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When not enough is too much: the role of insufficient glucocorticoid signaling in the pathophysiology of stress-related disorders.

Raison CL, Miller AH.
When not enough is too much: the role of insufficient glucocorticoid signaling in the pathophysiology of stress-related disorders.
American Journal of Psychiatry. 2003;160:1554-1565.

Summary

Emory University Department of Psychiatry and Behavioral Sciences faculty who are also members of the CDC/Emory University Collaborative CFS Research Program published this article under partial support of the CFS research program. The collaborative CFS Research Program is exploring the contribution of immune activation and dysfunction of regulatory neuroendocrine pathways to the pathophysiology of CFS. This article reviews current status of knowledge concerning glucocorticoid activity and neuroendocrine function.

Abstract

Objective: Previous theories have emphasized the role of excessive glucocorticoid activity in the pathology of chronic stress. Nevertheless, insufficient glucocorticoid signaling (resulting from decreased hormone bioavailability or reduced hormone sensitivity) may have equally devastating effects on bodily function. Such effects may be related in part to the role of glucocorticoids in restraining activation of the immune system and other components of the stress response, including the sympathetic nervous system (SNS) and corticotropin-releasing hormone (CRH).

Method: The literature on neuroendocrine function and glucocorticoid-relevant pathologies in stress-related neuropsychiatric disorders, including posttraumatic stress disorder and major depression was reviewed.

Results: Although not occurring together, both hypocortisolism and reduced responsiveness to glucocorticoids (as determined by dexamethasone challenge tests) were reliably found. Stress-related neuropsychiatric disorders were also associated with immune system activation/inflammation, high SNS tone, and CRH hypersecretion, which are all consistent with insufficient glucocorticoid-mediated regulation of stress hyperresponsiveness. Finally, antidepressants, a mainstay in the treatment of stress-related disorders, were regularly associated with evidence of enhanced glucocorticoid signaling.

Conclusions: Neuroendocrine data provide evidence of insufficient glucocorticoid signaling in stress-related neuropsychiatric disorders. Impaired feedback regulation of relevant stress responses, especially immune activation/inflammation, may, in turn, contribute to stress-related pathology, including alterations in behavior, insulin sensitivity, bone metabolism, and acquired immune responses. From an evolutionary perspective, reduced glucocorticoid signaling, whether achieved at the level of the hormone or its receptor, may foster immune readiness and increased arousal. Emphasis on insufficient glucocorticoid signaling in stress-related pathology encourages development of therapeutic strategies to enhance glucocorticoid signaling pathways.

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