Journal of Psychosomatic Research 56 (2004) 419 424

Associations between neuroendocrine responses to the Insulin Tolerance Test and patient characteristics in chronic fatigue syndrome
Jens Gaab *, Veronika Engert, Vera Heitz, Tanja Schad, Thomas H. Schu rmeyer, Ulrike Ehlert 1
Center for Psychobiological and Psychosomatic Research, University of Trier, Germany Received 9 April 2002; accepted 11 September 2002

Abstract Objective: Subtle dysregulations of the hypothalamic pituitary adrenal (HPA) axis have been proposed as an underlying pathophysiological mechanism in chronic fatigue syndrome (CFS). This study attempted to assess the relationship between patient characteristics and HPA axis functioning using a neuroendocrine challenge test. Method: A test battery designed to assess different dimensions of CFS was given to 18 CFS patients and 17 controls. To evaluate the integrity of the HPA axis, the Insulin Tolerance Test (ITT), a centrally acting neuroendocrine challenge test, was performed on patients and controls. ACTH, salivary free cortisol and total plasma cortisol levels were assessed as a measure of the HPA axis stress response. Correlations of patient characteristics were calculated with integrated responses for all endocrine parameters. Results: CFS patients had a significantly reduced area under the ACTH response curve (AUC) in the ITT. The AUC was significantly associated with the duration of CFS symptoms (r = .592, P = .005) and the severity of fatigue symptomatology (r = .41, P = .045). In addition, duration of CFS was correlated with the severity of fatigue symptoms (r = .38, P = .045). Similar associations were not observed for cortisol parameters. Conclusion: It has been postulated that neuroendocrine dysregulations observed in CFS are of an acquired nature. The results of a strong association between the integrated ACTH response and the duration of CFS emphasizes the need to consider factors known to be risk factors for the chronicity of CFS symptoms, such as profound inactivity, deconditioning and sleep abnormalities, as possible candidates for secondary causes of neuroendocrine dysregulations in CFS. D 2004 Elsevier Inc. All rights reserved.

Keywords: Chronic Fatigue Syndrome; HPA axis; Cortisol; ACTH, CRH, Symptoms; Inactivity; Duration; Depression; Anxiety

Introduction Chronic fatigue syndrome (CFS) is characterized by severe and disabling fatigue and fatigability, and an array of accompanying symptoms [1]. Its etiology is still subject to controversy, but given the multitude of conspicuous physiological and psychological findings that have been reported, it seems unlikely that CFS represents a unidimensional disease entity. For this reason, the need for an integrative approach to CFS has been articulated [2]. Several multidimensional illness models have been proposed, linking psychological factors, such as stress and psychiatric
* Corresponding author. Current address: Institute for Psychology, Clinical Psychology and Psychotherapy, University of Zu rich, Zu richbergstr. 43, CH-8044 Zu rich, Switzerland. Tel.: +41-1-6343096; fax: +411-6343696. E-mail address: jgaab@psychologie.unizh.ch (J. Gaab). 1 Current address: Institute for Psychology, Clinical Psychology II, 0022-3999/04/$ see front matter D 2004 Elsevier Inc. All rights reserved. doi:10.1016/S0022-3999(03)00625-1

illness, with immune [3,4] and endocrine [5] abnormalities frequently described in CFS patients. As it is highly adaptive to internal and external circumstances and is also of great importance for the regulation of several physiological systems, the hypothalamus pituitary adrenal (HPA) axis offers the possibility to link psychological and physiological findings in CFS. Subtle HPA axis dysregulations, probably of central origin, have been repeatedly reported (for review, see Ref. [6]). Furthermore, a diminished secretion of HPA axis hormones, such as cortisol and corticotropin releasing hormone (CRH), has been linked to CFS symptomatology [7]. According to a recent multidimensional illness model of CFS [8], cumulative life stress and psychiatric morbidity might result in an inability to mount an adequate HPA axis response to a stressor (i.e. an infection), and subsequently to an attenuation of regulatory or counter-regulatory effects of HPA axis hormones. These assumptions are substantiated by

