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Relationships Among Plasma Dehydroepiandrosterone Sulfate and Cortisol Levels, Symptoms of Dissociation, and Objective Performance in Humans Exposed to Acute Stress

Relationships Among Plasma Dehydroepiandrosterone Sulfate and Cortisol Levels, Symptoms of... ContextRecently, a growing body of research has provided evidence that dehydroepiandrosterone sulfate (DHEA-S) is involved in an organism's response to stress and that it may provide beneficial behavioral and neurotrophic effects.ObjectiveTo investigate plasma DHEA-S and cortisol levels, psychological symptoms of dissociation, and military performance.DesignProspective study.Setting and ParticipantsTwenty-five healthy subjects enrolled in military survival school.ResultsThe DHEA-S–cortisol ratios during stress were significantly higher in subjects who reported fewer symptoms of dissociation and exhibited superior military performance.ConclusionsThese data provide prospective, empirical evidence that the DHEA-S level is increased by acute stress in healthy humans and that the DHEA-S–cortisol ratio may index the degree to which an individual is buffered against the negative effects of stress.Dehydroepiandrosterone (DHEA) is an endogenous hormone secreted by the adrenal cortex in response to adrenocortiocotropin-releasing hormone (ACTH).Dehydroepiandrosterone and its sulfated derivative, DHEA-S, were originally thought to be produced in situ in brain tissue and were referred to as neurosteroids.At present, however, it is believed that the only source of brain DHEA-S is from the periphery.A growing body of research has provided evidence that DHEA-S is involved in an organism's response to stress and that it may provide beneficial behavioral and neurotrophic effects.In mice, DHEA-S release has been shown to be triggered by stress-induced release of ACTH and also exhibits memory-enhancing, antidepressant, anxiolytic, and antiaggression properties.Neuronal and glial survival and differentiation have also been shown to be enhanced by DHEA-S in dissociated cultures of mouse embryo brain and intact rats.Hippocampal neurotoxicity induced by corticosterone, oxidative stressors, and the glutamate agonist N-methyl-D-aspartate (NMDA) is prevented by DHEA-S.In addition, DHEA-S prevents corticosterone-induced performance decrements.Taken together, these findings suggest that DHEA-S may play a significant role in modulating vulnerability of the organism to negative consequences of stress.In humans, levels of DHEA-S peak around ages 20 to 25 years and then decline to values of 20% to 30% at approximately 70 to 80 years of age.Levels of DHEA-S are also reduced in a number of medical illnesses such as end-stage renal disease,liver disease,type 2 diabetes mellitus,coronary artery disease,and rheumatoid arthritis.Levels of DHEA-S have also been noted to be reduced in individuals with chronic fatigue syndrome,depression,anxiety,anorexia nervosa,and schizophrenia.In posttraumatic stress disorder (PTSD), levels of DHEA or DHEA-S have been variable. Levels have been noted to be increased in Israeli soldiers and Kosovo refugees with PTSD, but low in Kosovo refugees with PTSD who also had comorbid depression. Recently, increased release of DHEA was found in response to ACTH administration in women with PTSD but a negative relationship between the degree of ACTH-induced DHEA release and PTSD symptomatology (A.R., C.A.M., S.S., and D.C., unpublished data, 2004).Consistent with preclinical data regarding the balance of DHEA-S to glucocorticoid levels, the DHEA-S–cortisol ratio in humans has been significantly associated with the degree of functional impairmentor the response to clinical intervention.Taken together, these preclinical and clinical studies provide indirect evidence that the DHEA-S level and DHEA-S–cortisol ratio may play a role in modulating the impact of stress on a variety of processes in humans.The present study was designed to evaluate levels of DHEA-S and cortisol, the DHEA-S–cortisol ratio, and the relationship of these hormone indexes with stress-induced symptoms of dissociation and objective performance in military personnel participating in survival school training. Previous investigations have demonstrated that survival school represents a valid, reliable model for the study of acute, uncontrollable stress in humans.The results of these studies demonstrate that the stress experienced by subjects during survival school activates biological threat-response systems and elicits psychological symptoms of dissociation on a scale of magnitude comparable to the degree of arousal and dissociation noted in humans responding to real-world, threat-to-life experiences. Clinical studies have provided evidence that peritraumatic symptoms of dissociation represent a risk factor for the development of PTSDand that such symptoms are positively associated with the stress-induced release of glucocorticoids.On the basis of this and the preclinical and clinical literature suggesting that an increased DHEA-S–cortisol ratio may buffer against the negative impact of stress,we hypothesized that individuals with a higher DHEA-S–cortisol ratio during stress exposure would be protected from the negative impact of survival school stress as evidenced by fewer symptoms of dissociation and superior military performance.METHODSTwenty-six consecutively recruited active duty military personnel were the subjects of this study. One female subject was removed from the data set, resulting in a study population of 25. As designated by their military operational specialty, 8 subjects were naval aviators, and 17 were nonaviating marines. The mean age was 25 years (SD, 4.4 years). Six subjects (24%) were married, and 19 (76%) were single. The average number of years in the service was 4.6 (SD, 4.1).The methods used in this study have been reported in detail elsewhere.In brief, before enrollment in this investigation, each participant completed in-processing into the survival training course. Recruitment of subjects was conducted by the principal investigator (C.A.M.). All subjects gave written, informed consent. As per survival training course requirements, all subjects provided documentation of physical examination and medical and psychiatric clearance before enrollment. All subjects were free of illicit substances as documented by results of urine toxicologic screening.BASELINE ASSESSMENTFive days before stress exposure, baseline saliva samples were obtained at 4 PMon the second day of didactic (classroom) activities. Immediately following the collection of salivary samples, baseline plasma samples were collected by one of the current investigators and Vladimir Coric, MD. Baseline salivary samples were again collected at 7:45 AM. Subjects then completed a modified self-report version of the Clinician-Administered Dissociative States Scale (CADSS) to rate their symptoms of dissociation during the classroom phase.The CADSS assesses the frequency and intensity of state symptoms of dissociation. The items of the instrument are designed to assess how perceptually in touch (or out of touch) an individual is vis-à-vis his or her environment during specific conditions (nonstressed and stressed). Although some of the items on the scale ask about one's sense of physical