorders. Interested patients were only excluded from participating in the study if they had received a medical or psychiatric diagnosis defined as an exclusion criterion by the US definition (2, 32). Ten men and 13 women were selected from a cohort of 86 chronically fatigued subjects willing to participate in the study. Selection criteria were fulfillment of CFS symptom criteria of US and UK definitions (2, 32) in a screening questionnaire; acute onset of CFS; age between 30 and 50 years; no current antidepressant, anxiolytic, antibiotic, antihypertensive, or steroid medication; and no medical cause for the chronic fatigue in routine laboratory testing. Patients were admitted to a general hospital for 1 week. All patients were medically examined according to recent recommendations (2) and interviewed by a trained psychologist (J.G.), using a computer-aided standardized diagnostic interview (33) and a semistructured CFS interview. Two female patients were excluded from the study because of hormone levels indicative of thyroid hypofunction and primary adrenal insufficiency, diagnosed by a blunted cortisol response to Synacthen (Ciba, Wehr, Germany). All remaining 21 patients fulfilled US and UK consensus criteria for CFS. Patients were matched for age and sex with a total of 20 healthy volunteer control subjects, who were randomly recruited by phone. Control subjects were medication-free and underwent comprehensive medical examination for past and current health problems. Not all CFS patients underwent all tests; 3 female patients were unable to perform the ITT, leaving 18 patients who did perform the ITT. Also, not all control subjects underwent all tests; seven patients (three men and four women) did not perform the ITT. Therefore, four new control subjects (two men and two women) were recruited for this test; thus, 17 control subjects performed the ITT. The newly recruited control subjects did not differ in demographic variables and underwent the same procedures as the other control subjects. The new control subjects performed only the ITT.

All subjects provided written informed consent before participation in the study. Approval from the ethics committee was obtained.

Test Protocols
Each subject reported to the laboratory three times. In all experimental sessions subjects arrived 60 minutes before each test. They were taken into a separate room, and a venous catheter was inserted and kept patent with a lock. All subjects had to rest for at least 45 minutes. A baseline sample was collected immediately before each test began. After the Trier Social Stress Test (TSST) and the incremental cycle ergometry test (ERGO), all subjects were taken back into their room for further sampling. At all sample points blood and saliva samples were taken. The tests were performed in the following order: TSST, ERGO, and ITT. The time intervals were 24 hours between the TSST and the ERGO and 48 hours between the ERGO and the ITT. The TSST started between 10:00 hours and 11:00 hours, the ERGO at 14:00 hours, and the ITT at 09:00 hours.

Trier Social Stress Test.
The TSST has been repeatedly found to induce profound endocrine and cardiovascular responses in 70% to 80% of the subjects tested (34). After baseline samples of ACTH, plasma total cortisol (PC), and salivary-free cortisol (SC) were taken, subjects were introduced into the TSST (1 minute). They were given 3 minutes to prepare themselves for a fake job interview (5 minutes); this task was followed by a mental arithmetic task in front of an audience (5 minutes). Subjects were told that they would be videotaped for further analysis of their behavior. Immediately after the test a sample was taken, with further samples at 10, 20, 30, 45, and 60 minutes to assess ACTH, PC, and SC. To allow comparison of physiological stress responses between the groups, possible moderator factors (primary appraisal and coping functions) were assessed after the TSST. Cardiovascular responses were recorded for the whole testing period.

Incremental cycle ergometry test.
To test the integrity of the HPA axis under physical challenge, a standard cycle ergometry test was used, starting at 50 W for men and 30 W for women with 40-W increments every 3 minutes until exhaustion or predicted maximum heart rate (85% of 220 - age). Patients were not verbally encouraged during the test. All subjects were monitored throughout the test with continuous electrocardiographic, heart rate, and blood pressure monitoring. Subjects were asked to rate perceived exertion using the Borg scale (35). Blood samples for determination of ACTH, PC, and SC were taken immediately before and 1, 10, 20, 30, 45, and 60 minutes after the test.

Insulin tolerance test.
The ITT is considered the gold standard for testing the integrity of the entire HPA axis (36). Subjects were asked to fast overnight. After a 45-minute resting period a baseline sample was taken to measure blood glucose and endocrine parameters, and an intravenous bolus injection of 0.15 U/kg soluble insulin (H-Insulin, Hoechst, Frankfurt, Germany) was given. None of the tested subjects received intravenous or oral glucose during the ITT. Subjects were told that they could request intravenous glucose infusion to reduce symptoms of hypoglycemia. Samples for blood glucose, ACTH, PC, and SC determinations were collected at 20, 30, 45, 60, 90, and 120 minutes after the injection.

Sampling Methods and Biochemical Analyses
Ethylenediamine tetraacetate–treated blood samples were spun immediately at 4°C and stored at -20°C until assayed. Saliva was collected by the subjects using Salivette (Sarstedt, Rommelsdorf, Germany) collection devices and stored at room temperature until completion of the session. They were then stored at -20°C until biochemical analysis.

ACTH and PC were measured with two-site commercial chemiluminescence assays (CLIAs, Nichols Institute Diagnostics, Bad Nauheim, Germany). The free cortisol concentration in saliva (SC) was determined using a time-resolved immunoassay with fluorometric detection, as described in detail elsewhere (37). Inter- and intraassay coefficients of variance were below 10% for all analytes.