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empirical studies [9,10] and qualitative observations [11]. However, little is known about how possible HPA axis dysregulations persist. Several risk factors for chronicity of the syndrome have been identified, such as psychiatric illness, a somatic subjective illness model and avoidance of exercise and activity [12,13]. In addition, sleep dysregulations are common in CFS patients and may contribute to the symptoms reported [14]. All of these risk factors have been related to HPA axis dysregulations in CFS patients [8]. However, very few studies have examined the association between patient characteristics and hormonal variables in CFS patients. For example, Demitrack et al. [15] observed a significant positive correlation between evening basal adrenocorticotropic hormone (ACTH) levels and patients selfassessed fatigue in CFS patients. Based on the assumptions that these risk factors contribute to the chronicity of the syndrome and that HPA axis dysregulations are associated with CFS symptomatology and regarding the fact that little is known about whether observed HPA axis dysregulations in CFS patients are related on the one hand to patient characteristics and on the other hand to CFS symptoms, we assessed the associations between psychological morbidity, symptom severity, CFS duration and the extent of neuroendocrine dysregulations in CFS patients using a centrally acting stress paradigm.

and Statistical Manual of Mental Health Disorders, 4th edition [17] and a semistructured CFS interview, which concerned the severity and course of all symptoms required by the US and UK definitions [1,16]. All patients fulfilled US and UK consensus criteria for the diagnosis of CFS [1,16]. Patients were matched for age and gender with healthy volunteer controls, randomly recruited via telephone calls. Controls were medication-free and underwent comprehensive medical examination for past and current health problems. Control subjects were screened for any current or lifetime psychiatric symptoms or disorders by a clinical psychologist (JG). After subjects were provided with complete written and oral descriptions of the study, written informed consent was obtained. The study sample is part of a larger CFS patient cohort. The previous results of this cohort have been published elsewhere [18,19]. Procedure The Insulin Tolerance Test (ITT) is considered the gold standard for testing the integrity of the entire HPA axis [20]. Subjects were asked to fast overnight and the ITT began at 9 a.m. All subjects arrived 60 min before the ITT. They were taken into a separate room where a venous catheter was inserted and kept patent with a lock. After a 45-min resting period, a basal sample of blood glucose and endocrine parameters was taken and an intravenous bolus injection of 0.15 U/kg soluble insulin (H-Insulin Hoechst) was given. Blood glucose, ACTH, plasma total cortisol (PC) and salivary free cortisol (SC) samples were collected 20, 30, 45, 60, 90 and 120 min after the injection. Measures Sampling methods and biochemical analyses Ethylenediamine tetraacetate blood samples were spun immediately at 4jC and stored at 20jC 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. It was then stored at 20jC until biochemical analysis was carried out. ACTH and PC were measured with two-site commercial chemiluminescence assays (CLIA, 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 [21]. Inter- and intra-assay coefficients of variance were below 10% for all analytes. Psychometric measures and patient characteristics To assess the severity of the most prominent CFS symptom, subjects completed a German translation of the Fatigue Scale (FS) [22]. The FS is an 11-item self-report measure developed to assess fatigue. It consists of two

Methods Subjects The study was approved by the Ethical Committee of the Medical Council of Rheinland-Pfalz, Germany. Patients were contacted through a German self-help organization. Interested parties received a postal screening questionnaire, containing all symptoms required by the US and UK definitions of CFS [1,16]. Patients fulfilling the symptom requirements in this screening questionnaire were interviewed over the telephone and asked to disclose any diagnosed medical illnesses and psychiatric disorders. Prospective participants were only excluded from the study if they had received a medical or psychiatric diagnosis defined as an exclusion criterion by the US definition [1]. Selection criteria for participation in the study were fulfillment of CFS symptom criteria in the postal screening questionnaire, new or definite onset of CFS, age between 30 and 50, no current antidepressant, anxiolytic, antibiotic, antihypertensive and steroid medication and no medical cause for the chronic fatigue in routine laboratory testing. All patients were medically examined by the same physician (THS), according to recommendation [1]. They were also interviewed by a trained psychologist (JG). This consisted of a computer-aided standardized and structured diagnostic interview in accordance with the Diagnostical