self (eg, "Do you feel as if you are looking at things outside of your body?" and "Do you feel as if you are watching the situation as an observer or spectator?"), other items ask about cognitive or perceptual distortions (eg, "Do colors seem to be diminished in intensity?" "Do sounds almost disappear or become much stronger than you would have expected?" "Do you space out or in some way lose track of what is going on?" and "Do you see things as if you were in a tunnel, or looking through a wide-angle photographic lens?"). The self-report scale contains 19 items, each of which is rated by subjects on a Likert scale of 0 (not at all) to 4 (extremely). A total score of 76 is possible.STRESS SAMPLESAt the conclusion of the didactic phase of the training, soldiers participated in an experiential phase of survival training. During this phase, they were confined in a mock prisoner of war camp (POWC). In the POWC, each subject experienced various types of psychological stress. Broadly speaking, these included interrogations and problem-solving dilemmas designed to test the trainees' ability to use the information they learned during the didactic phase. As noted in previous publications,these interrogations result in robust increases in cortisol and catecholamine levels, heart rate, and subjective distress and significant reductions in testosterone level. During the POWC stage, subjects also underwent uniform food and sleep deprivation. Before interrogation stress, all subjects had been deprived of food for approximately 8 hours and were physically inactive. During the 30-minute exposure to interrogation stress, subjects remained standing and relatively immobile; they did not engage in exercise or physical exertion. Immediately after interrogation, subjects were moved to a second room identical in appearance to the first, where their blood and saliva samples were collected by the research team (C.A.M. and G.H.) between 4:30 and 5 PM. Subjects provided the saliva samples before the venipuncture. After this, subjects continued to undergo uniform sleep and food deprivation until their release from the POWC. All participants were monitored by the survival school medical staff during the POWC stage and received water on a uniform schedule.MILITARY PERFORMANCESurvival school instructors performed an objective appraisal of observable military-relevant performance of each participant during the POWC phase of survival school. These performance assessment scores are part of the survival school program and are not available to the public. The overall rating score, however, is designed to reflect how well a participant in training is able to demonstrate specific behaviors and problem-solving abilities while experiencing acute stress. The performance ratings are scored on a scale that ranges from 0 (no skills demonstrated) to a maximum score of 4 (excellent demonstration of skills). Because these performance scores were generated independent of the research team and the measures collected by the research team, they represent a double-blind opportunity to assess the relationship between operationally relevant military performance and the psychobiological measures that were of interest to the research team.RECOVERY SAMPLESTwenty-four hours after the conclusion of POWC stress, recovery plasma and saliva samples were collected in all subjects. Because of programmatic constraints within the Navy survival school program, the collection of recovery samples occurred at 7:45 AMand not 4 PMas in our previous investigations of the Army survival school program. In addition to providing blood and saliva samples, subjects once again completed the CADSS. Subjects were asked to complete the CADSS using the stress they experienced during the interrogation phase of the POWC as their reference point.Plasma samples were spun down in a refrigerated centrifuge, pipetted into microtubules, and frozen within 40 minutes of venipuncture. Samples were stored at −70°C from the time of initial collection until analyses were performed. Salivary samples were frozen and shipped with plasma samples to our laboratory within 24 hours of collection.SALIVARY CORTISOL ANALYSIS METHODSSaliva was collected in Salivette tubes (Sarstedt Inc, Newton, NC), centrifuged, and pipetted into two 1.5-mL plastic vials. The samples were shipped on dry ice to our laboratory and stored at −70°C until assayed. Salivary cortisol levels were analyzed by means of radioimmunoassay (IncStar Corp, Stillwater, Minn). The intra-assay and interassay coefficients of variation were 4.2% and 6.1%, respectively.PLASMA DHEA-S ANALYSIS METHODSFrozen plasma samples were used and processed in batch by means of DHEA-S commercial radioimmunoassay kits (Diagnostic Systems Laboratories, Inc, Webster, Tex). Determinations were performed on duplicate 10-mL plasma samples according to the manufacturer's recommendations, using supplied rabbit polyclonal anti-DHEA-S antibody–coated tubes. Plasma DHEA-S concentrations were measured with a sensitivity (detectability) of approximately 2 µg/dL and intra-assay and interassay coefficients of variation of 9% and 15%, respectively.DATA ANALYSISSeparate repeated-measures analyses of variance (ANOVAs) using the time factors baseline-stress and baseline-recovery were performed to detect whether exposure to stress significantly affected levels of plasma DHEA-S and plasma and salivary cortisol. To control for diurnal variation, the cortisol samples collected at the 4 PMpoint at baseline were compared with the cortisol samples collected at the stress time point. Similarly, the ANOVAs examining whether salivary cortisol levels had returned to the reference range after the conclusion of the training used the 7:45 AMsalivary cortisol samples, because these were closely associated with the time of saliva assessment on the day of recovery (7:45 AM).Pearson correlation analyses were used to evaluate the relationships among the assessed hormone levels (DHEA-S and cortisol) and the relationships among the hormones and the independent variables of age and weight.Spearman rank correlation analyses were used to compare the DHEA-S–salivary cortisol ratios from the baseline, stress, and recovery time points with psychological symptoms of dissociation (CADSS total scores) and military performance scores. Exploratory post hoc analyses were planned for individual CADSS items in the event that a significant relationship was observed between DHEA-S–cortisol ratios and CADSS total score.Finally, separate stepwise linear regression analyses were used to examine whether or how well the independent variables of age, rank, time in service, or the DHEA-S–salivary cortisol ratio would explain the variance in stress-induced symptoms of dissociation (the CADSS total score) and in objectively assessed military performance.RESULTSThe variables of age, rank, and time in the service did not contribute to variance in the hormone or the psychological data, and thus were removed from the analyses.PSYCHOLOGICAL MEASURESThe mean CADSS score at baseline was 1.0 (SD, 1.6), whereas the poststress CADSS score was 17.4 (SD, 13.0). This increase was statistically significant (F1,24= 40.8 [P<.001]). In the published literature this would be considered a moderate level of dissociation.MILITARY PERFORMANCE SCORESThe