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 – pitui- tary –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 = À.592, P = .005) and the severity of fatigue symptomatology (r = À.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 unidimen- sional disease entity. For this reason, the need for an integrative approach to CFS has been articulated [2]. Sev- eral multidimensional illness models have been proposed, linking psychological factors, such as stress and psychiatric illness, with immune [3,4] and endocrine [5] abnormalities frequently described in CFS patients. As it is highly adaptive to internal and external circum- stances and is also of great importance for the regulation of several physiological systems, the hypothalamus–pitui- tary–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]). Further- more, 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 0022-3999/04/$ – see front matter D 2004 Elsevier Inc. All rights reserved. doi:10.1016/S0022-3999(03)00625-1 * Corresponding author. Current address: Institute for Psychology, Clinical Psychology and Psychotherapy, University of Zu ¨rich, Zu ¨rich- bergstr. 43, CH-8044 Zu ¨rich, Switzerland. Tel.: +41-1-6343096; fax: +41- 1-6343696. E-mail address: jgaab@psychologie.unizh.ch (J. Gaab). 1 Current address: Institute for Psychology, Clinical Psychology II, Journal of Psychosomatic Research 56 (2004) 419 – 424