Neuroendocrine response to CRF stimulation in veterans with and without PTSD in consideration of war zone era

Background: Alterations in hypothalamic-pituitary-adrenal (HPA) axis activity have been observed in Gulf War veterans with posttraumatic stress disorder (PTSD) which differ from those observed in other veteran groups, raising the possibility that there is a unique neuroendocrine profile in this group of veterans. This study seeks to further characterize the effects of PTSD, military cohort (Vietnam, 1991 Gulf War, Operations Enduring Freedom/Iraqi Freedom (OEF/OIF)), and their interaction on the neuroendocrine response to synthetic corticotrophin-releasing factor (CRF) stimulation. Methods: 51 male veterans were studied consisting of 21 from the Vietnam era, 16 from the Gulf War era, and 14 from the OEF/OIF era. 16 of these veterans were deployed to a war zone and had chronic PTSD (PTSD+), 25 were deployed to a war zone and did not have chronic PTSD (PTSD-), and 10 were not deployed to a war zone and did not have PTSD (non-exposed). The participants underwent the CRF stimulation test in the afternoon (approximately 2:00 p.m.), which measures the integrity and sensitivity of the pituitary-adrenal axis. Plasma cortisol and adrenocorticotropic hormone (ACTH) were measured at baseline and at intervals over a 2. h period following intravenous administration of 1μg/kg of ovine CRF (o-CRF, max 100μg). In a small subset of participants, dehydroepiandrosterone (DHEA) and cortisol binding globulin (CBG) were also assessed. Results: There was a significant group by era interaction in the response of ACTH to CRF, in addition to a main effect of group (PTSD+, PTSD-, non-exposed). The interaction reflected that group differences were only evident in the Gulf War cohort; among Gulf War era veterans, the PTSD+ group had higher elevations in ACTH levels following CRF than the PTSD- group and the non-exposed group. Additionally, the peak change in ACTH was associated with a self-reported environmental exposure (pyridostigmine bromide ingestion) which has been found to be linked to the excess morbidity found in Gulf War veterans. Self-reported childhood trauma was greater in veterans of the Gulf War than Vietnam or OEF/OIF, but did not account for the observed differences. There was a significant effect of group on the cortisol response to CRF, reflecting greater responsivity in both of the deployed groups (PTSD+ and PTSD-) compared to the non-exposed group which could be accounted for by baseline differences in cortisol levels; unlike the ACTH response, the cortisol response did not differ by era. There were no effects of group, era, or their interaction on the DHEA and CBG response to CRF. Conclusions: A uniform pattern of PTSD-related alterations in the response to intravenous CRF was not found. Rather, PTSD-related alterations were found only in veterans of the 1991 Gulf War, and were characterized by an enhanced pituitary response to CRF which may reflect increased sensitivity of pituitary corticotrophs or CRF hyposecretion. Together with previous neuroendocrine findings, the data suggest the HPA axis is dysregulated in Gulf War veterans in unique ways which may reflect the long-term effects of environmental exposures in addition to disease effects. Further work is needed to characterize these effects and their impact on long-term psychological and medical outcomes.