mean, objectively assessed military performance rating for subjects was 2.3 (SD, 0.7), with a range of 1.0 to 3.8.HORMONE VALUESCompared with baseline, there was a significant increase in DHEA-S level in response to stress (baseline, 27.81 µg/dL [SD, 11.06 µg/dL] [SI units {calculated with a conversion factor of 0.02714}, 0.755 µmol/L {SD, 0.30 µmol/L}]; stress, 60.12 µg/dL [SD, 26.15 µg/dL] [1.63 µmol/L {SD, 0.71 µmol/L}]; F1, 21= 76.1 [P<.001]), and it remained significantly increased compared with baseline at the recovery time point (27.81 µg/dL [SD, 11.06 µg/dL] [0.755 µmol/L {SD, 0.30 µmol/L}] vs 37.32 µg/dL [SD, 16.98 µg/dL] [1.01 µmol/L {SD, 0.46 µmol/L}]; F1,18= 22.4 [P<.001]). The DHEA-S values at recovery were significantly reduced compared with the stress time point (F1,17= 68.2 [P<.001]). Plasma cortisol level was also significantly increased by exposure to survival school stress and remained significantly elevated compared with baseline at the recovery time point (baseline, 8.6 µg/dL [237.3 nmol/L] [SD, 3.8 µg/dL {104.8 nmol/L}]; stress, 31.1 µg/dL [858.0 nmol/L] [SD, 5.8 µg/dL {160.0 nmol/L}]; recovery, 19.9 µg/dL [549.0 nmol/L] [SD, 7.0 µg/dL {193.1 nmol/L}]) (F1,22= 168.2 [P<.001] and F1,23= 55.8 [P<.001], baseline vs stress and baseline vs recovery, respectively). Similarly, compared with baseline levels, salivary cortisol level was significantly increased by exposure to survival school stress (baseline, 0.14 µg/dL [3.9 nmol/L] [SD, 0.04 µg/dL {1.1 nmol/L}]; stress, 0.87 µg/dL [24.0 nmol/L] [SD, 0.45 µg/dL {12.4 nmol/L}]) (F1,24= 62.5 [P<.001]). However, compared with baseline morning values, morning salivary cortisol levels collected at recovery (recovery value, 0.49 µg/dL [13.5 nmol/L] [SD, 0.20 µg/dL {5.5 nmol/L}]) tended to be significantly higher only at the recovery time point (F1,24= 3.7 [P= .06]).CORRELATION ANALYSESNo significant correlations were observed between plasma levels of DHEA-S and cortisol or between plasma levels of DHEA-S and salivary levels of cortisol at any of the assessment time points (baseline and stress or recovery). Similarly, Spearman rank correlation analyses did not reveal a significant correlation between plasma cortisol level and poststress CADSS scores (r= 0.16; P= .41). However, there was a significant positive relationship between salivary cortisol level during stress exposure and the poststress CADSS scores (r= 0.4; P<.05) and a trend for a significant negative relationship between stress-induced levels of DHEA-S and poststress CADSS scores (r= −0.4; P= .08). Finally, as shown in Figure 1, there was a significant negative correlation between the DHEA-S–salivary cortisol ratio during stress and the poststress CADSS scores (r= −0.63; P= .002).Figure 1.Correlation between dehydroepiandrosterone sulfate (DHEA-S)–cortisol ratio and stress-induced symptoms of dissociation in 22 healthy subjects enrolled in military survival school (R2= 0.29; Spearman ρ = −0.63 [P= .002]).Analysis of individual CADSS items indicated that there were significant negative relationships between the DHEA-S–salivary cortisol ratio during stress and CADSS items 2 (feeling unreal as if in a dream; r= −0.44; [P<.04]), 6 (feeling disconnected from one's body; r= −0.54 [P= .009]), 10 (colors appearing to be diminished in intensity; r= −0.6 [P= .004]), 11 (feeling as if one is viewing the world in a tunnel or looking through a wide-angle lens; r= −0.6 [P= .003]), 15 (feelings of being spaced out or of losing track of what is going on; r= −0.44 [P= .04]), 16 (sounds disappearing or becoming much stronger than expected; r= −0.51 [P= .01]), 17 (things having a special sense of clarity; r= −0.49 [P= .02]), and 18 (feeling as if one is looking at world as if in a fog, people appearing far away or unclear; r= −0.72 [P<.001]).With regard to the relationship between objective military performance and the indexes of DHEA-S and cortisol levels and dissociation, as shown in Figure 2, there was a significant positive correlation between the DHEA-S–salivary cortisol ratio during stress and the military performance scores (r= 0.61 [P= .008]) and a significant negative correlation between stress-induced levels of salivary cortisol and military performance (r= −0.51 [P<.01]). In addition, and similar to the findings of our previous investigations, there was a significant negative relationship between stress-induced symptoms of dissociation (CADSS scores) and military performance (r= −0.51 [P<.01]).Figure 2.Correlation between dehydroepiandrosterone sulfate (DHEA-S)–cortisol ratio during stress and military performance in 18 healthy subjects enrolled in military survival school (R2= 0.37; Spearman ρ = 5.2 P= .03]).No significant relationships were observed between baseline hormone values, recovery hormone values, DHEA-S–cortisol ratios at baseline or at recovery, and the outcome measures of dissociative symptoms and military performance scores in response to stress.REGRESSION ANALYSESStepwise linear regression analysis using poststress CADSS dissociation scores as the dependent variable and the DHEA-S–salivary cortisol ratio and plasma levels of DHEA-S and cortisol during stress as the independent variables showed that the model was significant (F1,19= 7 [P= .02]). The adjusted multivariate coefficient of determination (R2) for the model was 0.24 for the predictor DHEA-S–salivary cortisol ratio during stress. The model did not improve when the variables plasma levels of DHEA-S and cortisol during stress were added. The standardized β coefficient value for DHEA-S–salivary cortisol ratio during stress was −0.53, with a tvalue of −2.6 (P= .02).Stepwise linear regression analysis using military performance scores as the dependent variable and the DHEA-S–salivary cortisol ratio and plasma levels of DHEA-S and cortisol during stress as the independent variables showed that the model was significant (F1,16= 5.6 [P= .03]). The adjusted multivariate coefficient of determination (R2) for the model was 0.23 for the predictor DHEA-S–salivary cortisol ratio during stress. The model did not improve when the variable plasma level of DHEA-S or cortisol during stress was added. The standardized β coefficient value for DHEA-S–salivary cortisol ratio during stress was 0.52, with a tvalue of 2.4 (P= .03).COMMENTThe principal finding of this study is that individuals with a higher DHEA-S–salivary cortisol ratio during stress experienced fewer symptoms of dissociation and exhibited superior military performance. Because indexes of dissociation and military performance presumably index central processes, the data herein provide support that in healthy humans, the ratio or balance between circulating levels of DHEA-S to unbound cortisol may help buffer against centrally mediated, negative effects of stress.One implication of the present findings is that a low DHEA-S–cortisol ratio may be associated with vulnerability to stress-induced symptoms of dissociation. In the future it may be fruitful to conduct clinical trials designed to prospectively evaluate whether augmentation of DHEA-S levels in humans, before the time of their exposure to stress, will confer a protective effect, as evidenced by diminished peritraumatic dissociation and improved cognitive performance.Military performance was significantly and positively associated with