Heart Rate
In the TSST heart rate was measured continuously at 1-minute intervals precision using wireless transmission (Sport Tester Profi, Polar Instruments, Gross-Gerau, Germany). Heart rate before and after the TSST was transformed into 10-minute intervals and considered as baseline. Heart rate responses in the TSST were summarized into 14 intervals of 1 minute duration. Heart rate in the ERGO protocol was determined every 3 minutes with the electrocardiogram.

Psychometric Assessment
All subjects completed a battery of questionnaires according to recent recommendations (38), including German versions of the Multidimensional Fatigue Inventory (MFI) (39), the Sickness Impact Profile (SIP) (40), the Hospital Anxiety and Depression Scale (HADS) (41), the Beck Depression Inventory (BDI) (42), and the revised 90-item Symptom Checklist (SCL-90-R) (43). After the TSST primary appraisal was assessed with 12 items addressing the perceived relevance, challenge, and threat. Also, problem- and emotion-focused functions of coping were assessed with a TSST-specific adaptation of the German version of the Ways of Coping Checklist (44).

Statistical Analysis
{chi}2 analysis was used to test significant differences in discrete variables; rank-order variables were analyzed with the Mann-Whitney U test; and repeated-measures ANOVA was used to analyze endocrine and heart rate responses in the tests. Repeated-measures ANCOVA was used to control for differences in endocrine baseline levels or when indicated. All reported results were corrected by the Greenhouse-Geisser procedure when assumptions of sphericity were violated. Newman-Keuls post hoc tests were calculated for significant effects. Correlations were computed as Pearson product-moment correlations. Psychological parameters were analyzed by Student’s t test, ANOVA, or MANOVA. Linear regression analyses were computed to analyze the impact of relevant factors on physiological stress responses. Reliability measures (Cronbach’s {alpha}) and principal component analysis with Varimax rotation were computed for psychometric data when appropriate. For all endocrine parameters, area under the initial response curve (AUCincrease), expressed as area under samples 1 to 3 for ACTH and samples 1 to 4 for cortisol parameters, and area under the total response curve (AUCtotal), expressed as area under all samples, were calculated using the trapezoidal method. Data were tested for normal distribution and homogeneity of variance using Kolmogorov-Smirnov and Levene’s test before statistical procedures were applied. The optimal total sample size of N = 40 to detect an expected effect size (ES) of 0.35 with a power >=0.90 and {alpha} = 0.05 was calculated a priori with G-Power statistical software (45). For all analyses the significance level was {alpha} = 5%. Unless indicated all results shown are mean ± SEM.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 SUBJECTS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Patients and Controls Characteristics
Sex ratio and number of subjects for the respective test, as well as mean age and body mass index, did not differ significantly between the groups (Table 1). Sixteen CFS patients reported an infectious onset of their symptoms. All patients reported an acute onset of their CFS symptoms (within 3 months). Mean duration of symptoms of patients was 67.4 months (range, 17–168 months). Four female subjects in each group used monophasic oral contraceptives. All patients were drug free for a minimum of 1 month, with the exception of the subjects using the oral contraceptives. One patient fulfilled criteria for a current episode of major depression. Because the exclusion of these subjects did not alter the results of the analysis, they were included in the reported analysis. Seven patients reported a past history of major depression, and four reported a past history of anxiety disorder. None of the control subjects reported any current or lifetime psychiatric disorder.


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  		TABLE 1. Demographic and Psychometric Characteristics of CFS Patients and Healthy Control Subjects
 
The MFI, BDI, HADS, SCL-90-R, and SIP scores of the CFS group were significantly higher than those of the control group and comparable to reported scores in previous studies (Table 1).

Trier Social Stress Test
The TSST caused significant endocrine responses (Table 2). All questionnaires used in the TSST were evaluated with regard to their psychometric properties using reliability measures (Cronbach’s {alpha}) and principal component analysis with Varimax rotation, showing satisfactory internal consistency and factorial validity (data not shown). Linear regression analysis did not reveal any significant influence on the physiological responses in all tested endocrine parameters (expressed as areas AUCincrease and AUCtotal) through primary appraisal and coping functions (data not shown). Also, MANOVAs did not reveal any significant differences in the retrospective primary appraisal (F(3,37) = 2.51; p = .07) or the employed coping strategies (F(2,38) = 0.30; p = .74).


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  		TABLE 2. Statistical Analyses (ANOVAs) for Endocrine Parameters in the Three Stimulatory Tests
 
Groups did not differ in their cardiovascular response (heart rate) during the TSST (F(4.4,166.2) = 0.63; p = .66), but CFS patients had a higher overall heart rate (F(1,38) = 4.42; p = .04).

ANOVA revealed significant group effects and response differences over time between the groups for ACTH in the TSST (Fig. 1, top), but not for PC (Fig. 1, middle) and SC (Fig. 1, bottom; see also Table 2). Newman-Keuls post hoc tests confirmed that CFS patients had significantly lower ACTH levels at baseline and immediately and 10 minutes after the TSST. The previous ANOVA results were confirmed through the comparison of both AUCs, with significantly reduced AUCtotal for ACTH in patients, but no differences in the cortisol parameters (Table 3). Controlling for baseline differences in the endocrine parameters with ANCOVAs abolished the interaction effects for ACTH responses (Table 4).



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  		Fig. 1. Endocrine responses in the TSST of CFS patients ({blacksquare}) and healthy control subjects (•).

