Psychoneuroendocrinology (2014) 40, 151—158

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Cortisol response to cosyntropin administration in military veterans with or without posttraumatic stress disorder Julia A. Golier a,b,*, Kimberly Caramanica a, Iouri Makotkine a,b, Leo Sher a,b, Rachel Yehuda a,b a b

Departments of Psychiatry, James J. Peters VA Medical Center, Bronx, NY, United States Mount Sinai School of Medicine, New York, NY, United States

Received 4 June 2013; received in revised form 16 October 2013; accepted 23 October 2013

KEYWORDS Post-traumatic stress disorder (PTSD); Veterans; Cosyntropin; Cortisol; ACTH

Summary Studies have demonstrated altered sensitivity of the hypothalamic-pituitary-adrenal (HPA) axis to its direct regulators in veterans with posttraumatic stress disorder (PTSD), but little is known about the adrenal response to hormonal stimulation in PTSD. An increased cortisol response to synthetic corticotropin-releasing factor (CRF) was recently found to be associated with war-zone deployment and not PTSD specifically. To more accurately assess whether there is altered adrenocortical responsivity to hormonal stimulation in relation to war-zone deployment or PTSD, we performed the low-dose cosyntropin stimulation test in a sample of 45 male veterans: 13 war-zone exposed veterans with chronic PTSD (PTSD+), 22 war-zone exposed veterans without chronic PTSD (PTSD-), and 10 veterans not exposed to a war-zone and without chronic PTSD (nonexposed). Plasma cortisol and ACTH were measured at baseline and at intervals over a one hour period following intravenous administration of 1 mg of cosyntropin. A significant main effect of group (PTSD+, PTSD , non-exposed) on the cortisol response to cosyntropin was observed. Cosyntropin-stimulated plasma cortisol levels were significantly higher in the PTSD+ and PTSD groups compared to the non-exposed group. A significant main effect of group was also observed on peak cortisol levels. These findings suggest that war-zone exposure itself has persistent effects on adrenocortical activity. Published by Elsevier Ltd.

1. Introduction

* Corresponding author at: James J. Peters VA Medical Center, OOMH; 130 West Kingsbridge Road, Bronx, NY 10468, United States. Tel.: +1 718 584 9000x5196; fax: +1 718 741 4775. E-mail address: [email protected] (J.A. Golier). 0306-4530/$ — see front matter. Published by Elsevier Ltd. http://dx.doi.org/10.1016/j.psyneuen.2013.10.020

Increasing evidence suggests that long-term alterations in hypothalamic-pituitary-adrenal (HPA) axis activity are associated with stress and posttraumatic stress disorder (PTSD), and that these changes play an important role in the pathophysiology of PTSD. HPA axis function in veterans with PTSD appears to be more susceptible to both stimulatory and

152 inhibitory influences by its hormonal regulators; indeed, exaggerated cortisol levels have been found in response to stress challenges (Bremner et al., 2003; Elzinga et al., 2003). There is also consistent evidence for increased suppression of cortisol and adrenocorticotropic hormone (ACTH) to the synthetic glucocorticoid dexamethasone (DEX) (Yehuda et al., 1993, 1995; de Kloet et al., 2007). Acute administration of synthetic glucocorticoids has also been linked with exaggerated effects on learning and memory - both deleterious and beneficial (Grossman et al., 2006; Vythilingam et al., 2006; Yehuda et al., 2007). In peripheral assays, enhanced glucocorticoid sensitivity of lysozyme activity (Yehuda et al., 2004) and inflammatory cytokine production (Rohleder et al., 2004) has been described. Given that altered glucocorticoid sensitivity has been described in multiple target systems in PTSD, it is important to understand the factors that impact glucocorticoid release in this disorder and to characterize the full range of regulatory influences that impact HPA axis activity in PTSD. Studies of the effects of corticotropin-releasing factor (CRF) stimulation on cortisol and ACTH release in PTSD have shown mixed results. An initial study in veterans showed a reduced ACTH and cortisol response in combat veterans with chronic PTSD compared to normal volunteers (Smith et al., 1989); an exaggerated ACTH and cortisol response was found in premenopausal women with PTSD compared to healthy nontraumatized subjects (Rasmusson et al., 2001). In response to human corticotropin-releasing hormone (CRH), no difference in ACTH or cortisol was found in PTSD patients compared to healthy controls (Kellner et al., 2003). More recently, war-zone deployed veterans with and without PTSD showed an enhanced cortisol response to CRF compared to non-exposed veterans, suggesting a role of combat exposure in HPA axis reactivity (Golier et al., 2012). However, since there were also effects of military cohort on the ACTH response to CRF, it is not possible to isolate the effect of CRF on cortisol. Therefore, the cortisol response to direct stimulation with cosyntropin was examined to allow for a direct assessment of the adrenal response to pharmacologic manipulation (Magnotti and Shimshi, 2008; Hamilton and Cotton, 2010) in male war-zone exposed veterans with and without PTSD and non-exposed veterans without PTSD. The low-dose (1 mg) cosyntropin test (a 1-24 corticotropin, a synthetic subunit of ACTH) was used rather than the conventional-dose short test (250 mg), as we hypothesized that veterans with PTSD would have an enhanced cortisol response to cosyntropin based on the evidence of increased HPA axis sensitization in PTSD, including emerging molecular evidence of altered glucocorticoid sensitivity in PTSD (Binder et al., 2008; Yehuda et al., 2009).