DHEA-S–cortisol ratios. Because the rating scales used by the military have not been made available to the public, the degree to which these scales relate to more traditional cognitive or psychological measures has not yet been fully established. However, in 3 separate investigations, psychological symptoms of dissociation—as measured by the CADSS—have been shown to be associated with poor military performance. Because the military performance scores reflect the capacity of soldiers' cognitive and decision-making abilities during stress, the present finding of a positive relationship between military performance scores and the DHEA-S–cortisol ratio adds weight to the idea that increased levels of DHEA-S are associated with an antistress effect on human cognition. These findings are consistent with those of previous clinical studies linking superior cognitive performance with higher concentrations of DHEA.Although no preclinical studies deal specifically with symptoms of dissociation, much is known about the relationship between levels of cortisol, DHEA-S, and glutamate and stress-induced neurotoxicity. However, it is not known at present whether stress-induced dissociation in humans is related to stress-induced neurotoxicity, as reported in the preclinical literature.A host of preclinical investigations have shown that glucocorticoids can be neurotoxic and that DHEA-S exerts a potent antiglucocorticoid effect peripherally and centrally.For example, prolonged exposure to high levels of circulating corticosterone in rats increases the age-related rate at which hippocampal pyramidal neurons are lost.Glucocorticoids have also been shown to potentiate neurodegeneration induced by anoxia and glutamate analogues. The neurotoxic effects of glucocorticoids can be attenuated or blocked by in vivo and in vitro administration of DHEA-S.Preclinical investigations suggest several possible mechanisms by which DHEA-S or DHEA may protect against dissociation or improve cognition in humans. For example, antiglucocorticoid effects of DHEA have been demonstrated in many tissues, including brain.Within the brain, region-specific metabolism of DHEA may ultimately control the nature of DHEA effects on cognition and behavior.For instance, 7α-hydroxylated metabolites of DHEA have been shown to interfere with the nuclear uptake of activated glucocorticoid receptors in the neurons of the hippocampus.Dehydroepiandrosterone also protects against excitatory amino acid– and oxidative stress–induced damage, restores cortisol-induced decrements in long-term potentiation, regulates programmed cell death, and promotes neurogenesis in the hippocampus.Thus it is possible that the military personnel exhibiting higher DHEA-S–cortisol ratios during extreme stress in this study came to survival training with brain structures and functional capacities that protected them from dissociation during the interrogation stress.Preclinical and clinical data suggest that the reduced levels of dissociation in subjects with an increased DHEA-S–salivary cortisol ratio during stress may be due, in part, to the action of DHEA-S at NMDA receptors and/or at the γ-aminobutyric acid–benzodiazepine receptor complex, perhaps at the level of the hippocampus or frontal cortex. Dehydroepiandrosterone sulfate serves as a negative modulator of the γ-aminobutyric acid–benzodiazepine receptor complex,and there is evidence of altered benzodiazepine receptor modulation and sensitivity in stress-related disorders characterized by symptoms of dissociation, such as PTSD.Furthermore, DHEA-S also positively modulates NMDA receptors, which have been implicated in dissociative phenomena in humans as assessed by the CADSS.Thus, it is reasonable to speculate that the reduced levels of dissociation in subjects with a high DHEA-S–cortisol ratio may be due, in part, to the effect of DHEA on NMDA receptors and/or the effect of DHEA at the γ-aminobutyric acid–benzodiazepine receptor complex, perhaps at the level of the hippocampus.There are several limitations to this study. First, all subjects in survival school training experienced food deprivation before stress exposure. Because dieting in clinically obese individuals has been reported to result in an increase in DHEA-S level,it is theoretically possible that the increase in DHEA-S levels noted in the present subjects may have been, in part, influenced by this factor. However, because food deprivation was kept uniform across subjects, this factor cannot account for the significant relationships between the DHEA-S–cortisol ratios and the symptoms of dissociation and military performance.All subjects also experienced sleep deprivation, raising the possibility that alterations in the diurnal variation in DHEA-S and cortisol levels may have contributed to the findings of this study. Although possible, this is unlikely to explain the present findings for 2 reasons. First, the findings of previous studies in military subjects exposed to high stress have shown that the diurnal variation of hormones is extremely small relative to the very large alterations of these hormones induced by exposure to acute stress.Second, sleep deprivation was kept uniform across all subjects.Another limitation is the relatively small number of subjects in this study. It is possible that the large amount of the variance explained in the regression analyses may be due to the relative homogeneity of these military personnel, and the present data may not generalize to the general population. 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disorder.Neuropsychopharmacology.1996;14:181-186.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8866701&dopt=AbstractDJJakubowiczNABeerRMBeerJENestlerDisparate effects of weight reduction by diet on serum dehydroepiandrosterone-sulfate levels in obese men and women.J Clin Endocrinol Metab.1995;80:3373-3376.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7593454&dopt=AbstractCorrespondence: Charles A. Morgan III, MD, MA, c/o 116A, National Center for Post-Traumatic Stress Disorder, Veterans Affairs New England Healthcare System, 950 Campbell Ave, West Haven, CT 06516 ([email protected]).Submitted for publication July 22, 2003; final revision received February 13, 2004; accepted February 18, 2004.This study was supported by US Army Research Institute for Environmental Medicine, Natick, Mass; the Robert Mitchell Center for Repatriated POW Studies, Pensacola, Fla; and the National Center for Post-Traumatic Stress Disorder, West Haven, Conn.We thank Jeremy Cordova, MS; CPO John Burkhart, USN; and Vladimir Coric, MD, whose assistance greatly facilitated the completion of this project.The views expressed in this article reflect those of the authors and do not represent those of the US government or the funding agencies. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png JAMA Psychiatry American Medical Association

Relationships Among Plasma Dehydroepiandrosterone Sulfate and Cortisol Levels, Symptoms of Dissociation, and Objective Performance in Humans Exposed to Acute Stress

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American Medical Association
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Copyright 2004 American Medical Association. All Rights Reserved. Applicable FARS/DFARS Restrictions Apply to Government Use.