 

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  		TABLE 3. Differences in AUCtotal for All Endocrine Parameters in the Three Stimulatory Tests
 

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  		TABLE 4. Results of ANCOVAs (Group by Time) Controlling for Basal Differences in Endocrine Parameters in the Three Stimulatory Tests
 
Incremental Ergometry Test
The ergometry protocol induced significant cardiovascular (F(5,40) = 216.47, p<.001; Fig. 2, top) and endocrine responses (Table 2). Also, subjects reported significant increases in perceived exertion during the ERGO (F(5,40) = 178.43, p<.001; Fig. 2, bottom). To test whether the two groups show different increases in perceived exertion (PE) with heart rate (HR), individual linear regression curves with PE as the dependent variable and HR as the independent variable were calculated, and the mean of the slope and the mean of the intercept of each group (PE-HR: CFS = 0.14 x HR - 3.54; control = 0.15 x HR - 5.72) were compared using the Mann-Whitney U test. No significant difference in slope (PE-HR: U = 180, Z = -0.28, p = .77) or intercept (PE-HR: U = 163, Z = 0.63, p = .45) was found.



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  		Fig. 2. Heart rate (top) and perceived exertion (bottom) in relation to exercise time in ERGO.

 
Because linear regression analysis revealed significant integrated ACTH responses by heart rate, workload, perceived exertion, and exercise duration (AUCincrease: adjusted r2 = 0.41, p = .02; AUCtotal: adjusted r2 = 0.37, p = .02), these were treated as covariates in the following analysis.

Groups differed significantly in their total response and in their ACTH responses over time in the ERGO (Fig. 3, top), but again no significant response differences were seen in the cortisol parameters (PC: Fig. 3, middle; SC: Fig. 3, bottom; see also Table 2). Newman-Keuls post hoc tests revealed significantly lower ACTH levels in CFS patients before and immediately and 10 minutes after the ERGO. Again these results were confirmed by group differences in AUCs. CFS patients showed significantly reduced AUCtotal for ACTH with no differences in the cortisol parameters (Table 3).



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  		Fig. 3. Endocrine responses in the ERGO of CFS patients ({blacksquare}) and healthy control subjects (•).

 
As in the TSST, controlling for baseline differences in the endocrine parameters with ANCOVAs abolished the interaction effects for ACTH responses (Table 4).

Insulin Tolerance Test
The ITT induced significant endocrine responses (Table 2) and a significant change in blood glucose levels (F(6,198) = 185.15, p<.001). All subjects reached an individual minimum blood glucose level of at least 30 mg/dl (Fig. 4).



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  		Fig. 4. Blood glucose response in the ITT of CFS patients ({blacksquare}) and healthy control subjects (•).

 
Total ACTH responses and ACTH responses over time in the ITT were significantly different between groups (Fig. 5, top; Table 2). No significant response differences were seen in the PC (Fig. 5, middle), but SC responses over time differed significantly between groups (Fig. 5, bottom; see also Table 2). Newman-Keuls post hoc tests revealed significantly lower ACTH levels at 30, 45, and 60 minutes and significantly higher SC levels at 45 and 60 minutes in CFS patients after the ITT. Controlling for baseline differences in the endocrine parameters with ANCOVAs did not alter the interaction effects for endocrine responses (Table 4).



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  		Fig. 5. Endocrine responses in ITT of CFS patients ({blacksquare}) and healthy control subjects (•).

 
Also, groups differed with regard to the AUCtotal of ACTH but not in both AUCtotal for PC and SC (Table 3). Concerning the blood glucose levels after the ITT, groups differed in their return to normal levels over time (F(3.96,130.7) = 6.75, p<.001), with CFS patients showing a significantly quicker and more pronounced increase after the trough levels (Fig. 5).

Associations and Comparisons of Endocrine Parameters Between Tests and Groups
To compare associations of endocrine responses between the tests, correlations between the AUCincrease of ACTH and cortisol parameters were calculated. High correlations were found for all parameters in the TSST (ACTH-PC: r = 0.67; ACTH-SC: r = 0.60; PC-SC: r = 0.67; all p < .00) and in the ERGO (ACTH-PC: r = 0.78; ACTH-SC: r = 0.62; PC-SC: r = 0.80; all p < .00), but in the ITT only the initial ACTH response was moderately associated with the initial PC response (ACTH-PC: r = 0.36, p = .03; ACTH-SC: r = 0.06, p = .72; PC-SC: r = 0.28, p = .11).

To estimate the reliability of the neuroendocrine tests used, correlations between different endocrine parameters were calculated. The AUCtotal for single endocrine parameters correlated significantly between the TSST and the ERGO (ACTH: r = 0.59, p < .001; total plasma cortisol: r = 0.65, p < .001; free salivary cortisol: r = 0.42, p = .007), but no significant associations for these parameters between the TSST or the ERGO and the ITT were found (data not shown).

Because distinct differences in the ACTH response over time were found in all tests, the overall ratio of ACTH to PC was calculated and compared between the groups. CFS patients had a significantly lower ACTH:PC ratio (Table 5), resulting in a 28% higher total response of total plasma cortisol for a given total response of ACTH.


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  		TABLE 5. Comparison of Endocrine Responses Between Groups
 
Also, CFS patients had significantly lower AUCtotal of ACTH responses (Table 5), resulting in a reduction of 37% AUCtotal of ACTH in all tests. MANOVA revealed that the differences of basal ACTH levels in CFS patients were a general phenomenon in all tests, with an average across all tests of a 33% lower basal ACTH in CFS patients (Table 5).

To control for the possible impact of gender differences in HPA axis functioning, we included gender as a second grouping variable in our calculations. The triple interactions of gender by group by time for ACTH responses were not significant in all tests (TSST: F(1.16,59.2) = 1.15, p = .31; ERGO: F (2.54,88.94) = 1.46, p = .23; ITT: F(2.27,7040) = 0.60, p = .57).


