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1.  Acute Hydrocortisone Treatment Increases Anxiety but Not Fear in Healthy Volunteers: A Fear-Potentiated Startle Study 
Biological psychiatry  2011;69(6):549-555.
Background
The debilitating effects of chronic glucocorticoids excess are well-known, but comparatively little is understood about the role of acute cortisol. Indirect evidence in rodents suggests that acute cortisone could selectively increase some forms of long-duration aversive states, such as “anxiety,” but not relatively similar, briefer aversive states, such as “fear.” However, no prior experimental studies in humans consider the unique effects of cortisol on anxiety and fear, using well-validated methods for eliciting these two similar but dissociable aversive states. The current study examines these effects, as instantiated with short- and long-duration threats.
Methods
Healthy volunteers (n = 18) received placebo or a low (20 mg) or a high (60 mg) dose of hydrocortisone in a double-blind crossover design. Subjects were exposed repeatedly to three 150-sec duration conditions: no shock; predictable shocks, in which shocks were signaled by a short-duration threat cue; and unpredictable shocks. Aversive states were indexed by acoustic startle. Fear was operationally defined as the increase in startle reactivity during the threat cue in the predictable condition (fear-potentiated startle). Anxiety was operationally defined as the increase in baseline startle from the no shock to the two threat conditions (anxiety-potentiated startle).
Results
Hydrocortisone affected neither baseline nor short-duration, fear-potentiated startle but increased long-duration anxiety-potentiated startle.
Conclusions
These results suggest that hydrocortisone administration in humans selectively increases anxiety but not fear. Possible mechanisms implicated are discussed in light of prior data in rodents. Specifically, hydrocortisone might increase anxiety via sensitization of corticotrophin-releasing hormones in the bed nucleus of the stria terminalis.
doi:10.1016/j.biopsych.2010.12.013
PMCID: PMC3116445  PMID: 21277566
Amygdala; anxiety; BNST; corticotropin-releasing hormone (CRH); cortisol; fear; predictability; startle reflex
2.  Association of Adrenal Function and Disease Severity in Community-Acquired Pneumonia 
PLoS ONE  2014;9(6):e99518.
Introduction
Rapid and accurate risk stratification in patients with community-acquired pneumonia (CAP) is an unmet clinical need. Cortisol to dehydroepiandrosterone (DHEA) ratio was put forward as a prognostic marker in sepsis. We herein validated the prognostic value of the adrenal hormones DHEA, DHEA-Sulfate (DHEAS), cortisol/DHEA-, cortisol/DHEAS- and DHEA/DHEAS – ratios in patients with CAP.
Methods
We assessed severity of illness using the pneumonia severity index (PSI) and measured adrenal hormone concentrations in 179 serum samples of prospectively recruited patients hospitalized with CAP. We calculated spearman rank correlation, logistic regression analysis and Kaplan Meier curves to study associations of adrenal hormones and outcomes.
Results
There was a significant correlation between PSI score and total cortisol (r = 0.24, p = 0.001), DHEAS (r = −0.23, p = 0.002), cortisol/DHEA (r = 0.23, p = 0.003), cortisol/DHEAS (r = 0.32, p = <0.0001) and DHEA/DHEAS (r = 0.20, p = 0.009). In age and gender adjusted logistic regression analysis, cortisol (OR: 2.8, 95% CI: 1.48–5.28) and DHEA (OR: 2.62, 95% CI: 1.28–5.34), but not DHEAS and the different ratios were associated with all-cause mortality. The discriminatory accuracy of cortisol and DHEA in ROC analysis (area under the curve) was 0.74 and 0.61. In Kaplan Meier analysis, patients in the highest deciles of cortisol and DHEA (p = 0.005 and p = 0.015), and to a lesser extent of cortisol/DHEAS ratio (p = 0.081) had a higher risk of death.
Conclusion
Cortisol, DHEAS and their ratios correlate with CAP severity, and cortisol and DHEA predict mortality. Adrenal function in severe pneumonia may be an important factor for CAP outcomes.
doi:10.1371/journal.pone.0099518
PMCID: PMC4049821  PMID: 24910975
3.  Fear Potentiation is Associated With Hypothalamic-Pituitary-Adrenal Axis Function in PTSD 
Psychoneuroendocrinology  2009;35(6):846-857.
Summary
A central problem in posttraumatic stress disorder (PTSD) is the inability to suppress fear under safe conditions. We have previously shown that PTSD patients cannot inhibit conditioned fear. Another relevant finding in PTSD is the hypersensitivity of the hypothalamic-pituitary adrenal (HPA) axis feedback. Given their common neurobiological pathways, alterations in HPA function in PTSD may be associated with impaired fear inhibition. The present study examined the relationship between HPA axis function and fear-potentiated startle and inhibition of conditioned fear in trauma-exposed individuals. We used a conditional discrimination procedure (AX+/BX−), in which one set of shapes (AX+) was paired with aversive airblasts to the throat (danger signal), and the same X shape with a different shape (BX−) were presented without airblasts (safety signal). The paradigm also included a transfer of fear inhibition test (AB). In addition to fear-potentiated startle, blood was drawn for neuroendocrine analysis and the dexamethasone suppression test (DEX) was performed; cortisol and ACTH were assessed at baseline and post-DEX. Ninety highly traumatized individuals recruited from Grady Hospital in Atlanta, GA participated in the study. The sample was divided into those who met DSM-IV criteria for PTSD (n=29) and Non-PTSD controls (n=61) using the PTSD symptom scale (PSS). Both groups showed significant reduction in cortisol and ACTH levels after DEX. Subjects with PTSD had higher fear-potentiated startle to the safety signal, BX− (F(1,88)=4.44, p<0.05) and fear inhibition trials, AB (F(1,88)=5.20, p<0.05), both indicative of less fear inhibition in the presence of B, compared to control subjects. In addition, fear-potentiated startle to AX+, BX−, and AB was positively correlated with baseline and post-DEX ACTH in PTSD subjects. These results suggest that impaired fear inhibition and associated alterations in HPA feedback may reflect amygdala hyperactivity in subjects with PTSD.
doi:10.1016/j.psyneuen.2009.11.009
PMCID: PMC2875386  PMID: 20036466
PTSD; Trauma; Physiology; Startle Response; HPA; Cortisol
4.  Decreased levels of dehydroepiandrosterone sulphate in severe critical illness: a sign of exhausted adrenal reserve? 
Critical Care  2002;6(5):434-438.