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2168-622X
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2168-6238
DOI
10.1001/archpsyc.61.8.819
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15289280
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Abstract

ContextRecently, a growing body of research has provided evidence that dehydroepiandrosterone sulfate (DHEA-S) is involved in an organism's response to stress and that it may provide beneficial behavioral and neurotrophic effects.ObjectiveTo investigate plasma DHEA-S and cortisol levels, psychological symptoms of dissociation, and military performance.DesignProspective study.Setting and ParticipantsTwenty-five healthy subjects enrolled in military survival school.ResultsThe DHEA-S–cortisol ratios during stress were significantly higher in subjects who reported fewer symptoms of dissociation and exhibited superior military performance.ConclusionsThese data provide prospective, empirical evidence that the DHEA-S level is increased by acute stress in healthy humans and that the DHEA-S–cortisol ratio may index the degree to which an individual is buffered against the negative effects of stress.Dehydroepiandrosterone (DHEA) is an endogenous hormone secreted by the adrenal cortex in response to adrenocortiocotropin-releasing hormone (ACTH).Dehydroepiandrosterone and its sulfated derivative, DHEA-S, were originally thought to be produced in situ in brain tissue and were referred to as neurosteroids.At present, however, it is believed that the only source of brain DHEA-S is from the periphery.A growing body of research has provided evidence that DHEA-S is involved in an organism's response to stress and that it may provide beneficial behavioral and neurotrophic effects.In mice, DHEA-S release has been shown to be triggered by stress-induced release of ACTH and also exhibits memory-enhancing, antidepressant, anxiolytic, and antiaggression properties.Neuronal and glial survival and differentiation have also been shown to be enhanced by DHEA-S in dissociated cultures of mouse embryo brain and intact rats.Hippocampal neurotoxicity induced by corticosterone, oxidative stressors, and the glutamate agonist N-methyl-D-aspartate (NMDA) is prevented by DHEA-S.In addition, DHEA-S prevents corticosterone-induced performance decrements.Taken together, these findings suggest that DHEA-S may play a significant role in modulating vulnerability of the organism to negative consequences of stress.In humans, levels of DHEA-S peak around ages 20 to 25 years and then decline to values of 20% to 30% at approximately 70 to 80 years of age.Levels of DHEA-S are also reduced in a number of medical illnesses such as end-stage renal disease,liver disease,type 2 diabetes mellitus,coronary artery disease,and rheumatoid arthritis.Levels of DHEA-S have also been noted to be reduced in individuals with chronic fatigue syndrome,depression,anxiety,anorexia nervosa,and schizophrenia.In posttraumatic stress disorder (PTSD), levels of DHEA or DHEA-S have been variable. Levels have been noted to be increased in Israeli soldiers and Kosovo refugees with PTSD, but low in Kosovo refugees with PTSD who also had comorbid depression. Recently, increased release of DHEA was found in response to ACTH administration in women with PTSD but a negative relationship between the degree of ACTH-induced DHEA release and PTSD symptomatology (A.R., C.A.M., S.S., and D.C., unpublished data, 2004).Consistent with preclinical data regarding the balance of DHEA-S to glucocorticoid levels, the DHEA-S–cortisol ratio in humans has been significantly associated with the degree of functional impairmentor the response to clinical intervention.Taken together, these preclinical and clinical studies provide indirect evidence that the DHEA-S level and DHEA-S–cortisol ratio may play a role in modulating the impact of stress on a variety of processes in humans.The present study was designed to evaluate levels of DHEA-S and cortisol, the DHEA-S–cortisol ratio, and the relationship of these hormone indexes with stress-induced symptoms of dissociation and objective performance in military personnel participating in survival school training. Previous investigations have demonstrated that survival school represents a valid, reliable model for the study of acute, uncontrollable stress in humans.The results of these studies demonstrate that the stress experienced by subjects during survival school activates biological threat-response systems and elicits psychological symptoms of dissociation on a scale of magnitude comparable to the degree of arousal and dissociation noted in humans responding to real-world, threat-to-life experiences. Clinical studies have provided evidence that peritraumatic symptoms of dissociation represent a risk factor for the development of PTSDand that such symptoms are positively associated with the stress-induced release of glucocorticoids.On the basis of this and the preclinical and clinical literature suggesting that an increased DHEA-S–cortisol ratio may buffer against the negative impact of stress,we hypothesized that individuals with a higher DHEA-S–cortisol ratio during stress exposure would be protected from the negative impact of survival school stress as evidenced by fewer symptoms of dissociation and superior military performance.METHODSTwenty-six consecutively recruited active duty military personnel were the subjects of this study. One female subject was removed from the data set, resulting in a study population of 25. As designated by their military operational specialty, 8 subjects were naval aviators, and 17 were nonaviating marines. The mean age was 25 years (SD, 4.4 years). Six subjects (24%) were married, and 19 (76%) were single. The average number of years in the service was 4.6 (SD, 4.1).The methods used in this study have been reported in detail elsewhere.In brief, before enrollment in this investigation, each participant completed in-processing into the survival training course. Recruitment of subjects was conducted by the principal investigator (C.A.M.). All subjects gave written, informed consent. As per survival training course requirements, all subjects provided documentation of physical examination and medical and psychiatric clearance before enrollment. All subjects were free of illicit substances as documented by results of urine toxicologic screening.BASELINE ASSESSMENTFive days before stress exposure, baseline saliva samples were obtained at 4 PMon the second day of didactic (classroom) activities. Immediately following the collection of salivary samples, baseline plasma samples were collected by one of the current investigators and Vladimir Coric, MD. Baseline salivary samples were again collected at 7:45 AM. Subjects then completed a modified self-report version of the Clinician-Administered Dissociative States Scale (CADSS) to rate their symptoms of dissociation during the classroom phase.The CADSS assesses the frequency and intensity of state symptoms of dissociation. The items of the instrument are designed to assess how perceptually in touch (or out of touch) an individual is vis-à-vis his or her environment during specific conditions (nonstressed and