While elevated GCs have become almost synonymous with “stress,” there is increasing evidence (Fries et al., 2005; Gunnar and Vazquez, 2006) that chronic stress (i.e. prolonged, repeated elevations in GCs and CRH drive on the pituitary) results in hypocortisolism --specifically, low early morning levels of cortisol and blunted ACTH and cortisol responses to stressors. Notably, evidence from the rodent indicates that hyporeactivity of the HPA axis to stressors immediately following chronic stress is more often observed to psychological as opposed to systemic (e.g. viral) stressors (Ostrander et al., 2006). This suggests the hypothesis that some aspects of hypocortisolism, specifically hyporeactivity to stressors, may be organized via impacts on limbic regulatory pathways and is a signature of chronic psychosocial stress (Fries et al., 2005). Prolonged or repeated elevations in glucocorticoids can have opposing effects on hypothalamic (down-regulation) and extra-hypothalamic (up-regulation) CRH (see review, Rosen and Schulkin, 1998). In addition, prolonged hypothalamic CRH drive on the pituitary can down-regulate pituitary sensitivity to ACTH. The result can be low cortisol basal production in the context of increased sensitivity of the amygdala/extended amygdala system (Yehuda, 2000).
