Does hypothalamic–pituitary–adrenal axis hypofunction in chronic fatigue syndrome reflect a ‘crash’ in the stress system?
Introduction
Chronic fatigue syndrome (CFS) consists of medically unexplained, incapacitating and persisting physical and mental fatigue, increased fatigability and widespread pain [1]. Although the condition remains an etiopathogenetic enigma [2], [3], [4], during the past decade more than a dozen of studies have provided evidence for HPA axis hypofunction in a substantial proportion of CFS patients. Particularly mild hypocortisolism (low to normal cortisol levels), blunted adrenocorticotropic hormone (ACTH) responses in challenge tests, and enhanced negative glucocorticoid feedback have been consistently demonstrated (see Ref. [5] for a review). More recent neuroendocrine CFS research, including population-based studies, came to largely similar conclusions [6], [7], [8], [9].
Given the symptomatic links between CFS and other hypocortisolism-based conditions (such as Addison’s disease) as well as the relative effectiveness of corticotherapy in CFS [5], it has been posited that HPA axis hypofunction may at least be involved in symptom propagation in CFS, even if the disturbances would be secondary to other factors [10], [11].
Yet, a crucial question remains whether this neuroendocrine dysregulation plays a role in the etiopathogenetic processes leading to the illness, or could be better viewed as a consequence of the illness, related to inadequate cognitions, attitudes and coping behaviours. In the following paragraphs, after critically reviewing the evidence for both viewpoints, we will formulate a comprehensive hypothesis on HPA axis hypofunction in CFS, that primarily reflects a fundamental and persistent dysregulation of the neurobiological stress system. Within a system-biological perspective, we will particularly focus on disturbances at the neuroendocrine–immune interface.
Section snippets
Is HPA axis hypofunction a consequence of CFS?
There is some evidence to suggest that neuroendocrine dysregulation in CFS is secondary. Indeed, changes in the HPA axis seem to be more pronounced the longer CFS exists [12], and HPA axis changes could not be detected in post-EBV infection and post-surgery patients who were fatigued at six months follow-up [13], [14]. However, the latter studies concerned broadly defined sub-acute or chronic fatigue, which may be different from more strictly defined CFS.
Furthermore, inadequate coping in CFS –
A vulnerability factor?
According to some authors, HPA axis hypofunction in CFS and other functional somatic syndromes may be based on a shared biological vulnerability with depression [22], e.g. via common genetically-determined impairment of stress response systems [23], [24]. However, this view is inherently problematic since depression includes melancholic and atypical subtypes, characterized by HPA axis hyper- and hypofunction, respectively [25], [26], [27].
The role of early adversities – though increasingly
CFS in a system-biological perspective
Although the evidence for all of the above views is insufficient, an HPA axis ‘switch’ in vulnerable individuals following prolonged physical and/or psychosocial stress seems to be a plausible etiopathogenetic hypothesis in CFS, from a clinical as well as research point of view. On the other hand, it should be acknowledged that a sharp ‘cause-or-consequence’ dichotomy cannot fully account for the complex neuroendocrine determination of the illness. A nonlinear or recursive way of
Diagnostic and therapeutic implications
Understanding CFS primarily as a dysregulation of the stress system may give impetus to current efforts to refine diagnostic criteria of the illness, by putting more emphasis on key-aspects of the patients’ illness experience, namely a dramatic loss of tolerance for all kinds of physical and mental load, including impaired recovery [73]. Moreover, this comprehensive, neurobiologically-based view on the etiopathogenesis of the illness could counterbalance tendencies to split up CFS into a
Research agenda
The above-described etiopathogenetic hypothesis on CFS may have important heuristic value, particularly since it may stimulate research on a dysregulated ‘crosstalk’ between the neuroendocrine and the immune system.
At the neuroendocrine side, further exploring long-term effects of – early and recent – life stress on HPA axis functioning seems to have high research priority. For example, large groups of CFS patients with and without well-defined childhood trauma, and with and without associated
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