stressed). Although some of the items on the scale ask about one's sense of physical self (eg, "Do you feel as if you are looking at things outside of your body?" and "Do you feel as if you are watching the situation as an observer or spectator?"), other items ask about cognitive or perceptual distortions (eg, "Do colors seem to be diminished in intensity?" "Do sounds almost disappear or become much stronger than you would have expected?" "Do you space out or in some way lose track of what is going on?" and "Do you see things as if you were in a tunnel, or looking through a wide-angle photographic lens?"). The self-report scale contains 19 items, each of which is rated by subjects on a Likert scale of 0 (not at all) to 4 (extremely). A total score of 76 is possible.STRESS SAMPLESAt the conclusion of the didactic phase of the training, soldiers participated in an experiential phase of survival training. During this phase, they were confined in a mock prisoner of war camp (POWC). In the POWC, each subject experienced various types of psychological stress. Broadly speaking, these included interrogations and problem-solving dilemmas designed to test the trainees' ability to use the information they learned during the didactic phase. As noted in previous publications,these interrogations result in robust increases in cortisol and catecholamine levels, heart rate, and subjective distress and significant reductions in testosterone level. During the POWC stage, subjects also underwent uniform food and sleep deprivation. Before interrogation stress, all subjects had been deprived of food for approximately 8 hours and were physically inactive. During the 30-minute exposure to interrogation stress, subjects remained standing and relatively immobile; they did not engage in exercise or physical exertion. Immediately after interrogation, subjects were moved to a second room identical in appearance to the first, where their blood and saliva samples were collected by the research team (C.A.M. and G.H.) between 4:30 and 5 PM. Subjects provided the saliva samples before the venipuncture. After this, subjects continued to undergo uniform sleep and food deprivation until their release from the POWC. All participants were monitored by the survival school medical staff during the POWC stage and received water on a uniform schedule.MILITARY PERFORMANCESurvival school instructors performed an objective appraisal of observable military-relevant performance of each participant during the POWC phase of survival school. These performance assessment scores are part of the survival school program and are not available to the public. The overall rating score, however, is designed to reflect how well a participant in training is able to demonstrate specific behaviors and problem-solving abilities while experiencing acute stress. The performance ratings are scored on a scale that ranges from 0 (no skills demonstrated) to a maximum score of 4 (excellent demonstration of skills). Because these performance scores were generated independent of the research team and the measures collected by the research team, they represent a double-blind opportunity to assess the relationship between operationally relevant military performance and the psychobiological measures that were of interest to the research team.RECOVERY SAMPLESTwenty-four hours after the conclusion of POWC stress, recovery plasma and saliva samples were collected in all subjects. Because of programmatic constraints within the Navy survival school program, the collection of recovery samples occurred at 7:45 AMand not 4 PMas in our previous investigations of the Army survival school program. In addition to providing blood and saliva samples, subjects once again completed the CADSS. Subjects were asked to complete the CADSS using the stress they experienced during the interrogation phase of the POWC as their reference point.Plasma samples were spun down in a refrigerated centrifuge, pipetted into microtubules, and frozen within 40 minutes of venipuncture. Samples were stored at −70°C from the time of initial collection until analyses were performed. Salivary samples were frozen and shipped with plasma samples to our laboratory within 24 hours of collection.SALIVARY CORTISOL ANALYSIS METHODSSaliva was collected in Salivette tubes (Sarstedt Inc, Newton, NC), centrifuged, and pipetted into two 1.5-mL plastic vials. The samples were shipped on dry ice to our laboratory and stored at −70°C until assayed. Salivary cortisol levels were analyzed by means of radioimmunoassay (IncStar Corp, Stillwater, Minn). The intra-assay and interassay coefficients of variation were 4.2% and 6.1%, respectively.PLASMA DHEA-S ANALYSIS METHODSFrozen plasma samples were used and processed in batch by means of DHEA-S commercial radioimmunoassay kits (Diagnostic Systems Laboratories, Inc, Webster, Tex). Determinations were performed on duplicate 10-mL plasma samples according to the manufacturer's recommendations, using supplied rabbit polyclonal anti-DHEA-S antibody–coated tubes. Plasma DHEA-S concentrations were measured with a sensitivity (detectability) of approximately 2 µg/dL and intra-assay and interassay coefficients of variation of 9% and 15%, respectively.DATA ANALYSISSeparate repeated-measures analyses of variance (ANOVAs) using the time factors baseline-stress and baseline-recovery were performed to detect whether exposure to stress significantly affected levels of plasma DHEA-S and plasma and salivary cortisol. To control for diurnal variation, the cortisol samples collected at the 4 PMpoint at baseline were compared with the cortisol samples collected at the stress time point. Similarly, the ANOVAs examining whether salivary cortisol levels had returned to the reference range after the conclusion of the training used the 7:45 AMsalivary cortisol samples, because these were closely associated with the time of saliva assessment on the day of recovery (7:45 AM).Pearson correlation analyses were used to evaluate the relationships among the assessed hormone levels (DHEA-S and cortisol) and the relationships among the hormones and the independent variables of age and weight.Spearman rank correlation analyses were used to compare the DHEA-S–salivary cortisol ratios from the baseline, stress, and recovery time points with psychological symptoms of dissociation (CADSS total scores) and military performance scores. Exploratory post hoc analyses were planned for individual CADSS items in the event that a significant relationship was observed between DHEA-S–cortisol ratios and CADSS total score.Finally, separate stepwise linear regression analyses were used to examine whether or how well the independent variables of age, rank, time in service, or the DHEA-S–salivary cortisol ratio would explain the variance in stress-induced symptoms of dissociation (the CADSS total score) and in objectively assessed military performance.RESULTSThe variables of age, rank, and time in the service did not contribute to variance in the hormone or the psychological data, and thus were removed from the analyses.PSYCHOLOGICAL MEASURESThe mean CADSS score at baseline was 1.0 (SD, 1.6), whereas the poststress CADSS score was 17.4 (SD, 13.0). This