Development of glucocorticoid resistance over one year among mothers of children newly diagnosed with cancer

Abstract

Chronic distress associates with peripheral release of cortisol and a parallel upregulation of innate inflammation. Typically, cortisol functions to down-regulate inflammatory processes. However, in the context of chronic stress, it is hypothesized that glucocorticoid receptors within immune cells become less sensitive to the anti-inflammatory effects of cortisol, resulting in increased systemic inflammation. Caring for a child newly diagnosed with cancer is a particularly provocative chronic stressor. Here, we examine evidence for the development of cellular resistance to glucocorticoids among 120 mothers (Aged 18-56 years; 86% Caucasian) across the 12 months following their child's new diagnosis with cancer. Measures of psychological distress, interleukin (IL)-6, and glucocorticoid resistance (GCR) were assessed 1, 6, and 12 months after the diagnosis. A latent factor for distress was derived from the covariation among symptoms of anxiety, depression, and post-traumatic stress. Latent change score models revealed a significant positive association between change in distress and change in GCR from 0 to 6 months, and 6 months-1 year. This finding provides initial evidence for a longitudinal association between change in maternal distress and change in GCR from the onset of a chronic stressor through one year. Although levels of IL-6 increased during the first six months after the child's diagnosis, the magnitude of this change was not related to change in distress or change in GCR. Given the possible health consequences of reduced immune sensitivity to glucocorticoids, future work should further explore this stress response and its clinical significance.

Caregiving alters immunity and stress hormones: a review of recent research

“…This implies that is it not the bioavailability of cortisol nor its receptor that is affected by caregiving but rather GR signalling/responsivity. Changes in distress over time among mothers of children newly diagnosed with cancer correlated with changes in glucocorticoid resistance over a 12-month period, particularly in those with increasing depression levels [14], which again illustrates the impact of the emotional response to caregiving not just the caregiving role itself. A commonly used model of the consequences of stress for cortisol is acute stress reactivity, generally studied in the context of a laboratory stress task as a predictor of future disease risk in those with exaggerated or low/blunted responses [32].…”

“…However, such consequences are not limited to older caregivers, but may be more apparent in those reporting high burden, or during specific stressful periods. For example, increased inflammatory cytokines have been shown to be specific to males with anxiety, high BMI, disrupted schedules, ages 30-39 years with high burden [12] and those with high grief in the presence of blame and anger [13] or in the 6-months post-diagnosis of a child with cancer in caregiving mothers [14], a particularly stressful period. In support of this idea about stressful time periods, not all markers of inflammation were raised among long-term caregivers [15] and in caregivers with low caregiving burden allostatic load (incorporating inflammatory markers) was lower than non-caregivers [16]; potentially indicating lower distress at less stressful periods.…”

“…Another important advancement is studies demonstrating altered glucocorticoid sensitivity, which influences inflammatory processes. In longitudinal studies, caregivers showed lower glucocorticoid receptor (GR) signaling [15] or increased glucocorticoid resistance [14] where no changes in cortisol itself were observed compared to controls. This implies that is it not the bioavailability of cortisol nor its receptor that is affected by caregiving but rather GR signalling/responsivity.…”

Mitochondrial respiratory capacity modulates LPS-induced inflammatory signatures in human blood

“…While mitochondria have been implicated as modulators as well as targets of LPS-induced inflammation in isolated macrophages ( Van den Bossche et al, 2016 ), our data illustrates a potential link between mitochondrial respiratory capacity and LPS sensitivity in human blood leukocytes. We speculate that changes in mitochondrial function could contribute to a small fraction glucocorticoid resistance in humans and animals chronically exposed to stress ( Niraula et al, 2018 ; Walsh et al, 2018 ), but testing this hypothesis requires further work.…”

Racial discrimination and leukocyte glucocorticoid sensitivity: Implications for birth timing

“…E. Miller, Cohen, & Ritchey, 2002; G. E. Miller, Gaudin, Zysk, & Chen, 2009; Powell et al, 2009; Walsh et al, 2017). Glucocorticoid sensitivity among stressed groups has been evaluated using several well-developed methods, including by identifying deviations from expected associations among in vivo glucocorticoid levels, cytokine levels, and patterns of leukocyte trafficking (e.g., Cohen et al, 2012; Cole, 2008; Cole, Mendoza, & Capitanio, 2009).…”