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 SUBJECTS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
Based on the assumption that a dysfunctional HPA axis is of etiological relevance in CFS, the present study set out to compare endocrine responses in CFS patients in three different, centrally acting tests with healthy age- and gender-matched control subjects.

All tests proved effective in activating the HPA axis. In all tests CFS patients had reduced baseline ACTH levels in comparison to the control subjects. CFS patients differed significantly in their ACTH responses over time and in their total ACTH response in all tests. Also, CFS patients had clearly reduced AUCtotals for the ACTH responses. However, the response over time differences disappeared in both TSST and ERGO, but not in the ITT, when ACTH baseline levels were included as covariates in the calculations. This indicates that CFS patients are able to mount a sufficient initial ACTH response under psychological and physiological stress, although on a lower level because the ACTH baseline differences were maintained throughout the initial response in the nonpharmacological stress tests and the AUCtotals of the ACTH responses were significantly lower. However, the relative ACTH response in the ITT was clearly reduced regardless of baseline differences. This is probably the result of the four- to five-fold higher potency of the ITT in comparison to the other two tests in terms of ACTH secretion. The ITT could be seen as a test of maximal ACTH capacity, whereas the TSST and the ERGO assess the functionality of pituitary corticotrophs under nonpharmacological and thus moderate stimulation. The reduced absolute ACTH responses of CFS patients did not result in reduced cortisol responses. This could be the result of an enhanced sensitivity of the adrenal gland, as indicated by the reduced ACTH:PC ratio of CFS patients in all tests. Interestingly, both percentile differences of the ACTH:PC ratio and AUCtotal of ACTH between CFS patients and healthy control subjects are of the same magnitude.

Although the testing procedures of the TSST and the ERGO were standardized, the capacity of both tests to induce HPA axis activation relies on intraindividual processes. Thus, these tests differ from pharmacological challenge tests, which exert their influence through normed doses of the respective agent. We therefore used measures to control for differences in relevant individual parameters and included them in our analysis. Groups did not differ significantly or substantially in these parameters. Because of these precautions and also considering that groups did not differ in their response relative to the baseline in these two tests, we are confident that the differences of ACTH responses over time are not due to differences in these parameters between groups but represent distinct dysregulations of the HPA axis.

CFS patients and control subjects did not differ significantly in the relationship between perceived exertion and heart rate during incremental exercise. Also, CFS patients did not show a different increase of perceived exertion over time in comparison to control subjects. Similar findings have been observed in two studies (46, 47), whereas in others investigators have found CFS patients to have higher perceived exertion (48–50). It is possible that differences between patient samples, such as physical fitness or somatic amplification, could account for the differences between our study and the other studies.

Endocrine responses in the TSST and the ERGO showed substantial consistency, confirming previous reports of intraindividual stability of endocrine responses to different stressors (51). The lack of a significant association between the endocrine responses in these two tests and the ITT could again be the result of the differences in their potency to elicit these responses. Although we carefully matched our sample for gender and we did not observe a significant influence of gender on the group differences in endocrine responses over time, the statistical power of the study design to detect small gender effects was low. Therefore, further research is needed to elucidate whether the observed predominance of female CFS patients (52) is related to gender differences in neuroendocrine functioning (53).

Our results confirm previous findings of a moderate HPA axis dysfunction with an enhanced sensitivity of the adrenal gland to ACTH and low basal and lower absolute (TSST and ERGO) and relative (ITT) ACTH responses, indicative of a secondary or tertiary origin of the HPA axis dysfunction (17). However, there is no indication of an either basal or reactive hypocortisolism, neither under physiological nor under supraphysiological stimulation through pharmacologically induced hypoglycemia. A lack of significant differences of cortisol responses between CFS patients and healthy control subjects has been frequently described in studies using central pharmacological stimulation of the HPA axis, for example, D-fenfluramine (22, 54, 55), ipsapirone (56), naloxone (57), CRH (17), and the ITT (22). Also, basal activity of the HPA axis, assessed by free cortisol levels in saliva, has been found to be normal (23, 24, 58). This is in contrast to other studies measuring basal urinary free cortisol (25, 59).