2. Methods 2.1. Subjects This study was approved by the institutional review boards (IRBs) of the Bronx VA Medical Center and the Mount Sinai School of Medicine. 13 male war-zone exposed veterans with chronic PTSD (PTSD+) (6 Vietnam era veterans, 3 Gulf War era veterans, 4 OIF/OEF era veterans), 22 male war-zone exposed veterans without chronic PTSD (PTSD ) (12 Vietnam

J.A. Golier et al. era veterans, 7 Gulf War era veterans, 3 OIF/OEF era veterans), and 10 male veterans not exposed to a war-zone and without chronic PTSD (non-exposed) (4 Vietnam era veterans, 3 Gulf War era veterans, 3 OIF/OEF era veterans) were studied. Subjects were recruited through print advertising, clinical referral, and flyers in the Bronx VA Medical Center.

2.2. Clinical evaluations After providing written informed consent, subjects underwent a complete medical and psychiatric examination including administration of the Structured Clinical Interview for DSM-IV (SCID) (First et al., 1995) and the Clinician Administered PTSD Scale (CAPS) (Blake et al., 1995). Subjects who had a major medical or neurological illness, a lifetime history of schizophrenia, bipolar disorder or obsessive-compulsive disorder, current alcohol or substance abuse/dependence, who were morbidly obese (BMI > 40), smoked an average of more than 2 packs of cigarettes/day, or who were taking steroids, anti-histamines, opioids, oral hypoglycemic agents, insulin, or psychiatric medications were excluded. More than two-thirds of study participants were not taking any medication; the most commonly reported medications taken were non-opioid analgesics, anti-hypertensives, lipid-lowering medications, and proton-pump inhibitors. Participants with a history of previous hypersensitivity reactions to ACTH or with a history of allergic illnesses were also excluded. Self-reported environmental and combat exposures were obtained based on questionnaires developed for use in the study of Gulf War veterans (Rosenheck, 1992; Wolfe et al., 2002). Participants also completed the Combat Exposure Scale (CES), a 34-item self-report questionnaire (Lund et al., 1984) and the Expanded Health Symptoms Checklist which inquires about health symptoms in nine domains (cardiac, dermatologic, musculoskeletal, gastrointestinal, genitourinary, neurological, neuropsychological, psychological, and pulmonary) (Proctor et al., 1998).

2.3. Cosyntropin Administration Test The low-dose cosyntropin stimulation test was performed at the General Clinical Research Center (GCRC) at the Mount Sinai School of Medicine. Subjects were asked to have a light breakfast at 8:00 a.m. and to refrain from eating until after the procedure upon admission to the outpatient GCRC. After placement of an indwelling venous (i.v.) catheter and 30 min of accommodation, blood samples were drawn at time 30 and 0 min, following which 1 mg of cosyntropin (Cortrosyn1, Organon) was administered as an i.v. bolus at approximately 2:00 p.m. Blood was drawn at +10, 20, 30, 40, and 60 min and analyzed for cortisol and ACTH. For some subjects dehydroepiandrosterone (DHEA) (n = 28) and cortisol binding globulin (CBG) (n = 13) were measured at +0, 30, 60, and 90 min. Frequent sampling points were used to ensure that peak cortisol values were captured, as the peak cortisol level can occur earlier or later than the 30 min interval typically used for the standard test. Blood samples for hormonal analysis were collected in EDTA containing tubes, placed on ice, and spun at 400  g in 4 8C. After centrifugation, plasma was separated from the rest of the blood and immediately frozen at 70 8C until

