Review article
Meta-analysis and meta-regression of hypothalamic-pituitary-adrenal axis activity in functional somatic disorders

https://doi.org/10.1016/j.biopsycho.2011.02.002Get rights and content

Abstract

Dysfunction of the hypothalamic-pituitary-adrenal (HPA) axis is the most investigated biological risk marker in functional somatic disorders (FSDs), such as chronic fatigue syndrome (CFS), fibromyalgia (FM), and irritable bowel syndrome (IBS). Our aim was to assess whether there is an association between basal hypocortisolism and FSD and to identify potential moderators of this association. Meta-analysis on 85 studies revealed that although basal cortisol levels were generally lower in FSD subjects compared to controls, this association did not reach statistical significance (SMD −0.07, 95% CI −0.17 to 0.04, p = 0.241). However, when the three FSD were assessed separately, statistically significant basal hypocortisolism was observed in CFS subjects compared to controls (SMD −0.14, 95% CI −0.28 to 0.00, p = 0.047), but not in FM or IBS. When all potential moderators were entered into a meta-regression analysis, only type of FSD and female gender were significant independent predictors of basal hypocortisolism. In conclusion, we did not find evidence to consider all three main FSD as hypocortisolemic disorders, as significant reduction in basal cortisol compared to healthy controls was only found in CFS and in females with FM, but not in IBS.

Research highlights

► Functional somatic disorders are often referred to as hypocortisolemic disorders. ► In this meta-analysis, we compared cortisol levels of patients with controls. ► Hypocortisolism was only observed in subjects with chronic fatigue syndrome. ► Hypocortisolism was not observerd in subjects with fibromyalgia or irritable bowel syndrome. ► Meta-regression revealed that female gender independently predicts hypocortisolism.

Introduction

Functional somatic disorders (FSDs) are syndromes of related physical complaints without known underlying conventional organic pathology. The main three disorders are chronic fatigue syndrome (CFS), fibromyalgia (FM), and irritable bowel syndrome (IBS); other examples include temporomandibular joint dysfunction, multiple chemical sensitivity and chronic pelvic pain (Wessely et al., 1999). Different FSD share a lot of similarities, for example in case definition and reported symptoms, but also in non-symptom specific associations such as sex, prognosis and response to treatment (Wessely et al., 1999). However, there are also disease-specific characteristics, including specific infections and premorbid levels of distress that may differentially precipitate FSD (Moss-Morris and Spence, 2006). Shared factors might underlie general susceptibility for the development of any FSD, whereas factors specific to individual FSD might shape their final manifestation (Aggarwal et al., 2006, Kato et al., 2009).

HPA axis dysfunction, the most widely investigated biological factor in the etiology of FSD, is one potential shared factor, as alterations in this stress responsive system have been reported for all main FSD (Tak and Rosmalen, 2007). A potential etiological link between the HPA axis and FSD emerges from the potential of HPA axis underactivity to increase symptoms through mechanisms such as increasing pain perception and causing fatigue (Lariviere and Melzack, 2000, Heim et al., 2000, Fries et al., 2005, Fabian et al., 2009). Some even already refer to FSD as hypocortisolemic disorders (Fries, 2008). However, narrative reviews conclude that findings on cortisol levels in CFS, FM, and IBS subjects compared to healthy controls are inconsistent: as well as mild hypocortisolism, normal or increased cortisol levels have also been reported (Mayer et al., 2001, Geenen et al., 2002, Cleare, 2003, Tak and Rosmalen, 2007). It remains to be elucidated why the presence of HPA axis alterations varies both within and among FSD. Moreover, if FSD are really characterized by HPA axis dysfunction, its position in the etiological pathway, if causally linked at all, is still elusive (Tak and Rosmalen, 2010). The idea of HPA axis dysfunction as a mediator between psychosocial stress and FSD has often been advanced, which is supported by the observation that retrospective psychosocial stress has been consistently associated with FSD (Barsky and Borus, 1999, van Houdenhove et al., 2005, Aggarwal et al., 2006, Deary et al., 2007) and has the capacity to induce hypocortisolism in the long-term (Ehlert et al., 2001, Miller et al., 2007, McEwen, 2007). However, HPA axis alterations could also be a consequence of factors such as concurrent stress, sleep disturbances, alcohol use, smoking, obesity, medication use, co-morbid depressive disorder, or physical inactivity (Geenen et al., 2002, Cleare, 2003). Twenty years of research has given rise to conflicting findings, suggesting a need for a systematic meta-analysis of previous research.