Introduction
Dehydroepiandrosterone (DHEA) and its sulphate (DHEAS) are pleiotropic adrenal hormones with immunostimulating and antiglucocorticoid effects. The present study was conducted to evaluate the time course of DHEAS levels in critically ill patients and to study their association with the hypothalamic–pituitary–adrenal axis.
Materials and method
This was a prospective observational clinical and laboratory study, including 30 patients with septic shock, eight patients with multiple trauma, and 40 age- and sex-matched control patients. We took serial measurements of blood concentrations of DHEAS, cortisol, tumour necrosis factor-α and IL-6, and of adrenocorticotrophic hormone immunoreactivity over 14 days or until discharge/death.
Results
On admission, DHEAS was extremely low in septic shock (1.2 ± 0.8 mol/l) in comparison with multiple trauma patients (2.4 ± 0.5 μmol/l; P < 0.05) and control patients (4.2 ± 1.8; P < 0.01). DHEAS had a significant (P < 0.01) negative correlation with age, IL-6 and Acute Physiology and Chronic Health Evaluation II scores in both patient groups. Only during the acute phase did DHEAS negatively correlate with dopamine. Nonsurvivors of septic shock (n = 11) had lower DHEAS levels (0.4 ± 0.3 μmol/l) than did survivors (1.7 ± 1.1 μmol/l; P < 0.01). The time course of DHEAS exhibited a persistent depletion during follow up, whereas cortisol levels were increased at all time points.
Conclusion
We identified extremely low DHEAS levels in septic shock and, to a lesser degree, in multiple trauma patients as compared with those of age- and sex-matched control patients. There appeared to be a dissociation between DHEAS (decreased) and cortisol (increased) levels, which changed only slightly over time. Nonsurvivors of sepsis and patients with relative adrenal insufficiency had the lowest DHEAS values, suggesting that DHEAS might be a prognostic marker and a sign of exhausted adrenal reserve in critical illness.
doi:10.1186/cc1530
PMCID: PMC130144  PMID: 12398784
adrenal insufficiency; dehydroepiandrosterone sulphate; multiple trauma; hypothalamic–pituitary–adrenal axis; sepsis
5.  HIV-1 clade C infection and Progressive Disruption in the Relationship Between Cortisol, DHEAS and CD4 cell numbers: A two-year follow-up study 
Background
It is well established that there is mutual interaction between the neuroendocrines and immune systems and that the disturbance in any one system could affect the function of the other. While there is a large body of evidence suggesting negative impact of human immunodeficiency virus type 1 B (HIV-1B) infection on both immune and neuroendocrine systems, the consequence of HIV-1 clade C infection (with structural differences from HIV-1B virus) on these systems is not clearly understood.
Methods
We carried out a 2-y longitudinal study on plasma profile of adrenocorticosteroids, including cortisol and DHEAS and their relationship with declining CD4+ cell counts in neurologically asymptomatic HIV-C infected individuals (N=84) in order to understand the impact of HIV-1 clade C infection on adrenocortical dysfunction and its relationship with the progressive decline in the cell mediated immunity.
Results
We found that while plasma cortisol levels increased significantly at baseline in HIV-1C infected individuals compared to those in HIV-negative controls (HIV-1C+, 9.83±0.39 vs. controls, 8.04±0.45; p< 0.01), there was a significant decrease in DHEAS in HIV-1C+ individuals, compared to that in HIV-negative controls (81.02 ± 4.9 vs. 185.1±12.03, p< 0.001), and consequently a significant increase in cortisol:DHEAS (Cortisol:DHEAS) ratio in HIV-1 clade C infected persons (0.19±0.002 vs. control 0.058±0.006; p<.0.001). Moreover, in HIV-1 C infected individuals, there was a strong positive correlation between DHEAS and CD4 cells (r=0.2; p<0.05), and a strong negative correlation between cortisol, as well as Cortisol:DHEAS ratio and CD4 cells (r= −0.25; p<0.01; and r= −0.31; p<0.001, respectively).
Conclusions
These findings suggest the persistent and progressive adrenocorical dysfunction during the asymptomatic phase of HIV infection, and that the evaluation of increase in plasma cortisol, a decrease in DHEAS, and an increase in Cortisol:DHEAS ratio may serve as important biomarkers preceding the impending down regulation of CD4 cell counts and progressive decline in the immune system function in HIV-1C infection. Furthermore, these findings may indicate the dysregulation of 3β-hydroxysteroid dehydrogenase (3β-HSD) activity, the enzyme involved in the biosynthesis of cortisol and DHEA through the pregnenolone-progesterone pathway, and that it may offer an opportunity for drug discovery targeting re-regulation of 3β-HSD activity for potential therapeutic application in HIV-1 C infection.
doi:10.1016/j.cca.2009.06.032
PMCID: PMC3980952  PMID: 19576195
HIV-1; Clade C; Cortisol; Cortisol:DHEAS (C/D) ratio; DHEAS; CD4 cell count; CD4:CD8 ratio; Body mass index (BMI); HAART
6.  Cortisol response to low dose versus standard dose (back-to-back) adrenocorticotrophic stimulation tests in children and young adults with thalassemia major 
Background:
Thalassemia major patients with repeated blood transfusion have high prevalence of endocrinopathies due to iron overload.
Materials and Methods:
We examined the adrenocortical function in 23 thalassemic patients (10 children and 13 young adults) aged 8-26 years. Serum cortisol and dehydroepiandrosterone sulfate (DHEA-S) concentrations were determined in each subject before blood transfusion both in basal condition and after low dose (LD) (1 μg), followed by standard dose (SD) (250 μg, respectively) with synthetic corticotrophin beta 1-24 ACTH (Synacthen, Ciba). Normal controls were a group of 13 age- and sex-matched normal subjects.