J. Gaab et al. / Journal of Psychosomatic Research 56 (2004) 419424 Table 1 Demographic and psychometric characteristics of CFS patients and healthy controls CFS Sex (male/female) Age (years)a BMIa 10/8 Controls 10/7 Test v2 = 0.04; P = .85

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Results Sample characteristics Gender ratio, number of subjects, mean age, and body mass index (BMI) did not differ significantly between the groups (Table 1). Mean duration of patients symptoms was 64.0 months, with a range from 17 to 168 months. Fourteen CFS patients reported an infectious onset of their symptoms. All patients reported onset of symptoms within 3 months. Eighteen CFS patients and 17 controls underwent the ITT. The HADS, SCL-90R, and SIP scores of the CFS group were significantly higher than those of the control group and comparable to reported scores in previous studies. One CFS patient fulfilled the criteria for a current episode of Major Depression. However, since the exclusion of this subject did not alter the results of the analysis, the patient was included in the reported analysis. None of the controls reported any current or lifetime psychiatric disorder. CFS patients had significantly higher FS total scores [CFS 26.0 (1.1) vs. controls: 10.1 (0.6)]. Integrated endocrine responses in the ITT Groups differed in baseline levels of ACTH [ F(1/33) = 5.65, P = .02], but not for plasma [ F(1/33) = 0.05, P = .82] or salivary cortisol [ F(1/33) = 0.73, P = .40]. In comparison to healthy controls matched for age and gender, CFS patients had a significantly reduced integrated ACTH response in the ITT [ F(1/32) = 4.92, P = .03] (Fig. 1). No significant differences were found for plasma total [ F(1/32) = 0.73, P = .40] and salivary free cortisol [ F(1/32) = 2.12, P = .15]. Associations between endocrine responses and patient characteristics To test for significant associations between patient characteristics and the extent of neuroendocrine alterations

35.4 (30 47) 36.4 (29 44) t(32) = 0.63; P = .53 22.7 24.4 t(32) = 1.43; P = .16 (17.6 26.8) (18.1 34.6) HADSb F(2/32) = 18.9; P < .001 Depression 7.3 (0.8) 1.1 (0.3) F(1/33) = 36.4; P < .001 Anxiety 6.3 (0.9) 2.5 (0.4) F(1/33) = 11.65; P = .002 SCL-90Rb F(2/32) = 8.92; P < 0.001 Anxiety 58.8 (2.1) 44.1 (1.5) F(1/33) = 29.3; P < .001 Phobic anxiety 53.7 (2.9) 45.1 (1.4) F(1/33) = 7.2; P = .01 Depression 60.3 (2.3) 43.0 (1.7) F(1/33) = 19.7; P < .001 Somatization 72.5 (2.6) 45.4 (1.5) F(1/33) = 90.1; P < 0.001 SIPb F(6/28) = 9.00; P < .001 Home 11.4 (2.5) 0.00 (0.0) F(1/33) = 34.5; P < .001 management Ambulation 6.4 (1.3) 0.00 (0.0) F(1/33) = 14.8; P < .001 Mobility 7.8 (2.1) 0.33 (0.2) F(1/33) = 9.7; P < 0.001 Alertness 33.7 (4.4) 0.00 (0.0) F(1/33) = 41.0; P < .001 behavior Sleep and rest 29.0 (4.2) 0.00 (0.0) F(1/33) = 26.1; P < .001 Social 16.7 (2.4) 0.94 (0.4) F(1/33) = 34.5; P < .001 Interaction
a b

Mean (range). Mean (S.E.M.).

scales which assess physical and mental fatigue. We used a 0, 1, 2, 3 scoring system and calculated a total score. An internal consistency (Cronbachs alpha) of a = 0.96 for the total score has been calculated on a larger CFS population (N = 193) (Gaab et al., unpublished data). Also, all subjects completed a battery of questionnaires including the Sickness Impact Profile (SIP) [23], the Hospital Anxiety and Depression Scale (HADS), measuring symptoms occurring during the last week [24] and the Symptom Checklist (SCL-90R), assessing symptoms experienced during the last 4 weeks [25]. All latter scales have been evaluated on German patient populations, with good validity and reliability. Duration of CFS was assessed in months since onset. Statistical analysis v2 analysis was used to test for significant differences in discrete variables. ANOVAs and ANCOVAs with endocrine baseline values as covariates were computed to analyze endocrine parameters between groups. Correlations were computed as Pearson product moment correlations. For all endocrine parameters, areas under the total response curve (AUC), 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 Levenes test before statistical procedures were applied. For all analyses, significance levels were a = 5%. Unless indicated all results shown are meansFstandard error of means (S.E.M.).