The primary purpose of this meta-analysis is to quantify the association between basal HPA axis function and FSD. We hypothesize that FSD are characterized by basal hypocortisolism. Additionally, we hypothesize that HPA axis dysfunction is a shared factor for all main three FSD (i.e., CFS, FM and IBS) and basal hypocortisolism therefore manifests irrespective of the diagnostic label of CFS, FM, or IBS. A second goal is to identify potential moderators of the association between HPA axis dysfunction and FSD, including gender, medication use, co-morbid depressive disorder, and physical inactivity.

Section snippets

Search strategy

We restricted our meta-analysis to CFS, FM and IBS because exploring literature searches only yielded a sufficient number of primary studies for those three FSD. Relevant articles were identified by searching the databases of Medline, Embase, and PsycINFO (January 1960–November 2009). A search string was formulated for searching Medline. The first component consisted of chronic fatigue syndrome, fibromyalgia, irritable bowel syndrome, and synonyms. The second component consisted of the terms

Search results and study characteristics

In total, we included 82 references, in which 85 case–control comparisons between FSD subjects and healthy controls were made (see Appendix B). Four of those 85 comparisons did not provide means and standard deviations and were therefore not included in the primary meta-analysis (Yatham et al., 1995, Strickland et al., 1998, Malt et al., 2002, Burr et al., 2009). Table 2 lists the 85 available comparisons, which together included 2148 FSD subjects and 1988 healthy controls. Forty studies

Discussion

The aims of this study were to assess whether FSD are characterized by HPA axis alterations and, if present, to examine by which variables this association is moderated. A meta-analysis of 85 studies demonstrated that baseline cortisol levels were not significantly different in FSD subjects as a whole compared to healthy controls, but were significantly lower in CFS when FSD were considered separately. Female gender, medication use, and presence of co-morbid depressive disorder were moderators

Conflict of interest

All authors declare that there are no conflicts of interest.

Acknowledgements

LMT is supported by a grant from the Nicolaas Mulerius Fund. AJC and SW are supported by the NIHR Biomedical Research Center at the South London and Maudsley NHS Foundation Trust and the Institute of Psychiatry (King's College, London). JGMR is supported by a VENI grant from the Netherlands Organisation for Scientific Research (grant 016.056.064). These organisations had no role in design and conduct of the study; collection, management, analysis, and interpretation of the data; and

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      However, the state of research on cortisol concentrations in medically unexplained symptoms is inconclusive. In functional somatic syndromes, a meta-analysis has found that certain subgroups of affected individuals, namely individuals with chronic fatigue syndrome or fibromyalgia syndrome (specifically women), had lower cortisol concentrations when compared to healthy controls, whereas others, namely those with irritable bowel syndrome, did not (Tak et al., 2011). Investigations into somatoform disorder, the DSM-IV predecessor of somatic symptom disorder, are scarce and have yielded contradictory findings: In one study, individuals with an abridged form of somatisation disorder had higher morning cortisol levels than healthy controls (Rief et al., 1998); in a second study by the same authors, neither diurnal nor nocturnal cortisol differed between individuals with abridged somatisation disorder and controls (Rief and Auer, 2000); in a third study, individuals with somatoform disorders had lower diurnal cortisol levels than healthy controls (Pedrosa Gil et al., 2008).

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