Results:
Using a peak total cortisol cutoff level of 550 nmol/L and increments of 200 μg above basal cortisol, adrenal insufficiency (AI) was demonstrated in 8 patients (34.7%) after the LD ACTH and in 2 patients (8.7%) after SD cosyntropin (ACTH) test, but none of the controls. Using a peak total cortisol cutoff level of 420 nmol/L and increments of 200 μg above basal cortisol, AI was demonstrated in 5 patients (21.7%) after the LD ACTH and in 2 patients after SD ACTH test (8.7%), but none of controls. All patients with biochemical AI were asymptomatic with normal serum sodium and potassium concentrations and had no history suggestive of adrenal pathology. The peak cortisol concentrations in thalassemic patients with impaired adrenal function both after 1 μg and 250 μg cosyntropin (294 ± 51 nmol/L and 307 ± 58.6) were significantly lower than those with patients with normal (454 ± 79.7 nmol/L and 546.1 ± 92.2 nmol/L, respectively) and controls (460.2 ± 133.4 nmol/L and 554.3 ± 165.8 nmol/L, respectively). Adolescents and young adults, but not children with thalassaemia, had significantly lower peak cortisol concentration after SD ACTH versus controls. Peak cortisol response to LD ACTH was correlated significantly with peak cortisol response to SD in all patients (r = 0.83, P < 0.0001). In adolescents and young adults with thalassemia, DHEA-S levels before and after LD ACTH stimulation were significantly lower and the cortisol/DHEA-S ratios were significantly higher than the controls.
Conclusion:
The use of LD ACTH test diagnoses more adrenal abnormalities versus SD ACTH in thalassemic patients. The relatively high prevalence of AI in thalassemic adolescents and young adults necessitates that these patients have to be investigated for AI before major surgery and those with impaired cortisol secretion should receive stress doses of corticosteroids during the stressful event.
doi:10.4103/2230-8210.122620
PMCID: PMC3872683  PMID: 24381882
Cortisol; dehydroepiandrosterone sulfate; low dose adrenocorticotropic hormone test; standard dose adrenocorticotropic hormone test; thalassemia
7.  Dynamics of Adrenal Steroids Are Related to Variations in Th1 and Treg Populations during Mycobacterium tuberculosis Infection in HIV Positive Persons 
PLoS ONE  2012;7(3):e33061.
Tuberculosis (TB) remains the most frequent cause of illness and death from an infectious agent, and its interaction with HIV has devastating effects. We determined plasma levels of dehydroepiandrosterone (DHEA), its circulating form DHEA-suphate (DHEA-s) and cortisol in different stages of M. tuberculosis infection, and explored their role on the Th1 and Treg populations during different scenarios of HIV-TB coinfection, including the immune reconstitution inflammatory syndrome (IRIS), a condition related to antiretroviral treatment. DHEA levels were diminished in HIV-TB and HIV-TB IRIS patients compared to healthy donors (HD), HIV+ individuals and HIV+ individuals with latent TB (HIV-LTB), whereas dehydroepiandrosterone sulfate (DHEA-s) levels were markedly diminished in HIV-TB IRIS individuals. HIV-TB and IRIS patients presented a cortisol/DHEA ratio significantly higher than HIV+, HIV-LTB and HD individuals. A positive correlation was observed between DHEA-s and CD4 count among HIV-TB individuals. Conversely, cortisol plasma level inversely correlated with CD4 count within HIV-TB individuals. M. tuberculosis-specific Th1 lymphocyte count was increased after culturing PBMC from HIV-TB individuals in presence of DHEA. We observed an inverse correlation between DHEA-s plasma level and Treg frequency in co-infected individuals, and CD4+FoxP3+ Treg frequency was increased in HIV-TB and IRIS patients compared to other groups. Strikingly, we observed a prominent CD4+CD25-FoxP3+ population across HIV-TB and HIV-TB IRIS patients, which frequency correlated with DHEA plasma level. Finally, DHEA treatment negatively regulated FoxP3 expression without altering Treg frequency in co-infected patients. These data suggest an enhancing role for DHEA in the immune response against M. tuberculosis during HIV-TB coinfection and IRIS.
doi:10.1371/journal.pone.0033061
PMCID: PMC3303789  PMID: 22431997
8.  The role of salivary cortisol and DHEA-S in response to sexual, humorous, and anxiety-inducing stimuli 
Hormones and behavior  2010;59(5):765-771.
Stress and anxiety are commonly thought to be detrimental to sexual function. Several studies in both the human and animal literature, however, have found that inducing anxiety can enhance sexual function in women. The mechanisms that explain a negative relationship between physical and psychological stress and sexual functioning are well documented, but little is known about how stress or anxiety might have a facilitatory effect on sexual arousal. As an initial step in exploring the relationship between anxiety and sexual arousal, the present study examined the role of the autonomic nervous system, and the adrenal hormones cortisol and dehydroepiandrosterone-sulfate (DHEA-S) in response to a sexual film, an anxiety-inducing film, and a humorous film. Nineteen premenopausal women (mean age 24.4 years) who were free from sexual difficulties came into the lab on three separate days. At each session they were shown an anxiety-inducing, sexually arousing, or humorous (control) film while their physiological arousal was measured. They also provided saliva samples before and after each film. Cortisol significantly decreased, while DHEA-S increased in the sexual and humorous conditions. Neither hormone changed significantly in the anxiety-inducing condition. Autonomic nervous system activity measured by heart rate and heart rate variability did not change in response to the sexual or anxiety-inducing films, but heart rate variability increased significantly in response to the humorous film. The cortisol/DHEA-S ratio at the post-sexual film time point was significantly negatively correlated with genital arousal (measured by vaginal pulse amplitude). Anxiety-inducing films did not result in a physiological stress response, which can explain why they do not impair sexual function.