Fig. 1. Integrated ACTH of CFS patients (gray) and controls (black) in the ITT.

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Table 2 Pearsons correlation ( P values are in parentheses) between patient characteristics and integrated endocrine responses AUC of ACTH response Duration of CFS FS total score HADS Depression scale HADS Anxiety scale SIP total score .59 (.005) .41 (.045) .53 (.014) .63 (.003) .29 (.12) AUC of PC response .10 (.34) .11 (.34) .09 (.36) .12 (.32) .38 (.32) AUC of SC response .06 (.41) .12 (.32) .31 (.11) .15 (.27) .32 (.09)

observed in CFS patients, indicated by the AUC of the ACTH, the plasma total (PC) and salivary free cortisol (SC) responses in the ITT, Pearson correlation coefficients were calculated (Table 2). Integrated responses of ACTH in the ITT were strongly associated with the duration of CFS (r = .59, P = .005). Correlations between both cortisol responses in the ITT and duration of CFS in months since onset were not significant. A significant negative association also existed between the severity of fatigue symptoms and the integrated ACTH response in the ITT (r = .41, P = .045). Similar to previous results, correlations between the AUCs of cortisol responses and the FS total score were not significant. Significant negative correlations were observed between the scores of the Depression and the Anxiety scale of the HADS and the integrated ACTH response in the ITT (r = .52, P = .014 and r = .63, P = .003). Cortisol parameters were not significantly correlated with the HADS scores. The extent of the functional impairment, as operationalized by the SIP total score, was not significantly associated with any endocrine parameter. In addition, duration of CFS was positively correlated with the severity of fatigue symptoms, indicated by the FS total score (r = .38, P = .045).

Discussion This study set out to assess the possible associations between patient characteristics and neuroendocrine dysregulations in CFS. In comparison to healthy controls matched for age and gender, CFS patients had a clearly reduced integrated ACTH response to the insulin challenge. However, cortisol responses were normal in CFS patients. This concurs with a postulated central origin of HPA axis dysregulations (i.e. a deficient CRH secretion), and a compensatory up-regulation of adrenal sensitivity [15]. The extent of the observed neuroendocrine dysregulation was strongly associated with the duration of CFS symptoms. Although the cross-sectional and correlative nature of this analysis cautions against a causal interpretation, we assume that the longer the respective patient has CFS, the more pronounced the attenuation of the ACTH response in

the ITT becomes. Furthermore, fatigue symptom severity was positively associated with the AUC of the ACTH response in the ITT and the duration of CFS. Also, we observed a strong negative correlation between the extent of depression and anxiety and the AUC of the ACTH response in the ITT. Interestingly, there were no associations between cortisol parameters and the described patient characteristics. Hypocortisolism has been discussed to be a possible endocrine correlate of medically unexplained symptoms, such as fatigue and pain [26]. Also, the administration of low doses of hydrocortisone has been shown to have some benefit in CFS patients [27]. Clearly, the role of cortisol in CFS needs further study. Patients for this study were recruited through a self-help organization. It is possible that this constitutes a selection bias and that therefore our sample differs from those used in other studies. Although we have not selected for patients without psychiatric comorbidity, the observed low psychiatric comorbidity in our sample could be the result of a selection bias. Given that self-help groups advocate a somatic etiology of CFS, it is possible that differences in the attribution of symptoms experienced partly explains the low number of psychiatric disorders in our sample, since an attribution to a biological cause seems to protect against psychological distress [28,29]. Also, unless our results are confirmed by studies using different patient samples (e.g. from primary or secondary care), the representativeness of our results cannot unrestrictively be assumed. Our findings confirm the assumptions of a psychoneuroendocrine model of CFS, with a central deficit of the HPA axis being related on the one hand to the severity of clinical symptoms and on the other hand to patient characteristics [8]. We observed a medium-sized correlation between symptom severity and the extent of the ACTH response, but no such association existed for cortisol parameters. Hypothalamic CRH is the principal modulator of the adaptive stress response, directly and indirectly coordinating adaptive autonomic, endocrine, immune, and behavioral stress responses. A deficient CRH secretion has been linked to chronic pain and fatigue syndromes [30,31] and atypical depressive symptoms, such as hypersomnia and anergia [32]. A diminished responsivity of pituitary corticotrophs has been observed after prolonged hypercortisolism [33]. However, hypercortisolism does not seem to be responsible for the diminished ACTH response in the ITT, as basal and reactive cortisol levels have been found to be normal [19] or reduced [34]. Because the responsivity of pituitary corticotrophs gradually improves after the normalization of high cortisol levels [33] and CFS is not characterized by hypercortisolism, the reduced ACTH response in the ITT could be explained by a permanent suppression of hypothalamic CRH secretion in CFS, for example, due to permanently enhanced negative feedback [18]. Our finding of a high correlation between the duration of illness and integrated ACTH response in the ITT is consistent with the