Cosyntropin stimulation test in military veterans analysis. Plasma cortisol was determined using a commercially-available radioimmunoassay (RIA) kit (DiaSorin Inc., Stillwater, MN). The GammaCoat [125I] cortisol RIA kit procedure is based on the competitive binding principles. 10 mL of calibrators and unknown EDTA plasma samples were incubated with cortisol tracer in antibody-coated tubes. After incubation, the content of the tube was aspirated and the tube was counted in the Apex automatic gamma counter (ICN Micromedic) for one minute. A calibrator curve was prepared with five serum calibrators ranging from 1 to 60 mg/dL. Unknown values were interpolated from the calibration curve using AGC software. All samples were run in duplicate. The intra- and inter-assay coefficients of variation for cortisol were 2.3% and 6.1%, respectively; the detection limit was 0.2 mg/dL. ACTH levels were determined using a RIA kit from Nichols Institute Diagnostics (San Juan Capistrano, CA) based on the binding of antibodies with high affinity and specificity for defined amino acid regions of the ACTH molecule. The intraand inter-assay coefficients of variation were 4.7% and 7.1% for ACTH, respectively. The detection limit for ACTH RIA assay was 1.0 pg/mL. Plasma DHEA was determined by aRIA kit from Diagnostic Systems Laboratories (Webster, TX). The procedure follows the basic principal of radioimmunoassay whereby there is competition between a radioactive and non-radioactive antigen for a fixed number of antibody binding sites. The amount of [125I] labeled DHEA bound to the antibody is inversely proportional to the concentration of DHEA present. After incubation of EDTA plasma with DHEA tracer in antibodycoated tubes at 37 8C for 2 h, the content of the tubes was decanted and the tubes were counted in the Apex automatic gamma counter (ICN Micromedic) for 1 min. Unknown values were interpolated from the calibration curve using AGC software. All samples were run in duplicate. The detection limit was 0.02 ng/ml and the intra- and inter-assay variability was 3.6% and 6.1%, respectively. Plasma CBG was determined by aRIA kit from ImmunoBiological Laboratories, Inc (Minneapolis, MN). A fixed amount of [125I] labeled CBG competes with the CBG to be measured in the sample or in the calibrator for a fixed amount of anti-CBG antibody sites, which are bound to the goat anti mouse (GAM) antibodies immobilized to the wall of a polystyrene tube. EDTA plasma samples (100 mL) were diluted 25 times in dilution buffer. After 2 h incubation at room temperature, an aspiration step terminates the competition reaction. The tubes were then washed with 2 ml of working wash solution and aspirated again. The tubes were counted in the Apex automatic gamma counter (ICN Micromedic) for 1 min. A calibration curve was plotted and the CBG concentrations of the samples were determined by dose interpolation from the calibration curve. The concentrations read on the calibration curve for the samples and controls were multiplied by 25 (dilution factor). All samples were run in duplicate. The detection limit was 0.25 mg/ml and the intraand inter-assay variability was 8.6% and 10.6%, respectively.

2.4. Statistical analysis Repeated measures ANCOVA was performed to examine the effect of time, group (PTSD+, PTSD , non-exposed), and combat era (Vietnam, Gulf, OIF/OEF) on the cortisol, ACTH,

153 DHEA, and CBG responses to cosyntropin. The main analyses of group and era were performed by ANCOVA on the cortisol and ACTH response to cosyntropin. In addition, peak and minimum post-cosyntropin cortisol and ACTH levels and cortisol and ACTH area under the curve (AUC) from baseline (T0) to T+60 were derived. The ratio of cortisol to ACTH for the change from baseline to T+60 was also calculated. Potential covariates (age, race, education, and BMI) were tested for their relationship to the cortisol and ACTH response to cosyntropin; race and BMI were found to have a significant interaction with time for the dependent cosyntropin response and were therefore included in the analyses. Although age at study entry was not associated with group, it was associated with combat era and was controlled for in our analyses. For all analyses involving hormone levels race, BMI, and age were used as covariates.