Concerning ACTH, the observed reduction in basal levels, the lower absolute response levels in the TSST and ERGO, and the reduced responses in the ITT could be the result of a deficient central drive of the HPA axis owing to either 1) hyporesponsive pituitary corticotrophs, 2) a deficient hypothalamic secretion of CRH, or (3) an enhanced negative feedback, although these explanations may not be mutually exclusive. Is has been postulated that down-regulation of the sensitivity of corticotrophs due to initial chronic hypersecretion of CRH is a possible underlying mechanism for the attenuated ACTH response observed in the CRH test (60, 61). Because the initial ACTH response of CFS patients in the TSST and the ERGO was normal, this explanation seems unlikely for these two tests. Although it may be possible that there is also a reduction in maximal secretory capacity of ACTH, as seen in the differences in both AUCs of ACTH in the ITT, the pituitary seems to be capable of eliciting a response of normal magnitude under nonpharmacological stimulation. The reported differences in basal and responsive ACTH levels could also be the result of a constantly reduced CRH drive. Indirect support for this assumption can be derived from contrasting responses to the selective serotonergic agonist D-fenfluramine in CFS and syndromes associated with CRH hypersecretion (62, 63). Although prolactin responses are exaggerated in CFS (55, 64), attenuated responses can be found in PTSD and major depression (55, 65). A deficient secretion of hypothalamic CRH has been associated with syndromes characterized by fatigue and associated symptoms, for example, atypical depression (66), seasonal affective disorder (67), nicotine withdrawal syndrome (68), postpartum "blues" (69), and Cushing’s disease (70). Although the latter two are most likely to be the result of a suppressed CRH system due to the feedback of high endogenous cortisol levels, there is no evidence that the same holds true for CFS since cortisol levels seem to be normal. Because the responsiveness of the pituitary corticotroph most likely gradually improves after normalization of cortisol levels (69), one would expect a permanent suppression of hypothalamic CRH secretion in CFS due to, for example, permanently enhanced central negative feedback. Enhanced negative feedback on the level of the pituitary, proposed as a possible explanation of the observed hypocortisolism (71) and the attenuated ACTH response in the CRH test (72) in PTSD, could have resulted in the attenuated ACTH levels seen in our sample. However, exposing Vietnam veterans with and without PTSD to combat sounds, no differences in basal and reactive ACTH levels in response to the stressor could be detected (73), thus showing a difference from our results. Another possible cause of the observed response differences could be an enhanced inhibitory tone due to changes in hippocampal and/or hypophyseal feedback regulation, resulting in a lower set point of central HPA activity (74). Postnatal handled rats have enhanced hippocampal negative feedback regulation due to an increase of glucocorticoid receptor gene expression, resulting in decreased hypothalamic CRH and arginine vasopressin expression (75).

Although the reported findings support the assumption that a central dysregulation of the HPA axis might be of importance (76–78), a possible role for cortisol still needs to considered. Administration of low doses of hydrocortisone has been shown to have some benefit in CFS patients (79), and an altered regulation of glucocorticoid effects on a cellular level has been reported (80).

Because CFS is often predated by psychological stress (12, 81), it would be tempting to assume a stress-related nature of the observed HPA axis dysfunctions. However, it cannot be ruled out that the endocrine disturbances are secondary to CFS characteristics, such as sleep disturbances (82) or prolonged inactivity. Future studies should include prospective study designs with repeated evaluation of the HPA axis over the course of the syndrome. Furthermore, neuroendocrinological evaluations of interventions aimed to alter activity behavior in CFS patients would offer valuable insights into the causes of HPA axis dysfunctions in CFS.

Received for publication May 11, 2001.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 SUBJECTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