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assumption of a hyporesponsive pituitary due to prolonged insufficient central priming [15]. It has been postulated that neuroendocrine dysregulations observed in CFS are of an acquired nature, most likely the consequences of traumatic and/or chronic stress [26]. While our finding of a strong association between the integrated ACTH response and the duration of CFS does not refute this assumption, it emphasizes the need to consider other factors known to be risk factors for the chronicity of CFS symptoms, such as psychological morbidity, profound inactivity, deconditioning, and sleep abnormalities. The finding of a strong negative association between anxiety and depression levels and observed ACTH response seems counterintuitive at first, since depressive and certain anxiety disorders have been associated with hyperresponsiveness of central stress systems [7]. However, the HADS anxiety and depression scores observed in our sample are not indicative for clinically relevant depression or anxiety and thus could also be considered as indicators for psychological distress. Given that the HPA axis is highly adaptive to perceived stressors, it is possible that the observed negative correlation is a consequence of perceived distress. For example, Vedhara et al. [35] observed a clear reduction in basal HPA axis activity in students undergoing an exam in comparison to the same population during a non-exam period. With regard to the possible influence of sleep problems on HPA axis functioning, Leese et al. [36], comparing endocrine responses to a CRH challenge test after night shift and day shift work, reported an attenuated integrated area under the response curve for both ACTH and cortisol after the night shift work. Similarly, a selective deprivation of Stage 4 sleep resulted in the experience of musculoskeletal pain, a symptom frequently experienced in CFS patients [37]. CFS patients often complain of sleep problems [38] and are frequently found to have objectively diagnosable sleep disorders [39]. The duration of CFS is of relevance for the development of physical deconditioning, which in its own right leads to many physiological abnormalities seen in CFS patients [40]. Almost all CFS patients report a profound reduction in activity levels compared to premorbid activity levels [11,41] and low levels of activity has been shown to be related to severe fatigue in CFS patients [42]. Prolonged bed rest and inactivity have been shown to have detrimental effects on normal physiological functioning [43 45] and treatments directed against rest and towards moderate and gradual increase in activity have shown to be of benefit in CFS [46]. Interestingly, it has been shown that the level of physical fitness influences the HPA axis activity (i.e. highly trained runners show HPA axis alterations consistent with mild hypercortisolism) [47,48]. In comparison to endurance trained subjects, sedentary men show attenuated absolute integrated ACTH responses to exercise [49]. Also, overtrained athletes, experiencing generalized apathy, lethargy and change of sleep pattern, had attenuated HPA axis responses to the ITT, which normalized with recovery [50].

Since sleep problems, inactivity and physical deconditioning are considered risk factors for chronicity and also influence HPA axis functioning, it seems possible that the observed strong association between the extent of endocrine dysregulation observed in CFS patients and the duration of symptoms is a consequence of this interaction. Given the cross-sectional design of the study, the small sample size and the correlational analysis, causal interpretations between the reported associations are clearly not feasible. Furthermore, we have not assessed physical activity, sleep problems, and physical fitness in our patients. Further prospective studies with a larger sample size and an inclusion of these factors are therefore necessary to clarify matters.

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