3. Results As shown in Table 1, the three groups did not differ significantly on multiple sociodemographic characteristics. As expected, the three groups did differ on self-reported measures of depression (Beck Depression Inventory (BDI)), combat exposure (Combat Exposure Scale (CES)), and eight of the nine domains derived from the Expanded Health Symptoms Checklist, with the PTSD+ group reporting more depressive and physical health symptoms than the PTSD- and nonexposed groups. Data on the neuroendocrine response to cosyntropin are found in Table 2. As can be observed in Fig. 1, there was an increase in cortisol levels in all three groups following the administration of cosyntropin. Based on repeated measures ANCOVA, there was a main effect of group on the cortisol response to cosyntropin (F(2,33) = 6.46, p = 0.004) and no significant interaction of group with time (F(6.50,107.18) = 1.52, p = 0.173) or a group by time by era interaction (F(12.99,107.18) = 0.99, p = 0.466). By post hoc testing, cortisol levels were significantly higher in the PTSD+ (adjusted mean (SE) 17.40 (1.52)) and PTSD (20.22 (1.13)) groups compared to the non-exposed group (13.26 (1.60), p’s = 0.036 and 0.001, respectively); no difference in stimulated cortisol levels were observed between the PTSD+ and PTSD group ( p = 0.137). In particular, there were significant group differences at baseline (T0) (F(2,33) = 3.34, p = 0.048), T+10 (F(2,33) = 6.65, p = 0.004), T+20 (F(2,33) = 11.30, p < 0.001), and T+30 (F(2,33) = 4.80, p = 0.015), but not at T+40 (F(2,33) = 3.21, p = 0.053) or T+60 (F(2,33) = 0.61, p = 0.551). The group differences in cortisol are not likely explained by differences in CBG (Fig. 2); in the subsample in whom it was measured (n = 13), there were no group differences in CBG at baseline (F(2,3) = 0.11, p = 0.899) and there was no effect of group (F(2,3) = 0.05, p = 0.951), era (F(2,3) = 0.62, p = 0.596), or an interaction of group by era (F(2,3) = 0.96, p = 0.477) on CBG in response to cosyntropin. There was also a significant main effect of group (F(2,33) = 6.07, p = 0.006) on peak cortisol levels. The adjusted mean peak cortisol levels were 21.65 (2.31) for those in the PTSD+ group, 27.02 (1.71) in the PTSD group, and 16.76 (2.43) for veterans in the non-exposed group. Peak cortisol levels were significantly higher in the PTSD group compared to the non-exposed group ( p = 0.001); differences

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Table 1

Baseline sociodemographic and self-reported physical and mental health characteristics. War-zone exposed

Age (yrs) Education (yrs) BMI Race African-American Caucasian Military Rank Enlisted NCO Officer Marital status Single Married/Living together Separated/divorced Widowed Employment status Full time Part time Unemployed Service Era Vietnam Gulf War OIF/OEF Beck Depression Inventory (BDI) Total Score Childhood Trauma Questionnaire (CTQ) Total Score Combat Exposure Scale (CES) Total Score Expanded Health Symptoms Checklist Cardiac Dermatologic Musculoskeletal Gastrointestinal Genitourinary Neurological Neuropsychological Psychological Pulmonary 1 2 3

Non war-zone exposed

PTSD+ (n = 13)

PTSD (n = 22)

PTSD (n = 10)

43.5 (13.9) 13.0 (3.3) 27.9 (5.3)

50.2 (11.3) 14.7 (2.8) 28.1 (4.4)

43.2 (12.2) 14.7 (2.8) 28.3 (4.9)

46.2% (n = 6) 53.8% (n = 7)

22.7% (n = 5) 77.3% (n = 17)

50.0% (n = 5) 50.0% (n = 5)

61.5% (n = 8) 30.8% (n = 4) 7.7% (n = 1)

31.8% (n = 7) 50.0% (n = 11) 13.6% (n = 3)

50.0% (n = 5) 40.0% (n = 4) 10.0% (n = 1)

15.4% 46.2% 30.8% 7.7%

27.3% 50.0% 22.7% 0.0%

40.0% 30.0% 30.0% 0.0%

Group difference

NS NS NS NS

NS

NS (n = 2) (n = 6) (n = 4) (n = 1)

(n = 6) (n = 11) (n = 5) (n = 0)

(n = 4) (n = 3) (n = 3) (n = 0) NS

38.5% (n = 5) 0.0% (n = 0) 61.5% (n = 8)

45.5% (n = 10) 9.1% (n = 2) 45.5% (n = 10)

60.0% (n = 6) 10.0% (n = 1) 30.0% (n = 3)

46.2% (n = 6) 23.1% (n = 3) 30.8% (n = 4)

54.5% (n = 12) 31.8% (n = 7) 13.6% (n = 3)

40.0% (n = 4) 30.0% (n = 3) 30.0% (n = 3)

NS

Cortisol response to cosyntropin administration in military veterans with or without posttraumatic stress disorder.

Studies have demonstrated altered sensitivity of the hypothalamic-pituitary-adrenal (HPA) axis to its direct regulators in veterans with posttraumatic...
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