  1. Wessely S, Chalder T, Hirsch S, Wallace P, Wright D. Psychological symptoms, somatic symptoms, and psychiatric disorder in chronic fatigue and chronic fatigue syndrome: a prospective study in the primary care setting. Am J Psychiatry 1996; 153: 1050–9.[Abstract/Free Full Text]
  2. Fukuda K, Straus SE, Hickie I, Sharpe MC, Dobbins JG, Komaroff A. The chronic fatigue syndrome: a comprehensive approach to its definition and study. International Chronic Fatigue Syndrome Study Group. Ann Intern Med 1994; 121: 953–9.[Abstract/Free Full Text]
  3. Swartz MN. The chronic fatigue syndrome—one entity or many? N Engl J Med 1988; 319: 1726–8.[Medline]
  4. Wessely S, Nimnuan C, Sharpe M. Functional somatic syndromes: one or many? Lancet 1999; 354: 936–9.[CrossRef][Medline]
  5. Swanink CM, Vercoulen JH, Bleijenberg G, Fennis JF, Galama JM, van der Meer JW. Chronic fatigue syndrome: a clinical and laboratory study with a well matched control group. J Intern Med 1995; 237: 499–506.[Medline]
  6. Strober W. Immunological function in chronic fatigue syndrome. In: Straus SE, editor. Chronic fatigue syndrome. Vol 1. New York: Marcel Dekker; 1994. p. 207–40.
  7. Surawy C, Hackmann A, Hawton K, Sharpe M. Chronic fatigue syndrome: a cognitive approach. Behav Res Ther 1995; 33: 535–44.[CrossRef][Medline]
  8. Cleare AJ, Wessely SC. Chronic fatigue syndrome: a stress disorder? Br J Hosp Med 1996; 55: 571–4.[Medline]
  9. Vollmer-Conna U, Lloyd A, Hickie I, Wakefield D. Chronic fatigue syndrome: an immunological perspective. Aust N Z J Psychiatry 1998; 32: 523–7.[CrossRef][Medline]
  10. Glaser R, Kiecolt-Glaser JK. Stress-associated immune modulation: relevance to viral infections and chronic fatigue syndrome. Am J Med 1998; 105: 35S–42S.[CrossRef][Medline]
  11. Demitrack MA. The psychobiology of chronic fatigue syndrome: the central nervous system as a common pathway. In: Demitrack MA, Abbey SE, editors. Chronic fatigue syndrome: an integrative approach to evaluation and treatment. New York: Guilford Press; 1997. p. 72–112.
  12. Theorell T, Blomkvist V, Lindh G, Evengard B. Critical life events, infections, and symptoms during the year preceding chronic fatigue syndrome (CFS): an examination of CFS patients and subjects with a nonspecific life crisis. Psychosom Med 1999; 61: 304–10.[Abstract/Free Full Text]
  13. Ware NC. Anthropological approach to chronic fatigue syndrome. In: Straus SE, editor. Chronic fatigue syndrome. Vol 2. New York: Marcel Dekker; 1994. p. 85–97.
  14. Sternberg EM. Hyperimmune fatigue syndromes: diseases of the stress response? J Rheumatol 1993; 20: 418–21.[Medline]
  15. Jefferies WM. Mild adrenocortical deficiency, chronic allergies, autoimmune disorders and the chronic fatigue syndrome: a continuation of the cortisone story. Med Hypotheses 1994; 42: 183–9.[CrossRef][Medline]
  16. Poteliakhoff A. Adrenocortical activity and some clinical findings in acute and chronic fatigue. J Psychosom Res 1981; 25: 91–5.[CrossRef][Medline]
  17. 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. J Clin Endocrinol Metab 1991; 73: 1224–34.[Abstract]
  18. Scott LV, Medbak S, Dinan TG. Desmopressin augments pituitary-adrenal responsivity to corticotropin-releasing hormone in subjects with chronic fatigue syndrome and in healthy volunteers. Biol Psychiatry 1999; 45: 1447–54.[CrossRef][Medline]
  19. Scott LV, Medbak S, Dinan TG. Blunted adrenocorticotropin and cortisol responses to corticotropin-releasing hormone stimulation in chronic fatigue syndrome. Acta Psychiatr Scand 1998; 97: 450–7.[Medline]
  20. Scott LV, Medbak S, Dinan TG. The low dose ACTH test in chronic fatigue syndrome and in health. Clin Endocrinol (Oxf) 1998; 48: 733–7.[CrossRef][Medline]
  21. Hudson M, Cleare AJ. The 1microg short Synacthen test in chronic fatigue syndrome. Clin Endocrinol (Oxf) 1999; 51: 625–30.[CrossRef][Medline]
  22. 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. Biol Psychiatry 1995; 37: 245–52.[CrossRef][Medline]
  23. Young AH, Sharpe M, Clements A, Dowling B, Hawton KE, Cowen PJ. Basal activity of the hypothalamic-pituitary-adrenal axis in patients with the chronic fatigue syndrome (neurasthenia). Biol Psychiatry 1998; 43: 236–7.[CrossRef][Medline]
  24. Wood B, Wessely S, Papadopoulos A, Poon L, Checkley S. Salivary cortisol profiles in chronic fatigue syndrome. Neuropsychobiology 1998; 37: 1–4.[CrossRef][Medline]
  25. Scott LV, Dinan TG. Urinary free cortisol excretion in chronic fatigue syndrome, major depression and in healthy volunteers. J Affect Disord 1998; 47: 49–54.[CrossRef][Medline]
  26. MacHale SM, Cavanagh JT, Bennie J, Carroll S, Goodwin GM, Lawrie SM. Diurnal variation of adrenocortical activity in chronic fatigue syndrome. Neuropsychobiology 1998; 38: 213–7.[CrossRef][Medline]
  27. Jeffcoate WJ. Chronic fatigue syndrome and functional hypoadrenia—fighting vainly the old ennui. Lancet 1999; 353: 424–5.[CrossRef][Medline]
  28. Chrousos GP. Stressors, stress, and neuroendocrine integration of the adaptive response. The 1997 Hans Selye Memorial Lecture. Ann N Y Acad Sci 1998: 851: 311–35.[Free Full Text]
  29. Wood GC, Bentall RP, Gopfert M, Dewey ME, Edwards RH. The differential response of chronic fatigue, neurotic and muscular dystrophy patients to experimental psychological stress. Psychol Med 1994; 24: 357–64.[Medline]