increase was statistically significant (F1,24= 40.8 [P<.001]). In the published literature this would be considered a moderate level of dissociation.MILITARY PERFORMANCE SCORESThe mean, objectively assessed military performance rating for subjects was 2.3 (SD, 0.7), with a range of 1.0 to 3.8.HORMONE VALUESCompared with baseline, there was a significant increase in DHEA-S level in response to stress (baseline, 27.81 µg/dL [SD, 11.06 µg/dL] [SI units {calculated with a conversion factor of 0.02714}, 0.755 µmol/L {SD, 0.30 µmol/L}]; stress, 60.12 µg/dL [SD, 26.15 µg/dL] [1.63 µmol/L {SD, 0.71 µmol/L}]; F1, 21= 76.1 [P<.001]), and it remained significantly increased compared with baseline at the recovery time point (27.81 µg/dL [SD, 11.06 µg/dL] [0.755 µmol/L {SD, 0.30 µmol/L}] vs 37.32 µg/dL [SD, 16.98 µg/dL] [1.01 µmol/L {SD, 0.46 µmol/L}]; F1,18= 22.4 [P<.001]). The DHEA-S values at recovery were significantly reduced compared with the stress time point (F1,17= 68.2 [P<.001]). Plasma cortisol level was also significantly increased by exposure to survival school stress and remained significantly elevated compared with baseline at the recovery time point (baseline, 8.6 µg/dL [237.3 nmol/L] [SD, 3.8 µg/dL {104.8 nmol/L}]; stress, 31.1 µg/dL [858.0 nmol/L] [SD, 5.8 µg/dL {160.0 nmol/L}]; recovery, 19.9 µg/dL [549.0 nmol/L] [SD, 7.0 µg/dL {193.1 nmol/L}]) (F1,22= 168.2 [P<.001] and F1,23= 55.8 [P<.001], baseline vs stress and baseline vs recovery, respectively). Similarly, compared with baseline levels, salivary cortisol level was significantly increased by exposure to survival school stress (baseline, 0.14 µg/dL [3.9 nmol/L] [SD, 0.04 µg/dL {1.1 nmol/L}]; stress, 0.87 µg/dL [24.0 nmol/L] [SD, 0.45 µg/dL {12.4 nmol/L}]) (F1,24= 62.5 [P<.001]). However, compared with baseline morning values, morning salivary cortisol levels collected at recovery (recovery value, 0.49 µg/dL [13.5 nmol/L] [SD, 0.20 µg/dL {5.5 nmol/L}]) tended to be significantly higher only at the recovery time point (F1,24= 3.7 [P= .06]).CORRELATION ANALYSESNo significant correlations were observed between plasma levels of DHEA-S and cortisol or between plasma levels of DHEA-S and salivary levels of cortisol at any of the assessment time points (baseline and stress or recovery). Similarly, Spearman rank correlation analyses did not reveal a significant correlation between plasma cortisol level and poststress CADSS scores (r= 0.16; P= .41). However, there was a significant positive relationship between salivary cortisol level during stress exposure and the poststress CADSS scores (r= 0.4; P<.05) and a trend for a significant negative relationship between stress-induced levels of DHEA-S and poststress CADSS scores (r= −0.4; P= .08). Finally, as shown in Figure 1, there was a significant negative correlation between the DHEA-S–salivary cortisol ratio during stress and the poststress CADSS scores (r= −0.63; P= .002).Figure 1.Correlation between dehydroepiandrosterone sulfate (DHEA-S)–cortisol ratio and stress-induced symptoms of dissociation in 22 healthy subjects enrolled in military survival school (R2= 0.29; Spearman ρ = −0.63 [P= .002]).Analysis of individual CADSS items indicated that there were significant negative relationships between the DHEA-S–salivary cortisol ratio during stress and CADSS items 2 (feeling unreal as if in a dream; r= −0.44; [P<.04]), 6 (feeling disconnected from one's body; r= −0.54 [P= .009]), 10 (colors appearing to be diminished in intensity; r= −0.6 [P= .004]), 11 (feeling as if one is viewing the world in a tunnel or looking through a wide-angle lens; r= −0.6 [P= .003]), 15 (feelings of being spaced out or of losing track of what is going on; r= −0.44 [P= .04]), 16 (sounds disappearing or becoming much stronger than expected; r= −0.51 [P= .01]), 17 (things having a special sense of clarity; r= −0.49 [P= .02]), and 18 (feeling as if one is looking at world as if in a fog, people appearing far away or unclear; r= −0.72 [P<.001]).With regard to the relationship between objective military performance and the indexes of DHEA-S and cortisol levels and dissociation, as shown in Figure 2, there was a significant positive correlation between the DHEA-S–salivary cortisol ratio during stress and the military performance scores (r= 0.61 [P= .008]) and a significant negative correlation between stress-induced levels of salivary cortisol and military performance (r= −0.51 [P<.01]). In addition, and similar to the findings of our previous investigations, there was a significant negative relationship between stress-induced symptoms of dissociation (CADSS scores) and military performance (r= −0.51 [P<.01]).Figure 2.Correlation between dehydroepiandrosterone sulfate (DHEA-S)–cortisol ratio during stress and military performance in 18 healthy subjects enrolled in military survival school (R2= 0.37; Spearman ρ = 5.2 P= .03]).No significant relationships were observed between baseline hormone values, recovery hormone values, DHEA-S–cortisol ratios at baseline or at recovery, and the outcome measures of dissociative symptoms and military performance scores in response to stress.REGRESSION ANALYSESStepwise linear regression analysis using poststress CADSS dissociation scores as the dependent variable and the DHEA-S–salivary cortisol ratio and plasma levels of DHEA-S and cortisol during stress as the independent variables showed that the model was significant (F1,19= 7 [P= .02]). The adjusted multivariate coefficient of determination (R2) for the model was 0.24 for the predictor DHEA-S–salivary cortisol ratio during stress. The model did not improve when the variables plasma levels of DHEA-S and cortisol during stress were added. The standardized β coefficient value for DHEA-S–salivary cortisol ratio during stress was −0.53, with a tvalue of −2.6 (P= .02).Stepwise linear regression analysis using military performance scores as the dependent variable and the DHEA-S–salivary cortisol ratio and plasma levels of DHEA-S and cortisol during stress as the independent variables showed that the model was significant (F1,16= 5.6 [P= .03]). The adjusted multivariate coefficient of determination (R2) for the model was 0.23 for the predictor DHEA-S–salivary cortisol ratio during stress. The model did not improve when the variable plasma level of DHEA-S or cortisol during stress was added. The standardized β coefficient value for DHEA-S–salivary cortisol ratio during stress was 0.52, with a tvalue of 2.4 (P= .03).COMMENTThe principal finding of this study is that individuals with a higher DHEA-S–salivary cortisol ratio during stress experienced fewer symptoms of dissociation and exhibited superior military performance. Because indexes of dissociation and military performance presumably index central processes, the data herein provide support that in healthy humans, the ratio or balance between circulating levels of DHEA-S to unbound cortisol may help buffer against centrally mediated, negative effects of stress.One implication of the present findings is that a low DHEA-S–cortisol ratio may be associated with vulnerability to stress-induced symptoms of dissociation. In the future it may be fruitful to conduct clinical trials designed to prospectively evaluate