Hypocortisolism is a frequent finding in individuals with chronic fatigue syndrome (CFS) with other research findings implying potential dysregulation of glucocorticoid signaling.
Glucocorticoid signaling is under the influence of several pathways, several of which are of interest in the study of CFS. Oxidative stress and decreased antioxidant capacity are known to disrupt the hypothalamic–pituitary–adrenal (HPA) axis (Epel et al., 2004) and the presence of histone deacetylases (HDAC) could also impact glucocorticoid signaling. The intent of this pilot study was to investigate the relationship among oxidative stress elements, select HDAC’s (2/3) and glucocorticoid receptor signaling in an elderly sample with CFS. Findings suggest increased histone deacetylase activity, lower total antioxidant power, in the context of decreased plasma cortisol and increased plasma dehydroepiandrosterone concomitant with decreased expression of the encoding gene for the glucocorticoid receptor. These findings support the presence of HPA axis dysregulation in elderly individuals with CFS.
In adult populations, dysregulation of the hypothalamic–pituitary–adrenal (HPA) axis is associated with chronic fatigue syndrome (CFS), suggesting an altered physiological response to stress (Johnson and DeLuca, 2005). Several studies have implicated glucocorticoid regulation with CFS, with a range of findings demonstrating that adults with CFS display lower levels of cortisol (Cleare, 2003 and Gaab et al., 2002), a possible lack of responsiveness on the part of the HPA axis to challenge (Dinan et al., 1997), a pattern of glucocorticoid resistance (Kavelaars et al., 2000), and disruption or dysregulation of the expected diurnal cortisol pattern among patients with CFS (Torres-Harding et al., 2008). Previously, we found decreased genetic expression of the glucocorticoid receptor (NR3C1) concomitant with low levels of plasma cortisol in those with CFS (Jason et al., 2010). The presence of decreased message in the face of decreased hormone led to a conceptualization of epigenetic dysregulation of GR signaling. Based on the literature, we concluded that HDAC’s were the most likely culprit. This pilot study was designed to test that belief.
Histone deacetylases (HDAC) are a group of enzymes with pronounced effects on gene regulation. These enzymes inhibit gene regulation through removal of acetyl groups, which ultimately decreases gene transcription (Yuan et al., 2009). This mechanism of action is the primary means through which glucocorticoids exert effects. HDAC’s appear to be recruited by glucocorticoids, and in turn suppress the encoding of inflammatory genes contributing to the overall anti-inflammatory action of glucocorticoid (Adenuga and Rahman, 2007). An increase in HDAC activity, in the presence of decreased glucocorticoid concentrations may reflect a dysregulation of pathway signaling that could contribute to a chronic pro-inflammatory state. While HDAC activity may suppress inflammation through effects on the NFκB pathway, elements of oxidative stress may still be able to initiate inflammation through effects on the activator protein-1 pathway (Rahman, 2003). Differential pathway activation may explain the divergent immunologic findings observed in those with CFS. Oxidative stress, a state of chronic inflammation, may decrease expression of HDAC providing a mechanism through which inflammatory processes can influence the expression of HDAC, thus influencing the expression of other genes and influencing cell proliferation. It is also possible that the activity of HDAC’s are reduced in certain disease states (Barnes, 2006). It is then important to investigate the relationship between oxidative stress and HDAC in those with CFS.
A close link between decreased glucocorticoid sensitivity and oxidative stress has been extensively described (Adcock et al., 2005), that could be applicable to CFS. Oxidative stress is linked with glucocorticoid resistance by affecting several aspects of GR activation and function including reduced GR nuclear transport (Okamoto et al., 1999), reduced GR transcription via decreases in histone deacetylase (HDAC) activity (Adcock et al., 2005) and decreased expression of glucocorticoid regulatory genes.
The primary intent of this pilot study was to determine the baseline characteristic of gene expression as it affects a discrete component of the HPA axis in a geriatric population with CFS. Specific hypotheses included that individuals with CFS would exhibit: (1) decreased expression of NR3C1 concomitant with decreased levels of plasma cortisol; (2) increased expression and activity on the part of class I HDAC’s. Plasma DHEA and total antioxidant power were evaluated in order to evaluate other variables that may influence cortisol secretion in this population.