  30. Lutgendorf SK, Antoni MH, Ironson G, Fletcher MA, Penedo F, Baum A, Schneiderman N, Klimas N. Physical symptoms of chronic fatigue syndrome are exacerbated by the stress of Hurricane Andrew. Psychosom Med 1995; 57: 310–23.[Abstract/Free Full Text]
  31. Herman JP, Cullinan WE. Neurocircuitry of stress: central control of the hypothalamo-pituitary-adrenocortical axis. Trends Neurosci 1997; 20: 78–84.[CrossRef][Medline]
  32. Sharpe MC, Archard LC, Banatvala JE, Borysiewicz LK, Clare AW, David A, Edwards RH, Hawton KE, Lambert HP, Lane RJ. A report—chronic fatigue syndrome: guidelines for research. J R Soc Med 1991; 84: 118–21.[Medline]
  33. Wittchen H-U, Pfister H. DIA-X-interviews. Frankfurt: Swets & Zeitlinger; 1997.
  34. Kirschbaum C, Pirke KM, Hellhammer DH. The ‘Trier Social Stress Test’—a tool for investigating psychobiological stress responses in a laboratory setting. Neuropsychobiology 1993; 28: 76–81.[Medline]
  35. Borg GA. Psychophysical bases of somatic stress. Med Sci Sports Exerc 1982; 14: 377–81.[Medline]
  36. Fish HR, Chernow B, O’Brian JT. Endocrine and neurophysiologic responses of the pituitary to insulin-induced hypoglycemia: a review. Metabolism 1986; 35: 763–80.[CrossRef][Medline]
  37. Dressendorfer RA, Kirschbaum C, Rohde W, Stahl F, Strasburger CJ. Synthesis of a cortisol-biotin conjugate and evaluation as a tracer in an immunoassay for salivary cortisol measurement. J Steroid Biochem Mol Biol 1992; 43: 683–92.[CrossRef][Medline]
  38. Vercoulen JH, Swanink CM, Fennis JF, Galama JM, van der Meer JW, Bleijenberg G. Dimensional assessment of chronic fatigue syndrome. J Psychosom Res 1994; 38: 383–92.[CrossRef][Medline]
  39. Smets EM, Garssen B, Bonke B, De Haes JC. The Multidimensional Fatigue Inventory (MFI) psychometric qualities of an instrument to assess fatigue. J Psychosom Res 1995; 39: 315–25.[CrossRef][Medline]
  40. Kessler S, Jaeckel W, Cziske R. Assessing health in musculoskeletal disorders—the appropriateness of a German version of the Sickness Impact Profile. Rheumatol Int 1997; 17: 119–25.[CrossRef][Medline]
  41. Herrmann C, Buss U, Snaith RP. HADS-D Hospital Anxiety and Depression Scale—Ein Fragebogen zur Erfassung von Angst und Depressivität in der somatischen Medizin. Bern: Verlag Hans Huber; 1995.
  42. Hautzinger M, Bailer M, Worall H, Keller F. Beck-Depressions-Inventar (BDI). Bern: Verlag Hans Huber; 1995.
  43. Franke G. Die Symptom-Checkliste von Derogatis—Deutsche Version. Göttingen: Beltz Test GmbH; 1995.
  44. Ferring D, Filipp SH. Bewältigung kritischer Lebensereignisse: Erste Erfahrungen mit einer deutschsprachigen Version der "Ways of Coping Checklist." Z Differentielle Diagnostische Psychol 1989; 10: 189–99.
  45. Buchner A, Faul F, Erdfelder E. G-Power: a priori, post-hoc, and compromise power analyses for the Macintosh (version 2.1.2). Trier, Germany: University of Trier; 1997.
  46. Sisto SA, LaManca J, Cordero DL, Bergen MT, Ellis SP, Drastal S, Boda WL, Tapp WN, Natelson BH. Metabolic and cardiovascular effects of a progressive exercise test in patients with chronic fatigue syndrome. Am J Med 1996; 100: 634–40.[CrossRef][Medline]
  47. Gibson H, Carroll N, Clague JE, Edwards RH. Exercise performance and fatigability in patients with chronic fatigue syndrome. J Neurol Neurosurg Psychiatry 1993; 56: 993–8.[Abstract]
  48. Riley MS, O’Brien CJ, McCluskey DR, Bell NP, Nicholls DP. Aerobic work capacity in patients with chronic fatigue syndrome. BMJ 1990; 301: 953–6.
  49. Fulcher KY, White PD. Strength and physiological response to exercise in patients with chronic fatigue syndrome. J Neurol Neurosurg Psychiatry 2000; 69: 302–7.[Abstract/Free Full Text]
  50. Mengshoel AM, Vollestad NK, Forre O. Pain and fatigue induced by exercise in fibromyalgia patients and sedentary healthy subjects. Clin Exp Rheumatol 1995; 13: 477–82.[Medline]
  51. Singh A, Petrides JS, Gold PW, Chrousos GP, Deuster PA. Differential hypothalamic-pituitary-adrenal axis reactivity to psychological and physical stress. J Clin Endocrinol Metab 1999; 84: 1944–8.[Abstract/Free Full Text]
  52. Wessely S, Chalder T, Hirsch S, Wallace P, Wright D. The prevalence and morbidity of chronic fatigue and chronic fatigue syndrome: a prospective primary care study. Am J Public Health 1997; 87: 1449–55.[Abstract/Free Full Text]
  53. Kirschbaum C, Kudielka BM, Gaab J, Schommer NC, Hellhammer DH. Impact of gender, menstrual cycle phase, and oral contraceptives on the activity of the hypothalamus-pituitary-adrenal axis. Psychosom Med 1999; 61: 154–62.[Abstract/Free Full Text]
  54. Yatham LN, Morehouse RL, Chisholm BT, Haase DA, MacDonald DD, Marrie TJ. Neuroendocrine assessment of serotonin (5-HT) function in chronic fatigue syndrome. Can J Psychiatry 1995; 40: 93–6.[Medline]
  55. Cleare AJ, Bearn J, Allain T, McGregor A, Wessely S, Murray RM, O’Keane V. Contrasting neuroendocrine responses in depression and chronic fatigue syndrome. J Affect Disord 1995; 34: 283–9.[CrossRef][Medline]
  56. Dinan TG, Majeed T, Lavelle E, Scott LV, Berti C, Behan P. Blunted serotonin-mediated activation of the hypothalamic-pituitary-adrenal axis in chronic fatigue syndrome. Psychoneuroendocrinology 1997; 22: 261–7.[CrossRef][Medline]