doi:10.1016/j.yhbeh.2010.12.011
PMCID: PMC3085649  PMID: 21195074
Cortisol; Dehydroepiandrosterone-sulfate; Human sexuality; Stress; Anxiety; Arousal; Humor
9.  The association of dehydroepiandrosterone (DHEA) and DHEA sulfate (DHEAS) with anxiety sensitivity and electronic diary negative affect among smokers with and without posttraumatic stress disorder 
Posttraumatic stress disorder (PTSD) is associated with increased smoking initiation, maintenance and relapse. Dehydroepiandrosterone (DHEA) and DHEA sulfate (DHEAS) are neurosteroids that have been associated with mood measures as well as smoking status, and nicotine is associated with increased DHEA and DHEAS levels. Given the difficulties with mood experienced by smokers with PTSD, the purpose of the current study was to evaluate the association between negative affect and anxiety sensitivity with DHEA and DHEAS levels. Ninety-six smokers with and without PTSD provided blood samples for neurosteroid analyses, and completed self-report measures of anxiety sensitivity and electronic diary ratings of negative affect. As expected, PTSD smokers reported higher levels of anxiety sensitivity (F[1,94]=20.67, partial η2= 0.18, p<.0001) and negative affect (F[1,91]=7.98, partial η2= .08, p=.006). After accounting for age and gender, DHEAS was significantly inversely associated with both anxiety sensitivity (F[3,92]=6.97, partial η2= 0.07, p=.01) and negative affect (F[3,87]=10.52, partial η2= 0.11, p=.002) across groups. Effect sizes indicated that these effects are moderate to high. No significant interactions of diagnosis and DHEA(S) levels with mood measures were detected. Given that nicotine is known to elevate DHEA(S) levels, these results suggest that DHEAS may serve as a biomarker of the association between mood and nicotine among smokers. Implications for the results include 1) the use of DHEAS measurement across time and across quit attempts; and 2) the potential for careful use of DHEA supplementation to facilitate abstinence during smoking cessation.
doi:10.1097/JCP.0b013e3182968962
PMCID: PMC3896952  PMID: 23771199
10.  Measuring anxious responses to predictable and unpredictable threat in children and adolescents 
Research has highlighted the need for new methods to assess emotions in children on multiple levels in order to gain better insight into the complex processes of emotional development. The startle reflex is a unique translational tool that has been utilized to study physiological processes during fear and anxiety in rodents and in human subjects. However, it has been challenging to implement developmentally-appropriate startle experiments in children. This paper describes a procedure that uses predictable and unpredictable aversive events to distinguish between phasic fear and sustained anxiety in children and adolescents. We investigated anxious responses, as measured with the startle reflex, in youth (N = 36, mean age[range] = 12.63 [7–17]) across three conditions: no aversive events (N), predictable aversive events (P), and unpredictable aversive events (U). Short-duration cues were presented several times in each condition. Aversive events were signaled by the cues in P, but were presented randomly in U. Participants showed fear-potentiated startle to the threat cue in P. Startle responses were also elevated between cues in U compared to N, suggesting that unpredictable aversive events can evoke a sustained state of anxiety in youth. This latter effect was influenced by sex, being greater in girls compared to boys. These findings indicate the feasibility of this experimental induction of the startle reflex in response to predictable and unpredictable events in children and adolescents, enabling future research on inter-individual differences in fear and anxiety and their development in youth.
doi:10.1016/j.jecp.2011.02.014
PMCID: PMC3110515  PMID: 21440905
fear; anxiety; unpredictability; psychophysiology; startle reflex; sex differences
11.  Renal clearance and daily excretion of cortisol and adrenal androgens in patients with rheumatoid arthritis and systemic lupus erythematosus 
Annals of the Rheumatic Diseases  2004;63(8):961-968.
Background: In rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE), patients demonstrate low levels of adrenal hormones.
Objective: To investigate whether increased renal clearance and daily excretion contribute to this phenomenon.
Methods: Thirty patients with RA, 32 with SLE, and 54 healthy subjects (HS) participated. Serum and urinary levels of cortisol, cortisone, 17-hydroxyprogesterone (17OHP), androstenedione, dehydroepiandrosterone (DHEA), and DHEA sulphate (DHEAS) were measured.
Results: Clearance of DHEAS and DHEA was lower in patients than in HS, and clearance of androstenedione was somewhat higher in patients than in HS, but daily excretion of this latter hormone was low. Clearance of cortisol, cortisone, and 17OHP was similar between the groups. The total molar amount per hour of excreted DHEA, DHEAS, and androstenedione was lower in patients than HS (but similar for cortisol). Serum DHEAS levels correlated with urinary DHEAS levels in HS and patients, whereby HS excreted 5–10 times more of this hormone than excreted by patients. Low serum levels of adrenal androgens and cortisol in patients as compared with HS were confirmed, and proteinuria was not associated with changes of measured renal parameters.
Conclusions: This study in patients with RA and SLE demonstrates that low serum levels of adrenal androgens and cortisol are not due to increased renal clearance and daily loss of these hormones. Decreased adrenal production or increased conversion or conjugation to downstream hormones are the most likely causes of inadequately low serum levels of adrenal hormones in RA and SLE.
doi:10.1136/ard.2003.014274
PMCID: PMC1755103  PMID: 15249323
12.  Measuring cortisol and DHEA in fingernails: A pilot study 
Purpose:
Abnormalities in both cortisol and dehydroepiandrosterone (DHEA) have been reported in psychiatric disorders. Analysis of saliva, urine and blood cortisol and DHEA levels provides an index of hormone levels over a short time period. Unlike such conventional measures, fingernails incorporate endogenous hormones that passively diffuse to the nail matrix from capillaries during keratinization. This study piloted the measurement of cortisol and DHEA levels in fingernails as a potential measure of their accumulated secretion of steroid hormones over a prolonged time period.
