Hypothalamic-pituitary-adrenal (HPA) axis dysfunction has been found in a high proportion of chronic fatigue syndrome (CFS) patients and includes enhanced corticosteroid-induced negative feedback, basal hypocortisolism, attenuated diurnal variation, and a reduced responsivity to challenge. A putative causal role for genetic profile, childhood trauma, and oxidative stress has been considered. In addition, the impact of gender is demonstrated by the increased frequency of HPA axis dysregulation in females. Despite the temporal relationship, it is not yet established whether the endocrine dysregulation is causal, consequent, or an epiphenomenon of the disorder. Nonetheless, given the interindividual variation in the effectiveness of existing biological and psychological treatments, the need for novel treatment strategies such as those which target the HPA axis is clear. 1. Introduction Chronic fatigue syndrome (CFS) is a debilitating illness which was classified as a neurological disease in 1993 by the World Health Organisation (WHO) [1]. Symptoms of CFS include persistent fatigue, difficulty with memory and concentration, a disturbed sleep pattern, and severe muscular-skeletal pain [2]. Post exertional exacerbation of symptoms is common but not invariable [3]. The symptoms displayed vary markedly from patient to patient; some patients remain bedridden for very long periods of time, while others are able to manage their fatigue by staying within their own energy boundaries [4]. Diagnostic reliability is enhanced by the use of operational criteria such the Centre for Disease Control and Prevention Criteria [5], the Oxford Criteria [6] or the International Consensus Criteria [7, 8]. However, the heterogeneous symptom profile and absence of clear biological markers militate against confidence in the validity of CFS as a unitary diagnosis. It is not known, for instance, whether there is a core set of biological processes which underlie all cases of CFS or whether there are multiple processes (and if so, whether or not these potentially disparate processes converge on a final common pathway) [9]. Dysregulation of the biological systems which mediate the response to stress potentially has an important role in the aetiopathogenesis of CFS [1, 4, 10]. The neurobiological stress system comprises a range of networks that form intricate pathways; an important part of this is the hypothalamic-pituitary-adrenal (HPA) axis [11–14] which is a self-regulated feedback system which contributes to the maintenance of homeostasis and which is impacted by multiple factors such
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