When not enough is too much: the role of insufficient glucocorticoid signaling in the pathophysiology of stress-related disorders
Raison CL and Miller AH;
Commented by , 30 Sep 2003
Aim of the study
To review the evidence for insufficient glucocorticoid signaling in the pathophysiology of stress-related disorders.
Method
A review (114 references) of the literature on the neuroendocrinology of stress and stress-related disorders, regarding in particular studies on:
(1) target tissues and systems whose function is regulated by glucocorticoids, such as the immune system, the sympathetic nervous system (SNS) and corticotropin-releasing hormone (CRH) pathways
(2) pathologies associated with stress that have been attributed to glucocorticoid excess, such as volumetric changes in the brain, insulin resistance and diabetes, osteoporosis, and behavioural alterations, and
(3) effects of antidepressants on glucocorticoid signaling.
Results
(1) Evidence for insufficiency of glucocorticoid signaling on target systems include reports on immune activation in major depression and in posttraumatic stress disorder (PTSD), increased CSF and plasma concentrations of catecholamines in patients with major depression and PTSD, and hyperactivity of CRH pathways in patients with major depression and PTSD.
(2) Recent studies concerning the effect of glucocorticoids on key brain structures, on glucose metabolism, on osteoporosis and on a syndrome called “sickness behavior” in stress-related disorders have led to conflicting results, suggesting that these pathologies may be linked to either glucocorticoid excess or insufficiency. In particular, damage to the brain, altered glucose metabolism, osteoporosis and “sickness behavior” may be linked to unrestrained inflammation and increased release of proinflammatory cytokines (as a result of insufficient glucocorticoid signaling.
(3) There is consistent evidence that successful treatment with antidepressants (the treatment of choice in stress-related disorders) is associated with normalization of insufficient glucocorticoid signaling.
Discussion
There are currently two main theories concerning the pathophysiology of stress-related psychiatric disorders. The first theory (the “glucocorticoid cascade hypothesis”) privileges the direct pathological potential of glucocorticoides in the development of stress-related disorders.
According to this theory, ongoing stress produces a prolonged overproduction of glucocorticoides, prolonged overproduction of glucocorticodes damages brain structures that are involved in the restraint of the hypothalamic-pituitary-adrenal (HPA) axis, decreased restraint of the HPH axis continues to drive glucocorticoid overproduction, prolonged overproduction of glucocorticoides leads to the behavioural and neurobiological consequences of stress.
The second theory (the “insufficient glucocorticoid signaling hypothesis”) privileges the pathological potential of insufficient glucocorticoid signaling in the development of stress-related disorders, either through hypocortisolism or through reduced responsiveness to glucocorticoids.
According to this second theory, decreased availability of glucocorticoids or decreased glucocorticoid responsiveness activate stress-responsive systems such as the immune system, the sympathetic nervous system (SNS) and the corticotropin-releasing hormone (CRH) pathways, and the activation of these systems leads to the behavioural and neurobiological consequences of stress.
This is an excellent review on a fascinating, controversial topic. The authors present a state of the art summary of currently available data concerning the role of glucocorticoids in stress-related disorders and discuss investigations that emphasize the significance of insufficient glucocorticoid signaling in the pathogenesis of these disorders.
The article is of major importance for all those who try to understand, research or treat PTSD and other stress-related disorders.