Method:
Thirty-three university students (18–24 years) provided fingernail samples on two occasions over a school semester. The visits were scheduled so nail cortisol and DHEA levels were collected from periods when students might be under different levels of stress.
Results:
During the putatively stressful period, the nail samples showed a significant increase in the cortisol: DHEA ratio (P = 0.0002) due to a significant decrease in the DHEA levels (P = 0.004) and a numerical but not statistically significant increase in the cortisol levels (P = 0.256).
Discussion:
This pilot study showed that nails can be used to measure cortisol and DHEA, a measure which may reflect environmental stress. More work is required to further validate this technique which may prove useful in studies of both healthy individuals and patient groups.
PMCID: PMC2951060  PMID: 20169040
stress; nails; cortisol; DHEA
13.  Increased serum dehydroepiandrosterone sulfate in the first episode but not in subsequent episodes in male patients with schizophrenia 
Background
Many studies have investigated the relationship between blood levels of dehydroepiandrosterone (DHEA) and its sulfate ester (DHEA-S), cortisol, progesterone, and testosterone and the onset, prognosis, symptom severity, and treatment response of schizophrenia. In the present study, we assessed potential differences in blood levels of neurosteroids between drug-naïve first-episode patients with schizophrenia (FES), and drug-free patients with schizophrenia who were not in the first episode but were in a phase of acute exacerbation (DFP).
Materials and methods
The present study included 32 male FES, 28 male DFP, and 24 male healthy controls (HC). Groups were compared in terms of blood levels of adrenocorticotropic hormone (ACTH), cortisol, testosterone, progesterone, and DHEA-S.
Results
Blood levels of ACTH, cortisol, testosterone, and progesterone were similar among the groups. The mean value of serum DHEA-S was significantly different among the groups (P<0.001). The value of serum DHEA-S was higher in the FES group than in the DFP and HC groups (both P<0.001). The mean values of serum DHEA-S in the HC and DFP groups were found to be similar (P=0.33).
Conclusion
We suggest that higher values of DHEA-S in the FES group compared with both the DFP and HC groups indicate that this neurosteroid response is unique to first-episode schizophrenia patients. Further studies are needed to investigate the difference in blood levels of neurosteroids in different groups in terms of age of diagnosis.
doi:10.2147/NDT.S61406
PMCID: PMC4011925  PMID: 24812513
neurosteroid; effect; psychosis
14.  Methodological Considerations in Use of the Cortisol/DHEA(S) Ratio in Adolescent Populations 
Psychoneuroendocrinology  2013;38(11):10.1016/j.psyneuen.2013.06.024.
Objective
The cortisol/DHEA(S) ratio has demonstrated utility in studies of HPA activity and psychopathology. However, use of the cortisol/DHEA(S) ratio in adolescent populations requires additional consideration of differential changes in DHEA(S) and cortisol during the course of puberty. This study examines the relationship between pubertal status and individual cortisol and DHEAS levels as well as with the cortisol/DHEAS ratio.
Method
Morning salivary cortisol and urinary DHEAS levels were obtained for 267 young adolescents at three time points, each approximately one year apart. Growth curve modeling and repeated measures ANOVA were used to assess the effect of adrenal development on individual hormone levels and on the total ratio.
Results
Pubic hair development was a significant predictor of change over time in DHEAS but not cortisol. Development was also a significant predictor of the cortisol/DHEAS ratio when raw cortisol and DHEAS values were used.
Conclusions
Our findings indicate that, when DHEAS levels were adjusted to control for pubertal status, the ratio demonstrated stability over time. This finding is in line with the hypothesis that the ratio may tap stable individual differences in HPA functioning.
doi:10.1016/j.psyneuen.2013.06.024
PMCID: PMC3812358  PMID: 23867118
Cortisol; DHEA; DHEAS; ratio; HPA axis; adolescent; puberty; adrenarche
15.  Dehydroepiandrosterone and Corticosterone Are Regulated by Season and Acute Stress in a Wild Songbird: Jugular Versus Brachial Plasma 
Endocrinology  2008;149(5):2537-2545.
Stress has well-known effects on adrenal glucocorticoid secretion, and chronic elevation of glucocorticoids can have detrimental effects on the brain. Dehydroepiandrosterone (DHEA), an androgen precursor synthesized in the adrenal glands or the brain itself, has anti-glucocorticoid properties, but little is known about the role of DHEA in the stress response, particularly in the brain. Here, we measured the effects of acute restraint on circulating corticosterone (CORT) and DHEA levels in wild song sparrows. Blood was collected from either the brachial or jugular vein. In songbirds, jugular plasma is enriched with neurally synthesized steroids, and therefore, jugular plasma is an indirect index of the neural steroidal milieu. Subjects were sampled during four times of year: breeding, molt, early nonbreeding, and mid-nonbreeding. Baseline CORT and DHEA levels showed similar seasonal changes; both steroids were elevated during the breeding season. Baseline CORT and DHEA levels were similar in jugular and brachial plasma. Acute stress had robust effects on CORT and DHEA that were season specific and vein specific. For CORT, during the molt, stress increased jugular CORT more than brachial CORT. For DHEA, during the breeding season, stress decreased jugular DHEA but not brachial DHEA. During the molt, stress increased jugular DHEA but not brachial DHEA. Acute stress did not affect brachial DHEA. These data suggest that acute stress specifically affects the balance between DHEA synthesis and metabolism in the brain. Furthermore, these results suggest that CORT and DHEA are locally synthesized in the brain during molt, when systemic levels of CORT and DHEA are low.
doi:10.1210/en.2007-1363
PMCID: PMC2878327  PMID: 18276756 CAMSID: cams343
16.  The Effects of Galantamine Hydrobromide Treatment on Dehydroepiandrosterone Sulfate and Cortisol Levels in Patients with Chronic Fatigue Syndrome 
Psychiatry Investigation  2009;6(3):204-210.
