Alterations in cortisol negative feedback inhibition as examined using the ACTH response to cortisol administration in PTSD
Introduction
Although a greater ACTH decline in response to low doses of oral DEX (Yehuda et al., 2004) has been observed in PTSD, these findings have not been informative about central glucocorticoid responsiveness since DEX poorly penetrates the brain when administered peripherally, acting primarily on glucocorticoid receptors (GR) on the pituitary (Miller et al., 1992, Cole et al., 2000). In contrast, cortisol has preferential access to the brain and affects feedback inhibition in multiple locations by binding to both mineralocorticoid receptors (MR) and GR (de Kloet et al., 1975).
Understanding the extent to which alterations in negative feedback inhibition occur at the level of the pituitary versus the brain in PTSD is critical to evaluating the role of glucocorticoids in PTSD pathophysiology. That central and peripheral negative feedback effects are differentially regulated is implied by observations of CRF hypersecretion in the face of normal or lower plasma cortisol levels in PTSD (Baker et al., 1999), since stress-induced elevations in glucocorticoids would theoretically constrain both the release of ACTH from the pituitary and the release of CRH from the hypothalamus, and is further highlighted by the uniformity in negative feedback effects on the peripheral HPA target organs — the pituitary and the adrenal—under conditions of CRF hypersecretion. Indeed, low doses of DEX produce comparable suppression of ACTH and cortisol in subjects with and without PTSD (Yehuda et al., 2004). Some regionally specific negative feedback effects may be consequences of differences in binding to MR or heterologous regulatory peptides such as vasopressin, and/or neurotransmitters that act differentially at discrete target organs of the HPA (de Kloet et al., 1975). In the current study, we examined the effects of exogenous cortisol in PTSD using a randomized, double—blind design, based on the methodology developed in the study of depression and dementia (Gispen-de Wied et al., 1998, de Leon et al., 1997).
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Participants
Thirty-one male veterans (age range 52–79 years) provided written informed consent to participate in a study approved by the IRB of Mount Sinai and Bronx Veterans Affairs. Subjects in the PTSD (+) group met diagnostic criteria for current or lifetime PTSD and were free of substance abuse/dependence, bipolar disorder, or psychosis. Subjects in the PTSD (−) group were free from any Axis I disorder. All participants were without medical, or neurological illness. Two subjects were taking
Characteristics of the sample
Demographic and clinical characteristics of the sample are shown in Table 1. The groups were comparable in age, education, body mass index, and ages of their first, focal and most recent traumatic experience.
A higher proportion of subjects in the PTSD(+) group than the PTSD(−) group had experienced combat trauma (78% (n=14) vs. 31% (n=4); (X2=6.85; df=1, p=0.009). The PTSD(+) group had significantly higher rates of current (X2=3.32, df=1, p=0.07) and lifetime major depression (X2=14.85, df=1, p
Discussion
The greater ACTH decline in response to exogenous cortisol administration reflects augmented negative feedback inhibition in PTSD. Although there is no way of assessing the relative proportion of cortisol effects occurring on sites influencing negative feedback inhibition in brain vs. those occurring in the pituitary, the findings suggest there may be PTSD-related difference in central feedback inhibition. The presence of alterations in central feedback inhibition would provide support for the
Acknowledgements
This work was supported by a VA Merit Review Grant (RY), and, in part by a grant (5 M01 RR00071) for the Mount Sinai General Clinical Research Center from the National Institute of Health. In particular, Vivian Mitropoulou at the General Clinical Research Center assisted in the logistics of the project. The authors also wish to thank Karina Stavitsky for coordinating this study, Drs. Lisa Tischler, Ellen Labinsky, and Alicia Hirsch for providing psychiatric diagnostic assessments, Dr. Linda
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