  57. Scott LV, Burnett F, Medbak S, Dinan TG. Naloxone-mediated activation of the hypothalamic-pituitary-adrenal axis in chronic fatigue syndrome. Psychol Med 1998; 28: 285–93.[CrossRef][Medline]
  58. Gaab J, Hüster D, Peisen R, Engert V, Heitz V, Schad T, Schürmeyer T, Ehlert U. The low-dose dexamethasone suppression test in chronic fatigue syndrome. Psychosom Med 2002; 64: 311–8.[Abstract/Free Full Text]
  59. Cleare AJ, Blair D, Chambers S, Wessely S. Urinary free cortisol in chronic fatigue syndrome. Am J Psychiatry 2001; 158: 641–3.[Abstract/Free Full Text]
  60. Scott LV, Dinan TG. The neuroendocrinology of chronic fatigue syndrome: focus on the hypothalamic-pituitary-adrenal axis. Funct Neurol 1999; 14: 3–11.[Medline]
  61. Hellhammer DH, Wade S. Endocrine correlates of stress vulnerability. Psychother Psychosom 1993; 60: 8–17.[Medline]
  62. Baker DG, West SA, Nicholson WE, Ekhator NN, Kasckow JW, Hill KK, Bruce AB, Orth DN, Geracioti TD Jr. Serial CSF: corticotropin-releasing hormone levels and adrenocortical activity in combat veterans with posttraumatic stress disorder [published erratum appears in Am J Psychiatry 1999 Jun;156:986]. Am J Psychiatry 1999; 156: 585–8.[Abstract/Free Full Text]
  63. Nemeroff CB, Widerlov E, Bissette G, Walleus H, Karlsson I, Eklund K, Kilts CD, Loosen PT, Vale W. Elevated concentrations of CSF corticotropin-releasing factor–like immunoreactivity in depressed patients. Science 1984; 226: 1342–4.[Abstract/Free Full Text]
  64. Sharpe M, Hawton K, Clements A, Cowen PJ. Increased brain serotonin function in men with chronic fatigue syndrome. BMJ 1997; 315: 164–5.[Free Full Text]
  65. Davis LL, Clark DM, Kramer GL, Moeller FG, Petty F. D-Fenfluramine challenge in posttraumatic stress disorder. Biol Psychiatry 1999; 45: 928–30.[CrossRef][Medline]
  66. Geracioti TD Jr, Loosen PT, Orth DN. Low cerebrospinal fluid corticotropin-releasing hormone concentrations in eucortisolemic depression. Biol Psychiatry 1997; 42: 165–74.[CrossRef][Medline]
  67. Joseph-Vanderpool JR, Rosenthal NE, Chrousos GP, Wehr TA, Skwerer R, Kasper S, Gold PW. Abnormal pituitary-adrenal responses to corticotropin-releasing hormone in patients with seasonal affective disorder: clinical and pathophysiological implications. J Clin Endocrinol Metab 1991; 72: 1382–7.[Abstract]
  68. Stratakis CA, Chrousos GP. Neuroendocrinology and pathophysiology of the stress system. Ann N Y Acad Sci 1995; 771: 1–18.[Abstract]
  69. Magiakou MA, Mastorakos G, Rabin D, Dubbert B, Gold PW, Chrousos GP. Hypothalamic corticotropin-releasing hormone suppression during the postpartum period: implications for the increase in psychiatric manifestations at this time. J Clin Endocrinol Metab 1996; 81: 1912–7.[Abstract]
  70. Dorn LD, Burgess ES, Dubbert B, Simpson SE, Friedman T, Kling M, Gold PW, Chrousos GP. Psychopathology in patients with endogenous Cushing’s syndrome: ‘atypical’ or melancholic features. Clin Endocrinol (Oxf) 1995; 43: 433–42.[Medline]
  71. Heim C, Ehlert U, Hellhammer DH. The potential role of hypocortisolism in the pathophysiology of stress-related bodily disorders. Psychoneuroendocrinology 2000; 25: 1–35.[CrossRef][Medline]
  72. Yehuda R, Giller EL, Southwick SM, Lowy MT, Mason JW. Hypothalamic-pituitary-adrenal dysfunction in posttraumatic stress disorder. Biol Psychiatry 1991; 30: 1031–48.[CrossRef][Medline]
  73. Liberzon I, Abelson JL, Flagel SB, Raz J, Young EA. Neuroendocrine and psychophysiologic responses in PTSD: a symptom provocation study. Neuropsychopharmacology 1999; 21: 40–50.[CrossRef][Medline]
  74. De Kloet ER, Vreugdenhil E, Oitzl MS, Joels M. Brain corticosteroid receptor balance in health and disease. Endocr Rev 1998; 19: 269–301.[Abstract/Free Full Text]
  75. Francis D, Diorio J, LaPlante P, Weaver S, Seckl JR, Meaney MJ. The role of early environmental events in regulating neuroendocrine development: moms, pups, stress, and glucocorticoid receptors. Ann N Y Acad Sci 1996; 794: 136–52.[Medline]
  76. Gold PW, Chrousos GP. The endocrinology of melancholic and atypical depression: relation to neurocircuitry and somatic consequences. Proc Assoc Am Physicians 1999; 111: 22–34.[CrossRef][Medline]
  77. Clauw DJ, Chrousos GP. Chronic pain and fatigue syndromes: overlapping clinical and neuroendocrine features and potential pathogenic mechanisms. Neuroimmunomodulation 1997; 4: 134–53.[Medline]
  78. Adler GK. Exercise and fatigue—is neuroendocrinology an important factor? J Clin Endocrinol Metab 2000; 85: 2167–9.[Free Full Text]
  79. Cleare AJ, Heap E, Malhi GS, Wessely S, O’Keane V, Miell J. Low-dose hydrocortisone in chronic fatigue syndrome: a randomised crossover trial. Lancet 1999; 353: 455–8.[CrossRef][Medline]
  80. Visser J, Blauw B, Hinloopen B, Brommer E, de Kloet ER, Kluft C, Nagelkerken L. CD4 T lymphocytes from patients with chronic fatigue syndrome have decreased interferon-gamma production and increased sensitivity to dexamethasone. J Infect Dis 1998; 177: 451–4.[Medline]
  81. Salit IE. Precipitating factors for the chronic fatigue syndrome. J Psychiatr Res 1997; 31: 59–65.[CrossRef][Medline]
  82. Leese G, Chattington P, Fraser W, Vora J, Edwards R, Williams G. Short-term night-shift working mimics the pituitary-adrenocortical dysfunction in chronic fatigue syndrome. J Clin Endocrinol Metab 1996; 81: 1867–70.[Abstract]



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