Objective
Mental fatigue, cognitive disorders, and sleep disturbances seen in chronic fatigue syndrome (CFS) may be attributed to cholinergic deficit. A functional deficiency of cholinergic neurotransmission may cause the hypothalamic-pituitary-adrenal axis hypoactivity seen in CFS. Therefore, we investigated the alterations in stress hormones such as cortisol and dehydroepiandrosterone sulfate (DHEAS) in CFS patients before and after 4-week administration of galantamine hydrobromide, a selective acetylcholinesterase inhibitor, and aimed to investigate whether there are any relationships between the probable hormonal changes and cholinergic treatment.
Methods
Basal levels of cortisol and DHEAS were measured in 29 untreated CFS patients who were diagnosed according to Centers for Disease Control (CDC) criteria and in 20 healthy controls. In the patient group, four weeks after 8 mg/d galantamine hydrobromide treatment, cortisol and DHEAS levels were measured again. After the treatment 22 patients who stayed in study were divided into two subgroups as responders and nonresponders according to the reduction in their Newcastle Research Group ME/CFS Score Card (NRG) scores.
Results
Important findings of this study are lower pre-and post-treatment cortisol levels and in all CFS patients compared to controls (F=4.129, p=0.049; F=4.803, p=0.035, respectively); higher basal DHEAS values and higher DHEAS/cortisol molar ratios which were normalized following four weeks' treatment with 8 mg/d galantamine hydrobromide in the treatment-respondent group (F=5.382, p=0.029; F=5.722, p=0.025, respectively).
Conclusion
The findings of the decrease in basal DHEAS levels and DHEAS/cortisol molar ratios normalizing with galantamine treatment may give some support to the cholinergic deficit hypothesis in CFS.
doi:10.4306/pi.2009.6.3.204
PMCID: PMC2796068  PMID: 20046396
Chronic fatigue syndrome; Cortisol; Dehydroepiandrosterone sulfate; Galantamine hydrobromide
17.  Association of DHEA, DHEAS, and cortisol with childhood trauma exposure and posttraumatic stress disorder 
There has been a great deal of interest in the role of the neuroendocrine hormones of the hypothalamic-pituitary-adrenal (HPA) axis on the expression of stress-related psychopathology such as posttraumatic stress disorder (PTSD). This investigation examined the association of PTSD and childhood maltreatment with three key HPA axis hormones: cortisol, dehydroepiandrosterone (DHEA), and dehydroepiandrosterone sulfate (DHEAS). Regression analyses were undertaken on a sample of 43 participants with and 57 participants without PTSD. Results demonstrated that after controlling for age, gender, and PTSD status, exposure to childhood maltreatment was significantly associated with cortisol secretion (F[4,95]=11.68, ΔR2=0.11, p=.0009) and cortisol/DHEA ratio (F[4,95]=6.20, ΔR2=.05, p=.01). PTSD status was not associated with any of these neuroendocrine variables. Findings are discussed in the context of the complexity of the relationship of these neuroendocrine variables with trauma exposure and trauma-related psychopathology. It is suggested that DHEA(S) or cortisol/DHEA(S) ratios may not be biomarkers of specific forms of psychopathology per se, but that instead, the severity and developmental timing of trauma may set the HPA axis in ways that are reflected in interactions among these neuroendocrine hormones. In adulthood, these HPA axis hormones may continue to be dynamically affected by personal and environmental resources.
doi:10.1097/YIC.0b013e328364ecd1
PMCID: PMC3951407  PMID: 23907073
posttraumatic stress disorder; DHEA; cortisol; child abuse
18.  Effect of prolonged stress on the adrenal hormones of individuals with irritable bowel syndrome 
Background
The purpose of this study was to investigate the effect of prolonged stress on the salivary adrenal hormones (cortisol, dehydroepiandrosterone [DHEA], DHEA-sulfate [DHEA-S]) of individuals with irritable bowel syndrome (IBS).
Methods
The participants were female college students, including 10 with IBS and 16 without IBS (control group), who were scheduled for a 2-week teaching practice at a kindergarten. Participants were asked to collect saliva for determining adrenal hormones immediately and 30 min after awakening and before sleep, 2 weeks before the practice, the first week of the practice, the second week of the practice, and a few days after the practice.
Results
Regarding cortisol/DHEA ratio, significantly increased levels were found during the first week of the practice, and a significant interaction between group and time was found; the ratio at 30 min after awakening in the IBS group was higher than that in the control group. For the other adrenal hormone indexes, no significant differences due to the presence of IBS were found.
Conclusions
Individuals with IBS showed an elevated cortisol/DHEA ratio after awakening compared with individuals without IBS, and the elevated ratio peaked under the prolonged stress. The present study suggests that the cortisol effect is dominant in individuals with IBS under prolonged stress.
doi:10.1186/s13030-015-0031-7
PMCID: PMC4308893  PMID: 25632298
Irritable bowel syndrome; Cortisol; Dehydroepiandrosterone; Saliva; Prolonged stress
19.  Stress Sensitivity in Metastatic Breast Cancer: Analysis of Hypothalamic-Pituitary-Adrenal Axis Function 
Psychoneuroendocrinology  2006;31(10):1231-1244.
The normal diurnal cortisol cycle has a peak in the morning, decreasing rapidly over the day, with low levels during the night, then rising rapidly again to the morning peak. A pattern of flatter daytime slopes has been associated with more rapid cancer progression in both animals and humans. We studied the relationship between the daytime slopes and other daytime cortisol responses to both pharmacological and psychosocial challenges of hypothalamic-pituitary-adrenal (HPA) axis function as well as DHEA in a sample of 99 women with metastatic breast cancer, in hopes of elucidating the dysregulatory process.