whether augmentation of DHEA-S levels in humans, before the time of their exposure to stress, will confer a protective effect, as evidenced by diminished peritraumatic dissociation and improved cognitive performance.Military performance was significantly and positively associated with DHEA-S–cortisol ratios. Because the rating scales used by the military have not been made available to the public, the degree to which these scales relate to more traditional cognitive or psychological measures has not yet been fully established. However, in 3 separate investigations, psychological symptoms of dissociation—as measured by the CADSS—have been shown to be associated with poor military performance. Because the military performance scores reflect the capacity of soldiers' cognitive and decision-making abilities during stress, the present finding of a positive relationship between military performance scores and the DHEA-S–cortisol ratio adds weight to the idea that increased levels of DHEA-S are associated with an antistress effect on human cognition. These findings are consistent with those of previous clinical studies linking superior cognitive performance with higher concentrations of DHEA.Although no preclinical studies deal specifically with symptoms of dissociation, much is known about the relationship between levels of cortisol, DHEA-S, and glutamate and stress-induced neurotoxicity. However, it is not known at present whether stress-induced dissociation in humans is related to stress-induced neurotoxicity, as reported in the preclinical literature.A host of preclinical investigations have shown that glucocorticoids can be neurotoxic and that DHEA-S exerts a potent antiglucocorticoid effect peripherally and centrally.For example, prolonged exposure to high levels of circulating corticosterone in rats increases the age-related rate at which hippocampal pyramidal neurons are lost.Glucocorticoids have also been shown to potentiate neurodegeneration induced by anoxia and glutamate analogues. The neurotoxic effects of glucocorticoids can be attenuated or blocked by in vivo and in vitro administration of DHEA-S.Preclinical investigations suggest several possible mechanisms by which DHEA-S or DHEA may protect against dissociation or improve cognition in humans. For example, antiglucocorticoid effects of DHEA have been demonstrated in many tissues, including brain.Within the brain, region-specific metabolism of DHEA may ultimately control the nature of DHEA effects on cognition and behavior.For instance, 7α-hydroxylated metabolites of DHEA have been shown to interfere with the nuclear uptake of activated glucocorticoid receptors in the neurons of the hippocampus.Dehydroepiandrosterone also protects against excitatory amino acid– and oxidative stress–induced damage, restores cortisol-induced decrements in long-term potentiation, regulates programmed cell death, and promotes neurogenesis in the hippocampus.Thus it is possible that the military personnel exhibiting higher DHEA-S–cortisol ratios during extreme stress in this study came to survival training with brain structures and functional capacities that protected them from dissociation during the interrogation stress.Preclinical and clinical data suggest that the reduced levels of dissociation in subjects with an increased DHEA-S–salivary cortisol ratio during stress may be due, in part, to the action of DHEA-S at NMDA receptors and/or at the γ-aminobutyric acid–benzodiazepine receptor complex, perhaps at the level of the hippocampus or frontal cortex. Dehydroepiandrosterone sulfate serves as a negative modulator of the γ-aminobutyric acid–benzodiazepine receptor complex,and there is evidence of altered benzodiazepine receptor modulation and sensitivity in stress-related disorders characterized by symptoms of dissociation, such as PTSD.Furthermore, DHEA-S also positively modulates NMDA receptors, which have been implicated in dissociative phenomena in humans as assessed by the CADSS.Thus, it is reasonable to speculate that the reduced levels of dissociation in subjects with a high DHEA-S–cortisol ratio may be due, in part, to the effect of DHEA on NMDA receptors and/or the effect of DHEA at the γ-aminobutyric acid–benzodiazepine receptor complex, perhaps at the level of the hippocampus.There are several limitations to this study. First, all subjects in survival school training experienced food deprivation before stress exposure. Because dieting in clinically obese individuals has been reported to result in an increase in DHEA-S level,it is theoretically possible that the increase in DHEA-S levels noted in the present subjects may have been, in part, influenced by this factor. However, because food deprivation was kept uniform across subjects, this factor cannot account for the significant relationships between the DHEA-S–cortisol ratios and the symptoms of dissociation and military performance.All subjects also experienced sleep deprivation, raising the possibility that alterations in the diurnal variation in DHEA-S and cortisol levels may have contributed to the findings of this study. Although possible, this is unlikely to explain the present findings for 2 reasons. First, the findings of previous studies in military subjects exposed to high stress have shown that the diurnal variation of hormones is extremely small relative to the very large alterations of these hormones induced by exposure to acute stress.Second, sleep deprivation was kept uniform across all subjects.Another limitation is the relatively small number of subjects in this study. It is possible that the large amount of the variance explained in the regression analyses may be due to the relative homogeneity of these military personnel, and the present data may not generalize to the general population. 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disorder.Neuropsychopharmacology.1996;14:181-186.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8866701&dopt=AbstractDJJakubowiczNABeerRMBeerJENestlerDisparate effects of weight reduction by diet on serum dehydroepiandrosterone-sulfate levels in obese men and women.J Clin Endocrinol Metab.1995;80:3373-3376.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7593454&dopt=AbstractCorrespondence: Charles A. Morgan III, MD, MA, c/o 116A, National Center for Post-Traumatic Stress Disorder, Veterans Affairs New England Healthcare System, 950 Campbell Ave, West Haven, CT 06516 ([email protected]).Submitted for publication July 22, 2003; final revision received February 13, 2004; accepted February 18, 2004.This study was supported by US Army Research Institute for Environmental Medicine, Natick, Mass; the Robert Mitchell Center for Repatriated POW Studies, Pensacola, Fla; and the National Center for Post-Traumatic Stress Disorder, West Haven, Conn.We thank Jeremy Cordova, MS; CPO John Burkhart, USN; and Vladimir Coric, MD, whose assistance greatly facilitated the completion of this project.The views expressed in this article reflect those of the authors and do not represent those of the US government or the funding agencies.

Journal

JAMA Psychiatry – American Medical Association

Published: Aug 1, 2004

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