We found that the different components of HPA regulation: the daytime cortisol slope, the rise in cortisol from waking to 30 minutes later, and cortisol response to various challenges, including dexamethasone (DEX) suppression, corticotrophin releasing factor (CRF) activation, and the Trier Social Stress Task, were at best modestly associated. Escape from suppression stimulated by 1 mg of dexamethasone administered the night before was moderately but significantly associated with flatter daytime cortisol slopes (r=0..28 to .30 at different times of the post dexamethasone administration day, all p<.01) . Daytime cortisol slopes were also moderately but significant associated with the rise in cortisol from waking to 30 minutes after awakening (r=.29, p=.004, N=96), but not with waking cortisol level (r=−0.13, p=.19). However, we could not detect any association between daytime cortisol slope and activation of cortisol secretion by either CRF infusion or the Trier Social Stress Task. The CRF activation test (following 1.5 mg of dexamethasone to assure that the effect was due to exogenous CRF) produced ACTH levels that were correlated (r=0.66 p<.0001, N = 74) with serum cortisol levels, indicating adrenal responsiveness to ACTH stimulation. Daytime cortisol slopes were significantly correlated with the slope of DHEA (r=.21, p=.04, N=95). Our general findings suggest that flatter daytime cortisol slopes among metastatic breast cancer patients may be related to disrupted feedback inhibition rather than hypersensitivity in response to stimulation.
doi:10.1016/j.psyneuen.2006.09.004
PMCID: PMC1790857  PMID: 17081700
Cortisol; HPA; stress; dexamethasone; CRF; metastatic breast cancer
20.  Trajectories of Dehydroepiandrosterone Sulfate Predict Mortality in Older Adults: The Cardiovascular Health Study 
Background
Dehydroepiandrosterone sulfate (DHEAS) has been proposed as an antiaging hormone, but its importance is unclear. Assessment of an individual’s ability to maintain a DHEAS set point, through examination of multiple DHEAS levels over time, may provide insight into biologic aging.
Methods
Using Cox proportional hazard models, we examined the relationship between DHEAS trajectory patterns and all-cause death in 950 individuals aged ≥65 years who were enrolled in the Cardiovascular Health Study and had DHEAS levels measured at three to six time points.
Results
Overall, there was a slight decline in DHEAS levels over time (−0.013 μg/mL/y). Three trajectory components were examined: slope, variability, and baseline DHEAS. When examined individually, a steep decline or extreme variability in DHEAS levels was associated with higher mortality (p < .001 for each), whereas baseline DHEAS level was not. In adjusted models including all three components, steep decline (hazard ratio [HR] 1.75, confidence interval [CI] 1.32–2.33) and extreme variability (HR 1.89, CI 1.47–2.43) remained significant predictors of mortality, whereas baseline DHEAS level remained unpredictive of mortality (HR 0.97 per standard deviation, CI 0.88–1.07). The effect of trajectory pattern was more pronounced in men than in women. Individuals with both a steep decline and extreme variability in DHEAS levels had a significantly higher death rate than those with neither pattern (141 vs 48 deaths per 1,000 person-years, p < .001).
Conclusions
Our data show significant heterogeneity in the individual trajectories of DHEAS levels and suggest that these trajectories provide important biologic information about the rate of aging, whereas the DHEAS level itself does not.
doi:10.1093/gerona/glp129
PMCID: PMC2773814  PMID: 19713299
DHEA; DHEAS; Mortality; Aging; Elderly
21.  Increased Acoustic Startle Responses in IBS Patients During Abdominal and Non-Abdominal Threat 
The Journal of urology  2009;181(5):2127-2133.
Background and Aims
Visceral hypersensitivity and symptom severity in Irritable Bowel Syndrome (IBS) are both exacerbated by stress. The eye-blink startle response represents a non-invasive measure of central defensive responding. Evidence for central hyperexcitability was studied in IBS patients by examining potentiation of the startle reflex to a nociceptive threat.
Methods
Acoustic startle responses were examined in female IBS patients (n=42) and healthy controls (n=22) during cued periods in which an aversive abdominal or biceps stimulation was impossible (safe), possible (imminent threat) or anticipated (period just before the imminent threat), and during a threatening context (muscle stimulation pads attached but no cues for stimulation).
Results
Both groups showed potentiation of startle responses during the imminent threat condition compared to both the anticipation and safe conditions. Compared to controls, IBS subjects showed significantly larger startle responses during anticipation and imminent threat conditions after receiving an initial aversive stimulation. There were no group differences during the context threat manipulation. Moreover, in IBS patients but not controls, higher neuroticism was associated with larger startle responses during safe and anticipation conditions but not imminent threat, whereas anxiety symptoms were negatively associated with startle magnitude during imminent threat.
Conclusions
Female IBS patients show increased startle responses to threat of aversive stimulation at both abdominal and non-abdominal sites compared to controls. The data represent the first demonstration of altered threat potentiated startle in a functional pain condition and provide support for the use of these paradigms in further evaluation of affective mechanisms in these disorders.
doi:10.1016/j.juro.2009.01.025
PMCID: PMC3094570  PMID: 19286199
Irritable bowel syndrome; functional bowel disorders; acoustic startle response; fear-potentiated startle
22.  Increased Acoustic Startle Responses in IBS Patients During Abdominal and Nonabdominal Threat 
Psychosomatic medicine  2008;70(8):920-927.
Background and Aims
Visceral hypersensitivity and symptom severity in Irritable Bowel Syndrome (IBS) are both exacerbated by stress. The eye-blink startle response represents a noninvasive measure of central defensive responding. Evidence for central hyperexcitability was studied in IBS patients by examining potentiation of the startle reflex to a nociceptive threat.
Methods
Acoustic startle responses were examined in female IBS patients (n = 42) and healthy controls (n = 22) during cued periods in which an aversive abdominal or biceps stimulation was impossible (safe), possible (imminent threat) or anticipated (period just before the imminent threat), and during a threatening context (muscle stimulation pads attached but no cues for stimulation).
Results
Both groups showed potentiation of startle responses during the imminent threat condition compared with both the anticipation and safe conditions. Compared with controls, IBS subjects showed significantly larger startle responses during anticipation and imminent threat conditions after receiving an initial aversive stimulation. There were no group differences during the context threat manipulation. Moreover, in IBS patients but not controls, higher neuroticism was associated with larger startle responses during safe and anticipation conditions but not imminent threat, whereas anxiety symptoms were negatively associated with startle magnitude during imminent threat.
Conclusions
Female IBS patients show increased startle responses to threat of aversive stimulation at both abdominal and nonabdominal sites compared with controls. The data represent the first demonstration of altered threat potentiated startle in a functional pain condition and provide support for the use of these paradigms in further evaluation of affective mechanisms in these disorders.
doi:10.1097/PSY.0b013e318186d858
PMCID: PMC4104120  PMID: 18842745
irritable bowel syndrome; functional bowel disorders; acoustic startle response; fear-potentiated startle
23.  Low Circulating Levels of Dehydroepiandrosterone in Histologically Advanced Nonalcoholic Fatty Liver Disease 
Hepatology (Baltimore, Md.)  2008;47(2):484-492.
The biological basis of variability in histological progression of nonalcoholic fatty liver disease (NAFLD) is unknown. Dehydroepiandrosterone(DHEA) is the most abundant steroid hormone and has been shown to influence sensitivity to oxidative stress, insulin sensitivity, and expression of peroxisome proliferator-activated receptor alpha and procollagen messenger RNA. Our aim was to determine whether more histologically advanced NAFLD is associated with low circulating levels of DHEA. Serum samples were obtained prospectively at the time of liver biopsy in 439 patients with NAFLD (78 in an initial and 361 in validation cohorts) and in controls with cholestatic liver disease (n = 44). NAFLD was characterized as mild [simple steatosis or nonalcoholic steatohepatitis (NASH) with fibrosis stage 0–2] or advanced (NASH with fibrosis stage 3–4). Serum levels of sulfated DHEA (DHEA-S) were measured by enzyme-linked immunosorbent assay. Patients with advanced NAFLD had lower plasma levels of DHEA-S than patients with mild NAFLD in both the initial (0.25 ± 0.07 versus 1.1 ± 0.09 µg/mL, P < 0.001) and validation cohorts (0.47 ± 0.06 versus 0.99 ± 0.04 µg/mL, P < 0.001). A “dose effect” of decreasing DHEA-S and incremental fibrosis stage was observed with a mean DHEA-S of 1.03 ± 0.05, 0.96 ± 0.07, 0.83 ± 0.11, 0.66 ± 0.11, and 0.35 ± 0.06 µg/mL for fibrosis stages 0, 1, 2, 3, and 4, respectively. All patients in both cohorts in the advanced NAFLD group had low DHEA-S levels, with the majority in the hypoadrenal range. The association between DHEA-S and severity of NAFLD persisted after adjusting for age. A relationship between disease/fibrosis severity and DHEA-S levels was not seen in patients with cholestatic liver diseases.
Conclusion
More advanced NAFLD, as indicated by the presence of NASH with advanced fibrosis stage, is strongly associated with low circulating DHEA-S. These data provide novel evidence for relative DHEA-S deficiency in patients with histologically advanced NASH.
doi:10.1002/hep.22063
PMCID: PMC2906146  PMID: 18220286
24.  Fear-Potentiated Startle Response Is Unrelated to Social or Emotional Functioning in Adolescents With Autism Spectrum Disorders 
It has been suggested that atypical amygdala function contributes to the social impairments characteristic of autism spectrum disorders (ASDs). Previous research has demonstrated that adolescents and adults with ASD generate normal response during a fear-potentiated startle paradigm, suggesting this aspect of amygdala function is intact and may not account for the social dysfunction associated with the condition. The amygdala also plays a crucial role in the expression of anxiety and may contribute to high rates of reported anxiety in individuals with ASD. The present study partially replicates prior work by examining the fear-potentiated startle response in adolescents with ASD, and extends this to investigate the relationship between startle response and anxiety. Eyeblink magnitude and latency (electromyographic activity; EMG) were collected from 20 adolescents with ASD and 19 typically developing (TD) age-matched adolescents during a fear-potentiated startle paradigm. Parent report and self-report of anxiety and additional psychiatric symptoms were collected. Parental reports indicated higher rates of associated psychopathology in adolescents with ASD compared with TD adolescents. Consistent with previous results, both groups showed normal potentiated startle response, and no group differences in EMG were found. Symptoms of anxiety and level of social impairment were unrelated to startle response. These findings held for all levels of anxiety, suggesting that within the context of the fear-potentiated startle paradigm, amygdala response is not associated with degree of atypical social or emotional functioning in ASD.
doi:10.1002/aur.1289
PMCID: PMC4141562  PMID: 23495221
autism spectrum disorders; anxiety; startle response; amygdala
25.  The Effort-reward Imbalance work-stress model and daytime salivary cortisol and dehydroepiandrosterone (DHEA) among Japanese women 
Scientific Reports  2014;4:6402.
We examined the influence of work-related effort–reward imbalance and overcommitment to work (OC), as derived from Siegrist's Effort–Reward Imbalance (ERI) model, on the hypothalamic–pituitary–adrenocortical (HPA) axis. We hypothesized that, among healthy workers, both cortisol and dehydroepiandrosterone (DHEA) secretion would be increased by effort–reward imbalance and OC and, as a result, cortisol-to-DHEA ratio (C/D ratio) would not differ by effort–reward imbalance or OC. The subjects were 115 healthy female nursery school teachers. Salivary cortisol, DHEA, and C/D ratio were used as indexes of HPA activity. Mixed-model analyses of variance revealed that neither the interaction between the ERI model indicators (i.e., effort, reward, effort-to-reward ratio, and OC) and the series of measurement times (9:00, 12:00, and 15:00) nor the main effect of the ERI model indicators was significant for daytime salivary cortisol, DHEA, or C/D ratio. Multiple linear regression analyses indicated that none of the ERI model indicators was significantly associated with area under the curve of daytime salivary cortisol, DHEA, or C/D ratio. We found that effort, reward, effort–reward imbalance, and OC had little influence on daytime variation patterns, levels, or amounts of salivary HPA-axis-related hormones. Thus, our hypotheses were not supported.
doi:10.1038/srep06402
PMCID: PMC4165940  PMID: 25228138

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